The skin, the body's largest organ, defends against ultraviolet (UV) radiation primarily through melanin produced by melanocytes. Complex signaling pathways, especially the PI3K/AKT pathway, regulate melanogenesis, which is required during pigmentation and melanocyte survival. Any disturbance in melanocyte function may result in pigmentary disorders, including vitiligo, a common depigmenting disorder with significant psychological impact. By examining histological, immunohistochemical, ultrastructural, and molecular events controlling melanocyte activity, we aimed to compare histological, immunohistochemical, ultrastructural, and molecular changes associated with Fr CO2 laser and platelet-rich plasma (PRP) treatment in stable vitiligo. Thirty-two patients with vitiligo and five healthy volunteers were enrolled. Lesions on each patient's limbs were divided into two groups, each receiving six treatment sessions at one-month intervals over six months. Four groups were studied: control (I) from healthy volunteers, vitiligo before treatment (II), Fr CO2 laser (III), and PRP (IV). Punch biopsy specimens were obtained before and after treatment for histological, immunohistochemical, and western blot analysis. Compared with the control group, the vitiligo group (II) showed epidermal degenerative alterations, loss of melanin, apoptotic melanocytes, down-regulation of Melan-A and IL-10 expression, ultrastructural changes, and down-regulation of p-AKT/AKT. Both treatment groups showed tissue-level improvement in melanin distribution, Melan-A-positive melanocyte counts, IL-10 expression, and ultrastructural features. The PRP group had better ultrastructural improvements. Western blotting showed that both treatment groups had elevated p-AKT/AKT levels, with the PRP group exhibiting the highest p-AKT level. Overall, PRP was associated with greater histological, ultrastructural, and molecular improvement than Fr CO2 laser under the conditions of the present study.
Lupus nephritis (LN) is initiated by immune-complex deposition, complement activation, and inflammation, but these mechanisms do not fully explain why some glomerular lesions resolve whereas others progress to podocyte depletion, glomerulosclerosis, and fibrosis. We present a conceptual spatial framework in which graded disruption of the podocyte organelle-contact network may contribute to this transition. The framework does not assume that contact-site abundance is uniformly protective or injurious. Contactome remodeling denotes an axis-specific change in contact distance, length, frequency, molecular composition, or organelle positioning, whereas contactome collapse is reserved for a composite state in which abnormalities across multiple contact axes are accompanied by concordant calcium, bioenergetic, redox, degradative, or cytoskeletal failure. Mitochondrial fragmentation, lysosomal redistribution, or urinary mitochondrial and podocyte-derived markers alone do not establish contactome collapse. Direct population-level three-dimensional mapping of podocyte contact sites in human LN biopsies is not yet available; therefore, the model remains a proposed organizing framework rather than an established human disease mechanism. The framework predicts that integrated contact-site metrics should provide information beyond isolated mitochondrial, autophagy, or cytoskeletal markers, precede established podocyte detachment, and improve risk prediction only after adjustment for histologic class, activity and chronicity, proteinuria, kidney function, treatment exposure, and competing kidney injury. These predictions can be tested and refuted through standardized human-biopsy morphometry, longitudinal LN models, perturbation-rescue experiments, and biopsy-linked biomarker cohorts.
This study elucidated the mechanism by which lysine-specific demethylase 1 A (KDM1A) promotes colorectal cancer (CRC) progression. We characterized KDM1A expression in CRC cells and tissues and examined its effects on malignant phenotypes, including proliferation, migration, invasion, and glycolysis. Mechanistically, we explored the relationship between KDM1A and hypoxia-inducible factor-1α (HIF-1α)/PDK4 pathway. The tumor-promoting role of KDM1A was further evaluated in a xenograft mouse model. The results showed that KDM1A was overexpressed in CRC cells and tissues. KDM1A knockdown inhibited CRC cell proliferation, migration, and invasion capabilities, and reduced glycolytic activity. Furthermore, KDM1A knockdown shortened the half-life of HIF-1α protein and increased its ubiquitination level, correlating with reduced PDK4 expression. HIF-1α overexpression partially reversed the PDK4 downregulation and glycolysis inhibition caused by KDM1A knockdown. PDK4 knockdown reproduced the metabolic inhibition phenotype of KDM1A deficiency, and KDM1A overexpression reversed the effects of PDK4 deficiency, confirming that KDM1A regulates glycolysis in a PDK4-dependent manner. KDM1A depletion suppressed in vivo tumor growth and decreased Ki-67 and HIF-1α expression levels. In conclusion, KDM1A supports PDK4 expression via HIF-1α stability, promoting glycolytic metabolism and driving CRC growth and metastasis.
Triple-negative breast cancer (TNBC) remains a significant therapeutic challenge due to its aggressive clinical course and inherent resistance to apoptosis. The overexpression of cellular Inhibitor of Apoptosis Protein 1 (cIAP1) serves as a critical molecular barrier to conventional treatments. This study aimed to elucidate the multimodal cell-death mechanisms of DEBIO 1143, a second-generation SMAC mimetic, in murine 4T1 and 4T1-HER2 cell lines using an integrated approach of 1-µs in silico molecular dynamics simulations and in vitro validation. Cell viability was determined via MTT assays at 24 and 48 h. Cell-death modalities were quantified using Annexin V-FITC/PI flow cytometry and monodansylcadaverine staining. Key regulatory proteins (LC3II, Beclin-1, RIP3, and cIAP1) were analyzed by Western blotting. Ligand-protein interactions were probed through molecular docking and 1-µs MD simulations. DEBIO 1143 demonstrated time- and dose-dependent cytotoxicity, with 48-h IC50 values of 36.20 µM for 4T1 and 22.45 µM for 4T1-HER2 cells. Western blotting confirmed complete cIAP1 depletion at 48 h, concomitant with the upregulation of RIP3, Beclin-1, and LC3II. Flow cytometry indicated a shift toward necroptosis-like regulated cell death, supported by a significant increase in autophagic vacuole density (p < 0.001). MD simulations revealed that DEBIO 1143 lacks high-affinity binding to RIP3, Beclin-1, or LC3II, suggesting that the upregulation of these mediators is a downstream cellular response to cIAP1 depletion rather than direct engagement. DEBIO 1143 was associated with reduced apoptotic cell death and increased necroptosis-like and autophagy-associated responses in TNBC cells. These findings support its development as a multimodal therapeutic strategy for aggressive breast cancer subtypes.
Psoriasis is a chronic immune-mediated skin disorder characterized by keratinocyte hyperproliferation and persistent inflammation. This study evaluated the therapeutic effects of Zhuhuang granules and investigated their underlying mechanism. Ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS), network pharmacology, and molecular docking were combined with an imiquimod (IMQ)-induced psoriasis-like mouse model and a HaCaT cell model stimulated with an M5 cytokine cocktail (interleukin-17A, interleukin-22, oncostatin M, interleukin-1α, and tumor necrosis factor-α). UPLC-MS/MS identified multiple compounds and 174 absorbed prototype components. Network analysis prioritized the hypoxia-inducible factor 1 subunit alpha gene (HIF1A), while molecular docking predicted potential interactions of gardenoside and kaempferol with the encoded hypoxia-inducible factor-1α (HIF-1α) protein. In the psoriasis mouse model, Zhuhuang granules dose-dependently alleviated erythema, scaling, and epidermal thickening, with methotrexate serving as a positive control. Zhuhuang granules also reduced reactive oxygen species (ROS), malondialdehyde, interleukin-17A, and interleukin-23 levels, restored glutathione levels and superoxide dismutase and catalase activities, and preserved mitochondrial membrane potential. In M5-stimulated HaCaT cells, Zhuhuang granule-containing serum inhibited proliferation and inflammatory cytokine release, reduced mitochondrial ROS, lactate, and mitochondrial DNA release, and improved mitochondrial membrane potential. These effects were accompanied by reduced HIF-1α and tumor necrosis factor receptor 1 protein levels and phosphoinositide 3-kinase phosphorylation. Molidustat attenuated these protective effects. Collectively, Zhuhuang granules ameliorate psoriasis-like alterations by suppressing HIF-1α-associated oxidative stress, inflammation, and mitochondrial dysfunction.
Dental and surrounding tissues are important sources of mesenchymal stem cells (MSCs), which are the major component of stem cell therapy. In addition to the self-renewal and multi-directional differentiation abilities, the immunoregulatory function of MSCs is of great interest to researchers, which suggests that MSCs can maintain their characteristics and functions in tissues affected by inflammation. This review first discussed the performance changes of inflammatory dental mesenchymal stem cells (i-dMSCs) from both in vivo and in vitro sources, exploring the effects of inflammation on dental mesenchymal stem cells (dMSCs) and the ability of dMSCs to resist the inflammatory microenvironment. Then, we summarized the relevant literature on methods to improve the function of i-dMSCs. Finally, clinical trials related to the preservation of dental and surrounding tissues affected by inflammation were mentioned, demonstrating the presence of functional MSCs in inflammatory tissues. Although further study is needed to support the clinical application of i-dMSCs, these results indicate that they have the potential to become the seed cell for stem cell therapy, providing new ideas for the field of regenerative medicine.
Alopecia is characterized by progressive follicular miniaturization and impaired regenerative capacity associated with abnormal hair cycling. Current therapies often provide limited or temporary benefits, highlighting the need for regenerative strategies targeting follicular restoration. This systematic review summarizes current experimental and clinical evidence regarding the regenerative potential of the secretome from adipose tissue-derived mesenchymal stem cells (AT-MSCs) as a cell-free therapeutic strategy for hair regeneration. In contrast to conventional cell transplantation, the biological effects of AT-MSCs secretome are mainly mediated through paracrine mechanisms involving a variety of bioactive molecules, including growth factors, cytokines, and extracellular vesicles such as exosomes. Evidence from experimental models indicates that treatment with MSCs-derived secretome supports dermal papilla cell expansion and triggers intracellular signaling mechanisms that regulate hair follicle growth, with the Wnt/β-catenin pathway playing a major role. In preclinical animal studies, administration of the secretome has been shown to accelerate the transition of hair follicles from the telogen phase to the anagen phase, accompanied by increased follicle density and improved perifollicular vascular development. Preliminary clinical findings also suggest improvements in hair density and hair shaft thickness, especially when secretome therapy is applied together with microneedling procedures or standard therapeutic approaches. The observed regenerative responses are believed to be mediated by several angiogenic growth factors, including vascular endothelial growth factor (VEGF), insulin-like growth factor-1 (IGF-1), and hepatocyte growth factor (HGF). In addition, these effects involve signaling pathways that regulate immune responses and inhibit apoptosis within the follicular microenvironment. However, variations in secretome production techniques, dosage approaches, and clinical research design restrict the interpretation of available data. Validating the safety, effectiveness, and therapeutic significance of AT-MSCs secretome in the treatment of alopecia requires extensive, well-controlled clinical trials and established manufacturing procedures.
BACKGROUND:Chronic wounds in diabetic patients, represent a significant clinical challenge due to impaired epidermal barrier function and deficient wound healing. The development of novel therapeutic strategies aimed at enhancing both barrier integrity and wound healing is therefore critical. Recent evidence suggests that histone deacetylase inhibitors (iHDACs) may modulate wound healing. OBJECTIVE:This study aimed to evaluate the effect of iHDACs, 1,3-Diphenylurea (DiPU), 2'-Aminoacetanilide (Ace), and Tert-butyl (2-aminophenyl) carbamate (N-boc), on epidermal barrier integrity and tight junction (TJ) protein expression, as well as their ability to promote wound healing and vascularization under diabetes conditions. METHODS:Diabetes was induced in mice by streptozotocin (STZ) administration. Full-thickness excisional wounds were created, and wound closure was quantified by digital planimetry. Tissue samples were analyzed by H&E and Masson's trichrome staining to assess histological changes and collagen deposition. claudin-1, ZO-1, and occludin were evaluated by immunohistochemistry. Vascularization was quantified by measuring microvessel density. RESULTS:Treatment with iHDACs improved re-epithelialization and increased the expression of tight junction proteins, suggesting restoration of molecular components associated with epidermal barrier integrity. Moreover, all treatments promoted wound closure. Macroscopic observations and quantitative analyses further demonstrated that N-boc and Ace significantly enhanced the formation of denser and more organized vascular networks in both healthy and diabetic mice, whereas DiPU produced a more moderate pro-angiogenic response in diabetic wounds. CONCLUSION:These findings indicate that iHDACs may offer therapeutic benefit by reinforcing epidermal barrier function and stimulating wound healing and vascularization, supporting their potential use as treatments for chronic wounds.
Background Lung adenocarcinoma (LUAD) is the most common subtype of non-small cell lung cancer, characterized by high incidence and mortality rates. Long noncoding RNAs (lncRNAs) have gained increasing attention for their regulatory roles in tumors, but the functions of many lncRNAs remain poorly understood. Previous studies have suggested that LINC02126 is downregulated in LUAD, yet its specific biological function remains unclear. This study aimed to investigate the role of LINC02126 in LUAD and to elucidate the underlying molecular mechanisms. Methods RT-qPCR and Western blotting were employed to detect mRNA and protein expression levels. Cell viability, proliferation, cell cycle distribution, apoptosis, migration, and invasion were assessed using CCK-8, colony formation, EdU, flow cytometry, wound healing, and transwell assays. MeRIP-qPCR, m6A-IP-qPCR, RNA pull-down, dual-luciferase reporter, and RNA stability assays were used to evaluate LINC02126 m6A modification and its interaction with YTHDC1. The target miRNA was identified via bioinformatics combined with dual-luciferase reporter, Ago2-RIP, and RNA pull-down assays. A nude mouse xenograft model was used to examine tumor growth in vivo. Results LINC02126 was significantly downregulated in LUAD and associated with poor prognosis. Overexpression of LINC02126 inhibited proliferation, migration, invasion, and EMT, while promoting apoptosis and cell cycle arrest. YTHDC1 bound to LINC02126 m6A sites and enhanced its stability. LINC02126 directly bound to and reduced miR-501–5p levels. Inhibition of miR-501–5p mimicked LINC02126’s antitumor effects, while miR-501–5p overexpression reversed them. In vivo, LINC02126 overexpression suppressed tumor growth and decreased miR-501–5p expression. Conclusion YTHDC1 enhanced LINC02126 stability via m6A modification, and LINC02126 inhibited LUAD progression through miR-501–5p.
Objective Ventilator-induced lung injury (VILI) poses a serious threat to patients receiving mechanical ventilation (MV). While studies suggest that α-lactalbumin hydrolysate (LAH) and anti-vascular endothelial growth factor (VEGF) agent can ameliorate inflammatory diseases, their efficacy in alleviating VILI remains poorly understood. This study aimed to investigate the preventive efficacy of LAH combined with Aflibercept (AFL, a VEGF trap) against VILI. Methods A mouse model of VILI was utilized to investigate the preventive potential of LAH and AFL on pulmonary damage and inflammatory responses. LAH (100 mg/kg) and AFL (10 mg/kg) were administered via gavage and intraperitoneal injection, respectively, prior to high tidal volume ventilation. Histopathological assessment of lung injury was performed through hematoxylin and eosin staining. To evaluate pulmonary vascular permeability, the lung wet-to-dry weight ratio was determined, and the total protein concentration in bronchoalveolar lavage fluid (BALF) was quantified. Apoptosis in lung tissues was analyzed via terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay. Neutrophil infiltration was assessed by measuring neutrophil counts and myeloperoxidase activity in BALF. The expression profiles of key molecular markers—including apoptosis-related proteins (Bax, Bcl-2), VEGF, constituents of the NOD-like receptor family pyrin domain‑containing 3 (NLRP3) inflammasome pathway, and inflammatory cytokines—were examined using quantitative real-time polymerase chain reaction, Western blot, enzyme-linked immunosorbent assay, and immunohistochemistry. Results LAH significantly attenuated lung pathological injury, apoptosis, and inflammation in VILI mice. Compared with normal controls, VEGF was pathologically upregulated in the lung tissues and BALF of VILI mice, and this elevation was reversed by LAH treatment. Further investigation revealed that AFL potentiated the inhibitory effects of LAH on lung injury and inflammation. Additionally, activation of the NLRP3/apoptosis-associated speck-like protein (ASC)/Caspase-1 inflammatory signaling pathway observed in VILI mice was significantly suppressed by the combined LAH and AFL treatment. Conclusion Collectively, the combination of LAH and AFL ameliorates MV-induced lung injury and inflammation by suppressing the NLRP3 inflammasome signaling pathway. This study highlights a potential therapeutic target and proposes a novel strategy for the clinical prevention of VILI.
Purpose This study aimed to evaluate the protective effects of melatonin on colon tissue integrity in rats exposed to low- and high-dose rate radiotherapy. Materials and methods Forty rats were randomly divided into: Group1 (Control) received no treatment. Group2 was exposed to a single dose of 8 Gy radiotherapy at a low-dose rate (LDR) of 400 MU/min. Group3 (LDR+Melatonin) received of 50 mg/kg melatonin, followed by 8 Gy LDR radiotherapy (400 MU/min) to the abdominopelvic region 15 min later. Group4 was treated with 8 Gy radiotherapy at a high-dose rate (HDR) of 1400 MU/min. Group5 (HDR+Melatonin) received 50 mg/kg melatonin 15 min before 8 Gy HDR radiotherapy (1400 MU/min). Colon tissues were harvested 48 h after radiotherapy for analyses. Results Radiotherapy induced damage to colon tissues, characterized by disruption of crypt architecture and depletion of goblet cells. Melatonin treatment effectively preserved these structures, exhibiting a protective effect (p < 0.001). The Bax/Bcl-2 ratio, a key marker of apoptosis, was significantly reduced in melatonin-treated groups compared to radiotherapy-only groups (p < 0.001), suggesting a reduction in apoptotic cell death. Furthermore, melatonin administration resulted in a substantial increase in total antioxidant status (T-AS) and a significant decrease in total oxidative status (T-OS) and oxidative stress index (O-SI) levels (p < 0.001). Conclusions Melatonin significantly mitigated radiation-induced oxidative stress and apoptosis in healthy colon tissue, as evidenced by the reduction in the Bax/Bcl-2 ratio. Melatonin may serve as an effective radioprotective agent, preserving the integrity of colon tissue during both low- and high-dose rate abdominopelvic radiotherapy.
Osteoporosis, a prevalent skeletal condition defined by diminished bone density and disrupted microarchitecture, dramatically elevates fracture risk. Its pathophysiology is now understood to extend beyond classic remodeling imbalances to include a pivotal shift in bone marrow mesenchymal stem cell (BMSC) differentiation, where adipogenesis is favored over osteogenesis—a key feature of aging and estrogen deficiency. The emerging "gut-bone axis" suggests that microbiota-derived metabolites can systemically influence skeletal homeostasis, presenting new therapeutic possibilities. This research uncovers the direct osteoanabolic and anti-adipogenic properties of Reuterin (3-hydroxypropionaldehyde, Reut), a principal antimicrobial metabolite from Lactobacillus reuteri. In vitro, Reut (5–20 μM) showed excellent cytocompatibility, dose-dependently boosting osteogenic differentiation (increased ALP activity and mineralization) while effectively suppressing adipogenic differentiation (decreased lipid accumulation) in BMSCs. Mechanistically, Reut specifically activated the canonical BMP-Smad pathway, demonstrated by the rapid phosphorylation and nuclear translocation of Smad1/5/9 and the upregulated expression of its direct targets (ID1, ID2). This activation was crucial, as the BMP receptor inhibitor LDN-193189 completely negated Reut's effects. In an ovariectomized (OVX) rat model, systemic Reut administration (10 mg/kg, every other day for 8 weeks) not only mitigated trabecular bone loss and enhanced biomechanical properties but also markedly reversed the OVX-induced expansion of marrow adipose tissue (MAT). Remarkably, the bone-preserving efficacy of Reut was statistically equivalent to that of teriparatide (TPTD), a clinically approved anabolic agent, while both treatments similarly and significantly countered the pathological marrow adiposity. These results establish Reut as a novel, gut microbiome-derived therapeutic metabolite that rectifies the fundamental lineage imbalance in osteoporosis by directly engaging the BMP-Smad pathway, offering a distinct postbiotic strategy for anabolic bone therapy.
Traumatic brain injury (TBI) is a critical reason of neurological impairment globally, with increasing evidence suggesting that its impact extends beyond the brain to peripheral organs. This study investigates the potential brain-lung crosstalk in mild repetitive TBI (RTBI) and explores the therapeutic potential of Infliximab (INF) and Lycopene (LYC) in mitigating the associated neuroinflammatory and pulmonary complications. Using a weight-drop rat model of mild RTBI, we tracked the histological changes and inflammatory markers in both brain and lung tissues across control, RTBI, and treatment groups with INF, LYC, and their combination. Our findings revealed that RTBI induced significant neuroinflammation and oxidative stress, characterized by sirtuin 1 (SIRT1) suppression, activation of NLRP3 (Nod-like receptor protein containing pyrin 3), apoptosis-associated speck-like protein containing a caspase-recruitment domain (ASC) and caspase-1 inflammasome, as well as elevated brain levels of tumor necrosis factor alpha (TNF-α) and nuclear factor kappa B (NF-ҡB). These changes were associated with the increased pulmonary micro-ribonucleic acid-21 (micRNA-21) expression, pulmonary inflammasome activation, and pyroptosis-associated damage, suggesting systemic inflammation and oxidative stress. However, the post-treatment with INF and LYC significantly reduced neuroinflammation, partially restored SIRT1 levels, and inflammasome activity. Therefore, these effects may contribute to the restoration of systemic homeostasis and attenuation of lung injury markers. Notably, the combination therapy showed superior protective effects compared with individual treatments. These results suggest an interconnected pathology of RTBI and lung injury, emphasizing how oxidative stress and systemic inflammation contribute to secondary organ damage. The anti-inflammatory and neuroprotective effects of INF and LYC highlight their potential as therapeutic agents for reducing multi-organ complications in RTBI. Further investigations are required to explore their translational applications in clinical settings and establish mechanistic and inter-organ relationships.
OBJECTIVES:Post-traumatic joint contracture (PTJC) is a debilitating fibrotic disorder whose underlying molecular drivers, particularly the involvement of cellular senescence, remain poorly elucidated. This study aimed to evaluate the therapeutic potential of Relaxin-2 (RLX-2) in attenuating knee joint fibrosis and to explore its regulatory effects on the cGAS-STING signaling axis. METHODS:In vitro fibrotic phenotypes were recapitulated using TGF-β1-stimulated rat synovial fibroblasts. An in vivo PTJC model was established via surgical trauma combined with internal fixation-induced immobilization in rats. The anti-fibrotic and anti-senescent properties of RLX-2 were characterized by quantifying markers such as Collagen I, α-SMA, p16, and p53. Transcriptomic profiling via RNA-sequencing was employed to identify potential signaling hubs. The mechanistic involvement of the cGAS-STING pathway was further interrogated using the pharmacological inhibitor H-151 in both experimental settings. RESULTS:In vitro, RLX-2 treatment exerted a concentration-dependent inhibitory effect on TGF-β1-induced fibrogenic transition and cellular senescence. In the rat model, intra-articular administration of RLX-2 resulted in a significant reduction in synovial hyperplasia and extracellular matrix deposition. These phenotypic improvements were associated with the downregulation of senescence markers in the synovium. Mechanistically, RNA-seq analysis pointed toward the cGAS-STING pathway as a primary target of RLX-2. RLX-2 administration was associated with decreased phosphorylation of STING and its downstream effector TBK1. Notably, pharmacological blockade of STING by H-151 partially phenocopied the protective effects of RLX-2, suggesting a coordinated regulation of fibrosis and senescence. CONCLUSION:Our findings demonstrate that RLX-2 attenuates post-traumatic knee joint fibrosis in rats, a process associated with the modulation of the cGAS-STING-senescence axis. These results suggest that targeting the cGAS-STING pathway may represent a viable strategy for managing PTJC, with RLX-2 serving as a promising pharmacological candidate for further clinical investigation.
BACKGROUND:Progresses in nanotechnology have remarkably contributed to the evaluation of improved strategies for cancer therapy. METHODS:Herein, magnesium oxide-bismuth oxide (Bi2O3-MgO) and folic acid-modified magnesium oxide-bismuth oxide nanoparticles (FA-Bi2O3-MgO NPs) were synthesized through Ferula assa foetida extract as a green reducing agent. The prepared nanomaterials were identified using various analytical techniques, containing powder X-ray diffraction (PXRD), Fourier transform infrared spectroscopy (FT-IR), field emission scanning electron microscopy (FESEM), energy dispersive X-ray spectroscopy (EDX), Zeta potential, and UV-visible (UV-vis) spectroscopy. The biological activity of the synthesized materials was evaluated using HCT116 colorectal cancer cells. RESULTS:PXRD analysis revealed that the average crystallite sizes were approximately 43.42 nm for Bi2O3-MgO and 57.90 nm for FA-Bi2O3-MgO NPs, indicating that the presence of folic acid contributed to an increase in particle size. Moreover, the presence of folic acid altered the structural appearance of Bi2O3-MgO NPs, changing their shape from a plate-like to a rod-shaped, with approximately 300-500 nm in length with a diameter around 50-60 nm in FA-Bi2O3-MgO NPs. The zeta potential findings showed a value of -27.9 mV for FA-Bi2O3-MgO NPs, which, compared to the Bi2O3-MgO NPs (-4.3 mV), this indicates an improvement in the colloidal stability of Bi2O3-MgO NPs. Cytotoxicity results indicated a significant decrease in the viability of HCT116 cells treated with FA-Bi2O3-MgO NPs after 24 h, indicating enhanced cytotoxicity potency after folic acid functionalization. FA-Bi2O3-MgO NPs were able to effectively inhibit metastatic behavior in HCT116 cells through significant suppression of cell migration. FA-Bi2O3-MgO NPs showed significant induction of apoptosis, causing 32.18% of cells to undergo apoptosis. Collectively, these in vitro findings demonstrate that FA-Bi2O3-MgO NPs are able to affect important HCT116 cell functions, including suppression of cell migration and activation of apoptotic pathways. CONCLUSION:Taken together, the results indicate that FA-Bi2O3-MgO NPs may serve as promising candidates for therapeutic applications in colon cancer management.
BACKGROUND:Endometrial cancer (EC) incidence is rising globally. Secreted Frizzled-Related Protein 1 (SFRP1) is often silenced in cancers, but its functional role in EC remains unclear. METHODS:Expression and clinical relevance of SFRP1 in EC were analyzed using GEPIA database and validated in clinical specimens via RT-qPCR. The functional impact of SFRP1 was assessed in EC cells through gain-of-function (overexpression plasmid) and loss-of-function (silencing siRNA) experiments. Key cellular phenotypes,including viability (CCK-8), proliferation (Ki-67 staining, colony formation), migration (wound healing), invasion (Transwell), and apoptosis (flow cytometry), were evaluated. In vivo tumor growth and metastasis were examined in BALB/c nude mice using subcutaneous xenograft and experimental lung colonization models. The involvement of Wnt/β-catenin pathway was analyzed by western blot. The epigenetic regulation of SFRP1 by DNA methyltransferase 1 (DNMT1) was investigated through methylation-specific PCR (MSP) and chromatin immunoprecipitation (ChIP)-qPCR. RESULTS:SFRP1 downregulation correlated with advanced grade and poor prognosis. Functionally, SFRP1 consistently inhibited proliferation, migration, invasion, and tumor growth while promoting apoptosis in both in vitro and in vivo models. Mechanistically, SFRP1 exerted anti-tumor effects by negatively regulating Wnt/β-catenin signaling, and its transcriptional repression was caused by DNMT1-mediated promoter hypermethylation. CONCLUSION:SFRP1 acts as a tumor suppressor in EC by inhibiting Wnt/β-catenin, and its downregulation is driven by DNMT1-mediated promoter methylation.
Polyethylene microplastics (PE-MPs) have recently emerged as ubiquitous environmental contaminants capable of penetrating biological systems and exerting toxic effects on vital organs. Experimental evidence indicates that oral exposure to PE-MPs induces biochemical, hepatic, and renal dysfunctions; however, dose-dependent metabolic and histopathological alterations following sub-acute exposure and subsequent recovery remain insufficiently characterized. Sixty male C57BL/6 mice were randomly allocated into four groups (n = 15/group): control, 6 µg/mL, 60 µg/mL, and 600 µg/mL PE-MPs. Animals received daily oral gavage of PE-MPs suspended in distilled water for 15 days. After treatment, eight animals from each group were sacrificed, while the remaining animals were allowed 15 days recovery period. Liver and kidney tissues were examined histologically using hematoxylin and eosin (H&E) and histochemical by periodic acid-Schiff (PAS) staining. Meanwhile, detection of apoptosis stained with acridine orange and DNA damage by comet assay in blood tissue. Many histopathological alternations, apoptosis, and genotoxicity were prominent in both liver and kidney tissue. The severity of harmful alternation increased progressively with escalating polyethylene microplastics exposure. Sub-acute oral exposure to polyethylene microplastics induces dose-dependent in hepatic, renal, blood tissues toxicity in mice. Although partial recovery occurs after exposure cessation, the findings highlight the cumulative and potentially irreversible toxic effects of PE-MPs.
Critical-sized and load-bearing bone defects remain major clinical challenges. The intrinsic regenerative capacity of bone is frequently insufficient to achieve complete functional repair. Recent advances in smart nanocomposite scaffolds have shifted bone tissue engineering from passive structural support toward biologically instructive platforms capable of dynamically regulating cellular behavior and tissue repair. These advances represent a major conceptual and mechanobiological transformation in scaffold design; however, they should not be interpreted as indicating widespread clinical readiness. Despite encouraging preclinical outcomes, most smart scaffold systems remain in the preclinical or early translational stage because critical challenges related to mechanical reliability, scalable manufacturing, long-term biosafety, and regulatory approval remain unresolved. This review examines the mechanobiological mechanisms by which smart nanocomposite scaffolds regulate bone regeneration, with particular emphasis on interactions between scaffolds and stem cells, immune modulation, angiogenic coupling, and translational feasibility. Key regenerative pathways involving osteoconduction, mechanotransduction, ion-mediated signaling, electrical conductivity, and stimuli-responsive activation are analyzed in relation to scaffold composition, nanotopography, and microenvironmental regulation. Comparative translational analysis is provided for bone marrow-derived mesenchymal stem cells, adipose-derived stem cells, induced pluripotent stem cell-derived progenitors, and emerging exosome-based acellular regenerative strategies. In addition, major translational barriers, including manufacturing scalability, mechanical limitations in load-bearing environments, regulatory complexity, long-term biosafety, and reproducibility of cell-based therapies, are critically analyzed. Overall, this review provides a mechanobiological and translational framework for development of clinically applicable smart biomaterials for next-generation bone regenerative engineering. This review presents an evidence-stratified translational framework linking mechanistic pathways to supporting study types and corresponding translational barriers.
Skeletal muscle in teleost fish is traditionally regarded as a contractile tissue supporting locomotion; however, increasing evidence in vertebrates suggests that muscle also participates in immune regulation, stress adaptation, and tissue homeostasis. Despite this, the baseline spatial distribution of immune- and stress-associated proteins in teleost skeletal muscle remains insufficiently characterized. Here, we applied an integrated multiscale imaging approach combining histology, histochemistry, immunohistochemistry, semithin sectioning, and transmission electron microscopy to define the structural organization and molecular landscape of skeletal muscle in the molly fish (Poecilia sphenops). Light microscopy revealed highly organized W-shaped myomeres separated by connective myosepta, while ultrastructural analysis demonstrated well-defined sarcomeric architecture with abundant mitochondria, sarcoplasmic reticulum, and glycogen deposits, consistent with high metabolic activity. Immunohistochemical analysis demonstrated constitutive localization of proteins associated with inflammatory signaling (IL-1β, NF-κB, iNOS), oxidative stress regulation (Nrf2), growth modulation (myostatin, TGF-β), calcium-binding and signaling (S100), and developmental regulation (SOX9) within skeletal muscle fibers. These findings establish the presence of a broad group of immune- and stress-related molecular components in teleost skeletal muscle under physiological conditions. Collectively, this study provides a comprehensive structural and molecular baseline map of P. sphenops skeletal muscle and introduces a reproducible multiscale imaging framework for comparative, environmental, and experimental investigations of muscle biology in teleosts.
Total parenteral nutrition (TPN) is essential for patients who cannot tolerate enteral nutrition, but prolonged exposure to soybean oil-derived lipid emulsions (SOLEs) has been associated with parenteral nutrition-associated liver disease (PNALD). Sole contains phytosterols, including stigmasterol (ST), which may contribute to hepatocellular oxidative stress and apoptosis. This study investigated whether ST and SOLE promote oxidative injury, mitochondrial dysfunction, and apoptosis-related signaling in human L02 liver cells. Cells were exposed to ST, 0.5% SOLE, or their combination for 24 or 48 h. Cell viability, intracellular reactive oxygen species (ROS), mitochondrial membrane potential, apoptosis-related proteins, Nrf2/Keap1 signaling, and pathway-level molecular interactions were assessed using MTT and trypan blue assays, DCFH-DA fluorescence, JC-1 staining, Western blotting, immunofluorescence, and enrichment/network analyses. ST reduced L02 cell viability in a dose- and time-dependent manner and increased intracellular ROS accumulation. SOLE exposure further enhanced oxidative stress, whereas NAC partially attenuated ROS accumulation, supporting the contribution of oxidative stress to ST-induced cytotoxicity. ST also disrupted mitochondrial membrane potential and altered apoptosis-related markers, including caspase-3, PARP1, BAX/BCL2-associated signaling, and Nrf2/Keap1 stress-response regulation. Pathway enrichment and interaction network analyses further supported convergence of oxidative stress, mitochondrial dysfunction, DNA damage response, and apoptosis-related pathways. These findings provide mechanistic in vitro evidence that phytosterol-derived soybean oil emulsion can promote hepatocellular oxidative injury and mitochondrial apoptosis, supporting further investigation of phytosterol-reduced lipid formulations to improve hepatic safety during long-term PN.
