Proximal tubular epithelial cells (PTEC) are constantly exposed to potentially toxic metabolites and xenobiotics. The regenerative potential of the kidney enables the replacement of damaged cells either via the differentiation of stem cells or the regain of proliferative properties of the PTEC. Nevertheless, it is known that renal function declines, suggesting that the deteriorated cells are not replaced by fully functional cells. To understand the possible causes of this loss of kidney cell function, it would be beneficial to understand the role of toxins during the regeneration process. Therefore, we investigated the sensitivity and function of human induced pluripotent stem cells (hiPSC), hiPSC differentiating, and hiPSC differentiated into proximal tubular epithelial-like cells (PTELC) to known nephrotoxins. hiPSC were differentiated into PTELC, exhibiting a similar morphology to PTEC, expressing prototypical PTEC markers and performing albumin endocytosis. When treated with two nephrotoxins, hiPSC and differentiating hiPSC were more sensitive to cisplatin than differentiated PTELC, whereas all stages were equally sensitive to cyclosporin A. Both toxins also had an inhibitory effect on albumin uptake. Our results suggest a high sensitivity of differentiating cells towards toxins, which could have an unfavorable effect on regenerative processes. To study this, our model of hiPSC differentiating into PTELC appears suitable.

The endophytic fungus Aspergillus sp. SPH2 was isolated from the stems of the endemic plant Bethencourtia palmensis and its extracts were found to have strong fungicidal effects against Botrytis cinerea and ixodicidal effects against Hyalomma lusitanicum at different fermentation times. In this study, the fungus was grown using three different culture media and two methodologies, Microparticulate Enhancement Cultivation (MPEC) and Semi-Solid Fermentation (SSF), to increase the production of secondary metabolites in submerged fermentation. The addition of an inert support to the culture medium (SSF) resulted in a significant increase in extract production. However, when talcum powder was added to different culture media, unexpected results were observed, with a decrease in the production of the biocompounds of interest. Metabolomic analyses showed that the production of aspergillic, neoaspergillic, and neohydroxyaspergillic acids peaked in the first few days of fermentation, with notable differences observed among the methodologies and culture media. Mellein production was particularly affected by the addition of an inert support to the culture medium. These results highlight the importance of surface properties and morphology of spores and mycelia during fermentation by this fungal species.

The ZX Spectrum was a popular 8-bit home computer by Sinclair Research in the 80s. Even though some of these computers may still work, the audio tapes, the TV with an analog tuner and the micro-switch joystick, used with the original ZX Spectrum, nowadays are outdated and hard to find in good working order or replicate. Since many other old closed systems are also very difficult to update to support modern peripherals, there is a necessity to provide a methodology to adapt such systems to support new peripherals while being compatible with existing software. The work proposed in this paper is focused on recreating a ZX Spectrum+/48k computer and interface it with modern peripherals on an FPGA. This is accomplished by adding a co-processor to assist with the control of the new peripherals which would either require to complex architectural changes to the original system and in the end it would perform poorly due to the low performance of the Z80 CPU. This work distances from previous ones on emulating a ZX Spectrum since it focuses on the use of different upgraded peripherals and the use of a NIOS II soft-processor as a co-processor to manage the SD Card accesses. A demonstration of the proposed modernized architecture was made by successfully running a diagnostics ROM and playing original ZX Spectrum games from an SD card for game with a PS/2 keyboard and a pair of joysticks.

Passive dynamics is an aspect of locomotion which is entirely dependent on the mechanical configuration and linkages of adjacent body segments. Tension distribution along mechanical linkages enables execution of movement patterns with reduced need for complex neurological pathways and may play a role in reestablishing postural stability following external disturbances. Here we demonstrate a uni-directional mechanical relationship between the equine forelimb and head, which may have implications for balance and forelimb loading in the horse. These observations suggest that forelimb and head movement coordination (observed in the horse during unrestrained locomotion) is largely controlled by the mechanical linkages between body segments, rather than being entirely dependent on neurological input as previously thought. This highlights the potential significance of research directed at investigating passively induced movements in understanding common locomotory patterns. Additionally, it suggests a mode of postural control which may provide instantaneous adjustments to postural disturbances, thus promoting rapid and efficient locomotion.

Abstract: In the Western of Mekong Delta belong to Vietnam a amount of alluvium sediments flows from upstream China to Vietnam, they are going from the river branches to in the Mekong Delta, then get out the Western Sea of Vietnam. This sediments accumulated gradually elevation the new land. The increase elevation of the land creates a fertile coastal plain where mangrove forests with a rich ecosystem of plants and animals. Over time, these forests change, with different plant species succeeding each other. This aims of this study to finding plant species in the forest, classification of forest types based on ecological regions, assessement the biodiversity of tree species, and compare the abundance communities, measuring the growth of the forest in these regions. In 2023, a comprehensive survey was conducted by using a systematic approach. The number of survey plots have done depend on the density of the forest, Base on the width of the forest range, the number of survey plots from 500m to 1,000m set up 1-2 plots, sub region set up from 10 to 15 plots. In total, 68 plots have done established in the erea, the area of plot is 100 square meters (10m x 10m). Using the statistical software in forestry to survey and analysis data. The result provided a complete picture of the tree species composition, distribution, and community structure characteristics in each ecological sub-region. The result of survey showed in the sub-region 1 have seven species as Sonneracia ovate, Rhzophora apiculata, Excoecaria agallochha, Avicennia officinalis, Avicennia alba, Agricerasvcoculatum, Bruguiera gymnorhiza. In the sub region 2 have eleven species as Sonneracia caseolaris, Annona reticulata, Lumnitzera littorea, Lumnizera racemosa, Rhizophora apiculata, Excoecaria agallocha, Avicennia officinalis, Avicennia alba, Hibiscus tillacerus, Bruguiera gymorhiza, Aericeras comiculatum. In the sub region 3 have eight as Sonratia caseolaris, Rhizophora mucronata, Rhizophora apiculata, Excoecaria agallocha, Avicennia marine, Avicennia alba, Bruguiera gymorhiza. In the region 4 have ten species as Sonneracia caseolaris, Sonneracia ovate, Lumnizera racemosa, Rhizophoa apiculata, Excoecaria agallocha, Avicennia marina, Avicennia officinalis, Aviecnnia alba, Bruguiera gymorhiza, Bruguiera cylindrica The total species of the mangrove forest in the Western Mekong Delta have 16 species from 11 plant families have been identified. Among these species have 6 dominant species include Avicennia oficinali),Avicennia alba, Rhizophora apiculata, Excoecaria agallocha, Someratia caseolaris, and Bruguiera yipamoriza. Two species easy grow on the new land are Avicennia officinalis Avicennia alba this findings show they can develope on the original new land for the shore of the Western Mekong Delta. The surveyed results also calculated the average of the height, diameter (D1.3), canopy, health of the nature mangrove tree for each sub region and total region. From these results showed the division of foresty structure, the structure of height, diameter (D1.3), canopy, vitality of the sub region and total region in the Western Mekong Delta.

Stroke is a global leading cause of death and disability. Knowledge of related guidelines is crucial for Emergency Department (ED) staff, influencing early diagnosis and timely treatment. We investigated Greek-Cypriot ED healthcare professionals' (nurses and physicians) knowledge in recognizing and managing stroke. A descriptive cross-sectional study spanned November 2019 to April 2020, encompassing four private and seven public EDs in the Republic of Cyprus. The data were collected through a self-reported questionnaire developed by the research team, consisting of 37 questions. Eight questions focused on sociodemographic and employment characteristics, 28 assessed knowledge in stroke recognition and management (each item was equally weighted without deliberate prioritization), and one question addressed self-assessment of knowledge in stroke care. 255 nurses [Response Rate (RR): 74.1%] and 26 physicians (RR: 47.3%) completed the questionnaire. The average correct response rate was 12.9 out of 28 statements (SD: 4.2), with nurses and physicians scoring 12.6 (SD: 4.1) and 15.7 (SD: 4), respectively. Work experience significantly influenced stroke knowledge, with all groups demonstrating superiority over those with less than one year of experience. Participants with previous training scored an average of 1.45 additional correct answers while educational attainment did not significantly influence stroke knowledge. Investigating stroke knowledge among Emergency Department nurses and physicians in the Republic of Cyprus revealed significant deficits. The study stresses targeted interventions, including, education, yearly examinations, workshops with hands-on training, and repeated training, to address these gaps and enhance the overall stroke care capabilities of the healthcare professionals.

In this work, several random Boolean networks (RBN) are generated and analyzed from two characteristics: their time evolution diagram and their transition diagram. To do this, its randomness is estimated using three metrics, of which algorithmic complexity is the only one capable of revealing both transitions towards the chaotic regime and the algorithmic contribution of certain states to the transition diagram and their relationship with the order they occupy in the temporal evolution of the respective RBN.

Preconditioned mesenchymal stem cells (MSCs) represent an advanced method to overcome the challenges related to their survival rate, differentiation, and activity maintenance. L-carnitine has demonstrated antioxidant and anti-apoptotic effects on injured cardiac cells. However, limited research has been conducted to explore their combined effect on cardiac tissue injury. Therefore, the present study aimed to conduct a comparative and comprehensive study investigating the role of L-carnitine-pre-treatment on the immunomodulation of inflammation, apoptosis, and differentiation of MSCs and their impact on cardiac toxicity induced by Doxorubicin (DOX). Rats were divided into group I (control), group II (DOX), group III (DOX+MSCs), group IV (DOX+L-carnitine), group V (DOX+L-carnitine pre-treated MSCs). CK-MB, troponin I, MDA, and catalase levels were improved in the treated groups (III, IV, and V). The degeneration and necrosis of the cardiomyocytes were reduced in the treated groups. They regained their normal architecture in the L-carnitine pre-treated MSCs group. These findings were augmented by analyzing the immunomodulators; NF-ҡβ, TNFα, and IL-1β, the proliferative indicators Ki-67, and hsp90, the cardiac differentiation marker TH and the apoptotic regulators; caspase 3 and Bcl2. These results demonstrate the optimal regenerative and therapeutic effects of L-carnitine pre-treated MSCs representing an efficient tool for future stem cell therapy.

Cisplatin is a widely used anticancer drug for treating solid tumors, but it is associated with severe side effects, including nephrotoxicity. Various studies have suggested that the nephrotoxicity of cisplatin could be overcome; nonetheless, an effective adjuvant drug has not yet been established. Oleanolic acid acetate (OAA), a triterpenoid isolated from Vigna angularis, is commonly used to treat inflammatory and allergic diseases. This study aimed to investigate the protective effects of OAA against cisplatin-induced apoptosis and necroptosis using TCMK-1 cells and a mouse model. In cisplatin-treated TCMK-1 cells, OAA treatment significantly reduced Bax and cleaved-caspase3 expression, whereas increased Bcl-2 expression. Moreover, in cisplatin-induced kidney injury mouse model, OAA treatment alleviated weight loss in the body and major organs and also relieved cisplatin-induced nephrotoxicity symptoms. RNA sequencing analysis of kidney tissues identified lipocalin-2 as the most upregulated gene by cisplatin. Additionally, necroptosis-related genes such as receptor interacting protein kinase (RIPK) and mixed lineage kinase domain like (MLKL) were identified. In vitro study, the phosphorylation of RIPKs and MLKL was reduced by OAA pretreatment in both cisplatin-treated cells and cells boosted by co-treatment with z-VAD-FMK. In conclusion, OAA could protect the kidney from cisplatin-induced nephrotoxicity and may serve as an anticancer adjuvant.

Neuroblastoma (NB) is a childhood cancer with heterogeneous characteristics, posing challenges to effective treatment. NBs express somatostatin receptors that facilitates the use of somatostatin analogs (SSTAs) as tumor-seeking agents for diagnosis and therapy. High-risk (HR) NBs often have gain-of-function mutations in the receptor tyrosine kinase anaplastic lymphoma kinase (ALK). Despite intensive multimodal treatment, survival rates remain below 40% for children with HR-NB. The aim of this work was to investigate the combined effect of the SSTA 177Lu-octreotide with the ALK inhibitor lorlatinib. Mice bearing human HR-NB CLB-BAR tumors were treated with lorlatinib, 177Lu-octreotide, combination of these pharmaceuticals or saline (control). Tumor volume was monitored and tumor samples were evaluated for cleaved caspase-3 and expression of 84 human genes involved in apoptosis. Combination treatment with 177Lu-octreotide and lorlatinib demonstrated synergistic antitumor effects. Increased number of cleaved caspase 3-positive cells was observed in tumors from mice treated with 177Lu-octreotide alone and in combination with lorlatinib. Modulation of Bcl-2 family gene expression was observed only in the presence of both 177Lu-octreotide and lorlatinib, with BID downregulated and HRK upregulated on days 2 and 7, respectively. The data suggests that ALK signaling pathway inhibition may contribute to radiosensitization in radionuclide therapy with 177Lu-octreotide.

Ovarian cancer poses a significant therapeutic challenge owing to the lack of specific targets for treatment. New treatment strategies are needed to improve patient outcomes and reduce the toxicity of existing therapies. This study aimed to investigate the synergistic effects of recombi-nant human apurinic/apyrimidinic endonuclease 1/redox factor 1 (rhAPE1/Ref-1) and aspirin on PEO14 and CAOV-3 ovarian cancer cells and human umbilical vein endothelial cells (HUVECs). Specifically, this study examined the mechanisms underlying the effect of rhAPE1/Ref-1 and as-pirin on cell death and the associated pathways. Cell viability was assessed using the MTT assay, and flow cytometry analysis and caspase-3/7 activity assays were conducted to determine apop-tosis. Western blotting was performed to evaluate the cleavage of poly(ADP-ribose) polymerase (PARP). Exposure to aspirin (3 mM) for 24 h did not affect cell viability in PEO14. Co-incubation of aspirin with rhAPE1/Ref-1 in PEO14 cells led to rhAPE1/Ref-1 acetylation and intracellular hyperacetylation. Co-treatment with aspirin (3 mM) and rhAPE1/Ref-1 induced a rhAPE1/Ref-1 concentration-dependent increase in cell death, particularly in PEO14 cells, as well as apoptosis, caspase-3/7 activation, and PARP cleavage. Furthermore, this combination treatment significantly increased paclitaxel-induced PEO14 cell death. Therefore, co-administration with rhAPE1/Ref-1 and aspirin is a potential strategy for ovarian cancer treatment.

There is an urgent need to develop new therapies for cancer treatment due to high rates of resistance and tumor relapse. Moreover, chemotherapy and radiation weaken the immune system and leave patients susceptible to sudden death from infections and organ failure since antineoplastic drugs lack specificity. Hence, scientists worldwide continue the search for natural alternatives with anticancer activities and fewer side effects. In this regard, traditional medicine offers strategies for preventing and treating numerous diseases and nowadays scientific studies worldwide highlight some of the mechanisms underlying their potential as an effective alternative for the management of cancer. In Mexico, Mayan healers have been prescribed mainly medicinal plants for more than 2,000 years. Furthermore, their ethnomedical knowledge has led to drug discovery or the development of herbal remedies. Medicinal plants from the genus of Cissus remain an important element of all indigenous medical systems in Mexico including the Mayan tribes in Yucatan, particularly for the management of gastrointestinal illnesses, sores, cutaneous diseases, and tumors. In this review, we present the reported bioactivities against cancer cells of the extract and compounds from the species of Cissus with a particular focus on recent studies on the phytochemistry of C. trifoliata which is widely distributed in Mexican territory and used for tumor management in traditional medicine.

High-temperature cooking process like frying, baking, smoking, or drying can induce chemical transformations in conventional food ingredients, causing deteriorative modifications. These reactions, including hydrolytic, oxidative, and thermal changes, are a common occurrence and can result in alterations to the food's chemical composition. In this study, a combination of sucrose and histidine (Su-Hi) was transformed through a process of charring or pyrolysis. The GC-MS profiling study showed that when sucrose and histidine (Su-Hi) are exposed to high temperatures (≈240°C), they produce carbonyl and aromatic compounds including beta-D-Glucopyranose, 1,6-anhydro (10.11 %), 2-Butanone, 4,4-dimethoxy- (12.89 %), 2(1H)-Quinolinone-hydrazine (5.73%), Benzenamine (6.35%), 2,5-Pyrrolidinedione, 1-[(3,4-dimethylbenzoyl)oxy]- (5.82%), Benzene-(1-ethyl-1-propenyl) (5.62%), and 4-Pyridinamine-2,6-dimethyl (5.52%). The compounds mentioned have the ability to permeate the cell membrane and contribute to the development of cell death by necrosis in human immune cells. The evidence available suggests that a specific set of pyrolytic compounds may pose a risk to immune cells. This investigation reveals the complex relationship between high-temperature cooking-induced transformations, compound permeation inside the cells, and downstream cellular responses, emphasizing the significance of considering the broader health implications of food chemical contaminants.

Chrysin, a flavonoid compound, has attracted interest as a therapeutic agent due to its anti-inflammatory, antidiabetic, antidepressant, and particularly its anticancer properties. Although studies have presented findings regarding the anticancer properties of chrysin, research on its molecular mechanisms of action remains largely insufficient. This research aimed to deeply investigate chrysin's effects on the breast cancer cell line, MDA-MB-231, in terms of proliferation, invasion, colony formation, and apoptosis. The XTT test results confirmed chrysin's cytotoxic effect on MDA-MB-231 cells, indicating a 48-hour IC50 value of 115.77 µM. Chrysin induced apoptosis in cells, as evidenced by Annexin V assay, and also reduced their colony-forming and invasion. Gene expression analyses showed elevated levels of APC, AXIN1, AXIN2, GSK3A, GSK3B, CK1α, CTNNB1, as well as apoptosis-related genes CASP3, -7, -9, and BAX. This increase was corroborated by the observed rise in protein levels of caspase 3/7 and GSK3B. Moreover, molecular docking results showed that chrysin interacted with genes in the WNT/β-catenin pathway and exhibited drug-like ADME properties. In conclusion, chrysin exhibits potential anticancer effects against MDA-MB-231 cells. It is hoped that these findings will advance preclinical and clinical studies on chrysin's potential in breast cancer treatment.

Licochalcone H (LCH), a regioisomer of licochalcone C derived from the root of Glycyrrhiza inflata. CRC treatment has always been challenged by the development of resistance. We investigated the antiproliferative activity of LCH in oxaliplatin (Ox)-sensitive and -resistant CRC cells. LCH significantly inhibited cell viability and colony growth in both Ox-sensitive and Ox-resistant CRC cells. We found that LCH decreased epidermal growth factor receptor (EGFR) and AKT kinase activities and related activating signaling proteins including phospho (p)-EGFR and pAKT. A computational docking model indicated that LCH may interact with EGFR, AKT1, and AKT2 at the ATP-binding sites. LCH induced ROS generation, as verified by N-acetyl-L-cysteine (NAC) treatment, and increased the expression of the ER stress markers. LCH treatment of CRC cells induced depolarization of MMP and increased. Multi-caspase activity was induced by LCH treatment and confirmed by Z-VAD-FMK treatment. LCH increased the number of subG1 cells and arrested the cell cycle at the G1 phase. LCH inhibits the growth of Ox-sensitive and Ox-resistant CRC cells by targeting EGFR and AKT, and inducing ROS generation and ER stress-mediated apoptosis. Therefore, LCH could be a potential therapeutic agent for improving not only Ox-sensitive but also Ox-resistant CRC treatment.

Background: In trials using normofractionated regimen, the radiation-induced lymphocyte apoptosis (RILA) and the chromosomal damage assays (CDA) have shown prognostic roles of radiation-induced adverse events. The main objectives here were to validate RILA and CDA in extreme and moderate hypofractionation regimens for breast (FAST) and prostate (CHHiP) cancers. Methods: Blood samples were collected from 400 volunteers included in FAST and CHHiP trials. The primary endpoints (PE) were first change in photographic breast appearance and first grade ≥2 RTOG bladder or bowel toxicity (BBT) in FAST and CHHiP, respectively. The secondary endpoints was first grade ≥2 breast clinical changes (BCC) in FAST and BBT using different scales in CHHiP. Results: 103 FAST and 297 CHHiP patients with lab and clinical data were included. In FAST trial, no significant association of RILA with the primary endpoint was observed. A significant association of higher RILA levels with lower risk of any RIAE was found. The risk of developing grade ≥2 RIAE decreased significantly for patients with RILA≥24% compared to those with RILA≤16% with a HR of 0.50 (95%CI 0.25-1.00, p=0.012). Concerning chromosomic aberrations, no significant associations were found with change in photographic breast appearance nor with the secondary endpoint of any RIAE. In CHHiP trial, a decreased risk of grade≥2 RTOG bladder or bowel RIAE was observed for increasing values of RILA (HR 0.97, 95%CI 0.94-1.01, p=0.11) but did not reach statistical significance. Concerning chromosomic aberrations, we found significant association of higher levels of micronuclei per cell with lower risk of gr2+ RTOGAE (p=0.021 for trend test across tertiles; p=0.023 for upper vs lower tertile). Conclusions: This study is the first to evaluate RILA and CDA as predictors of late effects after breast and prostate RT in the “hypofractionation” era. Development of toxicity biomarkers whatever the RT fractionation are urgently needed.

NCX 470, a nitric oxide (NO)-donating bimatoprost, was shown to ameliorate ocular hemodynamics and retinal physiology in rabbits following endothelin-1 (ET-1)-induced ischemia/reperfusion. Here we used the same model to compare NCX 470 (0.1% bid) to Lumigan® (bimatoprost 0.01% ophthalmic solution, LUM) and bimatoprost administered at equimolar dose as NCX 470 (0.072%, BIM). Intraocular pressure (IOP), ophthalmic artery resistive index (OA-RI) and electroretinogram (ERG) were computed prior to treatment and at various time-points thereafter. Gluthatione (GSH), 8-Hydroxy-2-deoxyguanosine (8-OH2dG), Interleukin-1beta (IL-1β), Tumor Necrosis Factor-alpha (TNF-α), Interleukin-6 (IL-6) and Caspase-3 protein expression and activity were determined in retina at week 6. ET-1 increased IOP (VEHIOP_Baseline=20.5±0.8 and VEHIOP_Week6=24.8±0.3mmHg) and OA-RI (VEHOA-RI_Baseline=0.36±0.02 and VEHOA-RI_Week6=0.55±0.01) while it reduced rod/cone responses. Oxidative stress, inflammation and apoptotic markers were also increased in ET-1-treated eyes. NCX 470 prevented IOP (NCX 470IOP_Week6=18.1±0.6mmHg) and OA-RI (NCX 470OA-RI_Week6=0.33±0.01) changes and restored ERG amplitude; these effects were only partially shared by LUM or BIM. Additionally, NCX 470 reduced oxidative stress, inflammation and apoptosis in retina of treated eyes. BIM and LUM were numerically less effective on these parameters. Data suggest that NCX 470 repeated ocular dosing ameliorates ocular hemodynamics and retinal cell dysfunction consequent to ischemia/reperfusion via both, NO- and bimatoprost-mediated mechanisms.

The voltage-gated potassium channel KV1.3 has been recognized as a tumor marker and represents a promising new target for the discovery of new anticancer drugs. We designed a novel structural class of KV1.3 inhibitors through structural optimization of benzamide-based hit compounds and structure-activity relationship studies. The potency, and selectivity of the new KV1.3 inhibitors were investigated using whole-cell patch- and voltage-clamp experiments. 2D and 3D cell models were used to determine antiproliferative activity. Structural optimization resulted in the most potent and selective KV1.3 inhibitor 44 in the series with an IC50 value of 470 nM in oocytes and 950 nM in Ltk cells. Kv1.3 inhibitor 4 induced significant apoptosis in Colo-357 spheroids, while 14, 37, 43, and 44 significantly inhibited Panc-1 proliferation.

β-apopicropodophyllin (APP), a derivative of podophyllotoxin (PPT), has been identified as a potential anti-cancer drug. This study tested whether APP acts as an an-ti-cancer drug and can sensitize colorectal cancer (CRC) cells to radiation treatment. APP had an anti-cancer effect against the CRC cell lines HCT116, and DLD-1, SW480 and COLO320DM with IC50 values of 7.88 nM, and 8.22 nM, 9.84 nM and 7.757 nM, respec-tively induction of DNA damage. Colonogenic and cell counting assays indicated that the combined treatment of APP and γ-ionizing radiation (IR) showed greater retardation of cell growth than either alone, suggesting that APP sensitizes CRC cells to IR. Annexin V-propidium iodide (PI) assays and immunoblot analysis showed that the combined treatment of APP and IR increased apoptosis in CRC cells compared with either APP or IR alone. Results obtained from the xenograft experiments also indicated that the combination of APP and IR enhanced apoptosis in in vivo animal model. Apoptosis induction by the combined treatment of APP and IR resulted from reactive oxygen species (ROS). Inhibition of ROS by N-acetylcysteine (NAC) restored cell viability and decreased the induction of apoptosis by APP and IR in CRC cells. Taken together, these results indicate that a combined treatment of APP and IR might promote apoptosis by inducing ROS in CRC cells.

Apoptosis is associated with numerous phenotypical characteristics, and is thus studied with many tools. In this study, we compared two broadly used apoptotic assays: TUNEL and staining with an antibody targeting the activated form of an effector caspase. To compare them, we developed a protocol based on commonly used tools such as filters, zprojection and thresholding. Even though it is commonly used in imageprocessing protocols, thresholding remains a recurring problem. Here we analyzed the impact of processing parameters and readout choice on the accuracy of apoptotic signal quantification. Our results show that TUNEL is quite robust, even if image processing parameters can allow or not to detect subtle differences of the apoptotic rate. On the contrary, images from anticleaved caspase staining are more sensitive to handle and proved to necessitate to be processed more carefully. We then developed an open source Fiji macro automatizing most steps of the image processing and quantification protocol. It is noteworthy that the field of application of this macro is wider than apoptosis as it can perfectly be used to treat and quantify other kind of images.

Diffuse large B cell lymphoma (DLBCL), the most frequent type of non-Hodgkin lymphoma in adulthood, remains challenging clinical issues. Despite enhanced remission rates can be achieved, there are one-third of patients who will not respond to current treatment or will relapse with resistant disease, necessitating ongoing efforts on effective treatment strategies and agents. The vacuole H+-ATPase inhibitor bafilomycin A1 is broadly used to block late stage of autophagy flux at high concentration. In this study, we show that, to our surprise, bafilomycin A1 effectively inhibited and killed DLBCL cells at nanomolar concentrations (5nM). Bafilomycin A1 targeted cell cycle regulators cyclin D1 and cyclin E2 to induce cell cycle arrest in G0/G1 phase. Meanwhile, it induced caspase-dependent apoptosis with concomitant cleaved caspase-3 and Parp. Furthermore, we found that bafilomycin A1 inhibited autophagy flux at both early and late stages of the autophagy flux through activating ERK and mammalian target of rapamycin signaling, as well as by inhibiting the degradation of autolysosomes. We speculated that bafilomycin A1 as autophagy inhibitor might enhance the effect of DLBCL chemotherapeutic drug rituximab. Accordingly, our results provided evidence that the combination of bafilomycin A1 with rituximab enhanced the inhibition of DLBCL cells notably. Taken together, our data suggest that bafilomycin A1 may be a promising candidate drug in the therapy of diffuse large B cell lymphoma.

Zika virus (ZIKV) is an emerging mosquito-borne flavivirus considered as a threat to human health due to large epidemics and serious clinical outcomes such as microcephaly in newborns. Like all flaviviruses, ZIKV relies on the cellular machinery to complete its viral cycle, with the endoplasmic reticulum (ER) being the critical site of viral replication factories. The sudden high protein load in the ER induces an ER stress to which the cell responds with an appropriate unfolded protein response (UPR) in an attempt to restore its disturbed homeostasis. When the restoration fails, the cell signaling leads to a programmed cell death by apoptosis with the upregulation of the UPR-induced C/EBP homologous protein (CHOP) which acts as the main trigger for this fatal outcome. Our previous studies have shown the ability of ZIKV to manipulate various cellular responses in order to optimize virus production. ZIKV is able to delay apoptosis to its benefit and although ER stress is induced, the UPR is not complete. Here we discovered that ZIKV impairs the expression of CHOP/DDIT3, the main factor responsible of ER-stress driven apoptosis. Surprisingly, the mechanism does not take place at the transcriptional level but at the translational level.

Ovarian cancer is the common cause of death among gynecological cancers. Although ovarian cancer initially responds to chemotherapy, the frequent recurrence in patients remains a therapeutic challenge. Pyruvate kinase M2 (PKM2) plays a pivotal role in regulating cancer cell survival. However, its therapeutic roles remain unclear. Here, we investigated the anticancer effects of compound 3K, a specific PKM2 inhibitor, on autophagic and apoptotic pathway regulation in SK-OV-3 (PKM2-overexpressing human ovarian adenocarcinoma cell line). The anticancer effect of compound 3K was examined using the MTT and colony formation assay in SK-OV-3. The results of tissue microarray showed that PKM2 expression positively correlated with the severity of the tumor. Moreover, the expression of pro-apoptotic proteins increased in SK-OV-3 following compound 3K treatment. Compound 3K induced AMPK activation, which was accompanied by the inhibition of mTOR. Additionally, this compound inhibited glycolysis, resulting in reduced proliferation in SK-OV-3. Compound 3K treatment suppressed tumor progression in vivo xenograft model. Our findings suggest that the inhibition of PKM2 by compound 3K affected Warburg effects and induced autophagic cell death. Therefore, the use of specific PKM2 inhibitors to block the glycolytic pathway and target cancer cell metabolism represents a promising therapeutic approach for treating PKM2-overexpressing ovarian cancer.

7β-(3-ethyl-cis-crotonoyloxy)-1α-(2-methylbutyryloxy)-3,14-dehydro-Z-notonipetranone (ECN), a sesquiterpenoid obtained from a natural origin (Tussilago farfara)has proved to be effective in minimizing various side effects associated with opioids and nonsteroidal anti-inflammatory drugs. The current study focused on investigating the effects of ECN on neuropathic pain induced by partial sciatic nerve ligation (PSNL) by mainly focusing on oxidative stress, inflammatory and apoptotic proteins expression in mice. Neuropathic pain was induced in mice by PSNL surgery performed on day 1 and ECN (1 and 10 mg/kg, i.p.), was administered once daily for 11 days, starting from the third day after surgery. ECN post-treatment was found to reduce hyperalgesia and allodynia in a dose dependent manner. ECN significantly reversed the severity of neuropathic pain by improving distress symptoms and survival rate. ECN remarkably reversed the histopathological abnormalities associated with oxidative stress, apoptosis and inflammation. Furthermore, ECN prevented the suppression of antioxidants (glutathione, glutathione-S-transferase, catalase, superoxide dismutase, NF-E2-related factor-2 (Nrf2), hemeoxygenase-1 and NAD(P)H: quinone oxidoreductase) by PSNL. Moreover, pro-inflammatory cytokines (tumor necrotic factor alpha, interleukin 1 beta, interleukin 6, cyclooxygenase-2 and inducible nitric oxide synthase) expression was reduced by ECN administration. Treatment with ECN was successful in reducing caspase-3 level consistent with the observed modulation of pro-apoptotic proteins. Additionally, ECN showed protective effect on the lipid content of myelin sheath as evident from FTIR spectroscopy which showed the shift of lipid component bands to higher values. Thus, anti-neuropathic potential of ECN might be due to inhibition of oxidative stress, inflammatory mediators and pro-apoptotic proteins.

Parkinson’s disease (PD) is a neurodegenerative disease that progresses with increasing age and some of its major symptoms include tremor, postural and movement related difficulties. Till date, the treatment of PD remains a challenge because available drugs only treat the symptoms of the disease or possess serious side effects. In light of this, new treatment options are needed, hence this study investigates the neuroprotective effects of an organic Boophone haemanthoides extract (BHE) and its bioactive compounds using an in vitro model of PD involving the toxin 1-methyl-4-phenylpyridinium (MPP+) and SH-SY5Y neuroblastoma cells. A total of seven compounds were isolated from BHE viz: distichamine (1), 1α,3α-diacetylnerbowdine (2), hippadine (3), stigmast-4-ene-3, 6-dione (4), cholest-4-en-3-one (5), tyrosol (6), and 3-hydroxy-1-(4`-hydroxyphenyl)-1-propanone (7). Six compounds (1, 2, 4, 5, 6, 7) were investigated and five showed neuroprotection alongside the BHE. This study gives insight into the bioactivity of the non-alkaloidal constituents of Amaryllidaceae since the isolated compounds and the BHE showed improved cell viability, increased ATP generation in the cells as well as inhibition of MPP+-induced apoptosis. Together, these findings support the claim that the Amaryllidaceae plant family could be a potential reserve of bioactive compounds for the discovery of neuroprotective agents.

Hizikia fusiformis is a common, edible marine alga found in Asia. Although the anticancer activity of its extracts has previously been investigated, its active compounds have not been identified. In this study, saringosterol acetate (SA) was isolated from H. fusiformis extracts by centrifugal partition chromatography (CPC) system (two phase solvents condition: n-hexane:ethyl acetate/methanol:water = 5:3:7:1, v/v), exhibited anticancer effects in the human lung adenocarcinoma epithelial cell line, A549, by inducing apoptosis and sub-G1 phase cell cycle arrest. In addition, SA increased the expression of the pro-apoptotic proteins, Bax and cleaved caspase 3, and decreased that of the anti-apoptotic protein Bcl-xL. Although, SA did not affect the expression of p53, induces expression of Bid and caspase 8. In conclusion, we suggested that SA induces apoptosis against A549 cells via Bid and caspase 8 dependent pathway.

Helicobacter pylori is a common human pathogen that causes gastroduodenal diseases. H. pylori genome consists of numerous restriction-modification (R-M) genes. It is established that N6-adenine methylation plays a crucial role in bacterial gene regulation and virulence, but not much is known about the role of C5-cytosine methylation. In this study, we examined the influence of an orphan cytosine methyltransferase, hpyAVIBM on gastric infection in mice and cultured cells. Histopathological staining showed that the deletion of hpyAVIBM in H. pylori strain SS1 had increased damaging hemorrhagic effects on the mice stomach. The gelatin-zymography result demonstrated that the mice infected with mutant SS1ΔhpyAVIBM had significantly up-regulated pro-MMP-9 than those infected with SS1. Additionally, ELISA results of pro-inflammatory cytokines proved that mutant strain caused significantly more inflammatory effect on mice stomach than its wild-type counterpart. The immunohistochemistry data showed that mutant strain caused attenuated epithelial cell damage. Co-culture studies of H. pylori with AGS (Human Gastric Adenocarcinoma cell line) cells revealed that SS1ΔhpyAVIBM instigated significantly more apoptotic death in the AGS cells compared to the wild-type strain. Our results indicated that DNA methylation by hpyAVIBM plays a crucial role in modulating virulence factors in bacterial cells and their interaction with the host cells.

Zika virus (ZIKV) is an emerging human mosquito-transmitted pathogen of global concern, known to be associated with complications such as congenital defects and neurological disorders in adults. ZIKV infection is associated with induction of cell death. However, previous studies suggest that the virally-induced apoptosis occurs at a slower rate compared to the course of viral production. In this present study, we investigated the capacity of ZIKV to delay host cell apoptosis. We provide evidence that ZIKV has the ability to interfere with apoptosis whether it is intrinsically or extrinsically induced. In cells expressing viral replicon-type constructions, we show that this control is achieved through replication. Finally, our work highlights an important role for anti-apoptotic Bcl-2 family protein in the ability of ZIKV to control apoptotic pathways, avoiding premature cell death and thereby promoting virus replication in the host-cell.

The cytostatic agent hydroxyurea (HU) has proven to be beneficial for a variety of conditions in the disciplines of oncology, hematology, infectious disease and dermatology. It disrupts the S-phase of the cell cycle by inhibiting the ribonucleotide reductase enzyme, thus blocking the transformation of ribonucleotides into deoxyribonucleotides, a rate limiting step in DNA synthesis. HU is listed as an essential medicine by the World Health Organization. Several studies have indicated that HU is well tolerated and safe in pregnant women and very young pediatric patients. To our knowledge, only a few controlled studies about the adverse effects of HU therapy have been done in humans. Despite this, the prevalence of central nervous system abnormalities, including ischemic lesions and stenosis have been reported. This review will summarize and present the effects of HU-exposure on the prenatal and perinatal development of the rat cerebellar cortex and deep cerebellar nuclei neurons. Our results call for the necessity to better understand HU effects and define the administration of this drug to gestating women and young pediatric patients.

As part of our ongoing silybin project, this study aims to introduce a basic nitrogen-containing group to 7-OH of 3,5,20-O-trimethyl-2,3-dehydrosilybin or 3-OH of 5,7,20-O-trimethyl-2,3-dehydrosilybin via an appropriate linker for in vitro evaluation as potential anti-prostate cancer agents. The synthetic approaches to 7-O-substituted-3,5,20-O-trimethyl- 2,3-dehydrosilybins through a five-step procedure and to 3-O-substituted-5,7,20-O-trimethyl-2,3- dehydrosilybins via a four-step transformation have been developed. Thirty-two nitrogen-containing derivatives of silybin have been achieved through these synthetic methods for the evaluation of their antiproliferative activities towards both androgen-sensitive (LNCaP) and androgen-insensitive prostate cancer cell lines (PC-3 and DU145) using WST-1 cell proliferation assay. These derivatives exhibited greater in vitro antiproliferative potency than silybin. Among them, 11, 29, 31, 37, and 40 were identified as five optimal derivatives with IC50 values in the range of 1.40–3.06 µM, a 17- to 52-fold improvement in potency as compared with silybin. All these five optimal derivatives can arrest the PC-3 cell cycle in the G0/G1 phase and promote PC-3 cell apoptosis. Derivatives 11, 37, and 40 are more effective than 29 and 31 in activating PC-3 cell apoptosis.

The toxic effects of 4-octylphenol (4-OP) have been studied in species such as mouse and fish; however, the toxic effects of 4-OP in male specific niche cells has not been researched. In this study, we investigated the molecular mechanism of toxicity of 4-OP in mouse TM4 Sertoli cells. TM4 cells were treated with four concentrations (0, 10, 30, and 50 µM/mL) of 4-OP at time points 24, 48, and 72 h. Cell viability and apoptosis assay was conducted following exposure. 4-OP significantly decreased cell viability in a concentration- and time-dependent manner, and increased apoptosis. Quantitative PCR analysis showed that Bad, Bax, and Bak mRNA expression levels were higher in exposed cells than in the control, but Bcl-2 expression was decreased. Western blotting revealed that 4-OP induced activities of caspase-3 and phosphorylation of Bad in a concentration- and time-dependent manner. Additionally, cytochrome C protein did not colocalize with mitochondria marker dye by 24 h. Cytochrome c protein expression increased in a time-dependent manner with 50 µM/mL. These results suggest that 4-OP induces mitochondria-mediated apoptosis by regulation of Bcl-2 family proteins and caspase-3 activation in male Sertoli cells.

Hepatitis C virus (HCV) represents a challenging global health threat in ~200 million infected individuals. Clinical data suggests that only ~10-15% of acutely HCV-infected individuals will achieve spontaneous viral clearance despite exuberant virus-specific immune responses, which is largely attributed to difficulties in recognizing the pathognomonic symptoms during the initial stages of exposure to the virus. Given the paucity of a suitable small animal model, it is also equally challenging to study the early phases of viral establishment. Further, the host factors contributing to HCV chronicity in a vast majority of acutely HCV-infected individuals largely remain unexplored. The last few years have witnessed a surge in studies showing that HCV adopts a myriad mechanisms to disconcert virus-specific immune responses in the host to establish persistence that includes, but not limited to viral escape mutations, viral growth at privileged sites, and antagonism. Here, we discussed a few hitherto poorly explained mechanisms employed by HCV that are believed to lead to chronicity in infected individuals. A better understanding of these mechanisms would aid the design of improved therapeutic targets against viral establishment in susceptible individuals.

Cryptotanshinone (CTT) is a natural product and a quinoid diterpene isolated from the root of the Asian medicinal plant, Salvia miltiorrhiza bunge. Notably, CTT has a variety of anti-cancer actions, including the activation of apoptosis, anti-proliferation, and a reduction in angiogenesis. We further investigated the anti-cancer effects of CTT in A549 and H460 which are NSCLC cell lines. CTT treatment in NSCLC cells reduced cell growth through PI3K/Akt/GSK3β pathway inhibition, G0 / G1 cell cycle arrest, and the activation of apoptosis. CTT induced increase of Bax and cleavage of apoptosis-related signaling such as caspase-3, caspase-9, poly-ADP-ribose polymerase (PARP), and Bax, as well as inhibition of anti-apoptosis related signaling such as Bcl-2, survivin, and cellular-inhibitor of apoptosis protein 1 and 2 (cIAP-1 and -2). It also induced G0/G1 phase cell cycle arrest by decreasing the expression of cyclin A, cyclin D, cyclin E, Cdk 2, and Cdk 4. In addition, CTT reduced the protein expression of the PI3K/Akt/GSK3β signaling pathway related to cell proliferation. These results highlight the latent potential of CTT as natural therapeutic agent for NSCLC.

Human influenza A viruses (IAVs) cause global pandemics and epidemics, which remain serious threats to public health because of the shortage of effective means of control. To combat the surge of viral outbreaks, new treatments are urgently needed. Developing new virus control modalities requires better understanding of virus-host interactions. Here we describe how IAV infection triggers cellular apoptosis, and how this process can be exploited towards development of new therapeutics, which might be more effective than the currently available anti-influenza drugs.

This study introduces a technique to uncover concealed patterns in satellite altimetry data, reflecting sea level variations in inland water bodies. We applied the methodology to the Caspian Sea, using altimetry data from four satellite missions over 27 years (1993-2020): TOPEX/Poseidon, Jason1, Jason2, and Jason3. The approach involves two steps: estimating sea level trends and identifying breakpoints that indicate trend shifts; and leveraging time lags between breakpoints at various locations to classify water drainage areas according to their degree of influence on each period. By revealing concealed patterns in the altimetry data, this technique can provide insights to understand the impacts of global warming and local climate changes on sea level fluctuations in the Caspian Sea. We hope that our study can facilitate subsequent interdisciplinary research on the intricate interplay between climate change and hydrological processes in inland water bodies.

Forage fish are crucial to human nutrition, especially in developing countries. However, in these countries, most forage fish catches are used to make aquafeeds for aquaculture, which leaves only a small quantity for direct human consumption. This practice increases fish prices in local markets and undermines people's nutrition. Overfishing forage fish for industrial purposes harms the ecosystem, reduces the catch of larger fish, and marginalizes local fishermen. Although previous discussions have touched qualitatively on the ethics and injustice of this practice, this article provides quantitative scales to measure the impact of the practice on the finances and forage fish consumption of low-income consumers using reasonable assumptions and literature values. Increasing the annual supply of forage fish by 25% to the 5 million MT of fresh fish markets globally could save consumers several billion US dollars annually. Families could consume a higher percentage of nutritious fish for less money. Furthermore, leaving forage fish in the sea could benefit wildlife and increase the capture of larger fish, such as mackerel, which are in demand in local markets and fished by local fishermen. The unintentional and involuntary contributions of low-income societies to enable the growth of high-value fish and shrimp for affluent societies seem unjust and warrant further investigation.

This study aimed to evaluate the discrepancies between genetic and visual coat color assignment in the Sarcidano Horse and to elucidate potential reasons. Individual DNA from 90 Sarcidano Horses was used for genetic assignment of coat color to explore the correspondence with individual forms containing phenotypical traits. The MC1R exon 1 and ASIP exon 3 have been genotyped and sequenced to obtain a picture of the coat color distribution in this breed. Surprisingly, once we compared the genetic results with the individual forms reporting the phenotypic data for each subject, a certain degree of non-correspondence between the phenotypic and genetic data in relation to coat color emerged. From the genetic analysis, Chestnuts (n = 58) resulted the most common Sarcidano Horse (n = 58), followed by a quite large number of Blacks (n = 28) and a very small number of Bays (n = 4), whereas phenotypic distribution resulted in 38 Chestnuts, 40 Bays, only 2 Blacks, and 10 Grays (without the possibility of recognizing the true color they carried). Chestnut resulted a very representative coat color, while many horses that visually identified as Bays were genetically Blacks. This discrepancy, that could be due to a variety of individual and external factors, including age, time of year, living situation and dietary condition, suggesting the importance of accurate coat color identification to ensure adequate features registration and reliable prediction of offspring’s coat color.

Introduction: Flow-cytometry (FC) is a powerful tool that can assist in lymphoma diagnosis in lymph node (LN) specimens. Although lymphoma diagnosis and classification are mainly based on tumor cell characteristics, surrounding cells are less employed in this process.Methods: We retrospectively investigated alterations in the ploidy status, proliferative cell fraction (PF) and the percentages of surrounding immune cells in 62 consecutive LN specimens with B-Cell Non-Hodgkin Lymphoma (B-NHL) that were submitted for FC evaluation between 2019-2022.Results: Compared with indolent B-NHLs, aggressive B-NHLs show increased DNA aneuploidy and PF, increased monocytes, immature-granulocytes, mature granulocytes, CD8⁺ T-cells, Double-Negative-T-cells and Double-Positive-T-cells, and decreased total CD45⁺ cells, total lymphocytes, CD4⁺ T-cells and CD4/CD8 ratio. Receiver operating characteristic analysis determined PF > 6.8% and immature-granulocytes > 0.9% as optimal cutoffs with highest specificity and sensitivity in differentiating aggressive and indolent B-NHLs.Conclusions: These findings further strength the diagnostic value of DNA content analysis by FC and suggest the utilization of tumor surrounding immune cells in NHL diagnosis and classification.

Cuproptosis, a copper-dependent cellular death mechanism, is typically overlooked in glioblastoma diagnosis. Lipoylation is needed for cuproptosis, and FDX1 controls this process. Cuproptosis in prognostic models may drive cancer treatment. This study evaluated cuproptosis and glioblastoma cell proliferation. The Cancer Genome Atlas provided annotated clinical, genetic mutation, and RNA sequencing data for the TCGA_GBM and TCGA_LGG cohorts. Patients with gliomas were randomly allocated to the validation or training cohort. Least absolute shrinkage and selection operator (LASSO) and multivariate Cox regression models were utilized to evaluate which model best predicted prognosis in the training cohort. The models' independent predictive power was evaluated throughout the cohort. A previous study revealed 19 genes related to ferroptosis. LncRNAs associated with cuproptosis were identified by coexpression analysis. Cox discovered 17 cuproptosis-associated lncRNAs and established a predictive model. The median risk score classified patients as high- or low-risk. K‒M survival analysis demonstrated significant differences in overall survival among risk categories. Principal component analysis (PCA) and receiver operating characteristic (ROC) curve analysis were used to test the model’s predictive power. Univariate and multivariate Cox regression analyses revealed risk score-related independent prognostic factors. Multivariate Cox regression analysis was used to construct a nomogram for marker-based prognosis. The risk category affected the tumour mutation rate. High-risk glioma patients benefit from immunotherapy. Glioma drug sensitivity was also substantially linked with the risk score. The expression of 17 cuproptosis-related long noncoding RNAs (lncRNAs) may assist in the stratification of glioma patient prognosis, molecular characteristics, cell cycle gene regulation pathways, the TME, and clinicopathological aspects. Our clinical sample and database analysis revealed that cuproptosis influences glioma prognosis and may guide therapy.

Recent advancements in gut microbiome research have highlighted the complex interplay between gut microbiota and various physiological and pathological processes, showing that gut microbiota plays a vital role in human health and disease. Imbalances in the gut microbiota, known as dysbiosis, have been associated with a range of health conditions, including gastrointestinal disorders, metabolic diseases, etc. In response to these findings, probiotics, prebiotics, synbiotics, and postbiotics have emerged as a promising therapeutic strategy to modulate gut microbiota composition and functionality. This review paper explores the latest research on how gut microbiota impacts host physiology, immune responses, and overall well-being. Furthermore, the paper delves into the therapeutic potential of probiotics, postbiotics, prebiotics, and synbiotics in therapeutic applications and curing various diseases. The paper also addresses the challenges and opportunities in the field, highlighting the need for personalized approaches to probiotic therapy and the importance of considering factors such as strain specificity, dosing, and safety.Overall, this review aims to provide a comprehensive overview of the evolving landscape of gut microbiota and probiotics, prebiotics, synbiotics, and postbiotics as novel therapeutic agents. It underscores the potential of harnessing the gut microbiome to improve health, prevent diseases, and complement traditional medical interventions. As research in this field continues to expand, a deeper understanding of the gut microbiota and probiotics, prebiotics, synbiotics, and postbiotics promises new avenues for preventive and therapeutic healthcare strategies.

Neurodegenerative diseases that include Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), Parkinson's disease (PD), Huntington's disease (HD), and multiple sclerosis (MS), arise due to numerous causes like protein accumulation and autoimmunity, characterized by neurologic depletion which lead to incapacity in normal physiological function such as thinking and movement in these patients. Glial cells perform a critical role in protective neuronal function; in the case of neuroinflammation, glial cell dysfunction can promote the development of neurodegenerative diseases. MiRNA participates in gene regulation and plays a vital role in many biological processes in the body; in the central nervous system (CNS), it can play an essential part in neural maturation and differentiation. In neurodegenerative diseases, miRNA dysregulation occurs, enhancing the development of these diseases. In this review, we discuss neurodegenerative diseases (Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and multiple sclerosis (MS)) and how miRNA is preserved as a diagnostic biomarker or therapeutic agent in these disorders. Finally, we highlighted miRNA as therapy.

Many cities are increasingly adopting blue-green infrastructure (BGI) to bolster resilience against environmental challenges. Beyond its well-acknowledged environmental benefits, the role of BGI in enhancing social resilience is becoming an equally important area of focus. However, the integration of BGI to foster social resilience presents complexities, stemming from the evolving and occasionally ambiguous definition of social resilience. Given its broad application across diverse disciplines, understanding and measuring social resilience proves difficult, posing challenges to understanding it within a BGI context. However, integrating BGI to support social resilience is complicated by the evolving and sometimes ambiguous definition of social resilience. This concept's broad applicability across various disciplines makes its understanding and measurement challenging, especially within the BGI context. Consequently, a clear need for a framework to effectively understand and measure social resilience in BGI settings exists. This paper synthesizes existing social resilience frameworks, particularly leveraging the comprehensive 5S framework by Saja et al. (2018), to create a new conceptual framework that addresses the unique social dimensions and benefits of BGI, incorporating insights from a broad literature review on social resilience. The framework is structured as a three-tier model centered around four key subdimensions of social resilience: social values, social capital, social structure, and social equity and their interrelationships. Characteristics and indicators are customized to support the BGI context integrating both physical and human dimensions within a mixed methods approach to measurement. Specifically, this research develops a conceptual BGI framework to probe into BGI practices and perspectives that enhance social resilience and considers demographic diversity and the spatial attributes of urban environments to understand how to foster more inclusive and socially resilient BGI spaces.

BackgroundAdvanced radiological stage of knee osteoarthritis (OA) and obesity are predictive of poorer and shorter response to viscosupplementation, but very few is known regarding the impact of other factors such as sport practice, comorbidities or anatomical features of OA. ObjectivesTo investigate the patient’s and OA characteristics associated with the duration of effectiveness (DE) of viscosupplementation in patients with knee OA.MethodsCross-sectional single center trial in patients with knee OA treated with intra-articular (IA) hyaluronic acid (HA) injection(s) within the previous 3 years. The investigator collected demographic and radiographic data (Kellgren grade, involved knee compartments), dosing regimen (single or repeat injections), presence and volume of joint effusion, previous or concomitant IA corticosteroid injection, number of previous viscosupplémentations and the comorbidities. The patient completed a questionnaire including the self-assessment of DE (number of weeks during which viscosupplementation was effective on symptoms), the activity level (sedentary, active, athletic), the level of sport activity (light, moderate or intensive). Predictors of DE were studied in univariate and multivariate analyses ResultsOne hundred five patients (149 knees) were analyzed (62% women, mean age 66.1 ± 13.2 years, mean BMI 27.5 ± 7.5 kg/m²). The mean DE was 48.2 + 24.8 weeks. In a bivariate analysis, the predictors of a shorter with DE were BMI >27.5kg/m2, more than 3 previous viscosupplémentations, Kellgren grade 4, sedentary patients, and more than 1 affected compartment. In the multivariate analysis, 4 independent factors remained associated with a shorter DE: BMI >27.5 kg/m2, knee multi-compartment damage, number of viscosupplements >3, sedentary lifestyle. A statistically significant association between a longer DE and treated arterial hypertension was found suggesting a beneficial effect of certain antihypertensive drugs. ConclusionThe study confirms the harmful influence of an increased BMI, It also shows that viscosupplementation is more effective in unicompartmental OA. Other points worth highlighting are the reduction in the duration of efficacy with repeated cycles of injections and the benefit of a regular physical activity.

The primary sources of particulate matter are linked to human activity. Certain particulate emissions, particularly those of a finer nature, can significantly impact human health, making them one of the most concerning pollutants. Ultrafine particles (UFP), which have a diameter of less than 100 nm, are of particular concern due to their impact on human health and the difficulty in controlling them. The concentration of ultrafine particles (UFP) in the workplace is a growing concern and is classified as an emerging risk. Workers may be exposed to UFP through inhalation, skin absorption, ingestion, or a combination of these routes. This study aims to determine the levels of UFP exposure among workers in environments with varying direct particle emission patterns. Measurements were conducted to compare the results with the levels recommended by the WHO. The study monitored industrial workplaces with direct particulate matter emissions, such as a carpentry and a bakery, as well as social sector sites without or almost without direct particle emissions, such as a school and a health clinic. One conclusion drawn from this study is that all tasks and occupations are susceptible to high levels of UFP, exceeding WHO recommended values in virtually all monitored environments. Therefore, monitoring and controlling UFP is crucial. Further in-depth studies on this subject are also necessary..

In his Cynefin classification of system behaviours, Snowden (2007), posits that his Simple (Clear ) and even Complicated system categories are sufficiently understandable to be amenable to the traditional methods of system analysis and modelling. Here, relationships between entities in the system are clear and unambiguous and they behave predictably. So, we can build mathematical “models” to describe how the system is expected to function in different situations. Leaving aside his fourth category, Chaotic, as too hard for the moment, this paper focusses on the third category, Complex systems. Yaneer Bar-Yam [1998] defined "complex systems" as systems that "have multiple interacting components, whose collective behaviour cannot be simply inferred from the behaviour of components." So, the traditional system modelling approach of decomposition into components and attempting to build up a picture of system performance from individual pieces, alone, is no longer appropriate for this class. The problem is that most of the methods we currently employ, and particularly the methods that attempt to make the case that these systems are safe, (such as Fault trees, FMEA. and Root Cause Analysis), rely on this decomposition into components and attempt to make the parts more reliable individually. Even the more systemic approaches, such as Reason’s (1990) Swiss Cheese Model, and Leveson’s System Theoretic Analysis (STPA) (2004), encourage adding layers of protection, barriers, strengthened control loops and better safety critical systems, in the hope that they are making the systems safer. But without a valid model to test the effectiveness of these add-ons, we cannot be sure that they will not have an opposite effect, of making the systems even more complex, unreliable and unpredictable. For complex systems, the careful gathering and documentation of system components and their relationships is still a necessary first step, but we need an additional capacity to model these complex systems to test out and prove they work safely and successfully in the real world. (not just draw fixed component relationships as system “models” (wiring diagrams)) In the last 10 years, an original approach developed by Hollnagel, (2012), to model systems as sets of interactive, interdependent “functions”, (abstracted from and independent of component details), has now been developed to the point where it can take the basic data and structures from the current component focussed system engineering “models”, such as MBSE( Goldberg (1994)), and can pull it all together in a dynamic system model from which analysts can discern how it really works in practice, and predict the emergent behaviours characteristic of complex systems. The paper describes how this methodology developed and how it is currently used to model real situations, to analyse incidents and anticipate events.

Punica granatum (PG) or Pomegranate is a bush, having many trunks and often get taller 1.8 to 4.7m long and their leaves are shiny and fleshy, approximately 7 to 8cm in length. Traditionally, it is used in diarrhea and dysentery due to its strong constricting property. Punica Granatum covering used in dysentery, diarrhea, piles, bronchitis. It is also used to minimize the risk of heart disease. The peel extract of Punica Granatum contain methanol and their dried peels has antidiarrheal venture, also help in wound healing activity. Peels of the pomegranate also holds around 60% of the fruit and they contain different types of ingredients including ellagitannins and proanthocyanidin compounds and minerals such as calcium, phosphorus, magnesium, potassium, flavonoids and sodium. Some animals were found in different local areas with both acute and chronic diarrhea. The condition of these animals were quite miserable because of dehydration and loss of electrolytes in the body cells of the animals. They were unable to move due to seriousness of the disease. 8 grams of PG Peel Powder mixed with 1 liter of water, 2 g of PG Peel Powder mixed with 250 ml water and 8 g of PG Peel Powder mixed with 1 liter of water were administrated orally by using sterilized bottles to the selected three cases. 3 days after the administration of different doses, all cases of diarrheal animals show a significant recovery. The condition of the animals seem to be healthier. Before administration of the pomegranate peel powder extract, all three cases had weak body structure due to diarrhea. Watery stool that may be yellow in color and mucus was also evident in the stool, due to this reason the patient calf was weak and depressed. In sometimes they also show unconsciousness and blood glucose levels seem to be reduced from the normal level.

The Lac Fallère area, located in the upper Clusellaz Valley (tributary of the middle Aosta Valley), is shaped in micaschist and gneiss referred to as the Mont Fort Unit (Middle Penninic) near the tectonic contact with calcschist and marble of the Aouilletta Unit (Combin Zone). Lac Fallère exibits an elongated shape and is hosted in a WSW–ENE trending depression, according to slope direction. This lake also shows a semi-submerged WSW–ENE rocky ridge, that longitudinally divides the lake. This evidence, in addition to the extremely fractured rocks, indicates the presence of a wide deep-seated gravitational slope deformation (DSGSD), even if this area is not yet included within the regional landslide inventory of the Aosta Valley Region. The Lac Fallère area also shows reliefs involved by glacial erosion (roche moutonnée), a wide cover of subglacial sediments and many moraines essentially referred to as Lateglacial. The DSGSD evolution in a glacial environment produced, as observed in other areas, significant effects both on the facies of Quaternary sediments and the formation of numerous and wide moraines. Glacial slope sectors and lateral moraines displaced by minor scarps and counterscarps and glaciers using trenches forming several arched moraines suggest an interplay between glacial and gravitational processes, which shared part of their evolution history.

The increasing prevalence of diabetes mellitus (DM) worldwide is a cause for global concern. Recent evidence suggests that the interaction between one’s diet and the gut microbiome are key modifiers of diabetes, highlighting the potential role of microbiome-modulating nutraceuticals. This bibliometric analysis examines literature published between 2012 and 2022 to explore trends in the latest research, with additional discussion on major takeaways and future directions. We selected and analyzed 640 articles from an initial pool of 4,099 from the Web of Science using Microsoft Excel 2016 and VOSviewer software (version 1.6.19). Our exploration covered the most common journals, countries, study designs, experimental subjects, types of DM, organisms and nutraceuticals studied, and the most cited articles. We also evaluated the most cited publications in terms of journals, organizations, and countries, along with the collaborative networks among authors, organizations and countries, and the co-occurrence of author keywords from the selection. It is evident from the increasing number of publications each year that this field has attracted growing attention over the last decade. Nonetheless, continued research is essential to sustain this trend. Our overarching study of diabetes research marks steady progress in understanding the role of—and potentially discovering applications of—microbiome modulation to enhance metabolic pathways and health outcomes. Advancements in this field may lead to potential therapeutic applications for specific diets and nutraceuticals that modulate the gut microbiota in DM.

Climate change related issues, such as yield decline, quality losses, accelerated phenology, extreme abiotic stress, pose growers new challenges in olive growing areas. Main cultural solutions that could alleviate stress and improve long-term sustainability of modern olive orchards are here briefly reviewed. Selecting varieties that are more resistant to drought or high temperatures would be the optimal solution to mitigate the effects of climate change, but the available scientific information is relatively scarce. Sustainability of irrigation implies that the less water is used, the better. Best results in terms of saving water and uniform application are obtained using micro-irrigation methods. Water can also be saved by not fully satisfying the tree water needs and different deficit irrigation strategies have been developed and tested for olive orchards. The use of green covers and the application of organic mulches and shredded pruning materials should be encouraged as these practices tend to stock carbon, increase organic matter content and water holding capacity of the soil. Olive orchards are efficient CO2 sinks as they can store considerable amounts of carbon in their organs and permanent structures. Using environmental friendly practices improves the ecosystem carbon budget and contributes to mitigate climate change.

Due to the advancement and availability of internet in present age, device tend to become wireless as well. Mobile ad-hoc network is a wireless environment that consist of advanced agility of nodes and does not contain on any central administrative authority. As it does not contain any central administrative authority so being wireless environment, the network is vulnerable to security threats and suffers in performance as well. Security of MANET is the core issue in this era, meanwhile the data is sent over untrustworthy network. Several techniques were proposed to secure data over Mobile Adhoc Network though cryptography that is one of the most reliable techniques to protect data. In our proposed methodology a Secure Cryptographic technique for Mobile Adhoc Networks (SCTMA) we proposed A Collusion attack prevention (CAP) scheme with ElGamal key generator along with DNA encryption Algorithm is used to make it more secure. The proposed scheme protects the network against collusion attacks and improves the performance as well. Performance analysis will be measured on the basis of key generation time, response time, encryption time and decryption time. The proposed scheme also protects the network against collusion attacks.

The primary objective of this research was to assess the energy consumption of the gas treatment units at Bonny NLNG Refinery, the first Gas Refinery in Rivers State, Nigeria, while utilizing semi-lean amine. To achieve this goal, a simulation of the units was conducted using the advanced software package Aspen Hysys (V.8.3). The simulation was designed to accurately represent the dynamic behavior of the refinery's gas treatment units, allowing for a comprehensive analysis of their energy usage. The research aimed to quantify the energy consumption of the gas treatment units and identify opportunities for energy optimization. By utilizing semi-lean amine, which is known to improve energy efficiency, the study sought to evaluate the potential energy savings that could be achieved in the refinery's operations. The simulation model incorporated the specific design and operational parameters of the gas treatment units at Bonny NLNG Refinery, including the gas flow rate, lean amine concentration, absorber pressure, stripping temperature, amine circulation rate, and acid gas removal efficiency. By considering these parameters, the simulation accurately represented the dynamic behavior of the gas treatment units, enabling a detailed analysis of their energy consumption. Through the simulation, various scenarios and operational conditions were evaluated to determine the optimal set of parameters that minimized energy consumption. The research also examined the trade-offs between energy consumption, acid gas removal efficiency, and other performance indicators, such as amine circulation rate and regeneration efficiency. The findings of this research have significant implications for the energy efficiency and sustainability of gas treatment operations at Bonny NLNG Refinery. By identifying opportunities for energy optimization and providing recommendations for the utilization of semi-lean amine, the study contributes to the development of more efficient and environmentally friendly gas treatment processes. Overall, this research combines advanced simulation techniques with a comprehensive analysis of energy consumption to provide valuable insights into the energy efficiency of gas treatment units at Bonny NLNG Refinery, enabling informed decision-making and potential improvements in energy utilization. By utilizing the percentage-based unit simulation approach, a detailed examination of the energy consumption patterns was obtained. This analysis provides valuable insights into the operational efficiency and determination of potential energy-saving opportunities within the gas treatment units. This study specifically focuses on the integration of an absorption column split stream (stream flow) and a flash unit as a potential means to reduce the energy consumption of gas treatment devices. The integration of these units aims to optimize the overall energy efficiency of the gas treatment process by recovering and utilizing waste heat and reducing energy losses. The absorption column split stream allows for the diversion of a portion of the gas stream to a flash unit before entering the absorber. The flash unit operates at a lower pressure, which facilitates the release of entrained hydrocarbons and reduces the overall energy requirements for gas treatment. By separating and recovering the hydrocarbons in the flash unit, energy losses associated with their absorption and subsequent regeneration are minimized. Through the simulation, the study analyzes the energy consumption patterns of the gas treatment units with and without the integration of the absorption column split stream and flash unit. Comparative assessments are conducted to evaluate the energy savings and overall operational efficiency achieved through this integration. The findings of this research will provide valuable insights into the potential energy-saving opportunities offered by the integration of the absorption column split stream and flash unit in gas treatment devices. It will help refine the design and operation of gas treatment units, enabling more energy-efficient processes in the gas refining industry. By optimizing energy consumption in gas treatment units, the study contributes to the industry's goals of reducing greenhouse gas emissions and improving sustainability. The integration of the absorption column split stream and flash unit offers a promising approach to enhance energy efficiency, reduce operational costs, and minimize environmental impact. Overall, this research underscores the importance of exploring innovative solutions, such as the integration of different process units, to achieve energy savings in gas treatment operations. Through a comprehensive analysis of energy consumption patterns, this study aims to provide practical recommendations for optimizing energy efficiency in gas treatment units, fostering a more sustainable and efficient gas refining industry.The research specifically explores the impact of integrating the absorption column split stream and flash unit when dealing with sour gas streams containing carbon dioxide concentrations of less than mole ℅, while utilizing MDEA fluid as the solvent. Through comprehensive analysis and simulation using advanced software tools, the study demonstrates that by incorporating the absorption column split stream and flash unit, a significant reduction in device energy consumption of up to 10% can be achieved. The integration of the absorption column split stream and flash unit offers promising opportunities to enhance the energy efficiency of gas treatment devices. By diverting a portion of the gas stream to the flash unit, the separation of hydrocarbons and the subsequent release of entrained hydrocarbons at lower pressure significantly reduce the overall energy requirements for gas treatment. The comprehensive analysis and simulation conducted in the research provide concrete evidence of the energy-saving potential of this integration. By quantifying the energy consumption patterns and comparing scenarios with and without integration, the study establishes the effectiveness of the approach and its impact on operational efficiency. The findings of the research highlight the importance of considering the specific gas composition and utilizing appropriate solvents, such as MDEA, for optimizing energy efficiency. The integration of the absorption column split stream and flash unit not only reduces energy consumption but also offers the potential for cost savings and environmental benefits. Overall, the research demonstrates that by incorporating the absorption column split stream

Rhombencephalosynapsis (RES) is a rare, congenital developmental disorder of the central nervous system. Even after many years of its identification, the etiology and pathogenesis of RES remain unclear. It occurs in combination with many syndromes and thus has overlapping symptoms. The clinical presentation of this disorder varies depending on the severity of the maldevelopment of vermis. Here, we present a case of a 60-year-old Indian female diagnosed with Rhombencephalosynapsis. Clinical and MRI characteristics of RES along with treatment options have been discussed.

In the present study, the effect of melatonin and sodium nitroprusside treatments on the improvement of high temperature tolerance in California Wonder green bell pepper plant was studied. For this purpose, a factorial experiment was conducted in form of a completely randomized design in three replications at Zabol University's Faculty of Agriculture. In this research, green bell pepper plants of Wonder cultivar were exposed to different temperature treatments (25°C, 35°C and 40°C) for 24 hours after being sprayed (foliar application) with 0μM, 50μM and 100μM concentrations of melatonin and Sodium nitroprusside. Results showed that Instantaneous leaf water consumption efficiency in 40°C temperature treatment with 50μM and 100μM melatonin increased. Also in 40°C temperature with 100µM melatonin, fruit dry weight in compared to control (0uM) 13.15% increased. Also, melatonin and sodium nitroprusside treatments in compared to control treatment improved fruit characteristics and reduced Appearance Characteristics of Fruit Marketability (ACFM) number. Under 40°C temperature treatment in compared to control temperature (25°C), fruit total soluble solids (TSS) 18.50% decreased also under 100μM melatonin treatment, fruit TSS 20.69% was increased compared to control treatment (0μM). Also fruit fructose at 40°C temperature in compared to 25°C temperature treatment 5.52% reduced. Fruit calcium at 35°C and 40°C temperature in compared to control temperature 6.96% and 15.65% decreased respectively. At temperature 35°C under foliar application of 100uM sodium nitroprusside, fruit copper in compared to control 28.93% increased.

Background: Resistance to antimalarial drugs often used in emerging countries, including combination therapies, has forced scientists to search for and develop drugs with novel mechanisms of action, especially resistance to Plasmodium falciparum and Plasmodium vivax, which are highly prevalent in Southeast Asia, Africa, and South America. Objective: evaluate whether there is a relationship between urinalysis and resistance to in-hospital treatment of malaria in Angola. Methodology: This was a cross-sectional, prospective study with a quantitative approach. Results: of the 214 patients, the resistance rate was 24.1%, men (53.6%), between 21 and 40 years old (72.7%), employees (46.4%), from peri-urban regions (77.7%), treated with artemether (90.9), with high parasitemia (57.7%) and after 5 days of treatment, remained hospitalized (61.4%). Was a significant relationship between resistance in unemployed individuals [OR: 0.03 (95% CI: 0.01-0.29), p =0.003] and high levels of parasitemia [OR: 1.09 (95% CI: 1.09-3.95), p=0.040], remained hospitalized for more than 5 days [OR: 5.28 (95% CI: 0.65-43.1), p=0.121] and death [OR: 2.59 (95% CI: 0.32-20.9), p=0.371] when compared with other subgroups. Was a significant relationship between resistance to clear urine [OR: 5.55 (95% CI: 0.72-42.7), p =0.016], few urinary crystals [OR: 11.3 (95% CI: 5.07-25.3), p <0.001] and who presented some microorganisms that were not bacteria or fungi [OR: 3.02 (95% CI: 1 .32-6.90), p=0.009]. Conclusion: urine results, especially the appearance of cloudy urine, the presence of few crystals, and the presence of other microorganisms that are not bacteria or fungi, may be clear signs of resistance to hospital treatment with injectable antimalarials.

In recent years, the emergence of the concept of immunometabolism has shed light on the pivotal role that cellular metabolism plays in both the activation of immune cells and the development of immune programs. The antiviral response, a widely distributed defense mechanism used by infected cells, serves to not only control infections but also to attenuates their deleterious effects. The exploration of the role of metabolism in orchestrating the antiviral response represents a burgeoning area of research, especially considering the escalating incidence of viral outbreaks coupled with the increasing prevalence of metabolic diseases. Here, we present a review of current knowledge regarding immunometabolism and the antiviral response during viral infections. Initially, we delve into the concept of immunometabolism by examining its application in the field of cancer—a domain that has long spearheaded inquiries into this fascinating intersection of disciplines. Subsequently, we explore examples of immune cells whose activation is intricately regulated by metabolic processes. Progressing with a systematic and cellular approach, our aim is to unravel the potential role of metabolism in antiviral defense, placing significant emphasis on the innate and canonical interferon response.

Student project management is becoming increasingly important in various settings such as technical clubs, planning clubs, and research laboratories. However, effective methodologies for managing student-led projects have not yet been established. This study aims to address key issues related to cost and motivation in student-led projects and propose effective improvement plans. The significance of this study lies in its potential to identify challenges faced in current student project management practices and offer solutions to mitigate risks. By sharing our findings, we aim to encourage further research on this topic and promote the adoption of effective methodologies for managing student-led projects.

To investigate the associated mechanisms concerning collagen and the expression of apoptosis-related proteins in porcine skin injuries induced by laser exposure, pig skin was treated with a 1064 nm laser. The healing process of the laser-treated areas, alterations in collagen structure, and changes in apoptosis were continuously observed and analyzed from 6 hours to 28 days post-irradiation. On the 28th day following exposure, wound contraction and recovery were notably sluggish in the medium-high dose groups, displaying more premature and delicate type III collagen within the newly regenerated tissues. The collagen density in these groups was roughly 37-58% of that in the normal group. Between days 14 and 28 after irradiation, there was a substantial rise in apoptotic cell count in the forming epidermis and granulation tissue of the medium-high dose group, in contrast to the normal group. Notably, the expression of proapoptotic proteins bax, caspase-3, and caspase-9 surged significantly 14 days after irradiation in the medium-high dose groups and persisted at elevated levels on the 28th day. During the later stage of wound healing, the augmented apoptotic cell population and insufficient collagen generation in the newborn skin tissue of the medium-high dose groups were closely associated with delayed wound recovery.

This theoretical study presents a novel perspective on the potential anti-inflammatory properties of Bromelain, a natural agent extracted from pineapple stems. The investigation explores the binding capabilities of Bromelain to Apoptosis-associated speck-like containing CARD (ASC), a crucial adapter molecule known for its involvement in inflammatory processes and inflammasome formation. For the first time, these findings suggest that Bromelain exhibits a notable affinity for ASC, indicating its promising role as a natural anti-inflammatory agent. This study sheds light on the molecular interactions that may contribute to Bromelain's therapeutic potential in modulating inflammatory responses.

The Fas associated Death Domain (FADD) is an adaptor protein that predominantly transduces apoptosis signal from death receptor (DR) to activate caspases, leading to the initiation of apoptotic signaling and the coordinated removal of damaged, infected, or unwanted cells. In addition to its apoptotic functions, FADD is involved in signaling pathways related to autophagy, cell proliferation, necroptosis, and cellular senescence, indicating its versatile role in cell survival and proliferation. The subcellular localization and intracellular expression of FADD play a crucial role in determining its functional outcomes, thereby highlighting the importance of spatiotemporal mechanisms and regulation. Furthermore, FADD has emerged as a key regulator in inflammatory signaling, contributing to immune responses and cellular homeostasis. This review provides a comprehensive summary and analysis of cellular dynamics of FADD in regulating of programmed cell death and inflammation through distinct molecular mechanisms associated with various signaling pathways.

Serelaxin (RLX), the recombinant form of human Relaxin-2 hormone, protects the heart from the ischemia/reperfusion (I/R)-induced damage due to its anti-inflammatory, anti-apoptotic and antioxidant properties. RLX exerts its actions by binding to its specific RXFP1 receptor whereby it regulates multiple cellular transduction pathways. In this in vitro study we offer first evidence for the involvement of AMP kinase/Sirtuin1 (AMPK/SIRT1) pathway in the protection afforded by RLX against H/R-induced damage in H9c2 cells. Treatment of the H/R-exposed cells with RLX (17 nmol L−1) enhanced SIRT1 expression and activity. Inhibition of SIRT1 signaling with EX527 (10 µmol L-1) reduced the beneficial effect of the hormone on mitochondrial efficiency and cell apoptosis. Moreover, RLX upregulated AMPK pathway, as shown by the increase in the expression of phospho-AMPK active protein. Finally, AMPK pathway inhibition by Compound C (10 and 20 μmol L−1) abrogated the increase in SIRT1 expression induced by RLX, thus suggesting the involvement of AMPK pathway in this effect of RLX. The results of this study strengthen the concept that RLX exerts its cardioprotective effects against H/R-induced injury by multiple pathways which also include AMPK/SIRT1.

Abstract Background: Gastric cancer, particularly adenocarcinoma, is a significant global health concern. Environmental risk factors, such as Helicobacter pylori infection and diet, play a role in its development. Purpose: This study aimed to characterize the chemical composition and evaluate the in vitro antibacterial and antitumor activities of AOME. Additionally, morphological changes in gastric cancer cell lines were analyzed. Study design: AOME was analyzed using HPLC-MS/MS and its antibacterial activity against H. pylori was assessed using the broth microdilution method. MIC and MBC values were determined, and positive and negative controls were included in the evaluation. Methods: Anticancer effects were assessed through in vitro experiments using AGS, KATO-III, and SNU-1 cancer cell lines. The morphological changes were examined through SEM and TEM analyses. Results: AOME contained several compounds, including caffeic acid, rutin, and hyperoside. The extract displayed significant antimicrobial effects against H. pylori, with consistent MIC and MBC values of 3.70 ± 0.09 mg/mL. AOME reduced cell viability in all gastric cancer cell in a dose and time-dependent manner. Morphological analyses revealed significant ultrastructural changes in all tumor cells lines, suggesting the occurrence of cellular apoptosis. Conclusions: This study demonstrated that AOME possesses antimicrobial activity against H. pylori and potent antineoplastic properties in gastric cancer cell lines. AOME holds promise as a natural resource for innovative nutraceutical approaches in gastric cancer management. Further research and in vivo studies are warranted to validate its potential clinical applications.

Metabolic bone diseases cover a broad spectrum of disorders that share alterations of bone metabolism leading to a defective skeleton, associated with increasing morbidity, disability, and mortality. There is a close connection between the etiology of metabolic bone diseases and genetic factors, being TP53 one of the genes associated therewith. The single nucleotide polymorphism (SNP) Arg72Pro of TP53 is a genetic factor associated with several pathologies, including cancer, stroke and osteoporosis. Here, we aim to analyze the influence of the TP53 Arg72Pro SNP on bone mass in the humanized Tp53 Arg72Pro knock-in mice. This work reported on the influence of TP53 Arg72Pro polymorphism in bone microarchitecture, OPG gene expression and apoptosis bone status. The results showed that the proline variant of TP53 Arg72Pro polymorphism (Pro72-p53) was associated with deteriorated bone tissue, lower OPG/RANK ratio and lower apoptosis in bone tissue. In conclusion, the TP53 Arg72Pro polymorphism modulates bone microarchitecture and may be a genetic biomarker to identify individuals with an increased risk of suffering metabolic bone alterations

This review provides information on acne transcriptomics allowing deeper insights into acne pathogenesis and isotretinoin´s mode of action. Puberty-induced insulin-like growth factor 1 (IGF-1), insulin and androgen signaling activate the kinase AKT and mechanistic target of rapamycin complex 1 (mTORC1). Western diet (hyperglycemic carbohydrates, milk/dairy products) as well co-stimulate AKT/mTORC1 signaling. AKT-mediated phosphorylation of nuclear FoxO1 and FoxO3 results in their extrusion into the cytoplasm, a critical switch, which enhances the transactivation of lipogenic and proinflammatory transcription factors including androgen receptor (AR), sterol regulatory element-binding transcription factor 1 (SREBF1), peroxisome proliferator-activated receptor γ (PPARγ), and signal transducer and activator of transcription 3 (STAT3) but reduces FoxO1-dependent expression of GATA binding protein 6 (GATA6), the key transcription factor of infundibular keratinocyte homeostasis. AKT-mediated phosphorylation of the p53-binding protein MDM2 promotes the degradation of p53. In contrast, isotretinoin enhances the expression of p53, FoxO1 and FoxO3 in sebaceous glands of acne patients. Overexpression of these proapoptotic transcription factors explains isotretinoin´s desired sebum-suppressive effect via induction of sebocyte apoptosis but also its adverse effects including teratogenicity (neural crest cell apoptosis), reduced ovarian reserve (granulosa cell apoptosis), risk of depression (apoptosis of hypothalamic neurons), VLDL hyperlipidemia, intracranial hypertension and dry skin.

The prevalent pathogens associated with bovine uterine infections are bacteria that appear to increase the host's susceptibility to secondary infections with other bacteria or viruses, among which BoHV-4 is the most frequently found. In this work, the study of the pathways of apoptosis induction was carried out on an experimental model of primary culture of endometrial cells, in order to know the implication of BoHV-4 and the presence of bacterial LPS in the pathogenesis of the bovine reproductive tract. For this, different staining techniques and molecular analysis by RT-PCR were used. The results obtained allowed us to conclude that the level of cell death observed in the proposed primary culture is directly related to the time of viral infection and the presence of LPS in BoHV-4 infection. The apoptosis indices in cells infected with BoHV-4, BoHV-4 + LPS presented a maximum that correlates with the appearance of the cytopathic effect, and the maximum viral titers in the model studied. However, morphological, biochemical and molecular changes were evident during both early and late stages of apoptosis. These findings provide information on the factors that may influence the pathogenesis of BoHV-4 and help to better understand the mechanisms involved in virus infection.

Rhabdomyosarcoma is a rare cancer arising in skeletal muscle that typically impacts children and young adults. It is a worldwide challenge in child health as treatment outcomes for metastatic and recurrent disease still pose a major concern for both basic and clinical scientists. The treatment strategies for rhabdomyosarcoma include multi-agent chemotherapies after surgical resection with or without ionization radiotherapy. In this comprehensive review, we first provide a detailed clinical understanding of rhabdomyosarcoma including its classification and subtypes, diagnosis, and treatment strategies. Later we focus on chemotherapy strategies for this childhood sarcoma and discuss the impact of three mechanisms that are involved in chemotherapy response including apoptosis, macro-autophagy, and the unfolded protein response. Finally, we discuss in vivo mouse and zebrafish models, and in vitro 3-dimensional bioengineering models of Rhabdomyosarcoma to screen future therapeutic approaches and promote muscle regeneration.

Green products have excellent potential for discovering and producing new medicinal products. In recent years, there is a growing interest towards the green synthesis of metal nanoparticles, particularly from plants sources. This eco-friendly approach was used in the recent research to biosynthesize zinc oxide nanoparticles (ZnO NPs) from Cissus antractica plant. The present study aims to examine the cell cytotoxicity, cell death, and pathways of apoptosis in lung cancer cells (A549) and inflammation properties treated with biosynthesized ZnO NPs. Additionally, synthe-sized ZnO nanoparticles were characterized using UV–vis spectroscopy, X-ray diffraction (XRD), Transmission electron microscopy (TEM), Fourier-transform infrared spectroscopy (FT-IR), and Energy-dispersive X-ray spectroscopy (EDS). The XRD and TEM analyses exhibited 31 nm as the size of synthesized nanoparticles, the pure crystal form of ZnO NPs, and the shape of the NPs as nearly spherical and hexagonal quartzite. The MTT assay used for cytotoxicity evaluation de-picted the significant toxic effect of CA-ZnONPs against the A549 lung cancer cells at concentra-tions up to 20 µg/mL than non-cancerous cells. Furthermore, we observed an elevated ROS level in cancer cells. These NPs also demonstrated dose-dependent ability to suppress colony for-mation and cell migration, which increases their potential as a lung cancer treatment. Further-more, The NPs formulation's ability to induce apoptosis in cancer cells was further supported by Hoechst and propidium iodide dye. Further, CA ZnO NPs increased the gene expression of BAX, Cyto-c, Caspase 3 and 9, but decreased the expression of Bcl-2, indicating that the nanoformulation triggered mitochondrial-mediated apoptosis. Besides, this study showed that NPs suppressed in-flammatory responses by subsequently decreasing reactive oxygen species (ROS) generation, downregulating the expression of the pro-inflammatory cytokines TNF-α, iNOS, COX-2, IL-6, IL-8, and NO. Moreover, the study's findings imply that Cissus antractica are a potential source with biosynthesize nanoparticles that can might be further investigated for the progress of an-ti-inflammatory and anti-cancer drugs with further study.

Epithelial cells can undergo apoptosis by manipulating the balance between pro-survival and apoptotic signals. In this work, we show that TRAIL-induced apoptosis can be differentially regulated by the expression of α(1,6)fucosyltransferase (FucT-8), the only enzyme in mammals that transfers the (1,6)fucose residue to the pentasaccharide core of complex N-glycans. Specifically, in the cellular model of colorectal cancer (CRC) progression formed using the human syngeneic lines SW480 and SW620, knockdown of the FucT-8-encoding FUT8 gene significantly enhanced TRAIL-induced apoptosis in SW480 cells. However, FUT8 repression did not affect SW620 cells, which suggests that core fucosylation differentiates TRAIL-sensitive premetastatic SW480 cells from TRAIL-resistant metastatic SW620 cells. In this regard, we provide evidence that phosphorylation of ERK1/2 kinases can dynamically regulate TRAIL-dependent apoptosis and that core fucosylation can control the ERK/MAPK pro-survival pathway in which SW480 and SW620 cells participate. Moreover, the depletion of core fucosylation sensitises primary tumour SW480 cells to the combination of TRAIL and low doses of 5-FU, oxaliplatin, irinotecan or mitomycin C. In contrast, combination of TRAIL and oxaliplatin, irinotecan or bevacizumab reinforces resistance of FUT8-knockdown metastatic SW620 cells to apoptosis. Consequently, FucT-8 could be a plausible target for increasing apoptosis and drug response in early CRC.

Background: Sulforaphane (SFN) is an isothiocyanate of vegetables origin with potent antioxidant and immunomodulatory properties. The pleiotropic activities characterization in human dendritic cells (DCs) is poorly summarized. The aim of this work was the study of the immunomodulatory power of SFN in response to an inflammatory microenvironment on human monocyte derived DCs (moDCs). Methods: The immunological response induced by SFN was studied, evaluating apoptosis and autophagy assays by flow cytometry in moDCs and cancer cell line (THP-1), including moDCs maturation, lymphocyte proliferation and cytokines production under different experimental conditions associated or not with an inflammatory microenvironment, which was induced by lipopolysaccharide (LPS). Results: Our results demonstrated that SFN can interact with moDCs, significantly reducing autophagy process and enhancing apoptosis, such as THP-1 cells, in chronic inflammatory microenvironment. Under this chronic inflammation, SFN modulated the phenotypical characteristics of moDCs, which reduction the expression of all markers (CD80, CD83, CD86, HLA-DR and PD-L1), and significantly reduced the Th2 proliferative response together with the reduction of the IL-9 and IL-13 levels. Although we did not find changes in the regulatory proliferative response, we observed an increase in IL-10 levels. Conclusion: These findings demonstrate that SFN exerts protective effects against LPS-induced inflammation through moDCs/T-cells modulation towards a regulatory profile. Therefore, SFN may be a potential candidate for use in the treatment of pathologies with an inflammatory profile.

The induction of macrophage death is regarded as a potential mechanism by which components secreted by Clostridium septicum are used to evade the innate immune response and cause tissue damage. This study aimed to determine the effect of partially purified fractions of extracellular proteins secreted by C. septicum on the death of mouse peritoneal macrophages. Elicited mouse peritoneal macrophages were incubated with partially purified fractions of proteins secreted by C. septicum into culture medium. After incubation, we found that the protein fraction with a molecular weight ≥ 100 kDa caused significant cell death in macrophages, changed cell morphology, increased markers of apoptosis and autophagy, and increased the expression (protein and mRNA) of IL-1 and TNFα. Our data suggest that the proteins secreted by C. septicum (MW ≥100kDa) induce cell death in macrophages by promoting autophagy-triggered apoptosis. This may contribute to our understanding of the molecular mechanism of immune evasion by C. septicum at the infection site.

Chickpea is an essential legume, a staple food in many cultures and contains nutrients with potential health benefits. The chickpea water (CPW) leached out after cooking is usually discarded, which may potentially have significant anti-cancer and other health beneficial properties. This study compared the in-vitro bioactivity of CPW with chickpea polyphenol extract (CPPE) to evaluate its impact on pathways of colorectal cancer progression and development. Morphological observation by APOPercentage, cell viability detection using a cytotoxic assay and cell migration-scratch assay points to measure rate of metastasis were employed. Overall antioxidant activity of CPW and CPPE were measured using ABTS and DPPH free-radical assays. At 50 µg/mL concentration and above, both CPW and CPPE extracts significantly reduce cell viability in HT-29 colon cancer cell lines (p < 0.05). Moreover, a quantitative analysis of the extent of apoptosis demonstrated that at 250 and 500 μg/mL concentrations, both extracts induced significant apoptosis compared to the untreated control. Meanwhile, the cell migration scratch area decreases by 34.42% and 15.27% when treated with CPW and CPPE, respectively. In summary, CPW demonstrated comparable in vitro anti-cancer properties and antioxidant activity in colorectal cancer cells to CPPE. Further, in vivo studies are warranted to evaluate the physiological bioactivity of CPW and CPPE in targeting pathways of cancer development and progression

Ovarian cancer (OC) is the most lethal gynecologic malignancy. Cannabis sativa is being used to treat different medical conditions. We sought to examine the effectiveness of combinations of cannabis compounds against OC. Cytotoxic activity was determined by XTT assay on HTB75 and HTB161 cell lines. Apoptosis and cell cycle were determined by fluorescence-activated cell sorting (FACS). Gene expression was determined by quantitative PCR. The two most active fractions, F5 and F7, from a high Δ9–tetrahydrocannabinol (THC) cannabis strain extract and their standard mix (SM) showed cytotoxic activity against OC cells. The most effective phytocannabinoid combination was THC+cannabichromene (CBC)+cannabigerol (CBG). F5, F7 and SM affected cell cycle, led to cell apoptosis and to a marked reduction in cell migration. Moreover, these fractions act in synergy with niraparib, and were ~50 fold more cytotoxic to OC cells than to normal keratenocytes. Niraparib+F7 treatment was effective on OC patient's cells. F7 and the niraparin+fraction (F5 and F7) treatments reduced Mitogen-Activated Protein Kinase 4 (MAPK4) gene expression; this reduction may act in synergy with the niraparib inhibition of Poly (ADP-ribose) polymerase 1 (PARP1) activity. Combinations of cannabis compounds and niraparib should be examined for efficacy in pre-clinical studies and clinical trials.

Vision is our primary sense as the human eye is the gateway for more than 65% of information reaching the human brain. Today’s increased exposure to different wavelengths and intensities of light from Light Emitting Diodes (LEDs) sources could induce retinal degeneration and accompanying neuronal cell death. Damage induced by chronic phototoxic reactions occurring in the retina accumulates over years and it has been suggested to be responsible for the etiology of many debilitating ocular conditions. In this work, we examined how LED stimulation affects vision by monitoring changes in the expression of death and survival factors as well as microglial activation in LED-induced damage (LID) of the retinal tissue. We found an LED exposure-induced increase in the mRNA levels of major apoptosis-related markers -BAX, Bcl-2, and Caspase-3 and an accompanying wide-spread microglial and Caspase-3 activation. Everyday LED light exposure was accounted for all the described changes in the retinal tissue of mice in this study, indicating that overuse of non-filtered direct LED light can have detrimental effects on the human retina as well.

Gastric cancer, also known as stomach cancer, is a cancer which develops from the lining of the stomach. Accumulated evidences and epidemiological studies have been indicated that natural products play an important role in gastric cancer prevention and treatment, although its mechanism of action did not elucidate yet. Particularly, experimental studies have been showed that natural products displayed a protective effect against gastric cancer via numerous molecular mechanisms such as suppression of cell metastasis, anti-angiogenesis, inhibition of cell proliferation, induction of apoptosis, and modulation of autophagy. Although chemotherapy remains the standard treatment for advanced gastric cancer along with surgery, radiation therapy, hormone therapy and immunotherapy, but its adverse side effects including neutropenia, stomatitis, mucositis, diarrhea, nausea, and emesis are well documented. Additionally, intake of naturally occurring phytochemicals could increase the efficacy of gastric chemotherapy and chemotherapeutics resistance. However, natural product structural stability and powerful bioactivity are important to develop novel treatments for gastric cancer that may minimize such adverse effects. Therefore, the purpose of this review is to summarize the potential therapeutic effects of natural products on prevention and treatment of gastric cancer with intensive molecular mechanisms of action, bioavailability, and safety efficacy.

GPR4, a member of proton activated GPCRs group. Previously we have reported that GPR4 is constitutively active at physiological pH and knockout of GPR4 has shown to protect dopaminergic neuronal cells from caspase-dependent mitochondrial apoptotic cell death. In this study we have investigated the role of GPR4 in 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP) treated mice model of Parkinson’s disease. Subchronic administration of MPTP in mice produces oxidative stress induced apoptotic cell death of dopaminergic neurons in the substantia nigra pars compacta (SNpc) and motor deficits. Treatment with NE52-QQ57, a selective antagonist of GPR4 reduced dopaminergic neuronal loss MPTP-intoxicated C57BL6/J mice and improved motor deficit and memory impairment. Co-treatment with NE52-QQ57 significantly decreases the protein level of proapoptotic marker (Bax), and increases the antiapoptotic marker (Bcl-2) in the SNpc and striatum tissue collected from the brain of MPTP inflicted mice. Further, MPTP induced activation of caspase 3 and cleavage of poly (ADP-ribose) polymerase (PARP) was significantly decreased in the SNpc and striatum tissue of NE52-QQ57 cotreated mice. Further mice receiving both MPTP and NE52-QQ57 mice showed significantly higher TH positive cells in the SNpc and striatum than MPTP treated mice alone. Moreover, NE52-QQ57 cotreatment improved the motor activity in the rotarod test and pole test and also improved spatial memory in Y maze test. Our findings suggest GPR4 as a potential therapeutic target for PD whereas the activation GPR4 is involved in the caspase mediated apoptotic cell death in SNpc and striatum of MPTP-intoxicated mice.

Background: Interleukin (IL)-33 is a member of interleukin (IL)-1 family of cytokines which has been linked to the development of inflammatory conditions and cancer in the gastrointestinal tract. This study is designed to investigate whether IL-33 has direct effect on human gastric epithelial cells (GES-1) and on human gastric adenocarcinoma cell line (AGS) and gastric carcinoma cell line (NCI-N87), assessing its role in regulation of cell proliferation and cell cycle, apoptosis and necrosis. Cell cycle regulation was also determined in ex vivo gastric cancer samples obtained during endoscopy and surgical procedures. Methods: cell lines and tissue samples underwent stimulation with rhIL-33. Proliferation was assessed by XTT and CFSE assay, we also evaluated apoptosis by Caspase 3/8 Activity assay and Annexin V assays. Cell cycle were analyzed by means of Propidium Iodine assay and gene expression regulation was assessed by RT-PCR Profiling. Results: we found that IL-33 has an antiproliferative and proapoptotic effect on cancer cell line, while it can stimulate proliferation and reduce apoptosis in normal epithelial cell line. These effects are also confirmed by the analysis of cell cycle gene expression which showed a reduced expression of proproliferative genes in cancer cells, in particular genes involved in G0/G1 and G2/M checkpoint. These results are confirmed by the gene expression analysis on surgical and bioptic specimens. Conclusions: the aforementioned results indicate that IL-33 may be involved in cell proliferation in an environment- and cell type-dependent fashion.

The aim of this study was to investigate the possible role of 99mTc-sestamibi in the regulation of cancer cell proliferation and apoptosis. To this end, Te in vivo values of 99mTc-sestamibi uptake have been associated to the in-situ expression of both Ki67 and caspase-3. For in vitro investiga-tions BT-474 cells were incubated with three different concentration of 99mTc-sestamibi: 10µg/ml –1µg/ml – 0,1µg/ml. Expression of caspase-3 and Ki67, as well as the ultrastructure of cancer cells, were evaluated at T0 and after 24, 48, 72 and 120 hours after 99mTc-sestamibi incubation. Ex vivo data strengthened the known association between the sestamibi uptake and the Ki67 expression. Linear regression analysis showed a significant association between the sestamibi uptake and the number of apoptotic cells evaluated as caspase-3 positive breast cancer cells. As concern the in vitro data, a significant decrease of the proliferation index was observed in breast cancer cells incubated with high concentration of 99mTc-sestamibi (10µg/ml). Amazingly, a significant increase in caspase-3 positive cells in cultures incubated with 10µg/ml 99mTc-sestamibi was observed. This study suggested the possible role of sestamibi in the regulation of pathophysiological process involved in breast cancer.

: Annona squamosa L. is an important medicinal plant used in traditional medicine for the treatment of various diseases. Different parts of A. squamosa L. have various therapeutic effects; however, the anticancer activity of the leaves has not yet been identified. In vitro, MTT, nuclear staining, and LDH assays were used to evaluate cell survival and proliferation in cells exposed to the extracts. The effect of the extracts on cell migration was investigated using a monolayer wound repair assay, and the apoptotic effects were evaluated using flow cytometry. A breast cancer model was used to study the effect of the extract on the tumor size, and the expression of different proliferative and apoptotic markers was evaluated by immunohistochemical analysis. At a concentration of 100 µg/mL, A. squamosa leaf extracts exerted strong antiproliferative and cytotoxic effects against various cell lines. The extracts reduced wound closure and strongly induced apoptosis. In vivo study, rats were sacrificed 24 h after the last injection, and tumor size, as well as the expression of proliferative and apoptotic markers, were observed to be greatly affected by treatment with the extracts. Therefore, A. squamosa leaf extract may be developed as a potential novel drug to treat breast cancer in the future

The probiotic bacterial strain Lactobacillus plantarum ZS2058 has been proved to manifest comprehensive functions, which were due to ability to synthesise conjugated fatty acids (CFAs). To investigate the specific functions of CFAs produced by this probiotic bacterium, α-linolenic acid was isomerized by Lactobacillus plantarum strain ZS2058, and two different conjugated α-linolenic acid (CLNA) isomers were successfully isolated. These isoforms, CLNA1 (c9, t11, c15-CLNA, purity 97.48%) and CLNA2 (c9, t11, t15-CLNA, purity 99.00%), both showed the ability to inhibit the growth of three types of colon cancer cells in a time- and concentration-dependent manner. In addition, the expression of MDA in Caco-2 cells was increased by CLNA1 or CLNA2, which indicated lipid peroxidation was related to the antiproliferation activity of CLNAs. Examination of the key protein of pyroptosis showed that CLNA1 induced the cleavage of caspase-1 and gasdermin-D, while CLNA2 induced the cleavage of caspase-4, 5 and gasdermin-D. The addition of relative inhibitors could alleviate the pyroptosis by CLNAs. CLNA1 and CLNA2 showed no effect on caspase-3, 7, 9 and PARP-1, which were key proteins associated with apoptosis. And no sub-diploid apoptotic peak appeared in the result of PI single staining test. In conclusion, CLNA1 activated caspase-1 and induced Caco-2 cell pyroptosis, whereas CLNA2 induced pyroptosis through the caspase-4/5-mediated pathway. The inhibition of Caco-2 cells by the two isomers was not related to apoptosis. This is the first report showing the ability of CLNAs to activate antioxidant defenses resulting in pyroptosis.

Relapsed leukemia following initial therapeutic response and remission is difficult to treat and causes high patient mortality. Leukemia relapse is due to residual quiescent leukemia cells that escape conventional therapies and later reemerge. Eliminating not only growing but quiescent leukemia cells is critical to effectively treating leukemia and preventing its recurrence. Such therapeutic agents, however, are lacking in the clinic. Here we report that a 4-arylmethyl derivative of the natural anticancer compound curcumin demonstrates a dual effect in eliminating both growing and quiescent leukemia cells. This curcumin derivative, C212, on the one hand, inhibits growing leukemia cells at a higher efficacy than curcumin by inducing apoptosis and cell cycle arrest; it, on the other hand, kills quiescent leukemia cells that are resistant to conventional chemotherapy drugs. Furthermore, C212 drives leukemia cells into and kills them at deep quiescence, avoiding the potential risk associated with awaking therapy-resistant subpopulation of quiescent leukemia cells. Lastly, we show that C212 induces apoptosis and drives cells into deep dormancy at least partially by binding to and inhibiting Hsp90, leading to client protein degradation and protein aggregation. Further elucidating the molecular mechanisms underlying the dual function of C212 in eliminating both growing and quiescent leukemia cells will aid the development of novel therapies against leukemia relapse.

The Signal Transducer and Activator of Transcription (STAT)3 and 5 are activated by many cytokine receptors to regulate specific gene expression and mitochondrial functions. Their role in cancer is largely context dependent as they can both act as oncogenes and tumor suppressors. We review here the role of STAT3/5 activation in solid cancers and summarize their association to survival in cancer patients. The molecular mechanisms that underpins the oncogenic activity of STAT3/5 signaling includes the regulation of genes that control cell cycle, cell death, inflammation and stemness. In addition, STAT3 mitochondrial functions are required for transformation. On the other hand, several tumor suppressor pathways act on or are activated by STAT3/5 signaling including the p19ARF/p53 pathway, tyrosine phosphatases, suppressor of cytokine signaling 1 and 3, the sumo ligase PIAS3, the E3 ubiquitin ligase TMF/ARA160 and the miRNAs miR-124 and miR-1181. Cancer mutations and epigenetic alterations may alter the balance between pro-oncogenic and tumor suppressor activities associated to STAT3/5 signaling explaining their context dependent association to tumor progression both in human cancers and animal models.

In this study, bioactive compounds present in chestnut shells (CS) - derived from the industrial peeling processing - were extracted through different procedures. The aqueous extracts were characterized and the highest extraction yield and total phenolic content was obtained by Conventional Liquid Extraction (CLE). Gallic and protocatechuic acids were the main simple phenols in the extract with 86.97 and 11.20 mg/g chestnut shells dry extract (CSDE), respectively. Six tumor cell lines (DU 145, PC-3, LNCaP, MDA-MB-231, MCF-7 and Hep G2) and one normal prostate epithelial cell line (PNT2) were exposed to increasing concentration of CSDE (1-100 µg/mL) for 24 h and cell viability was evaluated using MTT assay. A reduced rate in cell viability was observed in DU 145, PC-3, LNCaP and MCF-7 cells while viability of MDA-MB-231 and Hep G2 cells was not affected except for PNT2 cells at a concentration of 100 µg/mL. Furthermore, CSDE-at concentrations of 55.5 and 100 µg/mL- lead to a significant increase of apoptotic cells in DU 145 cells of 28.2% and 61%, respectively. In conclusion, our findings showed that CS might be used for the extraction of several polyphenols that may represent good candidates for alternative therapies or in combination with current chemotherapeutics.

Thienopyrimidines are a versatile group of compounds that contain a biologically active pharmacophore and reported to have anticancer efficacy in vitro. Here, we report for the first time, that thieno[3,2-d]pyrimidine - based compounds, designated the RP series, have efficacy in prostate cancer cells. The lead compound, RP-010, was efficacious in PC3 and DU-145 prostate cancer (PC) cells (IC50< 1µM). The cytotoxicity of RP-010 was significantly lower in normal cells. RP-010 (0.5, 1, 2, and 4 µM) arrested prostate cancer cells in the G2 phase of the cell cycle, induced mitotic catastrophe and apoptotic signaling in both PC cell lines. Mechanistic studies suggested that RP-010 (1 and 2 µM) inhibits the wingless-type MMTV (Wnt)/β-catenin signaling pathway, mainly by inducing β-catenin fragmentation, while down regulating important proteins in the pathway, i.e. LRP-6, DVL3, and c-Myc. Interestingly, RP-010 (1 and 2 µM) induced the nuclear translocation of the negative feedback proteins, Naked 1 and Naked 2, in the signaling pathway. In addition, RP-010 (0.5, 1, 2, and 4 µM) significantly decreased the migration and invasiveness of PC cells in vitro. Finally, RP-010 did not produce significant toxic effects in zebrafish at concentrations up to 6 µM. In conclusion, RP-10 is a promising anticancer compound in metastatic prostate cancer and did not produce overt toxicity in an in vivo zebrafish model. Future mechanistic and efficacy studies are needed in-vivo to optimize the lead compound RP-010 for clinical use.

Natural product especially secondary metabolites that produced by plants under the stressed condition shown to have a different pharmacological impact. Aeluropus lagopoides is one of the typical halophyte plants survivals under stressed conditions. It has been used for wound healing and as a painkiller. The bioactivity and the chemical composition of this plant have poorly investigated. Consequently, chemical components of A. lagopoides leaves were extracted using hexane (nonpolar), ethyl acetate (semi-polar), n-butanol (polar) to extract the most extensive variety of metabolites. The cytotoxicity and anticancer impact of extracted secondary metabolites evaluated against breast (MCF-7), colon (HCT-116), and liver (HepG2) cancer cell lines using SRB test. The mechanism of action verified by observing the appearance of apoptotic bodies using the fluorescent microscope while their antiproliferative impact had been evaluated using flow cytometer. Results revealed that secondary metabolites extracted using hexane and ethyl acetate were having the highest cytotoxicity and thus anticancer activity effect on HepG2 with IC₅₀ (24.29 ± 0.85, 11.22 ± 0.679 µg/mL) respectively. Where apoptotic bodies observed, flow cytometer results exhibited that secondary metabolites can inhibit cell cycle in G0/G1 phase. Accordingly, A. lagopoides hexane and ethyl acetate extracts may consider as a candidate anti-cancer drug.

Though Moracin D derived from Morus alba was known to have anti-inflammatory and antioxidant activities, the underlying antitumor mechanism of Moracin D was never unveiled so far. Thus, in the recent study, the apoptotic mechanism of Moracin D was elucidated in breast cancer cells. Herein, Moracin D exerted significant cytotoxicity in MDA-MB231 and MCF7 cells. Also, Moracin D increased sub G1 population, cleaved poly (ADP-ribose) polymerase (PARP) and attenuated the expression of pro-cysteine aspartyl-specific protease (procaspase 3), c-Myc, cyclin D1, B-cell lymphoma 2 (Bcl-2),and X-linked inhibitor of apoptosis protein (XIAP) in MDA-MB231 cells. Of note, Moracin D reduced expression of Forkhead box M1 (FOXM1), β-catenin, Wnt3a, and upregulated glycogen synthase kinase 3 beta (GSK 3β) on Tyr216 along with disturbed binding of FOXM1 with β-catenin in MDA-MB-231 cells. Conversely, GSK3β inhibitor SB216763 reversed the apoptotic ability of Moracin D to reduce expression of FOXM1, β-catenin, pro-caspase3 and pro-PARP in MDA-MB-231 cells. Overall, these findings provide novel insight that Moracin D inhibits proliferation and induces apoptosis via suppression of Wnt3a/FOXM1/β-catenin signaling and activation of caspase and GSK3β

Aims TRAIL is a promising anticancer agent that has the potential to sensitize a wide variety of cancer or transformed cells by inducing apoptosis. However, resistance to TRAIL is a growing concern. Current manuscript aimed to employing combination treatment to investigate resveratrol induced TRAIL sensitization in NSCLC. Method A549 and HCC-15 cells were used in experimental design. Cell viability was determined by morphological image, crystal violet staining and MTT assay. Apoptosis was evaluated by LDH assay, Annexin V and DAPI staining. Autophagy and apoptosis indicator protein were examined by western blotting. TEM and puncta assay were carried out to evaluate the autophagy. MTP and ROS activity were evaluated by JC-1 and H₂DCFDA staining. Findings Resveratrol is a polyphenolic compound capable of activation of tumor suppressor p53 and its pro-apoptotic modulator PUMA. Herein, we showed the p53-independent apoptosis by decrease the expression of phosphorylated Akt-mediated suppression of NF-κB that is also substantiated with the downregulation of anti-apoptotic factors Bcl-2 and Bcl-xl in NSCLC, resulting in an attenuation of TRAIL resistance in combined treatment. Furthermore, apoptosis was induced in TRAIL-resistant lung cancer cells with a co-treatment of resveratrol and TRAIL assessed by the loss of MMP, ROS generations which resulting the translocation of cytochrome c from the mitochondria into the cytosol due to mitochondrial dysfunction. Moreover, autophagy flux was not affected by resveratrol-induced TRAIL-mediated apoptosis in NSCLC. Significance Overall, targeting the NF-κB (p65) pathway via resveratrol attenuates TRAIL resistance and induces TRAIL-mediated apoptosis which could be the effective TRAIL-based cancer therapy regimen.

We previously found a novel a new sirtuin (SIRT) inhibitor MHY2256 that exerts anticancer activity through p53 acetylation in MCF-7 human breast cancer cells. Here, we investigated the anticancer activity of MHY2256 against hormone-related cancer, which is an endometrial cancer with poor prognosis. We found that MHY2256 markedly reduced cellular proliferation at low concentrations against Ishikawa endometrial cancer cells. The IC50 values of MHY2256 were much lower than that of salermide. Furthermore, MHY2256 significantly reduced the protein expression and activities of SIRT1, 2, and 3 with similar effects as salermide, a well-known SIRT inhibitor. Particularly, MHY2256 markedly inhibited tumor growth in a tumor xenograft mouse model of Ishikawa cancer cells. During the experimental period, there was no significant change in the body weight of mice treated with MHY2256. Detailed analysis of the sensitization mechanisms of Ishikawa cells revealed that late apoptosis was largely increased by MHY2256. Additionally, MHY2256 increased G1 arrest and reduced cell cyclic-related proteins, suggesting that apoptosis by MHY2256 was achieved by cellular arrest. Particularly, p21 was greatly increased by MHY225656, suggesting that cell cycle arrest by p21 is a major factor in MHY2256 sensitization in Ishikawa cells. We also detected a significant increase in acetylated p53, a target protein of SIRT1, in Ishikawa cells after MHY2256 treatment. In a mouse xenograft model, MHY2256 significantly reduced tumor growth and weight without apparent side effects. These results suggest that MHY2256 exerts its anticancer activity through p53 acetylation in endometrial cancer and can be used for targeting hormone-related cancers.

Both fibrosis and cirrhosis of the liver are the end results of most kinds of chronic liver damage and present a common but difficult clinical challenge throughout the world. The inhibition of the fibrogenic, proliferative, and migratory effects of hepatic stellate cells (HSCs) has become an experimental therapy for preventing and even reversing hepatic fibrosis. Furthermore, a complete understanding of the function of non-coding RNA-mediated epigenetic mechanisms in HSC activation may improve our perception of liver fibrosis pathogenesis. This review focuses on an evolving view of molecular mechanisms in which HSC activation by miR-29a signaling may moderate their profibrogenic phenotype, thus supporting the use of miR-29a agonists as a potential therapy for treating liver fibrosis in the future.

Research into the causes of neurotoxicity in Alzheimer’s Dementia (AD) has focused on neurofibrillary tangles and beta amyloid (Aβ) plaques. This paper proposes the heterodox theory that these hallmarks of AD are the visible effects, not direct causes of neuronal necrosis. Rather AD results from a combination of age-induced, disproportional decline in physiological support for aerobic metabolism, and dysregulation of the sleep cycle processes. The hypothesis is that the decimation of neurons in AD results from a combination of neurotoxicity and increased apoptosis caused by: 1. direct damage from toxic waste products of anaerobic glycolysis due to a progressive decline in the capacity of neurons to perform oxidative phosphorylation (OXPHOS) and an increased reliance on anaerobic glycolysis to meet metabolic needs; 2. impaired cellular repair and effluent release due to dysregulation of non-rapid eye movement (NREM) sleep allowing damage to cell membranes and synaptic junctions to accumulate inducing a chronic inflammatory response; 3. indirect damage from products produced by inflammatory reaction to toxic metabolites; 4. neuronal apoptosis from the AβPP-mediated pathway due to the age-induced decline of growth hormone (GH), GH-releasing hormone (GHRH) and insulin-like growth factor (IGF).

Traumatic brain injury (TBI) can result in persistent sensorimotor and cognitive deficits, which occur through a cascade of deleterious pathophysiological events over time. In this study, we investigated the hypothesis that neurodegeneration caused by TBI leads to impairments in sensorimotor function. TBI induces the activation of the caspase-3 enzyme, which triggers cell apoptosis in an in vivo model of fluid percussion injury (FPI). We analyzed caspase-3 mediated apoptosis by TUNEL staining and PARP and annexin V western blotting. We correlated the neurodegeneration with sensorimotor deficits by conducting the animal behavioral tests including grid walk, balance beam, inverted screen test, and climb test. Our study demonstrated that the excess cell death or neurodegeneration correlated with the neuronal dysfunction and sensorimotor impairments associated with TBI.

We evaluated oleanolic acid (OA)-induced anti-cancer activity, apoptotic mechanism, cell cycle status, and MAPK kinase signaling in DU145 (prostate cancer), MCF-7 (breast cancer), and U87 (human glioblastoma) cells. The IC50 values for OA-induced cytotoxicity were 112.57 in DU145, 132.29 in MCF-7, and 163.60 in U87 cells, respectively. OA (at 100 µg/mL) increased the number of apoptotic cells to 27.0% in DU145, 27.0% in MCF-7, and 15.7% in U87 cells, when compared to control cells. This enhanced apoptosis was due to increases in p53, cytochrome c, and Bax expression. OA-treated DU145 cells were arrested in G2 because of the activation of p-ERK and p21, and the decrease in cyclin B1 and cyclin E expression. Furthermore, OA-treated MCF-7 cells were arrested in G1 owing to the activation of p-JNK, p-ERK, p21, and p27, and the decrease in p-AKT, cyclin E, and CDK2. U87 cells also exhibited G1 phase arrest caused by the increase in p-ERK, p-JNK, p21, and p27, and the decrease in CDK2. Thus, OA arrests the cell cycle in different phases, and increases apoptosis in cancer cells. These results suggest that OA may alter the expression of cell cycle regulatory proteins in a cancer type-dependent manner.

This paper presents a methodology for the integration of Building Information Modeling (BIM) and Life Cycle Cost Analysis (LCCA) to assess the economic implications of designing aging-in-place (AIP) homes at the conceptual stage. With the global increase in the aging population, there is an increased demand for housing solutions tailored to the needs of elderly individuals. Focusing on the importance of the early phase of design, this study aims to improve the process of making efficient decisions by providing a comprehensive assessment of the life cycle costs associated with AIP homes. The study introduces a semi-automated model for the economic evaluation of AIP homes, enabling the estimation of costs throughout the houses’ entire life cycle, from design and construction to operation, maintenance, and eventual renovation or disposal. The said model facilitates the exploration of the long-term economic feasibility of design’s related decisions with an emphasis on the importance of considering the life cycle costs early during the design process to optimize the functionality and economic viability. By investing in accessible and universal design features upfront, the initial costs for modifications can lead to long-term savings by reducing the need for extensive retrofits. The model can easily do comparison between different design alternatives in terms of their lifecycle costs, allowing designers to assess the financial impact of using important features in their design such as wider doorways, accessible bathrooms, and elevators. Overall, this study provides valuable insights for designers and homeowners about the economic aspects of designing AIP homes as a support for efficient decision-making during the early stages of the design process.

In order to solve the problem of large eddy current loss and high temperature rise caused by large amount of permanent magnet, a new type of combined magnetic pole permanent magnet motor is proposed in this paper. The sinusoidal distribution subdomain model of non-uniform air gap rotor is established by using Laplace equation, and the analytical expression of eddy current loss of rotor in uniform air-gap and non-uniform air-gap is derived. The effect of rotor eccentricity on eddy current loss is obtained. According to the characteristics of distributed winding of non-uniform air gap combined pole permanent magnet motor, equivalent treatment is performed to obtain the equivalent thermal conductivity, so as to establish equivalent thermal network model of motor, calculate the temperature value of each component of the motor, and verify the correctness of the thermal network model through the method of magnetothermal bidirectional coupling. Finally, an experimental platform is set up to carry out temperature rise experiments on the two prototypes respectively. Experimental results show that the non-uniform air-gap rotor structure can effectively reduce the rotor eddy current loss and motor temperature rise, and also verify the accuracy of the analytical model calculation results.

Information geometry is a mathematical framework that analyses the structure of statistical models using concepts from differential geometry. It treats families of probability distributions as manifolds, where the parameters of each model determine the coordinate charts. By applying info-geometric tools, we can gain insights into the characteristics of these models. The approach involves characterizing the queueing system's manifold using information geometry and presenting the exponential of the information matrix. This integration of information geometry with queueing theory provides a novel perspective for analyzing the dynamics of queueing systems, incorporating relativistic and Riemannian concepts. Some applications to E-health are highlighted. Finally, closing remarks and the next phase of research.

Cooling fans are one of the critical components of air-forced (AF) dry-type transformers for regulating internal temperatures. Therefore, effective malfunction detection is crucial to maintain the transformer temperature within an acceptable range and prevent overheating. Regular maintenance occurs periodically and issues with cooling fans may arise between maintenance periods, leading to prolonged operation under malfunctioning conditions and potential failures. In addition, utilities typically have online information about whether a fan works or not without providing information about cooling fan malfunctioning circumstances. To address these challenges, this study proposes learning-based online monitoring techniques to detect malfunctions in AF transformer cooling fans. Random forests (RFs) and convolutional neural networks (CNNs) are developed to classify the audio signals from cooling fans into normal and malfunctioning classes. Unlike RFs, which require separate feature extraction, CNNs are trained based on spectrogram images derived from audio signals. Thus, various time-frequency techniques are utilized for feature extraction in RFs. Besides, multiple data augmentation techniques are employed to enhance the dataset size and diversity. Algorithmic performance is optimized through hyperparameter tuning and classifier threshold adjustment. Simulations reveal that CNNs outperform RFs, whereas the latter provides superior interpretability of acoustic features compared to the former.

The Parecis Basin is one of the largest intracratonic basins in Brazil. Despite its considerable size, the basin has yet to be extensively explored, with only five wildcat wells drilled for hydrocarbons. So far, no commercial discoveries have been announced. Regional studies have suggested Paleozoic sedimentation, while recent studies indicate a Neoproterozoic fill. However, no tectonic model accurately describes the basin’s development, and no detailed structural map for the entire basin has been published. The present work presents a new detailed structural map of the Parecis Basin based on a four-step interpretation workflow integrating seismic and gravimetric data. The first step includes converting the public 2D seismic lines to the depth domain. The second step is estimating the residual Bouguer anomaly, where the computed residual anomalies should relate to the basin’s tectonic features. The third step comprises the 2D forward modeling of the gravimetric anomalies using the 2D seismic interpretation as a constraint. The final step compiled all the interpreted features into our new structural map. This map reveals the top of the basement, forming a complex framework of horsts and grabens. Normal faults define the main structural style in the basin. Further, we could recognize thick, high-density bodies embedded in the crystalline basement. These bodies consist of Orosian-Calimian (1.8-1.6 Ga) mafic and ultramafic rocks, which may be a potential source for hydrogen exploration in the basin. Subsequent geophysical and geochemical surveys will assess the hydrogen potential in the area.

Infrastructure such as transport, electricity, telecommunications, and sanitation are indispensable drivers for improving the country’s social and economic development. The industrial, agricultural, fisheries and service sectors are also key tools for the country's economic growth. This study aims to analyze the influence of infrastructure development on Djibouti’s economic growth and determine the other economic sectors. This study employs multiple regression analyses from Eviews Software to establish a correlation between these variables and Djibouti’s economic growth, utilizing data spanning from the period 2013 to 2022. The results reveals that mobile cell phone subscriptions, and the people using the health service management, industry, and service have a positive and highly significant influence on Djibouti's economic growth. The study found that access to electricity has a positive influence on economic growth in Djibouti, but is not statistically significant. In addition, the study shows that agriculture, forestry, and fisheries have a negative influence on economic growth in Djibouti, but are statistically significant. Therefore, we recommend that the Government of Djibouti strengthen and ensure the benefit of developing electricity infrastructure in Djibouti and the agriculture, forestry, and fisheries sectors to achieve sustainable economic growth in the coming years.

Traditional methodologies for measuring combat effectiveness rely on various contribution factors, where the main challenge lies in the complexity and subjectivity of these factors. Using frontline variation to measure combat effectiveness circumvents the limitations of many previous methods regarding complexity and subjectivity. Employing this methodology, we have quantitatively measured the combat effectiveness of both parties in the Russo-Ukrainian War across various temporal scales. Utilizing the time series data derived from our measurements, we constructed Daily, Weekly, Monthly, and Annual Candlestick Charts to illustrate the variation trends in combat effectiveness between the two sides across different temporal scales. This comprehensive approach facilitated a nuanced and all-encompassing analysis of the conflict, capturing the intricate dynamics of individual military engagements and the broader strategic operations' context. This case underscores the distinctive utility of our method in quantifying combat effectiveness, offering detailed and strategically significant insights.

Driven by mounting environmental apprehensions stemming from the over dependence on fossil fuels in energy and transportation sectors, extensive exploration into alternative energy sources, particularly biomass, has stimulated profound research on harnessing the potential of computational and mathematical techniques. This comprehensive survey delves into optimal models and strategies, unveiling their pivotal role in the design of biomass gasification processes.of hydrogen through biomass gasification. In this study, we aim to provide a comprehensive overview of the computational and mathematical techniques employed in optimizing biomass gasification processes, with a specific focus on enhancing hydrogen yield. Through an extensive literature review, various models and strategies will be examined, including thermodynamic analysis, kinetic modeling, reactor design, and process optimization. By uncovering the power of these techniques, we aim to contribute to the advancement of sustainable and efficient biomass utilization for the hydrogen-based future economy.This paper aims to provide an updated and comprehensive coverage of the investigations conducted on the potential of producing hydrogen from biomass through gasification. To achieve this, we incorporate the latest works that have utilized numerical modeling, simulation, optimization techniques, process heat integration, and co-generation in their studies. By encompassing these aspects, we aim to offer a broader and more in-depth re-appraisal of the subject matter. This will ensure that readers gain a holistic understanding of the advances made in the field and the potential for sustainable hydrogen production of biomass gasification.Through a meticulous re-appraisal and analysis of each subject, we can identify their respective strengths and areas that require further research effort. By thoroughly examining numerical modeling, simulation, optimization techniques, process heat integration, and co-generation, we can assess their effectiveness and applicability in the context of biomass gasification for hydrogen production. This analysis shed light on the areas where these techniques excel, as well as pinpoint limitations or gaps in current understanding. By identifying these areas, we can highlight the need for further research and development, enabling us to make significant advancements in biomass gasification processes and pave the way for a sustainable and efficient hydrogen-based future economy..

The study explores how different dimensions of perfectionism influence psychological well-being (PWB) in emerging adults. Literature has deepened the relationships between maladaptive perfectionism (e.g., excessive self-criticism, perceived discrepancy from the standards) and low PWB. Less is known about whether and how adaptive perfectionism (e.g., pursuing personal standards) relates to PWB. Secondly, the study has investigated whether self-compassion (i.e., self-benevolence, seeing personal imperfections as a common condition) may mediate the relationships between adaptive/maladaptive perfectionism and PWB. Participants (N=217, 18-35 y. o.) completed self-report questionnaires measuring: adaptive/maladaptive perfectionism (Almost Perfect Scale-Revised, APS-R: high standards and order/discrepancy, respectively), PWB, and self-compassion (SCS). Adaptive perfectionism resulted associated with PWB, particularly higher presence of purpose in life, environmental mastery, self-acceptance, and personal growth. Conversely, discrepancy resulted the most robust predictor of low PWB (β=-.68), followed by high standards with a positive direction (β=.23; Rc²=.514, p&lt;.001). A strong negative association emerged between discrepancy and SCS (r=-.67, p&lt;.001). A mediation analysis shows that self-compassion has an indirect effect reducing the strength of the relationship between discrepancy and low PWB. Results suggest focusing on self-compassion as a buffer factor that reduces the negative impact of maladaptive perfectionism on psychological well-being. Implications for education and health psychology are discussed.

An Indo-French campaign was conducted during May 2014 at Gadanki (13.5^oN, 79.2^oE), India, for investigating gravity wave (GW) coupling between the lower and middle atmospheres using a suite of experimental techniques. In this paper we are presenting the sources for those GWs which are observed at airglow layer (~87 km) using (OH) Airglow Imager during the campaign. For this purpose we have developed a background model atmosphere by combining the ERA-Interim, MSIS E 90 model and HWM 07 model data sets. Uniqueness of the present study lies in using near-real time background atmosphere data from simultaneous radiosonde and SVU Meteor Radar covering both source and propagation/ dissipation regions of GWs. We have observed 17 wave events and used GROGRAT model for reverse tracing to locate the source(s). When we searched for the sources near the terminal points or along the ray path, deep convection is found to occur but no strong wind shear. This indicates that the source for the observed GWs is deep convection. We have also simulated small scale waves that can reach mesosphere during different seasons (background conditions). GWs with periods less than 100 minutes and horizontal wavelengths less than 200 km are mostly reaching the mesospheric altitudes. Interestingly, it is found that only few GWs that are generated in the troposphere reach the mesospheric altitudes during the monsoon season, though strong sources like convection and wind shear persist throughout this season. Thus, background wind plays significant role in deciding the propagation of GWs in to upper atmosphere.