Journal of Molecular Histology最新文献

CCT7, a member of the t-complex polypeptide 1 chaperone family, facilitates ATP-dependent protein folding; however, its role in development and progression of malignant tumors remains unclear. This study aimed to characterize the expression pattern of CCT7 in colonic adenocarcinoma (COAD) and evaluate its role in the initiation and development of COAD. Public bioinformatic databases were analyzed to assess CCT7 expression in COAD, and these findings were validated using human clinical specimens through immunohistochemistry (IHC) assay. The prognostic significance of CCT7 was examined using Kaplan–Meier method and Cox regression analysis. Gene Ontology-Biological Process (GO-BP) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were performed to explore the potential biological functions and downstream pathways associated with CCT7. CCK-8, colony formation and Transwell assays were conducted to determine the impact of CCT7 on cell proliferation, migration and invasion in COAD cell lines. Associations between CCT7 expression and immune cell infiltration or drug sensitivity were evaluated using single-sample gene set enrichment analysis and correlation analysis. Finally, immune checkpoint inhibitor therapy scores and their relationship with CCT7 expression were assessed using data from The Cancer Immunome Atlas. CCT7 expression was significantly up-regulated statistically in COAD tissues compared with normal colonic tissues (P< 0.05) and elevated CCT7 levels were associated with poorer prognosis of COAD patients (P< 0.05). GO-BP enrichment analysis indicated that CCT7 was primarily involved in the processes related to cell proliferation and microtubule organization (P< 0.05). Consistently, functional assays confirmed that CCT7 knockdown inhibited COAD cell proliferation, migration, and invasion (P< 0.05). CCT7 expression showed a negative correlation with infiltration of most immune cell types (P< 0.05) and demonstrated no significant association with predicted responses to PD-1 and CTLA-4 inhibitor therapies (P> 0.05). Moreover, drug sensitivity analyses showed that CCT7 affected the sensitivity of COAD samples to several anti-cancer drugs (P< 0.001). KEGG enrichment analysis revealed that CCT7 was associated with multiple pathways (P< 0.05). CCT7 may function as an oncogenic driver that promotes the malignant phenotype of COAD and represents a promising prognostic biomarker. It may also provide a valuable reference for guiding clinical therapeutic strategies in COAD.

Methotrexate (MTX), a chemotherapeutic and immunosuppressive drug, is well known to cause salivary gland (SG) toxicity. Although Withania somnifera (WS) exhibits strong antioxidant and cytoprotective properties, its potential to counteract MTX-induced SG injury remains poorly explored. The current study aimed to assess the protective effect of WS supplementation against MTX-induced toxicity in rat parotid and submandibular glands and to explore the underlying mechanisms. Forty adult male albino rats, each weighing ~ 200 g, were randomly allocated into four groups (n = 10): Control (distilled water orally/8 days), WS (300 mg/kg orally/8 days), MTX (single intraperitoneal injection of 60 mg/kg on day 4), and WS + MTX (WS/8 days with MTX on day 4). Glandular injury was assessed histologically using hematoxylin and eosin staining and immunohistochemically for cyclooxygenase-2 (COX-2) and cleaved caspase-3. Biochemical assays measured malondialdehyde (MDA) and total antioxidant capacity (TAC). p38 mitogen-activated protein kinase (p38 MAPK) and transient receptor potential canonical channel 1 (TRPC1) were quantified using ELISA. Gene expression of nuclear factor-κB (NF-κB) and C/EBP homologous protein (CHOP) was analyzed by qPCR. MTX induced acinar and ductal degeneration, cytoplasmic vacuolization, and nuclear pyknosis; increased MDA; reduced TAC; activated the p38 MAPK/NF-κB/COX-2 inflammatory axis; ER stress through the TRPC1/CHOP pathway; and elevated cleaved caspase-3 expression. Co-treatment with WS preserved glandular architecture, restored antioxidant balance, attenuated oxidative, inflammatory, and ER-stress responses, and suppressed the apoptosis. This demonstrates that WS supplementation provided protection against MTX-induced toxicity in both the parotid and submandibular glands largely through modulation of p38 MAPK/NF-κB/COX-2 and TRPC1/CHOP pathways.

Arrhythmias, driven by abnormal electrical activity and structural remodeling, are a leading cause of cardiovascular mortality. Despite advances in treatment methods, therapeutic limitations persist due to an incomplete understanding of the heterogeneous mechanisms involved. The phosphoinositide 3-kinase/protein kinase B (PI3K/AKT) signaling pathway, a central regulator of cellular survival, metabolism, and electrophysiology, has been identified as a key factor in arrhythmia development. This review summarises evidence indicating that dysregulated PI3K/AKT signaling promotes arrhythmias via four interconnected pathways: electrophysiological remodeling, oxidative stress and inflammation, autophagy and apoptosis, and fibrotic structural remodeling. Notably, under certain conditions, the PI3K/AKT signaling pathway exhibits bidirectional regulatory effects. Furthermore, evidence suggests that pharmacologically targeting the PI3K/AKT pathway exhibits significant anti-arrhythmic potential.

Cisplatin is a broad-spectrum anticancer drug with considerable place among chemotherapeutic agents. However, its adverse effect as nephrotoxicity limits its clinical use. Astaxanthin is a marine carotenoid with potent antioxidant and anti-inflammatory activity. The current work investigated the biochemical and molecular mechanisms of cisplatin-induced nephrotoxicity and astaxanthin's capacity to mitigate it. Animals were assigned to four groups: control group, astaxanthin group (25 mg/Kg intraperitoneal (i.p)) for 8 days, cisplatin group (6 mg/Kg, i.p) on the 3rd day of the experiment, and astaxanthin-cisplatin group. Biochemical, molecular, and histopathological assessments were performed to assess renal injury. Cisplatin-induced nephrotoxicity was evident by the elevated levels of blood urea nitrogen (BUN), creatinine, and renal tissue malondialdehyde (MDA) and decreased levels of reduced glutathione (GSH) in renal tissue. The cisplatin group revealed a marked rise in the gene expression of metastasis-associated lung adenocarcinoma transcription-1 (MALAT-1) and nuclear factor kappa-B (NF-κB), along with a marked reduction in the gene expression of nuclear factor erythroid 2-related factor (Nrf2), glutathione peroxidase 4 (GPX4), and microRNA(miR)-146a. The cisplatin also induced disturbed renal architecture, including shrunken glomeruli and vacuolated tubular epithelium with small dense nuclei, in addition to edema and infiltration in-between the renal parenchyma. These changes were associated with a significant increase in the immune expression of NF-κB, desmin, and Bax in the renal parenchyma. Interestingly, co-administration of astaxanthin significantly attenuated nephrotoxicity indices, gene expression variations, and histopathological changes. Taken together, findings in the current research suggested that astaxanthin protects against cisplatin-induced nephrotoxicity by inhibiting oxidative stress, inflammation, and ferroptosis via MALAT-1and miR-146a/ NF-κB /Nrf2/GPX4 signaling pathway.

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The DnaJ/Hsp40 family member B6 (DNAJB6) is a protein aggregation inhibitor, and its dysregulation has been associated with various diseases. Although early studies implicated DNAJB6’s role in tumor progression, its prognostic and immunotherapy predictive value across cancers remain undefined. Integrated multi-omics data analysis revealed significant upregulation of DNAJB6 in multiple tumors, particularly in liver hepatocellular carcinoma (LIHC), supported by immunohistochemistry of liver tumor tissues and Western blot assays in HepG2 cells, and poor prognosis in LIHC patients was linked to increased DNAJB6 expression. ROC and univariate Cox analyses established DNAJB6 as an independent prognostic factor in LIHC, with good predictive value. Enrichment, immune scoring and single-cell sequencing analyses indicated that DNAJB6 was linked to immune responses, especially with myeloid-derived suppressor cell (MDSC) and exhausted CD8⁺ T cell (T_ex). Cell experiments demonstrated that siRNA targeting DNAJB6 inhibited HepG2 cells from proliferating and migrating while inducing apoptosis. Furthermore, we predicted and experimentally confirmed that DNAJB6 silencing conferred gefitinib resistance in HepG2 cells. In conclusion, our findings highlighted the significance of DNAJB6 expression in determining LIHC prognosis and immunotherapy response, as well as its potential in developing novel anti-cancer drugs and enhancing immunotherapy.

Metabolic dysfunction-associated steatohepatitis (MASH) represents a growing public health concern. While metformin is widely used in managing MASH, its effects on steatosis-related microRNAs (miRNAs) and hepatic Aquaporin 9 (AQP-9) expression remain unclear. This study aimed to evaluate the impact of a high-fat diet (HFD) and metformin treatment on body weight, hepatic steatosis, oxidative stress, miRNA expression, and AQP-9 levels in a rat model. Twenty-four male Sprague-Dawley rats were randomly divided into four groups. The control group received a baseline diet. The other three groups first received a 9-week high-fat diet (HFD) to induce MASH. The MASH group received no treatment, while the other two HFD groups were given oral metformin (100 or 200 mg/kg/day) for 8 weeks. Serum ALT, AST, inflammatory markers (TNF-α, IL-6) and lipid profile were measured. Hepatic levels of MDA, GSH, and nitric oxide were analyzed. miR-122, miR-33a, miR-34a, and miR-24 expressions were quantified using qRT-PCR. Liver underwent histopathological evaluation (H&E staining) and immunohistochemical analysis for AQP-9. Metformin boosted liver function and alleviated hepatic oxidative stress and inflammation by increasing GSH and suppressing inflammatory markers (TNF-α, IL-6), NO, and MDA levels. It also decreased the expression of steatosis-associated miRNAs (miR-122, miR-33a, miR-34a, and miR-24) and AQP-9. Histological findings showed reduced steatosis, inflammation, and hepatocyte ballooning, with better outcomes observed at the higher metformin dose. Metformin exerts a hepatoprotective effect in MASH, likely through modulation of inflammation, miRNA expression and suppression of AQP-9, leading to improved biochemical and histological liver profiles.

Metabolic syndrome (MetS), often modeled by high-fat/fructose (HFF) diets, involves dyslipidemia, hypertension, insulin resistance, and liver dysfunction. While Rosuvastatin (ROSU) effectively manages dyslipidemia, its potential diabetogenic effects raise concerns. Obeticholic acid (OCA), an FXR agonist, offers metabolic benefits but requires direct comparison with ROSU in this context. This study aimed to assess and compare the effect of Obeticholic acid vs Rosuvastatin in a rat model of high-fat/fructose diet-induced metabolic dysfunction, assessing biochemical, histological, and molecular endpoints relevant to dyslipidemia, insulin resistance, hemodynamics, and hepatic and adipose tissue injury. 27 Adult male albino rats were divided into four groups (each group seven rats): group 1: normal control, group 2: high-fat/fructose (HFF) diet (25% fat, 10% fructose) for 8 weeks, group 3: HFF + Rosuvastatin (10 mg/kg/day orally), and group 4: HFF + Obeticholic acid (10 mg/kg/day orally). Treatments were administered orally from 5th week. The study assessed lipid profiles, atherogenic indices, glucose metabolism parameters (fasting glucose, insulin, HOMA-IR), blood pressure, liver function marker (ALT), and hepatic gene expression (AMPK, SREBP1-c, PPAR-γ). In addition to Liver and adipose tissue histopathology, area percentage of collagen fibers, adipocytes diameter, PPAR-γ, STAT3 and PCNA immunoexpression. ROSU demonstrated superior efficacy in lowering total cholesterol, LDL-C, triglycerides, and atherogenic indices compared to OCA. However, ROSU significantly increased insulin levels and insulin resistance, highlighting its diabetogenic potential. Conversely, OCA exhibited a more pronounced beneficial effect on lowering both systolic and diastolic blood pressure compared to ROSU. Crucially, OCA did not exacerbate insulin levels or resistance relative to the HFF control group. Both treatments comparably reduced elevated ALT levels and improved hepatic histology in the context of HFF diet-induced pathology, which was associated with upregulated PPAR-γ and STAT3 immunoexpression. Both ROSU and OCA reversed these alterations and normalized cellular proliferation, as evidenced by PCNA immunoexpression in liver and adipose tissues. Additionally, they beneficially modulated hepatic gene expression by upregulating AMPK and downregulating the lipogenic factors SREBP-1c and PPAR-γ. In conclusion, OCA represents an alternative antihyperlipidemic, particularly when blood pressure control is a priority or to avoid Rosuvastatin’s diabetogenic side effects. Given their comparable efficacy in improving liver dysfunction.

The study examined the features of the spatial organization and qualitative composition of the collagen matrix in prostate cancer (PCa) and the relationship of these parameters with the clinicopathological characteristics of the disease. Morphometric, histochemical (Masson’s trichrome staining, Picrosirius Red staining), and immunohistochemical methods were applied to analyze collagen architecture parameters in tumor tissue samples from 87 patients with stage II–IV PCa. Analysis of the quantitative parameters of the tumor collagen matrix showed that decreased collagen fiber length and width were associated with advanced tumor stages and the presence of metastases in pelvic lymph nodes and/or distant organs. An increase in collagen fiber density and alignment was observed in tumors of patients with metastases and elevated PSA levels. Qualitative assessment demonstrated that collagen fiber maturity (CMI) was lower in patients with metastases, whereas increased CMI values were associated with higher Gleason scores and grade groups. Immunohistochemical findings indicate variability in COL1A1 and COL3A1 expression within the PCa stroma; notably, COL3A1 expression was also detected in tumor cells. Elevated COL1A1 levels were recorded in PCa tissues of patients with T3-category tumors and increased PSA, whereas COL3A1 expression was primarily associated with metastatic status and higher histological grades. Correlation analysis confirmed a strong relationship between quantitative and qualitative parameters of collagen matrix architecture and the clinicopathological features of PCa. The findings suggest that the structural organization and composition of the collagen matrix play an important role in PCa progression and may serve as potential prognostic markers of disease course.

Diabetes Mellitus (DM) is a metabolic disease characterized by hyperglycemia resulting from impaired insulin secretion and resistance. Berberine (BBR) and N-acetylcysteine are anti-inflammatory and antiapoptotic compounds that have beneficial effects on diabetic complications. This study aimed to investigate the effects of BBR and NAC on the Hippocampus in an experimental diabetes model in rats. Rats were divided into 5 groups: control, diabetes (D), D + NAC, D + BBR, and D + BBR + NAC. STZ (45 mg/kg, i.p.) was administered to the other four groups except the control group. BBR and NAC (50 mg/kg/day) were given intragastrically (i.g.) to the treatment groups for 28 days. Decreased cell body size, pyknotic cells and necrotic neurons were observed in the D group. However, these pathological changes were largely improved in the D + BBR, D + NAC, and D + BBR + NAC. Stereologically, there was no significant difference between the groups in terms of hippocampus volume. The number of pyramidal neurons in CA1 was significantly decreased in the D group. But the number of CA1 pyramidal neurons was higher in both the alone and combined BBR and NAC treatment groups than in the D group. Expressions of Caspase-3, TNF-α, and IL-1β increased in the D group, while expressions of Bcl-2 and SYP decreased. But, BBR and NAC treatments decreased Caspase-3, TNF-α, and IL-1β expressions and increased Bcl-2 and SYP expressions. These results revealed that BBR and NAC can have an antidiabetic effect against the neuronal damage caused by diabetes in the hippocampus CA1 region, suppressing inflammation and apoptosis and preventing the decrease in the number of pyramidal neurons. Also, they reveal that they may modulate synaptic plasticity by increasing synaptophysin expression.

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Many investigations have indicated the significance of microRNAs (miRNAs) as potential biomarkers for early obesity in children. MiR-874-3p was revealed to be downregulated in overweight/obese children. However, the specific function and mechanism of miR-874-3p in the progression of childhood obesity remain unclear. Human Simpson-Golabi-Behmel syndrome (SGBS) adipocytes were stimulated with tumor necrosis factor α (TNF-α) to establish an in vitro cell model. CCK-8 assay and ELISA were used to assess cell viability and proinflammatory cytokine secretion, respectively. RT-qPCR was used for miR-874-3p expression analysis. Western blotting was utilized to evaluate protein levels of miR-874-3p downstream targets and nuclear factor kappa B (NF-κB) signaling-related markers. Luciferase reporter assay was conducted to verify the binding relation between miR-874-3p and nucleolin (NCL). MiR-874-3p overexpression attenuated TNF-α-induced inhibition of cell viability and promotion of proinflammatory cytokine production. Mechanistically, NCL served as a target of miR-874-3p, and overexpressing miR-874-3p inactivated NCL-mediated NF-κB signaling. Moreover, NCL upregulation reversed miR-874-3p overexpression-mediated effects on the viability and proinflammatory cytokines in SGBS adipocytes. MiR-874-3p alleviates TNF-α-induced inflammatory response in SGBS adipocytes by downregulating NCL and inactivating NF-κB signaling.