羟基红花红色素A抑制氧化应激和细胞凋亡改善OGD/R诱导的HT22细胞损伤

目的探讨羟基红花红色素A(HSYA)对氧糖剥夺/复糖复氧(OGD/R)损伤小鼠海马神经元(HT22)细胞的保护作用及其作用机制。方法体外培养HT22细胞,随机分为5组,分别为正常组,OGD/R组,HSYA低、中、高给药组(浓度分别为40、60、80 μmol·L-~1)。除正常组外,其余各组细胞在氧糖剥夺6 h后迅速复糖复氧12 h进行OGD/R造模并分组给药。采用CCK8法检测HT22细胞活力,倒置显微镜观察HT22细胞形态。试剂盒检测LDH、NO、GSH、MDA、SOD水平。采用Hoechst染色和流式细胞术检测HT22细胞凋亡情况,ELISA检测CytC释放情况,Western blot检测Bax、Bcl-2和cleaved-caspase3的蛋白表达情况,qRT-PCR检测Bax和Bcl-2的mRNA水平。结果与OGD/R组相比,HSYA低、中、高给药组细胞存活率显著升高(P<0.05,P<0.01),细胞形态显著改变,HT22细胞LDH、NO、MDA及细胞凋亡率显著降低,SOD和GSH水平升高(P<0.05,P<0.01),胞浆内CytC释放量显著降低(P<0.01),Bax的蛋白表达和mRNA水平显著降低,Bcl-2的蛋白表达和mRNA水平显著升高,cleaved-caspase3的蛋白表达降低(P<0.05,P<0.01)。结论 HSYA通过抑制氧化应激和细胞凋亡改善OGD/R诱导的HT22细胞损伤。     

LncRNA MIAT靶向 miR-204对氧糖剥夺 /复氧诱导 PC12细胞损伤的保护作用

目的 探究氧糖剥夺/复氧（OGD/R）诱导大鼠肾上腺髓质嗜铬瘤分化细胞株PC12细胞损伤的分子调控机制,以期为临床上靶向治疗缺血性卒中提供新的思路。方法 该研究于2021年6—12月进行,购买PC12细胞后对其进行OGD/R诱导,在诱导后的细胞中分别转染长链非编码RNA(LncRNA)心肌梗死相关转录本（MIAT）过表达载体及微RNA-204模拟物（miR-204mimic）,以对应的载体阴性对照（pcDNA3.1-NC）或模拟物阴性对照（mimic-NC）作为阴性对照,以未转染PC12细胞作为空白对照。使用实时荧光定量聚合酶链式反应（qRT-PCR）检测LncRNA MIAT与miR-204的表达;CCK-8与流式细胞术分别检测细胞活力与凋亡;Elisa试剂盒检测炎性因子白细胞介素（IL）-6、IL-1β,抗炎性因子IL-10的表达。RNA下拉检测MIAT在miR-204上的富集;通过starbase预测LncRNA MIAT与miR-204的结合位点,随后采取双萤光素酶报告实验验证LncRNA MIAT与miR-204的靶向结合。结果 与空白对照组[1.011±0.113,1.00...     

虎杖苷通过TLR4/NF-κB信号通路调控糖尿病肾病大鼠肾脏炎症作用的研究

目的：研究虎杖苷通过TLR4/NF-κB信号通路调控糖尿病肾病大鼠肾脏炎症作用的影响。方法：通过尾静脉注射链脲佐菌素,高脂饲料喂养建立糖尿病肾病大鼠模型。将成模的大鼠随机分为模型组、缬沙坦组（20 mg·kg^-1）、虎杖苷组（75 mg·kg^-1）、虎杖苷组（150 mg·kg^-1）,每组10只,日常进行高脂饮食喂养,连续灌胃给药90 d,每日1次。于第90天采集尿液,测量尿量及终点法测24 h尿白蛋白（UP）含量。通过HE染色观察大鼠肾脏组织的病理学变化。采用ELISA法检测肾组织中TGF-β1、FN纤维化指标表达及肾脏组织中炎症因子肿瘤坏死因子（TNF-α）、白介素-1β（IL-1β）、白介素-6（IL-6）的含量。Western blot法检测肾组织中Toll样受体4（TLR4）、髓样分化因子（Myd88）、核转录因子kappa B（NF-κB）的表达。结果：与模型组相比,虎杖苷组大鼠Scr、BUN、UP含量显著降低（P<0.05）。TGF-β1、FN纤维化指标明及炎症因子TNF-α、IL-1β、IL-6含量显减少（P<0.05）,TLR4、Myd88、NF-κB蛋白表达显著降低（P<0.05）。结论：虎杖苷对糖尿病肾病所引起的肾脏炎症有一定的保护作用,其作用机制可能与调节TLR4/NF-κB信号通路,降低肾脏组织的炎症因子含量,而起到抗炎的保护作用有关。     

A new compound W026B alleviates ischemic brain injury through inhibiting the production of inflammatory cytokines in pMCAO and tMCAO,and enhances the beneficial effect of tPA

Neruoprotection is considered as one of important therapeutic approaches forischemic stroke. Inflammation plays an important role in the pathogenesis of ischemic stroke, and the inhibition of inflammation in the ischemic brain tissue may provide neuroprotective effect. In this study, we observed the influence of permanent middle cerebral artery occlussion (pMCAO) and transient MCAO (tMCAO) on NF-κB level and production of several inflammatory cytokines in injured hemisphere in mice, investigated the regulative effect of a new compound W026B on these influences in the two MCAO models. In pMCAO model, 10 μg/kg and 100 μg/kg of W026B (i.v.) significantly reduced infarct volumes, 100 μg/kg of W026B significantly decreased neurologic deficit scores and brain water contents, and 10 μg/kg and 100 μg/kg of W026B reduced Evans blue exudation from ischemic brain tissue. The level of NF-κB was elevated by 17.6 times in injured hemisphere, and the levels of TNF-α, IL-1β and IL-17 were elevated by 2.3 times, 2.2 times and 3.8 times compared with the sham operation group, respectively, 100 μg/kg of W026B significantly reduced these inflammatory cytokines. In tMCAO model, the elevation of NF-κB, TNF-α, IL-1β and IL-17 was 2.3 times, 1.4 times, 1.5 times and 1.4 times compared with the sham operation group, respectively. Moreover, 100 μg/kg of W026B significantly decreased the levels of these inflammatory cytokines. In embolic MCAO mice model, W026B alone significantly reduced infarct volumes, and combined application with tPA further reduced infarct volume. In conclusion, W026B displayed significant protecive effect on three brain ischemia models. It could protect brain against injury induced by ischmia and ischemia-reperfusion through inhibiting the production of NF-κB, TNF-α, IL-1β and IL-17. These results suggest that W026B has a value for further study.     

溪黄草水提物对高糖诱导的大鼠HBZY-1细胞炎症反应和氧化应激的抑制作用以及对TLR 4/NF-κB/NLRP 3通路的作用

目的：溪黄草水提物（RWE）对高糖诱导的大鼠HBZY-1细胞炎症反应和氧化应激的抑制作用以及对TLR 4/NF-κB/NLRP 3通路的作用。方法：用高糖（HG,30 mmol·L^-1）孵育大鼠肾小球细胞株HBZY-1细胞,MTT法测定不同浓度RWE（5,10,20 mg·mL^-1）对HG环境下HBZY-1细胞增殖的影响,测定RWE对HG诱导的HBZY-1细胞氧化应激水平和炎性细胞因子表达的影响,同时测定其对细胞TLR4/NF-κB/NLRP3信号通路的影响。结果：HG能诱导HBZY-1细胞增殖,提高MDA、IL-6、IL-1β、TNF-α水平和TLR 4/NF-κB/NLRP 3信号通路的表达,降低SOD和GSH水平;RWE减弱细胞的增殖能力,降低MDA、IL-6、IL-1β和TNF-α的水平,提高SOD和GSH水平,抑制TLR 4/NF-κB/NLRP 3信号通路的表达。结论：RWE对HG诱导的HBZY-1细胞具有保护作用,其作用机制主要是抑制炎症反应和氧化应激,TLR 4/NF-κB/NLRP 3信号通路可能参与RWE对细胞的保护作用。     

Melatonin alleviates intestinal injury,neuroinflammation and cognitive dysfunction caused by intestinal ischemia/reperfusion

Intestinal ischemia/reperfusion (I/R) can cause multiple organ damage with extremely high morbidity and mortality. Melatonin has anti-inflammatory, anti-oxidative and anti-apoptotic effects against various diseases. This study aimed to explore whether melatonin had a protective effect against intestinal I/R-induced neuroinflammation and cognitive dysfunction, and investigate its potential mechanisms. In this study, melatonin was administered to the rats with intestinal I/R, then histological changes in intestine and brain (frontal cortex and hippocampal CA1 area) tissues and cognitive function were detected, respectively. The encephaledema and blood–brain barrier (BBB) permeability were observed. Moreover, the alterations of proinflammatory factors (tumor necrosis factor-α, interleukin-6 and interleukin-1β), oxidative response (malondialdehyde, superoxide dismutase, and reactive oxygen species), apoptosis and proteins associated with inflammation, including Toll-like receptor 4 (TLR4), myeloid differentiation factor 88 (Myd88) and phosphorylated nuclear factor kappa beta (NF-κB), and apoptosis (cleaved caspase-3) in brain tissues were examined. Furthermore, the expressions of TLR4, Myd88, and microglial activity were observed by multiple immunofluorescence staining. The results showed that intestinal I/R-induced abnormal neurobehavior and cerebral damage were ameliorated after melatonin treatment, which were demonstrated by improved cognitive dysfunction and aggravated histology. Furthermore, melatonin decreased the levels of proinflammatory factors and oxidative stress in plasma, intestine and brain tissues, attenuated apoptotic cell, and inhibited the expressions of related proteins and the immunoreactivity of TLR4 or Myd88 in microglia in brain tissues. These findings showed that melatonin might relieve neuroinflammation and cognitive dysfunction caused by intestinal I/R, which could be, at least partially, related to the inhibition of the TLR4/Myd88 signaling in microglia.     

Albiflorin attenuates inflammatory injury by regulating the TLR4 signaling pathway and its negative regulating factor Tollip in experimental models of ulcerative colitis

Albiflorin (AF) is the main active component extracted from Paeoniae Radix Alba. This study investigated the efficacyof AF in attenuating inflammatory injury by regulating the TLR4 signaling pathway and its negative regulating factor Tollip in an experimental ulcerative colitis (UC) model. We administrated trinitrobenzene sulfonic acid for 21 d to induce UC in rats. The efficacy of AF in attenuating UC was assessed using various biochemical markers, such as tumor necrosis factor-α (TNF-α), interleukin-1 (IL-1), interleukin-10 (IL-10), 5-hydroxytryptamine (5-HT), and tissue myeloperoxidase (MPO), along with histopathological studies on toll-like receptor-4 (TLR-4) signaling pathway and its negative regulating factor Tollip. The results showed that AF can significantly downregulate the levels of TNF-α, IL-1, IL-10, and 5-HT. AF decreased the activation of TLR4, MyD88, and NF-κB p65 protein expression by increasing Tollip expression. AF can relieve symptoms of UC by suppressing the activation of the TLR4 signaling pathway and upregulating its negative regulating factor Tollip. Therefore, AF may be a potential natural product for treating UC.     

Xiao-Xu-Ming decoction extract alleviates LPS-induced neuroinflammation associated with down-regulating TLR4/MyD88 signaling pathway in vitro and in vivo

In the present study, we aimed to investigate the effects of Xiao-Xu-Ming decoction extract (XXM) on lipopolysaccaride (LPS)-induced neuroinflammation invitro and invivo. Invitro, the microglia BV2 cells were treated with 200 ng/mL LPS for 24 h to induce inflammatory responses. Invivo, mice were treated with 5 mg/kg LPS to induce inflammatory responses. The NO level was determined by Griess Reagents. The levels of IL-1β, IL-6, TNF-α and MCP-1 were determined by ELISA. The expressions of Iba-1, TLR4 and MyD88 at the protein levels were determined by Western blotting analysis. The mRNA levels of TLR4 and MyD88 were determined by real-time PCR. Invitro, XXMsignificantly reduced the levels of various pro-inflammatory factors, including NO, IL-1β, IL-6 and TNF-α, induced by LPS in the supernatant of BV2 cells and suppressedexpressions of inflammatory proteins TLR4 and MyD88 induced by LPS in BV2 cells. Invivo, XXM significantly inhibited microglia activation, attenuated LPS-induced inflammatory factors and chemokine production, such as IL-1β, IL-6, TNF-α and MCP-1, andinhibited the expressions of inflammatory proteins including TLR4 and MyD88, in the cortex of LPS-induced mice. Our findings suggested that XXM could attenuate LPS-induced neuroinflammation via down-regulating TLR4/MyD88 signaling pathway.     

瑞舒伐他汀对慢性阻塞性肺疾病大鼠气道炎症的抑制作用及对TLR4/NF-κB信号通路的影响

目的：分析瑞舒伐他汀对慢性阻塞性肺疾病（COPD）大鼠气道炎症的抑制作用及对TLR4/NF-κB信号通路的影响。方法：利用烟熏及气道灌入脂多糖的方法建立大鼠COPD模型。60只SD大鼠随机分为对照组（n=20）、COPD组（n=20）、瑞舒伐他汀组（n=20）。瑞舒伐他汀组大鼠5.0 mg·kg^-1的瑞舒伐他汀,每日灌胃1次。检测各组大鼠的肺功能指标如肺活量（FVC）、呼气峰值流速（PEF）以及0.1 s呼气量（FEV0.1）及肺组织病理变化。酶联免疫吸附法检测血清白细胞介素（IL）-6、IL-8与肿瘤坏死因子（TNF）-α含量。Western印迹法检测肺组织NF-κB、黏附分子1、黏蛋白5AC、TLR4蛋白表达。荧光定量PCR法检测肺组织NF-κB、黏附分子1、黏蛋白5AC、TLR4 mRNA表达。结果：COPD组各项肺功能指标显著低于对照组（P<0.05）,瑞舒伐他汀组显著高于COPD组（P<0.05）。显微镜下观察,对照组肺泡组织结构正常。COPD组肺泡壁显著变薄,且肺泡出现破裂、融合,肺大疱形成,周围可见炎细胞浸润。瑞舒伐他汀组肺损伤明显轻于COPD组。COPD组IL-6、IL-8与TNF-α的含量显著高于对照组（P<0.05）,而瑞舒伐他汀组显著低于COPD组（P<0.05）。COPD组大鼠肺组织中黏附分子1、黏蛋白5AC、NF-κB及TLR4蛋白及mRNA水平均显著高于对照组（P<0.05）,而瑞舒伐他汀组显著低于对照组（P<0.05）。结论：瑞舒伐他汀可有效降低COPD大鼠气道炎性反应,其机制可能与降低NF-κB及TLR4表达,抑制TLR4/NF-κB信号通路活性,并降低黏液蛋白的高分泌状态,减轻气道炎性介质的释放有关。     

Maresin 1 alleviates dextran sulfate sodium-induced ulcerative colitis by regulating NRF2 and TLR4/NF-kB signaling pathway

ObjectiveUlcerative colitis (UC) is one of the most common gastrointestinal diseases, characterized as a chronic, relapsing inflammation that causes damage to the colonic mucosa. Maresin 1 (MaR1), a specialized proresolving mediator, has powerful anti-inflammatory activity that prevents the occurrence of various inflammatory diseases. The aim of this study was to explore the role and potential mechanism of MaR1 in DSS-induced ulcerative colitis.MethodsIn the present study, we established dextran sulfate sodium (DSS)-induced ulcerative colitis rat model in vivo. Rats with colitis received tail vein injection of MaR1, with or without intraperitoneal injection of ML385. The changes of body weight, colon length, disease activity index (DAI), colonic histopathology, inflammatory cytokines, the activity of myeloperoxidase (MPO) and reactive oxygen species (ROS), and infiltration of macrophages expressing F4/80 were analyzed for the evaluation of colitis severity. In addition, protein expressions were detected using western blot.ResultsMaR1 significantly reduced inflammatory cytokines production, and restored body weight, DAI and colonic histopathology. Besides, MaR1 improved the expression of tight junction (TJ) proteins and reduced the infiltration of neutrophil and macrophages, as well as a decreased activity of MPO and ROS. Meanwhile, MaR1 activated Nrf2 signaling and decreased toll-like receptor 4(TLR4)/nuclear factor-κB(NF-κB) activation. Furthermore, ML385, an inhibitor of Nrf2, significantly reversed the protective effect of MaR1.ConclusionMaR1 play a protective role in DSS-induced colitis by activating Nrf2 signaling and inactivating Nrf2-mediated TLR4/NF-κB signaling pathway, which mediate proinflammatory mediators and intestinal TJ proteins in rats, providing novel insights into the therapeutic strategy of colitis.     

MSCs 通过调控巨噬细胞极化维持 TBI 后免疫稳态的研究进展

摘要： 间充质干细胞 （MSCs） 是当前细胞治疗的研究热点, 其不仅具有多向分化潜能, 还能够调节颅脑创伤 （TBI）后组织损伤引发的炎症反应。继发于单纯机械损伤的神经炎症是引起神经细胞坏死和凋亡的重要因素, 即使在颅内压恢复正常后, 炎症反应仍持续造成神经细胞坏死。创伤后的炎症环境严重影响 TBI 患者的长期预后及行为功能恢复。MSCs 通过释放可溶性细胞因子, 如前列腺素 E2 （PGE2）、 肿瘤坏死因子刺激基因 6 蛋白 （TSG-6）、 白细胞介素 （IL） -1 和转化生长因子 （TGF） -β 等, 调节巨噬细胞/小胶质细胞的极化特性, 使其向抗炎型 M2 细胞极化, 减少促炎因子释放, 限制其对下游效应细胞的激活, 维持颅内免疫环境稳定。同时, MSCs 在一定条件下促进巨噬细胞/小胶质细胞向 M1 细胞极化, 激活组织修复和再生。巨噬细胞/小胶质细胞形成的免疫微环境也影响 MSCs 的存活和功能发挥, 两者相互影响, 为临床治疗TBI 继发炎症反应提供了新的思路。     

Resveratrol pretreatment alleviates NLRP3 inflammasome-mediated cardiomyocyte pyroptosis by targeting TLR4/MyD88/NF-κB signaling cascade in coronary microembolization-induced myocardial damage

Percutaneous coronary intervention and acute coronary syndrome are both closely tied to the frequently occurring complication of coronary microembolization (CME). Resveratrol (RES) has been shown to have a substantial cardioprotective influence in a variety of cardiac diseases, though its function and potential mechanistic involvement in CME are still unclear. The forty Sprague–Dawley rats were divided into four groups randomly: CME, CME + RES (25 mg/kg), CME + RES (50 mg/kg), and sham (10 rats per group). The CME model was developed. Echocardiography, levels of myocardial injury markers in the serum, and histopathology of the myocardium were used to assess the function of the cardiac muscle. For the detection of the signaling of TLR4/MyD88/NF-κB along with the expression of pyroptosis-related molecules, ELISA, qRT-PCR, immunofluorescence, and Western blotting were used, among other techniques. The findings revealed that myocardial injury and pyroptosis occurred in the myocardium following CME, with a decreased function of cardiac, increased levels of serum myocardial injury markers, increased area of micro-infarct, as well as a rise in the expression levels of pyroptosis-related molecules. In addition to this, pretreatment with resveratrol reduced the severity of myocardial injury after CME by improving cardiac dysfunction, decreasing serum myocardial injury markers, decreasing microinfarct area, and decreasing cardiomyocyte pyroptosis, primarily by blocking the signaling of TLR4/MyD88/NF-κB and also reducing the NLRP3 inflammasome activation. Resveratrol may be able to alleviate CME-induced myocardial pyroptosis and cardiac dysfunction by impeding the activation of NLRP3 inflammasome and the signaling pathway of TLR4/MyD88/NF-κB.     

Involvement of mitogen-activated protein kinase signaling pathways in microcystin-LR-induced apoptosis after its selective uptake mediated by OATP1B1 and OATP1B3.

The serine/threonine protein phosphatase (PP) 2A inhibitor, microcystin-LR, selectively induces liver damage and promotes hepatocarcinogenesis. It is thought that microcystin-LR affects hepatocellular viability mainly through inhibition of PP2A, partially through PP1, and, in addition, by generation of reactive oxygen species (ROS). However, the molecular basis of the selective liver damage and the balance between cell death and survival remained unclear. We analyzed the cytotoxicity of low doses of microcystin-LR using HEK293 cells stably expressing the human hepatocyte uptake transporters, organic anion transporting polypeptide (OATP)1B1 (HEK293-OATP1B1 cells) and OATP1B3 (HEK293-OATP1B3 cells). HEK293-OATP1B1 (IC(50) 6.6nM) and HEK293-OATP1B3 cells (IC(50) 6.5nM) were equally very sensitive to microcystin-LR. In contrast, control-vector-transfected (HEK293-CV) cells were resistant to microcystin-LR. Using HEK293-OATP1B3 cells, the cytotoxicity was attenuated by substrates and inhibitors of OATP1B3, including bromosulfophthalein, rifampicin, and cyclosporin A. Microcystin-LR was transported into HEK293-OATP1B3 cells with 1.2 microM Km value, and its uptake was inhibited by above substances. Accumulation of microcystin-LR in the HEK293-OATP1B1 and HEK293-OATP1B3 cells was increased in a dose-dependent manner but not in HEK293-CV cells. Cellular serine/threonine PP activity of HEK293-OATP1B3 cells was decreased by microcystin-LR but not in HEK293-CV cells. Apoptotic changes were observed after incubation of the HEK293-OATP1B3 cells with microcystin-LR. We found by FACS analysis that microcystin-LR induced apoptosis but not necrosis in HEK293-OATP1B3 cells. Microcystin-LR activated several mitogen-activated protein kinases (MAPKs) including ERK1/2, JNK, and p38 through inhibition of PP2A. In addition, the cytotoxicity of microcystin-LR was attenuated by the inhibitors of MAPK pathways, including U0126, SP600125, and SB203580. The ROS scavenger N-acetyl-L-cysteine partially attenuated the cytotoxicity of microcystin-LR. Thus, the present study demonstrates that microcystin-LR induces apoptosis through activation of multiple MAPK pathways subsequent to its selective uptake via OATP1B1 and OATP1B3 and followed by inhibition of PP2A, in addition to the ROS generation which might contribute to apoptosis.     

Cadmium-induced apoptosis in the BJAB human B cell line: involvement of PKC/ERK1/2/JNK signaling pathways in HO-1 expression

Heme oxygenase-1 (HO-1, EC 1.14.99.3) is a key enzyme in the cellular response to tissue injury and oxidative stress. It oxidizes heme, a pro-oxidant and toxic species, to biliverdin, CO, and free iron. Cytoprotection during the heat shock response is a complex phenomenon involving multiple inducible mechanisms. Several important pathways involving serine/threonine kinases mediate the induction of HO-1 in response to external stimuli.     

Zinc supplementation attenuates ethanol- and acetaldehyde-induced liver stellate cell activation by inhibiting reactive oxygen species (ROS) production and by influencing intracellular signaling

Background/aims

Zinc has been reported to prevent and reverse liver fibrosis in vivo; however, the mechanisms of its action are poorly understood. We therefore aimed to determine the antifibrotic potential of zinc.

Methods

Assessed was the influence of preincubation of rat HSCs with 30 μM ZnCl₂ on ethanol- (in the presence of 4-methyl pyrazole (4-MP)) or acetaldehyde-induced toxicity, apoptosis, migration, expression of smooth muscle α-actin (α-SMA) and procollagen I, release of reactive oxygen species (ROS), tumor necrosis factor-α (TNF-α), tumor growth factor-β1 (TGF-β1), metalloproteinase-2 (MMP-2) and tissue inhibitors of metalloproteinases (TIMPs) production. Intracellular signals such as nuclear factor-κB (NFκB), C-Jun N-terminal kinase (JNK) and p38 mitogen-activated protein kinase (p38 MAPK) induced by ethanol and its metabolite were also assessed.

Results

30 μM zinc protected HSCs against ethanol and acetaldehyde toxicity and inhibited their apoptosis. Zinc inhibited the production of ROS by HSCs treated with ethanol and acetaldehyde and inhibited their migration. Zinc also inhibited ethanol- and acetaldehyde-induced TGF-β1 and TNF-α production. Zinc down-regulated ethanol- and acetaldehyde-induced production of TIMP-1 and TIMP-2 and decreased the activity of MMP-2. In ethanol- and acetaldehyde-induced HSCs, zinc inhibited the activation of the p38 MAPK as well as the JNK transduction pathways and phosphorylation of IκB and Smad 3.

Conclusion

The results indicated that zinc supplementation inhibited ethanol- and acetaldehyde-induced activation of HSCs on different levels, acting as an antioxidant and inhibitor of MAPK, TGF-β and NFκB/IκB transduction signaling. The remarkable inhibition of several markers of HCS activation makes zinc a promising agent for antifibrotic combination therapies.