Experimental and Therapeutic Medicine
·
2022
·Vol. 24
·期 1
·1-11
·
IF 2.751
Lianjie Xu,Yurong Zhang,Nengbo Ji,Yan Du,Tao Jia,Shanshan Wei,Wei Wang,Shan Zhang,Wenhui Chen
Tanshinone IIA (TIIA) is a major component extracted from the traditional herbal medicine Salvia miltiorrhiza and has been indicated to play a role in the treatment of organ fibrosis. However, the evidence supporting its antifibrotic effect is insufficient and the underlying mechanism is unclear. To investigate the therapeutic effect of TIIA on non‑alcoholic steatohepatitis‑related fibrosis (NASH‑F), the present study used a methionine choline deficiency diet to induce NASH‑F in rats, and explored the effect of TIIA on the transforming growth factor‑β1 (TGF‑β1)/Smad signaling pathway. Wistar rats were randomly divided into control, NASH‑F and TIIA groups. After 8 weeks of treatment, the levels of serum markers associated with liver function and fibrosis were measured, liver fat vacuoles and inflammation were assessed by haematoxylin and eosin staining, and liver fibrosis was assessed by Masson's trichrome staining. TGF‑β1, Smad2, Smad3, Smad7 and α‑smooth muscle actin (α‑SMA) mRNA expression, and TGF‑β1, Smad2/3, phosphorylated (p)‑Smad2/3, Smad7 and α‑SMA protein levels were determined. The results revealed that TIIA could remarkably ameliorate liver fat vacuoles and inflammation in NASH‑F rats, and could decrease the levels of serum aspartate aminotransferase, alanine aminotransferase, total bilirubin, total bile acid, hyaluronic acid, type Ⅳ collagen, laminin and type III collagen, while increasing the levels of total cholesterol and triglycerides; however, this was not statistically significance. TIIA markedly suppressed the increased TGF‑β1, Smad2, Smad3 and α‑SMA mRNA expression levels observed in the liver of NASH‑F rats, while it increased the mRNA expression level of Smad7. Similarly, TIIA suppressed the increased TGF‑β1, p‑Smad2/3 and α‑SMA protein levels observed in the liver of NASH‑F rats, while it increased the protein expression level of Smad7 in vitro and in vivo. TIIA had no significant cytotoxic effect at 10, 20, 40 and 80 µmol/l on human LX‑2 cell. In conclusion, the findings of the present study indicated that TIIA alleviated NASH‑F by regulating the TGF‑β1/Smad signaling pathway. TIIA may be a useful tool in the prevention and treatment of NASH‑F.
研究领域:
药理学
·
肝病学
·
分子生物学
✓ 已验证
DOI
PubMed
高影响因子
MOLECULES
·
2018
·Vol. 23
·期 1
·215
·
IF 3.098
Xinyan Peng,Chongshan Dai,Quanwen Liu,Junke Li,Jingru Qiu
This study aimed to investigate the protective effect of curcumin against carbon tetrachloride (CCl4)-induced acute liver injury in a mouse model, and to explain the underlying mechanism. Curcumin at doses of 50, 100 and 200 mg/kg/day were administered orally once daily for seven days prior to CCl4exposure. At 24 h, curcumin-attenuated CCl4induced elevated serum transaminase activities and histopathological damage in the mouse’s liver. Curcumin pre-treatment at 50, 100 and 200 mg/kg significantly ameliorated CCl4-induced oxidative stress, characterized by decreased malondialdehyde (MDA) formations, and increased superoxide dismutase (SOD), catalase (CAT) activities and glutathione (GSH) content, followed by a decrease in caspase-9 and -3 activities. Curcumin pre-treatment significantly decreased CCl4-induced inflammation. Furthermore, curcumin pre-treatment significantly down-regulated the expression of TGF-β1 and Smad3 mRNAs (bothp< 0.01), and up-regulated the expression of nuclear-factor erythroid 2-related factor 2 (Nrf2) and HO-1 mRNA (bothp< 0.01) in the liver. Inhibition of HO-1 attenuated the protective effect of curcumin on CCl4-induced acute liver injury. Given these outcomes, curcumin could protect against CCl4-induced acute liver injury by inhibiting oxidative stress and inflammation, which may partly involve the activation of Nrf2/HO-1 and inhibition of TGF-β1/Smad3 pathways.Keywords:curcumin;acute liver injury;Nrf2/HO-1 pathway;oxidative stress;TGF-β1/Smad3 pathway
研究领域:
药理学
·
肝病学
·
分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
AQUACULTURE
·
2022
·
IF 5.135
Hua Rong,Haoran Zhang,Lijun Ning,Kun Wu,Samwel Mchele Limbu,Qingchao Shi,Chuanjie Qin,Xiaobo Wen
The swim bladder performs various functions in fish, is consumed by humans and can be processed into high-grade fish glue (traditional high-value tonic). However, little is known on the optimum amount of proline (Pro) required for promoting collagen synthesis and deposition in fish swim bladder and the regulatory mechanism. This study explored the effects and optimum amount of dietary Pro supplementation on collagen synthesis and deposition in Chu's croaker ( Nibea coibor ) swim bladder and its possible molecular mechanism. A total of 450 juvenile fish (8.64 ± 0.14 g) were randomly stocked into 18 cages (25 fish per cage) in triplicate and fed Pro supplemented diets (0, 5, 10, 15, 20 and 25 g kg −1 ) for eight weeks. Another 225 fish (11.62 ± 0.15 g) were distributed randomly into control, Pro and Pro diet plus injected with specific inhibitor of Smad3 (SIS3) in order to inhibit the transforming growth factor beta (TGF-β)/Smads pathway. Pro supplementation up-regulated significantly the expression of genes involved in TGF-β/Smads pathway such as collagen, type I, alpha 1 ( col1a1 ) and 2 ( col1a2 ), TGF-β and Smad2/3 , and increased collagen content in the Chu's croaker swim bladder ( P < 0.05). The optimum dietary Pro supplementation for deposition of collagen in Chu's croaker swim bladder was 19.36 g kg −1 . The collagen content in the swim bladder positively correlated significantly with the mRNA expression of col1a1 , col1a2 , TGF-β and Smad2/3 genes ( P < 0.05). The optimum dietary Pro supplementation for maximum synthesis of collagen in Chu's croaker swim bladder was 13.25, 13.32 and 15.94 g kg −1 based on mRNA expression of Smads2 , Smads3 and col1a2 genes, respectively. SIS3 down-regulated the expression of col1a1 , col1a2 , TGF-β and Smad2/3 genes, subsequently decreased collagen deposition in the swim bladder ( P < 0.05). These results suggest that 13.25 to 19.36 g kg −1 Pro supplementation improve collagen synthesis and deposition in Chu's croaker swim bladder. The TGF-β/Smad signaling pathway regulates collagen synthesis and deposition in Chu's croaker swim bladder. Our results provide an understanding on the molecular mechanism of collagen synthesis and deposition in fish for producing collagen required for human food and fish glue.
研究领域:
水产养殖
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分子生物学
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营养学
✓ 已验证
产品关联
DOI
高影响因子
KOREAN JOURNAL OF PHYSIOLOGY & PHARMACOLOGY
·
2021
·Vol. 25
·期 2
·131-137
·
IF 2.016
Jing Cheng,Chaoyang Ren,Renli Cheng,Yunning Li,Ping Liu,Wei Wang,Li Liu
Aging is the process spontaneously occurred in living organisms. Cardiac fibrosis is a pathophysiological process of cardiac aging. Mangiferin is a well-known C-glucoside xanthone in mango leaves with lots of beneficial properties. In this study, rat model of cardiac fibrosis was induced by injected with 150 mg/kg/d D-galactose for 8 weeks. The age-related cardiac decline was estimated by detecting the relative weight of heart, the serum levels of cardiac injury indicators and the expression of hypertrophic biomakers. Cardiac oxidative stress and local inflammation were measured by detecting the levels of malondialdehyde, enzymatic antioxidant status and proinflammatory cytokines. Cardiac fibrosis was evaluated by observing collagen deposition via masson and sirius red staining, as well as by examining the expression of extracellular matrix proteins via Western blot analysis. The cardiac activity of profibrotic TGF-β1/p38/MK2 signaling pathway was assessed by measuring the expression of TGF-β1 and the phosphorylation levels of p38 and MK2. It was observed that mangiferin ameliorated D-galactose-induced cardiac aging, attenuated cardiac oxidative stress, inflammation and fibrosis, as well as inhibited the activation of TGF-β1/p38/MK2 signaling pathway. These results showed that mangiferin could ameliorate cardiac fibrosis in D-galactose-induced aging rats possibly via inhibiting TGF-β/p38/MK2 signaling pathway.
研究领域:
药理学
·
心脏病学
·
老年学
·
分子生物学
✓ 已验证
DOI
高影响因子
Nano Materials Science
·
2024
·
IF 12.6
Ming Deng,Geliang Hu,Fan Liang,Qi Liao,Wanjun Ding,Bin He,Jianghua Ming,Hui Huang,Junqi Liu,Zhaohong Kong,Ping Xie
Objective To investigate the repair of spinal cord injury (SCI) in rats using 3D bioprinted decellularized extracellular matrix (dECM) hydrogel, neural stem cells (NSCs), and TGF-β1 monoclonal antibody. Methods The spinal cord-derived dECM hydrogel (SC-dECM-gel) was optimized for 3D printing. Rheological tests established a 3 % concentration as optimal. In vitro tests assessed the effects of TGF-β1 monoclonal antibody on NSC viability and differentiation. A rat SCI model was treated with the printed gel, and recovery was monitored using the Basso-Beattie-Bresnahan test and evoked potentials. Results The 3 % SC-dECM-gel showed superior rheological properties. TGF-β1 monoclonal antibody enhanced NSC survival and differentiation in vitro. In vivo, the 3D bioprinted gel significantly improved motor function and promoted neuronal regeneration. Conclusion 3D bioprinted SC-dECM-gel loaded with NSCs and TGF-β1 monoclonal antibody effectively restores motor function and promotes regeneration in SCI rats, offering a promising approach for SCI treatment.
研究领域:
再生医学
·
神经科学
·
生物材料学
✓ 已验证
DOI
高影响因子
DRUG DELIVERY
·
2022
·
IF 6.819
Xiaoxian Huang,Lingfei Han,Ruyi Wang,Wanfang Zhu,Ning Zhang,Wei Qu,Wenyuan Liu,Fulei Liu,Feng Feng,Jingwei Xue
The antitumor immune response induced by chemotherapy has attracted considerable attention. However, the immunosuppressive tumor microenvironment hinders the immune activation effect of cancer chemotherapy. TGF-β plays a key role in driving tumor immunosuppression and can prevent effective antitumor immune response through multiple roles. In this study, a dual-responsive prodrug micelle (PAOL) is designed to co-deliver LY2109761 (a TGF-β receptor I/II inhibitor) and oxaliplatin (OXA, a conventional chemotherapy) to remodel tumor microenvironment and trigger immunogenic cell death (ICD) to induce antitumor immunity response. Under hypoxia tumor environment, the polyethylene glycol shell of the micelle cleavages, along with the release of LY2109761 and OXA prodrug. Cytotoxic effect of OXA is then activated by glutathione-mediated reduction in tumor cells and the activated OXA significantly enhances tumor immunogenicity and promotes intratumoral accumulation of cytotoxic T lymphocytes. Meanwhile, TGF-β blockade through LY2109761 reprograms tumor microenvironment by correcting the immunosuppressive state and regulating tumor extracellular matrix, which further maintaining OXA induced immune response. Therefore, due to the capability of boosting tumor-specific antitumor immunity, the bifunctional micelle presents markedly synergistic antitumor efficacies and provides a potent therapeutic strategy for chemoimmunotherapy of solid tumors.
研究领域:
癌症生物学
·
药学
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免疫学
·
纳米技术
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Nature Communications
·
2023
·Vol. 14
·期 1
·1-19
·
IF 16.6
Da Xingwen,Li Ziyan,Huang Xiaofan,He Zuhan,Yu Yubing,Tian Tongtong,Xu Chengqi,Yao Yufeng,Wang Qing K.
Thoracic aortic aneurysm (TAA) is a localized or diffuse dilatation of the thoracic aortas, and causes many sudden deaths each year worldwide. However, there is no effective pharmacologic therapy. Here, we show that AGGF1 effectively blocks TAA-associated arterial inflammation and remodeling in three different mouse models (mice with transverse aortic constriction, Fbn1 C1041G/+ mice, and β-aminopropionitrile-treated mice). AGGF1 expression is reduced in the ascending aortas from the three models and human TAA patients. Aggf1 +/- mice and vascular smooth muscle cell (VSMC)-specific Aggf1 smcKO knockout mice show aggravated TAA phenotypes. Mechanistically, AGGF1 enhances the interaction between its receptor integrin α7 and latency-associated peptide (LAP)-TGF-β1, blocks the cleavage of LAP-TGF-β1 to form mature TGF-β1, and inhibits Smad2/3 and ERK1/2 phosphorylation in VSMCs. Pirfenidone, a treatment agent for idiopathic pulmonary fibrosis, inhibits TAA-associated vascular inflammation and remodeling in wild type mice, but not in Aggf1 +/- mice. In conclusion, we identify an innovative AGGF1 protein therapeutic strategy to block TAA-associated vascular inflammation and remodeling, and show that efficacy of TGF-β inhibition therapies require AGGF1.
研究领域:
心血管疾病
·
分子生物学
·
药理学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
CELLULAR AND MOLECULAR BIOLOGY
·
2024
·Vol. 70
·期 3
·95-101
·
IF 1.5
Shanfu Wang,Bing Xu,Heng Yin,Zhen Hua,Yang Shao,Jianwei Wang
Osteoporosis is a common chronic bone disorder in postmenopausal women. Ginsenosides are primary active components in ginseng and the effects of various ginsenoside variants in osteoporosis treatment have been widely revealed. We planned to explore the impact of ginsenoside Rc on bone resorption in an osteoporosis rat model. We used ovariectomized rats to assess the potential impact of ginsenoside Rc on osteoporosis. μ-CT was implemented for analyzing the microstructure of the distal left femur in rats. H&E staining together with Masson staining were applied for bone histomorphometry evaluation. ELISA kits were implemented to detect serum concentrations of TRACP-5b, OCN, CTX, as well as PINP. Ginsenoside Rc treatment lessened the serum levels of TRACP-5b as well as CTX, while increasing serum levels of OCN, and PINP of OVX rats. Moreover, we found that ginsenoside Rc contributed to the synthesis of type I collagen via increasing Col1a1 and Col1a2 levels in femur tissues of ovariectomized rats. Our findings also revealed that ginsenoside Rc activated the TGF-β/Smad pathway by increasing TGF-β as well as phosphorylated Smad2/3 protein levels. Ginsenoside Rc alleviates osteoporosis in rats through promoting the TGF-β/Smad pathway.
研究领域:
药理学
·
骨科
·
内分泌学
·
分子生物学
✓ 已验证
DOI
高影响因子
Nature Aging
·
2025
·
IF 19.4
Liu Liu,Wang Qianyue,Chen Meng,Zhou Haifeng,Li Xu,Yuan Ziqi,Hu Yong,Wang Chaoqun,Zhang Xiaohui,Hu Sheng,Wu Xiaoting,Li Meixin,Li Juanjuan,Chen Aijun,Yan Wei
Lung aging is a multifactorial series of molecular alterations that leads to gradual deterioration of lung function and increased vulnerability to cancer. Tumor communicates with host organs partially through extracellular vesicles; however, the mechanistic drivers and consequences of lung aging in the context of cancer remain unclear. Here we identify cancer cell-secreted dimethylarginine dimethylaminohydrolase-1 (DDAH1) protein induces citrulline accumulation and promotes lung fibrosis and aging. Mechanistically, our single-cell sequencing and genetic knockout mice evidence that citrulline availability elevation inhibits peptidyl arginine deiminase 4-mediated transforming growth factor-β1 (TGF-β1) citrullination, thereby inducing the TGF-β1/Smad3 signaling pathway in lung fibroblasts. Notably, vacuolar protein sorting assists the packaging of DDAH1 into the late endosomes. The administration of DDAH1 inhibitor reduces fibrosis and alleviates lung aging. Conclusively, our findings reveal tumor-derived DDAH1 protein contributes to citrulline accumulation to promote lung aging, shedding light on the treatment and diagnosis of tumors by inhibiting senescent lung fibroblasts.
研究领域:
肿瘤学
·
呼吸系统生物学
·
分子生物学
·
细胞衰老
·
信号转导
·
转化医学
·
肿瘤微环境
✓ 已验证
产品关联
DOI
PubMed
高影响因子
TOXICOLOGY AND APPLIED PHARMACOLOGY
·
2022
·
IF 4.46
Lin Leilei,Qiu Wenke,Luo Yuyuan,Lin Sihang,Sun Xue,Chen Weiqiang,Ye Lianbao,Wang Ying,Li Yan,Li Ming
Liver fibrosis has the potential to progress into liver cirrhosis , liver failure, and even death. Hepatic stellate cells (HSCs) activation play a central role in liver fibrosis, and persistently damaged hepatocytes secrete soluble factors that activate transdifferentiation of HSCs into myofibroblasts. Our previous studies indicated that fine particulate matter (PM2.5) can activate HSCs by stimulating hepatocytes to secrete TGF-β1. However, whether PM2.5 activates HSCs by regulating oxidative stress in hepatocytes remains uncertain. Oleanolic acid (OA) has been widely used in the clinic for hepatoprotection in Chinese medicine. In the present study, OA-loaded nanoparticles (OA-NP) with high solubility were used to attenuate the activation of HSCs induced by PM2.5-treated hepatocytes, and further studies were performed to explore the mechanism in which OA-NP plays a vital part. Our results showed that consistently PM2.5 treatment induced oxidative stress in hepatocytes. Moreover, the activation of HSCs induced by PM2.5-treated hepatocytes was reversed by antioxidant N -acetylcysteine treatment. Hence, PM2.5 may participate in the activation of HSCs by regulating oxidative stress in hepatocytes. Using a co-cultivation system, our results proved pretreatment with OA-NP significantly attenuates the activation of HSCs induced by PM2.5-exposed hepatocytes. In addition, the TGF-β1 expression and oxidative stress in hepatocytes with PM2.5 treated were reduced by the incubation with OA-NP. These observations demonstrated that OA-NP protects against the activation of HSCs by decreasing the TGF-β1 level and oxidative stress in PM2.5-exposed hepatocytes.
研究领域:
药理学
·
毒理学
·
细胞生物学
·
环境健康
✓ 已验证
DOI
PubMed
高影响因子
MOLECULAR AND CELLULAR PROBES
·
2020
·
IF 1.951
Yong Huang,Yuting Wang,Lixin Lin,Peng Wang,Lei Jiang,Jian Liu,Xueming Wang
Aim Keloid is a benign dermal tumor with excessive hyperplasia and deposition of collagen. As a common tumor suppressor gene , miR-133a-3p has not been studied in keloid. This study will delve into the specific mechanism of miR-133a-3p in keloid. Methods Normal skin fibroblasts and keloid fibroblasts (KFs) were first isolated from patients’ normal skin and keloid, and cells were identified by morphological observation and immunofluorescence. The expressions of miR-133a-3p and extracellular matrix (ECM)-associated markers (Collagen I, III and α smooth muscle activin) were detected by Quantitative Real Time-Polymerase Chain Reaction (qRT-PCR). Cell viability and apoptosis of KFs were examined by Cell Counting Kit-8 assay, flow cytometry, and Caspase-3 colorimetry . TargetScan predicted target gene for miR-133a-3p was verified by luciferase assay, qRT-PCR and Western Blot (WB). WB was used to study protein expression of TGFBR1, phosphorylated -Smad2 ( p -Smad2) and Smad2. Finally, a series of rescue experiments were performed to verify the intervention of target genes on miR-133a-3p. Results MiR-133a-3p was lowly expressed in keloid tissue and KFs. Overexpression of miR-133a-3p inhibited the expression of ECM-associated markers, reduced KFs viability, and promoted apoptosis. It was verified that interference regulator 5 (IRF5) is miR-133a-3p target gene. The rescue experiments showed that IRF5 reversed the effect of miR-133a-3p mimic on inhibiting fibrosis, and reversed the effects on promoting apoptosis and reducing cell proliferation . Conclusion Overexpressed miR-133a-3p inhibits fibrosis by down-regulating IRF5 and thus inhibiting the TGF-β/Smad2 pathway. And it also promotes KFs apoptosis and reduces proliferation.
研究领域:
分子生物学
·
细胞生物学
·
皮肤科
✓ 已验证
产品关联
DOI
PubMed
高影响因子
BIOCHEMICAL PHARMACOLOGY
·
2023
·
IF 5.8
Shuanghui Lu,Xiu Chen,Yujia Chen,Yingqiong Zhang,Jun Luo,Huidi Jiang,Luo Fang,Hui Zhou
Transforming growth factor-beta 1 (TGF-β1)-induced epithelial-mesenchymal transition (EMT) of renal tubular cells promotes renal fibrosis and the progression of chronic kidney disease (CKD). PDZ domain-containing 1 (PDZK1) is highly expressed in renal tubular epithelial cells; however, its role in TGF-β1-induced EMT remains poorly understood. The present study showed that PDZK1 expression was extremely downregulated in fibrotic mouse kidneys and its negative correlation with TGF-β1 expression and the degree of renal fibrosis. In addition, TGF-β1 downregulated the mRNA expression of PDZK1 in a time- and concentration-dependent manner in vitro . The downregulation of PDZK1 exacerbated TGF-β1-induced EMT upon oxidative stress, while the overexpression of PDZK1 had the converse effect. Subsequent investigations demonstrated that TGF-β1 downregulated PDZK1 expression via p38 MAPK or PI3K/AKT signaling in vitro , but independently of ERK/JNK MAPK signaling. Meanwhile, inhibition of the p38/JNK MAPK or PI3K/AKT signaling using chemical inhibitors restored the PDZK1 expression, mitigated renal fibrosis, and elevated renal levels of endogenous antioxidants carnitine and ergothioneine in adenine-induced CKD mice. These findings provide the first evidence suggesting a negative correlation between PDZK1 and renal fibrosis, and identifying PDZK1 as a novel suppressor of renal fibrosis in CKD through ameliorating oxidant stress.
研究领域:
肾病学
·
分子生物学
·
细胞生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）