LABORATORY INVESTIGATION
·
2019
·Vol. 100
·期 3
·378-386
·
IF 3.684
Lang Ping-Ping,Bai Jie,Zhang Yun-Long,Yang Xiao-Lei,Xia Yun-Long,Lin Qiu-Yue,Li Hui-Hua
Monocyte and adhesion infiltration into the arterial subendothelium are initial steps in hypertension development. The endothelial intercellular adhesion molecule-1 (ICAM-1) has been implicated in the recruitment and adhesion of leukocytes in several cardiac diseases. However, the role of ICAM-1 in angiotensin II (Ang II)-induced hypertension development remains unknown. Hypertension was induced by administering an infusion of Ang II (1000 ng/kg/min) to wild-type (WT) mice treated with an IgG control or ICAM-1 neutralizing antibody (1 and 2 mg/mouse/day, respectively). Blood pressure was determined using the tail-cuff system. Vascular remodeling was assessed by performing a histological examination. Inflammation and reactive oxygen species (ROS) levels were determined by using immunostaining. Vascular dysfunction was assessed by aortic ring assay. The expression of fibrotic markers, cytokines and NOX was evaluated by quantitative real-time PCR analysis. Our results demonstrate that Ang II infusion markedly increased the ICAM-1 level in the aorta. Blocking ICAM-1 with a neutralizing antibody significantly attenuated Ang II-induced arterial hypertension, vascular hypertrophy, fibrosis, macrophage infiltration, and ROS production and improved vascular relaxation. In conclusion, ICAM-1-mediated monocyte adhesion and migration play a critical role in Ang II-induced arterial hypertension and vascular dysfunction. ICAM-1 inhibitors may represent a new therapeutic strategy for the treatment of this disease.
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npj Regenerative Medicine
·
2023
·Vol. 8
·期 1
·1-17
·
IF 7.2
Zhao Chuanrong,Yang Qianru,Tang Runze,Li Wang,Wang Jin,Yang Fangfang,Zhao Jianan,Zhu Juanjuan,Pang Wei,Li Ning,Zhang Xu,Tian Xiao Yu,Yao Weijuan,Zhou Jing
Healing of the cutaneous wound requires macrophage recruitment at the sites of injury, where chemotactic migration of macrophages toward the wound is regulated by local inflammation. Recent studies suggest a positive contribution of DNA methyltransferase 1 (Dnmt1) to macrophage pro-informatory responses; however, its role in regulating macrophage motility remains unknown. In this study, myeloid-specific depletion of Dnmt1 in mice promoted cutaneous wound healing and de-suppressed the lipopolysaccharides (LPS)-inhibited macrophage motility. Dnmt1 inhibition in macrophages eliminated the LPS-stimulated changes in cellular mechanical properties in terms of elasticity and viscoelasticity. LPS increased the cellular accumulation of cholesterol in a Dnmt1-depedent manner; cholesterol content determined cellular stiffness and motility. Lipidomic analysis indicated that Dnmt1 inhibition altered the cellular lipid homeostasis, probably through down-regulating the expression of cluster of differentiation 36 CD36 (facilitating lipid influx) and up-regulating the expression of ATP-binding cassette transporter ABCA1 (mediating lipid efflux) and sterol O-acyltransferase 1 SOAT1 (also named ACAT1, catalyzing the esterification of cholesterol). Our study revealed a Dnmt1-dependent epigenetic mechanism in the control of macrophage mechanical properties and the related chemotactic motility, indicating Dnmt1 as both a marker of diseases and a potential target of therapeutic intervention for wound healing.
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BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
·
2022
·
IF 3.322
Wei Sun,Jing Liu,Renhao Zhao,Teng Yang,Zhichen Zheng,Tongyu Zhang,Guofeng Wang
Background and Purpose: To investigate the biological role of interferon α/β receptor 2 (IFNAR2) in type 1 diabetes (T1D). Methods First, IFNAR2 mRNA and protein expression levels in serum of T1D patients and healthy controls were detected by RT-qPCR and Western blot . For experimental studies, 80 male C57BL/6 mice were randomly divided into 4 groups with 20 mice in each group: the control group, the T1D group, the T1D + ad-con group and the T1D + ad-si-IFNAR2 group. The T1D mouse model was generated by multiple intraperitoneal injections of small doses of streptozotocin (STZ). Body weight and blood glucose levels were measured weekly until 6 weeks. After 6 weeks, all mice were sacrificed and the levels of insulin (Ins), tumor necrosis factor α (TNF-α), interleukin 4 (IL-4), IL-6, and type I interferon γ (IFN-γ), IFNAR2 protein expression, the number of dendritic cells (DCs), and changes in islet β cells were assessed. Results IFNAR2 mRNA and protein expression levels in serum of T1D patients were significantly higher than those in healthy controls ( P < 0.05). Furthermore, IFNAR2 protein expression, number of DCs, and IFNAR2 mRNA, blood glucose, TNF-α, and IFN-γ levels were significantly upregulated in T1D mice compared with the control group ( P < 0.05), while weight, and Ins, IL-6, and IL-4 levels were decreased ( P < 0.05). However, knockdown of IFNAR2 reversed these trends. There was no significant difference in markers between the T1D + ad-con group and the T1D group ( P > 0.05). Conclusions Knockdown of IFNAR2 reduced the inflammatory response and improved islet function of T1D mice.
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ACS Omega
·
2025
·
IF 4.3
Komal Hayat,Danwen Qiu,Yuanyuan Wang,Palmer Sivoko Imbenzi,Faez Iqbal Khan,Magdalini Matziari
In the search for effective HIV-1 protease inhibitors, the design of symmetrical phosphinic pseudopeptides derived from a dual addition of hypophosphorous acid to acrylates (PACs) has emerged as a promising strategy due to their nonhydrolyzable nature and high affinity for this protease. In this study, we report the synthesis, in vitro evaluation, and docking studies of a series of new symmetrical phosphinic inhibitors, synthesized via simple and cost-effective procedures. This approach overcomes the complexities of previous methods and utilizes commercially or readily available reagents. The synthesized PACs, featuring various P2 and P2’ substituents, have been evaluated for their inhibitory activity against the HIV-1 protease. Among them, the PAC-Phe-Val derivative (9c) demonstrated potent inhibition, with an IC50 value of 33 nM, comparable to the FDA-approved Darunavir. Resolution of the isomers of 9c revealed the most potent candidate, with an IC50 value of 1 nM. Molecular docking studies revealed strong hydrogen bonding interactions between PAC-Phe-Val and key active site residues, suggesting a stable and effective binding profile. The compound’s structure–activity relationship (SAR) was explored, identifying crucial features for its inhibitory potency. This work highlights the potential of symmetrical phosphinic pseudopeptides as HIV-1 protease inhibitors and provides a foundation for further development of these compounds as novel antiretroviral therapies. Future research will focus on optimizing the pharmacokinetic properties and evaluating resistance profiles, aiming to advance the next generation of HIV treatments.
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Foods
·
2025
·Vol. 14
·期 24
·4323
·
IF 5.1
Yazhen Liu,Jiaqi Huang,Ji Yu,Luxin Fu,Ronglong Huang,Jing Liu,Bailin Deng,You-Bao Zhong,Duanyong Liu,Haimei Zhao
(1) Background: Ulcerative colitis (UC) is a persistent inflammatory condition of the intestine, characterized by dysregulated T cell-mediated immune responses. Curcumin (CUR), a common food additive and health supplement, is noted for possessing anti-inflammatory and immunomodulatory properties. Nevertheless, the molecular mechanisms underlying its therapeutic effects remain incompletely elucidated. This research aims to investigate the therapeutic mechanisms of CUR in UC, focusing on its role in restoring T cell homeostasis by modulating TIGIT and Neuropilin-1 (NRP1). (2) Methods: We employed a DSS-induced murine colitis model, combined with network pharmacology, molecular docking, protein–protein interaction docking, molecular dynamics simulations, andinvitroassays with Jurkat T cells. (3) Results: CUR markedly ameliorated clinical manifestations and histopathology in DSS-treated mice, restoring the balance of T cell and memory T cell subsets. Computational predictions and experimental validation showed that CUR downregulated TIGIT and NRP1 expression in inflamed colonic tissue and directly inhibited their expression in activated T cellsinvitro. (4) Conclusions: This study reveals a novel immunoregulatory mechanism of this natural compound. These findings suggest CUR modulates TIGIT/NRP1 to inhibit excessive T cell activation and restore immune homeostasis in UC.
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CANCER LETTERS
·
2017
·
IF 6.375
Weishan Zhuge,Ruijie Chen,Katanaev Vladimir,Xidan Dong,Khan Zia,Xiangwei Sun,Xuanxuan Dai,Miao Bao,Xian Shen,Guang Liang
Colon cancer is one of the leading causes of cancer-related deaths. A natural sesquiterpene lactone, costunolide (CTD), showed inhibition of cancer development. However, the underlying mechanisms are not known. Here, we have examined the therapeutic activity and novel mechanisms of the anti-cancer activities of CTD in colon cancer cells. Using SPR analysis and enzyme activity assay on recombinant TrxR1 protein, our results show that CTD directly binds and inhibits the activity of TrxR1, which caused enhanced generation of ROS and led to ROS-dependent endoplasmic reticulum stress and cell apoptosis in colon cancer cells. Overexpression of TrxR1 in HCT116 cells reversed CTD-induced cell apoptosis and ROS increase. CTD treatment of mice implanted with colon cancer cells showed tumor growth inhibition and reduced TrxR1 activity and ROS level. In addition, it was observed that TrxR1 was significantly up-regulated in existing colon cancer gene database and clinically obtained colon cancer tissues. Our studies have uncovered the mechanism underlying the biological activity of CTD in colon cancer and suggest that targeting TrxR1 may prove to be beneficial as a treatment option.
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Frontiers in Molecular Neuroscience
·
2020
·
IF 4.057
Chen Rong,Cao Xing,Luo Wenxiu,Yang Haodi,Luo Xinya,Yu Juming,Luo Jiaming
Multiple sclerosis (MS) is an inflammatory autoimmune disease affecting the central nervous system (CNS) that currently does not have any effective treatment. Experimental autoimmune encephalomyelitis (EAE) is often employed as a model to mimic the clinical manifestations of MS, mainly CNS demyelination. Coagulation is known to participate in crosstalk with inflammation and autoimmunity. We herein explored the correlation between the coagulation cascade and CNS immune diseases in vitro using primary astrocytes isolated from mice and in vivo using a mouse model of EAE. We showed that dabigatran, a clinical oral anti-coagulant drug, suppressed the thrombin-induced activation of astrocytes, and the underlying mechanisms are related to the activity of protease-activated receptor-1 (PAR-1), sphingosine-1-phosphate (S1P), and sphingosine kinases (SphKs). Importantly, dabigatran effectively recovered neurological function, reduced inflammation in the spinal cord, and prevented spinal cord demyelination caused by EAE. We suggest that dabigatran, a specific inhibitor of thrombin, antagonized the effect of thrombin in astrocytes by limiting the activation of PAR-1, in turn downregulating SphK1 and disrupting S1P receptor signaling. These findings reveal critical information about the relationship between coagulation mechanisms and CNS immune diseases and will contribute to the clinical translation and development of therapeutic strategies against MS.
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BIOMEDICINE & PHARMACOTHERAPY
·
2020
·
IF 4.545
Tian Lan,Lihang Zhuang,Shengwen Li,Guizhi Yang,Yuanyuan Xuan,Jiao Guo
Sphingosine kinase 1 (SphK1) plays critical roles in the activation of hepatic stellate cells (HSCs) and liver fibrosis. Our previous study found that polydatin ameliorates chronic liver injury and fibrosis by inhibiting oxidative stress. However, whether polydatin exerts an anti-fibrotic effect on liver fibrosis dependent on SphK1 signaling is unknown. We aimed to investigate the role of polydatin in SphK1, which mediates HSC activation and liver fibrosis. C57BL/6 mice were induced using CCl 4 5 μL g −1 i.p. twice a week for 6 weeks and treated with or without polydatin. Human immortalized HSC line (LX-2) was induced using platelet-derived growth factor-BB (PDGF-BB) or adenovirus-SphK1 and treated with polydatin. Hepatic macrophage filtration, collagen deposition, expression of α-smooth muscle, active caspase-3, and terminal deoxynucleotidyl transferase dUTP nick end labeling-positive cells were markedly increased in mice induced by CCl 4 for 6 weeks. In contrast, polydatin attenuated collagen synthesis and hepatocyte apoptosis. Furthermore, polydatin exhibited significant anti-proliferative activity against PDGF-BB-induced activated hepatic stellate cells (HSCs). SphK1 was strongly induced in mice exposed to CCl 4 , whereas its expression and activity were inhibited by polydatin treatment. Finally, SphK1 overexpression in LX-2 cells promoted proliferation of activated HSCs, which could not be reversed by polydatin treatment. These results demonstrate that polydatin attenuates HSC proliferation and activation through inhibition of SphK1 signaling, contributing to the suppression of liver fibrosis.
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Kidney360
·
2025
·
IF 3
Li Jiachang,Ma Yuhan,Wang Yanni,Chen Yizhi,Wei JiaLi
Plain Language Summary Background: Hyperuricemia is a common metabolic disorder and a risk factor for multiple diseases, including CKD. Hyperuricemic nephropathy (HN) affects many individuals with hyperuricemia, yet its molecular mechanisms are not fully understood, and effective treatments are lacking. Methods: In vitro, human tubular epithelial cells (HK-2) were exposed to uric acid for 36 hours, followed by transfection with microRNA mimic or FIH-1 siRNA. In vivo, HN was induced in mice using potassium oxonate (PO) and adenine (Ad) for two weeks. miR-295 mimic or anti-miR-295 was administered via tail vein injection, and mice were sacrificed for analysis. Results: We demonstrated a significant increase of miR-295 in renal tubular cells in HN mice. Hyperuricemia led to the activation of hypoxia inducible factor-1α (HIF-1α), and inhibition of HIF-1α by YC-1 (a HIF-1α inhibitor) prevented the increase of miR-295. ChIP assay further verified HIF-1α binding to the miR-295 gene promoter directly. Functionally, Inhibition of miR-295 led to increased cell death and tubulointerstitial fibrosis in HN mice, whereas supplementation of miR-295 mimic had kidney protective effects in this model. miR-295 suppressed the expression of factor inhibiting hypoxia-inducible factor-1 (FIH-1) in both in vitro and in vivo models of HN. Luciferase microRNA target reporter assay further verified FIH-1 as a direct target of miR-295.In addition, knockdown of FIH-1 inhibits tubular cell apoptosis and profibrotic cytokines production in HK2 cells during uric acid treatment. Conclusions: This study reveals a HIF-1α/miR-295/FIH-1 positive feedback loop that regulates tubular damage and fibrosis in HN. Plain Language Summary This study explores the molecular mechanisms of hyperuricemic nephropathy (HN), a kidney condition linked to high uric acid levels. Researchers found that in mice with HN, the microRNA miR-295 increased in kidney cells. The study identified a feedback loop involving miR-295, HIF-1α, and FIH-1, where HIF-1α activates miR-295, which then suppresses FIH-1. Inhibition of miR-295 led to increased cell death and fibrosis, while supplementation with miR-295 mimic had protective effects against kidney damage. Inhibiting HIF-1α prevented miR-295 increase. These findings suggest potential therapeutic targets for treating HN by modulating this molecular pathway. Text is machine generated and may contain inaccuracies. FAQ
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Journal of Materials Chemistry B
·
2020
·Vol. 9
·期 3
·648-657
·
IF 5.344
Yujie Zhang,Mingxin Wu,Di Tan,Quan Liu,Re Xia,Min Chen,Yuangang Liu,Longjian Xue,Yifeng Lei
Diabetes and its complications have become crucial public health challenges worldwide. In this study, we aim to develop a dissolving and glucose-responsive insulin-releasing microneedle (MN) patch system, for minimally invasive and glucose-responsive insulin delivery for type 1 diabetes therapy. The MNs were composed of dissolving and biodegradable gelatin and starch materials, which encapsulated glucose-responsive insulin-releasing gold nanocluster (AuNC) nanocarriers. The fabricated MNs had a complete and uniform structure, consisting of an array of 11 × 11 conical needles, with a needle height of 756 μm, a bottom diameter of 356 μm, a tip diameter of 10 μm, and a tip-to-tip distance of 591 μm. The encapsulated AuNC nanocarriers as additives in the MNs enhanced the mechanical strength of the MNs, and facilitated the penetration of the MNs into the skins of mice. Moreover, the AuNC nanocarrier drugs in the MNs enabled MN patches with a glucose-responsive insulin releasing behavior. With one transdermal application of MN patches on the dorsal skin of mice, the MN patches effectively regulated the BG levels of mice in normoglycemic ranges for 1 to 2 days, and effectively alleviated the diabetic symptoms in type 1 diabetic mice. This dissolving and glucose-responsive insulin-releasing MN patch system realized a closed-loop administration of insulin with minimal invasion, providing great potential applications for type 1 diabetes therapy.
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INTERNATIONAL BIODETERIORATION & BIODEGRADATION
·
2022
·
IF 4.907
Zhuang Ke,Shen Wang,Weixian Dai,Weibin Jia,Yang Mu,Jiandong Jiang,Kai Chen
Plasmids disseminate pollutant-catabolic genes through horizontal transfer and contribute to the catabolic potential of the host microbial community . Genetic bioaugmentation of conjugative catabolic plasmids has recently been considered an effective and novel approach for long-term bioremediation of contaminated sites. In this study, we engineered an IncP-1 β -2 subgroup plasmid pDCA-1 from Achromobacter sp. ANB-1 for its potential application in genetic bioaugmentation. A dcaA1A2B cluster responsible for the deamination of chloroaniline to chlorocatechol and a 1,2-dioxygenase gene ( ccdC ) for the ring cleavage of chlorocatechol were found to locate on the broad host range plasmid pDCA-1. Insertion of an amidase gene ( phh or tccA2 ) at the accessory region of plasmid pDCA-1 greatly expanded its catabolic substrate spectrum from chloroaniline (3-chloroaniline and 3,4-dichloroaniline) to herbicides (linuron, propanil, propham, and chlorpropham), bacteriostatic agent (triclocarban), plant regulator (forchlorfenuron), and insecticide (diflubenzuron). Taking advantages of high-throughput cell sorting and 16S rRNA gene-based amplicon sequencing, we depicted the diversity of bacterial recipients for the engineered plasmid pDCA-1- gfp-phh in a soil bacterial consortium, showing an excellent conjugative transfer capacity of the pDCA-1 derivative to various Gram negative and even positive strains in natural environment. All in all, the engineered plasmid pDCA-1 had a great potential in genetic bioaugmentation of the sites contaminated with chloroanilines and their derivatives.
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CRYSTENGCOMM
·
2017
·Vol. 19
·期 17
·2349-2358
·
IF 3.474
Yu-Peng Zhou,Zhang-Wen Wei,Zhuo-Jia Lin,Hui-Tao Ling,Zhengang Guo,Mei Zhang,Chi-Keung Lam,Bao-Hui Ye,Hsiu-Yi Chao
With the idea of supramolecular hosts encircling monoanions, a series of urea-containing trinuclear cationic copper complexes were designed, prepared and structurally analyzed. Copper(I) acetylides [Cu3(μ-dppm)3(μ3-η1-CCC6H4-4-NHC(O)NHC6H4-4-R)2]+ (dppm = bis(diphenylphosphino)methane; R = NO2 (1), CF3 (2), Cl (3), H (4), tBu (5), and OCH3 (6)) were prepared with F−, BF4−, or NO3− present as the anion. Eight 1-D anion coordination polymers (ACPs), 1·F, 2·F, 3·BF4, 4·F, 5·F, 5·BF4, 5·NO3 and 6·0.5F·0.5BF4, were clearly determined by X-ray diffraction. Diversity in the polymeric architecture is generated by both the choice of R-group used and anion present. 2·F, 3·BF4, 4·F, and 5·F show linear 1-D structures; 5·BF4 and 5·NO3 feature single-stranded helical structures; 1·F and 6·0.5F·0.5BF4 exhibit meso-helical structures. Solid state UV-vis absorption and luminescence properties are also discussed.
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