Frontiers in Physiology
·
2020
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IF 3.367
Song Manyu,Wang Chaoran,Yang Haotian,Chen Yongping,Feng Xiujing,Li Bei,Fan Honggang
Chronic stress leads to immunosuppression and induces splenocyte apoptosis. STAT3 is a transcription factor that regulates immunity and apoptosis; however, it is unclear whether the increased expression of phosphorylated STAT3 (p-STAT3) observed in chronic stress is related to splenocyte apoptosis. To explore the relationship between splenocyte apoptosis and STAT3 in chronic stress, we treated rats undergoing a 21-day chronic restraint stress program with the STAT3 inhibitor S3I-201. This chronic stress model was verified by observing rats’ behavior and measuring their serum corticosterone levels. Chronic stress led to increased expression of anti-inflammatory cytokines, and p-STAT3 inhibition enhanced splenocyte apoptosis in chronic stress. We detected key proteins in three apoptotic pathways to determine which pathway mediated increasing splenocyte apoptosis and found that the death receptor pathway was the main apoptotic pathway that occurred in the spleen during chronic stress. The unfolded protein response (UPR) was also activated, but the Bcl-2 family was not involved in chronic stress. P-STAT3 inhibition had no influence on the Bcl-2 family and the death receptor pathway; however, p-STAT3 inhibition disrupted the pro-survival function of the UPR by decreasing the expression of ATF6α and p-IRE1α. Furthermore, p-STAT3 inhibition activated endoplasmic reticulum stress by promoting the expression of CHOP, p-JNK, and procaspase-12. Collectively, these findings indicate that the increased p-STAT3 expression during chronic stress may promote splenocyte survival by activating the UPR. Consequently, STAT3 and the UPR may be considered as potential therapeutic targets for chronic stress in the future.
研究领域:
免疫学
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压力生物学
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细胞生物学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
·
2026
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IF 4.3
Zihang Yuan,Jie Wang,Haoran Zhang,Yingying Miao,Yuanyuan Chai,Anqin Li,Qianhui Tang,Qingyu Chen,Luyong Zhang,Qinwei Yu,Zhenzhou Jiang
Effective first-line treatments for cholestasis are limited, leading to poor outcomes and liver transplantation after ursodeoxycholic (UDCA)/obeticholic acid (OCA) intolerance. We investigated the role of cholangiocyte sphingosine-1-phosphate receptor 1 (S1PR1) in cholestasis pathogenesis to identify new therapeutic targets. We generated cholangiocyte-specific S1pr1 knockout mice ( S1pr1 ΔIBEC ). Cholestasis models included bile duct ligation (BDL) (14 days) and 0.5% cholic acid (CA) diet (4 months). The level of Sphingosine-1-phosphate (S1P) and its receptor, especially S1PR1 in cholangiocytes were significantly increased in both BDL or 0.5% CA diet models. Sphingosine kinase 1 (SphK1)-derived S1P from hepatic stellate cells (HSCs)/endothelial cells activated cholangiocyte S1PR1, promoting Stat3 phosphorylation and releasing interleukin-6 (IL-6)/C-C motif chemokine (CCL) 7, which remodeled the inflammatory microenvironment and exacerbated liver injury. S1PR1 deletion significantly reduced liver injury, fibrosis, and inflammation. Likewise, treatment with a specific inhibitor of cholangiocyte S1PR1, W146, slightly improved liver injury induced by BDL. The functional effect of S1PR1 in cholangiocyte was further strengthened by our design of the nanoparticle-delivered W146. This demonstrated that cholangiocytes-specific deletion of S1PR1 can alleviate liver fibrosis and injury caused by biliary obstruction or chronic cholestasis, which helps to develop S1PR1 as a target for the treatment of liver fibrosis and cholestasis.
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DOI
PubMed
高影响因子
Frontiers in Pharmacology
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2024
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IF 4.4
Ma Yucong,Ye Suping,Sun Kunpeng,Gu Yue
Curcumin (CUR) possesses the capability to inhibit various inflammatory factors, exert anti-inflammatory effects, and alleviate asthma attacks; however, its hydrophobicity and instability significantly impede its clinical application. In this study, we synthesized CUR-loaded nanoparticles (CUR-NPs) and evaluated their impact on the proliferation, migration, and inflammatory infiltration of mouse airway smooth muscle cells (ASMCs), while investigating their underlying mechanisms. To achieve this objective, ASMCs were isolated from BALB/c mice and subjected to TGF-β1-induced cell proliferation and migration. Our findings demonstrate that CUR-NPs effectively regulate the release of CUR within cells with superior intracellular uptake compared to free CUR. The CCK-8 assay results indicate that the blank carrier does not exhibit any cytotoxic effects on cells, thus rendering the impact of the carrier itself negligible. The TGF-β1 group exhibited a significant increase in cell proliferation, whereas treatment with CUR-NPs significantly suppressed TGF-β1-induced cell proliferation. The findings from both the cell scratch assay and transwell assay demonstrated that TGF-β1 substantially enhanced cell migration, while CUR-NPs treatment effectively attenuated TGF-β1-induced cell migration. The Western blot analysis demonstrated a substantial increase in the expression levels of TGF-β1, p-STAT3, and CTGF in ASMCs following treatment with TGF-β1 when compared to the control group. Nevertheless, this effect was effectively counteracted upon administration of CUR-NPs. Furthermore, an asthma mouse model was successfully established and CUR-NPs were administered through tail vein injection. The serum levels of TGF-β1 and the expression levels of TGF-β1, p-STAT3, and CTGF proteins in the lung tissue of mice in the model group exhibited significant increases compared to those in the control group. However, CUR-NPs treatment effectively attenuated this change. Our research findings suggest that CUR-NPs possess inhibitory effects on ASMC proliferation, migration, and inflammatory infiltration by suppressing activation of the TGF-β1/p-STAT3/CTGF signaling pathway, thereby facilitating inhibition of airway remodeling.
研究领域:
药理学
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呼吸病学
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纳米技术
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免疫学
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细胞生物学
✓ 已验证
DOI
PubMed
高影响因子
TOXICOLOGY LETTERS
·
2022
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IF 4.271
Yishuang Luo,Jinyu Kang,Jia Luo,Zheng Yan,Shengtao Li,Zhuoheng Lu,Yufei Song,Xie Zhang,Julin Yang,Aiming Liu
The development of cholestatic liver injury (CLI) involves inflammation, but the dominant pathway mediating the chemotaxis is not yet established. This work explored key signaling pathway mediating chemotaxis in CLI and the role of Kupffer cells in the inflammatory liver injury. Probe inhibitors T-5224 (100 mg/kg) for AP-1 and C188–9 (100 mg/kg) for STAT3 were used to validate key inflammatory pathways in alpha-naphthylisothiocyanate (ANIT, 100 mg/kg)-induced CLI. Two doses of GdCl 3 (10 mg/kg and 40 mg/kg) were used to delete Kupffer cells and explore their role in CLI. Serum and liver samples were collected for biochemical and mechanism analysis. The liver injury in ANIT-treated mice were significantly increased supported by biochemical and histopathological changes, and neutrophils gathering around the necrotic loci. Inhibitor treatments down-regulated liver injury biomarkers except the level of total bile acid . The chemokine Ccl2 increased by 170-fold and to a less degree Cxcl2 by 45-fold after the ANIT treatment. p-c-Jun and p-STAT3 were activated in the group A but inhibited by the inhibitors in western blot analysis . The immunofluorescence results showed AP-1 not STAT3 responded to inhibitors in ANIT-induced CLI. With or without GdCl 3 , there was no significant difference in liver injury among the CLI groups. In necrotic loci in CLI, CXCL2 colocalized with hepatocyte biomarker Albumin, not with the F4/80 in Kupffer cells. Conclusively, AP-1 played a more critical role in the inflammation cascade than STAT3 in ANIT-induced CLI. Hepatocytes, not the Kupffer cells released chemotactic factors mediating the chemotaxis in CLI.
研究领域:
肝病学
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免疫学
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分子生物学
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药理学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
American Journal of Translational Research
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2018
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IF 3.061
Qin Zhu,Peifen Zheng,Xinyu Chen,Feng Zhou,Qiaona He,Yuefeng Yang
Ulcerative colitis (UC) is a chronic and nonspecific intestinal inflammatory disease, which may increase the risk of colon cancer. Andrographolide is a main active component of Andrographis paniculata . The anti-inflammatory ability of andrographolide suggested its potential therapeutic effect against UC. In the present study, elevated serum concentrations of proinflammatory factors, including (TNF)-α, interleukin (IL)-1β, IL-6 and IL-23, as well as increased percentages of Th17 cells (IL-17+CD4+ cells) in CD4+ cells were detected in UC patients compared to that in healthy donors. These data suggested that Th17 immune responses may involve in the pathogenesis of UC. Experimental colitis mouse model was then established. The results of hematoxylin and eosin staining demonstrated the therapeutic effect of andrographolide on colitis. Enzyme-linked immunosorbent assay (ELISA), flow cytometry and western blotting analyses showed that andrographolide could decreased the levels of proinflammatory factors TNF-α, IL-1β, IL-6 and IL-17A in the serum and in the colon tissues, reduced the percentages of Th17 cells in CD4+ cells, and suppressed the levels of IL-23, IL-17A, ROR-γt (key transcription factor of Th17 cells) and p-STAT3 in the colon tissues. Further, peripheral blood mononuclear cells (PBMCs) were isolated from UC patients and treated with various concentrations of andrographolide (0, 10, 20 and 30 μg/ml). Andrographolide also showed inhibitory effects on the levels of proinflammatory factors, the percentages of Th17 cells and the expression of relative proteins. Similar results were obtained in lipopolysaccharide-treated normal PBMCs. These data suggested that andrographolide may inhibit Th17 immune response via STAT3 signaling. In conclusion, we demonstrated that andrographolide inhibited the activity of IL-23/IL-17 axis and down-stream pro-inflammatory factors so as to suppress inflammation response, resulting in the relieving of UC.
研究领域:
免疫学
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药理学
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炎症性肠病
✓ 已验证
DOI
PubMed
高影响因子
International Journal of Medical Sciences
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2017
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IF 2.399
Lin Yu,Xiaofeng Wu,Min Chen,Huarong Huang,Yan He,Huaqian Wang,Dongli Li,Zhiyun Du,Kun Zhang,Susan Goodin,Xi Zheng
Background : Docetaxel is the first-line treatment for castration-resistant prostate cancer (CRPC). The limited survival benefit associated with the quick emergence of resistance and systemic toxicity diminishes its efficacy in high-dose monotherapy. YK-4-279 is a small molecule inhibitor of ETV1 that plays an important role in the progression of prostate cancer. The aim of this study was to evaluate the hypothesis that the combination of docetaxel and YK-4-279 will have a synergistic effect on inhibiting growth and accelerating apoptosis in human prostate cancer cells. Methods : Cell growth assessed using CCK-8 and trypan blue exclusion assays. Cell apoptosis was determined by morphological assessment in cells stained with propidium iodide. Standard scratch migration and Matrigel-coated transwell invasion assays were used to assess cell migration and invasion, respectively. Western blotting was used to investigate the levels of ETV1, AR, PSA, p-STAT3, survivin, Bcl-2, and p-Akt in prostate cancer cells. Results : The combination of low-dose docetaxel and YK-4-279 synergistically inhibited growth and induced apoptosis in human prostate cancer cells. The combination also more efficiently suppressed the migration and invasion of LNCaP and PC-3 cells. The combination of low-dose docetaxel and YK-4-279 caused a stronger decrease in the levels of ETV1, AR, PSA, p-STAT3, survivin, Bcl-2, and p-Akt in LNCaP cells and of p-Akt, Bcl-2, and p-STAT3 in PC-3 cells compared with either drug alone. Conclusions : These data suggest that the combination of docetaxel and YK-4-279 may be an effective approach for inhibiting the growth and metastasis of prostate cancer. This could permit a decrease in the docetaxel dose necessary for patients with CRPC and thereby lower its systemic toxicity.
研究领域:
肿瘤学
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药理学
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分子生物学
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细胞生物学
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产品关联
DOI
PubMed
高影响因子
Journal of Advanced Research
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2022
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IF 12.822
Ying Zhu,Anni Wang,Shuya Zhang,Jisu Kim,Jiaxuan Xia,Fengxue Zhang,Dan Wang,Qi Wang,Jianxin Wang
Introduction Inherent or acquired resistance to paclitaxel (PTX) is a pivotal challenge for chemotherapy treatment of multidrug-resistant (MDR) breast cancer. Although various targeted drug-delivery systems, including nanoparticles and liposomes, are effective for MDR cancer treatment, their efficacy is restricted by immunosuppressive tumor microenvironment (TME). Methods Ginsenosides Rg3 was used to formulate unique Rg3-based liposomes loaded with PTX to establish Rg3-PTX-LPs, which were prepared by the thin-film hydration method. The stability of the Rg3-PTX-LPs was evaluated by particle size analysis through dynamic light scattering. The active targeting effect of Rg3-based liposomes was examined in an MCF-7/T xenograft model by an in a vivo imaging system. To evaluate the antitumor activity and mechanism of Rg3-PTX-LP, MTT, apoptosis assays, TAM regulation, and TME remodeling were performed in MCF-7/T cells in vitro and in vivo. Results Rg3-PTX-LPs could specifically distribute to MCF7/T cancer cells and TME simultaneously, mainly through the recognition of GLUT-1. The drug resistance reversing capability and in vivo antitumor effect of Rg3-PTX-LPs were significantly improved compared with conventional cholesterol liposomes. The TME remodeling mechanisms of Rg3-PTX-LPs included inhibiting IL-6/STAT3/p-STAT3 pathway activation to repolarize protumor M2 macrophages to antitumor M1 phenotype, suppressing myeloid-derived suppressor cells (MDSCs), decreasing tumor-associated fibroblasts (TAFs) and collagen fibers in TME, and promoting apoptosis of tumor cells. Hence, through the dual effects of targeting tumor cells and TME remodeling, Rg3-PTX-LPs achieved a high tumor inhibition rate of 90.3%. Conclusion Our multifunctional Rg3-based liposome developed in the present study offered a promising strategy for rescuing the drug resistance tumor treatment.
研究领域:
药学
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肿瘤学
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纳米技术
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癌症治疗
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产品关联
DOI
PubMed
高影响因子
CHEMICAL ENGINEERING JOURNAL
·
2025
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IF 13.2
Jun Tao,Hui Deng,Zhengnan Li,Liping Cao,Yanfei Rao,Zhanhai Yin
The progression and severity of osteoarthritis (OA) are significantly associated with intra-articular synovitis, with the imbalance of M1/M2 macrophages serving as a critical driving factor in the pathogenesis of synovitis. In this study, we developed macrophage-targeted nanomicelles capable of scavenging reactive oxygen species (ROS) and releasing hydrogen sulfide (H 2 S). These nanomicelles were encapsulated within injectable methacrylate gelatin (GelMA) porous hydrogel microspheres, thereby creating a new H 2 S gas therapy platform for the treatment of osteoarthritis. In vitro experiments demonstrated that GelMA@FPLBD actively targeted macrophages, efficiently removed ROS, and gradually released H 2 S. This process inhibited the expression of phosphorylated extracellular signal-regulated kinase (p-ERK) and phosphorylated signal transducer and activator of transcription 3 (p-STAT3) in activated macrophages, thereby suppressing M1 polarization and promoting M2 polarization, resulting in significant anti-inflammatory effects. In vivo experiments utilizing a destabilization of the medial meniscus (DMM)-induced osteoarthritis (OA) rat model further revealed the anti-inflammatory and cartilage-protective properties of GelMA@FPLBD, effectively mitigating the progression of OA. Therefore, this study indicates that GelMA@FPLBD, functioning as a H 2 S gas therapy platform, holds significant promise for the treatment of osteoarthritis (OA).
研究领域:
药理学
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纳米技术
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骨科
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炎症研究
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产品关联
DOI
高影响因子
CHEMICAL ENGINEERING JOURNAL
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2023
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IF 15.1
Jiale Chen,Zhixiang Mu,Dongfan Chen,Chen Huang,Ting Jin,Lin Li,Youyun Zeng,Qiang Zhou,Yanmei Zhang,Hongli Mao,Hui Deng,Xinkun Shen,Hong Yang,Xiaojun Cai
Smart hydrogel dressings capable of simultaneously highly effective antimicrobial, anti-inflammatory, and promoting re-epithelialization and angiogenesis are urgently needed for the management of diabetic wounds. Herein, a H 2 S-releasing multifunctional hydrogel was developed by utilizing the dynamic Schiff base reaction between carboxymethyl chitosan (CMC) and polyhexamethylene guanidine (PHMG)-modified aldehyde F108 (PFC). Diallyl trisulfide (DATS) was encapsulated into the PFC nanoparticles. Apart from possessing the essential properties necessary for an idealized hydrogel dressing, such as excellent injectability, tissue adhesion, self-healing, and stimulus–response degradation, the [email protected] &CMC also utilized the synergistic effect of the PHMG and DATS to provide an efficient antimicrobial effect; the H 2 S was slowly released from the DATS under the action of GSH and exerted excellent anti-inflammatory effects, by inhibiting the expression of p-ERK and p-STAT3 in activated macrophages, and promoting macrophage polarization to the M2 phenotype. Strikingly, following the completion of the efficient antimicrobial and anti-inflammatory effects, the continuously generated H 2 S further significantly accelerated the proliferation, migration, and vascularization of endothelial cells by extending the activation of the p-p38 and p-ERK1/2. Owing to superior performances, [email protected] &CMC significantly promoted the healing of diabetic wounds induced by streptozotocin with good biocompatibility. This study demonstrates that [email protected] &CMC is a versatile hydrogel dressing with great potential for the management of diabetic wounds.
研究领域:
生物医学工程
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材料科学
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药剂学
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伤口愈合
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糖尿病管理
✓ 已验证
产品关联
DOI
高影响因子
Asian Pacific Journal of Tropical Medicine
·
2019
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IF 1.772
Ni Pan-Li,Tian Shu-Hong,Yang Zhao-Xin,Zhang Jun-Qing,Yang Fan,Zhong Li-Fan,Gan Lian-Fang,Huang Mian-Qing,Huang Ling
Objective: To explore the effect of Feng-liao-chang-wei-kang ( FLCWK ) on acute and chronic gastroenteritis, synergistic effect on the growth inhibitory effect with 5-fluorouracil (5-FU) on colorectal cancer and its underlying mechanisms. Methods: In the in vitro study, HT-29 cells were divided into 5-FU alone, FLCWK alone and coadministration groups. The MTT assay was used to analyze the proliferation of HT-29 cells at 24 h. Flow cytometry was used to observe the apoptosis, cycle of colorectal cancer HT-29 cells at 24 h. In the in vivo experiment, The subcutaneous transplantation tumor model of colorectal cancer HT-29-Luc was established with nude mice. All mice were randomly divided into 5-FU alone, FLCWK alone and coadministration groups according to body weight. During administration, the Interactive Video Information System small animal live imaging system was used to monitor the growth of subcutaneous transplantation in nude mice. The model of colitis-associated colorectal cancer (CACC) was established with BALB/c mice. BALB/c mice were randomly divided into the normal control group, the model control group, and the FLCWK group. At the end of the administration, the pathological status was detected by HE staining. Cell apoptosis of tumor tissue tumor and colon tissues were observed by TUNEL staining and TUNEL green fluorescence. The protein expression of Caspase 3, p-STAT3, Bcl-2, Bax and P-gp in tumor tissues tumor and colon tissues were tested by using immunohistochemical assay. Results: FLCWK and 5-FU coadministration suppressed HT-29 cell viability and induced S phase arrest and apoptosis compared to treatment with 5-FU alone. Furthermore, compared to treatment with 5-FU alone, coadministration of FLCWK and 5-FU obviously reduced tumor volume and weight and induced apoptosis through decreasing p-STAT3 and P-gp and increasing Caspase 3 protein expression in a murine xenograft tumor model. Moreover, the result revealed decreased number and size of tumors following FLCWK protective administration, downregulated p-STAT3 and Bcl-2 levels and upregulated Bax and Caspase 3 expression in mice with CACC. Conclusions: FLCWK has synergistic effects with 5-FU on colorectal cancer by suppressing the STAT3 pathway and downregulating P-gp expression. Furthermore, FLCWK administration suppresses CACC tumorigenesis by inhibiting the STAT3 pathway.
研究领域:
肿瘤学
·
药理学
·
分子生物学
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细胞生物学
✓ 已验证
产品关联
DOI
高影响因子
TOXICOLOGY
·
2024
·
IF 4.8
Ruoyun Dong,Li Li,Hongmei Chang,Guanling Song,Sixiu Liu
Titanium dioxide nanoparticles (TiO 2 NPs) can reduce sperm number, but the mechanisms of defective spermatogenesis induced by TiO 2 NPs have not been studied through cell-cell interactions at present. A kind of biomimetic three-dimensional blood−testis barrier microfluidic chip capable of intercellular communication was constructed with soft lithography techniques, including Sertoli cell (TM4), spermatogonia (GC-1) and vascular endothelial cell units, to study the mechanisms of TiO 2 NPs-induced defective spermatogenesis. TM4 and GC-1 cells cultured in TiO 2 NPs exposure and control chips were collected for transcriptomics and metabonomics analysis, and key proteins and metabolites in changed biological processes were validated. In TM4 cells, TiO 2 NPs suppressed glucose metabolism, especially lactate production, which reduced energy substrate supply for spermatogenesis. TiO 2 NPs also decreased the levels of key proteins and metabolites of lactate production. In GC-1 cells, TiO 2 NPs disturbed chemokine signaling pathways regulating cell proliferation and interfered with glutathione metabolism. The Cxcl13, Stat3 and p-Stat3 levels and cell proliferation rate were decreased, and the GSR, GPX4 and GSH contents were increased in GC-1 cells in chips under TiO 2 NPs treatment. The decrease in energy substrate supply for spermatogenesis and inhibition of spermatogonia proliferation could be the main mechanisms of defective spermatogenesis induced by TiO 2 NPs.
研究领域:
纳米技术
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生殖生物学
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细胞生物学
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分子生物学
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毒理学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Asian Journal of Pharmaceutical Sciences
·
2024
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IF 10.7
Kang Qian,Peng Yang,Yixian Li,Ran Meng,Yunlong Cheng,Lingling Zhou,Jing Wu,Shuting Xu,Xiaoyan Bao,Qian Guo,Pengzhen Wang,Minjun Xu,Dongyu Sheng,Qizhi Zhang
Alzheimer's disease is a neurodegenerative disease induced by multiple interconnected mechanisms. Peptide drug candidates with multi-modal efficacy generated from fusion strategy are suitable for addressing multi-facet pathology. However, clinical translation of peptide drugs is greatly hampered by their low permeability into brain. Herein, a hybrid peptide HNSS is generated by merging two therapeutic peptides (SS31 and S-14G Humanin (HNG)), using a different approach from the classical shuttle-therapeutic peptide conjugate design. HNSS demonstrated increased bio-permeability, with a 2-fold improvement in brain distribution over HNG, thanks to its structure mimicking the design of signal peptide-derived cell-penetrating peptides. HNSS efficiently alleviated mitochondrial dysfunction through the combined effects of mitochondrial targeting, ROS scavenging and p-STAT3 activation. Meanwhile, HNSS with increased Aβ affinity greatly inhibited Aβ oligomerization/fibrillation, and interrupted Aβ interaction with neuron/microglia by reducing neuronal mitochondrial Aβ deposition and promoting microglial phagocytosis of Aβ. In 3 × Tg-AD transgenic mice, HNSS treatment efficiently inhibited brain neuron loss and improved the cognitive performance. This work validates the rational fusion design-based strategy for bio-permeability improvement and efficacy amplification, providing a paradigm for developing therapeutic peptide candidates against neurodegenerative disease.
研究领域:
神经科学
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药理学
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生物技术
·
分子生物学
✓ 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）