Search Results (3,232)

Mitochondrial dysfunction and impairment of high-energy phosphate transfer are increasingly recognised as shared pathogenic features across neurological disorders. Because neurons require large amounts of ATP to sustain synaptic transmission, ion gradients, axonal transport, and intracellular signalling, they are especially vulnerable to disturbances in energy metabolism. Neurological dysfunction, therefore, cannot be explained solely by reduced mitochondrial ATP production. It also involves failure of the creatine kinase/phosphocreatine (CK/PCr) and adenylate kinase/AMP-activated protein kinase (AK–AMPK) systems, which normally support local ATP buffering, high-energy phosphate transfer, and intracellular energy homeostasis. In parallel, extracellular ATP-dependent purinergic dysregulation contributes to glia-mediated inflammation, synaptic dysfunction, and cell death, linking intracellular energy failure to abnormal intercellular signalling. In this review, we integrate these mechanisms into a shared pathological continuum of disrupted energy homeostasis. We then compare Alzheimer’s disease, Parkinson’s disease, and epilepsy as representative disorders with shared and disease-specific manifestations of this continuum, characterised respectively by chronic cerebral energy crisis, selective metabolic fragility, and acute energy overload with purinergic dysregulation. Finally, we discuss how this comparative perspective may help identify shared therapeutic opportunities while preserving disorder-specific interpretation. Full article

Protein–protein interactions (PPIs) represent a vast and largely underexplored landscape of therapeutic targets, yet their structural features—including large, flat, and dynamic interfaces—have historically limited their druggability. In this context, cyclic peptides have emerged as a powerful class of PPI modulators, sitting at the interface between biologics and small molecules, and thus garnering key advantages of both classes. Their conformational constraint enhances binding affinity, proteolytic stability and, in some instances, cell permeability, thus enabling access to intracellular targets. This review provides an updated overview of cyclic peptides as modulators of PPIs, focusing on both conceptual foundations and practical strategies for their discovery and optimization. The main discovery approaches include natural sources, de novo design based on secondary structure mimetics, high-throughput screening, and computational approaches. Integration of these complementary strategies is crucial to enhance success rates in the discovery of effective and developable cyclic peptides. Accordingly, the present review aims to provide a practical guide for researchers entering this rapidly growing field, outlining current opportunities, methodological advances, and remaining challenges in the development of cyclic peptide-based PPI modulators. Full article

Tuberculosis (TB) remains a leading cause of death from a single infectious agent, and its outcome is shaped not only by Mycobacterium tuberculosis (Mtb) itself, but also by the host’s metabolic state. This review synthesises current understanding of how Mtb reprograms macrophage immunometabolism and how this reprogramming propagates to a systemic level, culminating in skeletal muscle dysregulation and TB-associated cachexia. We describe the molecular mechanisms by which Mtb subverts phagosomal maturation, the glycolytic (Warburg-like) switch governed by HIF-1α and accumulation of immunomodulatory tricarboxylic acid cycle intermediates, and the M1/M2 polarisation balance that dictates bacterial containment versus persistence. We then trace the cytokine- and metabolite-mediated circuits (TNF-α, IL-6, IL-1β, lactate, ketone bodies, free fatty acids) that link infected macrophages to ubiquitin–proteasome and autophagy–lysosome-driven muscle proteolysis, mitochondrial dysfunction and oxidative stress. Building on these mechanisms, we propose an immunometabolic and muscle-derived biomarker framework that, although still requiring clinical validation, may offer value for diagnosis, host-response stratification and treatment monitoring, and we discuss host-directed therapeutic strategies that target macrophage metabolism and muscle preservation. By integrating immunity, metabolism and systemic pathology at the molecular level, this work highlights translational opportunities relevant to the host immunity, diagnosis and treatment of tuberculosis. Full article

Pandemic response requires not only epidemiological control but also the allocation of limited social resources across competing uses. This paper develops an integrated economic–epidemiological framework to examine how resources should be allocated among goods production, preventive intervention, and therapeutic intervention during an infectious disease outbreak. Building on the susceptible–infected–recovered (SIR) model, the analysis treats the infection rate and the recovery rate as policy-sensitive variables shaped by preventive and therapeutic resource allocation. The objective is intentionally parsimonious and focuses on output preservation and resource allocation under epidemic constraints; infections affect the economy indirectly by reducing effective labor input and output. Two epidemiological environments are considered: one with permanent immunity after recovery and another with possible reinfection. The results reveal a robust timing pattern across both environments. Preventive allocation tends to peak before the surge in infections, whereas therapeutic allocation tends to move more closely with the infection trajectory. The analysis also makes explicit the opportunity cost of intervention: allocating more resources to prevention or treatment reduces the resources available for goods production. Phase-diagram representations clarify the mechanism behind this timing distinction, and sensitivity analyses over alternative curvature parameters confirm that the qualitative ordering of the peaks is robust. These findings suggest that the effectiveness of pandemic response depends not only on the total amount of intervention resources, but also on their timing and functional allocation. By linking epidemic dynamics, resource scarcity, and policy timing within a unified optimization framework, the paper contributes to economic–epidemiological modeling and offers implications for pandemic preparedness, health-system resilience, and the design of response strategies for future infectious disease emergencies. Full article

Hepatocellular carcinoma (HCC) remains one of the leading causes of cancer-related mortality worldwide and is characterized by extensive vascularization, aggressive progression, and limited therapeutic responsiveness. Angiogenesis plays a central role in HCC development by supporting tumor growth, metabolic adaptation, invasion, and metastatic dissemination. Although anti-angiogenic therapies targeting the vascular endothelial growth factor (VEGF) pathway have improved clinical management, their overall survival benefit remains modest because of compensatory signaling, adaptive resistance, and the highly complex nature of the tumor microenvironment (TME). Astrocyte elevated gene-1/metadherin (AEG-1/MTDH) has emerged as a multifunctional oncogene that functions by orchestrating interconnected angiogenic, inflammatory, metabolic, and immune-regulatory programs within the hepatic tumor microenvironment. AEG-1 regulates angiogenesis through modulation of VEGF-family signaling, NF-κB activation, hypoxia-responsive pathways, PI3K/AKT signaling, endothelial remodeling, and translational control of pro-angiogenic mediators. Emerging evidence further implicates AEG-1 in hypoxia adaptation, immune evasion, extracellular vesicle signaling, and metabolic reprogramming, supporting its role as a systems-level regulator of HCC angiogenesis. This review summarizes the current understanding of the molecular mechanisms through which AEG-1 regulates angiogenesis in HCC, discusses its interactions with the TME and anti-angiogenic resistance pathways, and highlights future translational opportunities for developing multi-targeted therapeutic strategies beyond conventional VEGF-centric approaches. Full article

Silicon is among the most abundant elements on Earth, yet its incorporation into organic molecules is atypical in most biological contexts. However, the strategic introduction of silicon, in line with the demonstrated success of the incorporation of other bio-orthogonal elements, has emerged as a powerful approach in medicinal chemistry, enabling access to small molecules with unique chemical, physical, and biological properties that offer improved potency, stability, tolerability, or bioavailability profiles for the discovery and development of anticancer therapeutics. In this review, we describe the direct connection between reactivity and physiochemical paradigms of different classes of organosilicon-containing functional groups and their strategic deployment in small molecule design, including silanes, silyl ethers, siloxanes, and organosilicates. Specifically, we aimed to demonstrate how these strategies can be informed by first principles of reactivity in organosilicon containing functional groups, in both synthetic small molecules and bioactive natural products. Particular emphasis is placed on how silicon replacement and addition can be leveraged beyond simple isosteric carbon replacement, and how consequent structure–activity relationships arising from installation of diverse organosilicon motifs can also serve a unique role in unveiling new aspects of biological mechanism and function. Ultimately, the growing body of literature in applications of organosilicon-containing anticancer small molecules and the increasing sophistication and selectivity of synthetic methods used to construct these motifs will undoubtedly continue to expand the appreciation of organosilicon-based functional groups in the medicinal chemist’s toolbox. Full article

Enzymatic nanomotors (EMNMs) represent an emerging class of intelligent nanosystems that exploit enzymatic biocatalysis to generate autonomous motion within biological environments, including complex cellular and tissue contexts within living organisms. Owing to their ability to utilize endogenous biofuels, high biocompatibility, and capacity for targeted propulsion, EMNMs have demonstrated considerable potential in diverse biomedical applications. These include targeted drug delivery, cancer therapy, diagnostics, and bioimaging, as well as the traversal of biological barriers. This review comprehensively discusses the mechanisms underlying enzyme-driven propulsion, nanomotor design strategies, and their current and prospective applications in medicine, while also addressing major challenges associated with enzymatic stability, biocompatibility, motion control, and clinical safety. Furthermore, future perspectives are highlighted, including enzyme cascade systems, intelligent nanomotor swarms, biodegradable materials, and strategies facilitating clinical translation. As a representative example of practical application, curcumin was employed as a model therapeutic agent due to its well-established anticancer, anti-inflammatory, and antioxidant properties, enabling evaluation of the nanomotors’ capability for controlled, pH-responsive release of therapeutic cargo. Nanophytomedicine enhances the therapeutic efficacy of phytochemicals by improving their stability, bioavailability, and targeted delivery through nanocarrier systems. The integration of phytotherapy with nanotechnology offers promising opportunities for the development of safer and more effective therapeutic strategies. Full article

Bone metastasis develops within a specialized marrow ecosystem where hematopoiesis, immune regulation, vascular trafficking, and skeletal remodeling intersect. Neutrophil-lineage cells occupy a unique position in this setting because they are generated, retained, mobilized, aged, and reprogrammed within the same bone marrow niches that disseminated tumor cells exploit for homing and survival. This review examines how neutrophils, tumor-associated neutrophils, immature neutrophils, low-density neutrophils, and PMN-MDSCs shape skeletal colonization. We discuss tumor-to-marrow signaling, CXCR2-dependent recruitment, CXCR4/CXCL12-mediated marrow retention, neutrophil–circulating tumor cell interactions, vascular arrest, dormancy escape, NET-mediated matrix remodeling, immune suppression, and effects on osteoclast–osteoblast coupling. Evidence is strongest in breast and prostate cancer models, where pathways such as CXCL5/CXCR2, CTNND1–CXCR4/CXCL12, PR3–RAGE, and DKK1–CKAP4–STAT6–CHI3L3 link neutrophil-lineage cells to skeletal progression and immunotherapy resistance. However, several mechanisms, including CTC–neutrophil clustering and NET-driven dormancy awakening, remain partly extrapolated from non-skeletal models. We therefore emphasize evidence hierarchy, methodological limitations, and therapeutic opportunities, arguing that selective reprogramming or functional inhibition of pro-metastatic neutrophil states may be more promising than indiscriminate neutrophil depletion in metastatic bone disease. A clearer understanding of these context-dependent neutrophil programs may help refine biomarker development and guide combination therapies for patients with skeletal metastases. Full article

Myeloid-derived suppressor cells (MDSCs) are a heterogeneous population of immature myeloid cells that accumulate in cancer and represent one of the major drivers of tumor-associated immunosuppression. MDSCs actively contribute to tumor progression by inhibiting both innate and adaptive immune responses, promoting angiogenesis, metastatic dissemination, and resistance to immunotherapy. Two major subsets have been identified, polymorphonuclear (PMN-) and monocytic (Mo-) MDSCs, each characterized by distinct phenotypic, metabolic, and suppressive properties. Within the tumor microenvironment (TME), MDSCs establish a complex network of interactions with T-, B-, NK-cells, dendritic cells, and macrophages, thereby orchestrating immune escape and tumor persistence. Recent evidence highlights the pivotal role of metabolic rewiring in regulating MDSC survival and suppressive activity. Enhanced aerobic glycolysis, fatty acid oxidation, amino acid depletion, reactive oxygen species (ROS) production, and adenosine metabolism collectively sustain MDSC-mediated immune dysfunction and shape the immunosuppressive TME. In particular, the crosstalk between PMN-MDSCs and NK cells has emerged as a critical mechanism of tumor immune evasion, leading to impaired NK cell cytotoxicity, altered activating receptor expression, and defective cytokine production. In this review, we summarize the current knowledge on the phenotypic and functional heterogeneity of MDSCs, their metabolic adaptations, and their interactions with immune effector populations in cancer. Furthermore, we discuss emerging therapeutic strategies aimed at targeting MDSC recruitment, differentiation, metabolic pathways, and suppressive functions. Understanding the molecular and metabolic mechanisms governing MDSC biology may provide novel opportunities to overcome tumor-induced immunosuppression and improve the efficacy of current cancer immunotherapies. Full article

Beyond their established role in lipid digestion, bile acids function as key metabolic and immune signaling molecules. This review synthesizes recent advances in bile acid metabolism within the context of gout and hyperuricemia, proposing a gut–liver–joint crosstalk framework. Dysregulated bile acid metabolism—characterized by a reduced total bile acid pool, decreased hydrophobic secondary bile acids, elevated 12α-hydroxy bile acids, and impaired enterohepatic circulation—has been mechanistically linked to both hepatic urate overproduction via the PPAR-α/xanthine oxidase pathway and monosodium urate crystal-induced NLRP3 inflammasome activation, although human causal evidence remains to be established. The nuclear receptor FXR suppresses NLRP3 at the transcriptional level, while the membrane receptor TGR5 acts post-translationally through Cyclic adenosine monophosphate/Protein Kinase A (cAMP/PKA) and Glucagon-like peptide-1 (GLP-1) signaling. Gut microbiota dysbiosis amplifies these abnormalities through a vicious cycle of reduced bile acid signaling, increased intestinal permeability, and systemic endotoxemia. Based on these insights, we summarize five therapeutic strategies: FXR modulators, TGR5 agonists, microbiota-based interventions, natural products, and ursodeoxycholic acid replacement therapy. Future research should prioritize gout-specific preclinical models, clinical trials of TGR5 agonists, standardized microbiota-based therapies, dual-target molecules, and personalized patient stratification based on bile acid profiles. Full article

One of the most pressing challenges facing healthcare today is the rise of biofilm infections and antibiotic-resistant bacteria, which demand entirely new therapeutic strategies beyond conventional antibiotic reliance. A biofilm is a structured community of microorganisms encased in a self-produced extracellular polymeric substance (EPS) matrix, which confers resistance to host immune defenses and antimicrobial agents. Accumulating evidence demonstrates that plant-derived secondary metabolites—including flavonoids, phenolic acids, tannins, terpenoids, and alkaloids—exert potent antibacterial and antibiofilm activities through diverse mechanisms of action. These natural compounds inhibit biofilm formation by disrupting bacterial adhesion, suppressing quorum sensing, degrading the EPS matrix, and impairing bacterial motility. Beyond independent bioactivity, phytochemicals demonstrate significant synergistic potential when combined with conventional antibiotics, revitalizing antimicrobial efficacy against drug-resistant pathogens. Nanoformulation and biogenic carrier technologies further enhance the bioavailability and therapeutic potency of these compounds. Despite these advances, critical challenges persist, including poor bioavailability, physicochemical instability, dose-dependent toxicity, and the risk of resistance development. This review presents a critical and integrative analysis of the pharmacological mechanisms of plant secondary metabolites, with particular emphasis on their role in combating biofilm-associated infections and antibiotic resistance, and discusses translational opportunities including structure–activity relationship (SAR)-guided optimization, high-throughput screening platforms, and advanced drug delivery systems. Collectively, plant secondary metabolites represent a scientifically compelling and clinically relevant pipeline for the development of next-generation antimicrobial and antibiofilm therapeutics. Full article

Emerging viral diseases continue to pose major challenges to global health, creating demand for materials that can support pathogen control, diagnosis, and therapy. Owing to their tunable structures and versatile biointerfaces, metal–organic frameworks (MOFs) have attracted increasing attention in anti-pathogen applications. While previous studies have often focused on individual functions such as catalysis, biosensing, or drug delivery, a broader perspective on the functional development of MOF-based systems remains limited. In this Review, we summarize recent advances in MOF-enabled pathogen inactivation, diagnostic biosensing, host-directed intervention, and virus-inspired therapeutic platforms. Emerging opportunities in antiviral drug discovery and artificial intelligence-assisted materials design are also discussed. In addition, key challenges associated with structural stability, biosafety, scalable fabrication, and clinical translation are highlighted. This Review provides an overview of current progress and outlines perspectives for the future development of MOF-based anti-pathogen technologies. Full article

Background: Alcohol-related liver disease (ALD) affects 4.8% of the global population. Among these patients, between 13.4% and 19.6% suffer from alcoholic hepatitis (AH), which, in its severe form, is associated with significant short- and long-term mortality. Current therapeutic options are limited, offering only modest short-term survival benefits. Recent studies suggest that microbiota-based therapies may offer a novel therapeutic opportunity for patients with ALD. Methods: Databases including Embase, Medline, and CENTRAL were searched until 4 February 2026. The pre-registered protocol on PROSPERO (CRD42023467455) was followed without deviation. Studies comparing adult patients with ALD, treated with fecal microbiota transplantation (FMT) or standard of care (SOC), were included. Outcomes investigated included overall survival, alcoholic recidivism, adverse events (AEs), and disease severity scores. Risk of bias (ROB) was assessed using the ROBINS-I and ROB 2 tools. Hazard ratios (HR) were calculated for FMT versus SOC groups. Results: Overall, 10 studies were eligible for inclusion, with 339 patients eligible for synthesis. In these patients, FMT was associated with significantly improved overall survival compared to the SOC, with an HR of 0.50 (95% confidence interval (CI): 0.35–0.72; p = 0.0002). When comparing FMT with pentoxifylline, the HR was 0.45 (95% CI: 0.21–0.96; p = 0.0345), and when FMT was compared with nutritional support alone, the HR was 0.36 (95% CI: 0.19–0.66; p = 0.0001). But FMT did not reach statistical significance when compared to glucocorticoids. ROB analysis showed a moderate to high risk of bias, and the overall certainty of evidence was low. Discussion: FMT is a promising therapeutic option for improving short- and medium-term survival in patients with severe alcoholic hepatitis (SAH), particularly in those who are ineligible or unresponsive to corticosteroid therapy. However, given the risk of bias and low certainty of evidence, clinical significance remains uncertain. Confirmation in well-designed studies is needed. Full article

Oncology conditions are increasingly defined by their molecular profiles, and drug repurposing exploits this new evidence to identify new therapeutic uses of authorized/investigational medicinal products outside their original indication(s). This scoping review mapped original research published between January 2022 and December 2024 to determine the impact of automated processes and artificial intelligence in generating oncology candidates for drug repositioning, and 42 individual projects met the eligibility criteria and were analyzed. The included studies demonstrate extensive use of computational approaches for candidate prioritization, large-scale data integration, and hypothesis generation in oncology drug repurposing, creating opportunities for positive impact on efficiency. The included projects most commonly were target-oriented and disease-oriented and used multiple databases and computational validation procedures, while experimental and clinical validation were less frequently reported. The available open-access literature suggests substantial activity in China and India, which can support the notion that digitalization represents an important instrument in healthcare systems of low- and middle-income countries but should be interpreted cautiously. While the search was limited to PubMed and open-access English-language publications, we identified a relatively small number of drug-oriented projects, the importance of providing publicly accessible source code to reduce development costs, and the predominant role of academic institutions. Full article