Journal of Molecular Histology最新文献

CMSS1, a protein-coding gene, acts as an oncogene in several cancers. However, the role of CMSS1 in triple-negative breast cancer (TNBC) are not clear. Our experiment aims to reveal the biological, prognosis, immunological effects and the underlying mechanism of CMSS1 in TNBC. In this study, CMSS1 expression was markedly up-regulated in tumor tissues of breast cancer than normal tissues. Higher expression of CMSS1 was markedly related with low RFS, shorter overall survival time, later TNM stage and lymph node metastasis. Besides, CMSS1 expression was markedly up-regulated in TNBC cells compared with normal breast epithelial MCF-10 A cells. CMSS1 knockdown repressed the viability and invasion of TNBC cells, inhibited CD8 + T cells apoptosis and decreased PD-L1 expression. Furthermore, CXCL8 overexpression reversed the inhibition effects of CMSS1 on CXCL8, CXCR1, CXCR2 and PD-L1 expression, TNBC cells viability, invasion and apoptosis of CD8 + T cells. Moreover, CMSS1 knockdown repressed tumor volume and weight, decreased PD-L1 expression, promoted CD8 positive staining in xenograft nude mice. Thus, our data verified that CMSS1 was highly expressed in TNBC, and high CMSS1 expression indicated poor prognosis. CMSS1 interference restrained the viability, invasion and immune escape of TNBC cells via CXCL8-CXCR1/2 pathway.

Graphical abstract

CMSS1 promoted CXCL8-CXCR1/immune escape pathway to accelerate the invasion and immune escape of TNBC. The upregulation of CMSS1 promoted the expressions of CXCL8, CXCR1 and CXCR2 to accelerate the proliferation, invasion and immune escape of TNBC cells

The aim of this paper was to investigate the mechanism of saffron extract (SE) in promoting the polarization of macrophages towards M2 and thereby promoting burn wound healing by modulating the nuclear factor E2-related factor 2 (Nrf2)/heme oxygenase-1 (HO-1)/NOD-like receptor family pyrin domain-containing 3 (NLRP3) cascade. A burn model was induced in mice, which were treated with SE to burn wounds. Wound characteristics were observed, and wound healing rate and wound contraction rate were measured. Wounds were examined pathologically using hematoxylin-eosin staining, macrophage surface markers were identified by immunofluorescence staining, and cytokine levels were measured with enzyme-linked immunosorbent assay. In vitro experiments were conducted to investigate the effects of SE on lipopolysaccharide-induced polarization of mouse macrophages (RAW 264.7) and on proliferation and migration of mouse embryonic fibroblasts (NIH3T3). Proteins related to the Nrf2/HO-1/NLRP3 cascade were measured by Western blot. SE effectively promoted burn wound healing, inhibited inflammatory response during wound healing and promoted macrophage M2 polarization in burn model mice. SE induced macrophage M2 polarization in vitro and promoted NIH3T3 cell proliferation and migration. Regulation of the Nrf2/HO-1/NLRP3 cascade by SE was observed, and Nrf2 knockdown negated the SE-driven M2 polarization of macrophages and the increased proliferation and migration of NIH3T3 cells in a co-culture environment. SE promotes burn wound healing by modulating the Nrf2/HO-1/NLRP3 cascade to promote macrophage M2 polarization.

Epstein–Barr virus-associated gastric cancer (EBVaGC) was one of four subtypes of GC and exhibits distinct molecular and clinical characteristics. Exosomes, which serve as important means of intercellular communication in the tumor microenvironment, play a key role in the transmission of the information between tumor cells and the microenvironment. This study aimed to investigate whether EBV-encoded microRNAs (miRNAs) can enter the receptor cells via exosomes and perform their function. Total exosomes were extracted from the culture medium using a total exosome isolation reagent and identified by nanosight tracking analysis, transmission electron microscopy, and Western blotting. Quantitative reverse-transcription polymerase chain reaction detected the expression profiles of EBV-encoded miRNAs in EBV-positive GC cell lines and exosomes. Immunofluorescence techniques were used to detect the uptake of exosomes by the receptor cells. The effects of exosomes derived from different cells and their potential mechanisms were further investigated using Cell-Counting Kit-8, colony formation assay, flow cytometry analysis, transwell assay, and immunofluorescence techniques. The expression profiles of miRNAs in EBV-positive GC cells and exosomes were different. miR-BART2-5p and miR-BART11-5p, which were transmitted to the receptor cells through exosomes, could activate the Wnt/β-catenin pathway and promote migration of receptor cells. EBV may transform the microenvironment into a tumor-promoting environment that induces EBVaGC through exosomes.

This study evaluated the clinical significance of miR-567 in atherosclerosis and its regulatory effect on PDGF-BB-induced VSMCs, aiming to identify a novel biomarker for the risk and progression of atherosclerosis. The study enrolled 113 atherosclerosis patients and 126 non-atherosclerosis patients. Serum miR-567 level was compared between the two groups and its significance in disease severity was assessed. T/G human VSMC was induced with PDGF-BB, and based on this cell model, the regulatory effect and potential mechanism of miR-567 was estimated. miR-567 was upregulated in atherosclerosis patients and showed diagnostic significance (AUC = 0.875). miR-567 was positively correlated with homocysteine, total cholesterol, and low-density lipoprotein, and negatively correlated with high-density lipoprotein (r > 0.7, P < 0.0001). miR-567 was upregulated in PDGF-BB-induced VSMCs, and silencing miR-567 showed protective effect on PDGF-BB-induced VSMCs. CSF1R was negatively correlated with miR-567. Silencing CSF1R reversed the protective effect of miR-567 silencing on PDGF-BB-induced VSMCs.

Acute pancreatitis (AP) is a rapid-onset inflammatory disorder of the pancreas, characterized by premature activation of pancreatic digestive enzymes and the development of systemic inflammatory responses. Severe AP is associated with a mortality rate of 10–40%, highlighting the urgent need for effective and targeted therapeutic interventions. Obtusifolin (OBT), a natural compound from Senna obtusifolia, exhibits anti-inflammatory and wound-healing properties. The current study aimed to investigate the effect of OBT against inflammation and tissue injury associated with AP. In vitro, lipopolysaccharide (LPS) and TGF-β-induced differentiation models were employed to investigate the anti-inflammatory and anti-fibrotic effects of OBT in pancreatic stellate cells (PSCs) and PANC-1 cells. In vivo, a cerulein-induced acute pancreatitis mouse model was employed to evaluate the therapeutic potential of OBT through histopathological analysis, ELISA, immunohistochemistry, and western blotting. In vitro results revealed that OBT treatment significantly suppressed the LPS/TGF-β-induced pro-inflammatory and ECM marker expression in PSCs and PANC-1 cells, respectively. In mice, cerulein induction notably increased the pancreatic edema, acinar necrosis, inflammatory infiltration, hemorrhage in tissues of cerulein control, on the other hand, treatment with OBT significantly attenuated the same. Further, OBT treatment significantly reduced the cerulein-induced elevation of inflammatory marker expression (Tnfa, Ccl2, Cxcl10, and Il6), serum α-amylase, β-amylase, and IL-1β levels in a dose-dependent manner. Furthermore, immunohistochemistry and western blot analysis confirmed that OBT ameliorates pancreatitis by modulating the NFκB signaling. These results indicate that obtusifolin attenuates acute pancreatitis by inhibiting inflammatory responses and preserving pancreatic tissue integrity, supporting its potential as a therapeutic candidate for managing acute pancreatitis.

Graphical Abstract

Obtusifolin exhibits therapeutic potential against acute pancreatitis by suppressing NFκB-mediated inflammatory and fibrotic signaling.

Exosomes derived from mesenchymal stem cells (MSC-exo) have the potential to regulate cancer progression by delivering various molecules, including long noncoding RNAs (lncRNAs). This study aimed to investigate the functional role and underlying mechanism of exosomal LINC00900, derived from human adipose-derived mesenchymal stem cells (MSCs), in thyroid cancer (TC). MSC-exo was isolated from conditioned medium using differential ultracentrifugation, observed under transmission electron microscopy, and identified through western blotting and an uptake assay. Cell viability, apoptosis, cell cycle progression, and invasion were evaluated by cell counting kit-8 (CCK-8) assay, terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay, flow cytometry, and transwell invasion assay, respectively. RNA-pull down and RNA immunoprecipitation assays were conducted to evaluate the interaction between LINC00900 and polypyrimidine tract binding protein 1 (PTBP1). A mouse model with subcutaneous xenografts of the TC cell line TPC-1 was used to assess tumor growth in vivo. The isolated MSC-exo exhibited classic exosome characteristics and could effectively be delivered to TPC-1 cells. MSC-exo significantly inhibited the proliferation of TPC-1 cells and promoted their apoptosis, as evidenced by a decreased optical density value and an increased percentage of apoptotic cells. Following incubation with MSC-exo, LINC00900 expression was markedly increased in TPC-1 cells. Overexpression of LINC00900 or inhibition of PTBP1 suppressed cell proliferation, elevated G0/G1 ratio, and promoted cell apoptosis. Additionally, LINC00900 expression was reduced, while PTBP1 protein levels were increased, in cancer tissues from TC patients. Furthermore, PTBP1 was identified as a target of LINC00900 and was negatively regulated by it. LINC00900 was also confirmed to inhibit cell autophagy by downregulating PTBP1. In vivo, MSC-exo inhibited tumor growth and autophagy while promoting apoptosis in TPC-1 cell xenografts. In conclusion, MSC-Exo carrying LINC00900 can effectively inhibit tumor cell growth in TC via suppression of PTBP1.

Studies have underlined the relevance of plants as sources of medicament for diabetes mellitus its sequelae. This research sought to appraise the renal-protective effect of the polyphenolic-rich extract of Phylanthus niruri (PEPN) leaves in Wistar rats made diabetic with streptozotocin. Fifty-six rats were arbitrarily grouped into seven places (n = 8). Standard procedure was used to extract polyphenols from the leaves using 80% acetone. Experimental groups included normal control, diabetic untreated, as well as diabetic groups managed with 5/500 mg/kg bw glibenclamide/metformin and diabetic groups each treated with 50, 75, 100 and 125 mg/kg bw PEPN. The study lasted for 28 days. After treatment period, standard procedures were used to evaluate activities of antioxidant enzymes and kidney injury markers in the kidney, while levels of creatinine, urea and uric acid were measured in the serum. Findings show that treatment of diabetic rats with PEPN led to a significant (p < 0.05) lowering of serum uric acid, urea and creatinine when compared with diabetic control group. Similarly, the administration of PEPN led to a significant (p < 0.05) elevation of enzymatic functions of superoxide dismutase and catalase in the kidney, with a concomitant reduction in malondialdehyde. In addition, PEPN therapy in diabetic rats with PEPN significantly (p < 0.05) diminished mRNA levels of kidney injury marker 1 and neutrophil gelatinase-associated lipocalin in the kidney when compared to untreated diabetic rats. Therefore, it could be concluded that PEPN could confer renoprotection in diabetic rats by enhancing the antioxidant system and suppression of kidney injury marker genes.

Sepsis-induced acute lung injury (ALI) is a life-threatening condition characterised by a systemic inflammatory response to infection, often progressing multiorgan failure. Lipopolysaccharide (LPS), a well-established bacterial endotoxin, is widely used to induce experimental sepsis and associated with pronounced inflammation, oxidative stress, and extensive tissue injury. Voacangine (VCG), an indole alkaloid derived from Voacanga foetida, possesses recognised antitumor, antioxidant, and anti-inflammatory properties. Accordingly, the present study investigated the antioxidant and anti-inflammatory potential of VCG in mitigating LPS-induced ALI in mice, with particular emphasis on the PERK/PI3K and TLR4/NF-кB/IL-1β signaling pathways. Mice were randomly divided to six groups: Normal control (NC); LPS (100 μg/kg body weight, intraperitoneally); LPS + dexamethasone (DEX) (2 mg/kg b.w.); LPS + VCG (2.5, 5, and 10 mg/kg b.w.), respectively. We evaluated inflammatory cell infiltration, antioxidant status, pro-inflammatory cytokine levels, liver toxicity markers, histopathological alterations in liver and lung tissues, and ELISA-based biochemical indices. Our findings showed that LPS administration markedly increased (p < 0.05) inflammatory cell counts, lipid peroxidation, cytokine release, and hepatotoxicity markers, while significantly decreasing (p < 0.05) endogenous antioxidant enzyme activities relative to the NC group. VCG treatment dose-dependently attenuated lipid peroxidation, hepatic toxicity enzymes, pro-inflammatory cytokines, and immune cell infiltration, and ameliorated histopathological damage, while restoring antioxidant enzyme activities, thereby preventing organ dysfunction. Furthermore, VCG effectively inhibited activation of the PERK/PI3K and TLR4/NF-кB/IL-1β pathways.

Background

Shen-Ling-Bai-Zhu-San (SLBZS), a classic formula, shows excellent therapeutic effects on ulcerative colitis (UC). However, its pharmacological mechanism remains unclear. This study aims to explore the SLBZS’s mechanism on mitophagy and inflammation in UC.

Method

The UC rat model was constructed using 4.5% DSS. The in vivo effects of SLBZS on mitophagy and inflammation were investigated by combining the autophagy inhibitor 3-MA. Caco-2 cells were co-treated with DSS and LPS to mimic UC-like inflammatory. The main active components of SLBZS were analyzed by HPLC. Combined with 3-MA or knockdown of Nrf2, the mechanism by which the main active component of SLBZS Ginsenoside Rg1 affected oxidative stress and inflammation was investigated.

Results

SLBZS administration alleviated colonic injury in UC rats, reduced disease activity index, increased colonic length, promoted ZO-1, occludin, LGR5, and MUC-2 expressions, decreased ROS production, MDA level, and TNF-α, IL-1β, IL-6, IL-17, and p62 expressions, increased SOD and GSH-PX levels, mitochondrial membrane potential, and PINK1, TOM20, Nrf2, LC3, PINK1, and Parkin levels. 3-MA prevented this phenomenon, indicating that SLBZS inhibited UC inflammation by enhancing mitophagy. The molecular docking results showed that Ginsenoside Rg1 bound to Nrf2. The interaction between Nrf2 and PINK1 was confirmed. Mechanistically, Ginsenoside Rg1 relieved oxidative stress and inflammation in UC-like Caco-2 cell model by Nrf2/PINK1/Parkin pathway-mediated mitophagy.

Conclusion

Our results indicated that the Ginsenoside Rg1 promoted Nrf2/PINK1/Parkin pathway-mediated mitophagy, thereby alleviating UC, suggesting that Ginsenoside Rg1 could serve as a promising therapeutic agent for clinical UC, with the Nrf2/ PINK1/Parkin axis representing a potential strategy.

Sennoside A (SA), a frequently-used powerful laxative in clinic. Although the protective effect of SA has been recognized in digestive diseases, diabetes and nephropathy, it is still unclear whether it exerts the protective function in sepsis-induced acute kidney injury (AKI). The research aimed to disclose the regulatory mechanism of SA in sepsis-associated AKI. We utilized the cecal ligation and puncture (CLP) and by administering SA (15, 30 and 60 mg/kg), and employing HE and TUNEL staining of the pathological changes of kidney tissue. Detecting BUN and Creatinine levels to evaluate kidney dysfunction. By using ELISA and western blotting assays, Fe²⁺, ACSL4, GPX4, MDA, GSH, IL-6, TNF-α and IL-1β were detected to assess the function of SA in sepsis-triggered ferroptosis, oxidative stress and inflammatory response. SIRT1, Ac-NF-κB p65 and Ac-Foxo1 protein levels were investigated to unearth the regulatory mechanisms. SA ameliorated kidney histological damage and kidney function in sepsis-induced AKI mice. SA inhibited ferroptosis and oxidative stress through declining Fe²⁺ level, elevating GPX4 and GSH levels, but suppressing ACSL4 and MDA levels. IL-6, TNF-α and IL-1β levels were reduced by SA administration in sepsis mice. In terms of mechanism, SIRT1 expression was dramatically enhanced by SA, leading to a reduction of downstream molecules (Ac-NF-κB p65 and Ac-Foxo1). Ultimately, the protective function of SA was abrogated by SIRT1 inhibitor (EX527). SA played a protective role in sepsis-induced AKI by regulating SIRT1 pathway. This innovative research mechanism might provide theoretical foundation for sepsis-triggered AKI treatment.