BACKGROUND:Esophageal stricture (ES), a common complication after endoscopic submucosal dissection (ESD), is the consequence of excessive fibrosis and scar formation. The fibroblast-to-myofibroblast differentiation is a key characteristic in the pathogenesis of ES, but the molecular basis remains poorly understood. METHODS:According to the human transcriptome sequencing analysis, which utilized different expression gene analysis and weighted gene co-expression network analysis, the potential gene associated with ES was explored. Furthermore, we utilized the rat model of ES and the temporal progression of ES after drug treatment to elucidate the role of DPP4 in ES. Subsequently, we identified a significant association between DPP4 and the progression of ES. Finally, we validated our conclusions through experiments on Bama pigs. RESULTS:DPP4 expression was consistently elevated in both human ES tissues and the rat ES model. Upon inhibition of DPP4, the proliferative activity of ES primary cells and the expression of fibrosis-related genes were markedly suppressed. In rats, treatment with a DPP4 inhibitor significantly alleviated ES, which was accompanied by a significant reduction in collagen content and downregulation of fibrosis-related targets. These effects were observed in conjunction with changes in the Hippo-YAP pathway, although the data primarily support a parallel association rather than a hierarchical regulatory relationship between DPP4 and this pathway. CONCLUSIONS:Our findings suggest that DPP4 may contribute to the remodeling of the regenerative microenvironment in ES, with its expression and function occurring in parallel with alterations in the Hippo-YAP pathway. Direct mechanistic evidence establishing a linear upstream-downstream relationship between DPP4 and Hippo-YAP signaling remains to be further elucidated.
BACKGROUND:Ischemic stroke triggers neuroinflammation and oxidative stress, leading to neuronal damage. Kojic acid (KA) has exhibited neuroprotective properties in other neurological pathologies but suffers from poor bioavailability. This study investigated whether KA encapsulated in nanostructured lipid carriers (KA-NLC) exerts protective effects against cerebral ischemia. METHODS:Eighty adult male Wistar rats were subjected to transient middle cerebral artery occlusion (MCAO) or control procedures and allocated into 10 experimental groups (n = 8 per group): intact, sham, MCAO, vehicle, three free-KA solution groups (10, 20, and 40 mg/kg), and three KA-NLC groups (1, 2, and 4 mg/kg). Functional outcomes were assessed using neurological scoring and Rota-Rod, Morris water maze, and shuttle box tests. Brain water content, hippocampal histology, and cerebrospinal fluid cytokine levels (interleukin-10 [IL-10], tumor necrosis factor-α [TNF-α]) were also evaluated. RESULTS:Treatment with low and medium doses of KA-NLC and medium and high doses of free KA significantly reduced brain edema and improved neurological scores, motor coordination, and memory performance compared to the MCAO group. These functional improvements were associated with a significant increase in anti-inflammatory IL-10 and a modulation of TNF-α. Histological examination confirmed neuroprotection, with KA-NLC preserving hippocampal CA1 neural integrity. The high dose of KA-NLC and the low dose of free KA however were ineffective. CONCLUSIONS:Nanoformulated KA confers significant neuroprotection against ischemic stroke by reducing edema, modulating inflammation, and preserving neuronal integrity, presenting a promising therapeutic strategy.
BACKGROUND:Ovarian cancer (OC) is often diagnosed at advanced stages, with extensive peritoneal carcinomatosis (PC) and poor prognosis. Although intraperitoneal drug delivery systems (iDDS) are promising for targeting residual microscopic disease after cytoreductive surgery, reproducible murine PC models remain limited. We compared two OVCAR-3-based intraperitoneal engraftment strategies (diffuse vs. localized) and assessed the impact of inoculum density and basement membrane extract (BME) supplementation to identify a robust model for iDDS evaluation. METHODS:Immunodeficient female nu/nu mice were engrafted with luciferase-expressing OVCAR-3 cells. For localized implantation, 1 × 106 or 4 × 106 cells were implanted into the preperitoneal space behind the rectus abdominis; after assessment, the 1 × 106 group was tested with basement membrane extract (BME). In the intraperitoneal dissemination model, 1 × 106 cells were injected with BME to promote diffuse peritoneal spread. Tumor progression was monitored weekly using bioluminescence imaging (BLI), and animals were sacrificed for macroscopic, histological, and immunohistochemical analyses. RESULTS:In the localized model, no differences were detected between 1 × 106 and 4 × 106 cells; therefore, 1 × 106 was selected for subsequent experiments. BME increased early tumor volume and attenuated the initial BLI decline, but signal and tomographic measurements progressively decreased. Histology revealed extracellular matrix remodeling, apoptosis, and tumor regression, indicating limited long-term viability. In contrast, the intraperitoneal injection model generated a clinically relevant dissemination pattern. After an initial decrease, BLI increased steadily, and necropsy confirmed tumor nodules along abdominal organ surfaces. CONCLUSIONS:The intraperitoneal injection model with BME more accurately reproduced human PC progression and distribution, providing a platform for preclinical testing of localized iDDS.
BACKGROUND:Head and neck squamous cell carcinoma (HNSCC) is characterized by clinically undetectable early metastasis and a poor prognosis at locally advanced and recurrent metastatic stages. Platinum-based resistance remains a major limitation to treatment efficacy. Currently, no reliable biomarkers are available to identify lymph node metastasis or to predict therapeutic sensitivity. Therefore, this study aimed to develop a predictive model to address these clinical challenges. METHODS:Four cell lines (CAL-27, FaDu, Leuk1, NOEC) were employed to establish zebrafish cell-derived xenograft (zCDX) models and assess the differential metastatic potential. Surgical or biopsy samples from, respectively, 20 and 14 HNSCC patients were used for building and validating the zebrafish patient-derived xenograft (zPDX) models. Cisplatin-sensitive HNSCC cell lines (CAL-27 and FaDu) and their cisplatin-resistant sublines (CAL-27-DDP and FaDu-DDP) were established, and the differential responses to cisplatin were evaluated in both murine and zCDX models. Additionally, to assess the patient-specific therapeutic efficacy of cisplatin, zPDX models were generated from four patient-derived surgical specimens and a supplementary biopsy for preliminary validation. RESULTS:The zebrafish xenograft model recapitulated the invasive phenotype of the HNSCC cell lines. The model distinguished between metastatic and non-metastatic disease with high accuracy (AUC = 0.98). It faithfully reproduced the cisplatin sensitivity and resistance patterns identified in corresponding in vitro and murine models. Moreover, it showed strong concordance with patient-specific cisplatin responses. CONCLUSIONS:The zPDX model provides a rapid, efficient, clinically applicable platform for predicting metastasis and evaluating platinum-based therapy responses in HNSCC, facilitating the design of scientifically grounded personalized treatment.
The tree shrew (Tupaia belangeri) is an emerging animal model for human diseases, yet the status of the critical tumor suppressor TP53 in its subspecies and spontaneous tumors is unknown. We sequenced the entire TP53 coding region from two subspecies, T. b. yaoshanensis and T. b. chinensis, and analyzed two spontaneous sarcomas from T. b. yaoshanensis using histopathology, immunohistochemistry, and cDNA sequencing with clonal validation. TP53 showed 99.5% nucleotide identity between subspecies, with a single fixed non-synonymous substitution (D42G) in T. b. yaoshanensis predicted to be functionally neutral. All residues corresponding to human cancer hotspots were strictly conserved, and structural modeling confirmed high similarity to human p53 (RMSD = 0.6 Å). Critically, we identified TP53 sequence variants in both spontaneous tumors: a missense variant (Ser175Gly) in the DNA-binding domain of a liposarcoma and another (Met344Thr) in the tetramerization domain of a myxofibrosarcoma. Computational prediction suggested both missense variants are tolerated (SIFT scores 0.61 and 0.77), and their functional significance remains to be determined. This study provides preliminary evidence of TP53 variants in spontaneous tree shrew tumors and reveals natural subspecies variation. The high conservation of p53 reinforces the tree shrew's relevance as a model for TP53-related cancer research, although further functional studies are needed.
BACKGROUND:Knee osteoarthritis (KOA) is a chronic joint disorder. Current treatment options offer limited benefit. Adipose-derived mesenchymal stem cells (ADSCs), known for their chondrogenic potential and anti-inflammatory and immunomodulatory functions, have gained growing interest in regenerative therapy. Acupoint interventions are widely recognized for analgesic and anti-inflammatory effects. Combining ADSCs with acupoint-targeted delivery may represent a novel therapeutic approach. This study evaluated the therapeutic efficacy and underlying mechanisms of ADSC injection into the KI10 acupoint in mitigating KOA-related cartilage damage. METHODS:KOA models were established in male Sprague-Dawley rats, followed by ADSC injection into the KI10 acupoint. Pain, motor function, and joint structural changes were assessed through ethological testing, imaging, histopathology, transmission electron microscopy, and molecular analyses. TMT-based proteomics was used to identify mechanistic pathways, and the α7nAChR antagonist methyllycaconitine citrate (MLA) was used to validate the pathways. RESULTS:ADSC injection into the KI10 acupoint significantly reduced pain and improved motor performance in KOA rats. Imaging and histological analysis revealed significant decreases in synovial inflammation and cartilage degeneration. Transmission electron microscopy confirmed diminished chondrocyte injury. Proteomic analysis indicated activation of the cholinergic anti-inflammatory pathway, and MLA administration reversed these therapeutic benefits, verifying pathway involvement. CONCLUSIONS:ADSC injection into the KI10 acupoint effectively attenuates cartilage injury and inflammation in KOA by activating the PGE2-mediated α7nAChR/NF-κB signaling pathway. This combined strategy harnesses the complementary advantages of stem cell therapy and acupoint-targeted intervention, offering a promising therapeutic avenue for KOA.
BACKGROUND:Hypoxic pulmonary hypertension (HPH) is a progressive chronic disorder characterized by elevated mean pulmonary arterial pressure. It severely impairs right ventricular function and ultimately causes right ventricular failure. Clarifying the complex pathogenesis of HPH remains a critical challenge. METHODS:Rat HPH models were established by exposure to a hypobaric hypoxia chamber for 4 consecutive weeks. Lung tissues were harvested for RNA sequencing. The Coding-Non-Coding Index (CNCI) and Coding Potential Calculator (CPC) were used to construct a competing endogenous RNA (ceRNA) network. Pulmonary artery endothelial cells were transfected with modified lncRNA-92467 or miR-205-5p to assess their regulatory functions. Finally, mice were injected with AAV-Control or AAV-PTPRM shRNA (2.5 × 1011 v.g./mL per mouse). Hemodynamic and echocardiographic analyses were performed to evaluate the in vivo role of PTPRM. RESULTS:We identified that lncRNA-92467 functions as a competing endogenous RNA (ceRNA) by competitively binding to miR-205-5p, thereby upregulating its target gene PTPRM. Knockdown of lncRNA-92467 significantly promoted pulmonary artery endothelial cell proliferation and migration. These effects were abolished by a miR-205-5p inhibitor, which also restored PTPRM expression. Functional assays confirmed that miR-205-5p enhanced cell proliferation and migration while inhibiting apoptosis; these effects were reversed by PTPRM overexpression. In vivo, exogenous PTPRM overexpression attenuated HPH progression in mice. Mechanistically, PTPRM directly targeted cell adhesion molecules (CAMs), which increased catenin production, thereby inhibiting abnormal cell proliferation and migration and promoting apoptosis. CONCLUSIONS:Our findings reveal a novel lncRNA-92467/miR-205-5p/PTPRM/CAMs regulatory axis in HPH pathogenesis. These results suggest that PTPRM may serve as a promising therapeutic target for HPH.
BACKGROUND:Anxiety-depressive disorder (ADD) is one of the important subtypes of depression, which has been shown to be closely related to neuroimmune abnormalities. Currently, specific biomarkers have not been identified as diagnostic, differential, and therapeutic targets. This study aimed to explore the molecular mechanisms and diagnostic biomarkers of ADD and elucidate its association with neuroinflammation. METHODS:Differentially expressed circadian rhythm-related genes were screened. Key genes were identified by machine learning. An ADD rat model was established using chronic restraint stress combined with corticosterone administration. Using AAV virus tools for KLF-10 overexpression and knockout (KLF10-OE and shKLF10), depression-like and anxiety-like behaviors were evaluated through behavioral experiments, pathological changes in the hippocampus and amygdala were observed by Nissl staining, cytokine levels were detected by ELISA, molecular co-localization was performed by RNAscope ISH and immunofluorescence, and molecular expression of NF-κB/NLRP3 pathway was detected by Western blot and qRT PCR. RESULTS:Nine circadian rhythm-related genes showed significant differential expression, with KLF10 identified as a diagnostic biomarker. KLF10 overexpression ameliorated depressive-like and anxiety-like behaviors, and reduced pro-inflammatory factors (IL-1β, TNF-α) and increased anti-inflammatory factors (IL-10, TGF-β) in both brain and serum, the treatment can be blocked by PMA. KLF10 suppressed IκB-α phosphorylation-mediated NF-κB nuclear translocation and inhibited downstream molecules. CONCLUSION:KLF10 mitigates hippocampal-amygdala neuroinflammation by downregulating the NF-κB/NLRP3 pathway, thereby alleviating a ADD symptoms, and represents a potential diagnostic biomarker and therapeutic target.
Abstract Background Venous malformations (VMs) are congenital vascular anomalies characterized by abnormal vascular proliferation, with limb VMs often leading to functional impairment and physical discomfort. However, the cellular heterogeneity and underlying molecular mechanisms driving pathological proliferation in limb VMs remain incompletely elucidated. Methods In this study, we collected 10 tissue samples including specimens from 5 limb VM patients and 5 normal control tissues and performed single‐nucleus RNA sequencing (snRNA‐seq) to comprehensively map the cellular landscape of VMs. We first identified distinct cell subpopulations covering vascular endothelial cells, vascular smooth muscle cells, and immune cells, and compared gene expression levels between VM and normal tissues. Afterward, we conducted weighted gene co‐expression network analysis (hdWGCNA) and constructed the protein–protein interaction (PPI) network to screen critical proliferation‐related genes in VMs. We further analyzed the signaling pathways associated with these candidate genes and carried out subsequent functional validation experiments to explore the biological role of core gene TEK in proliferative vascular endothelial cells (PVECs). Besides, we also analyzed the characteristic pathways of the PVEC subpopulation to clarify its proliferation‐related molecular features. Results We found obvious expression differences of genes in various cell subpopulations between VM and normal tissues. Three genes, namely tyrosine protein kinase receptor (TEK), Fms‐like tyrosine kinase 1 (FLT1), and EGF‐like domain multiple 7 (EGFL7), were identified as key proliferation‐related genes with significant upregulation in VM lesions, and these three genes were closely associated with the activation of PI3K/AKT/mTOR, IL6/JAK/STAT3, and TNF‐α/NF‐κB pathways. Functional experimental results showed that TEK knockdown could significantly inhibit proliferative vascular endothelial cell (PVEC) proliferation and promote cell apoptosis, and reverse the abnormal activation of inflammatory pathways. As a vital pathogenic cell subpopulation, PVECs facilitated abnormal vascular proliferation through activating pathways including the G2/M checkpoint and E2F targets. Conclusions Collectively, our study systematically elucidated the cellular heterogeneity framework and proliferation mechanisms of limb VMs, identifying TEK, FLT1, and EGFL7 as key regulators of pathological proliferation. These findings provide new insights into the pathogenesis of VMs and lay a foundation for developing precise therapeutic strategies targeting proliferation‐related pathways.
Abstract Background Hepatomegaly in hemolytic disorders, including in thalassemia, is a common complication, primarily due to hemosiderosis and activation of extramedullary hematopoiesis. Globin chain imbalance leads to chronic hemolysis and ineffective erythropoiesis, which are associated with suppression of hepcidin expression. Reduced hepcidin levels may increase iron absorption and accumulation, contributing to oxidative stress and liver tissue damage. Iron chelation therapy, such as deferipron, is effective but has side effects, so safer alternatives are needed. Sappanwood (Caesalpinia sappan L.) contains the active compound brazilin, which chelates iron and exhibits antioxidant activity, potentially reducing oxidative stress, improving iron metabolism disorders, and reducing hepatomegaly. This study aims to evaluate the potential of sappanwood extract as a natural iron chelator and antioxidant. Methods This experimental study used male Wistar rats (180–250 g) with a model of iron overload hemolytic anemia, which were divided into normal controls, negative controls (phenylhydrazine 40 mg/kg BW), positive controls (deferiprone 75 mg/kg BW), and sappanwood extract (SWE) treatment (50, 100, 200 mg/kg BW) for 14 days. The parameters measured included iron metabolism, hepatomegaly, liver function, hepcidin‐related gene expression, and oxidative stress. Data were analyzed using ANOVA, with p < 0.05 considered significant. Results The results showed that administration of 100 mg/kg BW SWE provided optimal improvement (p < 0.05), including reductions in hepatomegaly, SGPT, hemosiderin, lipid peroxidation, bilirubin, extramedullary hematopoiesis, and modulation in iron‐related gene expression, including Hamp, Bmp6, Epo, and Ftl. Conclusions These findings confirm the potential of sappanwood as a potential therapeutic candidate for the management of iron overload in thalassemia.
Abstract Background Post‐traumatic stress disorder (PTSD) is a complicated neuropsychiatric disorder that is marked by long‐term neuroinflammation, oxidative stress, and poor neuroplasticity in stress‐sensitive brain areas. Hesperidin is a citrus‐derived flavanone glycoside that has been reported to have multitarget neuroprotective effects with antioxidant, anti‐inflammatory, and neurotrophic regulatory activities. However, its integrated effects across convergent pathological pathways in validated PTSD models remain insufficiently defined. Methods Male Wistar rats were subjected to the single prolonged stress (SPS) paradigm and treated with hesperidin (50, 100, and 200 mg/kg), fluoxetine (20 mg/kg), or vehicle for 14 days. Biochemical assessments (malondialdehyde [MDA], catalase [CAT], superoxide dismutase [SOD]) and immunohistochemical measurements of neuronal and glial integrity (NeuN, glial fibrillary acidic protein [GFAP], brain‐derived neurotrophic factor [BDNF]) in the hippocampus, amygdala, and prefrontal cortex were performed. Results SPS exposure induced marked oxidative imbalance, evidenced by increased MDA levels and reduced CAT activity, alongside significant upregulation of tumor necrosis factor α (TNF‐α), interleukin 6 (IL‐6), and IL‐1β, increased astrocytic reactivity (GFAP), and reduced BDNF expression. Hesperidin treatment significantly attenuated lipid peroxidation, partially restored CAT activity, and suppressed pro‐inflammatory cytokines, with the most pronounced effect observed for IL‐1β. Notably, hesperidin reduced astrocytic activation and preserved neuronal morphology, while enhancing BDNF expression in a dose‐dependent manner, with optimal effects at 50–100 mg/kg. Conversely, there was little group variation in the activity of SOD, implying pathway‐selective redox regulation. Conclusion Hesperidin has multipathway, coordinated, modulatory effects on oxidative stress, neuroinflammation, glial activation, and neurotrophic signaling in the SPS model of PTSD. These findings support its utility as a mechanistic probe for interrogating convergent stress‐related neuropathological pathways.
BACKGROUND:Silicosis is a progressive, irreversible fibrotic lung disease caused by long-term exposure to crystalline silica. Although the anti-fibrotic tetrapeptide Ac-SDKP has shown promise in reducing fibrosis, the specific molecular mechanisms through which it modulates apoptosis in silica-induced lung injury remain unclear, particularly the role of heat shock protein 27 (HSP27). METHODS:Wistar rats were divided into groups including control, model (2-week, 3-week, and 4-week), and Ac-SDKP prevention/treatment groups. In vitro, MEF and A549 cells were treated with TGF-β1 and Ac-SDKP to observe the effects on apoptosis-related proteins. Additionally, HSP27 interference vectors were constructed to study its role in regulating apoptosis via FAS/FASL and mitochondrial pathways in both in vivo and in vitro models. RESULTS:In vivo, Ac-SDKP administration alleviated silica-induced pulmonary fibrosis and reduced apoptosis in lung tissue. In contrast, in vitro, TGF-β1 stimulation suppressed apoptosis in A549 and MEF cells, whereas Ac-SDKP restored apoptotic activity by regulating the HSP27-mediated FAS/FASL and mitochondrial pathways. Moreover, AAV9-mediated knockdown of HSP27 in mice enhanced apoptosis and attenuated fibrosis, confirming the anti-apoptotic role of HSP27 in silicosis. CONCLUSION:These findings reveal that Ac-SDKP exerts context-dependent modulation of apoptosis through HSP27-protecting acutely injured alveolar epithelial cells in vivo while reinstating apoptotic signaling in EMT-adapted A549 and MEF cells in vitro. Thus, targeting HSP27 may offer a promising therapeutic strategy to restore apoptotic-fibrotic equilibrium in silicosis and related pulmonary fibrotic disorders.
BACKGROUND:The gut's impact on kidney health can be observed through its influence on the gut-kidney axis. However, using paraprobiotic and postbiotic agents may improve gut health and kidney function by affecting signaling pathways. This study aims to assess the anti-inflammatory and autophagy-inducing properties of native postbiotics and paraprobiotics to enhance kidney health by targeting the gut-kidney axis. METHODS:In this animal experiment, colitis was induced in male C57Bl/6 mice using dextran sulfate sodium (DSS), and mice were treated with postbiotics and paraprobiotics consisting of four Lactobacillus and two Bifidobacterium strains. A quantitative polymerase chain reaction assay was conducted to evaluate the gene expression involved in the autophagy process in the kidney. RESULTS:A significant decrease in weight and colon length and an increase in disease activity index and pathological changes were observed in the DSS group. However, the paraprobiotic and postbiotic mixtures, with more emphasis on postbiotics, were effective in preventing these changes caused by DSS. Exposure to DSS resulted in the downregulation of autophagy-related genes, but this difference was not statistically significant. Both the paraprobiotics and postbiotics increased the expression of genes. The postbiotic mixture had a more pronounced effect in increasing the expression of atg7, atg12, and beclin. CONCLUSIONS:Our native postbiotics and paraprobiotics indicated an effective role in reducing inflammation, especially gut and kidney inflammation, through the gut-kidney axis. The administration of these beneficial agents with the least side effects could be considered a suitable complementary treatment for controlling symptoms in patients with inflammatory-related disease.
BACKGROUND:Lymph node (LN) fibrosis occurs in a variety of pathological conditions, including HIV infection, obesity, cancer, and tissue injury. Fibroblastic reticular cells (FRCs) play a critical role in maintaining LN architecture and immune homeostasis, whereas their dysregulation promotes extracellular matrix (ECM) deposition and immune dysfunction. Transforming growth factor-β1 (TGF-β1) is a key profibrotic cytokine. However, reliable and convenient animal models for investigating LN fibrosis remain limited. METHODS:This study comprehensively compared four induction methods: footpad injection of TGF-β1, lymphatic vessel ligation, inguinal subcutaneous injection of TGF-β1, and direct intra-LN injection of TGF-β1. Histological analysis, transcriptomic profiling, flow cytometric analysis, and safety evaluation were performed to assess fibrosis and immune alterations. RESULTS:Among the four approaches, inguinal subcutaneous and intra-LN injection of TGF-β1 successfully induced LN fibrosis without causing significant injury to major organs. Notably, the intra-LN injection model induced fibrosis in both cortical and medullary regions of LNs. Comparing the transcriptomic data of fibrotic and non-fibrotic LNs demonstrated marked changes in fibrosis-related genes, including pro-fibrogenic mediators, collagens and basement membrane-related genes, and TGF-β1-associated signaling pathways. In two fibrotic models, we also noticed increased macrophage infiltration and a drop in CD8+ T cells, suggesting an immune suppressive microenvironment. Furthermore, inhibition of collagen cross-linking partially alleviated fibrotic remodeling in fibrotic LNs. CONCLUSION:We established and characterized two mouse models of LN fibrosis induced by TGF-β1 administration. These models provide valuable tools for investigating the mechanisms of LN fibrosis and its impact on local immune regulation, and may facilitate the development of therapeutic strategies targeting fibrotic LNs.
Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by amyloid-β (Aβ) deposition. The liver-brain axis underscores the central role of the liver in modulating cognitive function through multidimensional regulatory mechanisms. As a core metabolic and detoxification organ, the liver also helps maintain cerebral homeostasis via pathways including the urea cycle, antioxidant systems, ketone body metabolism, and bile acid regulation. Dysfunction of these processes may lead to ammonia accumulation, exacerbated oxidative stress, and Aβ clearance, thereby accelerating the pathological progression of AD. Liver-derived factors such as apolipoprotein E (APOE), C-reactive protein (CRP), fibroblast growth factor 21 (FGF21), and insulin-like growth factor 1 (IGF-1) significantly increase the risk of AD through dual mechanisms-inhibiting Aβ clearance and activating neuroinflammation, thereby directly affecting cognitive function via modulation of inflammation, metabolism, and blood-brain barrier (BBB) integrity. Neural interfaces formed by the hypothalamic-pituitary-target gland axis and the vagus nerve enable communication from the liver to the brain, with emerging evidence also supporting a reverse influence from the brain to the liver. Emerging technologies such as molecular tracing and nanocarriers provide new tools for deciphering dynamic interactions within the liver-brain axis. Liver-targeted metabolic interventions show potential for reversing cognitive impairment. Unlike previous reviews that mainly focused on single pathways, this review conceptualizes the liver-brain axis as a multidimensional regulatory network in AD. By clearly linking network nodes to potential therapeutic interventions, it provides us with a novel framework that not only describes the various mechanisms but also focuses on identifying actionable targets for disease prevention and treatment.
Abstract The objective of this review was to synthesize evidence from animal models on the effects of intermittent hypobaric hypoxia (IHH), cold exposure, and their combinations, with or without exercise, on skeletal muscle recovery after fatigue or injury. The review systematically examined controlled animal studies evaluating hypoxia‐ or cold‐based interventions for muscle recovery. The data sources PubMed, SPORTDiscus, Web of Science, and Scopus were searched up to July 2025 following PRISMA guidelines (PROSPERO CRD420251013029). Studies deemed eligible for inclusion were interventional animal studies assessing IHH, cold exposure, or combined protocols and reporting functional, physiological, or mechanistic outcomes. Risk of bias was evaluated using RoB 2. Five studies met inclusion criteria. IHH protocols simulated ~4000–4500 m for several hours per day, while cold exposure used ~4°C; some studies added low‐intensity treadmill exercise. IHH alone enhanced muscle regeneration, reduced fibrosis, and improved contractile force compared with passive recovery. Combined with aerobic exercise, IHH maintained oxidative capacity and increased PGC‐1α and VEGF expression, supporting angiogenesis. Cold exposure elevated mitochondrial complex expression but increased oxidative stress, whereas IHH improved redox balance. IHH plus light exercise also raised circulating CD34+ and endothelial progenitor cells, suggesting improved repair capacity. Overall risk of bias was rated as “some concerns,” mainly due to limited reporting of randomization. Our conclusion is that IHH shows potential to enhance muscle regeneration and redox balance in animal models. Its application in athletic recovery is promising, but standardized protocols and human trials are required before translation.
BACKGROUND:Hypertrophic scars (HS) are a common fibrotic disorder in skin wound healing, characterized by excessive fibroblast proliferation and abnormal collagen deposition, with an incidence reaching 40%-70% in burn patients. Current treatments (e.g., corticosteroid injections) face challenges such as high recurrence rates and significant adverse effects, highlighting the urgent need for reliable animal models to investigate pathogenesis and develop novel therapies. METHODS:Forty-eight male Sprague-Dawley (SD) rats were used to systematically compare modeling efficacy across auricular (3.5 mm corneal trephine), dorsal (linear incision/tension/full-thickness excision), and caudal (linear incision/tension) sites. Each subgroup contained 12 rats (n = 12/group). Scar formation was evaluated over 60 days via macroscopic observation, Vancouver Scar Scale (VSS) scoring, H&E/Masson staining (fibroblast density/collagen deposition), and immunofluorescence α-smooth muscle actin (α-SMA), transforming growth factor beta (TGF-β), type I collagen/type III collagen (COL I/III). RESULTS:The caudal tension group demonstrated optimal outcomes, with scar thickness (0.394 ± 0.006 mm), fibroblast density (1079 ± 118 cells/mm2), and collagen deposition (90.6% ± 2.4%) significantly higher than other groups (***p < 0.001), alongside sustained upregulation of α-SMA and TGF-β. The auricular site was excluded due to rapid self-healing. CONCLUSION:The tension method on the tail is a simple, stable, and clinically relevant HS model, effectively replicating human pathological features and providing an ideal platform for disease mechanism research and drug screening.
Abstract Background Parkinson's disease (PD) is a neurodegenerative disorder characterized by progressive degeneration of midbrain substantia nigra dopaminergic neurons, resulting in striatal dopamine depletion and motor dysfunction. While this pathological cascade is well‐established, its underlying mechanisms remain elusive. Methods To further investigate the pathological mechanisms of PD, we performed single‐cell RNA sequencing of the midbrain and striatum from Hua‐Syn (SNCA*A53T) transgenic (A53T) mice as a PD model. Results Analysis of 22 865 midbrain and 32 117 striatal cells revealed cell‐type‐specific risk association. Glial populations (astrocytes, microglia, oligodendrocytes) showed significant enrichment for PD‐risk genes. Variance‐based clustering identified PD‐enriched subclusters exhibiting upregulated inflammatory pathways, apoptotic pathways, proteostasis disruption, glutamatergic signaling dysregulation, and mitochondrial respiratory chain defects. Transcriptional regulation analysis identified genes associated with PD specific activity, including Rorb and Foxc1 in the midbrain and Dbx2 and Klf13 in the striatum. Cell–cell interactions showed that cell‐to‐cell signaling was enhanced, and the SEMA and CCL neuroinflammatory axes were specifically activated in the PD group. Conclusions Our integrative analysis delineates the cellular and molecular architecture of the pathological process triggered by the expression of A53T mutant α‐synuclein, and provides a framework for targeted therapeutic development.
The Nuclear Factor of Activated T Cells (NFAT) family comprises closely related transcription factors. Numerous biological processes including angiogenesis, invasion, migration, proliferation, and cell survival are regulated by the NFAT family. NFATs are overexpressed and have increased transcriptional activity in a variety of human solid tumors and hematological cancers. Beyond tumor cell-intrinsic roles, NFAT has also emerged as an important regulator of the tumor microenvironment (TME), where it can influence immune cell behavior and contribute to mechanisms of immune evasion. The discovery of the multifaceted functions of NFATs has driven the need to further unveil their role in cancer and provide new insights into other potential roles. This review provides a comprehensive narrative synthesis of current molecular and clinical studies, with particular emphasis on how NFAT shapes tumor immune interactions and modulates the TME. By integrating findings across different cancer types, we highlight how NFAT may contribute to both tumor progression and immune regulation. The review concludes by highlighting significant knowledge gaps and recommending future paths for translational and therapeutic research to leverage NFAT signaling as a potential target in precision cancer therapy.
