Materials Today Bio
·
2025
·
IF 10.2
Yingchun Zhao,Ying Qu,Changshun Huang,Chengzhilin Li,Wenyu Zhang,Xinyu Wang,Wenlong Duan,Qingbin He,Yachao Zhang,Jianwei Jiao,Runxiao Zheng
Systemic inflammation, excessive reactive oxygen species (ROS) and mitochondrial impairment are the main cause of multi-organ dysfunction syndrome in sepsis. Nevertheless, the pharmaceuticals currently in development focus solely on a single mechanism of disease, which is evidently inadequate. Herein, a precision nanodrug delivery system (MSe-NAD + /Nes) has been designed, incorporating mesoporous selenium nanozymes (MSe NPs) and leveraging a neutrophil-targeting strategy, to accomplish accurate delivery and mitigate inflammation. Upon reaching the inflammatory region, MSe NPs destroys selenium bonds and releases NAD + under the action of ROS, which in turn supplements the NAD + pool and promotes the recovery of mitochondrial function. Moreover, MSe NPs are capable of efficiently eliminating ROS by mimicking the activity of glutathione peroxidase (GPx), thus preventing the activation of the NLRP3 inflammasome. In vivo administration has indicated that MSe-NAD + /Nes efficiently alleviates organ oxidative stress, restores ATP levels, attenuates systemic hyperinflammation, and facilitates rapid organ repair. This study presents a potential modality of inflammation remission via ROS scavenging and mitochondrial repairment for the reliable and safe therapy of sepsis.
研究领域:
纳米医学
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免疫学
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药理学
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炎症研究
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细胞生物学
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PubMed
高影响因子
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
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2018
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IF 4.816
Yao Xu,Shujun Chen,Ying Cao,Pingzheng Zhou,Zhipeng Chen,Kui Cheng
Toll-like receptor 4 (TLR4) initiates innate immune response to release inflammatory cytokines and has been pathologically linked to variety of inflammatory diseases. Recently, we found that Carvedilol , as the classic anti-heart failure and anti-inflammatory clinic drug, could inhibit the TLR4 signaling in the TLR4 overexpressed cells. Herein, we have designed and synthesized a small library of novel Carvedilol derivatives and investigated their potential inhibitory activity. The results indicate that the most potent compound 8a (SMU-XY3) could effectively inhibited TLR4 protein and the LPS triggered alkaline phosphatase signaling in HEK-Blue hTLR4 cells. It down regulated the nitric oxide (NO) in both RAW264.7 cells and BV-2 microglial cells, in addition to blocking the TNF-α signaling in ex-vivo human peripheral blood mononuclear cells (PBMC). More interestingly, 8a shows higher affinity to hyperpolarization-activated cyclic nucleotide-gated 4 (HCN4) over HCN2 , which probably indicates the new application of TLR4 inhibitor 8a in heart failure, coronary heart disease , and other inflammatory diseases.
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高影响因子
PHYTOMEDICINE
·
2026
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IF 11.3
Cong Liu,Huan Zhang,Huihui Zhang,Yi Zhao,Chen Wu,Qinxiong Lin,Yubin Luo,Liangkai Wei,Jianqiu Chen,Xinyu Rao,Siyi Xiong,Hanmeng Shen,Shuyan Hong,Zhaohua Shi,Shijin Yin,Zhou Lan,Lvyi Chen
Chebulic acid, gallic acid, and corilagin predominated among the seven quantified analytical markers in the TRP aqueous extract. • TRP acts as a potent microbiota modulator to ameliorate renal injury. • The lysophospholipid-TLR4 axis serves as one of the pathological drivers of HUA-associated chronic renal injury. • LPC 16:0 and LPC 18:1 trigger renal inflammation by activating the TLR4 pathway. Background Hyperuricemia (HUA) is a metabolic disorder with an escalating global prevalence, and its progression to HUA-associated nephropathy represents an important contributor to chronic kidney injury. Emerging evidence highlights a bidirectional relationship between uric acid and lipid metabolism, with dyslipidemia contributing to the pathological progression of HUA-related complications. Triphala (TRP), a classic Tibetan herbal formula with broad metabolic regulatory properties, was selected as a potential intervention for the complex metabolic disturbances associated with HUA. However, its therapeutic efficacy and the precise molecular mechanisms underlying its effects in HUA remain to be fully elucidated. Purpose This study aimed to investigate the protective effects of TRP on hyperuricemia-associated nephropathy and to elucidate the underlying mechanisms. Methods High-performance liquid chromatography (HPLC) was first employed to identify and quantify seven representative constituents in the TRP aqueous extract. To evaluate the efficacy of TRP, an HUA mouse model was established through the combined administration of intraperitoneal potassium oxonate injections and a yeast-containing diet. A multi-omics strategy integrating 16S rRNA sequencing, metabolomics and lipidomics elucidated TRP's impact on the gut microbiota and host metabolism. Critically, fecal microbiota transplantation (FMT), TLR4 blockade experiments, and in vitro assays were employed to evaluate the contribution of TRP-modulated microbiota and the LPC-TLR4 pathway to the protective effects of TRP. Results HPLC identified chebulic acid, gallic acid, and corilagin as the major representative constituents of TRP aqueous extract. TRP dose-dependently reduced serum uric acid, improved renal function by lowering serum creatinine (Cr) and blood urea nitrogen (BUN) levels, increased the fractional excretion of uric acid (FEUA), and alleviated tubular injury and fibrosis. These improvements were accompanied by normalized urate transporters (downregulated URAT1/GLUT9; restored OAT1/OAT3) and suppressed renal inflammatory cytokines. Multi-omics analysis revealed that TRP reversed HUA-induced dysbiosis by suppressing opportunistic pathogens (e.g., Parasutterella, Allobaculum ) and enriching beneficial genera (e.g., Bifidobacterium, Akkermansia ), specifically reducing pro-inflammatory LPC (e.g., LPC16:0, LPC18:1). TRP and FMT effectively inhibited the TLR4/MyD88/NF-κB signaling axis and reduced LPC accumulation within the kidney. In vitro experiments validated that these specific LPC directly trigger TLR4 expression and TNF-α release, confirming the potential role of the microbiota-driven lysophospholipid-TLR4 pathway in HUA-associated chronic renal inflammation. Conclusion TRP ameliorates HUA and renal inflammation by remodeling the gut microbiota to suppress the aberrant accumulation of pro-inflammatory lysophospholipids, thereby deactivating the TLR4-mediated inflammatory cascade. These findings establish the gut microbiota-glycerophospholipid metabolism-renal inflammation axis as a potential therapeutic target and validate TRP as a relevant strategy for targeting the gut microbiome to treat systemic metabolic disease. Download: Download high-res image (331KB) Download: Download full-size image
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Scientific Reports
·
2025
·Vol. 15
·期 1
·39418
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IF 3.9
Liu Huan,Zou Qin,Xiang Tao,Zhu Rui,Chen Zigui,Chen Rui
Subarachnoid hemorrhage (SAH) is a common cerebrovascular disease that can lead to cognitive impairment. Although tetrandrine (Tet) has been proposed as a potential therapeutic agent, its efficacy in the treatment of SAH has not been fully explored. To investigate Tet effects on SAH, a rat model was established and divided into an SAH + vehicle and an SAH + Tet group. Cognitive function and behavioral performance were assessed using the Morris water maze and open field tests. Inflammatory cytokine levels were measured by ELISA, and hippocampal injury was evaluated by hematoxylin-eosin (HE) staining. Neuronal loss was quantified using Nissl staining, while neuronal density was assessed via immunofluorescence. The expression of the TLR4/NF-κB signaling pathway related-proteins was examined by Western blotting, and 16 S rRNA sequencing was conducted to determine differences in gut microbiota composition across the groups. Tet treatment significantly reduced mNSS and SAH assessment scores in SAH rats, suggesting an improvement in neurological and cognitive function. Behavioral analysis demonstrated that Tet increased escape latency, movement speed, and total distance in the Morris water maze. Histological staining revealed attenuated hippocampal damage and decreased neuronal death in the Tet-treated group. These neuroprotective effects were accompanied by reduced expression of TLR4 and NF-κB pathway components, as well as decreased secretion of LPS, TNF-α, IL-1β, and IL-6. Notably, Tet modulated the gut microbiota, restoring microbial diversity and abundance, and this modulation was associated with changes in the CYP51 metabolic pathway. Tet improves cognitive function and reduces neuronal injury in SAH rats by regulating the gut microbiota and its associated CYP51 metabolic pathway, thereby suppressing activation of the TLR4/NF-κB signaling cascade.
研究领域:
神经科学
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药理学
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胃肠病学
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微生物组研究
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高影响因子
DYES AND PIGMENTS
·
2023
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IF 4.5
Meng-Nan Li,Jing-Yu Zhao,Gang Zhang,Yu-Jie Xu,Jian-Feng Ge,Ru Sun
In this paper, several novel nitrogen-containing heterocycle dyes 1a-c with large conjugated planar structures based on naphthyridine derivatives were designed and synthesized, which had excellent optical properties and biological applications. Optical test showed the maximum absorption wavelengths of 1a-c were in the range of 443–485 nm, while the maximum emission wavelengths located at 523–610 nm in difference solvents. Furthermore, they exhibited polarity related fluorescence intensity changes with high fluorescence quantum yields, even up to 88% ( 1a in THF). Moreover, the transient absorption spectra revealed the excited-state lifetime of dye 1a became shorter with the increase of solvent polarity. Density functional theory calculations are also used to help explain the effect of the polarity of solvents on their fluorescence properties. Interestingly, the dyes 1a-c were somewhat toxic to cancer cells, while had an obvious growth-promoting effect on normal cells. Additionally, 1a-c with excellent lipid droplet (LD) targeting could be used for long-term observation of targeted cellular lis) hysiological activity and further applied to dynamic monitoring of changes in LDs polarity stimulated by TLR4 activator (LPS) in living cells. Overall, the excellent optical properties and biocompatibility of 1a-c indicate that they can serve as fluorescent probes for biological applications, and the results have important implications for understanding the physiological functions of LDs, especially in terms of morphological and polar changes.
研究领域:
生物化学
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细胞生物学
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分子生物学
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高影响因子
Journal of Toxicologic Pathology
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2022
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IF 1.25
Wen-Ling Mou,Shi-Ru Chen,Zhen-Ting Wu,Li-Hua Hu,Ji-Ye Zhang,Hong-Jie Chang,Hang Zhou,Ying Liu
Liver fibrosis results from liver inflammation and progresses to liver cirrhosis or liver cancer. It is known that nonalcoholic liver disease is mediated by the Toll-like receptor 4 (TLR4)/myeloid differentiation factor-2 (MD-2)–tumor necrosis factor-alpha (TNF-α) signaling pathway. This study aimed to investigate whether alcoholic liver disease is also mediated by this pathway. To this end, we first established rat models of liver fibrosis by administering alcohol. Next, the rats were injected with anti-TLR4 and anti-MD-2 antibodies. Real Time Quantitative PCR (RT-qPCR) and Western blotting were used to detect the activation of the TLR4/MD-2–TNF-α signaling pathway and hepatic stellate cells (HSCs). Moreover, the expression of molecules related to liver fibrosis was estimated. The morphology of rat liver tissue was observed through hematoxylin–eosin staining and Masson staining. For in vitro studies, Kupffer cells (KCs) isolated from the liver were transfected with si-TLR4 and si-MD-2 and co-cultured with HSCs to determine the activity of HSCs. It was found that alcohol treatment activated the TLR4/MD-2–TNF-α signaling pathway and upregulated the molecules associated with liver fibrosis. However, inhibition of TLR4 and MD-2 partially reversed this trend. Notably, in vitro studies indicated that knockdown of TLR4 and MD-2 in KCs partially inhibited LPS-induced activation of KCs and HSCs. Overall, this study showed that alcohol induces liver fibrosis via the LPS-TLR4/MD-2–TNF-α signaling pathway.
研究领域:
分子生物学
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免疫学
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病理学
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药理学
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DOI
PubMed
高影响因子
FISH & SHELLFISH IMMUNOLOGY
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2026
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IF 4.2
Hongying Zhang,Ru Guo,Youjuan Wu,Jiajun Huang,Zijia Yin,Kaiwen Zhao,Xuefeng Liu,Meifeng Li,Zeyin Jiang,Shanghong Wang,Lihua Fan,Chengyu Hu,Xiaowen Xu
Diniconazole-induced neurodevelopmental disorders are associated with immune inflammatory responses triggered through the TLR4/MyD88 signaling pathway. • Diniconazole-induced immune-inflammatory responses activated oxidative stress, ultimately triggering apoptosis in brain tissues. • The antioxidant astaxanthin effectively mitigated diniconazole-induced neurotoxicity by suppressing immune-inflammatory-indcued oxidative stress and apoptosis. Diniconazole, a widely used triazole fungicide in agriculture and aquaculture, poses potential threats to aquatic organisms and human health, yet its toxic effects and underlying mechanisms remain poorly understood. This study employed zebrafish as a model to systematically investigate the developmental neurotoxicity of diniconazole through both in vitro and in vivo assays. Phenotypic observations revealed that diniconazole exposure caused severe developmental abnormalities in early-life zebrafish, including reduced body length, decreased heart rate, lowered hatching success, and yolk sac edema. Transcriptome analysis revealed that diniconazole exposure significantly downregulated the extracellular matrix receptor interaction pathway and upregulated the retinol metabolism pathway, leading to neurodegenerative-like conditions in zebrafish embryos. Using transgenic zebrafish Tg ( Eno2:GFP ) and histological examination, we confirmed that diniconazole significantly impaired neurodevelopment and induced brain cell injury accompanied with compromised locomotor activity and activated immune-inflammatory responses. Mechanistic investigations demonstrated that neurodevelopmental disruption caused by diniconazole was linked to immune-inflammatory responses triggered through the TLR4/MyD88 signaling pathway. Subsequently, diniconazole-induced immune-inflammatory responses activated oxidative stress, ultimately triggering apoptosis in brain tissues. Notably, the antioxidant astaxanthin effectively mitigated diniconazole-induced neurotoxicity by suppressing immune-inflammatory-induced oxidative stress and apoptosis. This study provides the comprehensive evidence that diniconazole induces severe neurotoxicity in zebrafish through triggering TLR4/MyD88-induced immune-inflammatory responses, offering insights into risk assessment and potential therapeutic strategies for diniconazole exposure.
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高影响因子
ENVIRONMENTAL POLLUTION
·
2024
·
IF 7.6
Xin-Ran Ge,Yi Zhao,Hao-Ran Ren,Fu-Wei Jiang,Shuo Liu,Ming Lou,Yi-Feng Huang,Ming-Shan Chen,Jia-Xin Wang,Jin-Long Li
As the most produced phthalate, di-(2-ethylhexyl) phthalate (DEHP) is a widely environmental pollutant primarily used as a plasticizer, which cause the harmful effects on human health. However, the impact of DEHP on spleen and its underlying mechanisms are still unclear. Pyroptosis is a novel form of cell death induced by activating NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasomes and implicated in pathogenesis of numerous inflammatory diseases. The current study aimed to explore the impact of DEHP on immune inflammatory response in mouse spleen. In this study, the male ICR mice were treated with DEHP (200 mg/kg) for 28 days. Here, DEHP exposure caused abnormal pathohistological and ultrastructural changes, accompanied by inflammatory cells infiltration in mouse spleen. DEHP exposure arouse heat shock response that involves increase of heat shock proteins 60 (HSP60) expression. DEHP also elevated the expressions of toll-like receptor 4 (TLR4) and myeloid differentiation protein 88 (MyD88) proteins, as well as the activation of NF-κB pathway. Moreover, DEHP promoted NLRP3 inflammasome activation and triggered NLRP3 inflammasome-induced pyroptosis. Mechanistically, DEHP drives splenic inflammatory response via activating HSP60/TLR4/NLRP3 signaling axis-dependent pyroptosis. Our findings reveal that targeting HSP60-mediated TLR4/NLRP3 signaling axis may be a promising strategy for inflammatory diseases treatment.
研究领域:
毒理学
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免疫学
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细胞生物学
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PubMed
高影响因子
JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY
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2024
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IF 5.7
Yi Zhao,Zi-Yan Hu,Ming Lou,Fu-Wei Jiang,Yi-Feng Huang,Ming-Shan Chen,Jia-Xin Wang,Shuo Liu,Yu-Sheng Shi,Hong-Mei Zhu,Jin-Long Li
Di-2-ethylhexyl phthalate (DEHP) is frequently used as a plasticizer to enhance the plasticity and durability of agricultural products, which pose adverse effects to human health and the environment. Aquaporin 1 (AQP1) is a main water transport channel protein and is involved in the maintenance of intestinal integrity. However, the impact of DEHP exposure on gut health and its potential mechanisms remain elusive. Here, we determined that DEHP exposure induced a compromised duodenum structure, which was concomitant with mitochondrial structural injury of epithelial cells. Importantly, DEHP exposure caused duodenum inflammatory epithelial cell damage and strong inflammatory response accompanied by activating the TLR4/MyD88/NF-κB signaling pathway. Mechanistically, DEHP exposure directly inhibits the expression of AQP1 and thus leads to an inflammatory response, ultimately disrupting duodenum integrity and barrier function. Collectively, our findings uncover the role of AQP1 in phthalate-induced intestinal disorders, and AQP1 could be a promising therapeutic approach for treating patients with intestinal disorders or inflammatory diseases.
研究领域:
毒理学
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胃肠病学
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分子生物学
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PubMed
高影响因子
COMPARATIVE BIOCHEMISTRY AND PHYSIOLOGY C-TOXICOLOGY & PHARMACOLOGY
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2025
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IF 4.3
Xinhao Ye,Shiyi Duan,Hao Wang,Shimei Xiao,Mijia Li,Wei Yuan,Yan Zhao,Yiyue Zhang,Keyuan Zhong
The inflammatory response is a core protective physiological process against stimuli like infection or injury, and can be initiated by autoimmune disorders. It is primarily characterized by neutrophil-dominated leukocytosis and may lead to multiple organ dysfunction in severe cases. Environmental factors play an important role in the inflammatory response. Rare earth elements are not essential elements for living organisms. However, owing to large-scale mining and use, their concentrations in the environment have increased. Thus, rare earth elements are now considered emerging environmental pollutants, and the risks that rare earth elements pose to human health need further investigation. In this study, zebrafish were used as experimental animals, and zebrafish embryos were exposed to the different concentrations of lanthanum chloride (0, 5, 15, and 25 mg/L) to analyze its effect on embryo development and immune system. The number and distribution of zebrafish neutrophils as well as changes in oxidative stress and the expression of genes related to inflammation were analyzed. The results indicated that lanthanum chloride exposure reduced the heart rate, shortened the body length, and increased the yolk area of zebrafish embryos. In addition, exposure to lanthanum chloride caused the diffusion of neutrophils, leading to inflammation in zebrafish. Concurrently, the exposure led to the accumulation of reactive oxygen species in zebrafish, which subsequently resulted in the upregulation of malondialdehyde, catalase, and superoxide dismutase levels. Further experiments revealed that exposure to lanthanum chloride led to the upregulation of several inflammation-related genes, such as IL-6 , IL-8 , IL-10 , and cxcl-c1c , as well as certain TLR4/NF-κB signaling-related genes, including TLR4 , MyD88 , NF-κB P65 , IL-1β , and TNF-α . The TLR4/NF-κB signaling pathway inhibitor andrographolide can alleviate the inflammatory response induced by lanthanum chloride exposure. In conclusion, lanthanum chloride induced inflammation in zebrafish by activating the TLR4/NF-κB signaling pathway. The study results can provide a reference for evaluating the health risks of rare earth elements in humans.
研究领域:
毒理学
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环境科学
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免疫学
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分子生物学
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水生毒理学
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PubMed
高影响因子
Frontiers in Immunology
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2026
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IF 5.9
Jiangjiang Fu,Gangchen Cheng,Zhongxi Lyu,Zezhi Fan,Feiyang Li,Zhifang Xu,Bo Chen,Yongming Guo,Yuhan Liu,Hui Zhang,Yuan Xu,Yi Guo
Introduction: The acupuncture acupoint is the critical initial site for the therapeutic efficacy of electroacupuncture (EA). Previous studies have confirmed that the NF-κB pathway within the acupoint region mediates the therapeutic effects of acupuncture. Therefore, this study focuses on an in-depth investigation of the MD2/TLR4/NF-κB axis. Methods: The mouse model of adjuvant-induced arthritis (AIA) was established via intraplantar injection of Complete Freund’s Adjuvant (CFA). EA intervention was applied bilaterally to the Zusanli (ST36) acupoints, and behavioral, molecular, and immunological approaches were integrated to investigate the role of MD2 in EA-mediated analgesia. Results: EA increased paw thermal withdrawal thresholds (PTWTs) in AIA mice (P < 0.05), accompanied by higher levels of MD2, TLR4, p65, and the phosphorylated form of p65 (p-p65) at the acupoint. Co-immunoprecipitation (Co-IP) confirmed binding between MD2 and TLR4 in ST36 acupoint, while immunofluorescence (IF) revealed co-localization of TLR4 with fibroblasts and mast cells in ST36, suggesting these immune cells are critical targets for signal activation. Lentivirus-mediated knockdown of MD2 in the acupoint partially reversed EA’s analgesic effects and suppressed downstream TLR4/NF-κB pathway activation, whereas MD2 overexpression elicited a partial analgesic effect and promoted pathway activation. Together with spinal cord proteomics data, these findings indicate that modulating MD2 in the acupoint can regulate spinal cord-related signaling pathways. Mechanistically, EA dynamically regulates the equilibrium of the Grem1/BMP4/COX2 axis in the spinal dorsal horn via activation of the MD2/TLR4/NF-κB pathway cascade, achieving systemic analgesia. Conclusion: This study provides molecular evidence supporting the "acupoint priming" theory in acupuncture and highlights MD2 as a potential therapeutic target for pain management.
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高影响因子
Small
·
2026
·
IF 11.8
Junyan Liu,He Ke,Lingyu Su,Zhirou Lin,Chong Liu,Shilong Jiang,Hong Huang,Chengxian Guo,Qinghua Zhang,Huifang Tang,Zhaoqian Liu,Wenhu Zhou,Qi Pei,Qianfei Cui
Osteoarthritis (OA) is a degenerative joint disease, for which effective disease-modifying therapies remain lacking. Here, we report yam-derived nanovesicles (YDNVs) as a plant-derived exosome-like nanoplatform with intrinsic therapeutic activity for OA treatment. YDNVs exhibited typical nanoscale vesicular characteristics and were efficiently internalized by chondrocytes via clathrin-mediated endocytosis. Through enzymatic pretreatment and multi-omics analyses, RNA-particularly microRNAs (miRNAs)-was identified as the primary bioactive component mediating their anti-inflammatory effects. Mechanistic studies further confirmed that aof-miR168a directly binds to the 3′ untranslated regions of TLR4 and TRAF6, thereby suppressing downstream inflammatory signaling. To enhance targeting and therapeutic efficacy, a cartilage-targeting peptide-modified system (YDNVs-CAP) was engineered via membrane insertion of a cholesterol-anchored conjugate. This modification significantly improved cellular uptake, cartilage targeting, and intra-articular retention. Functionally, YDNVs-CAP effectively alleviated inflammation, oxidative stress, and extracellular matrix degradation in vitro, and markedly attenuated OA progression in a destabilization of the medial meniscus (DMM) mouse model. Collectively, this study establishes an RNA-mediated therapeutic mechanism for plant-derived nanovesicles and highlights YDNVs-CAP as a promising biomimetic nanoplatform for disease-modifying OA therapy.
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