Search Results (9,260)

Obesity is among the top contributing factors for non-communicable chronic disease development and has attained menacing global proportions, affecting approximately one of eight adults. Phytochemicals that support energy metabolism and prevent obesity development have been the subject of intense research endeavors over the past several decades. Cycloastragenol is a natural triterpenoid compound and aglycon of astragaloside IV, known for activating telomerase and mitigating cellular aging. Here, we aim to characterize the effect of cycloastragenol on lipid metabolism in a glucose-induced obesity model in Caenorhabditis elegans. We assessed the changes in the body length, width, and area in C. elegans maintained under elevated glucose through automated WormLab system. Lipid accumulation in the presence of either cycloastragenol (100 μM) or orlistat (12 μM), used as a positive anti-obesity control drug, was quantified through Nile Red fluorescent staining. Furthermore, we evaluated the changes in key energy metabolism molecular players in GFP-reporter transgenic strains. Our results revealed that cycloastragenol treatment decreased mean body area and reduced lipid accumulation in the C. elegans glucose-induced model. The mechanistic data indicated that cycloastragenol suppresses the nuclear hormone receptor family member NHR-49 and the delta(9)-fatty-acid desaturase 7 (FAT-7) enzyme, and activates the 5′-AMP-activated protein kinase catalytic subunit alpha-2 (AAK-2) and the protein skinhead 1 (SKN-1) signaling. Collectively, our findings highlight that cycloastragenol reprograms lipid metabolism by down-regulating the insulin-like receptor (daf-2)/phosphatidylinositol 3-kinase (age-1)/NHR-49 signaling while simultaneously enhancing the activity of the AAK-2/NAD-dependent protein deacetylase (SIR-2.1) pathway. The anti-obesogenic potential of cycloastragenol rationalizes further validation in the context of metabolic diseases and obesity management. Full article

National Tuberculosis Reference Laboratories (NTRLs) are central to tuberculosis (TB) control programs. Between 2018 and 2024, the Republic of Congo, a country of 6 million inhabitants, achieved a transformative strengthening of its TB diagnostic system, coordinated by the NTRL. Strategic investments, supported mainly by international partners, enabled a substantial decentralization of services, expanding the diagnostic network from 38 to 113 diagnostic and testing centers and increasing GeneXpert sites from 3 to 31. The expansion of the diagnostic network and specimen referral system was associated with a reduced structural gap in diagnostic coverage by extending access to GeneXpert testing to a larger number of peripheral and previously underserved centers. Critically, the establishment of a BSL-3 laboratory and the deployment of advanced assays like Xpert MTB/XDR ended the reliance on overseas testing by introducing in-country capacity for multidrug-resistant and pre-extensively drug-resistant TB detection. These systemic improvements were associated with significant positive outcomes, including an annual molecular testing surging from 11,609 in 2022 to over 27,000 in 2024 and bacteriological confirmation rates rising from 34 to 73%. This comprehensive laboratory systems strengthening, which also facilitated cross-programmatic initiatives like HIV and Mpox testing integration, underscores how sustained investment in infrastructure, logistics, and quality management is fundamental to improving case detection, surveillance, and progress toward the WHO End TB Strategy milestones. Full article

Purpose: The reversible deviant in epigenomic modulations is the highlight of developing new anti-cancer drugs, necessitating the use of fisetin as an epigenetic modifier in the study. Methods: In silico and molecular studies were performed to analyze the modulatory effect of fisetin on various writers and erasers. Further, whole genome DNA methylation sequencing and expression studies were performed. Global DNA methylation-LINE 1 kit was used to check global DNA methylation. Additionally, the effect of fisetin on migration was evaluated by colony, scratch, and invasion assays and qPCR and protein expression studies of migration-related genes were carried out on HeLa cells. Results: In silico studies have supported that fisetin interacts with writers and erasers in their catalytic site and the simulation studies showed minimum fluctuations in energy and temperature over a 10 ns timescale indicating that these complexes are likely to remain stable. Fisetin (20–50 µM) dose-dependently inhibited DNA methyltransferases (DNMT), histone deacetyl transferases (HDAC), histone acetyl transferases (HAT), and histone methyltransferases (HMT) activities at 48 h, with inhibition ranging from 24 to 72% compared to the control. The expression and enzymatic activity of these proteins, along with various H4 and H3 modification marks, were observed to be altered following fisetin treatment at 48 h. Fisetin treatment reduced promoter methylation in various tumor suppressor genes ranging from 15.29% to 76.23% and leading to the corresponding reactivation of important tumor suppressor genes; however, it did not lead to any alteration in the global DNA methylation compared to untreated controls linked with the anti-migratory properties of fisetin as the percentage of migrated cells dropped from ~40% to ~8%. Conclusions: This study gives a mechanistic insight of fisetin as a potential epigenetic modifier in HeLa cells. Full article

Despite growing interest in South African medicinal plants, advanced metabolomic workflows that integrate positive (ESI+) and negative (ESI−) ionization modes in UPLC-MS/MS remain sparsely applied to South African flora, and especially to Acorus calamus and Lippia javanica species. Herein, application of a dual-polarity (positive (ESI+) and negative (ESI−) ionization modes) using an untargeted UPLC–MS/MS workflow, integrated with HEK293T cytotoxicity screening, to map their metabolomes, and rank potential signature metabolites for targeted antiviral follow-up. SwissADME supported in silico drug-likeness. Neither plant extract was cytotoxic across the concentration range, with absorbance-based cell viability of 73.82% for L. javanica and 77.23% for A. calamus at 250 µg/mL, and fluorescence-based cell viability ≥59.87% and ≥55.89%, respectively. Dual-polarity expanded coverage with ESI− yielded 312 features, compared with 225 with ESI+, consistent with the predominance of acidic phenolics in plant species. Unsupervised and supervised models segregated the plant species (PCA PC1/PC2 variance: ESI+ 89.4%/3.0%; ESI− 93.5%/1.8%; R²X(cum) = 0.799). Differential analysis identified 118 significant features in ESI+ with 80 up-regulated, 38 down-regulated, and 139 in ESI− with 96 up-regulated, 43 down-regulated. The ESI− showed the wider dynamic range. Chemotypes enriched among significant metabolites include flavonols of 3-O-methylkaempferol, apigenin, and conjugates of Pollenin A, iridoid glycosides of oleoside, forsythoside B, and jasmonate-pathway oxylipins of 7-epi-12-hydroxyjasmonic acid and its glucoside. These also include caryoptosidic acid and catechin-7-glucoside, which are ionized in both modes, pinning the increase in biomarker robustness. In conclusion, a dual-mode UPLC–MS/MS approach, integrated with cytotoxicity exploration, delivers a complementary metabolome coverage and a safety awareness for shortlisting of potential signature metabolites from L. javanica and A. calamus. Moreover, in vitro inhibition of SARS-CoV-2 papain-like protease (PL^pro) by these plants links chemical signatures to antiviral relevance. Shortlisted significant metabolites that demonstrated favorable drug-likeness include flavonol scaffolds of 3-O-methylkaempferol, Pollenin A, and jasmonate-pathway derivatives of 7-epi-12-hydroxyjasmonic acid. Moreover, the dual ionization mode may eliminate ionization bias, broaden metabolome coverage, and yield a mechanism-ready shortlist of metabolites from South African medicinal plants for downstream antiviral investigation. Full article

Ovarian cancer (OC), the third most common gynecologic malignancy, is characterized by high mortality largely driven by chemotherapy resistance, leading to recurrence and metastasis. Using transcriptomic data from GSE73935, we constructed a weighted gene co-expression network and identified eight hub genes (IGF1R, CDH2, PDGFRA, CDKN1A, SHC1, SPP1, CAV1 and FGF18) associated with cisplatin resistance, among which CDH2 emerged as the most clinically relevant candidate. CDH2 demonstrated moderate diagnostic potential (AUC = 0.792) and was markedly upregulated in cisplatin-resistant A2780/CP70 cells. Independent validation using clinical single-cell RNA-seq data (GSE211956) confirmed its selective enrichment in resistant tumor cell subpopulations. Gene set enrichment analysis linked elevated CDH2 expression to p53 signaling, DNA replication, nucleotide excision repair, and Toll-like receptor pathways, with qPCR supporting upregulation of key downstream genes in resistant cells. Immune deconvolution further indicated that high CDH2 expression correlated with increased infiltration of NK cells, Tregs, macrophages, and neutrophils, and immunohistochemistry verified CDH2 overexpression in cisplatin-resistant tissues. In addition, virtual screening and drug sensitivity profiling identified several FDA-approved agents with potential relevance to CDH2-associated drug response. These findings indicate that CDH2 may serve as a candidate marker associated with cisplatin response in OC, and its association with immune cell infiltration provides further insight into mechanisms potentially underlying chemoresistance. Full article

Background: Personal protective measures help prevent infection and disease transmission during health crises such as Coronavirus disease 2019 (COVID-19). Populations facing barriers to adhering to these measures are more vulnerable to the health crisis. This study investigated the association of social drivers of health (SDoH), self-efficacy, and adverse substance use behavior changes with ability to practice COVID-19 personal protective behaviors among persons who inject drugs (PWID) with hepatitis C virus (HCV) infection history. Methods: This study used the Hepatitis C Real Options (HERO) study’s COVID-19 survey data (n = 157). The association of inability to practice COVID-19 personal protective behaviors (hand washing, social distancing, etc.) with (a) SDoH difficulties (employment, housing, etc.); (b) adverse substance use behavior change (overdose, injecting behavior, etc.); and (c) self-efficacy was tested using logistic regression. Results: Inability to practice any personal protective behaviors was more likely among those experiencing any vs. no SDoH difficulties [adjusted odds ratio (aOR) (95% confidence interval (CI))] = 4.57 (1.57, 16.40); p = 0.003] but less likely for those with higher overall self-efficacy [aOR (95% CI) = 0.55 (0.32, 0.93); p = 0.025] and self-efficacy for setting goals [aOR (95% CI) = 0.63 (0.40, 0.96); p = 0.031]. The association between adverse substance use behavior changes and the outcome was not significant. Conclusions: Greater SDoH difficulties and lower self-efficacy were associated with greater inability to practice COVID-19 personal protective behaviors. Interventions to meet SDoH-related challenges and increase self-efficacy could help encourage practice of personal protective behaviors and economically reduce disease burden during health crises. Full article

Upon RNA virus infection, viral RNA is sensed by the RIG-I-like receptors (RLRs), which signal through the adaptor protein VISA/MAVS to induce an innate antiviral response. How the VISA-mediated innate antiviral response is regulated and whether it can be targeted for drug development against diseases caused by RNA virus infection needs to be further investigated. Here we report that physalin F, a natural secosteroid isolated from Physalis angulata L., inhibits innate immune response to RNA virus. Mechanistically, physalin F binds to and promotes the activation of the mitochondrial m-AAA protease AFG3L2, which subsequently mediates the degradation of VISA. Knockdown of AFG3L2 promotes RLR-mediated innate antiviral signaling, whereas physalin F inhibits innate immune response to RNA virus both in cells and mice. Our study discovers physalin F as an inhibitor of VISA-mediated innate antiviral response as well as a candidate compound for the treatment of related diseases. More importantly, our findings suggest that AFG3L2 constitutively mediates degradation of VISA under physiological conditions, which represents a novel negative regulatory mechanism of RLR-mediated innate antiviral response. Full article

Immunotherapy has become a promising treatment for gastric cancer. However, its effectiveness varies significantly across subtypes because of heterogeneous immune microenvironments and genomic alterations. Here, we established Immune&Driver molecular subtypes CS1 and CS2 by systematically integrating multi-omics data for immune-related and driver genes. CS1 was linked to a better prognosis, while CS2 represented a poorer prognostic phenotype. CS1 displayed enhanced genomic instability, marked by higher mutation frequency and chromosomal alterations. In contrast, CS2 exhibited higher immune activity, with a higher density of immune cell infiltration and increased expression of chemokines and immune checkpoint genes. Among FDA-approved anti-cancer agents included in a pan-cancer drug sensitivity prediction framework, CS1 was predicted to be more sensitive to conventional chemotherapeutic agents, whereas CS2 was predicted to be more responsive to immune-related agents. In melanoma datasets, a CS2-like transcriptomic pattern was associated with improved response to anti-PD-1 therapy, with the combination of anti-PD-1 and anti-CTLA-4 showing more favorable response patterns compared to anti-PD-1 monotherapy. Additionally, we developed an immunotherapy response prediction model using PCA-based logistic regression according to the transcriptional expression of CS biomarkers. The model was trained in melanoma immunotherapy cohorts and validated across independent melanoma datasets, and it further achieved a higher AUC in an external gastric cancer cohort treated with anti-PD-1 therapy. Collectively, this study highlights immune and genomic heterogeneity in gastric cancer and provides a hypothesis-generating framework for exploring immunotherapy response. Full article

Introduction: Chagas disease, caused by the protozoan Trypanosoma cruzi, remains a major public health concern due to the limited effectiveness of current treatments, especially in the chronic stage. Objective: Here, we wanted to advance a library of 30 N,N′-disubstituted diamines as promising antichagasic agents and gain insight into the mechanism of action. Methods: The library was evaluated for activity against the T. cruzi amastigote stage and trypanocidal efficacy. In addition, selected compounds were tested as potential polyamine transport inhibitors, and a fluorescent analog was employed to investigate compound internalization. Results: Five compounds exhibited potent activity (pIC₅₀ > 6.0), particularly those with short aliphatic linkers (3–6 carbon atoms), suggesting a structure–activity relationship favouring shorter chains. Mechanistic studies showed that compound 3c strongly inhibited polyamine transport, a vital pathway in T. cruzi, though this was not a universal mechanism among active hits, indicating the potential for multiple targets. A fluorescent analog confirmed intracellular uptake in amastigotes but lacked antiparasitic activity, likely due to disrupted pharmacophoric features. Importantly, none of the compounds demonstrated trypanocidal activity in long-term assays, and some showed cytotoxicity, particularly in the benzyloxy-substituted series. Conclusions: These findings position N,N′-disubstituted diamines as a viable scaffold for Chagas disease drug discovery. However, further optimization is required to enhance selectivity, achieve trypanocidal effects, and better understand the underlying mechanisms of action. Full article

Background: Metabolically associated fatty liver disease (MASLD) constitutes a major burden. Glucagon-like peptide-1 agonists (GLP-1) could improve hepatic steatosis as well as weight loss. However, the effect of GLP-1 agonists on patients with and without diabetes and the effect of newer drugs (dual and triple agonists) are unclear. Objective: To investigate the effect of GLP-1 agonists, including dual and triple agonists, in patients with metabolic-associated liver steatosis and steatohepatitis, while exploring their effect on patients with and without type 2 diabetes. Methods: We searched PubMed, Scopus, and Web of Science in October 2025 for randomized parallel controlled trials that investigated the effect of GLP-1 agonists in patients with MASLD or metabolic-associated steatohepatitis (MASH). We assessed the quality of the included studies using Cochrane ROB2. We performed the analysis using RevMan 5.4. We performed subgroup analysis based on the status of diabetes, the control group, and the class of GLP-1 agonist (single, dual, or triple). Results: We included twenty studies. Compared to the control group, GLP-1 agonists were associated with a statistically significant increase in the resolution of MASH without worsening fibrosis (RR 3.03, p < 0.0001) and at least one stage of liver fibrosis without the worsening of MASH compared to the control group (RR: 1.45, p < 0.00001). GLP-1 agonists were associated with a statistically significant weight reduction (SMD −1.11, p < 0.0001), glycosylated hemoglobin (SMD −0.81, p < 0.00001), levels of aspartate aminotransferase (SMD −0.48, p = 0.008), and alanine aminotransferase (SMD −0.54, p = 0.008). However, in patients without type 2 diabetes, GLP-1 agonists had no significant effect on weight loss (SMD −0.97, p = 0.12) or improvement in fibrosis (RR 1.54, p = 0.24). There was a statistically significant increase in the overall adverse events (RR 1.10, p < 0.00001), while there was no significant difference in serious adverse events (p = 0.35). Conclusions: GLP-1 agonists improved liver fibrosis, steatohepatitis, weight loss, HbA1c, and liver enzymes in patients with MASLD or MASH. Overall, GLP-1 agonists were associated with a significantly higher risk of adverse events compared to the control, while serious adverse events were comparable between both groups. There was no significant effect on weight loss or improvement in fibrosis in patients without type 2 diabetes. However, there was a limited number of studies in this population. Thus, further research is needed before recommendations can be made for this subgroup. Full article

Introduction: Overweight and obesity are becoming increasingly prevalent. Incretin-based obesity treatments—glucagon-like peptide-1 receptor agonists (GLP-1 RAs) and dual glucagon-like peptide-1 receptor/glucose-dependent insulinotropic polypeptide receptor agonists (GIP/GLP-1 RAs or dual agonists)—are a major stride in the evolution of obesity management. However, like weight loss with other means, they are associated with an inadvertent significant loss of lean body mass, including muscle. This has led to a resurgence in research for the preservation of lean body mass, the loss of which occurs with weight loss. The purpose of this narrative review is to discuss the mechanisms involved with lean body loss and capture the research landscape of the different classes of pharmacological agents being developed to address this problem. Methodology: We queried PubMed, Medline, and Scopus for randomized controlled trials and phase II or phase III trials using key words to capture the breath of this topic—obesity, weight loss, muscle loss, lean mass, and muscle preservation. Animal studies were excluded. We analyzed the studies conducted to date. Results: Weight loss, regardless of the method used to achieve it, is inadvertently accompanied by lean body mass loss, to varying degrees. There are several mechanisms that govern the loss of lean body mass and, more specifically, the loss of muscle mass; as such, several classes of medications have been explored, targeting different pathways and receptors—including bimagrumab (activin receptor agonist), tesamorelin (growth hormone releasing hormone agonists), and enobosarm (selective androgen receptor modulator). Most of these drugs are in the early phases of research development, but some show great promise. Conclusion: This narrative review attempts to detail the physiology of muscle mass loss when accompanied by weight loss and identify pharmacological targets that can be utilized to minimize it with mechanisms, effects, side effects, and research developmental progress. Full article

Breast cancer is a significant public health concern, with triple-negative breast cancer (TNBC) being the most aggressive subtype characterized by considerable heterogeneity and the absence of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) expression. Currently, there are no practical alternatives to chemotherapy, which is associated with a poor prognosis. Therefore, developing new treatments for TNBC is an urgent need. Reactive oxygen species (ROS) and redox adaptation play central roles in TNBC biology. Targeting the redox state has emerged as a promising therapeutic approach, as it is vital to the survival of tumors, including TNBC. Although TNBC does not produce high levels of ROS compared to ER- or PR-positive breast cancers, it relies on mitochondria and oxidative phosphorylation (OXPHOS) to sustain ROS production and create an environment conducive to tumor progression. As a result, novel treatments that can modulate redox balance and target organelles essential for redox homeostasis, such as mitochondria, could be promising for TNBC—an area not yet reviewed in the current scientific literature, thus representing a critical gap. This review addresses that gap by synthesizing current evidence on TNBC biology and its connections to redox state and mitochondrial metabolism, with a focus on innovative strategies such as metal-based compounds (e.g., copper, gold), redox nanoparticles that facilitate anticancer drug delivery, mitochondrial-targeted therapies, and immunomodulatory peptides like GK-1. By integrating mechanistic insights into the redox state with emerging therapeutic approaches, I aim to highlight new redox-centered opportunities to improve TNBC treatments. Moreover, this review uniquely integrates mitochondrial metabolism, redox imbalance, and emerging regulated cell-death pathways, including ferroptosis, cuproptosis, and disulfidptosis, within the context of TNBC metabolic heterogeneity, highlighting translational vulnerabilities and subtype-specific therapeutic opportunities. Full article

Disease-specific diversity in RNA transcripts stems from RNA splicing, ribosomal abnormalities, and other factors. However, the mechanisms underlying the regulation of rRNA expression in the nucleolus and mRNA expression in the cytoplasm during cancer and neuronal differentiation remain largely unknown. In this article, we review current knowledge and discuss the regulatory mechanisms of rRNA and mRNA expression in human diseases using the splicing model of PUF60 (poly(U) binding splicing factor 60)—also known as FUSE-binding protein-interacting repressor (FIR) (FUBP1-interacting repressor), RoBPI, SIAHBP1, and VRJS (Gene ID: 22827). Noncoding RNAs, much like coding RNAs, have been found to be translated into proteins with significant physiological functions. Splicing is also involved in dominant ORF RNAs implicated in the expression of both noncoding and coding RNAs. Here, we analyze recent findings regarding gene splicing, ribosome formation, and the determination of selected ORFs (dominant ORFs) in a system modeled on FIR splicing in two databases (RefSeq and ENSEMBL). rRNA transcription affects ribosomes, whereas mRNA expression and splicing affect the intracellular proteome. Our objective is to develop efficient methods for identifying biomarkers for disease diagnosis and therapeutic targets. In the field of cancer treatment, therapeutic drugs targeting intracellular signaling have proven effective. Full article

Background: Melanin protects skin and hair from the effects of ultraviolet (UV) radiation damage, which contributes to all forms of skin cancer, including melanoma. Human melanocytes produce two main types of melanin: eumelanin provides effective photoprotection, and pheomelanin offers less protection against UV-induced skin damage. The agouti signaling protein (ASIP) antagonizes the melanocortin-1 receptor (MC1R), hinders melanocyte signaling, and shifts pigmentation toward pheomelanin, promoting UV vulnerability. In this study, we aim to discover compounds that inhibit ASIP–MC1R interaction and effectively preserve eumelanogenic signaling. Methods: The ASIP–MC1R interface-based pharmacophore model from ASIP is implicated in MC1R receptor protein engagement. We performed virtual screening with a validated pharmacophore model for ~4000 compounds curated from ZINCPharmer and applied drug-likeness filters, viz. ADMET and toxicity profiling tests. Further, the screened candidates were targeted for docking to the ASIP C-terminal domain corresponding to the MC1R-binding moiety. Top compounds underwent a 100-nanosecond (ns) run of molecular dynamics (MD) simulations to assess complex stability and persistence of key contacted residues. Results: Sequential triage, including pharmacophore, ADME–toxicity (ADMET), and docking/ΔG, yielded a focused group of candidates against ASIP antagonists with a favorable fit value. The MD run for 100 ns supported pose stability at the targeted pocket. Based on these predictions and analyses, compound ZINC14539068 was screened as a new potent inhibitor of ASIP to preserve α-MSH-mediated signaling of MC1R. Conclusions: Our in silico pipeline identifies ZINC14539068 as a potent inhibitor of ASIP at its C-terminal interface. This compound is predicted to disrupt ASIP–MC1R binding, thereby maintaining eumelanin-biased signaling. These findings motivate experimental validation in melanocytic models and in vivo studies to confirm pathway modulation and anti-melanoma potential. Full article

The overprescription of gastroprotectants, in particular acid suppressants in dogs, is of increasing concern in veterinary medicine. There have been specific guidelines published to document the appropriate use of this class of drugs; however, the injudicious use of gastroprotectants continues to be a concern and is often not evidence-based. The primary objective of the present study was to evaluate the veterinary prescription of gastroprotectants for dogs in Spain. A survey employing a snowball recruitment effect was distributed among small animal medicine veterinarians practicing in Spain. A total of 265 veterinarians participated in the survey. Proton pump inhibitors (PPIs) were found to be the most commonly prescribed gastroprotectant utilised by 50.6% of the participants. Veterinarians with fewer years of clinical experience and those focusing on the fields of internal medicine, emergency, and anaesthesia were more likely to adhere to evidence-based guidelines in their prescribing practices. Those who prescribed gastroprotectants less frequently tended to rely on PPIs and on international consensus guidelines. Although the main indications in which Spanish veterinarians used gastroprotectants was supported by scientific evidence, the injudicious administration of this class of drugs for disorders lacking robust scientific evidence or recommendations was well documented. Full article