Current hypotheses implicate insulin resistance of the brain as a pathogenic factor in the development of Alzheimer’s disease and other dementias, Parkinson’s disease, type 2 diabetes, obesity, major depression, and traumatic brain injury. A variety of genetic, developmental, and metabolic abnormalities that lead to disturbances in the insulin receptor signal transduction may underlie insulin resistance. Insulin receptor substrate proteins are generally considered to be the node in the insulin signaling system that is critically involved in the development of insulin insensitivity during metabolic stress, hyperinsulinemia, and inflammation. Emerging evidence suggests that lower activation of the insulin receptor (IR) is another common, while less discussed, mechanism of insulin resistance in the brain. This review aims to discuss causes behind the diminished activation of IR in neurons, with a focus on the functional relationship between mitochondria and IR during early insulin signaling and the related roles of oxidative stress, mitochondrial hypometabolism, and glutamate excitotoxicity in the development of IR insensitivity to insulin.

Background: Single nucleotide polymorphisms (SNPs) in the SLC10A1 gene, coding for a functional receptor of hepatitis B virus (HBV), sodium taurocholate co-transporting polypeptide (NTCP), may influence the susceptibility, the outcome, and disease course of HBV infection in some populations. Aim: to determine the prevalence of SNPs of NTCP gene, rs2296651 and rs943277, and their relationship with chronic HBV infection in a group of Egyptian patients. Methods: 137 patients with HBV and 65 healthy controls were enrolled, and the patients were divided into two groups; group I chronic HBV infection (68 patients with normal ALT and minimal or no liver necroinflammation or fibrosis) and group II chronic hepatitis B (69 patients with elevated ALT and moderate or severe liver necroinflammation). They were subjected to full history taking, clinical examination, laboratory investigations, abdominal ultrasound, and liver stiffness measurement using both Echosens® Fibroscan and acoustic radiation force impulse (ARFI). Real time PCR TaqMan 5’ allelic discrimination assay was applied to detect the SNPs in NTCP gene, rs2296651 and rs943277. Results: On studying the rs2296651 variant, all controls and patients had genotype GG without any significant association with HBV infection or disease progression. However, the rs943277 variant in all controls and 98% of patients had genotype GA, except for two chronic HBV infection patients who had genotype AA, but no significant difference between patients and controls was found. The non-invasive methods for liver fibrosis assessment ARFI, AST/platelet's ratio (APRI), and fibrosis-4 score (FIB-4) could predict the stages of fibrosis in agreement with Fibroscan with AUCOR 0.8, 0.79, and 0.76, respectively. Conclusion: These findings may suggest that there is no relation between these SNPs of the NTCP gene and susceptibility or chronicity of HBV infection in the Egyptian population. We also suggest that the use of the non-invasive methods for liver fibrosis assessment, ARFI, FIB-4, and APRI may decrease the need for liver biopsies in prediction of significant hepatic fibrosis in chronic HBV patients.

Sepsis is associated with dysregulated cortisol secretion, leading to abnormal levels of cortisol in the blood. In the early stages of sepsis, cortisol levels are typically elevated due to increased secretion from the adrenal glands. However, as the disease progresses, cortisol levels may decline due to impaired adrenal function, leading to relative adrenal insufficiency. The latter is thought to be caused by a combination of factors, including impaired adrenal function, decreased production of corticotropin-releasing hormone (CRH) and adrenocorticotropic hormone (ACTH) by the hypothalamus and pituitary gland, and increased breakdown of cortisol by enzymes such as 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2). The dysregulation of cortisol secretion in sepsis is thought to contribute to the pathophysiology of the disease by impairing the body's ability to mount an appropriate inflammatory response. The actions of cortisol are mediated through two types of corticosteroid receptors: the mineralocorticoid receptor (MR) and the glucocorticoid receptor (GCR). In sepsis, the expression and activity of GCR is altered, contributing to the pathophysiology of the disease. GCR expression and activity are typically downregulated in sepsis, impairing the body's ability to mount an appropriate inflammatory response. Given the dysregulation of cortisol secretion and corticosteroid receptors in sepsis, there has been considerable interest in the use of steroids as a treatment for sepsis. The rationale for steroid-based treatment is to supplement the body's endogenous cortisol production, restore normal cortisol levels, and improve the body's ability to mount an appropriate inflammatory response. However, the use of steroids in sepsis remains controversial, and clinical trials have yielded mixed results. Some studies have shown that steroid-based treatment can improve shock reversal, reduce the need for vasopressors, and improve overall survival in patients with septic shock, whereas other studies have found no benefit or even harm from steroid-based treatment in sepsis.

Glioblastoma (GBM) is the most common and aggressive adult brain cancer with an average survival rate of around 15 months in patients receiving standard treatment. Oncolytic adenovirus expressing therapeutic transgenes represent a promising alternative treatment for GBM. Of the many human adenoviral serotypes described to date, adenovirus 5 (Ad5) has been most utilized clinically and experimentally. However, the use of Ad5 as an anti-cancer agent may be hampered by naturally high seroprevalence rates to Ad5 coupled with infection of healthy cells via native receptors. To explore whether alternative natural adenoviral tropisms are better suited to GBM therapeutics, we pseudotyped an Ad5 based platform with the fiber knob protein from alternative serotypes. We demonstrate that the adenoviral entry receptors coxsackie and adenovirus receptor (CAR) and CD46 are highly expressed by both GBM and healthy brain tissue, whereas Desmoglein 2 (DSG2) is expressed at low level in GBM. We demonstrate that adenoviral pseudotypes, engaging CAR, CD46 and DSG2, effectively transduce GBM cells. However, the presence of these receptors on non-transformed cells presents the possibility of off-target effects and therapeutic transgene expression in healthy cells. To enhance specificity of transgene expression to GBM, we assessed the potential for tumour specific promoters hTERT and survivin to drive reporter gene expression selectively in GBM cell lines. We demonstrate tightly GBM specific transgene expression using these constructs, indicating that the combination of pseudotyping and tumour specific promoters approaches may enable the development of efficacious therapies better suited to GBM.

Alzheimer’s disease (AD) represents the most prevalent type of dementia in elderly people, primarily characterized by brain accumulation of beta-amyloid (Aβ) peptides, derived from Amyloid Precursor Protein (APP), in the extracellular space (amyloid plaques) and intracellular deposits of the hyperphosphorylated form of the protein tau (p-tau; tangles or neurofibrillary aggregates). The Nerve growth factor receptor (NGFR/p75NTR) represents a low-affinity receptor for all known mammalians neurotrophins (i.e., pro-NGF, NGF, BDNF, NT-3 e NT-4/5) and it is involved in pathways that determine both survival and death of neurons. Interestingly, also Aβ peptides can blind to NGFR/p75NTR making it the “ideal” candidate in mediating Aβ-induced neuropathology. Besides pathogenesis and neuropathology, several data indicated that NGFR/p75NTR could play a key role in AD also from a genetic perspective. Other studies suggested that NGFR/p75NTR could represent a good diagnostic tool, as well as a promising therapeutic target for AD. Here, we comprehensively summarize and review the current experimental evidence on this topic.

L-17 is a thiadiazine derivative with putative anti-inflammatory, neuroprotective, and antidepressant-like properties. In this study, we applied combined in silico, ex vivo, and in vivo electrophysiology techniques to reveal the potential mechanism of action of L-17. PASS 10.4 Professional Extended software suggested that L-17 might have pro-cognitive, antidepressant, and antipsychotic effects. Docking energy assessment with AutoDockVina predicted that the binding affinities of L-17 to the serotonin transporter (SERT) and serotonin receptors 3 and 1A (5-HT3 and 5-HT1A) receptors are compatible to the selective serotonin reuptake inhibitor (SSRI) fluoxetine and selective antagonists of 5-HT3 and 5-HT1A receptors, granisetron and WAY100135, respectively. Acute pre-treatment with L-17 robustly increased c-Fos immunoreactivity in the amygdala (central nucleus), suggesting increased neuronal excitability in this brain area after L-17 administration. Acute L-17 also dose-dependently inhibited of 5-HT neurons of the dorsal raphe nucleus (DRN). This inhibition was partially reversed by subsequent administration of WAY100135, suggesting the involvement of extracellular 5-HT. Based on in silico predictions, c-Fos immunohistochemistry, and in vivo electrophysiology, we suggest that L-17 is a potent 5-HT reuptake inhibitor and/or partial 5-HT1A receptor antagonist. Thus, L-17 might be a representative of a new class of antidepressant drugs. Since L-17 also possesses neuro- and cardio-protective properties, it can be useful in post-stroke and post-myocardial infarction (MI) depression. In general, combined in silico predictions and ex vivo neurochemical and in vivo electrophysiological assessment might be a useful strategy for early preclinical assessment of the affectivity and neural mechanism in action of the novel CNS drugs.

Fifty years on from the classical fluid-mosaic model of Singer and Nicolson, current views of the plasma membrane portray a much more complex view of this interface region. Compartmentalization, together with transbilayer and lateral asymmetries, provide the structural foundation for functional specializations at the cell surface, including the active role of the lipid microenvironment in the modulation of membrane-bound proteins. The chemical synapse, the site where neurotransmitter-coded signals are decoded by neurotransmitter receptors, adds another layer of complexity to the plasma membrane architectural intricacy, mainly due to the need to accommodate a sizeable number of molecules in a minute subcellular compartment with dimensions barely reaching the micrometer. In this review, we discuss how Nature has developed suitable adjustments to accommodate different types of membrane-bound receptors and scaffolding proteins via membrane microdomains, and how this “efford-sharing” mechanism has evolved to optimize crosstalk or separation or coupling where/when appropriate. To this end, we use a fast ligand-gated neurotransmitter receptor, the nicotinic acetylcholine receptor, and a second-messenger G-protein coupled receptor, the cannabinoid receptor, as paradigmatic example.

Mexico shows a high birth prevalence of congenital hypothyroidism (CH) due to thyroid dysgenesis (TD). PAX8 defects underlie only 1% of these cases and NKX2-1 does not seem to be involved. Here, we analyzed other TD-related genes in 128 non-related Mexican patients (females 77.3%; 6 months to 16.6 years) with non-syndromic CH-TD diagnosis established by clinical evaluation, thyroid hormone serum profiling, and scintigraphy (74%) or ultrasonography (26%). We performed Sanger sequencing of FOXE1, NKX2-5, and TSHR and evaluated copy number variations (CNVs) in TSHR, FOXE1, PAX8, and NKX2-1 by multiplex ligation-dependent probe amplification. Odds ratios for TD risk were explored for FOXE1 polyalanine stretches [polyAla-rs71369530] in cases and controls (N=116). Five rare missense changes cataloged as benign (NKX2-5:p.(Ala119Ser)-rs137852684), of unknown significance (FOXE1:p.(Ala335Gly)-rs543372757; TSHR:p.(Asp118Asn)-rs1414102266), and likely pathogenic (FOXE1:p.(Gly124Arg)-rs774035532; TSHR:p.(Trp422Arg)-rs746029360) accounted for 1.5% (N=2/128) of clinically relevant genotypes (supported in part by protein modeling) in CH-TD. No CNVs were identified, nor did polyAla >14 alanines in FOXE1 significantly protect against TD. The present and previously published data collectively show that small clinically relevant germline variants in PAX8, FOXE1, and TSHR are found in only a very small proportion (2.5%) of isolated CH-TD Mexican patients.

HIV-associated neurocognitive disorders (HAND) persist despite the advent of antiretroviral therapy (ART), suggesting underlying systemic and central nervous system (CNS) inflammatory mechanisms. The endogenous cannabinoid receptors 1 and 2 (CB1 and CB2) modulate inflammatory gene expression and play an important role in maintaining neuronal homeostasis. Cannabis use is disproportionately high among people with HIV (PWH) and may provide a neuroprotective effect for those on ART due to its anti-inflammatory properties. However, expression profiles of CB1 and CB2 in the brains of PWH on ART with HAND have not been reported. In this study, biochemical and immunohistochemical analyses were performed to determine CB1 and CB2 expression in brain specimens of HAND donors. Immunoblot revealed CB1 and CB2 were differentially expressed in frontal cortices from HAND brains compared to neurocognitively unimpaired (NUI) brains from PWH. CB1 expression levels negatively correlated with memory and information processing speed. CB1 was primarily localized to neuronal soma in HAND brains versus a more punctate distribution on neuronal processes of NUI brains. CB1 expression was increased in cells with glial morphology and showed increased colocalization with an astroglial marker. These results suggest that targeting the endocannabinoid system may be a potential therapeutic strategy for HAND.

Retinitis pigmentosa-59 (RP59) is a rare, recessive form of RP, caused by mutations in the gene encoding DHDDS (dehydrodolichyl diphosphate synthase). DHDDS forms a heterotetrameric complex with Nogo-B Receptor (NgBR; gene NUS1) to form a cis-prenyltransferase (CPT) enzyme complex, which is required for synthesis of dolichol, which in turn is required for protein N-glycosylation as well as other glycosylation reactions in eukaryotic cells. Herein, we review the published phenotypic characteristics of RP59 models extant, with an emphasis on their ocular phenotypes, based primarily upon knock-in of known RP59-associated DHDDS mutations as well as cell type- and tissue-specific knockout of DHDDS alleles in mice. We also briefly review findings in RP59 patients with retinal disease and other patients with DHDDS mutations causing epilepsy and other neurologic disease. We discuss these findings in the context of addressing “knowledge gaps” in our current understanding of the underlying pathobiology mechanism of RP59, as well as their potential utility for developing therapeutic interventions to block the onset, or to dampen the severity or progression, of RP59.

Regeneration of peripheral nerves depends on the ability of axons to navigate through an altered extracellular environment. It has been suggested that Schwann cells facilitate this process through their secretion of neuropeptides and proteases. Using the RT4-D6P2T Schwann cell line (RT4), we have previously shown that RT4 cultures endogenously express the neuropeptide PACAP, and respond to exogenous stimulation by inducing the expression of tissue plasminogen activator (tPA) and urokinase plasminogen activator (uPA) through PAC1 receptor activation. In this study, based on recent findings showing that doxycycline and minocycline act as positive allosteric modulators (PAMs) of the PAC1 receptor, we tested if treatment with these tetracyclines could induce the expression and activity of tPA and uPA in RT4 cells. Using ELISA and zymographic analyses, we demonstrate that doxycycline and minocycline reliably induce the secretion and activity of both tPA and uPA, which is paralleled by an increased expression levels, as shown by immunocytochemistry and Western blots. These actions were mediated, at least in part, by the PAC1 receptor, as PACAP6-38 mitigated tetracycline-induced expression and activity of tPA and uPA. We conclude that doxycycline and minocycline can act as PAMs of the PAC1 receptor to promote proteolytic activity in RT4 cells.

Current hypotheses implicate insulin resistance of the brain as a pathogenic factor in the development of Alzheimer’s disease and other dementias, Parkinson’s disease, type 2 diabetes, obesity, major depression, and traumatic brain injury. A variety of genetic, developmental, and metabolic abnormalities that lead to disturbances in the insulin receptor signal transduction may underlie insulin resistance. Insulin receptor substrate proteins are generally considered to be the node in the insulin signaling system that is critically involved in the development of insulin insensitivity during metabolic stress, hyperinsulinemia, and inflammation. Emerging evidence suggests that lower activation of the insulin receptor (IR) is another common, while less discussed, mechanism of insulin resistance in the brain. This review aims to discuss causes behind the diminished activation of IR in neurons, with a focus on the functional relationship between mitochondria and IR during early insulin signaling and the related roles of oxidative stress, mitochondrial hypometabolism, and glutamate excitotoxicity in the development of IR insensitivity to insulin.

Despite innovative advances in anti-infective therapies and vaccine development technologies, community-acquired pneumonia (CAP) remains the most persistent cause of infection-related mortality globally. Confronting the ongoing threat posed by Streptococcus pneumoniae (the pneumococcus), the most common bacterial cause of CAP, particularly to the non-immune elderly, remains challenging due to the propensity of the elderly to develop invasive pneumococcal disease (IPD), together with the predilection of the pathogen for the heart. The resultant development of often fatal cardiovascular events (CVEs), particularly during the first seven days of acute infection, is now recognized as a relatively common complication of IPD. The current review represents an update on the prevalence and types of CVEs associated with acute bacterial CAP, particularly IPD. In addition, it is focused on recent insights into the involvement of the pneumococcal pore-forming toxin, pneumolysin (Ply), in subverting host immune defenses, particularly the protective functions of the alveolar macrophage during early-stage disease. This, in turn, enables extra-pulmonary dissemination of the pathogen, leading to cardiac invasion, cardiotoxicity and myocardial dysfunction. The review concludes with an overview of the current status of macrolide antibiotics in the treatment of bacterial CAP in general, as well as severe pneumococcal CAP, including a consideration of the mechanisms by which these agents inhibit the production of Ply by macrolide-resistant strains of the pathogen.

Abstract: The kallikrein-kinin system consists of the two kininogen substrates, present in blood plasma, and of two serine proteases, the plasma and tissue kallikreins. The action of the latter on kininogens produce small peptides, the kinins, short lived but endowed by powerful pharmacologic actions on blood vessels and other tissues. Many recent and exciting therapeutic developments in the field are briefly summarized. Notably, various novel strategies are being clinically developed to inhibit the formation of bradykinin or block its receptors in the management of hereditary angioedema. The interventions include orally bioavailable drugs, biotechnological proteins, and gene therapy. These approaches are currently explored in a variety of other inflammatory and thrombotic disorders. Harnessing controlled kinin formation is also of potential therapeutic interest as shown by the clinical development of recombinant tissue kallikrein for ischemic stroke and renal disease. Biomarkers of a kinin-mediated disorders, frequently implicating edemas, include the consumption of kininogen(s), plasma kallikrein activity, and the detection of circulating kinin metabolites such as fragments BK_1-5 and BK_2-9. Novel opportunities to clinically apply the underexploited drugs of the kallikrein-kinin system are briefly reviewed. This personal perspective is offered by an observer of, and a participant in drug characterization during the last 4 decades.

Autoimmune thyroid disease refers to a spectrum of various diseases, with two extremes of clinical presentation, hypo-thyroidism (Hashimoto's thyroiditis), and hyperthyroidism (Graves-Basedow disease). Both conditions are character-ized by presenting a cellular and humoral autoimmune reaction, with an increase in the synthesis and secretion of an-tibodies directed towards various thyroid antigens, together with a phenomenon of thyrocyte necrosis and apoptosis (in Hashimoto's thyroiditis) and a persistent thyrotropin-receptor stimulation (in Graves-Basedow disease). The diagnosis of both entities is based on the clinical, laboratory and imaging findings. In this review, the usefulness of thyroid antibodies in the diagnostic approach to autoimmune thyroid disease is de-scribed.

Naltrexone (NTX) is a potent opioid antagonist with good blood-brain barrier permeability, targeting different endogenous opioid receptors, particularly the mu-opioid receptor (MOR). Therefore, it represents a promising candidate for drug development against drug addiction. However, the details of the molecular interactions of NTX and its derivatives with MOR are not fully understood, hindering ligand-based drug discovery. In the present study, taking advantage of the high-resolution X-ray crystal structure of the murine MOR (mMOR), we constructed a homology model of the human MOR (hMOR). A solvated phospholipid bilayer was built around the hMOR and submitted to microsecond (µs) molecular dynamics (MD) simulations to obtain an optimized hMOR model. NTX and its derivatives were docked into the optimized hMOR model and submitted to µs MD simulations in an aqueous membrane system. The MD simulation results were submitted to Molecular Mechanics Generalized-Born surface area (MMGBSA) binding free energy calculations and principal component analysis. Our results revealed that NTX and its derivatives showed differences in protein-ligand interactions; however, they shared contact with residues at TM2, TM3, H6, and TM7. The binding free energy and principal component analysis revealed the structural and energetic effects responsible for the higher potency of NTX compared to its derivatives.

Adrenergic receptor β3 (ADRβ3) is a member of the rhodopsin-like G protein-coupled receptor family. The binding of the ligand to ADRβ3 activates adenylate cyclase and increases cAMP in the cells. ADRβ3 is highly expressed in white and brown adipocytes and controls key regulatory pathways of lipid metabolism. Trp64Arg (W64R) polymorphism in the ADRβ3 has been associated with the early development of type 2 diabetes mellitus, lower resting metabolic rate, abdominal obesity, and insulin resistance. It is unclear how the substitution of W64R affects the functioning of ADRβ3. This study was initiated to functionally characterize this obesity-linked variant of ADRβ3. We evaluated in detail the expression, subcellular distribution, and post-activation behavior of the WT and W64R ADRβ3 using a single cell quantitative fluorescence microscopy. When expressed in HEK 293 cells, ADRβ3 shows a typical distribution displayed by other GPCRs with a predominant localization at the cell surface. Unlike Adrenergic receptor β2 (ADRβ2), agonist induced desensitization of ADRβ3 does not involve loss of cell surface expression. WT and W64R variant of ADRβ3 displayed comparable biochemical properties and there was no significant impact of the substitution of Tryptophan with Arginine on the expression, cellular distribution, signaling, and post-activation behavior of ADRβ3. The obesity-linked W64R variant of ADRβ3 is indistinguishable from the WT ADRβ3 in terms of expression, cellular distribution, signaling, and post-activation behavior.

Burn injury serves as an example of a condition with a robust inflammatory response. The elevation of circulating interleukins (IL)- 1 beta and -6 in children with severe burn injury up-regulate the parathyroid calcium sensing receptor (CaSR) resulting in hypocalcemic hypoparathyroidism with urinary calcium wasting. This effect protects the body from the hypercalcemia resulting from bone resorption liberating calcium into the circulation. Extracellular calcium can exacerbate and prolong the inflammatory response by stimulating mononuclear cell chemokine production as well as the NLRP3 inflammasome of the innate immune system, resulting in increased IL-1 production by monocytes and macrophages. Interestingly, the CaSR response to inflammatory cytokines disappears with age, potentially trapping calcium from bone resorption in the circulation and allowing it to contribute to increased inflammation and possibly increased calcium deposition in small arteries, , such as the coronaries, as conditions with increased chronic inflammation, such as spinal cord injury, osteoarthritis and rheumatoid arthritis have an incidence of cardiovascular disease and coronary artery calcium deposition significantly higher than the unaffected age-matched population.

Different dopamine receptor (DR) subtypes are involved in pathophysiological conditions such as Parkinson´s Disease (PD), schizophrenia and depression. While many DR-targeting drugs have been approved by the FDA, only a very small number is truly selective for one of the DR subtypes. Additionally, most of them show promiscuous activity at related G-protein coupled receptors, thus suffering from diverse side-effect profiles. Multiple studies have shown that combined in silico / in vitro approaches are a valuable contribution to drug discovery processes. They can also be applied to divulge the mechanisms behind ligand selectivity. In this study, novel DR ligands were investigated in vitro to assess binding affinities at different DR subtypes. Thus, nine D2R/D3R-selective ligands (micro- to nanomolar binding affinities, D3R-selective profile) were successfully identified. The most promising ligand exerted nanomolar D3R activity (KI = 2.3 nM) with 263.7-fold D2R/D3R selectivity. Subsequently, ligand selectivity was rationalized in silico based on ligand interaction with a secondary binding pocket, supporting selectivity data determined in vitro. The developed workflow and identified ligands could aid in the further understanding of structural motifs responsible for DR subtype selectivity, thus, benefitting drug development in D2R/D3R-associated pathologies like PD.

Advances in nanomedicine bring the attention of researchers to the molecular targets which can play a major role in the development of novel therapeutic and diagnostic modalities for cancer management. The choice of a proper molecular target can decide on the efficacy of the treatment and endorse the personalized medicine approach. Gastrin-releasing peptide receptor (GRPR) is a G-protein-coupled membrane receptor, well known to be overexpressed in numerous malignancies including pancreatic, prostate, breast, lung, colon, cervical and gastrointestinal cancers. Therefore, many research groups express a deep interest in targeting GRPR with their nanoformulations. A broad spectrum of the GRPR ligands has been described in the literature, which allows tuning of the properties of the final formulation, particularly in the field of the ligand affinity to the receptor and internalization possibilities. Hereby the recent advances in the field of applications of various nanoplatforms which are able to reach the GRPR expressing cells are reviewed.

Monoclonal antibodies (mAbs) are an important treatment option for COVID-19 caused by SARS-CoV-2, especially in immunosuppressed patients. However, this treatment option can become ineffective due to mutations in the SARS-CoV-2 genome, mainly in the receptor binding domain (RBD) of the spike (S) protein. In the present study 7950 SARS-CoV-2 positive samples from the Uppsala and Örebro regions of central Sweden collected between March 2022 and May 2023 were whole-genome sequenced using next-generation sequencing, mainly with the Nanopore sequencing method. Pango lineages were determined and all single nucleotide polymorphism (SNP) mutations that occurred in these samples were identified. The dominant sublineages changed over time and mutations conferring resistance to currently available mAbs became common. Notable ones are R346T and K444T mutations in the RBD that confer significant resistance against tixagevimab and cilgavimab mAbs. Further, mutations conferring a high-fold resistance to bebtelovimab, such as the K444T and V445P mutations, were also observed in the samples. This study highlights that resistance mutations have over time rendered currently available mAbs ineffective against SARS-CoV-2 in most patients. Therefore, there is a need for continued surveillance of resistance mutations and the development of new mAbs that target more conserved regions of the RBD.

This last decade, chimeric antigen receptor (CAR) T-cell therapy has become a real treatment option for patients with B-cell malignancies, while multiple efforts are being made to extend this therapy to other malignancies and broader patient populations. However, several limitations remain, including those associated with the time-consuming and highly personalized manufacturing of autologous CAR-Ts. Technologies to establish “off-the-shelf” allogeneic CAR-Ts with low alloreactivity are currently being developed, with a strong focus on gene editing technologies. Although these technologies have many advantages, they have also strong limitations including double-strand breaks in the DNA with associated multiple safety risks as well as the lack of modulation. As an alternative, non-gene editing technologies provide an interesting approach to support the development of allogeneic CAR-Ts in the future, with possibilities of fine-tuning gene expression and easy development. Here we will review the different ways allogeneic CAR-Ts can be manufactured and discuss which technologies are currently used. The biggest hurdles for successful therapy of allogeneic CAR-Ts will be summarized and finally an overview of the current clinical evidence for allogeneic CAR-Ts in comparison to its autologous counterpart will be given.

Multiple myeloma (MM) has witnessed improved patient outcomes through advancements in therapeutic approaches. Notably, allogeneic stem cell transplantation, proteasome inhibitors, immunomodulatory drugs, and monoclonal antibodies have contributed to enhanced quality of life. Recently, a promising avenue has emerged with chimeric antigen receptor (CAR) T cells targeting B-cell maturation antigen (BCMA), expressed widely on MM cells. To mitigate risks associated with allogenic T cells, we investigated the potential of BCMA CAR expression in natural killer cells (NKs), known for potent cytotoxicity and minimal side effects. Using the NK-92 cell line, we co-expressed BCMA CAR and soluble tumor necrosis factor-related apoptosis-inducing ligand (sTRAIL) employing the PiggyBac transposon system. Engineered NK cells (CAR-NK-92-TRAIL) demonstrated robust cytotoxicity against a panel of MM cell lines and primary patient samples, outperforming unmodified NK-92 cells with a mean difference in viability of 45,1% (± 26,1%, depending on the target cell line). Combination therapy was explored with the proteasome inhibitor bortezomib (BZ) and γ-secretase inhibitors (GSI), leading to a significant synergistic effect in combination with CAR-NK-92-TRAIL cells. This synergy was evident in cytotoxicity assays where a notable decrease in MM cell viability was observed in combinatorial therapy compared to single treatment. In summary, our study demonstrate the therapeutic potential of the CAR-NK-92-TRAIL cells for the treatment of MM. The synergistic impact of combining these engineered NK cells with BZ and GSI supports further development of allogeneic CAR-based products for effective MM therapy.

Depression and obesity are highly comorbid with one another, with evidence for bidirectional causal links between each disorder and a shared biological basis. The available evidence suggests that genetic factors play a major role in influencing both the occurrence of comorbid depression and obesity, their courses, and their response to existing treatments. The current paper is a scoping review of studies that have evaluated the contribution of specific genetic variants to the comorbidity between obesity and depression. Based on a search of the PubMed and EMBASE databases, 28 studies were included in this review, covering 54 candidate genes. Positive associations were identified for fourteen genetic loci (AKR1C2, APOA5, COMT, DAT1, FTO, KCNE1, MAOA, MC4R, MCHR2, NPY2R, NR3C1, Ob, PCSK9 and TAL1). Replicated findings across two or more independent samples were observed for the FTO and MC4R genes. Many of these gene products represent novel molecular targets for the pharmacological management of obesity which are not pharmacologically influenced by existing anti-obesity or antidepressant medications. The implications of these associations for future drug development are discussed, with an emphasis on recent evidence on the polygenic architecture of comorbid depression and obesity, and on a precision medicine approach to these conditions.

(1) Background: Co-morbidities such as hypertension and cardiovascular disease are major risk factors for severe COVID-19. The renin-angiotensin-system (RAS) is critically involved in their pathophysiology and is counterbalanced by both angiotensin-converting enzyme 2 (ACE2), the functional receptor of SARS-CoV-2, and the kallikrein-kinin-system (KKS). Considerable research interest with respect to COVID-19 treatment is, thus, currently directed towards the components of these systems. In an earlier study, we noticed significantly reduced carboxypeptidase N (CPN, KKS member) activity and partially excessive angiotensin-converting enzyme (ACE, RAS member) activity in the sera of both hospitalized (HoP) COVID-19 patients and a sub-group of covalescent patients, while in the majority of the probands recovering from the disease these values had returned to normal. The data had been obtained using bradykinin (BK) as a reporter peptide, which is a target of both CPN and ACE, and they were supplemented by serum proteomics of the same patient cohort. We hypothesized that the data could be indicative of Long COVID, which had not been fully appreciated at the time of our study.; (2) Methods: The data were re-evaluated in the light of Long COVID. The recent literature on the RAS in COVID-19, antihypertensiva, and Long COVID was briefly reviewed.; (3) Results: While the levels of the BK serum degradation products should return to normal concentrations during convalescence, this was not true for some patients. This could be due to persisting liver problems, because CPN is synthesized there, but also to a dysregulated RAS. This was not reflected in the levels of selected RAS/KKS serum proteins like angiotensinogen (AGT), although AGT correlated with disease severity in HoP. However, standard tests in routine patient care in Long COVID often come back normal, and it may be that BK degradation is specific in some pathophysiologies. Moreover, the HoP group was sub-divided based on the serum protein profiles and COVID-19 severity.; (4) Conclusions: We point out two insights: 1) Sensitive technology such as omics methods might provide unexpected significant differences within the pre-defined patient groups of a clinical study. Those can only be explored, if the cohorts are large enough and properly matched with respect to the parameters known beforehand (e.g., age, gender, co-morbidities). 2) Results of the BK-reporter serum protease activity assay could be indicative of persisting liver problems and/or potentially of Long COVID. Clinical studies are required to test this hypothesis.

G-protein-coupled receptors (GPCRs) are ubiquitous sensors and regulators of cellular functions. Each GPCR exists in complex aggregates with multiple resting and active conformations. Designed to detect weak stimuli, GPCRs can also activate spontaneously, resulting in basal ligand-free signaling. Agonists trigger a cascade of events leading to an activate agonist-receptor-G protein complex with high agonist affinity. However, the ensuing signaling process can further remodel the receptor complex to reduce agonist affinity, causing rapid ligand dissociation. The acutely activated ligand-free receptor can continue signaling, as proposed for rhodopsin and  opioid receptors, resulting in robust receptor activation at low agonist occupancy with enhanced agonist potency. Continued receptor stimulation can further modify the receptor complex, regulating sustained ligand-free signaling - proposed to play a role in opioid dependence. Basal, acutely agonist-triggered, and sustained elevated ligand-free signaling could each have distinct functions, reflecting multi-state conformations of GPCRs. This review addresses basal and stimulus-activated ligand-free signaling, its regulation, genetic factors, and pharmacological implications, focusing on opioid and serotonin receptors, and the growth hormone secretagogue receptor (GHSR). Ligand-free signaling of intracellular 5-HT2A receptors could mediate therapeutic effects of psychedelic drugs. Research avenues are suggested to close gaps in our knowledge of ligand-free GPCR signaling.

Glutamate NMDA receptor (NMDAR) hypofunction has been proposed to underlie schizophrenia symptoms because administration of NMDAR antagonists reproduces behavioral and molecular schizophrenia-like phenotypes in healthy humans and animal models. However, the role of specific NMDAR subunits in these schizophrenia-relevant characteristics is largely unknown. Mounting evidence implicates the GluN2D subunit of NMDAR in some of these symptoms and pathology. Firstly, genetic and post-mortem studies show changes in the GluN2D subunit in people with schizophrenia. Secondly, the psychosis-inducing effects of NMDAR antagonists are blunted in GluN2D-knockout mice, suggesting that the GluN2D subunit mediates NMDAR antagonist-induced psychotomimetic effects. Thirdly, in the mature brain, the GluN2D subunit is relatively enriched in parvalbumin (PV)-containing interneurons, a cell type hypothesized to underlie the cognitive symptoms of schizophrenia. Lastly, the GluN2D subunit is widely and abundantly expressed early in development which could be of importance considering schizophrenia is a disorder that has its origins in early neurodevelopment. The limitations of currently available therapies warrant further research into novel therapeutic targets such as the GluN2D subunit which may help us better understand underlying disease mechanisms and develop novel and more effective treatment options.

Gamma-aminobutyric acid (GABA) and glycine act as inhibitory neurotransmitters. Three types of inhibitory neurons and terminals, GABAergic, GABA/glycine co-releasing, and glycinergic, are orchestrated in the spinal cord neural circuits and play key roles in the regulation of pain, locomotive movement, and respiratory rhythms. Herein, we first describe GABAergic and glycinergic transmission and inhibitory networks, which consist of three types of terminals, in the mature mouse spinal cord. Second, we describe the developmental formation of GABAergic and glycinergic networks, with specific focus on the differentiation of neurons, formation of synapses, maturation of removal systems, and changes in their action. GABAergic and glycinergic neurons are derived from the same domains of the ventricular zone. Initially, GABAergic neurons are differentiated and their axons form synapses. Some of these neurons remain GABAergic in lamina I and II. Many of GABAergic neurons convert to co-releasing state. The co-releasing neurons and terminals remain in the dorsal horn, whereas many of co-releasing ones ultimately become glycinergic in the ventral horn. During the development of terminals and the transformation from radial glia to astrocytes, GABA and glycine receptor subunit compositions markedly change, removal systems mature, and GABAergic and glycinergic action shifts from excitatory to inhibitory.

Objective: Type I interferon receptor (IFNAR) signaling contributes to several autoimmune and vascular diseases such as atherosclerosis and stroke. The purpose of this study was to assess the influence of IFNAR1 deficiency on the formation and progression of experimental abdominal aortic aneurysms (AAAs). Methods: AAAs were induced in type I interferon receptor subunit 1 (IFNAR1) deficient and wild type control male mice via intra-infrarenal aortic infusion of porcine pancreatic elastase. Immunostaining for IFNAR1 was evaluated in experimental and clinical aneurysms. The initiation and progression of experimental AAAs was assessed via ultrasound imaging prior to (day 0) and 3-, 7-, and 14-days following elastase infusion. Aneurysmal histopathology was analyzed at sacrifice. Results: Increased aortic medial and adventitial IFNAR1 expression was present in both clinical AAAs harvested at surgery and experimental AAAs. Following AAA initiation, wild type mice experienced progressive, time-dependent infrarenal aortic enlargement. This progression was substantially attenuated in IFNAR1 deficient mice. On histological analyses, medial elastin degradation, smooth muscle cell depletion, leukocyte accumulation and neoangiogenesis were markedly diminished in IFNAR1 deficient as compared to wild type mice. Conclusion: IFNAR1 deficiency limited experimental AAA progression in response to intra-aortic elastase infusion. Combined with clinical observations, these results suggest a regulatory role for IFNAR1 activity in AAA pathogenesis.

Vitamin B9(folate)/B12 deficiency is known to induce brain structural and/or functional retardations. Besides neural tube defects in case of major consequences, several mild deregulations also lead to deleterious effect after birth, and folate supplementation recommended in some countries usually stop at the end of the first trimester. Various hormonal receptors were shown to be deregulated in brain tissue under this context. The glucocorticoid receptor (GR) is particularly sensitive to epigenetic regulation and post-traductional modifications. In a mother-offspring rat model of vitamin B9/B12 deficiency, we investigated whether a prolonged folate supplementation could restore the GR signalization in the hypothalamus. Our data showed that a deficiency in folate and vitamin B12 during the in-utero and the early postnatal periods was associated with reduced GR expression inn the hypothalamus. We also described for the first time a new post-traductional modification of GR that impaired ligand binding and GR activation, leading to decreased the expression of one of the GR targets in the hypothalamus, AgRP. Moreover, this brain-impaired GR pathway was associated with behavioral perturbations during offspring growth. Importantly, perinatal and postnatal supplementation with folic acid helped restore GR mRNA level and activity in hypothalamus cells and improved behavioral deficits.

(1) Background: Obesity and its comorbidities can cause burdens and limitations. Bariatric surgery (BS) is indicated as a safe procedure to reduce body mass and improve present comorbidities. Yet, several complications were reported, like vitamin D [25(OH)D] deficiency. We evaluated if 25(OH)D serum levels relate to clinical characteristics, symptoms, or habits in women after their BS and whether the vitamin D receptor (VDR) gene's TaqI and FokI polymorphisms affected 25(OH)D levels and the total body bone mineral density (TBBMD). (2) Methods: This cohort cross-sectional comparative analytical prospective study consisted of 27 women, 61.6 ± 5.0 years, submitted to BS one year prior at a public reference hospital, DF-Brazil. All participants were asked to follow the physical and dietary activity recommendations and received vitamin D3 supplements. Their anthropometric, biochemical, and immunological measurements and blood samples were obtained. (3) Results: 73.3% of participants had low 25(OH)D levels, and their levels correlated positively with TBBMD and negatively with systolic pressure. VDR TaqI did not affect 25(OH)D levels, whereas VDR FokI's allele f presence correlated to a median rise in 25(OH)D levels. Neither polymorphism correlated to TBBMD. (4) Conclusions: 25(OH)D levels were positively correlated with TBBMD, negatively with systolic blood pressure, and were higher in those with the VDR FokI allele f.

Mouse models of alcohol use disorder (AUD) revealed a subtype of purinergic receptors (P2X4Rs) as a promising target for AUD drug development. We have previously demonstrated that residues at the transmembrane (TM)-ectodomain interface and within TM1 segment contribute to the formation of an ethanol action pocket in P2X4Rs. In the present study, we tested the hypothesis that there are more residues in TM segments, which are important for ethanol sensitivity of P2X4Rs. Using site-directed mutagenesis and two-electrode voltage-clamp electrophysiology in Xenopus oocytes, we found that arginine at position 33 (R33) in the TM1 segment plays a role in ethanol sensitivity of P2X4Rs. Molecular models in both closed and open states provided evidence for interactions between R33 and aspartic acid at position 354 (D354) of the neighboring TM2 segment. Further work with mixtures of wild-type (WT) and reciprocal single (R33D:WT, D354R:WT) and double (R33D-D354R:WT) mutants confirmed the importance of this interaction for ethanol sensitivity, ivermectin action and channel function. Additionally, our findings suggest that valine at TM1 position 49 plays a role in P2X4R function by providing flexibility during channel opening. Collectively, these findings identified new activity sites, and suggest the importance of TM1-TM2 interaction for channel function and ethanol sensitivity of P2X4Rs.

Correlations among estrus cycle, pyometra, and canine diabetes mellitus (CDM) have been described since the late 1950s, and substantial progress in understanding mechanisms beyond was achieved nowadays. Progesterone-related diabetes mellitus (PRDM) in dogs is known for its particular potential for diabetes remission. Thus, a deep understanding of the physiopathological aspects involved is crucial to postulate treatment guidelines to improve the PRDM remission rate, as well as to inform preventive measures. This narrative review aims to provide relevant detailed information on 1) canine estrus cycle and its impact on CDM etiology and management, 2) the role of pyometra as a further cause of insulin resistance, and 3) useful individual therapeutic and preventive strategies. Pharmacological annulment of progesterone effects, as well as inflammatory and progesterone-related conditions resolution in association with adequate exogenous insulin therapy, and residual beta cell function, are key aspects to achieve remission, or at least to improve diabetic clinical control. In this way, spaying should be considered mandatory in most PRDM cases. Preventive measures against CDM can include spaying recommendations; however, individual-based recommendations should be considered since castration may be associated with some long-term health issues.

Background: DSCAM-AS1 is a cancer-related long noncoding RNA with higher expression levels in Luminal A, B and HER2-positive Breast Cancer (BC), where its expression is strongly dependent on Estrogen Receptor Alpha (ERα). Methods: To decipher its function, DSCAM-AS1 expression was measured by qRT-PCR in tissue samples from 93 BC patients in addition to a meta-analysis of 30 gene expression datasets, together with the evaluation of its association with clinical data. By computational analyses of our RNA-Seq in MCF-7 cells, we investigated the DSCAM-AS1 knock-down effects at both gene and isoform levels. Results: We confirmed DSCAM-AS1 overexpression in high grade Luminal A, B and HER2+ BCs and found a significant correlation with disease relapse. 908 genes were regulated by DSCAM-AS1-silencing, primarily involved in cell cycle and inflammatory response. Noteworthy, the analysis of alternative splicing and isoform regulation revealed 2,085 splicing events regulated by DSCAM-AS1, enriched in differential polyadenylation sites and 3’UTR shortening events. Finally, the DSCAM-AS1-interacting splicing factor hnRNPL was predicted as the most enriched RBP for exon skipping and 3’UTR events. Conclusion: The relevance of DSCAM-AS1 overexpression in BC is confirmed by clinical data and further enhanced by its possible involvement in the regulation of RNA processing, which is emerging as one of the most important dysfunctions in cancer.

Alcohol use disorder (AUD) represents major public and socioeconomic issues. Alcohol exerts its phar-macological effects by altering different neurotransmitter systems, such as g-aminobutyric acid (GABA), glutamate, opioids, etc. Recent evidence suggests that the dynorphin (DYN)/kappa opioid receptor (KOR) system mediates the negative affective states associated with alcohol withdrawal. This system is also in-volved in stress-mediated alcohol intake in alcohol-dependent subjects. The DYN/KOR system probably exerts its action in the central nucleus of the amygdala (CeA) to mediate the negative affective states as-sociated with alcohol withdrawal. This article aims to review the current literature regarding the role of the DYN/KOR system in the actions of alcohol. We first review the literature regarding the effect of alcohol on the level of the peptide and its receptor, and the role of the endogenous DYN/KOR system in alcohol reward and negative affective states associated with alcohol withdrawal is then discussed. We also review the literature regarding the effects of KOR ligands on these processes.

The Influenza A Virus (IAV) represents an enveloped, positive-sense and single-stranded RNA-based virus that infects mammals mainly via the respiratory system, although other bodily systems are also infected and undergo various extents of inflammatory pathogenesis. There are two well-known strains of IAV that cause life-threatening disease in mammals; H1N1 and H5N1, and the first strain caused the 1918 IAV H1N1 pandemic that claimed between 30 and 50 million human lives. Due to the significant ability of IAV to evade important immune recognition, the virus was observed to favor the onset of secondary microbial infections (i.e. bacterial or fungal), as the overall performance of the immune system became transiently weakened during the viral infection. During the IAV H1N1 pandemic, many patients died as a result of bacterial pneumonia, as pathogenic bacteria, such as Streptococcus pneumoniae and Haemophilus influenzae, gained a wider opportunity to colonize and infect vital areas of the lower respiratory tract, and such a phenomenon led to the excessive, prophylactic usage of antibiotics due to the increased levels of panic, which in turn favored the natural selection of bacteria with genes that became resistant to such antibiotics. Antibiotics might be required for usage solely when bacteria are known to be colonizing vital areas of the human body, and this aspect is tricky, as colonization is asymptomatic and screening is consequently rare. Recently, new variants of the avian IAV H5N1 strain were transmitted from live, infected birds to mammals, including humans in some isolated cases, and given that there have already been several zoonotic spillover events overall since the beginning of 2023, we are rapidly approaching the time when a zoonotic spillover into humans will mark the first epidemic outbreak of the avian flu in humans. A lethality rate of 60% was projected by the World Health Organization, as the virus was shown to favor the development of life-threatening hyper-inflammatory responses at the levels of alveolar tissues constituted by Type II pneumocytes. There are hints that novel variants of H5N1 are capable of infecting the intestinal layer, as recently, two dolphins died as a result of ingesting infected birds within the area of the British Isles. IAV is known to suppress the production and transmission of Type I Interferons by expressing various non-structural proteins (NSPs), such as NSP1, which was found to be also packaged into exosomes and transmitted to neighboring uninfected cells, thereby preventing them from responding to the virus in the first place. A more pronounced rate of innate immune evasion would probably be observed in H5N1 IAV infection than in the infection caused by recent variants of H1N1 IAV. The H5N1 strain of IAV was also found to secrete a higher concentration of NSP1 than SARS-CoV-2, indicating the existence of an association to the greater mortality rate of H5N1 IAV infection. A direct, prophylactic stimulation of the interferon system using a reduced oral or nasal dosage of recombinant anti-inflammatory and anti-viral interferon glycoproteins may represent the most viable approach to prevent an emergence of a life-threatening H5N1 IAV pandemic. A similar non-invasive approach could be developed for an Marburg Virus (MARV) and a Nipah Virus (NiV) infection of humans, as risks of the emergence of a Marburg epidemic and also of a Nipah epidemic may be substantial at this stage as well. Clinical testing of clinical approaches as such could be of critical importance at the moment. Animals could also benefit from related clinical approaches. Somatic natural and adaptive lymphocytes treated with IFN I and III could also constitute a substantial approach of immunization and heavily favor an indefinite shift in the evolutionary battle between the host organism and microbes of public health concern.

The FDA has concluded that a biosimilar candidate capable of demonstrating pharmacodynamic biomarkers in a healthy subject need not be tested for clinical efficacy in patients, regardless of if the biomarker correlates with clinical response. Since monoclonal antibodies (mAbs) do not trig-ger pharmacodynamic response, they can be substituted with robust functional disqualifying them for this waiver that can be overcome by allowing comparison of functional properties that eventually result in clinical response. This suggestion is based on the FDA's preference for more sensitive testing methods. However, clinical efficacy testing in patients is the least sensitive method, as confirmed by statistical modeling, a fact that regulatory agencies need to admit. In this paper, I present a logical and rational argument to establish the biosimilarity of products that do not have pharmacodynamic biomarkers based on their orthogonally proven functional bio-similarity. This understanding will significantly lower the development cost of biosimilars, a goal that the FDA outlined in all its guidance. Keywords: biosimilarity 1; biosimilars 2; pharmacodynamic biomarkers 3; monoclonal antibodies 4; FDA 5; clinical efficacy testing in healthy subjects 6; clinical efficacy testing in patients 7; functional assays 8; receptor binding 9.

Androgen receptor signaling is crucial for prostate cancer growth and is positively regulated in part by intratumoral CYP3A5. As African American (AA) men often carry the wild type CYP3A5 and express high level of CYP3A5 protein, we blocked the wild type CYP3A5 in AA origin prostate cancer cells and tested its effect on androgen receptor signaling. q-PCR based profiler assay identified several AR regulated genes known to regulate AR nuclear translocation, cell cycle progression and cell growth. CYP3A5 processes several commonly prescribed drugs and many of these are CYP3A5 inducers or inhibitors. In this study, we test the effect of these commonly prescribed CYP3A5 inducers/inhibitors on AR signaling. The results show that the CYP3A5 inducers promoted AR nuclear translocation, downstream signaling and cell growth whereas CYP3A5 inhibitors abrogated them. The observed changes in AR activity is specific to alterations in CYP3A5 activity. Both the inducers tested demonstrated increased cell growth of prostate cancer cells, whereas the inhibitors showed reduced cell growth. Further, characterization and utilization of the observation that CYP3A5 inducers and inhibitors alter AR signaling may provide guidance to physicians prescribing CYP3A5 modulating drugs to treat comorbidities in elderly patients undergoing ADT, particularly AA.

We previously showed that mice with knockout in the peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PPARGC1A) gene encoding the PGC-1a protein and nuclear factor erythroid 2 like 2 (NFE2L2) gene, showed some features of the age-related macular degeneration (AMD) phenotype. To further explore the mechanism behind the involvement of PGC-1a in AMD pathogenesis we used young (3-month) and old (12-month) mice with knockout in the PPARGC1A gene and age-matched wild-type (WT) animals. An immunohistochemical analysis showed age-dependent different expression of markers of oxidative stress defense, senescence and autophagy in the retinal pigment epithelium of KO animals as compared with their WT counterparts. Multivariate inference testing showed that senescence and autophagy proteins had the greatest impact on the discrimination between KO and WT 3-month animals, but proteins of antioxidant defense also contributed to that discrimination. A bioinformatic analysis showed that PGC-1a might coordinate the interplay between genes encoding proteins involved in antioxidant defense, senescence and autophagy in the aging retina. These data support importance of PGC-1a in AMD pathogenesis and confirm the utility of mice with PGC-1a knockout as an animal model to study AMD pathogenesis.

The extremely controversial conclusions about the function of human interferon-gamma (hIFNγ) C-terminus as well as the lack of a consistent model explaining its role in the receptor binding prompted us to scrutinize the interaction of hIFNγ with its extracellular receptor hIFNGR1 in different scenarios by means of molecular dynamics simulations. We find that the two molecules alone fail to form a stable complex but the presence of heparan-sulfate-like oligosaccharides largely facilitates the process by both demobilizing the highly flexible C-termini of the cytokine and assisting in the proper positioning of its globule between the receptor subunits. An antiproliferative-activity essay on cells depleted from surface sulfation confirms qualitatively the simulation-based multistage complex-formation model. Our results reveal the key role of HS and its proteoglycans in all processes involving hIFNγ signalling.

This study continued the analysis of immunization with the receptor binding domain (RBD) associated with the adjuvants Dimethyldioctadecylammonium bromide (DDA) and Saponin (Sap) (RBD+DDA/Sap) or Aluminum hydroxide (AH) and outer membrane vesicles (OMVs) of Neisseria meningitidis (RBD+AH/OMV); from adult to old age and assessed maternal-fetal transference of antibodies. Outbred Swiss mice were immunized with 2 intramuscular (IM) doses with the antigenic preparations RBD+DDA/Sap, RBD+AH/OMV or RBD alone. The humoral immune response was evaluated using ELISA, avidity-ELISA, Immunoblotting and a Omicron-surrogate-neutralization assay (BA.1), while the cellular immune response was analyzed by ELISpot. Our previous work studied the IgG response; here, we verified that IgM levels were higher right after the immunization doses, but, as IgG, it persisted until 368 days after the immunization. The avidity of IgM increased from low to intermediate-to-high after the booster dose. RBD+DDA/Sap presented neutralizing indexes against Omicron at days 47 and 176, while RBD+AH/OMV showed neutralization on days 21, 47 and 176. Cellular response, measured 465 days after immunization, revealed IFN-Y and IL-4 secretion. The offspring of RBD+DDA/Sap had detectable antibodies, which decreased around 45 days after birth, the last point we analyzed. The results suggested that DDA/Sap is a promising adjuvant mixture to enhance humoral and cellular immune response against SARS-CoV-2, improving maternal-fetal transference of antibodies; cross-reactivity with Omicron variant; and the maintenance of antibodies for a long period.

Migraine is a debilitating neurological condition affecting millions of people worldwide. Until few years ago, preventive migraine treatments were based on molecules with pleiotropic targets, developed for other indications and discovered by serendipity to be effective in migraine prevention although often burdened by tolerability issues leading to low adherence. However, the progresses in unravelling the migraine pathophysiology allowed to identify novel putative targets as calcitonin gene-related peptide (CGRP). Nevertheless, despite the revolution brought by CGRP monoclonal antibodies and gepants, a significant percentage of patients still remains burdened by an unsatisfactory response suggesting that other pathways may play a critical role with an extent of involvement varying among different migraine patients. Specifically, neuropeptides of the CGRP family as adrenomedullin and amylin, molecules of the secretin family as pituitary adenylate cyclase-activating peptide (PACAP) and vasoactive intestinal peptide (VIP), receptors as transient receptor potential (TRP) channels, intracellular downstream determinants as potassium channels but also the opioid system and the purinergic pathway have been suggested to be involved in migraine pathophysiology. The present review provides an overview of these pathways highlighting, based on preclinical and clinical evidences as well as provocative studies, their potential role as future targets for migraine preventive treatment.

The conventional phytopathogen Pseudomonas syringae has been identified several significant virulence determinants against Caenorhabditis elegans, but their mechanisms of action remain elusive. Here, we report the nematicidal activity and action receptor of a methyl-accepting chemotaxis protein (MCP03) of a wild-type P. syringae MB03 against C. elegans. Purified MCP03 exhibited significant nematicidal toxicity against C. elegans, with a half-lethal concentration of 124.4 μg mL1, and detrimental effects on the growth and brood size of C. elegans. Additionally, MCP03-treated worms showed severe pathological destruction of the intestine and ovary, and depressed wrinkles of the cuticle. Through yeast two-hybrid assays, we identified a subunit of a COP9 signalosome, namely CSN-5, functionated as an action receptor of MCP03. In vitro pull-down and in vivo co-localization assays verified the binding interaction between MCP03 and CSN-5. RNA interference assays confirmed that MCP03 acts on CSN-5 to adversely affect the brood size, growth, and cuticle integrity of C. elegans. Following MCP03 infection, the expression of several genes relative to reproduction, growth, and cuticle formation, such as kgb-1, unc-98, and col-117, were significantly downregulated, which implicated the pathological changes of MCP03-treated nematodes. Thus, this study demonstrates that MCP03 acted on the receptor protein CSN-5 causing lethality and detrimental effects on the fertility, growth, and morphogenesis of C. elegans, which will provide new insights into the signaling pathways and mechanism underlying the nematicidal action of MCP03 towards C. elegans.

COVID-19 pandemic has spurred intense research efforts to identify effective treatments for SARS-CoV-2. In silico studies have emerged as a powerful tool in the drug discovery process, particularly in the search for drug candidates that interact with various SARS-CoV-2 receptors. These studies involve the use of computer simulations and computational algorithms to predict the potential interaction of drug candidates with target receptors. The primary receptors targeted by drug candidates include the RNA polymerase, main protease, spike protein, ACE2 receptor, TMPRSS2, and AP2-associated protein kinase 1. In silico studies have identified several promising drug candidates, including Remdesivir, Favipiravir, Ribavirin, Ivermectin, Lopinavir/Ritonavir, and Camostat mesylate, among others. The use of in silico studies offers several advantages, including the ability to screen a large number of drug candidates in a relatively short amount of time, thereby reducing the time and cost involved in traditional drug discovery methods. Additionally, in silico studies allow for the prediction of the binding affinity of drug candidates to target receptors, providing insight into their potential efficacy. However, it is crucial to consider both the advantages and limitations of these studies and to complement them with experimental validation to ensure the efficacy and safety of identified drug candidates.

Breast cancer is the most common cancer among women worldwide, and estrogen receptor-positive (ER+) breast cancer accounts for a significant proportion of cases. While various treatments are available, endocrine therapies are often the first-line treatment for this type of breast cancer. However, the development of drug resistance poses a significant challenge in managing this disease. ESR1 mutations have been identified as a common mechanism of endocrine therapy resistance in ER+ breast cancer. The first-generation selective estrogen receptor degrader (SERD) fulvestrant has shown some activity against ESR1 mutant tumors. However, due to its poor bioavailability and need for intramuscular injection, it may not be the optimal therapy for patients. Second-generation SERDs have been developed to overcome these limitations. These newer drugs have improved oral bioavailability and pharmacokinetics, making them more convenient and effective for patients. Several oral SERDs are now in phase III trials for early and advanced ER+ breast cancer. This review summarizes the background of oral SERD development, the current status, and future perspectives.

Diabetes mellitus (DM) and chronic kidney disease (CKD) are common in middle aged and elderly individuals. DM may accelerate the aging process, and the age-related declines in the estimated Glomerular Filtration Rate (eGFR), can pose a challenge to diagnose diabetic kidney disease (DKD) using standard diagnostic criteria especially with absence of severe albuminuria among the elderly. In the presence of CKD and DM, elderly patients may need multidisciplinary care due to susceptibility to various health issues e.g., cognitive decline, auditory or visual impairment, various comorbidities, complex medical regimens, and increased sensitivity to medication adverse effects. As a result, it can be challenging to apply recent therapeutic advancements for the general population to the elderly. We review the evidence that the benefits from these newer therapies apply equally to elderly and non-elderly patients and propose a framework for the management of DKD by discussing the nonpharmacological measures and pharmacological management with renin angiotensin system inhibitors (RASi), Sodium Glucose Co-Transporter two inhibitors (SGLT2i), non-steroidal mineralocorticoids receptor antagonists (MRAs), and Glucagon Like Peptide 1 Receptor Agonists (GLP1-RAs).

(1) Background: Heart failure (HF) is the final stage of multiple cardiac diseases, which has now become a severe public health problem worldwide. β-Adrenergic receptor (β-AR) overactivation is a major pathological factor associated with multiple cardiac diseases and mediates cardiac fibrosis and inflammation. Previous study has demonstrated that Bruton's tyrosine kinase (BTK) mediated cardiac fibrosis by TGF-β related signal pathways, indicating that BTK was a potential drug target for cardiac fibrosis. Zanubrutinib, a second-generation BTK inhibitor, has shown anti-fibrosis effects in previous research. However, it is unclear whether Zanubrutinib can alleviate cardiac fibrosis induced by β-AR overactivation;(2) Methods: In vivo: Male C57BL/6J mice were treated with or without the β-AR agonist isoproterenol (ISO) to establish cardiac fibrosis animal model. Here, results showed that BTK inhibitor Zanubrutinib (ZB) had a great effect on cardiac fibrosis and inflammation induced by β-AR. In vitro: Results showed that ZB alleviated β-AR-induced cardiac fibroblast activation and macrophage proinflammatory cytokine production. Further mechanism studies demonstrated that ZB inhibited β-AR-induced cardiac fibrosis and inflammation by BTK、STAT3、NF-κB and PI3K/Akt signal pathways both in vivo and in vitro; (4) Conclusions: our research provides evidence that ZB ameliorates β-AR-induced cardiac fibrosis and inflammation.

An array of diverse processes and factors have been linked to the pathoetiology and pathophysiology of Parkinson’s disease (PD), including systemic CNS factors. This article reviews some of the many processes and factors linked to the emergence and progression of PD that culminates in the loss of substantia nigra pars compacts (SNpc) in PD patients. It is proposed that SNpc astrocytes may be a key hub, with numerous systemic and CNS factors acting to suppress the astrocyte tryptophan-melatonin pathway, leading to a loss of astrocyte melatonin and lactate for SNpc dopamine neurons. Consequently, dopamine neurons show an increase in α-synuclein, oxidative stress and suboptimal mitochondrial function, partly due to the loss of melatonin induced PTEN-associated kinase (PINK)1/parkin and mitophagy. This leads to an increase in the major histocompatibility (MHC)-1 and the chemoattraction of CD8+ T cells that destroy SNpc dopamine neurons in an ‘autoimmune’/’immune-mediated’ manner. The upstream processes driving the end-point ‘chaos’ of SNpc dopamine neuron loss are proposed to be driven by the suppression of night-time pineal melatonin, gut microbiome derived butyrate and possibly bcl2-associated athanogene (BAG)-1, which all act to suppress the glucocorticoid receptor (GR) translocation to the nucleus in all systemic and CNS cells, thereby potentiating the effects of the rising levels of cortisol over the night and accelerated rise in the course of the cortisol awakening response (CAR). The potentiation of cortisol effects at the GR has consequences for the homeostatic regulation of the diverse array of systemic and CNS microenvironments, as well as a distinct regulation of different immune and glia cells. The morning CAR is classically proposed to ‘prepare the body for the coming day’. However, the differential regulation of the GR over the circadian rhythm at night would indicate that such preparation for the coming day may be powerfully determined by night-time factors and processes. The article integrates this systemic, night-time pathoetiology with the ‘immune-mediated’ processes that ultimately drive SNpc dopamine neuron loss. This has a number of novel future research and treatment implications.

The comprehensive anabolic effects of insulin throughout the body, in addition to the control of glycemia, also include ensuring lipid homeostasis and anti-inflammatory modulation, especially in adipose tissue (AT). The prevalence of obesity, defined as a body mass index (BMI) ≥ 30 kg/m2, has been increasing worldwide on a pandemic scale with accompanying syndemic health problems, including glucose intolerance, insulin resistance (IR) and diabetes. Impaired tissue sensitivity to insulin or IR paradoxically leads to diseases with an inflammatory component despite hyperinsulinemia. Therefore, an excess of visceral AT in obesity initiates chronic low-grade inflammatory conditions that interfere with insulin signaling via insulin receptor (INSR). Moreover, in response to IR, hyperglycemia itself stimulates a primarily defensive inflammatory response associated with the subsequent release of numerous inflammatory cytokines and a real threat of organ function deterioration. In this review, all components of this vicious cycle are characterized with particular emphasis on the interplay between insulin signaling and both the innate and adaptive immune responses related to obesity. Increased visceral AT accumulation in obesity should be considered the main environmental factor responsible for the disruption in the epigenetic regulatory mechanisms in the immune system, resulting in autoimmunity and inflammation.

The knowledge of COVID-19 impact on the human body has increased rapidly. Although many people recover from COVID-19, some continue to experience persistent symptoms that have been identified as Long COVID. This condition can have a severe impact on quality of life, and it remains a significant concern for medical professionals and researchers. One of the key components of the SARS-CoV-2 virus that enables it to enter human cells is the spike (S) protein. Recent studies have revealed a complex network of interactions between G proteins, spike (S) protein, and the Renin-Angiotensin System (RAS) may be responsible, at least in part, for long COVID. SARS-CoV-2 can also affect the brain, leading to neurological symptoms such as confusion, memory loss, and fatigue. Increasing evidence suggests that COVID-19 is not just a respiratory illness since it is likely that the virus could influence signal transduction pathways such as G-protein-coupled receptor (GPCR), among others, in the brain, either directly or indirectly, affecting neural functions. These interactions with the spike (S) protein and RAS, alongside the brain, are complex and require deep research to understand their implications for Long COVID-19 manifestation fully. While recent research has shed light on the complex interactions between G proteins, spike (S) protein, the brain, and the angiotensin system, this article explores these interconnected pathways and their implications for long COVID-19 manifestations. The present review summarises current research on different molecular mechanisms in Long COVID pathophysiology and may help identify possible targets or new strategies for the diagnosis and treatment.

De novo metastatic hormone-sensitive PC (mHSPC) accounts for 5-10% of all prostate cancer (PC) diagnoses but it is responsible for nearly 50% of PC-related deaths. Since 2015, the prognosis of mHSPC has slightly improved thanks to the introduction of new hormonal agents and chemotherapy combined with androgen deprivation therapy from the first-line setting. This review describes the current therapeutic opportunities in de novo mHSPC, focusing on potential molecular biomarkers identified in the main clinical trials that have changed the standard of care, the genomic features of de novo mHSPC, and the principal ongoing trials that are investigating new therapeutic approaches and the efficacy of a biomarker-guided treatment in this setting. The road towards a personalized treatment for de novo mHSPC is still long considering that the randomized clinical trials, which have furnished the basis of the current therapeutic options, stratified patients according to clinical criteria that not necessarily reflect the biological rationale of the chosen therapy. The role of transcriptomic profiling of mHSPC as predictive biomarker requires further validation, as well as it remains to ascertain how the genomic alterations detected in mHSPC, that are considered predictive in the castration-resistant disease, can be exploited in the mHSPC setting.

Alcohol effects on hepatic lipid metabolism through various mechanisms, leading synergistically to an accumulation of fatty acids (FA) and triglycerides. Obesity, as well as, the dietary fat [saturated fatty acids (FA) versus poly-unsaturated fatty acids (PUFA)] may modulate the hepatic fat. Alcohol inhibits adenosine monophosphate activated kinase (AMPK). AMPK activates peroxisome proliferators activated receptor a (PPARα) and leads to a decreased activation of sterol regulatory element binding protein 1c (SRABP1c). The inhibition of AMPK, and thus of PPARα results in an inhibition of FAs oxidation. This ß-oxidation is further reduced due to mitochondrial damage induced through cytochrome P4502E1 (CYP2E1) driven oxidative stress. Furthermore, the synthesis of FAs is stimulated through an activation of SHREP1. In addition, alcohol consumption leads to a reduced production of adiponectin in adipocytes due to oxidative stress and to an increased mobilization of FAs from adipose tissue and from the gut as chylomicrons. On the other side, the secretion of FAs via very low density lipoproteins (VLDL) from the liver is inhibited by alcohol. Alcohol also affects signal pathways such as early growth response 1 (Egr-1) associated with the expression of tumour necrosis factor  (TNF), and the mammalian target of rapamycin (mTOR) a key regulator of autophagy. Both have influence the pathogenesis of alcoholic fatty liver. Alcohol-induced gut dysbiosis is contributing to the severity of ALD by increasing metabolism of ethanol in the gut and promoting intestinal dysfunction. Moreover, pathogen associated molecular paterns (PAMPS) via specific Toll-like receptors (TLR) bacterial overgrowth is leading to the translocation of bacteria. Endotoxins, and toxic ethanol metabolites enter the enterohepatic circulation reaching the liver, inducing the activation of the nuclear factor kappa-B (NFB) pathway. Pro-inflammatory cytokines released in the process contribute to inflammation and fibrosis. In addition, cellular apoptosis is inhibited in the favor of necrosis.

Extensive evidence indicates that activation of P2X7 receptor (P2X7R), an ATP-gated ion channel highly expressed in immune and brain cells, is strictly associated with the release of extracellular vesicles. Through this process, P2X7R-expressing cells regulate non-classical protein secretion and transfer bioactive components to other cells, including misfolded proteins, participating in inflammatory and neurodegenerative diseases. In this review, we summarize and discuss the studies addressing the impact of P2X7R activation on extracellular vesicle release and their activities.

Studies on the neurobiological causes of anxiety disorders suggest that the GABA system in-creases synaptic concentration and enhances the affinity of GABAA (type A) receptors for ben-zo-diazepine ligands. Flumazenil antagonizes the benzodiazepine binding site of the GABA (γ-aminobutyric acid) type /benzodiazepine receptor (BZR) complex in the central nervous sys-tem (CNS). The integration of the metabolites of flumazenil by LC-tandem mass spectrometry will complete understanding of the in vivo metabolism of flumazenil and accelerate radio-pharmaceutical inspection and registration. The main goal of our study was to investigate using reversed-phase HPLC (PR-HPLC) coupled with electrospray ionization triple quadrupole tan-dem mass spectrometry (ESI-QqQ MS) for the identification of flumazenil and its metabolites in a hepatic matrix. And a carrier-free nucleophilic fluorination with automatic synthesizer for [18F]flumazenil which applied to in vivo nano-positron emission tomography (Nano-PET)/computed tomography (CT) imaging and ex vivo bio-distribution used to analyze in normal rats. The study showed that 50% of the flumazenil was bio-transformed at 60 min by the rat liver homogenate, while one metabolite (M1) was a methyl transesterification product of flumazenil. In a rat liver microsomes system, two metabolites were identified (M2 and M3) as its carboxylic acid and hydroxylated ethylester forms, respectively. [18F]flumazenil in vivo nanoPET/CT imag-ing and ex vivo bio-distribution assay also showed significant effects on GABAA receptor availa-bility in the amygdala, prefrontal cortex, cortex, and hippocampus in the rat brain, worriless about the formation of metabolites. We showed completion of the bio-transformed course of flumazenil by the hepatic system; and [18F]flumazenil can be a good ligand and serve as a PET agent for determination of GABAA/BZR complex for multiplex neurological syndromes in the clinical stage.

The purpose of this study is to characterize atmospheric pollution and its sources in two West African urban sites during the dry season (January 2009 in Bamako, Mali, and December 2009 in Dakar, Senegal). Particulate Matter (PM) source apportionment was performed using Principal Component Analysis (PCA) and Positive Matrix Factorization (PMF). Carbonaceous components, water-soluble inorganic compounds, and trace elements were analyzed from PM (TSP, PM10, and PM2.5) samples. The measured PM2.5 and PM10 concentrations were 5 to 10 times and 3 to 8 times higher than the 2005 WHO 24-hour standards, respectively. PCA and PMF analyses identify five sources in both cities. The sources contributing to aerosol concentrations (PM2.5 - PM10) in Bamako are motor vehicles (20-13%), solid fuel combustion (16-13%), crustal dust (24-30%), resuspended road dust (26-30%) and secondary aerosols (10-16%). During the sampling period in Bamako, dust was the most prevalent source, accounting for 63% of the total PM10 mass. In Dakar, the main identified sources were motor vehicles (28-19%), mineral dust (16-25%), industries and oil burn-ing (11-10%), sea salts (15-20%), and resuspended road particles (21-29%). The findings also indicate that anthropogenic emissions contribute significantly to the PM2.5 fraction, implying that populations are highly exposed to fine particles.

Biochemical recurrence (BCR) after primary treatments for prostate cancer (PC) is an extremely heterogeneous phase and at least a stratification in low and high-risk cases for early progression in metastatic disease is necessary. At now PSA-DT represents the best parameter to define low and high risk BCR PC, but a real precision medicine is strongly suggested to define a tailored management of patients with BCR. Before defining management, it is necessary to exclude the presence of low volume metastasis associated with PSA progression using new generation imaging preferably with PSMA PET/CT. Low risk BCR cases should be actively observed without early systemic therapies. Early treatment of low risk BCR with continuous androgen deprivation therapy (ADT) can produce disadvantages such the development of castration resistance before the appearance of metastases (non-metastatic castration resistant PC). Patients with high risk BCR benefit from early systemic therapy. The primary end point must be metastasis-free survival (MFS), even with the same overall survival (OS). The EMBARK study is able to impact on the management of high risk BCR, by introducing the concept of anticipation and intensification through the use of androgen receptor signaling inhibitors (ARSI) and ADT combination therapy. In high risk (PSA-DT ≤ 9 months) BCR cases, the combination of enzalutamide with leuprolide significantly improves MFS when compared to leuprolide alone, maintaining the quality of life unchanged in an asymptomatic phase of the disease. The possibility of using ARSI alone in this early disease setting is suggested by the EMBARK study (arm with enzalutamide alone) with less evidence than the intensification of the combination therapy. Continued use versus discontinuation upon reaching undetectable PSA levels of enzalutamide plus leuprolide intensified therapy needs to be better defined with further analysis. Real world analysis must verify the significant results obtained in the context of a phase 3 study.

Among the five human senses, light, sound, and force perceived by eye, ear, and skin, respectively are physical actions, and therefore can be easily measured and expressed as objective, univocal, and simple digital data with physical quantity. However, taste and odor molecules perceived by tongue and nose are chemical actions, it has been difficult to express them as objective and univocal digital data, since no reference chemicals can be defined. Therefore, while the recording, saving, transmitting to remote locations, and replaying human visual, auditory, and tactile information as digital data in digital devices has been realized (this series of data flow is defined as DX (digital transformation) in this review), the DX of human taste and odor information is not yet in the realization stage. Particularly, since there are at least 400,000 types of odor molecules and an infinite number of complex odors that are mixtures of these molecules, it has been considered extremely difficult to realize "human olfactory DX" by converting all odors perceived by the human olfaction into digital data. In this review, we discuss the current status and future prospects of the development of "human olfactory DX," which we believe can be realized by utilizing odor sensors that employ the olfactory receptors (ORs) that support human olfaction as sensing molecules (i.e., human OR sensor).

Background. The course of the COVID-19 epidemic process depends on population immunity which prevents pathogen spread among the population. Aim: to study the evolution of SARS-CoV-2 humoral immunity in the Belarusian population relative to COVID-19 pandemic dynamics. Materials and methods. The work was carried out according to a methodology for assessing population immunity developed by Rospotrebnadzor (Russia) and the Belarusian Ministry of Health with the participation of the St. Petersburg Pasteur Institute (SPPI), taking into account WHO recommendations. The study was approved by the Bioethics Committee of Belarus and the SPPI Bioethics Committee. Participant selection was carried out by questionnaire using a cloud (internet server) service. To monitor population immunity, a cohort of 4,661 people (participating in all stages of seromonitoring) was formed from the overall volunteer group. Volunteers were randomized by age group (1-17, 18-29, 30-39, 40-49, 50-59, 60-69, 70+ years), region, and professional group. For the detection of antibodies (Abs) to nucleocapsid (Nc) and S glycoprotein receptor-binding domain (RBD), corresponding assay systems were used following manufacturer instructions. The study was conducted in 4 stages according to a single scheme. Results. In the 1st stage (pandemic month 15), collective immunity was due mainly to Nc+RBD+ Ab status alone. By the 2nd stage (carried out after 4 months), their share decreased 1.2-fold, while the share of volunteers who had only RBD Abs increased 1.7-fold. In the 3rd and 4th stages (carried out after 9 and 19 months), the share of persons with RBD+Nc‒ compared to the 2nd stage decreased by 3.5%; the proportion of persons with Nc+RBD‒ Abs increased by 1.5-fold. The most important factor in population immunity was vaccination of the population, the coverage of which reached 70% by the 4th stage. Among vaccines, the Sputnik V and Sputnik Light vector designs were used most often. The whole-virion, inactivated BIBP-CorV vaccine was used less often. Conclusion. The evolution of collective SARS-CoV-2 humoral immunity included a set of changes in circulating Ab levels (Nc, RBD). The hybrid immunity formed helped to reduce the incidence to nearly zero.

HIV-1, like other viruses, represents an open thermodynamic system. This is why it is important to know its thermodynamic properties. Virus-host interactions are performed at the membrane as antigen-receptor binding. Antigen-receptor binding represents a chemical reaction, similar to protein-ligand interactions. The driving force for antigen-receptor binding is Gibbs energy of binding. Knowing Gibbs energy of binding, it is possible to estimate the rate of virus binding and entry into host cells. In this paper, binding equilibrium constants and standard Gibbs energies of binding between the HIV-1 gp120 antigen and the CD4 receptor have been reported at 4°C, 22°C and 37°C.

The emergence of CDK4/6 inhibitors, such as palbociclib, ribociclib, and abemaciclib, has revolutionized the treatment landscape for hormone receptor-positive breast cancer. These agents have demonstrated significant clinical benefits in terms of both progression-free survival and overall survival. However, resistance to CDK4/6 inhibitors remains a challenge, limiting their long-term efficacy. Understanding the complex mechanisms driving resistance is crucial for the development of novel therapeutic strategies and improvement of patient outcomes. Translational research efforts, such as preclinical models and biomarker studies, offer valuable insight into resistance mechanisms and may guide the identification of novel combination therapies. This review paper aims to outline the reported mechanisms underlying CDK4/6 inhibitor resistance, drawing insights from both clinical data and translational research in order to help direct the future of treatment for hormone receptor positive metastatic breast cancer.

To map Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV 2) spreading and evaluate immune responses variations against this virus, it was essential to locally set up efficient serological tests. The SARS-CoV2 immunogenic proteins were very expensive and not affordable mainly for Low and Middle Income Countries (LMICs). For this purpose, the commonly used antigen, Re-ceptor-Binding Domain (RBD) of Spike S1 protein (S1RBD), was produced using the the Baculovirus Expression Vector System (BEVS) . During the current study, the expression of S1RBD was monitored using western blot under different culture conditions. Different parameters were studied: Multiplicity Of Infection (MOI), cell density at infection and harvest time. Hence, optimal conditions for efficient S1RBD production were identified: MOI 3; cell density at infection 2-3x 106 cells/mL and time post-infection (tpi or harvest time) of 72h and 72-96 h successively for expression in shake-flasks and 7L-bioreactor. A high production yield of S1RBD varying between 4mg and 70 mg per liter of crude cell culture supernatant was achieved, respectively, in shake-flasks and in 7L-bioreactor. Moreover, the produced S1RBD showed an excellent antigenicity potential against COVID-19 patient sera evaluated by western blot. Thus, additional serological assays, such as ELISA, were developed using the purified S1RDB (published by other research groups).

Aims: Anxiety, major depressive disorder and accelerated cognitive decline frequently complicate traumatic brain injury. Obesity and type 2 diabetes mellitus drive peripheral inflammation which can accelerate traumatic brain injury-associated neurodegeneration. The Zucker rat harbors G-protein coupled receptor agonist IgG autoantibodies and in vitro neurotoxicity caused by these autoantibodies was prevented by a novel synthetic fragment of the serotonin 2A receptor. The aim of the present study was to test whether genetic obesity manifested in Zucker diabetic fatty rat is associated with anxiety, depression and spatial memory impairment induced by mild traumatic brain injury. Furthermore, we investigated whether these neurobehavioral or neurodegenerative complications can be lessened by administration of a novel putative neuroprotective peptide. Methods: Age-matched lean and fatty diabetic Zucker rats were tested in the sucrose preference test (anhedonia), open field test in bright light (anxiety measure) and the Morris water maze (spatial memory) prior to receiving a sham-injury or lateral fluid percussion (LFP) mild traumatic brain injury. Behavioral testing was repeated at 1-week, 1-month, and 3-month intervals following injury. A synthetic peptide consisting of a portion of the 5- hydroxytryptamine (serotonin) 2A receptor (2 mg/kg) (or vehicle) was administered via intraperitoneal route every other day for 7 days after sham or LFP injury to lean rats or 7 days before and after sham or LFP injury to fatty rats. Results: Sucrose preference decreased transiently (one week after mild traumatic brain injury) in Zucker lean rats indicative of anhedonia. Baseline anxiety-like behavior (bright light, open field test) was lower in fatty vs. lean Zucker rats, and anxiety behavior increased significantly in fatty rats but not lean rats following mild traumatic brain injury. Mild traumatic brain injury impaired recall of spatial memory in fatty and lean rats, and the effect was longer-lasting in fatty rats. A synthetic peptide fragment of the 5-hydroxytryptamine 2A receptor enhanced recall of spatial learning one-week after sham injury in Zucker rats and it may have prevented ‘anhedonia’ one-week after TBI (LFP) in a subset of Zucker fatty and lean rats expressing near-normal baseline sucrose preference. Mean plasma 5-hydroxytryptamine 2A receptor autoantibody level (determined 2 weeks after injury) was 2.5-fold higher than background, but did not differ significantly in (sham- vs TBI) Zucker lean rats. Conclusions: These are the first data to suggest reduced baseline anxiety-like behavior in Zucker fatty (vs. lean) rats. The pronounced increases in anxiety , and spatial memory impairment experienced by Zucker fatty (vs lean) rats following mild traumatic brain injury may have accounted in part for absence of a 5-hydroxytryptamine 2A receptor peptide neuroprotective effect in brain- injured Zucker fatty rats.

The renin-angiotensin system (RAS) plays a role in cardiovascular homeostasis and hydro-electrolyte balance influencing organ function throughout the body. The classical view of RAS focused on a single biologically active metabolite, the octapeptide angiotensin (Ang)ll, created by the Angiotensin-converting enzyme (ACE). The past two decades have revealed new functions for intermediate products of the RAS beyond their role as substrates. Angiotensin 1-7 (Ang-(1—7), a RAS peptide product with actions at the Mas receptor, reportedly prevents cardiovascular disease-induced cognitive decline and cancer-induced bone pain (CIBP). However, Ang-(1—7) has a short half-life in vivo; here, we hypothesized that activating the MasR1 with a lactoside Ang-(1—7) analogue- PNA6-would attenuate inflammatory, cancer pain confined to the long bones, and chemotherapy-induced peripheral neuropathy (CIPN) for a longer-lasting efficacious therapeutic effect. PNA6, Asp-Arg-Val-Tyr-Ile-His-Ser-(O-β-Lact)-amide, was successfully synthesized on solid phase peptide synthesis (SPPS). PNA6 significantly reversed inflammatory pain induced by 2% carrageenan in mice. In a second study modeling a complex pain state, E0771 breast adenocarcinoma cells were implanted into the femur of female C57BLK/6J wild-type mice to induce cancer-induced bone pain (CIBP). Both acute and chronic dosing of PNA6 significantly reduced the spontaneous pain behaviors associated with CIBP. A third murine model of platinum drug-induced painful peripheral neuropathy was established using oxaliplatin. Mice in the oxaliplatin-vehicle treatment groups demonstrated significant mechanical allodynia compared to oxaliplatin- PNA6 treatment group mice. These data suggest that PNA6 is a viable lead candidate for treating chronic inflammatory and complex neuropathic pain.

N-methyl-D-aspartate receptors (NMDARs) are the main class of ionotropic receptor for the ex-citatory neurotransmitter glutamate. It plays a crucial role in the permeability of Ca2+ ions and excitatory neurotransmission in the brain. Being heteromeric receptors, they are composed of sev-eral subunits, including two obligatory GluN1 subunits (eight splice variants) and regulatory GluN2 (GluN2A~D) and/or GluN3 (GluN3A~B) subunits. Widely distributed in the brain, they regulate other neurotransmission systems and are therefore involved in essential functions such as synaptic transmission, learning and memory, plasticity, excitotoxicity. The present review will discuss the physiopathological impacts of NMDAR and particularly GluN2A and GluN2B subu-nits in cognitive processes and neurodegenerative diseases (Alzheimer's disease, Huntington's disease, Parkinson's disease). The pharmacology of different NMDAR antagonists and their po-tentialities will be presented. In particular, a focus will be given on fluoroethylnormemantine (FENM), an investigational drug with very promising developments as a tomography radiotracer for NMDARs, an anxiolytic in post-traumatic stress disorder and a neuroprotective agent in Alzheimer's disease.

Excessive high fat diet (HFD) consumption can induce food addiction which is believed to involve the communication between the hypothalamus and mesolimbic dopaminergic neurons, originating in the ventral tegmental area (VTA) and projecting to the nucleus accumbens (NAc). These brain regions are densely populated with opioid receptors, raising the possibility that these receptors, and particularly mu opioid receptors (MORs), are involved in mediating reward induced by palatable foods. This study sought to investigate the involvement of MORs in high fat diet (HFD)-induced reward and if there is any difference between male and female subjects in this response. We also assessed if exposure to HFD would potentiate the rewarding action of oxycodone, a relatively selective MOR agonist. The place conditioning paradigm was used to determine if conditioning for a short time (STC, 2 h) or long time (LTC, 16 h) with HFD induces reward or alters the rewarding action of oxycodone. Male and female C57BL/6J mice as well as MOR knockout and wildtype mice of both sexes were tested for basal place preference on day 1 and then conditioned with HFD in one chamber and regular chow diet (RCD) in another chamber and tested for place preference again after three sets of STC and again after a set of LTC. Each set consisted of two conditioning with RCD and two conditioning with HFD. Controls were conditioned with RCD in both conditioning chambers. Following the last place preference test, mice were treated with oxycodone and conditioned in the HFD-paired chamber and saline in the RCD-paired chamber for one hour once a day to explore the possibility if the HFD could alter oxycodone reward. The result showed that HFD induced conditioned place preference (CPP) in both male and female subjects following the LTC. This response was further potentiated after oxycodone conditioning. The latter response was mediated via MORs, as it was blunted in MOR knockout mice. However, HFD-induced CPP was observed following LTC in only female MOR knockout mice, suggesting for sexual dimorphism in this response.

Prolactin (PRL) is a pleiotropic hormone released from lactotrophic cells of the anterior pituitary gland that also originates from extrapituitary sources and plays an important role in regulating lactation in mammals, as well as other actions. Acting in an endocrine and paracrine/autocrine manner, PRL regulates the hypothalamic-pituitary-ovarian axis, thus influencing the maturation of ovarian follicles and ovulation. This review provides a detailed discussion of the current knowledge on the role of PRL in the context of ovulation and ovulatory disorders, particularly with regard to hyperprolactinemia, which is one of the most common causes of infertility in women. Much attention has been given to the PRL structure and the PRL receptor (PRLR), as well as the diverse functions of PRLR signaling under normal and pathological conditions. The hormonal regulation of the menstrual cycle in connection with folliculogenesis and ovulation, as well as the current classifications of ovulation disorders, are also described. Finally, the state of knowledge regarding the importance of TIDA (tuberoinfundibular dopamine), KNDγ (kisspeptin/neurokinin B/dynorphin) and GnRH (gonadotropin-releasing hormone) neurons in PRL- and kisspeptin (KP)-dependent regulation of the hypothalamic-pituitary-gonadal (HPG) axis in women is reviewed. Based on this review, a rationale for influencing PRL signaling pathways in therapeutic activities accompanying ovulation disorders is presented.

Arrestin-1, or visual arrestin, exhibits an exquisite selectivity for light-activated phosphorylated rhodopsin (P-Rh*) over its other functional forms. That selectivity is believed to be mediated by two well-established structural elements in the arrestin-1 molecule, the activation sensor detecting the active conformation of rhodopsin and the phosphorylation sensor responsive to the rhodopsin phosphorylation, which only active phosphorylated rhodopsin can engage simultaneously. However, in the crystal structure of the arrestin-1-rhodopsin complex there are arrestin-1 residues located close to rhodopsin, which do not belong to either sensor. Here we tested by site-directed mutagenesis the functional role of these residues in wild type arrestin-1 using direct binding assay to P-Rh* and light-activated unphosphorylated rhodopsin (Rh*). We found that many mutations either enhanced the binding only to Rh* or increased the binding to Rh* much more than to P-Rh*. The data suggest that the native residues in these positions act as binding suppressors, specifically inhibiting the arrestin-1 binding to Rh* and thereby increasing arrestin-1 selectivity for P-Rh*. This calls for the modification of a widely accepted model of the arrestin-receptor interactions.

Obesity is one of the most prevalent chronic diseases and has become a global epidemic. Obesity leads to a greater risk of breast cancer (BC), metastases, recurrence, and decreased survival. For sustained weight loss, bariatric surgery is effective as a long-term solution. Bariatric surgery is associated with improved outcomes of several cancers including BC, although the mechanisms mediating this protection are unknown. We hypothesized that elevated bile acid pools detected after bariatric surgery may be factors that contribute to improved BC outcomes. Indeed, patients with greater expression of the bile acid receptor FXR displayed improved survival in specific BC subtypes. Patients with tumors that are estrogen receptor negative (ER-) displayed significantly elevated survival with higher FXR (NR1H4) expression compared to lower expression. FXR is a nuclear hormone receptor activated by bile acids. Therefore, we posited that activating FXR using an established FDA-approved agonist would display anticancer effects. Indeed, FXR agonism by the bile acid mimetic known commercially as OCALIVA (“OCA”), or Obeticholic acid (INT-747), significantly reduced BC progression and overall tumor burden in a pre-clinical model. In human and murine BC analyses in vitro, agonism of FXR significantly and dose-dependently inhibited proliferation, migration, and viability. In contrast, synthetic agonism of another common bile acid receptor, the G protein-coupled bile acid receptor (GPBAR1, TGR5) which is mainly activated by secondary bile acids, failed to significantly alter cancer cell dynamics. In conclusion, agonism of FXR by primary bile acid memetic OCA yields potent anti-tumor effects potentially through inhibition of proliferation and migration and reduced cell viability. Findings suggest that FXR is a tumor suppressor gene with high potential for personalized therapeutic strategies for individuals with BC.

Despite the availability of effective vaccines against COVID-19, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) continues to spread worldwide, pressing the need for new vaccines with improved breadth and durability. We developed an adjuvanted subunit vaccine against SARS-CoV-2 using recombinant receptor-binding domain (RBD) of spike with synthetic adjuvants targeting TLR7/8 (INI-4001) and TLR4 (INI-2002), co-delivered with aluminum hydroxide (AH) or aluminum phosphate (AP). The formulations were characterized for the quantities of RBD, INI-4001, and INI-2002 adsorbed onto the respective aluminum salts. Results indicated that at pH 6, the uncharged RBD (5.73 ± 4.2 mV) did not efficiently adsorb to the positively charged AH (22.68 ± 7.01 mV), whereas it adsorbed efficiently to the negatively-charged AP (-31.87 ± 0.33 mV). Alternatively, pre-adsorption of the TLR ligands to AH converted it to a negatively-charged particle, allowing for the efficient adsorption of RBD. RBD could also be directly adsorbed to AH at a pH of 8.1, which changed the charge of the RBD to negative. INI-4001 and INI-2002 efficiently to AH. Following vaccination in C57BL/6 mice, both aluminum salts promoted Th2-mediated immunity when used as the sole adjuvant. Co-delivery with TLR4 and/or TLR7/8 ligands efficiently promoted a switch to Th1-mediated immunity instead. Measurements of viral neutralization by serum antibodies demonstrated that the addition of TLR ligands to alum also greatly improved the neutralizing antibody response. These results indicate that the addition of a TLR7/8 and/or TLR4 agonist to a subunit vaccine containing RBD antigen and alum is a promising strategy for driving a Th1 response and neutralizing antibody titers targeting SARS-CoV-2.

Tumour microenvironment, composed of pro- and anti-tumour immune cells, affects cancer cells behaviour. We aimed to evaluate if tumour-infiltrating lymphocyte (TIL) density and TILs subtypes in core biopsies at diagnosis of breast cancer patients could predict pathologic complete response (pCR; ypT0/is ypN0) from neoadjuvant systemic therapy (NST). The TIL subtypes were determined based on the proportions of presumably anti-tumour (CD8+, CXCL13+) and pro-tumour (PD-1+, FOXP3+) immune cells. A prospective, non-interventional study including 171 participants undergoing NST was performed. The median TIL density for the entire cohort was 10% (IQR: 3.5-23.8), and 59 (35%) patients achieved pCR. TIL density was positively associated with pCR (univariately and multivariably). In the multivariable logistic regression model, TIL density was an independent predictor of pCR (p=0.012, OR 1.27; 95% CI 1.05-1.54) when controlled for age (p=0.232), Ki-67 (p=0.001), node-negative status (p=0.024), and HER2+/triple negative vs luminal B-like subtype (p<0.001). In our sample, higher proportions of PD-1+ TILs and FOXP3+ TILs were associated with a higher probability of pCR but the association was not statistically significant. In the exploratory multivariable analysis, we showed that only higher CD8+ TILs were associated with pCR. In conclusion, TIL density and its subtypes are associated with pCR.

There is much concern about disruption of endocrine physiology regulated by steroid hormones in humans, other terrestrial vertebrates and fish by industrial chemicals, such as bisphenol A, and pesticides, such as DDT. These endocrine-disrupting chemicals influence steroid-mediated physiology in humans and other vertebrates by competing with steroids for receptor binding sites, disrupting diverse responses involved in reproduction, development and differentiation. Here I discuss that due to evolution of the progesterone receptor (PR) and mineralocorticoid receptor (MR) after ray-finned fish and terrestrial vertebrates diverged from a common ancestor, each receptor evolved to respond to different steroids in ray-finned fish and terrestrial vertebrates. In elephant shark, a cartilaginous fish, ancestral to ray-finned fish and terrestrial vertebrates, both progesterone and 17,20-beta-dihydroxy-progesterone activate the PR. During the evolution of ray-finned fish and terrestrial vertebrates, the PR in terrestrial vertebrates continued responding to progesterone and evolved to weakly respond to 17,20-beta-dihydroxy-progesterone. In contrast, the physiological progestin for the PR in zebrafish and other ray-finned fish is 17,20-beta-dihydroxy-progesterone, and ray-finned fish PR responds weakly to progesterone. The MR in fish and terrestrial vertebrates also diverged to have different responses to progesterone. Progesterone is a potent agonist for elephant shark MR, zebrafish MR and other fish MRs, in contrast to progesterone’s opposite activity as an antagonist for aldosterone, the physiological mineralocorticoid for human MR. These different physiological ligands for fish and terrestrial vertebrate PR and MR need to be considered in applying data for their disruption by chemicals in fish and terrestrial vertebrates to each other.

Background: The clinical impact of vasopressin in hemorrhagic shock remains largely unknown. Objective: This systematic review and meta-analysis was designed to investigate the effects of vasopressin receptor agonists during the resuscitation of hemorrhagic shock. Methods: A systematic search of PubMed (MEDLINE), Scopus, and PubMed Central was conducted for relevant articles. Preclinical (animal) and clinical studies were included. The primary objective was to investigate the correlation of vasopressin receptor agonist use with mortality and various hemodynamic parameters. Results: Data extraction was possible in 13 animal studies and two clinical studies. Differences in risk of mortality between patients who received a vasopressin receptor agonist were not statistically significant when compared to those who were not treated with such agents [RR (95%CI): 1.17 (0.67, 2.08); p=0.562; I2 = 50%]. The available data were insufficient to conduct a meta-analysis assessing the effect of vasopressin receptor agonists on hemodynamics. Drawing safe conclusions from animal studies was challenging, due to significant heterogeneity in terms of species and dosage of vasopressin receptor agonists across studies. Conclusions: Differences in risk of mortality between patients who received a vasopressin receptor agonist were not statistically significant when compared to those who were not treated with such agents after hemorrhagic shock.

Orthologs of human glucocorticoid receptor (GR) and human mineralocorticoid receptor (MR) first appear in cartilaginous fishes. Subsequently, the MR and GR diverged to respond to different steroids: the MR to aldosterone and the GR to cortisol and corticosterone. We report that cortisol, corticosterone and aldosterone activate full-length elephant shark GR, and progesterone, which activates elephant shark MR, does not activate elephant shark GR. However, progesterone inhibits steroid binding to elephant shark GR, but not to human GR. Together, this indicates partial functional divergence of elephant shark GR from the MR. Deletion of the N-terminal domain (NTD) from elephant shark GR (truncated GR) reduced the response to corticosteroids, while truncated and full-length elephant shark MR had similar responses to corticosteroids. Swapping of NTDs of elephant shark GR and MR yielded an elephant shark MR chimera with full-length GR-like increased activation by corticosteroids and progesterone compared to full-length elephant shark MR. Elephant shark MR NTD fused to GR DBD+LBD had similar activation as full-length MR, indicating that the MR NTD lacked GR-like NTD activity. We propose that NTD activation of human GR evolved early in GR divergence from the MR.

SARS-CoV-2 Omicron variant spike RBD epitopes in complex with spike (S) -protein D614G mutations now predominate globally and increase infectivity by assembling more functional S proteins into the virion. On average, homeopathic medicine contains less than one molecule per dose on average. Single variable SphericalHarmonicY, LaguerreL, WhittakerM, SphericalBesselJ, LegendreP, LegendreQ, LaguerreL, ChebyshevT, and Hypergeometric1F1 Functions pFqarise in connection with the power series solution of the Schrodinger equation or in the summation of perturbation expansions in quantum mechanics. A quantum interpretation of the homeopathic method is presented here through a novel algebraic topology approach to supersymmetry and symmetry breaking in quantum fields and quantum gravity theory with the aim of developing a wide range of physical-based drug design applications in a Small Molecule Quantized Water Memory Network suggesting that the Hidden Black Hole Paradox of Information Loss might be solved under suitable conditions.

Chronic diseases, such as type 2 diabetes (T2D), are difficult to manage because they demand continuous therapeutic review and monitoring. Beyond achieving the target HbA1c, new guidelines for the therapy of T2D have been introduced with the new groups of antidiabetics (GLP-1ra and SGLT2-in). Despite new guidelines, clinical inertia, that can be caused by physicians, patients or healthcare system, results in T2D not being effectively managed. This opinion paper explores the shift in T2D treatment, challenging assumptions and evidence-based recommendations, particularly for family physicians, considering the patient's overall situation in decision-making. We looked for the possible reasons of clinical inertia and poor application of guidelines in the management of T2D. Guidelines for antidiabetic drugs should be more precise, providing case studies and clinical examples to define clinical contexts and contraindications. Knowledge communication can improve confidence and should include clear statements on areas of decision-making not supported by evidence. Precision medicine initiative in diabetes aims to identify subcategories of T2D patients (including frail patients) using clustering techniques from data science applications, focusing on CV and poor treatment outcomes. Clear, unconditional recommendations for personalized T2D management may encourage drug prescription, especially for family physicians dealing with diverse patient contexts and clinical settings.

Background: Prostate cancer is a global health concern, necessitating ongoing research to enhance our comprehension of its molecular foundations and develop more efficacious therapeutic approaches. Among the emerging protagonists in this arena is Speckle-type POZ (pox virus and zinc finger protein) (SPOP), an E3 ubiquitin ligase substrate adaptor protein. SPOP's recent ascent to prominence in prostate cancer research is attributed to its crucial role in regulating the Androgen Receptor (AR) signaling pathway. This systematic review aims to provide a comprehensive synthesis of existing knowledge concerning SPOP mutations in prostate cancer. It seeks to elucidate their significance in characterizing the disease and their potential as therapeutic targets. Methods: A systematic literature search was conducted in multiple databases, including PubMed, Web of science, Scopus and google scholar to identify relevant studies published up to September 2023. Eligible studies included investigations of SPOP mutations in prostate cancer and their implications. Data extraction, quality assessment, and synthesis were performed in conformity to the PRISMA guidelines. Results: The review revealed that SPOP mutations are recurrent events in prostate cancer, with a notable prevalence in specific molecular subtypes. These mutations primarily affect the MATH domain of SPOP, disrupting its substrate recognition function. Notably, SPOP mutations have profound consequences on the AR signaling pathway, leading to increased AR protein stability and transcriptional activity. The clinical implications of SPOP mutations remain diverse, with varying associations with prognostic outcomes. Conclusion: SPOP mutations represent a significant facet of prostate cancer biology, influencing disease heterogeneity and clinical behavior. While their precise prognostic significance is evolving, their functional impact on the AR pathway highlights their potential as therapeutic targets. This systematic review provides a comprehensive overview of SPOP mutations in prostate cancer, contributing to our understanding of the disease's molecular landscape and therapeutic avenues.

Partial negative allosteric modulators (NAM) of the mGlu5 receptor are an excellent alternative to full antagonists and NAMs because they retain some therapeutic effects and, at the same time, have a much broader therapeutic window. Here, we investigated whether partial mGlu5 NAM, M-5MPEP induced a fast and sustained antidepressant-like effect, characteristic of rapid-acting antidepressant drugs (RAADs) like ketamine, in C57BL/6J mice. M-5MPEP caused a rapid, dose-dependent antidepressant-like action in the tail suspension test (TST) 60 min after injection. This effect was antagonized by an AMPA receptor antagonist (NBQX) and a TrkB receptor antagonist (ANA-12) but not by 5HT1A and 5HT2A/2C receptor antagonists. Furthermore, M-5MPEP (30 mg/kg) induced sustained antidepressant-like effects 24 h after the last of four administrations. These effects were revealed in the splash test, designed to measure apathy-like state, and in the TST. Western blot and ELISA analyses indicated the involvement of the TrkB/BDNF pathway in the sustained M-5MPEP effects. Additionally, prolonged effects of M-5MPEP were entirely reversed by the TrkB receptor antagonist ANA-12 in both the splash test and the TST, confirming the critical role of TrkB receptor activation in the sustained antidepressant-like effect of M-5MPEP. Importantly, M-5MPEP enhanced the subthreshold dose of (R)-ketamine in the TST, indicating both substances' convergent mechanisms of action and the possibility of their practical use in treating depression.

Alterations in the hypothalamic-pituitary-adrenal (HPA) axis and associated changes in circulating levels of glucocorticoids are integral to an organism's response to stressful stimuli. Glucocorticoids acting via glucocorticoid receptors (GR) play a role in fertility, reproduction, placental function, and fetal development. GRs are ubiquitously expressed throughout the female reproductive system and regulate normal reproductive function. Stress induced glucocorticoids have been shown to inhibit reproduction and affect female gonadal function by supressing the hypothalamic-pituitary-gonadal (HPG) axis at each level. Furthermore, during pregnancy, a mother's exposure to prenatal stress or external glucocorticoids can result in long-lasting alterations to the fetal HPA and neuroendocrine function. Several GR isoforms generated via alternative splicing or translation initiation from the GR gene have been identified in the mammalian ovary and uterus. The GR isoforms identified include the splice variants, GRα and GRβ, GRγ and GR-P. Glucocorticoids can exert both stimulatory and inhibitory effects and both pro- and anti-inflammatory functions in the ovary, in vitro. In the placenta, thirteen GR isoforms have been identified in human, guinea pig, sheep, rat and mouse indicating it is conserved across species and may be important in mediating a differential response to stress. Distinctive responses to glucocorticoids, differential birth outcomes in pregnancy complications, and sex-based variations in the response to stress could all potentially be dependent on a particular GR expression pattern. This review provides an overview of the structure and function of the GR in relation to female fertility and reproduction and discusses the changes in GR and glucocorticoid signalling during pregnancy. This review will delve into the existing understanding of GR isoforms and explore the possible roles that these distinct isoforms may have in regulating glucocorticoid signalling, along with their impact on gonadal activity, placental function, and fetal growth.

Herpes simplex virus type 1 (HSV-1) is among the most widely spread viruses on the planet. However, the rate of binding to the receptor is not among the greatest ones. Gibbs energy of binding, which represents the driving force for antigen-receptor binding, of HSV-1 is less negative than can be expected. Furthermore, the Gibbs energy of biosynthesis of HSV-1 is among the most negative in nature. This implies high rate of multiplication of HSV-1. Obviously, HSV-1 uses specific strategy in virus-host interaction. While most other viruses increase infectivity through a high rate of antigen-receptor binding and cell entry/ highly negative Gibbs energy of binding, HSV-1 uses another strategy. It is related to a relatively slow reaction of antigen-receptor binding, which is followed by a higher rate of multiplication, which is a consequence of a highly negative Gibbs energy of biosynthesis. We can conclude empirically that both strategies are successful.

Understanding the complex interactions between metabolism and the immune system (“meta-flammation”) is crucial for the identification of key immunomodulatory factors as potential therapeutic targets in obesity and in cardiovascular diseases. Cathelicidin antimicrobial peptide (CAMP) is an important factor of innate immunity and is expressed in adipocytes. CAMP therefore might play a role as an adipokine in metaflammation and adipose inflammation. Toll-like receptor (TLR) 9 is another component of the innate immune system that is expressed and functionally active in adipocytes. The aim of the present study was to investigate the impact of TLR9 signaling on CAMP expression in adipocytes and in adipose tissue. CAMP gene expression in murine 3T3-L1 and human SGBS adipocytes and in murine and human adipose tissues was quantified by real-time PCR. TLR9 knockdown was applied in murine 3T3-L1 adipocytes via siRNA transfection. Adipocyte inflammation was induced in vitro by TNFα stimulation. Serum CAMP concentrations in TLR9 knockout (KO) and in wildtype mice were quantified by ELISA. CAMP gene expression was considerably increased in 3T3-L1 adipocytes during differentiation. TNFα significantly induced CAMP gene expression in mature adipocytes, which was antagonized by inhibitors of NF-κB and PI3K signaling. Cell-free nucleic acids (cfDNA) as endogenous TLR9 ligand significantly impaired CAMP gene expression, whereas synthetic agonistic and antagonistic TLR9 ligands had no effect. Cellular TLR9 knockdown reduced adipocyte CAMP gene expression in vitro and male TLR9 knockout mice exhibited lower systemic CAMP concentrations than wildtype mice. CAMP and TLR9 gene expression were correlated positively in murine and human subcutaneous but not in intraabdominal/visceral adipose tissues. These findings suggest a regulatory role of TRL9 in adipocytic CAMP expression as a novel putative molecular mechanism in adipose tissue innate immunity.

Global economic and social burden was caused by the SARS-CoV-2 spread worldwide. Despite the end of the pandemic, there is a concern about virulent evolving variants of the virus which can bypass the humoral immune response induced by vaccination or infection. Crucial to the viral entrance, amino acid residues in the RBM region, which interacts with cellular receptor ACE2, can elicit neutralizing antibody response. Herein we determine the immunogenicity of one-dose or heterologous dose vaccinated serum against wild-type and mutated RBM region. Despite low antibody response to wild-type SARS-CoV-2 RBM, omicron variants possess four mutations in RBM (S477N, T478K, E484A, F486V) that induce even less antibody titers. The most predominant responses were against IgA and IgG. While neutralizing antibodies (nAbs) predominantly target the RBD, our investigation revealed a diminished seroreactivity within the RBD's crucial region, the receptor-binding motif (RBM), potentially impacting the production of protective nAbs. S1WT and S2WT RBM peptides binding to nAbs were evaluated through microscale thermophoresis, and higher affinity (35 nM) was obtained for sequence S2WT (GSTPCNGVEGFNCYF), containing the FNCY patch. Our data indicates that SARS-CoV-2 RBM is not an immunodominant region in vaccinated individuals. Understanding the intricate dynamics of the humoral response and its interplay with viral evolution and host genetics is essential for the formulation of effective vaccination strategies, not only against SARS-CoV-2 but also for future emerging coronaviruses.

(1) Background: To investigate the effect of phosphohistone H3 (PHH3) and vitamin D receptor (VDR) in the risk assessment of endometriosis, in two cohorts of women with this pathology, those receiving hormonal treatment, and those without treatment; (2) Methods: In 60 cases of women with endometriosis, the paraffin-embedded endometriosis tissue samples, retrieved after surgery, were immunohistochemically (IHC) analyzed aiming to determine the expression status of PHH3 and VDR; (3) Results: The IHC positive index of PHH3 and VDR of these two groups were compared. PHH3 levels were positively correlated with vitamin D levels, both being increased in patients without treatment. Within the group without treatment, PHH3 and VDR expressions were positively associated; (4) Conclusions: IHC analysis of PHH3 and VDR can be used as an additional tool for risk stratification and prognostic assessment in patients with endometriosis.

This study investigated the impact of seven-strain probiotic supplementation on the frequency of T helper 17 (Th17) cells, regulatory T (T-reg) cells, Treg/Th17 ratio, and their gene expression in individuals with severe traumatic brain injury (STBI). Probiotics can influence the gut microbiota, modulate the immune response, and prevent or alleviate certain immune diseases. However, it is necessary to clarify whether probiotics can effectively impact Th cells in STBI patient. Despite the great attention to improving the immune system in most diseases, there is currently no accurate mechanism for the use of probiotics in diseases with damage to the head injury, which can be a basis for the use of probiotics. The primary objective of this study is to address this research gap. The present study was a randomized, double-blind, placebo-controlled trial that enrolled 48 STBI patients. They were treated with probiotics or placebo: 4 capsule/day for 14 days. The pre- and post-study evaluation included examining the frequency of Treg, Th17 cells, as well as the expression of associated immunological parameters (Foxp3 and RORγt) and Treg/Th17 ratio in both groups. No significant differences were found between the two groups in terms of subject characteristics (P>0.05). GCS scores at 14 days were significantly higher in the probiotic compared to the placebo group. The probiotic group showed a significant decrease in Th17 cell and RORγt gene expression (P = 0.022 and P< 0.001, respectively), a notable increase in T-reg and FoxP3 gene expression (P= 0.025 and P< 0.001, respectively), and a higher Treg/Th17 ratio compared to the placebo group. Our study provides promising evidence of the beneficial effects of seven-strain probiotic supplementation on Th cells in individuals with STBI.

Rabson-Mendenhall syndrome is a rare autosomal recessive disorder characterized by severe insulin resistance, resulting in early-onset diabetes mellitus. We are reporting the first case of Rabson-Mendenhall syndrome in a Paraguayan patient. The patient is a 5-year-old girl who presented with hypertrichosis, acanthosis nigricans, and nephrocalcinosis. Genetic testing by NGS revealed two pathogenic variants in exons 2 and 18 of the INSR gene; c.332G&gt;T (p. Gly111Val) and c.3485C&gt;T (p. Ala1162Val), in combined heterozygosis. The novel INSR c. 332G&gt;T variant leads to the substitution of glycine to valine at position 111 in the protein, and multiple in silico software predicted it as pathogenic. The c. 3485C&gt;T variant leads to the substitution of alanine to valine at position 1162 in the protein previously described for insulin resistance and Rabson-Mendenhall syndrome. The management of Rabson-Mendenhall syndrome is particularly challenging in children, and the use of metformin is often limited by its side effects. The patient was managed with nutritional measures due to the early age of onset. This report expands the knowledge of Rabson-Mendenhall syndrome to the Paraguayan population and adds a novel pathogenic variant to the existing literature.

Abstract: The glucocorticoid receptor (GR), including both alternative spliced isoforms (GRa and GRb), has been implicated in the development of primary open-angle glaucoma (POAG) and iatrogenic glucocorticoid-induced glaucoma (GIG). POAG is the most common form of glaucoma, which is the leading cause of irreversible vision loss and blindness in the world. Glucocorticoids (GCs) are commonly used therapeutically for ocular and numerous other diseases/conditions. One serious side effect of prolonged GC therapy is the development of iatrogenic secondary ocular hypertension (OHT) and OAG (i.e. GC-induced glaucoma (GIG)) that clinically and pathologically mimics POAG. GC-induced OHT is caused by pathogenic damage to the trabecular meshwork (TM), a tissue involved in regulating aqueous humor outflow and intraocular pressure. TM cells derived from POAG eyes (GTM cells) have lower expression of GRb, a dominant negative regulator of GC activity, compared to TM cells from age-matched control eyes. Therefore, GTM cells have a greater pathogenic response to GCs. Almost all POAG patients develop GC-OHT when treated with GCs, in contrast to a GC responder rate of 40% in the normal population. Increased expression of GRb can block GC-induced pathogenic changes in TM cells and reverse GC-OHT in mice. Endogenous expression of GRb in the TM may relate to differences in the development of GC-OHT among the normal population. A number of studies have suggested increased levels of endogenous cortisol in POAG patients as well as differences in cortisol metabolism, suggesting that GCs may be involved in the development of POAG. Additional studies are warranted to better understand the molecular mechanisms involved in POAG and GIG in order to develop new disease modifying therapies to better treat these two sight threatening forms of glaucoma.

Cytokines secreted by individual immune cells regulate tissue regeneration and allow communication between various cell types. Cytokines bind to cognate receptors and trigger the healing process. Determining the orchestration of cytokine interactions with their receptors on their cellular targets is essential to fully understand the process of inflammation and tissue regeneration. To this end, we have investigated the interactions of Interleukin-4 cytokine (IL-4)/Interleukin-4 cytokine receptor (IL-4R) and Interleukin-10 cytokine (IL-10)/Interleukin-10 cytokine receptor (IL-10R) using in situ Proximity Ligation Assays in a regenerative model of skin, muscle and lung tissues in the mini-pig. The pattern of protein-protein interactions was distinct for the two cytokines. IL-4 bound predominantly to receptors on macrophages and endothelial cells around the blood vessels while the target cells of IL-10 were mainly receptors on muscle cells. Our results show that in situ studies of cytokine-receptor interactions can provide unravel the fine details of the mechanism of action of cytokines.

We aimed to evaluate the magnesium content in human cirrhotic liver and its correlation with serum AST levels, expression of hepatocellular injury, and MELDNa prognostic score. In liver biopsies obtained at liver transplantation we measured the magnesium content in liver tissue in 27 cirrhotic patients (CIRs) and 16 deceased donors with healthy liver (CTRLs) by atomic absorption spectrometry and within hepatocytes in 15 CIRs using synchrotron-based X-ray Fluorescence Microscopy. In 31 CIRs and 10 CTRLs we evaluated the immunohistochemical expression in hepatocytes of the transient receptor potential melastatin 7 (TRPM7), a magnesium influx chanzyme also involved in inflammation. CIRs showed a lower hepatic magnesium content [117.2 (IQR 110.5-132.9) vs 162.8 (IQR 155.9-169.8) μg/g; p&lt;0.001] and a higher percentage of TRPM7 positive hepatocytes [53.0 (IQR 36.8-62.0) vs 20.7 (10.7-32.8) %; p&lt;0.001) than CTRLs. In CIRs, MELDNa and serum AST at transplant correlated: a) inversely with the magnesium content both in liver tissue and hepatocytes; b) directly with the percentage of hepatocytes stained intensely for TRPM7. The latter also directly correlated with worsening of MELDNa at transplant compared to waitlisting. Magnesium depletion and overexpression of its influx chanzyme TRPM7 in hepatocytes are associated with severity of hepatocyte injury and prognosis in cirrhosis. These data represent the pathophysiological basis for a possible beneficial effect of magnesium supplementation in cirrhotic patients.

Prostate cancer (PCa) is a major cause of cancer-related mortality worldwide, with a rising incidence observed over the years. The androgen receptor (AR) signaling pathway plays a pivotal role in male development and maintaining masculine characteristics. Dysregulation of AR signaling in prostate cancer can lead to disease progression and resistance to standard therapies. Understanding the intricate regulation and function of AR in both healthy and diseased states is crucial for developing effective treatment strategies. This review comprehensively explores the role of androgen receptors in prostate cancer susceptibility, disease progression, and treatment response by analyzing recent literature. An extensive search of peer-reviewed publications in major databases, including PubMed, Scopus, and Web of Science, was conducted using specific keywords related to androgen receptor, prostate cancer, disease progression, and treatment resistance. Relevant conference abstracts and clinical trial reports were also included. The review presents an overview of the role of androgen receptors in prostate cancer initiation, progression, and treatment resistance. It highlights emerging biomarkers associated with AR signaling dysregulation and their potential utility for early detection and personalized treatment approaches. Additionally, recent advances in targeting the AR pathway for novel therapeutic strategies to improve patient outcomes and overcome treatment resistance in advanced prostate cancer are discussed. The findings contribute to a comprehensive understanding of the AR signaling pathway in prostate cancer and offer insights into its multifaceted role in disease development and treatment response. They may pave the way for innovative therapeutic interventions and precision medicine approaches based on specific AR signaling profiles, enhancing patient care and reducing the burden of this lethal disease.

Spinal and bulbar muscular atrophy (SBMA), also known as Kennedy’s disease, is a debilitating neuromuscular disease characterized by progressive muscular weakness and neuronal degeneration, affecting 1-2 individuals per 100,000 globally. While SBMA is relatively rare, recent studies have shown a significantly higher prevalence of the disease within the indigenous population of Western Canada compared to the general population. The disease is caused by a pathogenic expansion of polyglutamine residues in the androgen receptor protein, which acts as a key transcriptional regulator for numerous genes. SBMA has no cure, and current treatments are primarily supportive and focused on symptom management. Recently, a form of precision medicine known as antisense therapy has gained traction as a promising therapeutic option for numerous neuromuscular diseases. Antisense therapy uses small synthetic oligonucleotides to confer therapeutic benefit by acting on pathogenic mRNA molecules, serving to either degrade pathogenic mRNA transcripts or helping to modulate splicing. Recent studies have explored the suitability of antisense therapy for the treatment of SBMA, primarily focused on antisense-mediated mRNA knockdown approaches. Advancements in understanding the pathogenesis of SBMA and the development of targeted therapies offer hope for improved quality of life for individuals affected by this debilitating condition. Continued research is essential to optimize these genetic approaches, ensuring their safety and efficacy.

Multilineage-differentiating stress-enduring (Muse) cells, a cell subgroup from mesenchymal stem cells (MSCs), are pluripotent cells with unique characteristics such as non-tumorigenic and pluripotent differentiation ability. After homing, Muse cells spontaneously differentiate into tissue component cells and supplement damaged/lost cells to participate in tissue repair. Importantly, Muse cells can survive in injured tissue for an extended period, stabilizing and promoting tissue repair. In addition, it has been confirmed that injection of exogenous Muse cells exerts anti-inflammatory, anti-apoptosis, anti-fibrosis, immunomodulatory, and paracrine protective effects in vivo. The discovery of Muse cells is an important breakthrough in regenerative medicine. The article provides a comprehensive review of the characteristics, sources, and potential mechanisms of Muse cells for tissue repair and regeneration. This review serves as a foundation for the further utilization of Muse cells as a key clinical tool in regenerative medicine.

OPMDs (Oral Potentially Malignant Disorders) are a group of disorders affecting the oral mucosa that are characterized by aberrant cell proliferation and a higher risk of malignant transformation. Vitamin D (VitD) and its receptor (VDR) have been extensively studied for their potential contributions to the prevention and therapeutic management of a range of diseases and neoplastic conditions, including oral cancer. Observational studies suggest correlations between VitD deficiency and higher cancer risk, worse prognosis, and increased mortality rates. Interestingly, emerging data also reveals a link between VitD insufficiency and the onset or progression of OPMDs. Understanding the role of the VitD-VDR axis not only in established oral tumors but also in OPMDs might thus enable early detection and prevention of malignant transformation. With this article, we want to provide an overview of current knowledge about OPMDs and VitD, and investigate their potential association and ramifications for clinical management of OPMDs.

Background: Prostate cancer remains a significant global health concern, and understanding the molecular drivers of this disease is crucial for developing effective diagnostic and therapeutic strategies. Steroid Receptor Coactivator-3 (SRC-3), a member of the SRC family, has emerged as a key player in prostate cancer pathogenesis. This review comprehensively examine the role of SRC-3 in prostate cancer, encompassing molecular mechanisms, clinical implications, and therapeutic opportunities. Methods: A systematic literature search following PRISMA guidelines was conducted in PubMed, PMC, and other relevant databases to identify studies that investigate SRC-3 in prostate cancer. A total of 67 articles were selected based on predetermined inclusion criteria. Results: 785 articles were retrieved from databases using specific keywords and MeSH terms related to SRC-3 and Prostate Cancer. After removing 461 duplicates, 260 articles were excluded based on title and abstract review. Subsequently, a comprehensive screening by three researchers resulted in 47 relevant articles for this systematic review. We summarize its contributions to AR-mediated transcriptional regulation, tumor growth, and metastasis. Evidence suggests that SRC-3 expression correlates with prostate cancer aggressiveness, disease recurrence, and poor patient outcomes. Its potential as a diagnostic biomarker and therapeutic target is explored, offering insights into personalized medicine approaches. Conclusions: SRC-3 plays a pivotal role in prostate cancer, influencing disease progression and clinical outcomes. Understanding the molecular intricacies of SRC-3 in prostate cancer offers new opportunities for precision medicine and innovative therapeutic approaches. This review provides a comprehensive overview of SRC-3's involvement in prostate cancer, emphasizing its clinical relevance and potential as a therapeutic target, ultimately contributing to improved patient care in the era of personalized oncology.

Abstract For the past 70 years, dopamine hypothesis has been the key working model in schizophrenia. This has contributed to the development of numerous inhibitors of dopaminergic signaling, antipsychotic drugs, which led to rapid symptom resolution but only marginal outcome improvement. Over the past decades, there was limited research on the quantifiable pathological changes in schizophrenia, including premature cellular/neuronal, senescence, brain volume loss, attenuation of gamma oscillations on electroencephalogram and oxidation of lipids in plasma and mitochondrial membranes. We surmise that aberrant activation of aryl hydrocarbon receptor by toxins derived from the gut microbes or the environment drives premature cellular, including neuronal, senescence, a hallmark of schizophrenia. Early brain aging promotes secondary changes, including impairment and loss of mitochondria, gray matter depletion, decreased gamma oscillations, and a compensatory metabolic shift to lactate and lactylation. The aim of this narrative review is twofold: 1. To summarize what is known about premature cellular/neuronal senescence in schizophrenia or schizophrenia-like disorders. 2. To discuss novel strategies for improving long-term outcome in severe mental illness with natural senotherapeutics, membrane lipid replacement, mitochondrial transplantation, microbial phenazines, novel antioxidant phenothiazines, inhibitors of glycogen synthase kinase-3 beta, and aryl hydrocarbon receptor.

Background. The type-2 sodium-glucose cotransporters inhibitors (SGLT2i) are a new relevant therapeutic option for patients affected by chronic heart failure with reduced ejection fraction (HFrEF). The aim of this study was to evaluate, in a real-world population from a single center, the feasibility of introducing SGLT2i and their interaction with other recommended drug classes. Methods. We evaluated the consecutive patients affected by chronic heart failure (CHF) since January 2022. At baseline clinical visit the therapy taken by the patients as well as that prescribed were accurately collected. During a 6-12 month follow-up the the changes in concomitant therapy were analyzed. Results. At baseline, among 350 patients evaluated, only 17 (5%) were already taking SGLT2i, 13 with HFrEF, 2 with CHF with mild reduced (HFmrEF) and 2 with preserved ejection fraction (HFpEF). After baseline evaluation, SGLT2i were prescribed to 220 (63%) of all the patients enrolled, among whom 178 (84%) of HFrEF patients, 25 (42%) of HFmrEF and 17 (22%) of HFpEF. After follow-up, SGLT2i therapy was highly tolerated and it was associated with a significant increased prescription of sacubitril/valsartan and a reduced use of diuretics. Finally, a significant improvement in functional status and left ventricular systolic function after SGLT2i therapy was observed. Conclusions. In this single center “real world” study, SGLT2i were prescribed in HFrEF patients most of all already in therapy with the other classes of drugs currently recommended for their treatment. Moreover, a further optimization in prescribed ther-apy was observed during a short term follow-up. These data further support the use of this thera-peutic approach in routine clinical practice.

The ability of recombinant, SARS-CoV-2 Spike (S) protein to modulate the production of two COVID-19 relevant, pro-inflammatory cytokines (IL-6 and IFN-γ) in PBMC cultures of healthy, pre-Covid-19 subjects was investigated. We observed that cytokine production was largely and diversely modulated by the S protein depending on antigen or mitogen stimulation, as well as on the protein source, insect (S-in) or human (S-hu) cells. While both proteins co-stimulated cytokine production by polyclonally CD3-activated T cells, PBMC activation by the mitogenic lectin Concanavalin A (Con A) was up modulated by S-hu protein and down-modulated by S-in protein. These modulatory effects were likely mediated by the S glycans as demonstrated by direct Con A-S binding experiments and use of yeast mannan as Con A binder. While being ineffective in modulating memory antigenic T cell responses, the S proteins and mannan were able to induce IL-6 production in unstimulated PBMC cultures and upregulate the expression of Mannose Receptor (CD206), a marker of anti-inflammatory M2 macrophage. Our data point to a relevant role of N-glycans, particularly N-mannosidic chains, decorating the S protein in the immunomodulatory effects here reported. These novel biological activities of the S glycan ectodomain may add to the comprehension of Covid-19 pathology and immunity to SARS-CoV-2.

Small peptides are an important component of the vertebrate immune system. They are important molecules for distinguishing proteins that originate in the host from proteins derived of a pathogenic organism, such as a virus or bacterium. Consequently, these peptides are central for the vertebrate host response to intracellular and extracellular pathogens. Computational models for prediction of these peptides have been based on a narrow sample of data with an emphasis on the position and chemical properties of the amino acids. In past literature, this approach has resulted in higher predictability than models that rely on the geometrical arrangement of atoms. However, protein structure data from experiment and theory are a source for building models at scale, and, therefore, knowledge on the role of small peptides and their immunogenicity in the vertebrate immune system. The following sections introduce procedures that contribute to theoretical prediction of peptides and role in immunogenicity. Lastly, deep learning is discussed as it applies to immunogenetics and the acceleration of knowledge by a capability for modeling the complexity of natural phenomena.

The pathophysiology of many mood disorders is closely related with abnormal stress response associated with the dysfunction of the hypothalamic-pituitary-adrenal (HPA) axis and cortisol overproduction. The hippocampus, key structure of the limbic system responsible for both cognitive and emotional spheres, is selectively vulnerable to excess of glucocorticoids (GCs) inducing neuroinflammation and neurodegeneration. The antiGC therapy of psychiatric diseases, in particular depressive disorders, may be a useful additional treatment. Among other approaches, targeting glucocorticoid receptors, abounded in the hippocampus, is regarded as highly promising. However, though the preclinical data provide firm evidence to the concept of antiGC therapy for stress-related diseases, clinical studies still are at the proof-of-concept stage. Noteworthy, chronic GC excess is associated not only with mood diseases, but also with cognitive decline, metabolic disorders, diabetes. Potentially, antiGC (HPA axis modifying) therapy may alleviate affective symptoms, cognitive disturbances, GC and insulin resistance and adverse side effects of conventional drugs through beneficial effects on hippocampal dysfunction and neurodegeneration, neuroinflammation, and neurogenesis. Since stress/GC-associated neuroinflammation-mediated pathology of the limbic system and, specifically, the hippocampus, is a general feature typical for many brain diseases, the concept of antiGC therapy may be extended, tested and validated in a wider spectrum of cerebral pathologies.

Periodontitis is a disease that originates from gingival tissue, and if left untreated, can cause inflammation to spread to deeper tissues, altering bone homeostasis, and even leading to tooth loss. When the bacteria in plaque reach sufficient numbers, the immune system responds by activating immune cells that will produce cytokines, including interleukin-1 (IL-1), interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-α). These immune signaling molecules will coordinate the inflammatory responses. IL-1 binds to the IL-1 receptor (IL-1R) on the surface of target cells, initiating an inflammatory response by activating intracellular signalling pathways. Inhibition of IL-1R can prevent the interaction of IL-1 with this receptor, thereby halting the activation of the inflammatory pathway. By substituting this connection with active anti-inflammatory substances, it is possible to prevent the contact between IL-1 and IL-1R. The licorice plant, Glycyrrhiza glabra, includes eight types of flavonoids with significant anti-inflammatory potential, namely isoliquiritigenin, glyzaglabrin, prunetin, shinpterocarpin, licochalcone A, glabridin, glisoflavone, and isoangustone A. This study aims to assess the potential of such flavonoids as candidates for periodontitis treatment through molecular docking, using AutoDock Tools v.1.5.6. All tested compounds showed highly stable bonds to IL-1R, with a binding affinity values below -7 kcal/mol. Van der Waals forces, hydrogen bonds, and hydrophobic bonds all contribute to the stability of these interactions. Among the eight tested compounds, glisoflavone, which has a Ki value of 90.89 nM and a ΔG value of -9.61 kcal/mol, has the highest binding stability to IL-1R.

This study delves into the realm of potential therapeutics for breast cancer by conducting a comprehensive docking simulation and virtual screening analysis using Autodock Vina Algorithm. The focus based on the human epidermal growth factor receptor 2 (HER2), a key protein associated with various cancers, particularly in the context of breast cancer.The results reveal compelling insights into the binding interactions of several natural compounds and drugs with HER2. Notably, Acebilustat, Bemcentinib, and Amentoflavone exhibit outstanding binding energies, averaging around -10 kcal/mol, suggesting strong and favorable interactions with the HER2 target.These encouraging findings not only emphasize the potential biological significance of these compounds but also hint at their potential usefulness in fighting breast cancer.Their promising binding affinities with HER2 position them as potential candidates for further investigation and development as therapeutic agents against breast cancer.

Neuropathic pain (NP) affects about the 8% of the general population. Current analgesic therapies have limited efficacy, making NP one of the most difficult to treat pain conditions. Evidence indicates that excessive oxidative stress can contribute to the onset of chronic NP and several natural antioxidant compounds have showed promising efficacy in NP models. Thus, the aim of the present study was to investigate the pain-relieving activity of honokiol (HNK)-rich standardized extract of Magnolia officinalis Rehder &amp; E. Wilson bark (MOE), well known for its antioxidant and anti-inflammatory properties, in the spared nerve injury (SNI) model. The molecular mechanisms were investigated in spinal cord samples from SNI mice and in LPS-stimulated BV2. MOE and HNK showed antioxidant activity. MOE (30 mg/kg p.o.), produced an antiallodynic effect in the absence of locomotor impairment. MOE treatment reduced spinal p-p38, p-JNK1, iNOS, p-p65, IL-1ß and Nrf2 overexpression, increased IL-10 and MBP levels and attenuated the Notch signaling pathway by reducing Jagged1 and NEXT. All these effects were prevented by the CB1 antagonist AM251. HNK reduced the proinflammatory state of LPS-stimulated BV2 cells and reduced Jagged1 overexpression. MOE and HNK, by modulating oxidative and proinflammatory responses, might represent interesting candidates for NP management.