Search Results (8,861)

The discovery of a mechanism by which bile acids (BAs) regulate fat synthesis by modulating the activation of the farnesoid X receptor (FXR) in the liver and intestines has highlighted the central role of BAs in triglyceride synthesis in the liver. FXR has been reported as a promising drug target for primary biliary cholangitis, metabolic-dysfunction-associated steatohepatitis, and metabolic-dysfunction-associated steatotic liver disease. A large number of FXR modulators with various chemotypes have been developed by many research groups. Although several FXR modulators are advancing into clinical trials, ongoing efforts aim to develop new FXR modulators that minimize the adverse effects associated with long-term administration. To develop drug candidates targeting FXR, various heterocyclic and/or fused heteroaromatic rings have been employed as the core and/or parts of the structures, out of which benzimidazole has been recognized as a valuable structural motif due to its synthetic accessibility and its versatility in constructing structurally diverse target molecules. Herein, we report on the development of FXR modulators incorporating benzimidazole as a fused heteroaromatic ring. Full article

In recent years, dietary intervention has garnered significant attention for T2DM prevention and adjunctive treatment. Lentinula edodes (commonly known as shiitake mushroom), a common edible fungus, has been demonstrated to improve T2DM, primarily attributed to its main bioactive components like peptides and polysaccharides, while their synergistic characteristics are still not fully explained. Therefore, this study investigated the anti-T2DM molecular mechanisms of L. edodes peptides and polysaccharides by integrating network pharmacology and molecular docking. First, systematic searches of the PubMed and HERB databases using keywords such as “Lentinula edodes peptides”, “Lentinula edodes polysaccharides” and “T2DM” and “Lentinula edodes/shiitake mushroom” yielded 25 peptides and 14 polysaccharides. Second, network pharmacology analysis revealed 541 common interaction targets between these peptides/polysaccharides and T2DM. Topological analysis further identified nine core targets: ESR1, MAPK1, AKT1, SRC, EGFR, STAT3, JUN, PIK3CA, and PIK3R1. Third, pathway enrichment analysis showed that these core targets were significantly enriched within the PI3K-Akt signaling pathway and the AGE-RAGE signaling pathway in diabetic complications, suggesting potential anti-T2DM effects through regulation of these key pathways. Finally, molecular docking validation ensured strong binding affinities between peptides/polysaccharides and some core targets, with particularly prominent binding capacities observed for peptides VF and LDELEK with EGFR; peptides KIGSRSRFDVT, LDYGKL, and EDLRLP along with polysaccharides D-glucan and β-glucan with PIK3CA; and peptide DVFAHF with PIK3R1. In summary, this study revealed that L. edodes peptides and polysaccharides may exert synergistic anti-T2DM effects via the regulation of key signaling pathways, including the PI3K-Akt signaling pathway, EGFR tyrosine kinase inhibitor resistance, and the AGE-RAGE signaling pathway in diabetic complications, through their actions on critical targets such as ESR1, PIK3CA, and PIK3R1. These results offer a synergistic mechanism for the anti-T2DM effect of L. edodes, which could be helpful for the development of functional foods and drugs derived from L. edodes. Full article

Biomolecules play pivotal roles in cellular signaling, metabolic regulation and the maintenance of physiological homeostasis in the human body, and their dysregulation is closely associated with the onset and progression of various human diseases. Consequently, the development of highly sensitive, selective, and stable detection platforms for these molecules is of significant value for drug discovery, pharmaceutical quality control, pharmacodynamic studies, and personalized medicine. In recent years, electrochemical biosensors, particularly those integrated with functional nanomaterials and biorecognition elements, have emerged as powerful analytical platforms in pharmaceutics and biomedical analysis, owing to their high sensitivity, exquisite selectivity, rapid response, simple operation, low cost and suitability for real-time or in situ monitoring in complex biological systems. This review summarizes recent progress in the electrochemical detection of representative biomolecules, including dopamine, glucose, uric acid, hydrogen peroxide, lactate, glutathione and cholesterol. By systematically summarizing and analyzing existing sensing strategies and nanomaterial-based sensor designs, this review aims to provide new insights for the interdisciplinary integration of pharmaceutics, nanomedicine, and electrochemical biosensing, and to promote the translational application of these sensing technologies in drug analysis, quality assessment, and clinical diagnostics. Full article

The incidence of primary liver cancer is increasing annually, with extremely high mortality and suboptimal therapeutic outcomes. The inefficient presentation of tumor antigens and low infiltration of specific cytotoxic T lymphocytes (CTLs) result in insufficient immunogenicity, which limits the efficacy of immunotherapy. Despite the popularity of immune checkpoint inhibitors (ICIs), insufficient immune activation means only a small subset of hepatocellular carcinoma (HCC) patients exhibit clinical responses to ICIs, showing significant inter-individual variability. The activation of the cyclic GMP-AMP synthase(cGAS)- stimulator of interferon genes(STING) pathway initiates the expression of type I interferons (IFNs) and inflammatory cytokines, promoting the formation of a pro-inflammatory environment at the tumor site. This pathway enhances anti-tumor immune responses by facilitating antigen processing and presentation, T cell priming and activation, and remodeling of the immunosuppressive microenvironment. Our research found that cucurbitacin B (CuB), a natural component derived from traditional Chinese medicine, had significant anti-hepatocellular carcinoma properties and exerted anti-tumor effects through the cGAS-STING pathway. Specifically, CuB regulated ferroptosis by down-regulating the expression of Solute Carrier Family 7 Member 11 (SLC7A11) and Glutathione Peroxidase 4 (GPX4) and upregulating the expression of Transferrin Receptor Protein 1 (TFR1) and Long-chain Acyl-CoA Synthetase 4 (ACSL4). These actions involved lipid substrates, iron ion homeostasis, and antioxidant defense systems. The release of mitochondrial DNA (mtDNA) triggered by ferroptosis activated the cGAS-STING immune signaling pathway, leading to the up-regulation of cGAS, phosphorylated STING (p-STING), phosphorylated TANK-binding kinase 1 (TBK1), phosphorylated Interferon regulatory factor3 (IRF3), and Interferon-β (IFN-β). This cascade activation pattern provides new insights into the drug treatment of tumors. Full article

Ocular disorders such as keratitis, glaucoma, age-related macular degeneration (AMD), diabetic retinopathy (DR), and dry eye disease (DED) are highly prevalent worldwide and remain major causes of visual impairment and blindness. Conventional therapeutic approaches for ocular diseases, such as eye drops, surgery, and laser therapy, are frequently hampered by limited drug bioavailability, rapid clearance, and treatment-related complications, primarily due to the eye’s unique anatomical and physiological barriers. Hydrogels, characterized by their three-dimensional network structure, high water content, excellent biocompatibility, and tunable physicochemical properties, have emerged as promising platforms for ophthalmic drug delivery. This review summarizes the classification, fabrication strategies, and essential properties of hydrogels, and highlights recent advances in their application to ocular diseases, including keratitis management, corneal wound repair, intraocular pressure regulation and neuroprotection in glaucoma, sustained drug delivery for AMD and DR, vitreous substitutes for retinal detachment, and therapies for DED. In particular, we highlight recent advances in stimuli-responsive hydrogels that enable spatiotemporally controlled drug release in response to ocular cues such as temperature, pH, redox state, and enzyme activity, thereby enhancing therapeutic precision and efficacy. Furthermore, this review critically evaluates translational aspects, including long-term ocular safety, clinical feasibility, manufacturing scalability, and regulatory challenges, which are often underrepresented in existing reviews. By integrating material science, ocular pathology, and translational considerations, this review aims to provide a comprehensive framework for the rational design of next-generation hydrogel systems and to facilitate their clinical translation in ophthalmic therapy. Full article

Background and clinical significance: Wiedemann–Steiner syndrome (WSS) is a rare autosomal dominant neurodevelopmental disorder caused by heterozygous pathogenic variants in the KMT2A gene, which encodes a histone lysine methyltransferase essential for chromatin regulation. Affected individuals commonly present with developmental delay, intellectual disability, behavioral disturbances, short stature, characteristic facial features, and hypertrichosis, along with variable additional congenital anomalies. Emerging genotype–phenotype correlations suggest two functional classes of KMT2A variants: loss-of-function variants, typically associated with the classic WSS phenotype and muscular hypotonia, and non-loss-of-function variants, which more often correlate with drug-resistant epilepsy and microcephaly. No recurrent variants or clear genotype–phenotype correlations have been established outside the CXXC domain, and most pathogenic variants are private or novel, contributing to phenotypic heterogeneity. Case presentation: We present a case of a 14-year-old female with a pathogenic nonsense truncating variant in the KMT2A gene and typical features of Wiedemann–Steiner syndrome. Additionally, the patient exhibited microcephaly and structural epilepsy due to neuronal heterotopy—features that are rarely described in individuals with truncating variants in this gene and have not been reported in the two published cases of individuals with the same mutation. Conclusions: This case highlights atypical genotype–phenotype correlations and expands the clinical spectrum of truncating KMT2A variants in Wiedemann–Steiner syndrome. Full article

Background: Mycoplasma pneumoniae pneumonia (MPP) is a common community-acquired pneumonia in children. Increasing drug resistance highlights the need for more effective treatments with fewer side effects. The Qingfei Tongluo Jiedu formula (QTJD) has demonstrated clinical efficacy against MPP; however, its underlying mechanisms remain unclear. This study aimed to explore the mechanism of QTJD on MPP using network pharmacology and in vitro experiments. Methods: Network pharmacology was used to identify the active compounds and signaling pathways of QTJD in MPP. QTJD-containing serum was prepared, and primary mouse lung and bone marrow cells were isolated to examine the effects of QTJD on macrophage polarization through butyric acid. Cell viability assays, flow cytometry, and quantitative reverse transcription-polymerase chain reaction were performed. GPR109^−/− cells were used to confirm the receptor mediating butyric acid’s action, and Western blotting was employed to assess the MAPK signaling pathway. Results: QTJD promoted macrophage polarization and alleviated the inflammatory response caused by Mycoplasma pneumoniae. High-performance liquid chromatography-electrospray ionization mass spectrometry combined with network pharmacology identified 20 active compounds. Protein-protein interaction analysis revealed 10 core target, including JUN and Tumor Necrosis Factor (TNF), while enrichment analysis highlighted pathways such as Mitogen-Activated Protein Kinase (MAPK) and Phosphoinositide 3-Kinase-Protein Kinase B. Experimental validation demonstrated that QTJD reduced M1 markers (CD86, CXCL10) by increasing butyrate levels (p < 0.01) and enhanced M2 markers (CD206, Arg-1, MRC-1), promoting M2 polarization. QTJD inhibited ERK1/2, p38, and JNK1/2 (p < 0.01). In GPR109A^−/− mice macrophages, QTJD suppressed p38 and JNK1/2 (p < 0.01) but showed no effect on ERK1/2 (p > 0.05), confirming involvement of the butyrate-GPR109A-MAPK pathway. Conclusions: QTJD effectively alleviates MPP by regulating macrophage polarization through the butyrate-GPR109A-MAPK pathway. Future studies should explore how QTJD modulates pulmonary immunity through gut microbiota and butyrate production and elucidate its immunoregulatory mechanisms along the gut-lung axis using multi-omics approaches. Full article

Aging and neurodegenerative diseases are characterized by common features involving bioenergetics deficiencies, oxidative stress and alterations of calcium buffering. Mechanisms of mitochondrial-targeted drugs include the modulation of electron transport chain and oxidative phosphorylation, the binding to mitochondrial lipids, free-radical scavenging, calcium signaling, and possible effects on mitochondrial biogenesis and dynamics and on the regulation of mitophagic pathways. One of the main sites of action of mitochondria-targeted drugs is the interaction with respiratory chain components. Mitochondrial-targeted compounds such as Mito-Q, and Mito-apocynin have been developed by conjugating triphenylphosphonium (TPP⁺) lipophilic cation group with natural molecules, therefore obtaining promising drugs for reestablishing the correct functioning of the mitochondrial respiratory chain. Stabilization of cardiolipin at the inner mitochondrial membrane by elamipretide or SkQ1 and mitochondria-targeted ROS scavengers can also offer a therapeutic approach to prevent bioenergetic impairment associated with several diseases. In addition, the modulation of calcium signaling can be achieved using both MCU agonists and antagonists representing another mitochondrial target for drug therapies development. Finally, potential strategies for treating neurodegenerative diseases based on the modulation of mitochondrial biogenesis, dynamics and/or mitophagic pathways are discussed. Full article

Background: Triple-negative breast cancer (TNBC) is an aggressive subtype of cancer with poor clinical outcomes. There is a critical need to identify novel, druggable targets for TNBC to improve therapy response and patient outcomes. Due to their roles in critical processes driving cancer progression, kinases have been a major focus of drug discovery efforts. The role of extracellular signal-regulated kinase 5 (ERK5) in mediating TNBC extracellular matrix (ECM) has previously been described in 2D culture and in vivo. Here, we characterized the impact of ERK5 on breast cancer biology in 2D culture, 3D spheroids, and our 3D breast adipose-macrophysiological system (BA-MaPS). Methods: We assessed migration changes in MDA-MB-231 parental and ERK5-knockout (ERK5-ko) cells cultured in the three in vitro models using transwell, scratch, and spheroid pseudo-migration assays. Differential gene expression among these cell lines in the three platforms was assessed by RNA sequencing and pathway analysis. Stromal remodeling of adipocytes and matrix was evaluated by H&E and Masson’s Trichrome. Results: Across the in vitro models, ERK5 deletion impaired TNBC cell migration. ERK5-mediated transcriptomic changes included genes associated with epithelial-to-mesenchymal transition (EMT) and migration, with further analysis showing significant alterations in core and associated matrisome. Histological staining corroborated the downregulation of collagen with ERK5 depletion in the BA-MaPS. The NFκB pathway was significantly upregulated only in the ERK5-ko 2D-cultured cells, not in 3D spheroids nor the BA-MaPS model. Conclusions: These results indicate a link between ERK5 and TNBC progression through regulation of TME remodeling, EMT, and cell motility. Differences in 2D culture, 3D spheroid, and BA-MaPS underscore the importance of using physiologically relevant models in breast cancer research. Full article

Intravenous thrombolysis with recombinant tissue-type plasminogen activator (tPA) remains a keystone of acute ischemic stroke treatment but in a subset of patients is complicated by angioedema, a potentially life-threatening adverse event largely mediated by bradykinin signaling. The unpredictable and idiosyncratic nature of this reaction has long suggested an underlying genetic contribution, yet its molecular architecture has remained poorly characterized. We hypothesized that alteplase-associated angioedema represents a multigenic susceptibility phenotype, arising from the convergence of rare genetic variants across multiple interacting physiological systems rather than from a single causal variant. To explore this hypothesis, we performed clinical exome sequencing in a cohort of 11 patients who developed angioedema following alteplase administration. Rather than identifying a shared pathogenic variant, we observed distinct yet convergent patterns of genetic vulnerability, allowing patients to be grouped according to dominant, but overlapping, biological axes. These included alterations affecting bradykinin regulation (e.g., ACE, SERPING1, XPNPEP2), endothelial structure and hemostasis (e.g., VWF, COL4A1), neurovascular and calcium signaling (e.g., SCN10A, RYR1), and vascular repair or remodeling pathways (e.g., PSEN2, BRCA2). Notably, many of the identified variants were classified as Variant of Uncertain Significance (VUS) or likely benign significance in isolation. However, when considered within an integrated, pathway-based framework, these variants can be interpreted as capable of contributing cumulatively to system level fragility, a phenomenon best described as “contextual pathogenicity”. Under the acute biochemical and proteolytic stress imposed by thrombolysis, this reduced physiological reserve may allow otherwise compensated vulnerabilities to become clinically manifest. Together, these findings support a model in which severe alteplase-associated angioedema appears as an emergent property of interacting genetic networks, rather than a monogenic disorder. This systems level perspective underscores the limitations of gene centric interpretation for adverse drug reactions and highlights the potential value of pathway informed, multi-genic approaches to risk stratification. Such frameworks may ultimately contribute to safer, more personalized thrombolytic decision, while providing a conceptual foundation for future functional and translational studies. Full article

Glioblastoma multiforme (GBM) is characterized by aggressive growth, extensive vascularization, high metabolic malleability, and a striking capacity for therapy resistance. Current treatments involve surgical resection and concomitant radiation therapy and chemotherapy, prolonging survival times marginally due to the therapy resistance that is built up by the tumor cells. A growing body of research has identified exosomes as critical enablers of therapy resistance. These nanoscale vesicles enable GBM cells to disseminate oncogenic proteins, nucleic acids, and lipids that collectively promote angiogenesis, maintain autophagy under metabolic pressure, and suppress apoptosis. As interest grows in targeting tumor communication networks, exosome-based therapeutic strategies have emerged as promising avenues for improving therapeutic outcomes in GBM. This review integrates current insights into two complementary therapeutic strategies: inhibiting exosome biogenesis and secretion, and engineering exosomes as precision vehicles for the delivery of anti-tumor molecular cargo. Key molecular regulators of exosome formation—including the endosomal sorting complex required for transport (ESCRT) machinery, tumor susceptibility gene 101 (TSG101) protein, ceramide-driven pathways, and Rab GTPases—govern the sorting and release of factors that enhance GBM survival. Targeting these pathways through pharmacological or genetic means has shown promise in suppressing angiogenic signaling, disrupting autophagic flux via modulation of autophagy-related gene (ATG) proteins, and sensitizing tumor cells to apoptosis by destabilizing mitochondria and associated survival networks. In parallel, advances in exosome engineering—encompassing siRNA loading, miRNA enrichment, and small-molecule drug packaging—offer new routes for delivering therapeutic agents across the blood–brain barrier with high cellular specificity. Engineered exosomes carrying anti-angiogenic, autophagy-inhibiting, or pro-apoptotic molecules can reprogram the tumor microenvironment and activate both the intrinsic mitochondrial and extrinsic ligand-mediated apoptotic pathways. Collectively, current evidence underscores the potential of strategically modulating endogenous exosome biogenesis and harnessing exogenous engineered therapeutic exosomes to interrupt the angiogenic and autophagic circuits that underpin therapy resistance, ultimately leading to the induction of apoptotic cell death in GBM. Full article

Inflammation is strongly related to the development of multiple chronic diseases, such as cardiovascular and autoimmune diseases, and is considered a crucial target for new therapeutic approaches, since it significantly impacts public health, contributes to high mortality rates, and decreases the quality of life. Conventional anti-inflammatory approaches are commonly used, but they present multiple limitations, such as undesirable side effects and low target-specificity. Medicinal plants and their bioactive phytochemical compounds have been studied in recent years and are considered promising alternatives to classical therapies. They are widely recognized for their capacity to modulate inflammatory pathways, regulate inflammatory responses, and consequently reduce inflammation and related symptoms. Although they are considered a good therapeutic alternative, their application in the human body is limited by certain characteristics, such as low solubility, which leads to rapid metabolism and excretion by the organism, significantly reducing bioavailability; for these reasons, the use of medicinal plants remains a biopharmaceutical challenge. Nanotechnology represents a promising tool in this context, since it can improve several characteristics of these compounds. By incorporating plant-derived compounds in nanosystems, considerable advantages, including sustained release, protection from degradation, an increase in the specificity to target tissues, and consequent reduction in toxicity, can be achieved. Thus, nanosystems promote more favorable therapeutic outcomes. This work aims to compile scientific evidence supporting the use of medicinal plants and their bioactive phytochemical compounds, incorporated in nanosystems, in inflammatory disorders. This review enlarges knowledge by integrating both in vitro and in vivo studies involving multiple medicinal plants and bioactive phytochemical compounds, describing their mechanisms of action and the nanosystems employed for drug delivery. In the future, the need for deeper mechanistic studies, the development of targeted and stimuli-responsive systems, and advancement toward clinically translatable, sustainable, and cost-effective plant-based nanotherapies is required. Full article

During viral infection, NLR family CARD domain-containing protein 5 (NLRC5) participates in innate immunity through multiple mechanisms. These include regulating type I interferon and related immune factor expression, as well as modulating immune cell functions, such as cytotoxic T lymphocytes (CTLs) and macrophages, thereby promoting antiviral defence and maintaining immune homeostasis. Our study demonstrates that (1) Enterovirus 71 (EV71) infection upregulates NLRC5 expression through the RIG-I-IRF3-mediated IFN-β pathway, which in turn promotes MHC-I molecule expression and (2) NLRC5 suppresses EV71 replication and simultaneously restrains excessive inflammatory responses by fine-tuning IFN-β production through a negative feedback loop. This loop operates via two distinct mechanisms, namely, direct downregulation of key IFN-β pathway mediators (e.g., RIG-I and IRF3) and binding to the 5′UTR of the EV71 genome to inhibit viral replication, thereby indirectly dampening the IFN-β signal. Furthermore, we show that EV71 activates the NLRC5-dependent MHC-I response in an IFN-β-dependent manner. Collectively, these results elucidate the dual role of NLRC5 during EV71 infection, offering novel insights into viral pathogenesis and highlighting potential targets for antiviral drug development. Full article

Background/Objectives: Ginger (Zingiber officinale Roscoe) is a flowering plant widely used as a spice and natural medicine for millennia. Ginger demonstrates multiple protective effects, regulates cholesterol, and may reduce the risk of cancer and colitis. However, little attention has been paid to its potential to cause herb–drug interactions (HDIs). The aim of this study was to investigate the interaction of ginger extract and its major components [⁶]-gingerol and [⁶]-shogaol with clinically relevant uptake and efflux transporters in vitro. Methods: Transporter-overexpressing cell lines of 25 uptake transporters and inside-out membrane vesicles containing 8 efflux transporters were employed to measure potential interactions. Results: Zingiber officinale extract at 150 µg/mL interacted with 17 of 33 transporters examined. These were further investigated for interactions with the purified active components. Seven and 16 transporters interacted with pure [⁶]-gingerol (100 µM) and [⁶]-shogaol (100 µM), respectively. To evaluate the risk of in vivo inhibition, IC₅₀ values were determined for the affected transporters. Based on standard risk assessment calculations, we confirmed previously reported inhibitory effects of ginger components on MDR1 (67.64 µM) and BCRP (9.931 µM), and revealed novel potential interactions with renal OAT3 (0.956 µM) and URAT1 (5.887 µM), hepatic OCT1 (4.287 µM) and BSEP (25.45 µM), and the ubiquitously expressed ENT1 (11.62 µM) ([⁶]-shogaol IC₅₀ values are shown in parentheses). Strong and isoform-selective inhibition of OAT3 by [⁶]-shogaol is particularly intriguing. Additionally, via cell viability experiments on a set of human cervical, breast, and oropharyngeal cancer cell lines, we demonstrated the antiproliferative effect of [⁶]-shogaol in vitro. Conclusions: Prolonged consumption of high-dose ginger supplements may pose a risk of transporter-mediated HDIs when consumed concomitantly with conventional medications. Our study encourages follow-up of the suspected effects in vivo. Full article

Non-AIDS-defining cancers (NADCs) have emerged as an increasingly prominent cause of non-AIDS-related morbidity and mortality among people living with HIV (PLWH). However, the scarcity of NADC clinical samples, compounded by privacy and security constraints, continues to present formidable obstacles to advancing pathological and clinical investigations. In this study, we adopted a joint analysis strategy and deeply integrated and analyzed transcriptomic data from 12,486 PLWH and cancer patients to systematically identify potential key regulators for 23 NADCs. This effort culminated in NADCdb—a database specifically engineered for NADC pathological exploration, structured around three mechanistic frameworks rooted in the interplay of immunosuppression, chronic inflammation, carcinogenic viral infections, and HIV-derived oncogenic pathways. The “rNADC” module performed risk assessment by prioritizing genes with aberrant expression trajectories, deploying bidirectional stepwise regression coupled with logistic modeling to stratify the risks for 21 NADCs. The “dNADC” module, synergized patients’ dysregulated genes with their regulatory networks, using Random Forest (RF) and Conditional Inference Trees (CITs) to identify pathogenic drivers of NADCs, with an accuracy exceeding 75% (in the external validation cohort, the prediction accuracy of the HIV-associated clear cell renal cell carcinoma model exceeded 90%). Meanwhile, “iPredict” identified 1905 key immune biomarkers for 16 NADCs based on the distinct immune statuses of patients. Importantly, we conducted multi-dimensional profiling of these key determinants, including in-depth functional annotations, phenotype correlations, protein–protein interaction (PPI) networks, TF-miRNA-target regulatory networks, and drug prediction, to deeply dissect their mechanistic roles in NADC pathogenesis. In summary, NADCdb serves as a novel, centralized resource that integrates data and provides analytical frameworks, offering fresh perspectives and a valuable platform for the scientific exploration of NADCs. Full article