Search Results (4,872)

Human papillomavirus (HPV) infection is a primary driver of cervical cancer. Integration of HPV into the human genome causes persistent expression of viral oncogenes E6 and E7, which promote carcinogenesis and disrupt host genomic function. However, the impact of integration on host gene expression remains incompletely understood. We used multimodal RNA sequencing, combining total RNA-seq and Cap Analysis of Gene Expression (CAGE), to clarify virus–host interactions after HPV integration. HPV-derived transcripts were detected in 17 of 20 clinical samples. In most specimens, transcriptional start sites (TSSs) showed predominant early promoter usage, and transcript patterns differed with detectable E4 RNA region. Notably, the high RNA expressions of E4 region and viral-human chimeric RNAs were mutually exclusive. Chimeric RNAs were identified in 13 of 17 samples, revealing 16 viral integration sites (ISs). CAGE data revealed two patterns of TSS upregulation centered on the ISs: a two-sided pattern (43.8%) and a one-sided pattern (31.3%). Total RNA-seq showed upregulation of 12 putative cancer-related genes near ISs, including MAGI1-AS1, HAS3, CASC8, BIRC2, and MMP12. These findings indicate that HPV integration drives transcriptional activation near ISs, enhancing expression of adjacent oncogenes. Our study deepens understanding of HPV-induced carcinogenesis and informs precision medicine strategies for cervical cancer. Full article

This study systematically analyzed the multidimensional effects of Lactobacillus fermentation on Pueraria lobata (PL) and investigated the potential mechanisms underlying its hypolipidemic activity. Results indicated that fermentation significantly increased the total acid content from 1.02 to 3.48 g·L⁻¹, representing a 2.41-fold increase. Although slight reductions were observed in total flavonoids (8.67%) and total phenolics (6.72%), the majority of bioactive components were well preserved. Other antioxidant capacities were retained at >74.71% of baseline, except hydroxyl radical scavenging. Flavor profiling showed increased sourness and astringency, accompanied by reduced bitterness, with volatile compounds such as β-pinene and trans-2-hexenyl butyrate contributing to a distinct aromatic profile. Untargeted metabolomics analysis revealed that fermentation specifically enhanced the abundance of low-concentration isoflavone aglycones, including daidzein and genistein, suggesting a compositional shift that may improve hypolipidemic efficacy. Integrated network pharmacology and computational modeling predicted that eight key components, including genistein, could stably bind to ten core targets (e.g., AKT1 and MMP9) primarily through hydrogen bonding and hydrophobic interactions, potentially regulating lipid metabolism via the PI3K-AKT, PPAR, and estrogen signaling pathways. This study reveals the role of Lactobacillus fermentation in promoting the conversion of isoflavone glycosides to aglycones in PL and constructs a multi-dimensional “components-targets-pathways-disease” network, providing both experimental evidence and a theoretical foundation for further research on the lipid-lowering mechanisms of fermented PL and the development of related functional products. Full article

Osteoarthritis (OA) is primarily a degenerative disease triggered by joint inflammation and oxidative stress. While Aster glehni is an edible and traditionally medicinal herb, the beneficial effect of A. glehni on OA progression remains unknown. This study aimed to investigate the effect of A. glehni extract (AGE) and its primary biological compound—3,5-dicaffeoylquinic acid (3,5-DCQA)—on inflammation and oxidative stress in chondrocytes. AGE effectively inhibited the expression of interleukin (IL)-6, cyclooxygenase (COX)-2, matrix metalloproteinase (MMP)-1, and MMP-13 in chondrocytes stimulated by IL-1β for 24 h. In contrast, 3,5-DCQA did not inhibit IL-6, COX-2, and MMP expressions under the same conditions. However, when chondrocytes were stimulated by IL-1β for a short duration (6 h), 3,5-DCQA suppressed IL-6, COX-2, and MMP expressions. The inhibition of IL-6, COX-2, and MMP expressions by AGE was associated with the p38 kinase and nuclear factor-κB signaling pathways, but not ERK and JNK signaling pathways. Furthermore, AGE prevented cell apoptosis and reduced intracellular reactive oxygen species levels in chondrocytes induced by hydrogen peroxide (H₂ O₂). AGE restored the decreased superoxide dismutase 1 and catalase mRNA expressions caused by H₂ O₂. Collectively, AGE may protect against cartilage deterioration by inhibiting inflammation and oxidative stress, making it a promising therapeutic agent for alleviating OA. Full article

Molecularly imprinted polymer (MIP) biosensors offer an attractive strategy for selective biomolecule detection, yet imprinting proteins with structural fidelity remains a major challenge. In this work, we present a rationally designed electrochemical biosensor for matrix metal-loproteinase-8 (MMP-8), a key salivary biomarker of periodontal disease. By integrating graphene oxide (GO) with electropolymerized poly(eriochrome black T, EBT) films on screen-printed carbon electrodes, the partially reduced GO interface enhanced electrical conductivity and facilitated the formation of well-defined poly(EBT) films with re-designed polymerization route, while template extraction generated artificial antibody-like sites capable of specific protein binding. The MIP-based electrodes were comprehensively validated through morphological, spectroscopic, and electrochemical analyses, demonstrating stable and selective recognition of MMP-8 against structurally similar interferents. Complementary density functional theory (DFT) modeling revealed energetically favorable interactions between the EBT monomer and catalytic residues of MMP-8, providing molecular-level insights into imprinting specificity. These experimental and computational findings highlight the importance of rational monomer selection and nanomaterial-assisted polymerization in achieving selective protein imprinting. This work presents a systematic approach that integrates electrochemical engineering, nanomaterial interfaces, and computational validation to address long-standing challenges in protein-based MIP biosensors. By bridging molecular design with practical sensing performance, this study advances the translational potential of MIP-based electrochemical biosensors for point-of-care applications. Full article

Background: Ultraviolet B (UVB) radiation accelerates skin aging by inducing oxidative stress, collagen degradation, and cellular senescence. Although Petasites japonicus is known for its antioxidant properties, its anti-photoaging potential remains underexplored. This research explored the protective properties of a hot water extract from P. japonicus leaves (KP-1) against photoaging caused by UVB exposure. Methods: Hairless mice were exposed to UVB three times per week and orally administered KP-1 for 13 weeks. Wrinkle formation, epidermal thickness, skin hydration, and collagen content were assessed. Protein expression related to MAPK/AP-1, TGF-β/Smad2/3, and p53/p21 pathways was analyzed by Western blotting. Results: KP-1 significantly reduced UVB-induced wrinkle area, epidermal and dermal thickening, and transepidermal water loss while restoring collagen density and skin hydration. KP-1 inhibited MMP-1 expression, enhanced COL1A1 levels, suppressed MAPK/AP-1 activation, and activated TGF-β/Smad2/3 signaling. It also balanced p53/p21 expression and restored cyclin D1 and CDK4 levels, thereby preventing UVB-induced senescence. Conclusions: The findings of this research revealed that KP-1 can serve as a promising natural substance for safeguarding the skin from damage and aging caused by UVB exposure. Full article

Background: Intervertebral disc degeneration (IVDD) is closely linked to low back pain (LBP), a leading cause of disability worldwide. IVDD is characterized by the loss of proteoglycans (PGs), extracellular matrix (ECM) degradation, and reduced hydration of the nucleus pulposus (NP). Extracellular vesicles (EVs) derived from human umbilical cord mesenchymal stem cells (hUC-MSCs) exhibit tissue repair and immunomodulatory effects and are emerging as promising cell-free therapeutics. Methods: We established a rat IVDD model via fluoroscopy-guided needle puncture of three consecutive coccygeal discs and confirmed degeneration through Alcian Blue and hematoxylin & eosin (H&E) staining. The gene expression of inflammatory and pain markers (ADRβ2, COMP, CXCL1, COX2, PPTA, MMP13, YKL40) was measured by qPCR. Subsequently, we implanted hUC-MSCs or EVs to evaluate their reparative potential. Results: Upregulation of inflammatory and pain genes in IVDD was associated with an immunomodulatory response. Tracking DiI-labelled hUC-MSCs and EVs revealed enhanced survival of hUC-MSCs, retention of EVs, and dispersion within rat tail discs; EVs showed greater retention than hUC-MSCs. Implanted EVs were internalized by NP cells and remained within degenerative IVDs. EVs passively diffused, accumulated at the injury site, interacted with host cells, and enhanced function, as shown by increased expression of human chondrocyte-related markers (SOX9, TGFβ1, TGFβ2, COL2) compared to hUC-MSC treatment. Histological analysis of two weeks post-transplantation showed NP cellular patterns resembling chondromas in treated discs. EVs integrated into and distributed within degenerated NP regions, with greater glycosaminoglycan (GAG) content. Conclusions: Overall, hUC-MSC EVs demonstrated superior regenerative capacity, supporting a safe, cell-free strategy for disc repair. Full article

Traumatic brain injury (TBI) disrupts the blood–brain barrier (BBB), resulting in increased permeability, neuronal loss, and cognitive dysfunction. This study investigates the therapeutic potential of thyroid hormone (T4) to reduce BBB dysfunction following moderate fluid percussion injury. T4 injection (intraperitoneal) after TBI restores the levels of pericytes and endothelial cells vital for BBB integrity, reduces edema by downregulating AQP-4 gene expression, and enhances levels of the tight junction protein ZO-1. T4 counteracts the TBI-related increase in MMP-9 and TLR-4, significantly reducing BBB permeability. Furthermore, T4 enhances the neuroprotective functions of astrocytes by promoting the activity of A2 astrocytes. Additionally, T4 treatment increases DHA levels (important for membrane integrity and function), stimulates mitochondrial biogenesis, and leads to a notable improvement in spatial learning and memory retention. These findings suggest that T4 has significant potential to reduce vascular leakage and inflammation after TBI, thereby improving cognitive function and maintaining BBB integrity. Full article

Chemotherapy-induced neurotoxicity (CIN) is a major barrier against optimal anticancer treatment. This study investigated the neuroprotective effects of the naturally occurring antioxidant, Coenzyme Q10 (CoQ10), against CIN using a model of induced pluripotent stem cell (iPSC)-derived neurons. iPSCs have consistently proven to be reliable for disease modeling and drug discovery. We employed cell viability, oxidative stress, and mitochondrial function assays to measure the effect of 10 μM CoQ10 on iPSC-derived motor neuron progenitors (iPSC-MNPs) that were exposed to five chemotherapeutic agents: 5-Fluorouracil, methotrexate, paclitaxel (0, 1, and 10 μM) and doxorubicin, and vincristine (0, 0.1, and 1 μM). Our findings show that CoQ10 significantly reversed the reduction in cell viability inflicted by the exposure of iPSCs-MNPs to all five chemotherapeutics. Moreover, CoQ10 treatment resulted in a marked reduction in intracellular ROS levels and enhancement of mitochondrial membrane potential (MMP) in a drug- and dose-dependent manners, highlighting its role in preserving mitochondrial health. This study is the first to explore the protective effects of CoQ10 against CIN using an iPSC-derived neuronal platform, offering insights into its potential therapeutic use. Further investigation is essential to validate these findings and to determine the behavioral effects of CoQ10 in in vivo models of CIN. Full article

Osteoarthritis (OA) is a degenerative joint disease characterized by progressive cartilage breakdown, synovial inflammation, and subchondral bone remodeling. Previous studies have shown that cellular communication network factor 3 (CCN3) expression increases with age in cartilage, and its overexpression promotes OA-like changes by inducing senescence-associated secretory phenotypes. This study aimed to investigate the effect of Ccn3 knockout (KO) on OA development using a murine OA model. Destabilization of the medial meniscus (DMM) surgery was performed in wild-type (WT) and Ccn3-KO mice. Histological scoring and staining were used to assess cartilage degeneration and proteoglycan loss. Gene and protein expressions of catabolic enzyme (Mmp9), hypertrophic chondrocyte marker (Col10a1), senescence marker, and cyclin-dependent kinase inhibitor 1A (Cdkn1a) were evaluated. Single-cell RNA sequencing (scRNA-seq) data from WT and Sox9-deficient cartilage were reanalyzed to identify Ccn3⁺ progenitor populations. Immunofluorescence staining assessed CD44 and Ki67 expression in articular cartilage. The effects of Ccn3 knockdown on IL-1β-induced Mmp13 and Adamts5 expression in chondrocytes were examined in vitro. Ccn3 KO mice exhibited reduced cartilage degradation and catabolic gene expression compared with WT mice post-DMM. scRNA-seq revealed enriched Ccn3-Cd44 double-positive cells in osteoblast progenitor, synovial mesenchymal stem cell, and mesenchymal stem cell clusters. Immunofluorescence showed increased CCN3⁺/CD44⁺ cells in femoral and tibial cartilage and meniscus. Ki67⁺ cells were significantly increased in DMM-treated Ccn3 KO cartilage, mostly CD44⁺. In vitro Ccn3 knockdown attenuated IL-1β-induced Mmp13 and Adamts5 expressions in chondrocytes. Ccn3 contributes to OA pathogenesis by promoting matrix degradation, inducing hypertrophic changes, and restricting progenitor cell proliferation, highlighting Ccn3 as a potential therapeutic target for OA. Full article

Based on monitoring data from 2019 to 2024 at 270 typical surface drinking water sources (SDWS) in the Pearl River Basin (PRB), the occurrence and health risks of metal and metalloid pollutants (MMPs) were analyzed from a large watershed scale and long-term evolution. The results indicated that the overall pollution status of 8 MMPs (As, Cd, Pb, Mn, Sb, Ni, Ba, V) were at a low level and the concentrations of Cd, Pb, Ni, Ba, and V exhibited downward trends from 2019 to 2024. The distribution of MMPs exhibited significant regional differences with the main influencing factors including geological conditions, industrial activities, and urban development. River-type drinking water sources might be more affected by pollution from human activities such as industrial wastewater discharge, and the concentration levels of MMPs were generally higher than those in lake-type drinking water sources. Monte Carlo simulation revealed that 33.08% and 12.90% of total carcinogenic risks (TCR) exceeded the threshold of 10⁻⁶ for adults and children, respectively. Ba and Ni were the main contributors to the TCR, while As posed a certain non-carcinogenic risk to children. Sensitivity analysis indicated that concentrations of As and Ba were the main factors contributing to health risks. Although highly stringent water pollution control and a water resource protection policy have been implemented, it is still suggested to strengthen the control of As, Ba, and Ni in industrial-intensive areas and river-type water sources in the PRB. Full article

Background: Diabetic eye surface disease, including dry eye syndrome, corneal neuropathy, and diabetic retinopathy, is a common complication of diabetes. Tear fluid biomarkers may aid in early diagnosis and disease monitoring. The objective of this systematic review was to identify and evaluate tear fluid biomarkers in diabetic ocular surface disease according to PRISMA guidelines. Methods: PubMed, Scopus, and Embase databases were searched through June 2025. Eligible studies included clinical and observational studies measuring proteins, lipids, cytokines, trace elements, or nucleic acids in tear fluids in patients with diabetes. Results: The search identified 198 studies, and of those, 30 studies were included, comprising 14 original investigations with 871 participants (133 with type 1 diabetes, 453 with type 2 diabetes, 16 with pre-diabetes, and 269 healthy controls). The main biomarker categories were cytokines (IL-6, IL-8, TNF-α, and MMP-9), neuropeptides (substance P, NPY), proteins (IGFBP-3, progranulin), lipids, glycans, microRNAs, circRNAs, and trace elements. Conclusions: More than a dozen biomarkers in the tear fluid have been identified that may reflect diabetes-related changes in the ocular surface. Tear fluid analysis may be a valuable tool in personalizing the diagnosis and treatment of diabetic ocular surface diseases, but further studies are needed to confirm its clinical significance. Full article

Background/Objectives: Stroke is the second leading cause of death worldwide. There is an unmet need to manage stroke pathophysiology, including L-glutamate (L-Glu)-mediated neurotoxicity. The acai berry (Euterpe sp.) contains phytochemicals with potentially nutraceutical content. The aim of this study was to assess the ability of acai berry extracts to counter L-Glu neurotoxicity using human differentiated TE671 cells. Methods: The cytotoxicity of L-Glu and acai berry extracts was quantified using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and lactate dehydrogenase (LDH) assays. Mitochondrial function was examined by a quantitation of cellular ATP levels, the maintenance of the mitochondrial membrane potential (MMP), and the production of reactive oxygen species (ROS). Whole-cell patch-clamp recordings monitored the activation of N-methyl-D-aspartate receptors (NMDARs). Candidate phytochemicals from acai berry extracts were modeled in silico for NMDAR binding. Results: L-Glu significantly reduced cell viability, ATP levels, the MMP, and increased cellular ROS. Generally, acai berry extracts alone were not cytotoxic, although high concentrations were detrimental to ATP production, maintenance of the MMP, and elevated ROS levels. Whole-cell patch-clamp recordings revealed that the combined addition of 300 µM L-Glu and 10 µM glycine activated currents in differentiated TE671 cells, consistent with triggering NMDAR activity. Acai berry extracts ameliorated the L-Glu-induced cytotoxicity, mitochondrial dysfunction, elevated ROS levels, and limited the NMDAR-mediated excitotoxicity (p < 0.001–0.0001). Several virtual ligands from acai berry extracts exhibited high-affinity NMDAR binding (arginine, 2,5-dihydroxybenzoic acid, threonine, protocatechuic acid, and histidine) as possible candidate receptor antagonists. Conclusions: Acai berry phytochemicals could be exploited to reduce the L-Glu-induced neurotoxicity often observed in stroke and other neurodegenerative diseases. Full article

Introduction: The Hedgehog (Hh) signaling pathway is aberrantly activated in various types of cancer and plays a critical regulatory role. However, its biological significance in gastric cancer remains unclear. In this study, the mechanism underlying the role of Hh in gastric cancer progression and prognosis was investigated through bioinformatics analysis as well as in vitro and in vivo experiments. Methods: In this study, a systematic analysis of scRNA-seq datasets and bulk RNA-seq datasets from gastric cancer patients derived from the GEO database and TCGA database was performed by us, which revealed the activation characteristics of Hh in different cell types within the gastric cancer tumor microenvironment (TME). Furthermore, through conducting multiplex immunofluorescence staining experiments on clinical gastric cancer samples, we clarified the association mechanism between fibroblasts with highly activated Hh and the gastric cancer tumor immunosuppressive microenvironment. Finally, by means of in vitro and in vivo experiments, we elucidated the key molecular mechanism by which fibroblasts with highly activated Hh remodel the gastric cancer tumor immunosuppressive microenvironment. Results: We identified a distinct subpopulation of fibroblasts, designated MMP1 + FIB, in the gastric cancer tumor microenvironment. Studies revealed that this subpopulation can significantly activate Hh, suggesting it may play a crucial role in the regulation of the TME. Subsequent mechanistic investigations further confirmed that MMP1 + FIB exhibits a significant correlation with the immunosuppressive state of the TME (R = 0.29, p = 2.5 × 10^−0.8). In terms of the specific functions, the complement system in this fibroblast subpopulation is significantly activated (p < 0.05); further studies demonstrated that MMP1 + FIB can induce the polarization of macrophages toward the M2 subtype (an immunosuppressive phenotype) by specifically secreting complement C3 protein. Collectively, these processes contribute to the establishment of an immunosuppressive TME and ultimately promote the proliferation and metastasis of gastric cancer cells. Discussion: Aberrant activation of the Hh signaling pathway promotes gastric cancer progression via the MMP1 + FIB–C3–macrophage axis, providing a potential therapeutic strategy for targeting the tumor microenvironment. Full article

Mpox virus (MPXV), a member of the Orthopoxvirus genus in the Poxviridae family, has long been endemic in Africa. The interaction between MPXV infection and peripheral immune responses is of great significance. However, the activation of signaling pathways and molecular changes in peripheral blood mononuclear cells (PBMCs) following MPXV infection remain poorly understood. This study evaluated the transcriptomic profiles of rabbit PBMCs during the mpox acute and recovery phases. The results showed that MPXV infection significantly altered the transcriptomic profiles of PBMCs. At 6 days post-infection, pathways related to pathogenic infection and IL-1 response were enriched, while at 14 days post-infection, the T cell receptor signaling pathway was enriched. During the mpox acute phase, inflammatory cytokines in serum such as IL-1α, IL-1β, IL-8, and IL-21 were upregulated, while MMP-9 and NCAM-1 were downregulated. In rabbits and rhesus monkeys, key genes upregulated in common during the mpox acute period were associated with the interferon pathway (e.g., the ISG15, OAS, and IFIT families), while downregulated genes were related to B-cell activation and differentiation (e.g., the MS4A1 and FCRL families). Additionally, rabbits developed protective immunity against reinfection, with neutralizing antibodies effectively activated. These findings provide insights into the molecular characteristics of PBMCs changes in in vivo models of MPXV infection, and offer references for the diagnosis, vaccine development, and therapeutic research of mpox. Full article

Shikonin, a dietary naphthoquinone phytochemical from the roots of Lithospermum erythrorhizon, has gained attention for its anticancer potential. Preclinical studies show that shikonin regulates multiple programmed cell death pathways, including apoptosis, necroptosis, ferroptosis, and pyroptosis, through mechanisms involving reactive oxygen species (ROS) accumulation, mitochondrial dysfunction, and kinase-mediated signalling. Beyond cytotoxicity, shikonin suppresses metastasis by blocking epithelial–mesenchymal transition (EMT) and downregulating matrix metalloproteinase-2 (MMP-2) and matrix metalloproteinase-9 (MMP-9). It also disrupts tumour metabolism by targeting pyruvate kinase isoform M2 (PKM2) and modulating the Warburg effect. Evidence further indicates that shikonin can enhance the efficacy of chemotherapy, targeted therapy, immunotherapy, and radiotherapy, thereby contributing to the reversal of therapeutic resistance. To address limitations related to solubility and bioavailability, novel formulations such as nanoparticles, liposomes, and derivatives like β,β-dimethylacrylshikonin have been developed, showing improved pharmacological profiles and reduced toxicity in experimental models. Overall, the current literature identifies shikonin as a promising dietary phytochemical with diverse anticancer activities, therapeutic synergy, and formulation advances, while highlighting the need for clinical studies to establish its translational potential. Full article