PeerJ
·
2023
·
IF 2.7
Zijia Wang,Ying Han,Ying Peng,Shuhui Shao,Huanquan Nie,Kun Xia,Haofeng Xiong,Tong Su
Objectives Cellular senescence is strongly associated with fibrosis and tumorigenesis. However, whether the epithelium of oral submucous fibrosis (OSF) undergoes premature senescence remains unclear. This study investigates the roles of senescent epithelial cells in OSF. Methods The immunohistochemistry and Sudan black B staining were performed to identify epithelium senescence in OSF tissues. Arecoline was used to induce human oral keratinocytes (HOKs) senescence. The cell morphology, senescence-associated β galactosidase activity, cell counting Kit 8, immunofluorescence, quantitative real-time PCR, and western blot assay were used to identification of senescent HOKs. The enzyme-linked immunosorbent assay was exerted to evaluate the levels of transforming growth factor β1 (TGF-β1) in the supernatants of HOKs treated with or without arecoline. Results The senescence-associated markers, p16 and p21, were overexpressed in OSF epithelium. These expressions were correlated with alpha-smooth actin (α-SMA) positively and proliferating cell nuclear antigen (PCNA) negatively. Moreover, Sudan black staining showed that there was more lipofuscin in OSF epithelium. In vitro, HOKs treated with arecoline showed senescence-associated characteristics including enlarged and flattened morphology, senescence-associated β galactosidase staining, cell growth arrest, γH2A.X foci, upregulation of p53, p21, and TGF-β1 protein levels. Moreover, senescent HOKs secreted more TGF-β1. Conclusions Senescent epithelial cells are involved in OSF progression and may become a promising target for OSF treatment.
研究领域:
肿瘤学
·
皮肤病学
·
分子生物学
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DOI
PubMed
高影响因子
Chinese Herbal Medicines
·
2026
·
IF 11.2
Aifen Liu,Jingyan Hu,Weili Yu,Chuanyu Cang,Chuanjing Shi,Xi Wang,Rui Wang,Xuanwei Cai,Fengbo Zhao,Lei Zhang
Objective Polycystic ovary syndrome (PCOS) is an endocrine and metabolic disorder characterized by ovulatory dysfunction. Formononetin (FMN), a bioactive compound derived from leguminous plants, including Glycyrrhiza uralensis , Trifolium pratense , and Astragalus membranaceus , exhibits anti-inflammatory and anti-fibrotic properties. This study aimed to evaluate the therapeutic effects of FMN in a PCOS rat model and elucidate its underlying molecular mechanisms. Methods A PCOS-like model was established in 3-week-old female Sprague-Dawley rats by daily dehydroepiandrosterone (DHEA) injections. The efficacy of FMN was assessed by monitoring estrous cycles, hormone levels, glucose tolerance, and ovarian tissue morphology. Network pharmacology and transcriptome sequencing were used to predict the molecular targets and signaling pathways of FMN. The binding and stabilizing effects of FMN on suppressor of cytokine signaling 3 (SOCS3) were confirmed using molecular docking, molecular dynamics (MD) simulations, and cellular thermal shift assay (CETSA)-Western blotting (WB) (CETSA-WB). The expression of SOCS3, inflammation- and fibrosis-related markers, and the components of the transforming growth factor beta1 (TGF- β 1)/Smad pathway were quantified by quantitative polymerase chain reaction (qPCR), Western blotting, and immunohistochemistry. Functional validation was performed using SOCS3 small interfering RNA (siRNA). Results DHEA successfully induced a PCOS-like phenotype, including disrupted estrous cycle, hyperandrogenism, an elevated luteinizing hormone to follicular stimulating hormone (LH/FSH) ratio, insulin resistance, and abnormal ovarian morphology. FMN treatment significantly reversed these abnormalities and reduced ovarian collagen deposition. Network pharmacology and transcriptome analyses indicated that the therapeutic efficacy of FMN was primarily attributable to its anti-fibrotic and anti-inflammatory properties, with SOCS3 identified as a potential key molecule. Molecular docking and MD simulations, along with CETSA-WB, further revealed that FMN directly binds to SOCS3, enhancing its stability and thereby inhibiting ovarian fibrosis in PCOS. Moreover, qPCR, Western blotting, and immunohistochemistry confirmed that FMN regulates the TGF- β 1/Smad signaling pathway. Importantly, SOCS3siRNA abolished fibrotic-related collagen levels and phosphorylated signal transducer and activator of transcription 3 (p-STAT3) expression, supporting the notion that FMN ameliorates PCOS-induced ovarian fibrosis via SOCS3. Conclusion FMN alleviated ovarian dysfunction and hyperandrogenism in DHEA-induced PCOS rats by stabilizing SOCS3 and inhibiting TGF- β 1/Smad signaling, thereby attenuating ovarian fibrosis and inflammation. This reveals a novel SOCS3-centered mechanism for FMN and underscores its therapeutic potential for PCOS.
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DOI
高影响因子
PLACENTA
·
2024
·
IF 3
Gaoying Wang,Ruirui Dong,Haijian Zhao,Ningzhen Ye,Jing Wang,Jing Cheng,Xinrui Shi,Liang Luo,Ting Zhang
Background Abnormal bile acid metabolism leading to changes in placental function during pregnancy. To determine whether endoplasmic reticulum protein 29 (ERp29) can mediate the pregnancy effects of cholestasis by altering the level of trophoblast cell apoptosis. Methods ERp29 in serum of 66 intrahepatic cholestasis of pregnancy (ICP) pregnant women and 74 healthy were detected by ELISA. Subcutaneous injection of ethinyl estradiol (E2) was used to induce ICP in pregnant rats. Taurocholic acid (TCA) was used to simulate the ICP environment, and TGF-β1 was added to induce the epithelial mesenchymal transformation (EMT) process. The scratch, migration, and invasion test were used to detect the EMT process. ERp29 overexpression/knockdown vector were constructed and transfected to verify the role of ERp29 in the EMT process. Downstream gene was obtained through RNA-seq. Results Compared with the healthy pregnant women, the expression levels of ERp29 in serum of ICP pregnancy women were significantly increased (P < 0.001). ERp29 in the placenta tissue of the ICP pregnant rats increased significantly, and the level of apoptosis increased. The placental tissues of the ICP had high expression of E-cadherin and low expression of N-cadherin, snail1, vimentin. After HTR-8/SVneo cells were induced by TCA, EMT was inhibited, while the ERp29 increased. Cell and animal experiments showed that, knockdown of ERp29 reduced the inhibition of EMT, the ICP progress was alleviated. Overexpression of FOS salvaged the inhibitory effects of ERp29 on cell EMT. Discussion The high level of ERp29 in placental trophoblast cells reduced FOS mRNA levels, inhibited the EMT process and aggravated the occurrence and development of ICP.
研究领域:
妇产科学
·
分子生物学
·
细胞生物学
·
病理学
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DOI
PubMed
高影响因子
PHYTOTHERAPY RESEARCH
·
2026
·
IF 8.1
Jing Qin,Huanhuan Huang,Mengzhen Xu,Lin Zhu,Haoli Liu,Xinyu Qian
Laminin promotes tumor progression, but its role in small-cell lung cancer (SCLC) remains unclear. Curcumol, a natural compound from Curcumae Rhizoma, has anti-tumor activity. Here, we tested the hypothesis that Curcumol disrupts Laminin–Integrin β1 interaction to suppress SCLC. SBC-2 and H69 cells were cultured on Laminin-coated substrates. Cell functions were assessed by Transwell migration, colony formation, and MTT assays. Molecular mechanisms were investigated through qRT-PCR, Western blot, molecular docking, Co-IP, and Dot blot assays. Target specificity was confirmed by Integrin β1 mutagenesis. The therapeutic efficacy of Curcumol was evaluated in xenograft mouse models. Laminin enhanced malignant phenotypes in SCLC cells, accompanied by the activation of FAK/ERK and TGF-β/Smad2/3 pathways. Curcumol inhibited the laminin-promoted malignant phenotypes and epithelial–mesenchymal transition (EMT) in SCLC cells and suppressed the expression of related proteins. Mechanistic studies revealed that Curcumol directly bound to Integrin β1, competitively inhibiting the binding of Laminin to Integrin β1 and the activation of downstream signaling. Target specificity was validated through mutagenesis studies, where Curcumol exhibited reduced efficacy in Integrin β1-mutant cells. In vivo, Curcumol (100 mg/kg, oral) attenuated Laminin-driven tumor growth, suppressed EMT and FAK/ERK signaling, with no detectable toxicity. Integrin β1 is a key mediator of Laminin's pro-tumorigenic effects in SCLC. Curcumol disrupts Laminin–Integrin β1 interaction, inhibits FAK/ERK signaling and EMT, and suppresses tumor progression, representing a promising therapeutic strategy.
✓ 已验证
DOI
PubMed
高影响因子
BIOTECHNIC & HISTOCHEMISTRY
·
2026
·
IF 1.4
Ying Xun,Xiaoli Wang,Lili Chen,Yu Fu,Xiang Wu,Wenqing Zeng
Glucose-lowering treatment and antidiabetic drugs show great potential for preventing and intervening in diabetes mellitus (DM)-associated cognitive dysfunction or advanced dementia. This study delves into the role and mechanism of low-carbohydrate diet (LCD) combined with Xiaokeping (XKP) on these conditions. Type 2 diabetes (T2D) rat models were constructed via high-fat diet and streptozotocin (STZ) injection, and treated with LCD and XKP alone or in combination for 8 weeks. Body weight and indicators of blood glucose and lipids were determined. Additionally, memory and spatial learning abilities were assessed. Tissue staining of the hippocampus was used to observe pathological changes. Oxidative stress, levels of inflammatory factors, and phosphatidylinositol 3-kinase (PI3K)/Akt serine/threonine kinase (Akt) were analyzed. The results demonstrated that LCD and/or XKP treatment recovered body weight, blood glucose, and lipid balance, while enhancing spatial memory and attenuating lesion in the hippocampus of diabetic rats. LCD and/or XKP treatment increased superoxide dismutase, decreased malondialdehyde, interleukin-1β/6, and tumor necrosis factor alpha level in the hippocampus of diabetic rats, which suggests a reduction in oxidative stress and neuroinflammation. Moreover, LCD and/or XKP treatment activated the PI3K/Akt pathway. LCD combined with XKP displayed superior efficacy compared to monotherapy. Collectively, LCD combined with XKP mixture improves cognitive decline of T2D rats by suppressing oxidative stress and neuroinflammation in the hippocampus, through a mechanism involving the activation of the PI3K/Akt pathway.
✓ 已验证
DOI
PubMed
高影响因子
JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY
·
2021
·
IF 5.279
Miao Song,Yilong Cui,Qi Wang,Xuliang Zhang,Jian Zhang,Menglin Liu,Yanfei Li
Aluminum (Al)-induced bone formation and metabolism disorder through inhibition of the TGF-β1/Smad signaling pathway is one of the important mechanisms of bone impairment. Ginsenoside Rg3 (Rg3), a specific biological effector molecule, can provide protection to bones. Previously, we demonstrated that Rg3 can reverse aluminum chloride (AlCl3)-induced oxidative stress and metabolic disorder of bones; however, whether the TGF-β1/Smad signaling pathway is involved in it remains unclear. First, we found that Rg3 attenuated Al-induced bone impairment in vivo and in vitro by relieving structural damage to the femur, increasing MC3T3-E1 cell activity, differentiation, mineralization, inhibition of cell apoptosis, and upregulating the extracellular matrix (ECM) synthesis and the expression of TGF-β1/Smad signaling pathway key factors. Subsequently, in the signal pathway intervention experiment, the protective effect of Rg3 on bone impairment induced by Al was weakened; these results indicate that activating the TGF-β1/Smad signaling pathway is one of the mechanisms of Rg3-attenuated Al-induced bone impairment.
研究领域:
药理学
·
毒理学
·
骨生物学
·
信号转导
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DOI
PubMed
高影响因子
Chinese Medicine
·
2024
·
IF 5.3
MingShan Zhang,YuFei Zhang,JingGang He,XinRui Wang,YinYin Wang,LinYan Li,Ling Tao,Min Zhang,Xiangchun Shen
Background Diabetic cardiomyopathy (DCM), characterized by myocardial fibrosis, is a major cause of mortality and morbidity in diabetic patients; the inhibition of cardiac fibrosis is a fundamental strategy for treating DCM. Gastrodin (GAS), a compound extracted from Gastrodia elata protects against DCM, but the molecular mechanism underlying its antifibrotic effect has not been elucidated. Methods In vivo, the effects of GAS were investigated using C57BL/6 mice with DCM, which was induced by administering a high-sugar, high-fat (HSF) diet and streptozotocin (STZ). We assessed the cardiac function in these mice and detected histopathological changes in their hearts and the degree of cardiac fibrosis. In vitro, neonatal rat cardiac fibroblasts (CFs) were transformed into myofibroblasts by exposing them to high glucose combined with high palmitic acid (HG-PA), and CFs were induced by pEX-1 (pGCMV/MCS/EGFP/Neo) plasmid-mediated overexpression of KLK8, which contains the rat KLK8 gene. The KLK8 siRNA was knocked down to study the effects of GAS on CF differentiation, collagen synthesis, and cell migration by specific mechanisms of action of GAS. Results GAS attenuated pathological changes in the hearts of DCM mice, rescued impaired cardiac function, and attenuated cardiac fibrosis. Additionally, the results of molecular docking analysis showed that GAS binds to kinin-releasing enzyme-related peptidase 8 (KLK8) to inhibit the increase in protease-activated receptor-1 (PAR-1), thus attenuating myocardial fibrosis. Specifically, GAS attenuated the transformation of neonatal rat CFs to myofibroblasts exposed to HG-PA. Overexpressing KLK8 promoted CF differentiation, collagen synthesis, and cell migration, and KLK8 siRNA attenuated HG-PA-induced CF differentiation, collagen synthesis, and cell migration. Further studies revealed that a PAR-1 antagonist, but not a PAR-2 antagonist, could attenuate CF differentiation, collagen synthesis, and cell migration. Additionally, GAS inhibited KLK8 upregulation and PAR1 activation, thus blocking the differentiation, collagen synthesis, and cell migration of HG-PA-exposed CFs and triggering TGF-β1/Smad3 signaling. Conclusion GAS alleviated pathological changes in the hearts of DCM model mice induced by an HSF diet combined with STZ. KLK8 mediated HG-PA-induced differentiation, collagen synthesis, and the migration of CFs. GAS attenuated the differentiation, collagen synthesis, and migration of CFs by inhibiting the KLK8-PAR1 signaling axis, a process in which TGF-β1 and Smad3 are involved. Graphical Abstract Supplementary Information The online version contains supplementary material available at 10.1186/s13020-024-01035-4.
研究领域:
医学
·
药理学
·
分子生物学
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DOI
PubMed
高影响因子
MOLECULAR PHARMACEUTICS
·
2024
·
IF 4.5
Tingjun Dong,Ning Yang,Jian Qin,Chengcheng Zhao,Tingyu Gao,Hao Ma,Caili Zhu,Huan Xu
Renal fibrosis plays a key role in the pathogenesis of chronic kidney disease (CKD), in which the persistent high expression of transforming growth factor β1 (TGF-β1) and α-smooth muscle actin (α-SMA) contributes to the progression of CKD to renal failure. In order to improve the solubility, bioavailability, and targeting of tanshinone IIA (Tan IIA), a novel targeting material, aminoethyl anisamide-polyethylene glycol-1,2-distearoyl-sn-glycero-3-phosphate ethanolamine (AEAA-PEG-DSPE, APD) modified Tan IIA liposomes (APD-Tan IIA-L) was constructed. An animal model of glomerulonephritis induced by doxorubicin in BALB/c mice was established. APD-Tan IIA-L significantly decreased blood urea nitrogen and serum creatinine (SCr), and the consequences of renal tissue oxidative stress indicators showed that APD-Tan IIA-L downregulated malondialdehyde, upregulated superoxide dismutase, catalase, and glutathione peroxidase. Masson’s trichrome staining showed that the deposition of collagen in the APD-Tan IIA-L group decreased significantly. The pro-fibrotic factors (fibronectin, collagen I, TGF-β1, and α-SMA) and epithelial–mesenchymal transition marker (N-cadherin) were significantly inhibited by APD-Tan IIA-L. By improving the microenvironment of fibrotic kidneys, APD-Tan IIA-L attenuated TGF-β1-induced excessive proliferation of fibroblasts and alleviated oxidative stress damage to the kidney, providing a new strategy for the clinical treatment of renal fibrosis.
研究领域:
药理学
·
肾脏病学
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产品关联
DOI
PubMed
高影响因子
Biomolecules
·
2020
·Vol. 10
·期 3
·398
·
IF 4.082
Shan Shan Qi,Hong Xing Zheng,Hai Jiang,Li Ping Yuan,Le Chen Dong
Diabetic nephropathy (DN) is one of the most important complications of diabetes, and the leading cause of end-stage renal disease (ESRD). While Chromium picolinate (CrPic) supplementation has been found to be effective in treating diabetes, its effects on diabetic-induced nephropathy have not been studied. Therefore, in this study, CrPic (1 mg kg−1d−1) was administered to a DN rat model by oral gavage for eight weeks to investigate its effects. The results show that CrPic supplementation caused a decrease in levels of blood glucose, serum insulin, blood urea nitrogen (BUN), serum creatinine, and urinary albumin in DN rats. It also reversed renal pathological changes, including renal glomerular sclerosis and interstitial fibrosis. In addition, the oxidative defense system in the kidneys of DN rats was found to be improved; the biological activities of superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPX) increased; and the content of malondialdehyde (MDA) lowered. Immunohistochemical results reveal that the expression levels of renal transforming growth factor-β1 (TGF-β1), Smad 2, and Smad 3 decreased significantly in the kidneys of rats in the CrPic-treated group. CrPic administration was thus found to ameliorate diabetic nephropathy in SD rats via an antioxidative stress mechanism, as well the ability to inhibit TGF-β1/Smad2/3 expression. This study suggests that CrPic could be a potential renal-protective nutrient against diabetic nephropathy.Keywords:diabetic nephropathy;chromium picolinate;renal fibrosis;antioxidative stress
研究领域:
内分泌学
·
肾病学
·
药理学
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产品关联
DOI
PubMed
高影响因子
ADVANCED FUNCTIONAL MATERIALS
·
2024
·
IF 18.5
Jie Liao,Xiaoming Li,Huiqi Yang,Wei He,Bingbing Wang,Shuyu Liu,Yubo Fan
Postoperative adhesion (POA) has emerged as a prevalent clinical challenge in soft tissue repair, emphasizing the critical need for preventive measures. However, the complex POA development process makes POA prevention from a single aspect insufficient. Hence, a curcumin-loaded poly-L-lactic acid-poly (caprolactone) micro-nano conjugated fibrous membrane (PAPC MCFM (cur)) is engineered to synergistically prevent POA from multiple perspectives, in which poly (caprolactone) (PCL) nanofibers (118 ± 12 nm) with low orientation traverse the oriented poly-L-lactic acid (PLLA) microfibers (2.0 ± 0.3 µm). The PAPC MCFM not only significantly improves the mechanical properties of the anisotropic fibrous membrane (AIFM) that the modulus of elasticity and the tensile strength in the direction vertical to microfiber orientation increase by 4.5 and 13.0 times, respectively, but also can further enhance the “contact guidance effect” of AIFM, i.e., hindering fibroblast adhesion, proliferation, and differentiation to myofibroblast through inhibiting integrin β1 activation, vinculin expression and focal adhesion (FA) formation, and the nuclear localization activation of yes-associated protein (YAP). Except for these effects, PAPC MCFM loading with 2.5 mg mL −1 curcumin can further prevent POA by delivering anti-inflammatory, antioxidant, and antibacterial properties, and by suppressing fibrosis through decreased transforming growth factor-β1(TGF-β1) expression, showing effective POA prevention in rat abdominal cavity and rabbit dura mater models.
研究领域:
生物医学工程
·
材料科学
·
组织工程
·
药剂学
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产品关联
DOI
高影响因子
Applied Materials Today
·
2022
·
IF 8.663
Jiaxin Zhang,Mingxi Yang,Xiaoduo Tang,Shuang Li,Junhu Zhang,Laijin Lu,Quan Wang,Bai Yang
Radiation enteritis is an unavoidable complication of radiotherapy for pelvic tumors that seriously affects the prognosis of cancer patients. The fundamental mechanism inducing cell death and tissue injury is the generation of excessive reactive oxygen species (ROS) by ionizing radiation. In the present study, we developed novel S-doped red fluorescent carbonized polymer dots (S-rCPDs) with high biocompatibility and efficient ROS-scavenging capability to act as an intestinal protective agent against radiation damage. The S-rCPDs significantly eliminates cellular ROS and alleviates DNA damage under X-ray radiation. To achieve drug accumulation within the distal intestine, S-rCPDs loaded pH-controlled release polymer microspheres ( [email protected] ) is produced via microfluidic technology. In vivo experimental results show that oral administration of [email protected] effectively suppresses the secretion of pro-inflammatory cytokines and alleviates acute radiation intestinal injury, with a better protective effect than amifostine, which is hereto the only clinically approved radioprotector. Moreover, the as-prepared [email protected] could stabilize the balance of intestinal flora and continuously downregulate the expression of transforming growth factor β1 (TGF-β1), eventually inhibiting the progression of chronic intestinal fibrosis. This study provides a novel strategy for whole-course treatment of radiation enteritis using CPDs-based materials, which could inspire the development of other radioprotective nano-drugs.
研究领域:
放射肿瘤学
·
药学
·
纳米技术
·
胃肠病学
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产品关联
DOI
高影响因子
PEST MANAGEMENT SCIENCE
·
2021
·Vol. 78
·期 4
·1500-1507
·
IF 4.845
Xiao Xu,Qian Ding,Xiu Wang,Ruijie Wang,Farman Ullah,Xiwu Gao,Dunlun Song
BACKGROUND The peach-potato aphid, Myzus persicae (Sulzer) (Hemiptera: Aphididae), is a major pest worldwide. The intensive use of insecticides has led to the development of resistance against neonicotinoid insecticides. The R81T mutation in the nicotinic acetylcholine receptor (nAChR) beta1 subunit is considered a crucial mechanism adaptation to neonicotinoid resistance in M. persicae and Aphis gossypii . RESULTS Resistance-related mutations (R81T and V101I) were detected in the imidacloprid-resistant M. persicae AH19 population. The V101I mutation is reported for the first time. The V101I and R81T mutations existed separately, indicating that the two mutations evolved independently. Imidacloprid resistance in the AH19 population was stable without insecticide exposure. Four mutant strains were selected from the population with stable resistance. The resistance of the AH19-T, AH19-I, and AH19-TI strains to imidacloprid, thiamethoxam, and dinotefuran was significantly increased compared with the AH19-W strain. Synergism bioassays showed that the inhibition of three detoxification enzymes did not affect imidacloprid resistance in the AH19-T and AH19-I strains. Expression of nAChR β1 subunits in the AH19-W, AH19-T, and AH19-I strains remained unchanged. CONCLUSION The V101I mutation is associated with neonicotinoid resistance in M. persicae . The resistance of the AH19-T and AH19-I strains to neonicotinoids appears to be mainly due to the R81T and V101I mutations, whereas these mutations, together with changes in the cytochrome P450 monooxygenases and nAChR expression may be responsible for the development of neonicotinoid resistance in the AH19-TI strain. © 2021 Society of Chemical Industry.
研究领域:
昆虫学
·
分子生物学
·
害虫管理
✓ 已验证
DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）