Obesity is a metabolic disorder characterized by the accumulation of excess body fat, which has been linked to skeletal muscle and motor behavior changes. Despite the high prevalence of obesity among children and adolescents in Mexico, it has mostly been studied using adult obese animal models. The objective of the present study was to analyze open-field locomotor activity and dendritic length and dendritic spine density in layer V pyramidal neurons of the primary motor cortex (M1) in adolescent (60-day-old) obese Zucker diabetic fatty (ZDF) rats of both sexes. Long-Evans (LE) rats were used as the control group. Female ZDF rats exhibited increased body weight, Lee index, and abdominal circumference. In contrast, male ZDF rats showed a shorter body length together with increased Lee index and abdominal circumference. However, ZDF rats of both sexes displayed elevated triglyceride and cholesterol levels. In addition, hyperglycemia was observed in male ZDF rats. Female ZDF rats showed decreased exploratory activity. The dendritic length of the basilar arbor of M1 neurons was significantly shorter in female and male ZDF rats, with ZDF males exhibiting a smaller basilar arbor than ZDF females. This last result was also observed in the apical arbor of these neurons. There was also a decrease in basilar and apical dendritic spine density in ZDF rats of both sexes. Our results indicate that female ZDF rats show alterations in exploratory behavior and dendritic arborization, whereas ZDF males are affected in terms of dendritic arborization in M1 neurons, which suggests sex differences in the effects of obesity in adolescent Zucker rats.
Lipopolysaccharide (LPS) is a component of the Gram-negative bacterial cell wall and is considered a potent inflammatory inducer. Empagliflozin (EMPA) is a sodium-glucose co-transporter 2 inhibitor used in treatment of type 2 diabetes mellitus. Interleukin-6/Janus kinase/signal transducer and activator of transcription 3 (IL-6/JAK/STAT3) signaling pathway is essential in driving inflammation, fibrosis, and epithelial–mesenchymal transition (EMT). Tracheal basal stem cells are responsible for epithelial regeneration after injury. This study aimed to investigate the potential protective effects of EMPA against LPS-induced tracheal injury, with emphasis on EMT and tracheal basal stem cells. Sixty adult male rats were allocated into four groups: control; EMPA, which received EMPA (10 mg/kg/day) via oral gavage for 28 days; LPS, which received single intratracheal dose of LPS (5 mg/kg) on day 1; and LPS + EMPA, which received single LPS dose and EMPA for 28 days. Tracheal specimens were processed for biochemical, histological, immunohistochemical and RT-quantitative real-time PCR analysis. Compared to the LPS group, the LPS + EMPA group showed marked improvement of histological, ultrastructural ,and biochemical alterations including maintenance of epithelial and cilia integrity, decreased lipid peroxidation, stimulated antioxidant enzyme activities, reduced serum inflammatory cytokines, increased percentage area of E-cadherin (an epithelial marker) immunostaining, decreased percentage area of fibrosis, vimentin (a mesenchymal marker), and pro-apoptotic Bax; and enhanced percentage area of cytokeratin 5/6 (CK5/6) (stem cell marker). Moreover, EMPA downregulated the IL-6/JAK/STAT3 pathway involved in EMT. In conclusion, EMPA alleviated LPS-induced tracheal injury through its antioxidant and anti-inflammatory properties, downregulation of IL-6/JAK/STAT3 signaling pathway, and preservation of the tracheal basal stem cells.
Lymph node metastasis in esophageal squamous cell carcinoma (ESCC) is associated with poor prognosis, and screening for potential biomarkers of metastasis is significant for improving the prognosis of ESCC. After batch effect removal and integration of two ESCC transcriptome datasets (GSE157804, GSE118493), differentially expressioned gene analysis was performed. The intersection of differentially expressed genes was obtained to identify characteristic genes associated with lymph node metastasis in ESCC. GO/KEGG enrichment analyses were conducted for the characteristic genes. The top 10 pathways and pathway genes based on q-value were selected to construct a PPI network. Hub genes were identified and intersected with the characteristic genes to determine key genes. GO/KEGG enrichment, expression level analysis, and immune infiltration analysis were performed for the key genes. Immunohistochemistry was used to validate the expression levels of key genes in clinical samples. A cell model with regulated expression of key genes was established to verify their impact on the invasive and migratory capabilities of ESCC cells and epithelial-mesenchymal transition (EMT), as well as ECM‑related gene expression. A total of 542 characteristic genes associated with lymph node metastasis in ESCC were identified through differential gene analysis, which were mainly enriched in extracellular matrix-related pathways. PPI network analysis identified 63 hub genes, and the intersection with characteristic genes resulted in 20 key genes, which were also primarily enriched in extracellular matrix-related pathways. Expression level analysis showed that key genes such as STAT1, STAT2, IFIT1, and IFIT3 were highly expressed in metastatic ESCC tissues compared to primary sites and adjacent non-tumor tissues. Immune infiltration analysis revealed a significant positive correlation between IFIT3, STAT1, STAT2, and M1 macrophage polarization. Immunohistochemical analysis indicated high expression of STAT1 in ESCC patient samples with lymph node metastasis. Upregulation of STAT1 in ESCC cells enhanced cell invasion, migration, EMT levels and ECM‑related gene expression, while downregulation of STAT1 expression suppressed these processes. Consistently, an additional gain‑of‑function experiment further confirmed these promoting effects. STAT1 serves as a biomarker for lymph node metastasis in ESCC. The expression level of STAT1 is positively correlated with the degree of lymph node metastasis in ESCC clinical samples. Overexpression of STAT1 promotes the invasion, migration, EMT and ECM‑related gene expression of ESCC cells, while the downregulation of STAT1 inhibits these effects.
To investigate the therapeutic effect of Kushen Tongguan Pill (KSTG) on benign prostatic hyperplasia (BPH) induced by castration combined with testosterone propionate in rats, and to explore its underlying mechanism associated with the Toll-like receptor 4/nuclear factor κB (TLR4/NF-κB) signaling pathway. A rat BPH model was established by castration combined with subcutaneous injection of testosterone propionate. Rats were randomly divided into sham group, BPH group, and low-, medium-, and high-dose KSTG groups (2.52, 5.04, and 10.08 g/kg). After 4 weeks of intervention, prostate wet weight was weighed and prostate index was calculated； histopathological changes were observed by hematoxylin-eosin (HE) staining; collagen deposition and fibrosis were evaluated by Masson’s trichrome staining; the expression of α-smooth muscle actin (α-SMA) was detected by immunohistochemistry; serum testosterone (T), estradiol (E2), and dihydrotestosterone (DHT) levels were measured by enzyme-linked immunosorbent assay (ELISA); peripheral white blood cell and neutrophil counts were measured using an automated hematology analyzer; toluidine Blue staining was performed to observe mast cell infiltration in prostate tissue to assess local chronic inflammation. RT-qPCR was used to detect the mRNA expression of key pathway molecules including TLR4, NF-κB p65, IKKα, and IKKβ, as well as inflammatory markers TNF-α, IL-1β, MCP-1, and iNOS in prostate tissue. Western blotting was performed to analyze the protein expression of key pathway molecules including TLR4, MyD88, IκBα, p-IκBα, NF-κB p65, and p-NF-κB p65, as well as the inflammatory marker iNOS in prostate tissue. For in vitro experiments, KSTG-containing serum was used to treat LPS/IFN-γ-induced THP-1-derived macrophages. The mRNA expression of M1 polarization markers (CD86, TNF-α, IL-6) in macrophages was determined by RT-qPCR. Subsequently, the conditioned medium from each macrophage group was collected, and its effect on WPMY-1 cell proliferation was evaluated by CCK-8 assay. Compared with the BPH group, KSTG dose-dependently reduced prostate volume, wet weight, and prostate index (P < 0.05) and improved the pathological morphology of glandular hyperplasia and interstitial thickening. KSTG dose-dependently reduced serum E2 levels and the E2/T ratio, and significantly decreased the abnormally elevated serum DHT levels (P < 0.05). KSTG also reduced peripheral white blood cell and neutrophil counts, downregulated the mRNA expression of TNF-α and IL-1β, and decreased the protein expression of iNOS in prostate tissue (P < 0.05). Toluidine blue staining further revealed that KSTG treatment reduced mast cell infiltration in the prostate, corroborating the alleviation of local inflammation (P < 0.05). Western blotting showed that KSTG significantly inhibited the protein expression of TLR4 and MyD88 in prostate tissue and suppressed the phosphorylation of IκBα and NF-κB p65 (P < 0.05). In vitro, KSTG-containing serum inhibited the mRNA expression of M1 polarization markers CD86, TNF-α, and IL-6 in THP-1-derived macrophages (P< 0.05). Moreover, the conditioned medium of macrophages pretreated with KSTG significantly attenuated the pro-proliferative effect on WPMY-1 cell proliferation (P < 0.05). This study has demonstrates that the KSTG Pill can significantly regulate M1 macrophage polarization to alleviate the prostatic hyperplasia and related hormonal level in the BPH rats. Its therapeutic mechanism is closely related to suppression of aberrant activation of the TLR4/MyD88/NF-κB signaling pathway in the prostate tissue, thereby reducing the polarization of macrophages to the M1 phenotype and the release of downstream pro-inflammatory factors. These findings provides experimental support for its clinical application, and and valuable insights for the development of novel BPH treatment strategies targeting the immune-inflammatory microenvironment.
Prolonged healing of skin wounds remains a major clinical challenge. This study employed network pharmacology combined with in vivo experimental validation to investigate the mechanisms of Panax notoginseng (PN) in treating skin wounds. Network pharmacology identified 156 targets and 115 signaling pathways, with top core targets (TNF, IL-6, IL-10) enriched in NF-κB, MAPK, and JAK-STAT pathways. Molecular docking showed favorable binding affinities between PN components (Ginsenoside Rb₁, Rd, Re, Rg₁, Notoginsenoside R₁) and key target proteins. In vivo, 48 SD rats were randomly divided into a PN group and a control group with a full-thickness skin excision model. The PN group showed significantly smaller wound areas at days 4 and 7 (P < 0.05), with reduced inflammatory cell infiltration and enhanced fibroblast proliferation at day 7. qRT-PCR and ELISA demonstrated that TNF-α was significantly lower in the PN group at days 4 and 7 (P < 0.01), IL-6 was lower at all time points (P < 0.01), and IL-10 was lower at days 1 and 7 (P < 0.01). These findings suggest that PN modulates the inflammatory cytokine network (TNF-α, IL-6, IL-10) in a time-dependent manner, consistent with the regulation of the “inflammation initiation → repair transition” temporal sequence, representing a promising natural agent for regulating the inflammatory phase of skin wound healing.
Endometriosis (EMs) is a widespread gynecological disease, affecting approximately 6–10
DNA methylation is considered a well-regulated mechanism involved in cellular differentiation, particularly in the differentiation of mesenchymal stem cells into chondrocytes. TET family proteins potentially regulate demethylation by the oxidative conversion of 5-methylcytosine (5-mC) into hydroxymethyl cytosine (5-hmC) and then into formylcytosine (5-fC) and carboxyl cytosine (5-caC) in a series of reactions. However, the precise role of TET proteins and the impact of 5-hmC dynamics during chondrocyte differentiation remain unclear. This study aimed to investigate the potential association of 5-hydroxymethylation with TET family proteins and human telomerase reverse transcriptase (hTERT) gene expression during the differentiation of human mesenchymal stem cells (hMSCs) into chondrocytes. Methodology involves hMSCs differentiation into chondrocytes over 16 days of culture, with successful differentiation confirmed by Alcian Blue staining and chondrogenic marker gene (ACAN and COL2A1). Gene and protein expressions of TET1, TET2, TET3, and hTERT were analyzed through real-time polymerase chain reaction (RT-PCR) and western blot. Global changes in DNA 5-hmC level quantified using dot blot and enzyme-linked immunosorbent assay (ELISA). Locus-specific changes within the hTERT promoter gene were analyzed through locus-specific PCR. We observed a substantial increase in the expression levels of TET family proteins TET1 and TET2, as well as high global 5-hmC levels during chondrocyte differentiation. However, human telomerase reverse transcriptase (hTERT) expression was reduced both at the messenger RNA (mRNA) and protein levels throughout the differentiation process. Furthermore, epigenetic analysis revealed that elevated 5-hmC enrichment at the hTERT promoter region was strongly associated with the downregulation of hTERT expression. Our findings suggest that 5-hmC may serve as a potential epigenetic biomarker and regulatory element in chondrocyte differentiation, offering new insights into skeletal development and cartilage-related disorders.
Prostate cancer ranks second among the most common malignant neoplasms in men worldwide. Fruit extracts with potential anti-prostate cancer properties have gained increasing attention, with the most notable belonging to the Annonaceae family, including Araticum (Annona crassiflora Mart). In this study, we aimed to evaluate the chemopreventive and anti-inflammatory potential of Araticum seed extract (Annona crassiflora Mart) on the ventral prostate lobe of Transgenic Adenocarcinoma of the Mouse Prostate (TRAMP) model. Sixty male TRAMP mice, aged 8 and 12 weeks, were divided into four groups: two groups received the extract at a dose of 100 mg/kg body weight, and two control groups received equivalent volumes of water and DMSO (Dimethyl Sulfoxide). After 30 days, animals were euthanized and ventral prostate samples were collected for morphological evaluation by light microscopy, immunohistochemistry, and Western blotting. Treatment with Araticum seed extract delayed the progression of premalignant and malignant lesions (HGPIN and adenocarcinoma) and preserved healthy tissue. The extract showed antiproliferative activity, reducing PCNA, IGFR-1, and AR protein levels. Inflammatory signaling was suppressed via Toll-like receptor pathways, with decreased NFκB, TNF-α, and other inflammatory markers. Moreover, the extract reduced BCL-2 expression and promoted caspase activation, suggesting pro-apoptotic protection. In conclusion, treatment with Araticum seed extract demonstrated promising chemopreventive activity, effectively reducing the progression of epithelial lesions in the ventral prostate lobe of TRAMP mice and may be suggested as a potential chemopreventive agent in combined prostate cancer therapies.
Although ferroptosis contributes to tumor progression, the key regulators of this process in nasopharyngeal carcinoma (NPC) remain largely unknown. TRIM26, an E3 ubiquitin ligase, has not been systematically studied in NPC or ferroptosis. Ferroptosis-related NPC genes were screened using GeneCards, FerrDb, and UbiBrowser2.0 databases. TRIM26 expression in NPC cells was determined via RT-qPCR and Western blot. TRIM26 overexpression models were established in C666-1 and NPC/HK1 cells, and a ZEB1 rescue model was further constructed in C666-1 cells. Cell viability, migration, and invasion were tested using CCK-8, wound healing, and Transwell assays. Ferroptosis was evaluated using C11-BODIPY581/591 probe, malondialdehyde (MDA), glutathione (GSH), and Fe²⁺ measurements. Co-immunoprecipitation, ubiquitination, and cycloheximide chase assays were performed to investigate TRIM26 regulation of ZEB1. Dual-luciferase reporter assays and ChIP-qPCR were conducted to verify the transcriptional regulation of SLC7A11 by ZEB1. In vivo validation was conducted using a subcutaneous xenograft model. TRIM26 was significantly downregulated in NPC cells, most markedly in C666-1 cells. TRIM26 overexpression remarkably inhibited NPC cell viability, migration, and invasion. It markedly promoted ferroptosis, with increased lipid peroxidation, elevated MDA and Fe²⁺ levels, reduced GSH content, and downregulated GPX4 and SLC7A11. Mechanistic studies revealed that TRIM26 interacted with ZEB1, promoted its ubiquitination, and accelerated its protein degradation. Furthermore, ZEB1 directly regulated SLC7A11 transcription through binding to its promoter region. ZEB1 overexpression significantly reversed the ferroptotic phenotype induced by TRIM26. In vivo, TRIM26 overexpression inhibited xenograft tumor growth and activated ferroptosis, whereas co‑overexpression of ZEB1 partially attenuated these tumor-suppressive effects. TRIM26 activates ferroptosis by promoting the ubiquitination and degradation of ZEB1 protein, thereby inhibiting NPC growth and progression. The TRIM26-ZEB1 axis may represent a potential molecular target for NPC.
Radiotherapy is an effective treatment for head and neck cancer; however, it also induces alterations in healthy oral tissues. Although late radiation-induced damage has been extensively investigated, the early progression of morphological and extracellular matrix changes in the periodontal ligament (PDL) remains poorly understood. This study investigated early radiation-induced changes in collagen organisation, the type I-to-type III collagen ratio, and matrix metalloproteinase-2 (MMP-2) expression in the lingual PDL of rat incisors. Adult Wistar rats were allocated to four irradiated groups (n = 5 per group) and exposed to a single 15 Gy X-ray dose directed to the head. Animals were euthanized at 4, 9, 14, or 25 days after irradiation. A non-irradiated control group was euthanized on day 4. Left hemimandibles were fixed, decalcified, embedded in paraffin, and sectioned. Histological analyses were performed using hematoxylin and eosin, Masson’s trichrome, and Picrosirius Red staining under polarized light. MMP-2 expression was evaluated by immunohistochemistry and quantified by grayscale pixel intensity analysis. Irradiation induced progressive alterations in the lingual periodontal ligament. Fibroblast nuclei exhibited morphological features consistent with cellular injury beginning on day 4, with increasing changes at subsequent time points. These changes were accompanied by progressive disorganisation of collagen bundles, increased interfibrillar spaces, and loss of normal extracellular matrix architecture. Picrosirius Red analysis demonstrated a reduction in the type I-to-type III collagen ratio on days 4, 9, and 14 after irradiation, supporting the morphological changes observed with H.E and Masson’s trichrome staining. MMP-2 expression increased significantly on day 4, reached its highest level on day 9, and then progressively decreased on days 14 and 25. A single dose of X-ray irradiation induces early morphological and extracellular matrix alterations in the rat incisor periodontal ligament. The temporal association between increased MMP-2 expression, collagen fibre disorganisation, and a decreased type I-to-type III collagen ratio suggests that MMP-2 is associated with the early extracellular matrix remodelling observed on days 4 and 9 after irradiation. The subsequent decline in MMP-2 expression was accompanied by an apparent partial restoration of collagen fibre organisation on days 14 and 25.
Acampe papillosa (Lindl.) Lindl. has long been used to cure a variety of illnesses, including rheumatism and traumatic tissue injuries. Nevertheless, there is a dearth of comprehensive information on its phytochemical composition and pharmacological actions. Therefore, here, we present the first thorough pharmacological and histopathological analysis of Acampe papillosa seed methanolic extract (ME-APS), together with in silico molecular docking studies, hepatoprotective, wound-healing, and anti-inflammatory properties. Before pharmacological evaluations, safety was assessed through oral and dermal toxicity studies. The anti-inflammatory activity of ME-APS was tested using carrageenan and formalin-induced paw oedema models, and the wound healing potential was observed using incision and excision wound models. Hepatoprotective activity was studied in the CCl4-induced hepatotoxicity model in rats. In oral (up to 5000 mg/kg) and dermal (10
Chronic kidney disease (CKD) is associated with sensorineural hearing loss, but the mechanisms linking renal injury to cochlear dysfunction remain incompletely defined. Because lipocalin-2 (LCN2/NGAL) is markedly increased in CKD and has been implicated in endothelial dysfunction and barrier injury, we investigated whether LCN2 contributes to cochlear damage in a mouse model of CKD. Male C57BL/6J mice underwent 5/6 nephrectomy, and CKD mice received either an anti-LCN2 monoclonal antibody or an isotype control three times weekly for seven weeks beginning one week after completion of surgery. Auditory function, cochlear morphology, blood–labyrinth barrier integrity, cochlear perfusion, and LCN2-associated signaling were assessed using auditory brainstem responses, distortion product otoacoustic emissions, whole-mount immunofluorescence, FITC–dextran extravasation, Western blotting, quantitative PCR, and laser Doppler flowmetry. CKD mice developed elevated auditory brainstem response thresholds, reduced distortion product otoacoustic emission amplitude at a single primary tone pair with f2 = 8.0 kHz, outer hair cell loss, and a reduction in the number of CtBP2-positive presynaptic ribbon puncta per inner hair cell. These changes were accompanied by increased serum and cochlear LCN2, upregulation of 24p3R/SLC22A17 and NLRP3, increased blood–labyrinth barrier permeability, reduced claudin-5 and ZO-1 expression, impaired cochlear blood flow, stria vascularis atrophy, and decreased expression of strial ion-transport genes. Anti-LCN2 antibody treatment improved auditory thresholds and otoacoustic emission responses, attenuated outer hair cell and synaptic injury, reduced vascular leakage, partially restored tight junction and ion-transport gene expression, and improved cochlear perfusion, without measurably lowering serum blood urea nitrogen or creatinine. These findings support a possible contribution of LCN2 to CKD-associated cochlear vascular dysfunction and hearing loss. Targeting LCN2 may represent a therapeutic strategy for preserving hearing in CKD, although validation in additional CKD models, both sexes, and human tissues is required.
Mastitis is a major inflammatory disorder of the mammary gland that causes substantial economic losses in the dairy industry, with Staphylococcus aureus (S. aureus) being one of the predominant causative pathogens. The current treatment options are limited by antimicrobial resistance and drug residues. Therefore, alternative therapeutic strategies are needed. The present study aimed to evaluate the anti-inflammatory and antioxidant effects of an ethnoveterinary oil (EO) formulation in an experimental model of S. aureus–induced mastitis. The EO formulation was prepared according to a standardized traditional ethnoveterinary composition. Mastitis was induced in healthy lactating primiparous Wistar rats by intramammary infusion of S. aureus (2 × 108 CFU/mL), and the twenty-four female Wistar rats were divided into four groups of 6: normal control (NC), mastitis control (MT), standard drug–treated (MT + DEX), and MT + EO-treated groups. The chemical composition of EO was characterized by GC–MS analysis, which identified 21 bioactive compounds, predominantly erucic acid, along with phenolic compounds, fatty acid derivatives, terpenoids, and steroidal constituents known for their anti-inflammatory potential. Biochemical analyses revealed that EO significantly restored endogenous antioxidant enzyme activities and reduced lipid peroxidation in mammary tissues. Furthermore, EO significantly decreased myeloperoxidase (MPO) levels and N-acetyl-β-D-glucosaminidase activity, indicating reduced neutrophil infiltration and protection against epithelial cell damage. The levels of Pro-inflammatory cytokines were markedly elevated in mastitis control group whereas EO treatment significantly suppressed their production. In addition, EO downregulated the gene expression of Toll like receptor-2 (TLR-2) and Nicotinamide adenine dinucleotide phosphate (NADPH) oxidase 2 (NOX-2), suggesting modulation of key inflammatory and oxidative stress–related pathways. Histopathological and special staining analyses further confirmed the preservation of mammary gland architecture and attenuation of inflammatory infiltration following EO treatment. Collectively, these findings demonstrate that EO exerts potent anti-mastitic effects through the combined modulation of oxidative stress and inflammatory responses and may serve as a promising natural therapeutic alternative for the management of S. aureus associated mastitis in Wistar rat model.
Schisandra chinensis polysaccharide (SCP) has demonstrated antidiabetic properties in previous studies; however, the mechanisms underlying its regulation of autophagy in pancreatic protection remain poorly understood. This study investigated how SCP modulates autophagic pathways to alleviate diabetic pathology. Diabetic rats were administered SCP orally, followed by histopathological and biochemical assessments of pancreatic islet function and tissue damage. Beta-TC-6 pancreatic β-cells were exposed to SCP to evaluate cellular viability, insulin secretion, and autophagic processes using immunohistochemistry, Western blotting, immunofluorescence, and transmission electron microscopy. SCP dose-dependently attenuated diabetes-associated weight loss, reduced hyperglycemia, and improved β-cell function. Histological examination revealed amelioration of pancreatic islet disorganization, diminished collagen deposition, and reduced basement membrane thickening. Mechanistically, SCP enhanced autophagic activity in pancreatic tissues and Beta-TC-6 cells by inhibiting the PI3K/AKT/mTOR signaling cascade, with high-dose SCP exhibiting efficacy comparable to that of metformin. Chloroquine co-treatment abolished these effects, confirming autophagy dependence. This study demonstrates that SCP alleviates diabetes by restoring β-cell function and inducing protective autophagy via the inhibition of the PI3K/AKT/mTOR pathway. These findings indicate SCP as a potential candidate for diabetes therapy.
Lung adenocarcinoma (LUAD), characterized by its complex molecular heterogeneity and resistance to both conventional and targeted therapies, poses significant therapeutic challenges. Therefore, the identification of novel molecular targets is crucial for enhancing therapeutic strategies and improving patient outcomes. This study investigates the role of mitochondrial ribosomal protein S17 (MRPS17) in the progression of LUAD, with a specific focus on its interaction with the PI3K-AKT-mTOR signaling pathway. We conducted functional assays to assess cell proliferation, migration, invasion, and apoptosis in MRPS17-manipulated LUAD cell lines. Further, we explored the epigenetic regulation by TET1 through methylation analysis and investigated the downstream effects on the PI3K-AKT-mTOR pathway using Western blotting and reporter assays. Analysis revealed that MRPS17 is upregulated in LUAD tissues and is associated with a poor prognosis. In cellular models, MRPS17 overexpression was shown to promote proliferation, migration, and invasion, whereas its knockdown induced apoptosis and diminished tumorigenic capabilities both in vitro and in vivo. Importantly, TET1 was identified as a crucial regulator of MRPS17, acting through the demethylation of its promoter to enhance MRPS17 expression and subsequently activate the PI3K-AKT-mTOR pathway. MRPS17 significantly contributes to LUAD progression by enhancing tumor aggressiveness through the PI3K-AKT-mTOR pathway. The TET1-mediated demethylation of MRPS17 introduces a novel epigenetic mechanism that could be leveraged for targeted therapeutic interventions. This study not only provides foundational insights into the molecular biology of LUAD but also highlights the potential of MRPS17 as a prognostic marker and therapeutic target.
Excessive sucrose consumption is associated with various metabolic disorders, including obesity, diabetes, and liver dysfunction. Although oxidative stress is a well-established mechanism contributing to these conditions, its effects on matrix metalloproteinase (MMP) activity in the liver remain poorly understood. This study evaluated the impact of a high-sucrose diet on oxidative stress, MMP-2 and MMP-9 activities, insulin signaling and collagen deposition in the liver of Swiss mice. Male Swiss mice (protocol no. 7,422,050,723) were divided into 2 groups with 16 animals each—control and high-sucrose diet—and were fed for 4 weeks. Liver samples were collected for histomorphological analysis of steatosis, inflammatory infiltrates, and collagen deposition, as well as for biochemical evaluation of antioxidant enzyme activity, oxidative stress markers, MMP activity, and AKT phosphorylated at serine 473. The high-sucrose diet induced metabolic imbalance, steatosis, and inflammatory infiltration, accompanied by oxidative stress in the liver, evidenced by reduced catalase activity (CAT) and glutathione levels (GSH), along with increased protein carbonyls (PCO) and thiobarbituric acid reactive substances (TBARS) levels. Additionally, MMP-9 activity and collagen deposition were higher in mice fed the high-sucrose diet. Notably, AKT phosphorylation at Ser-473 residue was reduced, indicating impaired insulin signaling. These findings suggest that a high-sucrose diet induces hepatic oxidative stress, disrupts insulin signaling, and promotes MMP-9 activation, potentially contributing to liver histopathological changes and dysfunction.
The pathological mechanisms underlying cardiac fibrosis after isoproterenol (ISO)-induced cardiac injury remain poorly understood. Additionally, the biological function of ACTG1 in cardiovascular diseases has not been fully elucidated. This study aims to explore the role of ACTG1 and its regulatory mechanism in ISO-triggered cardiac injury and fibrosis. We established ISO-induced cardiomyocyte injury models and TGF-β1-stimulated vascular endothelial cell-endothelial-to-mesenchymal transition (EndoMT) models in vitro, and then evaluated the effects of ACTG1 silencing on cardiomyocyte functions and EndoMT progression in vascular endothelial cells. Conditioned medium (CM) and a TGF-β1 neutralizing antibody were applied to explore the paracrine crosstalk between cardiomyocytes and vascular endothelial cells. In vivo, an ISO-induced mouse model of cardiac injury was constructed to verify the regulatory effects of ACTG1 silencing on myocardial injury, fibrosis, inflammation, and EndoMT. The in vitro results demonstrated that ISO treatment upregulated ACTG1 expression at both the mRNA and protein levels in cardiomyocytes. Moreover, ACTG1 silencing attenuated ISO-induced cardiomyocyte injury and partially suppressed TGF-β1-mediated EndoMT in vascular endothelial cells. Further mechanistic experiments revealed that ACTG1 silencing in ISO-induced cardiomyocytes hindered EndoMT progression in vascular endothelial cells. TGF-β1 neutralization assays further confirmed that TGF-β1 acted as a key paracrine mediator linking cardiomyocyte activation to endothelial EndoMT. In addition, the silencing of ACTG1 in vivo attenuated myocardial injury, reduced collagen deposition, improved cardiac function, and downregulated the expression of EndoMT-related proteins in ISO-treated mice. ACTG1 exacerbated ISO-induced cardiomyocyte injury and facilitated EndoMT to promote cardiac injury and fibrosis, supporting ACTG1 as a promising therapeutic target for the treatment of cardiac injury.
Parkinson’s disease (PD) is a progressive neurodegenerative disorder characterized by dopaminergic neuronal loss, oxidative stress (OS), and α-synuclein pathology. As OS is a major contributor to neuronal injury in PD, therapeutic approaches targeting redox homeostasis have attracted increasing interest. Rotenone (RTN)-induced Parkinsonian-like features closely resemble key aspects of human PD. Myricetin (MYR), a natural flavonol with antioxidant and anti-apoptotic properties, has emerged as a potential neuroprotective agent. This study aimed to evaluate the neuroprotective effects of MYR against RTN-induced neurotoxicity in rats using behavioral, biochemical, and histopathological assessments. Twenty-eight Wistar albino rats (14 males and 14 females) were randomly assigned to control, RTN (3 mg/kg, s.c. for 6 days), and RTN+MYR (5 mg/kg i.p. plus RTN) groups, with equal sex distribution among the experimental groups. Behavioral performance was assessed using rotarod, accelerod, open field, cylinder, hot plate, and tail flick tests by investigators blinded to group allocation. Brain tissues were analyzed for OS markers and histopathological changes in the cerebral cortex, cerebellum, and hippocampus. RTN significantly impaired motor coordination and exploratory behavior, as evidenced by reduced performance in rotarod, accelerod, open field, and cylinder tests. Hot plate latency was prolonged, whereas tail flick responses remained unchanged. RTN markedly increased malondialdehyde (MDA), total oxidant status and oxidative stress index (OSI) levels while reducing antioxidant defenses, including catalase, glutathione peroxidase and glutathione. Histopathological evaluation revealed widespread neuronal degeneration and hemorrhage in the cerebrum, Purkinje cell loss in the cerebellum, and neuronal shrinkage in the hippocampus. MYR co-treatment significantly improved motor performance and attenuated OS, as indicated by reduced MDA levels and OSI values, along with mitigation of neuronal degeneration. MYR attenuated RTN-induced neurotoxicity and was associated with improved behavioral performance, reduced OS, and preservation of neuronal morphology. These findings support the protective potential of MYR against RTN-induced neurotoxicity exhibiting Parkinsonian-like features. Further studies using therapeutic treatment paradigms are required before clinical translation to PD can be considered.
Cerebral ischemia–reperfusion (I/R) injury triggers a complex cycle of biochemical disturbances that accelerate neuronal death and functional deterioration. Among the various regulated cell death pathways involved, ferroptosis has recently emerged as a central mechanism linking iron imbalance, lipid peroxidation, and oxidative damage. Excessive generation of reactive oxygen species (ROS) during reperfusion overwhelms endogenous antioxidant defenses, disrupts mitochondrial function, and enhances lipid peroxidation, thereby initiating ferroptotic signaling. Iron overload—driven by increased transferrin receptor expression, ferritinophagy, and Fenton chemistry—further amplifies lipid peroxide accumulation and GPX4 inactivation, establishing a self-propagating cycle of oxidative injury. Several key signaling pathways modulate this interplay between oxidative stress and ferroptosis. Activation of Nrf2 promotes the transcription of antioxidant and iron-regulatory genes, offering substantial protection against ferroptotic damage. In contrast, HIF-1α exerts a dual role; although it supports metabolic adaptation and angiogenesis under hypoxia, its prolonged activation may promote lipid peroxidation and ferroptotic vulnerability. Casein kinase 2 (CK2) also contributes to the redox landscape by regulating the activity of NADPH oxidase, STAT3/SOD2, and HIF-1α, leading to context-dependent protective or detrimental outcomes. This review examines the molecular crosstalk between oxidative stress and ferroptosis in ischemia–reperfusion injury and summarizes key pharmacological and natural agents that target these pathways to achieve neuroprotection. In response to recent translational concerns, the review further emphasizes cell-type-specific ferroptotic vulnerability, GPX4-independent defense systems, blood–brain barrier and pharmacokinetic barriers, clinical readiness, safety limitations, and unresolved controversies that must be addressed before ferroptosis-targeted interventions can be advanced for stroke therapy.
Patients with AML have a poor prognosis due to recurrence and high-risk genetic factors. lncRNA OIP5-AS1 exhibits differential expression among AML patients with varying genetic risks. The aim of this study is to examine the clinical value and regulation mechanisms of OIP5-AS1 in AML. RT-qPCR was used to evaluate the OIP5-AS1, miR-15a-5p, and FOXO1 levels in patients with AML and cells, as well as the mRNA levels of Bcl-2, Bax, and Caspase-3 in AML cell. The CCK-8 test was employed to measure cell proliferation. Apoptosis rates were detected by flow cytometry. DLR experiments validated the interaction between OIP5-AS1, miR-15a-5p, and FOXO1. Compared with the controls, AML patients exhibited notably elevated levels of OIP5-AS1 and FOXO1, along with markedly reduced miR-15a-5p expression. Furthermore, OIP5-AS1 levels effectively differentiate patients with AML from controls. Patients in the high OIP5-AS1 level group exhibited lower 5-year survival rates. Knockdown of OIP5-AS1 elevated miR-15a-5p levels, reduced cell proliferation capacity, and notably increased apoptosis. Furthermore, FOXO1, as a target gene of miR-15a-5p, showed a positive correlation with OIP5-AS1 level and a negative correlation with miR-15a-5p level. OIP5-AS1 exhibits significant diagnostic and prognostic value in AML, showing promise as a novel clinical biomarker. Knockdown of OIP5-AS1 leads to upregulation of miR-15a-5p level, thereby influencing proliferation and apoptosis processes in AML cells. This mechanism may provide a new therapeutic target for improving the prognosis of AML patients.
