Search Results (3,027)

Shuanghuanglian oral liquid (SHL) is widely used in companion animals and poultry, but its molecular mechanism in pneumonia–myocarditis comorbidity and heart–lung inflammatory crosstalk remains largely unclear. This computational study investigated the conserved AKT1/HIF1A-mediated immunoregulatory mechanism of SHL and its cross-species translational potential in veterinary medicine. Network pharmacology was integrated with GO, KEGG, and Reactome enrichment analyses, protein–protein interaction network construction, ADMET evaluation, cross-species sequence homology analysis (human, dog, cattle, and pig), molecular docking, and molecular dynamics simulation. A total of 61 active compounds, 251 putative targets, and 52 common targets associated with pneumonia and myocarditis were identified. These targets were mainly enriched in inflammation- and immune-related pathways, including TNF, IL-17, AGE–RAGE, and PPAR signaling. AKT1 and HIF1A showed high sequence conservation across species (85–98%). Key compounds exhibited favorable binding affinity to AKT1, and molecular dynamics simulation suggested the stability of the Baicalein–AKT1 complex. ADMET analysis suggested favorable pharmacokinetic properties and low predicted toxicity. These findings suggest that SHL may potentially alleviate pneumonia and myocarditis through modulation of the conserved AKT1/HIF1A axis and support its potential as a complementary therapeutic approach for managing heart–lung inflammatory diseases in multiple livestock species. This entirely computational study highlights promising mechanisms that should be further validated in vivo. Full article

Background/Objectives: Metabolic syndrome (MetS) is a pressing global health challenge comprising obesity, hyperglycemia, hypertension, and hyperlipidemia. Conventional polypharmacy often presents long-term compliance issues and side effects. Eucommia ulmoides Oliv., a traditional medicinal and edible plant rich in iridoids, lignans, flavonoids, and polysaccharides, has emerged as a promising natural intervention. This review aims to systematically summarize the bioavailability and multifaceted pharmacological mechanisms of E. ulmoides and its bioactive components in alleviating MetS. Methods: We comprehensively reviewed the recent in vitro and in vivo literature to map the functional evidence, specific signaling pathways, and gut microbiota–host interactions associated with E. ulmoides extracts and its key phytochemicals (e.g., asperuloside) against various metabolic dysfunctions. Results: Current evidence indicates that E. ulmoides operates through a “multi-component, multi-target, and multi-pathway” paradigm. For hyperlipidemia and obesity, it activates hepatic lipid metabolism (PPARα/CPT1A, FXR/CYP7A1) and mitigates oxidative stress (Nrf2/ARE). Furthermore, it dose-dependently reshapes the gut microbiota by enriching beneficial bacteria like Akkermansia and increasing butyrate production, exerting profound gut–liver axis regulation. It also ameliorates hypertension by activating the ACE2-Ang-(1–7)-Mas axis, improves insulin resistance via the AMPK/PI3K/Akt cascade, and manages hyperuricemia by modulating XOD and renal transporters. Notably, the low oral bioavailability of its glycosides highlights the crucial role of gut microbial hydrolysis in its efficacy. Conclusions: E. ulmoides holds substantial therapeutic potential as a multi-target natural supplement for MetS. However, future translational applications necessitate large-scale randomized clinical trials, multi-omics studies to further clarify host–microbiome interactions, and the development of standardized formulations to ensure clinical efficacy. Full article

Carbonyl stress, chronic inflammation, and progressive tissue injury accompany type 2 diabetes mellitus (T2DM) and obesity. Yet, the molecular systems that connect these processes with cardiac, vascular and neuronal complications are incompletely defined. This review examines the AGE–RAGE–DIAPH1 axis as a mechanistic link between metabolic dysfunction and diabetic myocardial and neuronal injury, with emphasis on vascular and myocardial remodeling and emerging implications for autonomic neuronal vulnerability. We summarize current evidence on the formation and accumulation of advanced glycation end-products and other RAGE ligands in metabolic disease, DIAPH1’s structural and signaling role as an intracellular effector of RAGE, and the cellular consequences of pathway activation in vascular, neural, and cardiac tissues. Across experimental models, this signaling axis promotes oxidative stress and inflammatory activation, leading to endothelial dysfunction and barrier failure. Subsequent fibrotic remodeling provides a biologically plausible route through which metabolic stress may be translated into persistent organ injury. In the heart, these mechanisms are linked to coronary microvascular dysfunction, altered cardiomyocyte phenotype, calcium handling abnormalities, and myocardial fibrosis. In the autonomic nervous system, limited but emerging data connect RAGE activation to oxidative injury and mitochondrial dysfunction, abnormal neuronal excitability, and structural vulnerability. Direct evidence linking DIAPH1 to autonomic neurons is lacking. We also review biomarker candidates related to this pathway, including circulating AGEs and soluble RAGE isoforms, skin AGE measurements, imaging markers of myocardial remodeling, and autonomic functional measures. Finally, we discuss pharmacological and natural compounds that target AGE formation, ligand accumulation, RAGE signaling, or intracellular protein interactions linked to this axis. Overall, the available evidence supports the AGE–RAGE–DIAPH1 axis as a credible mechanistic concept and a potentially informative translational hypothesis in T2DM. However, the AGE–RAGE component is supported more strongly than DIAPH1-specific involvement in human diabetic myocardial disorder or cardiovascular autonomic neuropathy. The value of DIAPH1 as a biomarker or therapeutic target in these neurocardiac complications remains to be established. Full article

Avian influenza virus (AIV), a zoonotic pathogen capable of cross-species transmission, poses a significant global health threat due to its rapid evolutionary adaptation. This review consolidates evidence from the past decade on AIV-autophagy interactions, emphasizing mechanistic insights and therapeutic potential. Research indicates that various AIV strains can trigger autophagosome formation via viral components, although the completeness of autophagic flux is not fully understood. These virus–host interactions are notably influenced by viral genotypes (e.g., H5N1 vs. H9N2) and host species (avian vs. mammalian). Current studies suggest that modulating autophagy may reduce AIV-induced acute lung injury, with pharmacological agents showing potential in mitigating inflammatory responses. We systematically explore three research areas: (1) strain-specific mechanisms of autophagy induction, (2) host-specific autophagic responses in poultry and human models, and (3) the therapeutic potential of stage-specific autophagy manipulation. This synthesis clarifies critical knowledge gaps, particularly the need for standardized autophagic flux assessment in avian cells, while providing a conceptual framework for developing autophagy-targeted strategies against AIV pathogenesis. Full article

Aging is associated with a rising burden of chronic metabolic, cardiovascular, musculoskeletal, and neurodegenerative diseases that share interconnected pathological mechanisms, including oxidative stress, chronic inflammation, mitochondrial dysfunction, metabolic imbalance, and immune dysregulation. Because these disorders arise from complex and overlapping biological disturbances, conventional single-target therapies often provide only limited benefit. In this context, traditional Chinese herbal medicines, characterized by multi-component and multi-target actions, are being re-evaluated using modern pharmacological and systems biology approaches. Among these, Astragalus membranaceus and Cordyceps species have attracted attention as representative tonic medicines with long-standing traditional use and growing biomedical relevance. Their principal bioactive constituents, including polysaccharides, saponins, flavonoids, sterols, and nucleoside derivatives such as cordycepin, exert pleiotropic effects on inflammatory signaling, redox homeostasis, mitochondrial function, metabolic regulation, and immune responses. This review summarizes current evidence on bioactive derivatives from Astragalus and Cordyceps in aging-related chronic and neurodegenerative disorders, including diabetes, cardiovascular dysfunction, osteoarthritis, cancer, Alzheimer’s disease, and Parkinson’s disease. It focuses on mechanistic findings from cellular and animal studies and critically discusses key translational challenges, such as compositional variability, poor bioavailability, lack of standardized preparation, limited clinical validation, and safety concerns related to toxicity and herb–drug interactions. Full article

Human ageing and longevity are increasingly understood as biologically integrated and heterogeneous processes shaped by interactions among genetic susceptibility, epigenetic remodelling, and environmental modulation. This narrative review examines these interconnections within a nutrigenomic framework, with particular emphasis on how inherited variation and epigenetic plasticity may influence responses to ageing-related interventions. A structured literature search was conducted in PubMed, Scopus, Web of Science, and Embase, focusing on English-language studies published during the last 10 years. The review was organized into three major domains: (i) genetic determinants of longevity, (ii) epigenetic mechanisms of ageing, and (iii) intervention-responsive pathways relevant to precision geroscience. Current evidence supports a polygenic model of longevity in which loci such as FOXO3 and APOE show the most consistent human associations, while telomere maintenance, insulin/IGF-1 and mTOR signalling, sirtuins, Klotho, inflammatory mediators, and DNA repair remain biologically important but variably supported at the variant level. Epigenetic mechanisms, including DNA methylation drift, epigenetic clocks, histone modifications, chromatin remodelling, heterochromatin loss, and non-coding RNA regulation, provide an environmentally responsive interface linking genetic background to ageing phenotypes. Nutritional, pharmacological, behavioural, and circadian interventions converge on overlapping molecular pathways involving AMPK, mTOR, FOXO, sirtuins, autophagy, mitochondrial maintenance, and inflammatory signalling, although human evidence remains heterogeneous and biomarker modulation should not be equated with clinically meaningful slowing of organismal ageing. Overall, this review highlights the value of integrating genetics, epigenetics, and intervention biology to support a more cautious and translationally relevant model of healthy ageing. It also underscores the need for precision nutrigeroscience approaches that account for tissue context, baseline physiology, and inter-individual molecular variability. Full article

Background and Objectives: Muscle symptoms are the most visible adverse event attributed to statins, but terminology is often imprecise. Most patients report myalgia or nonspecific aches, whereas objective myopathy, inflammatory or necrotizing myositis, rhabdomyolysis, and anti-HMGCR immune-mediated necrotizing myopathy are uncommon and clinically distinct entities. To provide a clinically oriented narrative synthesis of statin-associated muscle symptoms (SAMS) and severe statin-associated myotoxicity, and to propose a practical prevention, evaluation, and management algorithm. The classification of muscle events is used to standardize terminology and avoid diagnostic confusion, not to create a new formal taxonomy. Materials and Methods: A clinically oriented narrative review was performed using PubMed, Google Scholar, and major society documents published from January 2021 to April 2026. Eligible sources addressed SAMS, statin myopathy/myositis, rhabdomyolysis, anti-HMGCR immune-mediated necrotizing myopathy, nocebo/drucebo effects, pharmacogenetics, drug interactions, diagnosis, or management. The final evidence set comprised 55 verifiable sources, including blinded randomized or n-of-1/crossover evidence; meta-analyses; clinical statements and reviews; pharmacovigilance analyses; pharmacogenetic guidance; mechanism-focused reviews; anti-HMGCR series; and lipid-lowering guideline/treatment studies. Because the review was narrative, no pooled estimate or formal PRISMA screening log was generated. Results: Blinded evidence indicates only a small absolute excess of muscle pain with statins, concentrated mainly in the first year of therapy, and that most muscle symptoms reported during statin therapy are not pharmacologically caused by the statin. N-of-1 and crossover trials show that symptom intensity is often similar during statin and placebo periods, consistent with an important nocebo/drucebo contribution. Severe muscle toxicity can nevertheless occur, especially when systemic statin exposure is increased by a high dose, interacting drugs, frailty, renal or hepatic impairment, hypothyroidism, transporter or metabolic genotypes, or intense unaccustomed exercise. Statin choice matters chiefly through dose, pharmacokinetics, and interaction burden. Conclusions: SAMS are common as reported clinical problems, but confirmed statin-caused muscle injury is substantially less frequent than routine clinical attribution suggests. Permanent discontinuation should be reserved for carefully assessed cases. A structured approach—baseline risk assessment, selective CK measurement, exclusion of alternative causes, correction of modifiable risks, dechallenge/rechallenge, statin switching, dose reduction, and combination with non-statin therapy—preserves cardiovascular benefit while protecting the rare patient with genuine toxicity. Full article

Highlighting its pivotal role in modern pharmacology, the gut microbiome is emerging as a key determinant of drug efficacy, toxicity, and bioavailability. This review proposes the Gut Microbiome Dependency Continuum, a four-layer framework describing progressively deeper levels of microbiome involvement in drug discovery and therapeutic function. The first layer, intact functional microbiome-dependent therapeutics and includes interventions such as faecal microbiota transplantation and defined microbial consortia. The second layer, microbiome-modulated approved drugs include widely used therapeutics whose pharmacokinetics or pharmacodynamics are strongly influenced by microbial metabolism. Examples include metformin, irinotecan, levodopa, and digoxin, where gut microbial interactions influence efficacy, toxicity, and inter-individual variability in treatment outcomes. The third layer, microbiota-transformable natural products, encompasses dietary and plant-derived compounds such as polyphenols, ginsenosides, alkaloids, fibres, isoflavones, lignans, and glucosinolates. Their biological activity depends on microbial biotransformation into bioactive metabolites. The fourth layer, engineered microbiome therapeutics, includes synthetic biology approaches such as programmable microbial systems, engineered probiotics, CRISPR-based microbiome editing, and microbiome-responsive drug delivery systems. It also includes synthetic microbial consortia, enabling targeted sensing, therapeutic delivery, and ecological reprogramming of gut microbial communities. Altogether, these layers define a continuum in which the gut microbiome evolves from a passive modulator to an essential metabolic organ and ultimately a programmable therapeutic platform. The article provides an integrated framework for microbiome-informed drug discovery. It also supports the development of precision, ecology-aware, and engineered microbial therapeutics. Full article

Inflammatory bowel disease (IBD) is a chronic relapsing disorder associated with dysregulated interactions among the gut microbiota, mucosal immunity, and the intestinal barrier. Although current treatments have improved disease control, incomplete response, adverse effects, and relapse remain common. Berberine, a natural isoquinoline alkaloid, has gained attention as a multitarget compound with potential relevance to IBD. This narrative review summarizes evidence published up to March 2026 on the pharmacological basis, delivery optimization, clinical translation, and microbiota–immune–barrier axis regulation of berberine in IBD. Current evidence suggests that berberine may reshape gut microbial communities, regulate mucosal immune responses, and support epithelial barrier repair, thereby contributing to the restoration of intestinal homeostasis. Emerging formulation strategies, particularly microbiota-responsive and intestine-targeted delivery systems, may improve local exposure and strengthen its therapeutic potential. However, the current evidence is still dominated by preclinical studies. Clinical data remain limited, and the causal links among microbial remodeling, immune modulation, and barrier restoration are not yet fully defined. Future work should prioritize mechanistic validation, clinically relevant delivery design, and well-controlled clinical trials to clarify the role of berberine in personalized IBD management. Full article

Neurodegenerative diseases are increasingly recognized as disorders of due to disrupted cellular homeostasis, with mitochondrial dysfunction playing a central and early role in disease progression. This review explores the intricate relationship between mitochondrial function and neuronal health, emphasizing the pivotal role of the solute carrier family 25 (SLC25) transporters in maintaining mitochondrial homeostasis. We provide a comprehensive overview of mitochondrial biology in the central nervous system, including energy metabolism, calcium signaling, redox regulation, organelle interactions and mitochondrial dynamics. We delve into the SLC25 transporter family, highlighting their transport mechanisms, substrates and roles in brain metabolism and neuroprotection. SLC25 on one hand and proteins involved in the regulation of mitochondrial morphology and calcium signaling on the other hand are two sides of the same coin influencing each other. A critical analysis follows, examining how mitochondrial dysfunction contributes to mitochondrial abnormalities in a spectrum of neurodegenerative diseases, including Alzheimer’s disease, Parkinson’s disease, ALS and rare mitochondrial encephalopathies. Finally, we assess emerging therapeutic strategies targeting mitochondrial pathways and SLC25 function, including metabolic modulation, gene therapies, antioxidants and pharmacological agents. This review underscores mitochondria and the SLC25 transporters as promising targets for disease-modifying interventions in neurodegeneration and raises key questions about the causality between mitochondrial failure and neuronal death. Full article

Pharmacological intervention is central to cancer therapy, but overcoming drug resistance is limited by severe adverse effects. Rational drug combinations can improve efficacy and reduce toxicity, yet identifying effective pairs is challenging due to the vast combinatorial space. Structure-activity relationship (SAR) modeling offers an in silico approach to predict drug synergy. To create SAR models, training sets were built from the NCI-ALMANAC database, containing cytotoxicity profiles of ~5000 drug pairs per NCI-60 cell line. SAR models were developed using the PASS DDI (Prediction of Activity Spectra for Substances with the Drug-Drug Interaction) platform, which encodes chemical structures into PoSMNA (Pairs of Substances Multilevel Neighborhoods of Atoms) descriptors and applies a Bayesian-like algorithm to uncover structure–activity patterns. Model performance was assessed using leave-one-out compounds out cross-validation (LOO CO CV), with predictive accuracy quantified by the area under the ROC curve (AUC). A total of 104 SAR models demonstrated robust predictive performance, with AUC values exceeding 0.7 (mean AUC = 0.75), enabling the prediction of synergistic effects for compound combinations across 45 cancer cell lines. These models have been implemented in the CLC-Pred Synergy web application, providing a practical tool for in silico screening of anticancer drug combinations. Full article

Background/Objectives: Natural products have long been regarded as a cornerstone in the discovery and development of novel therapeutic agents. Accumulating evidence indicates that natural products represent promising pharmacological candidates for cancer treatment. This review provides a holistic overview of novel identified natural products as a continuing source of bioactive compounds, with particular emphasis on recent advances and their applications in anticancer therapy over the past five years. Methods: A literature search was conducted using PubMed, Scopus, and Web of Science to identify relevant studies published within the past five years. Predefined keywords and Boolean operators (e.g., “natural products”, “anticancer”, “drug discovery”, “secondary metabolites”, “signaling pathways”, “epigenetics”) were applied, with search strategies adapted to each database. Eligible studies included original research articles and reviews reporting on newly identified natural products with anticancer activity, with emphasis on chemical diversity, biological effects, and molecular mechanisms of action. Additional references were identified through manual screening of bibliographies. The selected literature was evaluated using a qualitative, interpretative approach consistent with narrative review methodology, and findings were critically synthesized and thematically organized. Results: Growing evidence indicates that multiple newly identified natural products target mitochondrial metabolism and interact with alternative tubulin binding sites, thereby highlighting their potential as anticancer agents. In addition, emerging compounds have been shown to affect DNA integrity and transcriptional regulation, while also acting as systems-level modulators of key oncogenic signaling pathways, including PI3K/Akt, NF-κB, and MAPK. Recent studies further demonstrate that natural products can modulate multiple layers of epigenetic regulation, including DNA methylation, histone acetylation, histone methylation, and non-coding RNA networks. Conclusions: Current evidence supports the concept that natural products primarily function as multi-target biological modulators rather than classical single-target inhibitors in cancer biology. A persistent challenge remains the translational gap between preclinical efficacy and clinical application, as the majority of naturally derived candidate compounds remain confined to in vitro or early in vivo validation. Future progress will therefore depend on systematically aligning the multi-target pharmacology of natural products with defined cancer vulnerabilities and clinically actionable therapeutic strategies. Full article

The most recent research has demonstrated that oscillatory nano-structures found on the lumenal walls of deep cerebral veins likely contribute significantly to the regulation of the function of deep cerebral veins. The oscillatory nano-structures consist of very small, intricately organized “nanoflaps,” each consisting of a hinge element with an attached lipid bilayer architecture. These nanoflaps have distinct mechanical properties, are in close proximity to mechanically sensitive protein assemblies, and therefore it is hypothesized that the nanoflaps generate rhythmic oscillations that control the distribution of both pressure and fluid flow through the veins and also regulate the metabolic condition of the surrounding tissue. In addition, the behavior of the nanoflaps indicate that there exists a hitherto unappreciated level of venous biomechanics at the nanometer scale that regulates the hydraulic stability of the veins and may also contribute to the structural integrity of the surrounding tissues. The purpose of this review is to provide a theoretical framework for understanding the recent discoveries of the structure, oscillation and hydrodynamic effects of nanoflaps, including resonance drift, waveform irregularity, and multi-scale biomechanical interactions. Additionally, this review will present the idea that disruption of the normal oscillatory processes that occur in the nanoflaps may lead to the development of abnormal micro-environments in the early stages of neurodegenerative diseases, abnormalities of compliance, dysautonomic states, traumatic injury and micro-circulatory stress. Finally, this review will describe several pharmacological strategies that may be used to stabilize the oscillations generated by the nanometer-scale oscillatory nano-structure by modifying the torque applied to the hinge, the viscoelasticity of the membrane and the feedback pathways for mechanotransduction. Full article

Marine-derived collagen peptides exhibit potent intestinal barrier protection; however, their gastrointestinal fate and molecular targets remain unclear, limiting their practical applications. This study investigated the digestive stability and transepithelial transport of GPSGPQGSR, a mucoprotective peptide from Alaska pollock (Gadus chalcogrammus) skin, using simulated gastrointestinal digestion, a Caco-2 cell transport model, and an UPLC-QTOF-MS/MS. The results showed that GPSGPQGSR was a digestion-resistant peptide that reached the intestinal epithelium intact. Although brush border membrane enzymes partially hydrolysed the peptide, 42.16% of intact GPSGPQGSR remained in the luminal compartment after 2 h of incubation. No intact peptide was detected in the basolateral compartment. Molecular docking and 100 ns molecular dynamics simulations identified TLR2 (−14.936 kcal/mol) and PAR2 (−10.154 kcal/mol) as high-affinity extracellular targets of GPSGPQGSR, with stable peptide–receptor interactions and extensive hydrogen bonding networks between the peptide and each receptor (RMSD of 1.8 Å and 2.2 Å, respectively). Pharmacological blockade of TLR2 or PAR2 abolished the protective effects of GPSGPQGSR. These findings demonstrate that GPSGPQGSR acts as a digestion-resistant extracellular signalling peptide that reaches the intestinal epithelium intact and protects barrier function through apical TLR2 and PAR2, providing a mechanistic basis for the rational development of marine collagen peptides for improving intestinal health. Full article

Cordyceps militaris, a medicinal and edible mushroom, is renowned for its bioactive constituents and health-promoting effects. This study investigated the effects of vacuum freeze drying (VF), vacuum drying (VD), oven drying (OV), and sun drying (SU) on the metabolite profiles and antioxidant activities of C. militaris. VF showed the highest levels of total phenolics, total carotenoids, cordycepin, and N⁶-(2-hydroxyethyl)-adenosine, whereas VD better preserved total flavonoids. VF- and VD-treated samples also exhibited stronger antioxidant capacities than those processed by OV and SU in 1,1-diphenyl-2-picrylhydrazyl radical (DPPH•), 2,2′-azino-bis (3-ethylbenzothiazoline-6-sulfonic acid) radical (ABTS^•+), hydroxyl radical (•OH), and ferric reducing antioxidant power (FRAP) assays. Metabolomics analysis identified 193 significantly altered metabolites after drying treatments. VF, VD, and SU increased carbohydrates, vitamins, and phenolic acids, while leading to reductions in amino acids, nucleotides, and fatty acids. KEGG analysis revealed that drying significantly affected pathways related to purine and pyrimidine metabolism, amino acid biosynthesis, and phenylpropanoid biosynthesis. Network pharmacology further identified 8 key compounds potentially associated with antioxidant effects through interactions with 37 core targets. These findings highlight the importance of selecting appropriate drying methods to preserve the bioactive compounds and functional quality of C. militaris. Full article