Search Results (4,139)

Complex Regional Pain Syndrome (CRPS) is a chronic pain disorder with several sensory, autonomic, motor, and trophic symptoms. Diagnosis is based on clinical criteria like the Budapest Criteria, but there are limitations to those criteria, especially for pediatric cases and different clinical presentations. Technical testing—including laboratory tests, electrophysiological studies, sensory and autonomic function tests, and more advanced imaging—provides supportive, but not definitive, evidence. Biomarkers such as certain microRNAs, inflammatory mediators, and autoantibodies may offer the potential for improved diagnostic accuracy, although they have not yet been adequately validated. New imaging techniques, including ultrasound elastography and neuroimaging, have identified both peripheral and central pathophysiological changes in CRPS. We can improve our diagnosis of CRPS by integrating standardized clinical criteria with technical evaluations and biomarker improvements; this should serve to make diagnosis earlier, reduce diagnostic delay, and promote individualized treatment. Full article

As apex predators, felids (Felidae) face unresolved phylogenetic controversies due to their recent rapid speciation and remarkable morphological conservatism. Previous studies, often relying on a limited number of genetic markers, were constrained by insufficient data and conflicting phylogenetic signals, leaving these disputes unresolved. Therefore, establishing a robust phylogenetic framework based on larger-scale genomic data is crucial. This study integrated complete mitogenomes from 37 species representing all major felid genera to characterize genomic diversity, selection pressures, and phylogenetic relationships. Results revealed conserved gene content and arrangement patterns but significant intergenic variation in nucleotide composition, with the light-strand encoded ND6 exhibiting pronounced strand-specific bias. Nucleotide diversity was highest in ND4L (Pi = 0.132) and ATP6 (Pi = 0.131), suggesting their utility as novel markers for species delimitation and population studies. Selection pressure analysis indicated strong purifying selection on cytochrome oxidase subunits (e.g., COX1 Ka/Ks = 0.00327) but relaxed constraints on ATP8 (Ka/Ks = 0.12304). Phylogenies reconstructed from the complete 13PCGs + 2rRNAs dataset (showing high congruence between maximum likelihood and Bayesian methods) clearly delineated Felidae into two primary clades (Pantherinae and Felinae), confirming monophyly of all genera and positioning Neofelis nebulosa as the basal lineage within Pantherinae. Crucially, exclusion of ND6 (12PCGs + 2rRNAs) yielded topologies congruent with the complete 13PCGs + 2rRNAs dataset, whereas single-gene or limited multi-gene datasets produced inconsistent trees (particularly at genus-level nodes). This demonstrates that near-complete mitogenomic data (≥12PCGs + 2rRNAs) are essential for reconstructing robust felid phylogenetic frameworks. Our study provides insights into carnivoran mitogenome evolution. Full article

Background/Objectives: Population aging and its associated chronic conditions have become an unprecedented challenge in the United States and worldwide. Many aged individuals experience certain forms of cognitive decline, which increases their risk of developing a pre-dementia condition called mild cognitive impairment and even dementia. No effective pharmacological treatments are available to treat normal age-associated cognitive decline or mild cognitive impairment. Our previous study has shown the potent anti-inflammatory effects of shiitake mushroom-derived vesicle-like nanoparticles (S-VLNs) in vitro and in an acute inflammatory disease model. In this study, we aimed to investigate the potential benefits of orally administered S-VLNs in aged mice. Methods: S-VLNs were extracted from fresh shiitake mushrooms. S-VLNs in phosphate-buffered saline (PBS) or vehicle only was orally administered to 13-month-old male C57BL/6J mice weekly for 9 months. These mice were subjected to a series of physiological tests, followed by euthanasia at 22 months of age. Their fecal samples were subjected to 16S rRNA and untargeted metabolomics analyses, followed by comprehensive bioinformatics analyses. Results: The long-term oral administration of S-VLNs significantly improved the cognitive function of aged mice. Orally administered S-VLNs did not travel to the brain. Instead, they impacted the composition of the gut microbiota and reshaped the fecal metabolome. Functional predictions of the gut microbiota and fecal metabolome suggested that S-VLNs regulated tryptophan metabolism. Specifically, S-VLNs markedly decreased the tryptophan-related metabolite kynurenic acid (KYNA). The integrative analyses of omics data identified a strong correlation between 18 gut bacterial genera and 66 fecal metabolites. KYNA was found to highly correlate with five genera positively and twelve genera negatively. Conclusions: The oral intake of S-VLNs represents a new and superior dietary approach with the ability to modulate the gut microbiota and fecal metabolome and to improve cognitive function during aging. Full article

Chronic periodontitis has emerged as a potential modifiable risk factor for several tumors, yet its role remains underexplored beyond epidemiological associations. This perspective review examines the immunological and molecular interplay between periodontitis and various cancers—including prostate, colorectal, oral squamous cell carcinoma, and oral potentially malignant disorders—highlighting shared inflammatory mediators and immune dysregulation. Special attention is given to immune cell profiles, cytokine expression, dysbiosis, and common miRNA signatures. Recent evidence suggests that periodontitis may act not only as a co-factor in tumor development but also, in some contexts, as a marker of therapeutic response, particularly in patients undergoing immune checkpoint inhibitor therapy. In our view, future research should prioritize mechanistic studies to define common immune–inflammatory pathways and clarify whether periodontitis functions as a field cancerization process or as a facilitator of malignant transformation in already compromised tissues. The relationship between cancer and periodontitis underscores the need to integrate oral health into oncologic care and immunotherapy management. Full article

MicroRNAs (miRNAs), as an integral component of gene regulatory networks, play a critical role in post-transcriptional regulation, maintaining a dynamic balance between miRNA biogenesis and turnover essential for maintaining cellular homeostasis. The regulation of miRNA turnover, particularly through target-directed microRNA degradation (TDMD), is emerging as a key mechanism in gene expression control in response to physiological, developmental, and environmental changes. This process is mediated by the ubiquitin–proteasome system (UPS), where the E3 ligase ZSWIM8 functions as an adaptor to facilitate the recognition and degradation of Argonaute (AGO) proteins, essential components of the miRNA-induced silencing complex (miRISC), thus negatively regulating gene expression. The ZSWIM8–UPS axis contributes to the precise modulation of miRNA levels by targeting AGO proteins for degradation, thereby influencing miRNA stability and function. This review summarizes the mechanisms underlying ZSWIM8-mediated TDMD, its molecular interactions, and the potential therapeutic applications of targeting miRNA turnover pathways. By understanding the regulation of miRNA degradation, we aim to inform future strategies for the clinical manipulation of miRNA-based therapeutics. Full article

Pneumonia caused by Pneumocystis jirovecii poses a serious threat, particularly to immunocompromised patients such as those with HIV/AIDS, transplant recipients, or individuals undergoing chemotherapy. Its diagnosis is challenging because current methods, such as microscopy and certain molecular tests, have limitations in sensitivity and specificity, and require specialized equipment, which delays treatment initiation. In this context, CRISPR-Cas12-based methods offer a promising alternative: they are rapid, highly specific, sensitive, and low-cost, enabling more timely and accessible detection, even in resource-limited settings. We developed a simple and rapid detection platform based on the CRISPR-Cas12 coupled with lateral flow strips. A guide RNA was designed against DHPS, β-tubulin, and mtLSU rRNA genes. The guide corresponding to β-tubulin showed high sensitivity in the detection of P. jirovecii to produce a detectable fluorescence signal within the first 20–30 min. In addition, it demonstrated high specificity for P. jirovecii when DNA from other microorganisms was used. When coupled with lateral flow strips, high sensitivity and specificity were also observed for detecting positive samples, without the need for genetic amplification. CRISPR-Cas12 successfully detected P. jirovecii infection in an initial diagnostic application, demonstrating the potential of this method for integration into public health diagnostic systems, particularly in field, due to its adaptability, speed, and ease of use. Full article

Background/Objectives: Ulcerative colitis (UC) incidence has risen alarmingly worldwide, posing significant clinical challenges due to limitations of therapeutic efficacy and side effects of current drugs. While Polygonatum kingianum polysaccharides (PKPs) exhibit anti-inflammatory and antioxidant properties, their anti-colitis potential remains unexplored. This study aimed to validate the protective effects of PKPs against dextran sulfate sodium (DSS)-induced colitis and elucidate its mechanisms. Methods: Acute UC was induced in C57BL/6J mice by 3% DSS. PKPs (125 mg/kg) were administered via gavage for 10 days. Integrated approaches included histopathology, tight junction protein (ZO-1/Occludin/Claudin-1) immunohistochemistry, inflammatory/oxidative markers (ELISA), Nrf2 pathway proteins (Western blot), 16S rRNA gut microbiota sequencing, fecal untargeted metabolomics (UHPLC-MS), short-chain fatty acids (SCFAs) analysis and combined analysis. Results: PKPs significantly alleviated colitis phenotypes: reduced weight loss, lowered disease activity index (DAI), and attenuated colon shortening. They restored intestinal barrier integrity by upregulating tight junction proteins and reducing plasma Diamine Oxidase (DAO)/D-lactate (D-Lac)/Endotoxin (ET). PKPs suppressed pro-inflammatory cytokines (TNF-α/IL-1β/IL-6) while elevating IL-10, activated the Nrf2/HO-1/NQO1 antioxidant pathway, and reduced oxidative stress (MDA decreased, SOD/GSH increased). Multi-omics revealed PKPs enriched beneficial bacteria (Blautia, Odoribacter, Rikenellaceae_RC9_gut_group), restored SCFAs (acetate/propionate/butyrate), and modulated metabolic pathways (sphingolipid/linoleic acid metabolism). Conclusions: PKPs ameliorate DSS-induced colitis through multi-target mechanisms: (1) preserving intestinal barrier function, (2) suppressing inflammation and oxidative stress via Nrf2 activation, (3) restoring gut microbiota balance and SCFA production, and (4) regulating host-microbiota metabolic interactions. These findings support PKPs as a promising dietary supplement for UC management. Full article

Cardiovascular-kidney-metabolic (CKM) syndrome is a multifaceted, systemic disorder characterized by the interplay of cardiovascular disease (CVD), chronic kidney disease (CKD), type 2 diabetes mellitus (T2DM), and obesity. This review synthesizes current and emerging therapeutic strategies aimed at addressing the shared pathophysiologic mechanisms driving CKM progression, such as insulin resistance, inflammation, oxidative stress, and neurohormonal activation. Established pharmacotherapies that include sodium-glucose cotransporter 2 (SGLT2) inhibitors, glucagon-like peptide-1 receptor agonists (GLP-1 RAs), and nonsteroidal mineralocorticoid receptor antagonists like finerenone have demonstrated robust efficacy in reducing cardiovascular events, slowing renal decline, and improving metabolic outcomes. Additionally, novel agents targeting lipoprotein(a), interleukin-6, and hepatic fat accumulation are expanding the therapeutic landscape. RNA-based therapies, including antisense oligonucleotides (ASOs) and small interfering RNAs (siRNAs), are designed to modulate lipoprotein(a) and PCSK9 expression. Artificial intelligence (AI) is also emerging as a transformative tool for personalized CKM management, enhancing risk prediction and clinical decision-making. The review highlights the relevance of metabolic dysfunction-associated steatotic liver disease (MASLD) as a CKM modifier and discusses the approval of resmetirom, a selective thyroid hormone receptor β agonist, for noncirrhotic MASH. By integrating evidence from clinical trials, mechanistic studies, and emerging technologies, this review provides a comprehensive resource for clinicians and researchers navigating the evolving field of CKM syndrome. Full article

Subclinical coronary atherosclerosis (SCA) is an early stage of coronary artery disease (CAD) that often goes unrecognized until clinical events occur. Identifying circulating molecular biomarkers could improve early diagnosis and risk assessment in asymptomatic individuals. This study employed a two-phase approach to identify plasma extracellular vesicle (EV)-derived microRNAs (miRNAs) associated with SCA. In the discovery phase, plasma samples from male participants were analyzed using Affymetrix GeneChip miRNA 4.0 microarrays. Differentially expressed miRNAs were refined through bioinformatic analysis, cross-species comparison with murine data, and target gene prediction. In the validation phase, six candidate miRNAs were quantified by RT-qPCR in an independent cohort. Six miRNAs were differentially expressed between individuals with SCA and controls. Among these, the combination of miR-146b-5p, miR-4701-3p, and miR-1180-3p demonstrated a high discriminative capacity for SCA (AUC = 0.8281; sensitivity = 93.75%; specificity = 93.75%). Functional enrichment analysis revealed that predicted target genes are involved in key atherosclerosis-related pathways, including inflammation, lipid metabolism, and vascular remodeling. EV-derived miRNAs may serve as non-invasive biomarkers for the early detection of coronary atherosclerosis. These findings provide insight into the molecular processes underlying subclinical vascular disease and support the integration of EV-associated miRNAs into preventive cardiology strategies. Full article

Lipid metabolism is a fundamental biological process that ensures energy homeostasis and cellular integrity. This is an essential and complex biochemical process that is involved in energy storage and the maintaining of normal biological functions. Disorders of lipid metabolism are an urgent health problem, bringing about metabolic syndromes such as obesity, hepatic steatosis, adipose tissue dysfunction, diabetes, cardiovascular diseases, and certain cancers. An increasing body of research has emphasized the pivotal function of ncRNAs, particularly miRNAs, lncRNAs, and circRNAs, in controlling lipid metabolism and associated diseases. To identify novel therapeutic targets, it is necessary to understand the molecular mechanisms by which ncRNAs are involved in the pathobiology of lipid-associated diseases. This review summarizes the research findings on the role of ncRNA in lipid metabolism and the underlying mechanisms, emphasizing their potential as therapeutic targets for lipid-related diseases. Full article

Deoxyribonucleic acid (DNA) vaccines have re-emerged as a versatile and scalable platform by advances in synthetic biology and delivery systems, positioning them as powerful tools in the post-mRNA vaccine era. Historically considered less potent than viral or mRNA-based platforms, recent breakthroughs have dramatically improved their immunogenicity, safety, and precision. These innovations include synthetic gene circuits, self-amplifying DNA (saDNA), and DNA-encoded monoclonal antibodies (DMAbs), which enable programmable expression and robust immune activation. Clinically, DNA vaccines are expanding into diverse applications, from infectious disease prevention to therapeutic cancer immunotherapy and treatment of immune-mediated conditions. Compared to mRNA vaccines, DNA vaccines offer compelling advantages in terms of thermal stability, ease of manufacturing, and long-term storage. Furthermore, novel adjuvants, electroporation methods, and formulation strategies such as lyophilization and encapsulation continue to broaden their clinical potential. This review explores the full scope of DNA vaccine technology and its engineering foundations, emerging disease applications, and interdisciplinary innovations, while evaluating its comparative performance and future role in global vaccine strategy. With an emphasis on both mechanistic insights and translational feasibility, we propose a roadmap to integrate DNA vaccines into the next generation of precision immunotherapy. Full article

Background/Objectives: Rheumatoid arthritis (RA) is a chronic autoimmune disorder marked by persistent synovial inflammation, progressive joint destruction, and systemic complications. Despite significant progress in targeted therapies, major clinical challenges persist, including heterogeneous treatment responses and therapeutic resistance. This review aims to critically evaluate emerging immunomodulatory strategies—focusing on immune checkpoints, microRNAs (miRNAs), and cell-based therapies—as potential diagnostic and therapeutic tools. Methods: This non-systematic literature review involved a comprehensive analysis of recent studies to investigate emerging immunomodulatory strategies in RA. Special attention was given to immune checkpoint pathways—cytotoxic T-lymphocyte antigen 4 (CTLA-4); programmed death-1 (PD-1) and its ligand, PD-L1; and inducible T-cell costimulator (ICOS)—as well as cell-based therapies. Additionally, miRNA-based interventions were examined for their diagnostic and therapeutic potential. Results: Immune checkpoint modulation has demonstrated preclinical efficacy in attenuating inflammatory responses and restoring immune tolerance. Concurrently, miRNAs have emerged as both biomarkers and therapeutic agents, with exosome-based delivery systems enhancing their function. Cell-based therapies have shown robust immunoregulatory effects with acceptable safety profiles. Notably, integrative strategies that combine checkpoint inhibitors, cell-based interventions, and miRNA delivery exhibit synergistic effects and offer a promising avenue for personalised treatment, when guided by molecular and transcriptomic profiling. The majority of these approaches remain at the preclinical or early translational stage. Conclusions: Targeted immunomodulation is poised to transform RA management. The integration of cell therapies, checkpoint inhibition, and miRNA manipulation with omics technologies holds promise for enhancing therapeutic precision and safety. Advancing towards personalised immunotherapy will necessitate a multidisciplinary and patient-centred effort. Full article

Metastasis is the main cause of failure in anticancer therapies, and is frequently related to poor prognosis for patients. The true challenge in extending cancer patient life expectancy, eventually managing cancer as a chronic disease with periodic but controllable relapses, relies on the development of effective therapeutic strategies specifically targeting key mechanisms involved in the metastatic cascade. Traditional chemotherapy with alkylating agents, microtubule inhibitors, and antimetabolites has shown limited efficacy against metastatic cells, largely due to the emergence of chemoresistant populations that undergo epithelial-to-mesenchymal transition (EMT), promoting the colonization of distant organs and sustaining metastatic progression. This scenario has spurred significant efforts to identify small molecules and biologics capable of interfering with specific steps in the metastatic process. In this review, we provide an overview of recent advances involving small interfering RNAs (siRNAs) and microRNAs (miRNAs) in cancer therapy. Although most of these agents are still under investigation and have not yet been approved for clinical use, insights into their development stage offer valuable information to identify new targets in the ongoing fight against metastasis. Particular emphasis is placed on the role of chemical modifications applied to siRNAs, such as backbone, sugar, terminal, base, and conjugation changes, and how these factors influence their stability, immunogenicity, and targeting precision. By integrating these aspects into the discussion, this review provides a focused and up-to-date resource for researchers in medicinal chemistry, drug delivery, and pharmaceutical formulation, where molecular design plays a critical role in therapeutic success. Full article

Background: Major depressive disorder (MDD) is a prevalent and disabling psychiatric illness with complex etiologies involving both genetic and environmental factors. While environmental stress is a known risk factor of MDD, the molecular mechanisms linking stress exposure to persistent depressive phenotypes remain incompletely understood. Methods: We established a 24-hour restraint stress-induced depression model in mice and performed integrated transcriptomic and proteomic analyses of the medial prefrontal cortex (mPFC) to investigate stress-related molecular alterations. Results: Behavioral assessments confirmed persistent depression-like phenotypes, including anhedonia and behavioral despair, lasting up to 35 days post-stress. RNA sequencing identified differentially expressed genes related to dopaminergic signaling and oxidative stress. Proteomic analysis identified 105 differentially expressed proteins involved in immune response and energy metabolism. Integrated multi-omics analysis highlighted convergent disruptions in immune regulation, metabolism, and epigenetic processes. Notably, clemastine exerts its antidepressant-like effects in part by mitigating neuroinflammation and preserving mitochondrial function. Conclusions: These findings provide novel insights into the molecular basis of stress-induced depression and suggest that clemastine is a potential therapeutic candidate. Full article

A comprehensive comparative analysis was conducted on the nucleotide and amino acid sequences of intact phiLM21-like prophages (phiLM21-LPhs), which currently represent the most prevalent prophages in Sinorhizobium meliloti—a symbiotic partner of Fabaceae plants. Remarkably, the nucleotide sequences of 25 phiLM21-LPhs, identified across 36 geographically dispersed S. meliloti strains, covered no more than 34% of the phiLM21 phage genome. All prophages were integrated into specific isoacceptor tRNA genes and carried a tyrosine-type integrase gene; however, this integration did not exhibit features of tRNA-dependent lysogeny. Only one-fifth of phiLM21-LPhs encoded the minimal set of regulators for lysogenic/lytic cycle transitions, while the remainder contained either uncharacterized regulatory elements or appeared to be undergoing genomic “anchoring” within the host bacterium. The phiLM21-LPhs harbored open reading frames (ORFs) of diverse origins (phage-derived, bacterial, and unknown), yet over half of these ORFs had undeterminable functions, representing genetic “dark matter”. The observed diversification of intact phiLM21-like prophages likely stems from recombination events involving both virulent/temperate phages and phylogenetically remote bacterial taxa. The evolutionary and biological significance of the substantial genetic “dark matter” within these prophages in soil saprophytic bacteria remains an unresolved question. Full article