Medicine and Pharmacology

Abstract: Objective: The purpose of this preliminary study was to evaluate the use of the Zipf-Mandelbrot (ZM) law to mathematically model the percentage occurrence of adverse drug reactions (ADRs), as a function of rank, reported to the US FDA Adverse Event Monitoring System (AMES). Methods: Six commonly used hospital-based medications were examined. Nonlinear curve fitting of the two ZM coefficients was utilized to model the percentage occurrence of ADRs in a hierarchical or rank order for each drug examined. Results: The reported complications and their associated occurrence rates for all six medications were accurately modelled using the ZM law. Those medications which have a greater percentage of reported ADRs within their first ten ranks have a greater negative slope. Furthermore, a natural logarithmic transformation of both the reported FDA data and the predicted values utilizing the ZM law demonstrated a consistent statistically significant near-linear correlation. The ratio of the coefficients of the ZM law, a∙b^(-1), was also found to be a potentially useful index which allows for describing and comparing the overall shape of the medication-specific distributions. Conclusions: Based upon this preliminary examination, the ZM law appears to be applicable to the mathematical modeling of US FDA reported ADRs. Additional research to assess and utilize this law for the analysis, economic management, and possible improvement in patient outcome may be warranted.

Abstract: Acute pain remains one of the most prevalent and burdensome clinical challenges requiring pharmacological intervention, yet opioids — with their well-documented risks of respiratory depression, addiction, and overdose — remain a cornerstone of moderate-to-severe pain management in the absence of efficacious alternatives. Suzetrigine (VX-548) is a novel preferential inhibitor of the voltage-gated sodium channel isoform Nav1.8, recently approved by the US Food and Drug Administration for the treatment of moderate-to-severe acute pain. Through specific inhibition of Nav1.8, which is expressed predominantly in nociceptive sensory neurons of the peripheral nervous system, suzetrigine offers a mechanistically targeted approach to reduce pain at the level of the primary afferent, bypassing the central nervous system circuitry involved in opioid-associated adverse effects. In this review, we examine both the scientific foundation and clinical utility of suzetrigine, integrating evidence from molecular and structural biology, electrophysiology, preclinical animal models, and Phase II and III randomized controlled clinical trials. We discuss the unique allosteric mechanism by which suzetrigine selectively inhibits Nav1.8 to suppress nociceptor excitability, and review six trials, five of which show evidence demonstrating significant analgesic efficacy relative to placebo, and a favorable safety profile. We discuss key limitations of the current clinical evidence base including modest, and sometimes nonexistent efficacy, albeit at the tested doses. Overall, suzetrigine may serve as a proof-of-concept for the development of other sodium channel isoform-specific modulators as targeted therapeutic intervention for a range of diseases. Moreover, the development of cost-effective alternatives to prescription opioids may have substantial population health benefits. Further study with more varied pain types with longer durations including thoroughly examining sex differences with suzetrigine as a monotherapy (i.e. with no use of “rescue” medications) relative to prescription opioids or nonsteroidal anti-inflammatory drugs (NSAIDs) will provide valuable information that could widely benefit acute pain patients and form a scaffolding to bridge the gap between the well-established preclinical foundation and clinical research to enhance the quality of life of those currently living with chronic pain.

Abstract:

limiting systemic exposure. We assessed whether co-therapy with the selective cyclooxygenase-2 (COX-2) inhibitor etoricoxib and the corticosteroid betamethasone provides antinociceptive and anti-edema activity in complete Freund’s adjuvant–induced arthritis (AIA) in rats. Methods: Male Wistar rats (n = 10/group) were allocated to seven groups: intact, AIA disease control, indomethacin 5 mg/kg, etoricoxib 8 mg/kg, betamethasone 0.022 mg/kg, low-dose combination (4 + 0.011 mg/kg) and full-dose combination (8 + 0.022 mg/kg), administered orally once daily from Day 4 to Day 28. Paw edema, von Frey withdrawal thresholds and clinical arthritis score were assessed longitudinally as area-under-the-curve (AUC). Terminal joint tissues were profiled for cytokines, prostaglandin pathway mediators and immune cell markers. Results: Both combinations reduced edema and improved mechanical thresholds versus disease control. The full-dose combination produced the greatest restoration of integrated mechanical sensitivity and arthritis index, exceeding either monotherapy, consistent with additive activity of two mechanistically complementary agents. The low-dose combination achieved improvements equivalent to full-dose monotherapies, a pattern consistent with a dose-reduction effect. Biomarker shifts indicated attenuated prostaglandin signaling and a pro-resolving cytokine balance, with macrophage-associated markers trending toward intact levels. Conclusions: These findings support further evaluation of etoricoxib–betamethasone co-therapy for acute inflammatory conditions.

Abstract: Long‑acting injectable (LAI) formulations have transformed adherence in several psychiatric conditions, yet no depot antidepressant currently exists. People with major depressive disorder (MDD) remain at risk of accidental overdose from prescribed oral medications, particularly during periods of cognitive impairment or crisis. Artificial intelligence (AI)–driven molecular modelling now enables the design of antidepressant compounds optimised for slow‑release, water‑based depot systems that avoid the fibromas and granulomatous reactions associated with oil‑based injectables. This study outlines an AI‑enabled workflow for generating a novel antidepressant molecule with favourable receptor‑binding properties, low toxicity, and compatibility with biodegradable, aqueous depot carriers. The resulting formulation has the potential to reduce overdose risk, improve adherence, and decrease the burden of frequent GP prescribing.

Abstract: In pregnancy physiologically based pharmacokinetic (PBPK) modelling within PK-Sim/Mobi, pregnancy stage is canonically parameterised on the fertilisation-age (FA) timescale, yet PK-Sim’s physiology database is indexed by chronological “Age”. The Open Systems Pharmacology (OSP) pregnancy framework therefore encodes FA on a dummy “Age” axis (30.00 years = FA 0 weeks; 30.75 years = FA 38 weeks) and generates pregnancy physiology vectors from FA 0 – 38 weeks discretised at 1-day intervals for database ingestion. Although the anchor points are publicly documented, an explicit closed-form transform and week-resolved lookup suitable for deterministic reproduction of daily physiology grids has not been routinely foregrounded in the literature or repository instructions. A unique affine mapping is derived, implied by the anchors, that provide forward and inverse equations in week- and day-space, quantifying rounding error in terms of FA-day misalignment, and supply a fertilization week (1-38) table for implementation-ready pregnancy virtual population creation in PK-Sim.

Abstract: Background/Objective: Vitamin K (VK) comprises a family of quinone compounds with potential involvement in cell death-related pathways through their redox properties. However, consistent findings have not been obtained regarding the clinical significance of VK in breast cancer (BC). Thus, we used the FDA Adverse Event Reporting System (FAERS) to examine the co-reporting patterns of BC-related adverse-event terms among VK-related reports. Methods: Reporting disproportionality analysis was conducted using FAERS data spanning the first quarter of 2004 to the third quarter of 2024. BC-related reports were defined using all valid Preferred Terms included in the relevant narrow-scope Standardized MedDRA Query (SMQ). Reporting odds ratios (RORs) and proportional reporting ratios were calculated for all VK types and each homolog, followed by exploratory comparisons with other compounds containing quinone structures. Results: In total, 32,156 VK-related reports were identified, including 136 BC-related reports. VK-related reports showed significantly lower reporting disproportionality for breast cancer-related reports (ROR = 0.486, 95% confidence interval = 0.411–0.575). In homolog-specific analyses, similar trends were observed for the quinone-type homologs phytomenadione, menatetrenone, and menadione, whereas no significant reporting disproportionality was detected for the hydroquinone-type homolog menadiol. Conclusions: The differences in reporting patterns among quinone-type VK homologs, hydroquinone-type VK, and other quinone-containing compounds suggest that differences in redox properties may be partially related to the structure of reporting disproportionality. Although this study did not demonstrate causality or clinical efficacy, it provides a hypothesis-generating basis for linking basic, epidemiological, and clinical research using FAERS data. Future validation through mechanistic research and analytical epidemiological studies with stricter control of confounding is warranted.

Abstract: This research explores the aromatase-inhibitory and estrogen-agonistic/antagonistic properties of two natural naphthoquinones, α- and β-lapachone, which are known for their anticancer effects. Initial tests showed that both lapachones inhibit aromatase in the sub-micromolar range, with IC₅₀(β) = 0.78 ± 0.06 μM and IC₅₀(α) = 10.6 ± 2.4μM, similar to the steroidal aromatase inhibitor Exemestane (IC₅₀: 0.02-0.2 μM). A molecular docking study comparing these compounds with androstenedione, one of the native aromatase substrates, identified their binding sites and specific interactions with the enzyme. The Yeast Estrogen Screening assay indicated that both compounds lacked hERα-agonistic activity but exhibited antagonistic effects, similar to 4-Hydroxytamoxifen (Afimoxifene; IC₅₀ = 0.81 ± 0.65 μM). The IC₅₀ values were 0.33 ± 0.24 μM for β-lapachone and 48.3 ± 18.9 μM for α-lapachone. Overall, the study propose unexplored mechanism of action and highlights the dual role of α- and β-lapachones: inhibiting estrogen synthesis and serving as potent, selective estrogen receptor modulators, emphasizing their potential in cancer treatment, especially for hormone-dependent cancers.

Abstract: Background: The adaptogen concept, first formalized over half a century ago, describes pharmacological agents that increase nonspecific resistance to stress. Despite extensive clinical evidence supporting the efficacy of adaptogenic botanicals, the concept has re-mained largely phenomenological, lacking a mechanistic framework compatible with modern molecular pharmacology. This has limited its acceptance in evidence-based medi-cine. Aims: We propose that hydroponically cultivated red Panax ginseng preparation HRG80, with its chemically reproducible composition and multilevel evidence base, constitutes a case study through which the mechanistic basis of adaptogenic action can be examined across molecular, cellular, neurophysiological, and clinical levels. Methods: We identified all published preclinical and clinical studies conducted on HRG80 through PubMed, Scopus, and manual citation tracking (last search: March 2026). Ten published studies met the inclusion criterion, including three randomized, dou-ble-blind, placebo-controlled clinical trials and two open-label trials, encompassing ap-proximately 440 human subjects. One manuscript in preparation and one unpublished preclinical gut-brain axis dataset were included with appropriate caveats. We integrated transcriptomic, electrophysiological, in vitro, in vivo, and clinical evidence into a pro-posed mechanistic model. Results: The converging evidence supports a three-tier temporal model of adaptogenic ac-tion. The acute tier (minutes to hours) involves modulation of NMDA and Kainate gluta-mate receptors, enhancing hippocampal long-term potentiation. The subacute tier (days to weeks) involves activation of CREB signaling and the slit-robo axonal guidance pathway, producing structural neuroplasticity functionally equivalent to brain-derived neu-rotrophic factor stimulation. The chronic tier (weeks to months), based on in vitro evidence in non-neuronal models, involves DNMT inhibition and epigenetic reprogramming, sug-gesting a potential mechanism for durable changes in cellular stress resilience. Tran-scriptomic analysis identified 1,061 genes uniquely modulated by the whole extract and not by isolated ginsenosides, consistent with the hypothesis that the adaptogenic effect is an emergent property of the phytochemical network. Preliminary preclinical data from a gut-brain axis model suggest that HRG80 protects intestinal barrier integrity and attenu-ates neuroinflammation, providing a plausible systemic pathway from oral intake to cen-tral effects. Conclusion: HRG80 provides convergent multilevel evidence suggesting that adaptogenic nonspecificity may reflect a hierarchically organized multi-specificity operating across distinct temporal scales. If confirmed by independent replication and further mechanistic studies, this framework could offer a template for the systematic investigation of other adaptogenic botanicals.

Abstract: Severe cutaneous adverse reactions (SCARs) are rare, life-threatening drug hypersensitivity syndromes. Although pharmacovigilance can identify drugs disproportionately reported with SCARs, it does not reveal which local chemistries recur among them. To address this, we assessed whether drugs with disproportionate SCAR reporting in the FDA Adverse Event Reporting System (FAERS) share interpretable chemical motifs. We screened FAERS data from 2004Q1 to 2024Q3, identified 5523 drugs with available Simplified Molecular-Input Line-Entry System (SMILES) representations, and constructed a signal-enriched dataset of 1676 compounds with nominally significant broad-SCAR associations after excluding predefined therapeutic/supportive confounders. Compounds were assigned to positive-signal [natural logarithm of reporting odds ratio (lnROR) > 0, n = 1219] or nonpositive-signal (lnROR ≤ 0, n = 457) classes and encoded with 9753 explicitly mappable atom-centered local substructure descriptors. A light gradient boosting machine classifier evaluated using repeated nested cross-validation (six-fold outer × 50 repeats) achieved moderate but stable internal discrimination (mean area under the receiver operating characteristic curve = 0.7041 ± 0.0337). SHapley Additive exPlanations (SHAP) analysis revealed a clear fragment-level contrast: allylamine-like, ethanolamine, and diaminopropane-related motifs were associated with higher positive-signal class probability, whereas phenol and pyrimidine motifs were associated with corresponding lower probability. The phenol fragment (Oc1ccccc1) was the most influential feature overall (mean |SHAP| = 0.1727), followed by an allylamine-like fragment (0.1031). These findings suggest that broad-SCAR concern detected in the FAERS is not chemically random within the selected dataset. Overall, the proposed framework should be viewed not as a direct predictor of absolute clinical SCAR risk but as an interpretable structure-guided safety-screening approach to prioritize compounds and motif families for further SCAR-focused evaluation.

Abstract: Background: Oral administration remains the preferred delivery route for supplements and bioactive compounds, yet the mucosal barrier restricts systemic exposure of most therapeutic agents to a small fraction of the administered dose. Enzymatic degradation, pH-dependent instability, and limited paracellular transport collectively constrain bioavailability, particularly for hydrophilic nutrients, peptides, and mineral ions. Framework: This paper proposes a three-mechanism framework to explain how a class of surface-active mineral oxide delivery systems may enhance mucosal absorption through established biological pathways. The framework is grounded entirely in peer-reviewed physiology and pharmacology independent of any proprietary formulation data. Mechanisms: The three proposed mechanisms are: (1) a low-dose, transient reactive oxygen species (ROS) pulse that reversibly modulates tight junction proteins, expanding paracellular permeability within a well-characterized physiological range; (2) surface-mediated delivery of mineral oxide species directly to mucosal epithelial cells, bypassing the portal circulation route that limits conventional oral mineral delivery; and (3) activation of the NRF2-KEAP1-ARE pathway in mucosal cells, upregulating endogenous antioxidant defenses through hormetic adaptation. These mechanisms are supported by the established biology of hormesis, tight junction physiology, mineral pharmacology, and redox signaling. Comparison to Existing Approaches: Liposomal encapsulation protects cargo from gastric degradation but achieves typical oral bioavailability of 1 to 15 percent for peptide cargo and faces instability challenges in the gastrointestinal environment. The mineral oxide delivery approach described here modifies the absorption environment itself rather than encapsulating cargo, representing a mechanistically distinct and potentially complementary strategy. Conclusion: This framework offers a biologically plausible, citation-supported basis for enhanced oral and sublingual delivery of nutrients and peptide compounds. Controlled clinical pharmacokinetic studies are needed to confirm these mechanisms and quantify the magnitude of bioavailability enhancement in human subjects.

Abstract: Background/Objectives: Drug supply disruptions represent an increasingly serious problem for health systems worldwide, with systemic antibiotics among the most frequently affected therapeutic categories. Although regulatory authorities have repeatedly signaled this risk, comparative studies analyzing patterns of antibiotic shortages across multiple countries simultaneously remain scarce. Methods: We performed a cross-sectional comparative analysis based on data from public national shortage registries in seven jurisdictions: Belgium, France, Germany, Romania, Spain, the United States (FDA), and the Kingdom of Saudi Arabia. All records corresponding to systemic antibiotics in ATC group J01 were extracted, harmonized, and analyzed, with the active substance (INN) as the unit of analysis. The association between critical drug status according to the EMA list and the multinational recurrence of shortages was assessed using chi-square tests, the Mann–Whitney U test, and multivariate logistic regression. To verify the robustness of the results, a sensitivity analysis was also performed using alternative thresholds for jurisdictions. Results: A total of 350 shortage records were mapped, corresponding to 64 unique active pharmaceutical ingredients. On average, each active substance was reported as out of stock in 3.48 jurisdictions (SD = 1.46). Macrolides (J01F) and quinolones (J01M) exhibited the widest geographic spread of shortages. Antibiotics included on the EMA’s list of critical medicines were reported as missing in multiple countries simultaneously significantly more frequently than those not included on this list (82.86% vs. 37.14%; χ² = 71.99, p < 0.001; Cramer’s V = 0.454). In the multivariate logistic regression model, EMA critical medicine status remained an independent predictor of multinational recurrence of shortages (OR = 8.29; 95% CI: 4.93–13.94; p < 0.001), while the injectable route of administration did not reach the threshold for statistical significance (OR = 0.78; p = 0.341). Sensitivity analysis confirmed that this association remains statistically significant regardless of the threshold chosen. Conclusions: Shortages of systemic antibiotics tend to occur simultaneously in multiple countries, and drugs designated as critical by the EMA are disproportionately affected. The results suggest that the identified weaknesses are not specific to a single health system but reflect structural fragilities in international antibiotic supply chains. This underscores the need for internationally coordinated strategies, both for monitoring the availability of essential antibiotics and for preventing and managing shortages.

Abstract:

Shinorine, a naturally occurring UV-absorbing compound belonging to the class of mycosporine-like amino acids (MAAs), has attracted considerable attention for its applications in pharmaceuticals, cosmetics, and biomaterials. However, conventional production methods based on extraction from marine organisms are constrained by low yield, limited availability, and environmental sustainability concerns. In this study, we developed a microbial cell factory for the efficient biosynthesis of shinorine in Escherichia coli. Specifically, the transaldolase gene in the pentose phosphate pathway (PPP) was precisely disrupted to block the metabolic conversion of sedoheptulose-7-phosphate (S7P), thereby enhancing its intracellular accumulation. In parallel, a cyanobacterial shinorine biosynthetic gene cluster (Ava_3858–Ava_3855) was heterologously expressed in the engineered strain, enabling the reconstruction of a functional biosynthetic pathway utilizing S7P as a key precursor. This integrated metabolic engineering strategy effectively overcomes the limitations of traditional extraction methods and significantly improves shinorine production. Moreover, the approach provides a versatile framework for the microbial synthesis of other high-value natural products, with broad implications for sustainable biomanufacturing.

Abstract:

Cocaine use disorder (CUD) remains a significant global health issue, with no FDA-approved pharmacological treatments. Cannabidiol (CBD), a non-psychoactive phytocannabinoid primarily derived from Cannabis sativa L., has demonstrated promising results in preclinical research to disrupt the consolidation and retrieval of drug-associated memories, thereby reducing relapse behaviors linked to substance use disorders such as cocaine dependence. This study evaluates the effects of a non-psychoactive cannabis extract (NPCE) on the reinstatement and reconsolidation of cocaine-induced conditioned place preference (CPP) in CD1 male mice—processes that, to our knowledge, have not been previously examined. The results showed that NPCE significantly inhibited both priming -induced and stress-induced reinstatement of cocaine-induced CPP, suggesting its potential to disrupt drug-associated memories. Additionally, NPCE effectively impaired the reconsolidation of cocaine-induced CPP, suggesting an effect on memory reconfiguration lasting at least two weeks. Additionally, NPCE alone did not produce any effect on CPP acquisition. These findings underscore the potential of NPCE, in targeting memory-related mechanisms underlying cocaine addiction, specifically in the reconsolidation and reinstatement. These results indicated that NPCE may reduce relapse risk by modulating drug-reward memories, potentially through interactions with CB1 receptors and other molecular signaling pathways like serotonergic receptors. This research contributes to the growing body of evidence, which suggests that cannabinoids, particularly non-psychoactive extracts, could offer novel therapeutic options for treating CUD. Further studies are needed to explore the individual effects of other cannabinoids on cocaine dependence and to assess clinical applicability of these findings.

Abstract: Background/Objectives: Astragalus root, a traditional Chinese herbal remedy, has shown potential benefits against diabetic nephropathy (DN). However, the mechanisms driving its effects remain poorly understood. This study explored the molecular pathways through which Astragalus root improves DN. Methods: To identify possible targets and mechanisms of Astragalus root in DN treatment, we applied network pharmacology, molecular docking, molecular dynamics simulation, and in vitro assays. Results: Network pharmacology screening uncovered 46 overlapping targets between Astragalus root and DN. Protein-protein interaction (PPI) network analysis identified five core candidate targets: CASP3, VEGFA, CTNNB1, MYC, and PRKCB. KEGG pathway analysis indicated that the AGE-RAGE signaling pathway was the most significantly enriched. Molecular docking revealed that quercetin, β-carotene, daidzein, capsaicin, and kaempferol—major bioactive components of Astragalus root—bound strongly to each of the five core targets. Molecular dynamics simulations further confirmed the conformational stability of kaempferol when complexed with these target proteins. In vitro experiments showed that kaempferol markedly reduced protein levels of α-SMA, Col I, and Col IV; lowered secretion of TNF-α, IL-6, and IL-1β; and decreased ROS and MDA content. Additionally, kaempferol's therapeutic effects were mediated through suppression of the AGE-RAGE-PKC-TGF-β signaling axis. Conclusions: This work identified kaempferol, a bioactive ingredient of Astragalus root, as a potential therapeutic agent against DN, along with its target pathways. These findings provide a scientific foundation for its clinical translation.

Abstract: Transthyretin amyloidosis (ATTR) is a progressive disease caused by the dissociation of the transthyretin (TTR) tetramer, leading to amyloid fibril formation. Although pharmacological stabilizers have been developed, preventive strategies for wild-type ATTR (ATTRwt) have not been established. This study developed a computational model to predict TTR binding activity from chemical structure and to apply the model to screen food-derived compounds as potential preventive candidates. A machine learning model was constructed using TTR-8-anilino-1-naphthalenesulfonic acid displacement assay data from the Tox24 Challenge. The model achieved root mean square error and R² values of 21.34 and 0.64, respectively, on an external test dataset. Using an integrated dataset compiled from multiple literature sources, the predicted TTR binding activity exhibited a significant positive correlation with amyloid fibril formation inhibition (Spearman’s ρ = 0.602, p < 0.001). The model was then applied to the PhytoHub database, identifying 63 candidate compounds with high predicted binding activity, predominantly polyphenols, found in 126 food sources. These results suggest that the proposed in silico method is useful for identifying potential TTR stabilizers from food-derived compounds and may contribute to the exploration of effective preventive strategies for ATTRwt.

Abstract: Aging is associated with chronic, low-grade inflammation (“inflammaging”), which contributes to neuropsychiatric and neurodegenerative disorders such as depression, Alzheimer’s disease, and Parkinson’s disease. Conventional pharmacotherapies often provide limited benefit in older adults and are further complicated by polypharmacy and drug-drug interactions. Psilocybin, a serotonergic psychedelic acting primarily as a 5-HT2A receptor agonist and currently undergoing accelerated clinical development, has emerged as a potential multimodal therapeutic agent addressing these challenges. Acting via its active metabolite psilocin, 5-HT2A-mediated signaling biases cortical glutamatergic transmission, enhances TrkB/BDNF pathways, and modulates neuro-immune cascades (including NF-κB), with convergent systems-level effects such as re-organization of the default mode network. Human studies report acute reductions in TNF-α with variable effects on IL-6 and CRP, consistent with an immunomodulatory profile. Pharmacokinetically, psilocybin shows properties advantageous in geriatric care: rapid onset, short half-life, and predominant phase-II glucuronidation, reducing interaction risk. Controlled studies demonstrate rapid antidepressant and anxiolytic effects in major depressive disorder, treatment-resistant depression, and existential distress, with emerging feasibility signals in neurodegeneration. Together, these find-ings support the hypothesis that a time-limited, mechanism-based intervention may improve mood and cognition while attenuating inflammation. This review integrates current evidence on psilocybin’s neuroimmune and pharmacokinetic mechanisms rel-evant to aging, outlining its potential role in inflammation-related disorders and high-lighting the need for targeted studies in older adults, who remain underrepresented in psychedelic research.

Abstract: The interplay between the environmental exposome and the cancer genome remains a critical "blind spot" in precision oncology. While somatic mutational signatures genomic fossils imprinted by exposures such as ultraviolet radiation, tobacco smoke, and industrial pollutants are well characterized for their etiological significance, their functional impact on therapeutic efficacy remains largely unexplored. We hypothesized that these environmental "genomic scars" induce distinct pharmacogenomic vulnerabilities (collateral sensitivity) and resistance mechanisms (collateral resistance) that vary by geographical exposure patterns. Here, we present the first global "Geo-Pharmacogenomic" atlas, integrating 41 COSMIC mutational signatures with drug response profiles from 1,001 cancer cell lines across four large-scale pharmacogenomic screens (GDSC1, GDSC2, CTRP, CCLE). By harmonizing disparate drug sensitivity metrics and applying rigorous statistical controls for tissue lineage, we identified and validated 608 significant signature-drug interactions (P < 0.01). We demonstrate that UV-associated signature SBS7a is a broad-spectrum driver of therapeutic resistance, conferring intrinsic insensitivity to BRAF inhibitors (PLX-4720, P < 10^-4) and Notch inhibitors globally. Conversely, we uncover a novel synthetic lethal vulnerability wherein pollution-driven oxidative stress (SBS18) sensitizes tumors to p38 MAPK inhibition (VX-702, r = -0.45, P < 10^-9). Synthesizing these findings with satellite-derived atmospheric data (World Bank/NASA AOD), we constructed a Kriging-interpolated risk surface spanning 122 nations. This analysis predicts distinct "Resistance Landscapes with high-intensity drug resistance predicted in pollution-dense megacities (e.g., Beijing, New Delhi) challenging the paradigm of uniform drug efficacy. Our results establish environmental history as a functional biomarker, necessitating a paradigm shift towards geographically stratified precision medicine.

Abstract: Selected organic sunscreens from different chemical families were investigated in the context of their ability to inhibit butyrylcholinesterase using novel Multiple Linear Regression, Artificial Neural Network and Support Vector Regression models based on a set of six independent variables commonly associated with compounds’ absorption and distribution properties. It was established that the descriptors that have a particularly strong, positive influence on the ability of compounds to inhibit BChE expressed as pIC₅₀ are the count of rotatable bonds (nRot) and lipophilicity (log D); pIC₅₀ is negatively correlated with flexibility (Flex), fraction of sp3 carbon atoms (F_sp3), caco-2 permeability (caco2) and plasma protein binding ability (PPB). The sunscreens that are likely to be particularly strong BChE inhibitors are Ethylhexyl Triazone (ET), Diethylhexyl Butamido Triazone (DOBT), Octocrylene (OCR) and Diethylamino Hydroxybenzoyl Hexyl Benzoate (DHHB), although in must be stressed that ET and DOBT are outside the chemical space of the reference compounds.

Abstract: The application of computational technologies in veterinary biochemistry and toxicology is revolutionizing translational science and making it more compatible with the One Health approach. With the distinction between animal, human, and environmental health diminishing in importance, technologies like molecular modelling, systems toxicology, vetinformatics, and artificial intelligence (AI) help in making integrated and predictive decisions. This brief review aims to highlight advancements in computational veterinary biochemistry and toxicology with special emphasis on its importance for One Health, food safety, and antimicrobial resistance (AMR). Advances in predictive toxicology, multi-omics, and AI offer new and innovative solutions for the early detection of biochemical disorders, simulation of toxicant exposure, and prediction of AMR in different species. These advancements highlight the importance of making connections between laboratory science and policy-making for animal health with the help of a multidisciplinary computational approach for global food security and AMR in a data-driven world.

Abstract: Dimethyl fumarate (DMF), a fumaric acid ester, is approved for psoriasis and multiple sclerosis due to its antioxidant and anti-inflammatory properties mediated via Nrf2 activation. Nrf2 regulates genes that protect cells from oxidative stress, a key factor in neurodegenerative diseases such as Alzheimer's disease (AD), which is characterized by amyloid-β and tau accumulation and lipid peroxidation. This systematic review aimed to evaluate preclinical evidence for DMF as a potential therapeutic agent in AD models through Nrf2 activation. A comprehensive literature search identified in vitro, in vivo, and combined preclinical studies assessing DMF in AD models. Studies were screened using predefined inclusion and exclusion criteria, with quality assessment and flow chart analysis applied. Eighteen studies were ultimately included in the analysis. Results consistently demonstrated that DMF activates the Nrf2 pathway, enhancing antioxidant and anti-inflammatory gene expression. DMF treatment reduced amyloid-β and tau protein levels, mitigated oxidative stress, and improved cognitive performance in animal models. In conclusion, preclinical evidence suggests DMF is a promising candidate for AD treatment by targeting oxidative stress and neuroinflammation via Nrf2 activation. Further preclinical studies, particularly on ferroptosis mechanisms, as well as well-designed clinical studies are warranted to clarify its full therapeutic potential.