Search Results (13,199)

Background: Diffuse Large B-cell Lymphoma (DLBCL) is a biologically heterogeneous subtype of non-Hodgkin’s lymphoma (NHL), accounting for 30–40% of cases worldwide. Despite the incorporation of rituximab into standard chemo-immunotherapy regimen, approximately one-third of patients present with relapsed or refractory disease, implicating the need for improved prognostic markers and therapeutic targets. Gene expression profiling successfully classified DLBCL into Germinal Center B-cell-like (GCB) and non-GCB subtypes, which differ in genetic alterations, response to therapy, and clinical outcome. While intrinsic tumor biology has been extensively studied, the contribution of the tumor microenvironment (TME) to disease progression and therapeutic resistance still remains incompletely understood. Methods: In this study, we investigated the mutational landscape of stromal-related genes in DLBCL and evaluated their impact on gene expression, downstream signaling pathways, and tumor progression. Results: A total of 176 DLBCL patients were screened, of which 113 were enrolled based on availability of complete clinical data. The cohort demonstrated male predominance (male:female ratio: 2.1:1), advanced disease stage in 72.6% of patients, and elevated serum lactate dehydrogenase levels in 57.5%. Based on immunohistochemistry, 43.4% cases were classified as GCB-DLBCL and 56.6% as non-GCB DLBCL. Although the International Prognostic Index (IPI) retained prognostic significance for event-free survival (EFS) and overall survival (OS), considerable heterogeneity was observed within similar risk groups. Whole-exome sequencing (WES) uncovered recurrent somatic mutations in key oncogenic and epigenetic regulators, including TNFAIP3, NFIB, NOTCH1, TSC2, EZH2, EP300, KMT2D, and B2M, with subtype-specific distribution. Pathway enrichment analysis implicated role of Notch, Wnt, mTOR, JAK-STAT, TGF-β, and antigen-presentation pathways. Comprehensive WES analysis identified multiple novel mutations in genes associated with the stromal/extracellular matrix with distinct patterns in GCB and non-GCB DLBCL, accompanied by concordant alterations in gene expression profiles, suggesting functional relevance within the TME. Functional validation through primary cell culture demonstrated significantly elevated Th2 (IL-4, IL-6, IL-10) and Th17 (IL-17) cytokines in co-cultures containing both neoplastic cells and stromal components, underscoring the role of TME in DLBCL progression. Conclusions: Taken together, this study provides novel insights into stromal mutational signatures and cytokine-mediated tumor–stroma interactions, offering potential prognostic biomarkers and therapeutic targets for the improved management of DLBCL. Full article

The gut microbiome, often termed the human “second genome”, profoundly influences host physiology through metabolic interactions, immune modulation, and gut–brain axis signaling. Dysbiosis is implicated in the pathogenesis of obesity, inflammatory bowel disease (IBD), malignancies, and neuropsychiatric disorders. However, traditional gut microbiota interventions, such as probiotic supplementation and fecal microbiota transplantation (FMT), still exhibit significant limitations in precision therapeutics. Probiotic intervention fails to achieve precise regulation at the strain or genetic level, and although FMT demonstrates definitive efficacy against recurrent Clostridioides difficile infection (rCDI), its therapeutic outcomes and safety profiles show marked interindividual variability in ulcerative colitis (UC), metabolic syndrome, and other diseases, with insufficient treatment specificity to meet the practical demands of clinical precision intervention. Recent advancements in genome editing technologies, particularly Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)–CRISPR-associated (Cas) proteins systems and base editors, have enabled targeted functional manipulation of specific gut commensals and optimization of community architectures. These engineered strategies, combined with sophisticated delivery systems, demonstrate substantial potential in disease treatment, diagnostic monitoring, and immune modulation. This review systematically examines core editing methodologies, innovative delivery platforms, and targeted design strategies, elucidating their applications in metabolic disorders, IBD, cancer immunotherapy, and neuropsychiatric conditions. We critically analyze current technical bottlenecks and biosafety concerns while prospecting future directions, including in situ editing, artificial intelligence (AI)-driven design, and personalized engineering. Collectively, these insights aim to facilitate the clinical translation of gut microbiome engineering from bench to bedside. Full article

Natural products are the fundamentals of drug discovery due to their exceptional structural diversity and biological activity’s evolutionary optimization. The review provides a critical and integrative analysis of natural products in pharmaceutical chemistry, highlighting their significance for current biomedicine and pharmacotherapy. The review is organized around a system that connects structure, function, and translation, focusing on structural analysis, scaffold design, and mechanistic understanding in major disease-relevant therapeutic areas. Investigations on representative compounds like paclitaxel, artemisinin, and curcumin are presented to explain the way molecular architecture regulates pharmacological activity, drug selectivity, and clinical performance. The review evaluates significant medicinal chemistry strategies, including semisynthetic modification, prodrug design, and scaffold optimization, and their crucial roles in enhancing potency, pharmacokinetics, and safety. We critically examine the latest advancements in drug delivery technologies, particularly those based on nanotechnology and carrier-free methods, regarding their translational potential and regulatory concern. Current challenges pertaining to pharmacokinetics and ADMET properties, as well as the standardization of analysis, are also examined, emphasizing their impact on reproducibility in research. Researchers investigate the role and limitations of emerging fields such as genome mining, synthetic biology, and network pharmacology in enhancing discovery pipelines. Thus, this review integrates chemical, pharmacological, and translational approaches and suggests an effective strategy to overcome challenges in the development of natural products as the next generation of precision medicine therapeutic agents. Full article

CRC remains a major cause of cancer-related morbidity and mortality worldwide. In recent years, the gut microbiota has gained increasing attention in CRC research. Intestinal microbes are not passive bystanders in tumor development. They may promote persistent inflammation, disrupt epithelial barrier integrity, alter microbial metabolites, and affect host immune and signaling pathways. Emerging evidence also suggests that microbiota-related metabolites and microbial functional alterations may influence host epigenetic regulation, including DNA methylation and chromatin-associated signaling, thereby further shaping colorectal carcinogenesis. Together, these changes can create a microenvironment that favors tumor initiation and progression. Several bacterial species, including Fusobacterium nucleatum, Parvimonas micra, and Peptostreptococcus anaerobius, have been repeatedly associated with CRC. In contrast, beneficial commensal microbes and their metabolites, especially short-chain fatty acids, may help maintain intestinal homeostasis and limit tumor-promoting processes. Because the gut microbiota is strongly shaped by diet, lifestyle, and environmental exposure, regional differences are also relevant. This is particularly important in Sichuan, China, where distinctive dietary habits and environmental features may influence microbial patterns associated with CRC risk and disease behavior. This review summarizes the main mechanisms linking the gut microbiota to CRC, examines the regional context of Sichuan, China, and discusses current and emerging clinical strategies. These include dietary intervention, probiotics, fecal microbiota transplantation, and microbiome-informed approaches to prevention, diagnosis, and treatment. Full article

Multiple Sclerosis (MS) is a neuroinflammatory disorder in which genetic and environmental factors contribute to disease onset. Evidence implicates the inflammasome pathway in MS pathophysiology. However, the interaction between inflammasome-related genetic variants and 25-OH-vitamin D₃ (25(OH)D₃) levels remains unclear. 105 MS patients and 109 healthy controls were enrolled. Genotyping of NLRP3 (rs10754558, rs3806265) and NLRC4 (rs479333) polymorphisms was performed using real-time PCR. Serum 25(OH)D₃ levels were measured by high-performance liquid chromatography. Clinical severity was assessed using the Expanded Disability Status Scale (EDSS), Multiple Sclerosis Severity Score (MSSS), annualized relapse rate (ARR), and age at onset. MS patients showed significantly lower serum 25(OH)D₃ levels than controls. Genotype distributions did not differ significantly under an additive model; however, the NLRP3 rs10754558 GG genotype was more frequent in MS patients under a recessive model and was significantly associated with disease status after adjustment for sex. Subjects carrying the GG genotype also had significantly lower serum 25(OH)D₃ levels than CC/CG carriers, independently of sex. No significant associations were observed for NLRP3 rs3806265 or NLRC4 rs479333, and none of the investigated variants was associated with EDSS, MSSS, ARR, or age at onset. The NLRP3 rs10754558 polymorphism may be associated with MS susceptibility and reduced circulating vitamin D levels, suggesting a potential link between inflammasome-related genetic variability and immunometabolic regulation in MS. Full article

With colorectal cancer (CRC) accounting for over 1.9 million new cases and 930,000 deaths globally in 2020, there is a critical need for innovative indicators to forecast disease advancement and therapeutic outcomes. The gut microbiome has emerged as a fertile area for discovering such diagnostic and prognostic signals. This narrative review collected current evidence on intestinal microorganisms and their metabolic products as candidate markers for CRC control. Intestinal communities influence malignancy through diverse mechanisms, including metabolic shifts, immune modulation, inflammation, proliferation/apoptosis regulation, genotoxicity, and mucosal barrier disruption. Pathogenic species, such as Fusobacterium nucleatum and enterotoxigenic Bacteroides fragilis, facilitate tumorigenesis via FadA-mediated signaling and Th17/IL-17 responses. In contrast, beneficial taxa like Faecalibacterium prausnitzii and Akkermansia muciniphila provide protective effects through short chain fatty acid production. Macrophage phenotype physiological equilibrium is altered and inflammatory status fluctuates under the former. Metabolically, hydrogen sulfide damages mitochondrial DNA and secondary bile acids stimulate cellular proliferation. While 16S rRNA sequencing and shotgun metagenomics are established detection strategies, innovative platforms like organoids and gene arrays remain in the exploratory stage. Clinical data indicates that F. nucleatum aligns with advanced tumor stage, and its combined detection with colibactin-producing E. coli achieves high sensitivity for early-stage screening. Additionally, A. muciniphila levels can anticipate the efficacy of PD-1 blockade immunotherapy. Microbiota-derived tools represent a transformative direction in oncology. Future research must focus on standardizing protocols and validating multi-marker panels to enhance clinical translation. Full article

Three-dimensional (3D) bioprinting has rapidly evolved into a controlling platform for the fabrication of patient-specific biomedical implants, with growing importance in advanced drug delivery systems. Beyond structural tissue engineering, bioprinted constructs now function as programmable therapeutic depots capable of localized, sustained, and stimuli-responsive drug release. This review focuses on recent biomaterial design strategies that enable precise control over drug encapsulation, retention, and release kinetics within 3D bioprinted architectures. The physicochemical and mechanical properties of bioinks, including crosslinking density, porosity, degradation behavior, viscoelasticity, and swelling characteristics, directly influence drug loading efficiency and release dynamics under physiological conditions. The rational tuning of these parameters allows the development of constructs that provide spatially controlled and temporally regulated therapeutic delivery. Recent advances in predictive modeling, such as finite element modeling (FEM), data-driven machine learning approaches, and ML, have significantly improved the ability to correlate material composition, printing parameters, and structural geometry with drug diffusion and degradation-mediated release mechanisms. These tools facilitate the optimization of printing variables including extrusion pressure, nozzle diameter, and layer resolution to ensure structural fidelity while maintaining therapeutic functionality. Emerging strategies incorporating multi-material printing, gradient architectures, and stimuli-responsive biomaterials have expanded the potential of 3D bioprinting for combination therapies and personalized medicine. This review discusses key challenges in translating bioprinted drug delivery systems into clinical applications, including the standardization of drug release characterization methods, and long-term stability assessment. Full article

Neuropathic pain remains a major clinical challenge due to its complex pathophysiology and limited treatment efficacy. Recent evidence suggests that vitamin D, beyond its classical role in bone and mineral metabolism, exerts neuroprotective and immunomodulatory effects that may influence pain perception. This review synthesizes current findings on the relationship between vitamin D status and neuropathic pain, highlighting potential mechanisms such as modulation of neuroinflammation, regulation of neuronal excitability, and influence on neurotransmitter pathways. Observational studies frequently report an association between vitamin D deficiency and increased pain severity, while interventional trials indicate that supplementation may alleviate neuropathic symptoms in specific populations. However, results remain heterogeneous, and mechanistic studies are still emerging. Understanding the interplay between vitamin D and neuropathic pain could open new avenues for adjunctive therapeutic strategies and personalized medicine approaches. Further high-quality clinical trials and mechanistic research are warranted to clarify causality and optimize clinical applications. Full article

Background: Rotenone is a widely used environmental pesticide, and epidemiological studies suggest that exposure is associated with an increased risk of Parkinson’s disease (PD); however, the molecular toxicological basis of this association remains incompletely defined. Ferroptosis is an iron-dependent, lipid peroxidation-driven form of regulated cell death that is relevant to PD and other neurodegenerative disorders. In this study, we provide disease-contextual functional evidence linking ferroptosis to rotenone-induced PD-like neurotoxicity. Methods: We combined network toxicology, human PD substantia nigra transcriptomic analysis using GSE7621, and SH-SY5Y cell-based validation. Rotenone-associated targets were predicted and analyzed for ferroptosis-related enrichment, PD transcriptomic signatures were used for disease-contextual candidate prioritization, and selected findings were validated using qPCR, CCK-8, Western blotting, C11-BODIPY lipid peroxidation staining, and transmission electron microscopy. Results: By further integrating a human PD substantia nigra transcriptomic dataset (GSE7621), we prioritized an 11-gene, PD-contextualized ferroptosis-associated candidate module (LIPF, FAM170A, MCHR1, IL17A, MYB, GFAP, ARMC3, GKN1, GATA3, IL17F, and TEKT1). In SH-SY5Y cells, rotenone exposure consistently upregulated this candidate transcriptional module, and this induction was broadly attenuated by the ferroptosis inhibitor ferrostatin-1 (Fer-1). In parallel, orthogonal functional assays supported an iron- and lipid peroxidation-driven injury state under rotenone exposure that was suppressible by ferroptosis inhibition and iron chelation. Finally, we further performed an exploratory drug–gene association screen to prioritize clinically available candidates, and a limited qPCR check suggested that several selected compounds partially attenuated representative hub-gene induction under rotenone exposure. Conclusions: Collectively, these findings provide disease-contextual and experimentally supported evidence linking rotenone exposure to ferroptosis-associated neurotoxicity, and identify a ferroptosis-responsive transcriptional module for future hypothesis-driven mechanistic investigation. Full article

Drug exposure during pregnancy and early life is typically considered a short-term clinical intervention rather than a determinant of long-term pharmacological outcomes. Consequently, the developmental context is largely absent from drug discovery and drug development paradigms, where efficacy, safety and target engagement are evaluated predominantly in adult, steady-state systems. This disconnect may contribute to unexplained variability in drug response and toxicity later in life. Pregnancy is accompanied by dynamic remodeling of the maternal gut microbiota and its metabolic output, generating bioactive microbial metabolites that regulate immune tone, metabolic homeostasis and the expression of drug-metabolizing enzymes and transporters. These microbial signals intersect with pharmacological interventions across gestation, shaping maternal pharmacokinetics, placental regulation and fetal drug exposure during developmentally sensitive windows. Importantly, microbiota–drug interactions initiated during pregnancy do not terminate at birth. Instead, they extend into infancy through vertical microbial transmission, breast milk-mediated metabolic signaling, and the immaturity of neonatal drug-handling systems, collectively contributing to developmental programming of drug responsiveness beyond early life. In this review, we propose a microbiota-informed framework that reframes perinatal drug exposure as a developmentally embedded signal operating across a maternal–placental–infant continuum. This perspective introduces a missing developmental dimension into drug discovery and highlights new opportunities to improve translational predictability and precision pharmacotherapy across the life course. Full article

Background/Objectives: Plant-based diets are increasingly adopted by families with young children, yet their potential effects on bone development and metabolic regulation during early childhood remain insufficiently understood. This study aimed to evaluate body composition, bone mineral density (BMD), biochemical markers of bone turnover, and adipokine profiles in healthy children aged 5–6 years adhering to lacto-ovo-vegetarian or omnivorous diets. Methods: A cross-sectional analysis was conducted in a well-characterized cohort of 90 healthy normal-weight children consuming either lacto-ovo-vegetarian or omnivorous diets. Body composition and bone mineral density were measured using dual-energy X-ray absorptiometry, and circulating markers of bone formation, resorption, and adipokines were determined using ELISA methods. Correlation analyses were performed to examine the relationships between anthropometric variables, bone parameters, and adipokines. Results: No significant differences were observed between vegetarian and omnivorous diets in anthropometric characteristics, bone mineral content (BMC), or BMD, indicating comparable skeletal status. However, vegetarian children exhibited significantly higher levels of bone turnover markers, including bone alkaline phosphatase (BALP) (p = 0.023) and C-terminal telopeptide of type I collagen (CTX-I) (p = 0.035), and a lower osteocalcin OC/CTX-I ratio (p = 0.027). These findings may suggest a subtle imbalance in bone remodeling dynamics in these children, although their clinical significance remains uncertain. Additionally, higher levels of carboxylated osteocalcin (Gla-OC) (p = 0.022) and an increased carboxylated to undercarboxylated OC (Gla-OC/Glu-OC) ratio (p = 0.005) were observed in vegetarian children. Among adipokines, vegetarian children showed lower HMW adiponectin levels (p = 0.05) and a lower HMW/total adiponectin ratio (p = 0.012). Correlation analyses revealed distinct metabolic patterns between groups. In vegetarian children, bone parameters were primarily associated with lean mass, indicating the predominant role of mechanical factors in skeletal development. In contrast, omnivorous children demonstrated a more integrated relationship between bone indices and adipokines. Conclusions: In conclusion, while a lacto-ovo-vegetarian balanced diet supports normal bone mass in early childhood, it may be associated with subtle alterations in bone metabolism and its regulatory pathways, including adipokine profiles. These findings highlight the importance of adequate dietary planning and underscore the need for longitudinal studies to determine long-term effects on bone status. Full article

Background/Objectives: This study explored parents’ perspectives regarding digital media use in children and adolescents with neurodevelopmental disorders (NDs) and examined how these views vary according to family and clinical characteristics. Methods: Data were collected from an Italian survey involving 352 families. Items assessed the perceived effects of digital devices on child development and parenting, awareness of screen time guidelines, and use of time- and content-limiting tools. Quantitative analyses were complemented by a reflexive thematic analysis of open-ended responses describing how digital media influenced parenting. Results: Parents expressed divergent attitudes towards digital media, with broadly similar proportions reporting positive, neutral, and negative views regarding both child development and parenting. More favourable views were associated with greater perceived benefits for children and were more frequent among parents of children with more severe functional disabilities. About half had discussed screen use with health professionals, and most were aware of existing guidelines. Thematic analysis identified six themes related to digital parenting: educational means (digital devices as tools for communication, learning, and socialisation), entertainment (screens as a source of leisure or behavioural management), reward (digital media used as reinforcement), screen time as a “necessity” (technology as an integral and sometimes rehabilitative part of daily life), negative effects on the child (concerns about detachment, reduced social interaction, and mood dysregulation), and parental behaviour and attitudes (reflecting the emotional burden of regulation and broader beliefs about digital media). Conclusions: Parents of children with NDs navigate digital media use through a complex balance of perceived risks and benefits. Findings highlight the need for family-centred guidance and assistive technology approaches that promote digital inclusion while addressing parental stress and regulatory challenges. Full article

Background: Treatment-resistant depression (TRD) represents a major clinical challenge and is increasingly associated with persistent neuroinflammatory processes. Evidence suggests that dysregulation of the immune system, particularly the imbalance between pro-inflammatory and anti-inflammatory cytokines, contributes to poor therapeutic response. In this context, interleukin-10 (IL-10) has emerged as a key mediator in regulating the inflammatory response. Objective: To systematically analyze the evidence on neuroimmune dysregulation in depression, with an emphasis on TRD, and to evaluate the potential role of IL-10 as a biomarker and modulator of therapeutic response. Methods: A systematic review was conducted in accordance with PRISMA guidelines. Fourteen studies were included, comprising randomized clinical trials, longitudinal studies, a prospective cohort study, and exploratory designs. Methodological quality was assessed using the RoB 2 tool and complementary approaches. Data were integrated through a qualitative analysis focused on inflammatory biomarkers and clinical outcomes. Results: The studies consistently showed an association between elevated levels of pro-inflammatory cytokines, such as IL-6 and TNF-α, and the severity of depressive symptoms, as well as reduced response to conventional treatments. Immunomodulatory interventions, including ketamine, pentoxifylline, and minocycline, were associated with clinical improvement, particularly in patients with elevated baseline inflammation. IL-10 appears to be involved in counter-regulatory neuroimmune processes associated with inflammatory balance. Conclusions: Neuroinflammation plays a central role in TRD. IL-10 may serve as a relevant biomarker and a potential target for personalized therapeutic strategies informed by immune profiles, through modulation of neuroinflammatory pathways. Full article

Introduction: SGLT2 inhibitors reduce renal composite endpoints and proteinuria, yet RCTs uniformly show an acute eGFR dip within 2 weeks to 2 months after initiation. However, demographic and clinical predictors of an acute eGFR dip demonstrate considerable heterogeneity across studies. This study aims to identify urinary protein biomarkers of this early eGFR dip and integrate them with routine variables to build a clinically actionable prediction model. Methods and analysis: This three-stage proteomics study includes retrospective discovery, prospective internal validation, and external validation cohorts (total n ≈ 600–700). DIA mass spectrometry will screen for urinary proteins associated with ≥10% eGFR decline at 1 month post-SGLT2i initiation in CKD stages 3–4. Top candidates (FDR < 10%, FC > 1.5, ion intensity > 1 × 10⁴, unique gene families) will be validated by ELISA. A LASSO-logistic regression model will integrate the top three proteins with seven routinely available clinical variables: age, BMI, diabetes status, heart failure, systolic blood pressure, baseline eGFR, and diuretic use. Model performance will be assessed using the C-statistic, NRI, IDI, and calibration metrics. Adaptive stopping rules are pre-specified. Ethics and dissemination: Approved by the Ethics Review Committee at Chinese PLA General Hospital (S2025-859-02, 2025KY126-KS002), all participants will provide written informed consent prior to enrollment, and the study will adhere to the Declaration of Helsinki. Data will be pseudonymized and stored securely according to institutional regulations. Findings will be published in peer-reviewed journals and presented at international nephrology conferences. Trial Registration: Registered Report Identifier: ChiCTR2600119772. Date of registration: 3 March 2026. Full article

C. asiatica (L.) Urban is a medicinal plant widely used in traditional Asian medicine with potential geroprotective properties. Its major bioactive compounds—including asiaticoside, madecassoside, asiatic acid, and madecassic acid—exhibit antioxidant, anti-inflammatory, regenerative, neuroprotective, and cytoprotective activities. Experimental studies demonstrate modulation of signaling pathways involved in oxidative stress, inflammation, apoptosis, extracellular matrix remodeling, and cellular survival, including NF-κB, PI3K/Akt/mTOR, MAPK, Nrf2/HO-1, and TGF-β/Smad pathways. Preclinical evidence further indicates attenuation of cellular senescence, improvement of mitochondrial function, enhanced collagen synthesis, and regulation of cytokine production. In experimental models, C. asiatica has shown beneficial effects on wound healing, skin aging, neuroinflammation, β-amyloid aggregation, neuroplasticity, metabolic dysfunction, and vascular protection. Preliminary preclinical findings also suggest possible effects on telomerase activity and telomere maintenance. However, clinical translation remains limited due to insufficient randomized controlled trials, low oral bioavailability of triterpenoids, variability in extract standardization, and limited pharmacokinetic and long-term safety data. This narrative review summarizes the phytochemistry, molecular mechanisms, pharmacological activities, and potential geroprotective applications of c. asiatica, highlighting its translational relevance in healthy aging and age-related disorders while emphasizing the need for standardized clinical studies. Full article