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
Heliyon
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2024
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IF 3.4
Fanzhuo Zeng,Anqi Chen,Wei Chen,Shuai Cheng,Sen Lin,Rongcheng Mei,Xifan Mei
Background Spinal cord injury (SCI) is a serious and difficult to treat traumatic disease of the central nervous system. Spinal cord injury causes a variety of detrimental effects, including neuroinflammation and ferroptosis, leading to chronic functional impairment and death. Recent studies have shown that microglia/macrophages (M/Ms) at the injury site remain primarily in the pro-inflammatory state, which is detrimental to recovery. However, information on the factors behind pro-inflammatory polarization skew in the injured spinal cord remains unclear. In this study, we found that Tumor Necrosis Factor-α(TNF-α) ablation protected after SCI by suppressing neuroinflammation and ferroptosis. Though using TNF-α knock out mice (TNF−/−), we induced downregulation of TNF-α in M/Ms and further investigated its effect on SCI outcome. In TNF−/− mice, significant behavioral improvements were observed as early as 7 days after injury. We showed that TNF-α inhibition promote injury-mediated M/Ms polarization from pro-inflammatory to anti-inflammatory phenotype in vivo. Furthermore, accumulated iron in M/Ms after SCI increased the expression of TNF-α and the population of M/Ms to pro-inflammatory phenotype. Moreover, zinc supplement reduced the secondary damage caused by iron overload. In conclusion, we found that knock out of TNF-α promotes recovery of motor function after spinal cord injury in mice by inhibiting ferroptosis and promoting the shift of macrophages to an anti-inflammatory phenotype, indicating that there is great potential for this therapy to SCI.
研究领域:
神经科学
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免疫学
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药理学
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细胞生物学
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DOI
PubMed
高影响因子
CHEMICAL ENGINEERING JOURNAL
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2026
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IF 12.5
Li Qiao,Xue-Tian Qian,Yi-Gang Zhang,Xia-Feng Peng,Qi Liu,Shi-Qi Chang,Chang Cui,Feng Zhang,Shu-Kui Wang,Ning-Ping Huang
A novel Eudragit S100-coated and mannose-modified liposome enables colon-specific and macrophage-targeted siRNA delivery. EML/siRNA exhibit excellent stability, biocompatibility, and efficient intracellular delivery siRNA. • The nanocarrier protects TNF-α siRNA from Gastrointestinal (GI) degradation and achieves responsive release in the colon. • Treatment in IBD models significantly downregulates pro-inflammatory cytokines and promotes tissue repair. • The platform provides a targeted and improved therapeutic strategy for precise IBD management. Inflammatory bowel disease (IBD) is a chronic and clinically important intestinal disorder with rapidly rising global incidence and prevalence. While biological therapies targeting tumor necrosis factor-alpha (TNF-α), a key cytokine in IBD pathogenesis, have shown clinical efficacy, their use is often limited by systemic adverse effects. RNA interference (RNAi) offers a promising strategy for precise gene silencing, yet its therapeutic application is constrained by the poor stability and inefficient in vivo delivery of small interfering RNA (siRNA). To overcome these challenges, we developed a macrophage-targeted, colon-specific liposomal system for delivering TNF-α siRNA. The liposomes were functionalized with mannose to selectively engage the mannose receptor (MR, CD206), highly expressed on macrophages, and coated with Eudragit S100 (ES100), a pH-responsive polymer that shields siRNA from gastrointestinal degradation and enables site-specific release in the colon. The resulting ES100-coated, mannose-modified liposomes (EML/siRNA) demonstrated enhanced cellular uptake and efficient siRNA delivery to macrophages both in vitro and in vivo. In animal models of IBD, treatment with EML/siRNA significantly downregulated pro-inflammatory cytokine, alleviated intestinal inflammation, and promoted mucosal tissue repair, as evidenced by histopathological analysis. This study introduces a dual-functional nanotherapeutic platform that combines targeted RNAi-mediated TNF-α silencing with colon-specific delivery and mucosal protection, offering a promising and refined therapeutic strategy for IBD. Download: Download high-res image (159KB) Download: Download full-size image
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高影响因子
MICROCHEMICAL JOURNAL
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2025
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IF 5.1
Tiantian Wang,Yanli Zhou,Lantao Liu,Hui Dong,Yinghan Xu,Yidan Sun,Yaocun Yue,Jiaqing Tian,Maotian Xu
Abnormal Tumor necrosis factor-α (TNF-α) levels in serum are closely linked to Alzheimer's disease onset, progression, and severity. Highly sensitive and specific detection of TNF-α offers a key biomarker for early diagnosis and disease evaluation, providing significant clinical value for improved disease management. In this study, an iridium complex [(piq)₂Ir(dpppy)] containing a cyclometalated ligand was used as a novel and highly efficient electrochemiluminescence (ECL) luminophore to construct an ultrasensitive electrochemical biosensor for the detection of TNF-α. First, the TNF-α antibody was immobilized in the microplate reactor, and a quasi-specific sandwich immunoassay was performed. Subsequently, aptamers modified with silver nanoparticles-which were in-situ generated on the C-rich sequence-modified aptamer, captured the TNF-α antigen. After dissociation with nitric acid, the solution containing Ag + was transferred to the electrode surface modified with the cyclometalated iridium complex for ECL signal detection. The constructed immunosensor not only exhibited a wide linear range of 0.001 ng mL −1 –100 ng mL −1 , but also showed excellent recovery in human serum samples, ranging from 98.6 % to 101.7 %, with a relative standard deviation of 0.66 %–3.8 %. This strategy not only enhanced the detection sensitivity due to the efficient performance of the iridium complex in the 3 LCπ − π* state, but also this strategy of this biosensor effectively maintained the specificity and stability.
研究领域:
生物化学
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生物传感器
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免疫学
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电化学
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医学诊断
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DOI
高影响因子
Cell Host & Microbe
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2022
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IF 31.316
Haiyang Lu,Xiaoqiang Xu,Di Fu,Yubei Gu,Rong Fan,Hongmei Yi,Xiangyi He,Chaofu Wang,Binshen Ouyang,Ping Zhao,Li Wang,Pengpeng Xu,Shu Cheng,Zhifeng Wang,Duowu Zou,Lizhong Han,Weili Zhao
Summary Microbiota-induced tumorigenesis is well established in solid tumors of the gastrointestinal tract but rarely explored in hematologic malignancies. To determine the role of gut microbiota in lymphoma progression, we performed metagenomic sequencing on human primary gastrointestinal B cell lymphomas. We identified a distinct microbiota profile of intestinal lymphoma, with significantly decreased symbiotic microbes, particularly the genus Eubacterium and notably butyrate-producing Eubacterium rectale . Transfer of E. rectale -deficit microbiota of intestinal lymphoma patients to mice caused inflammation and tumor necrosis factor (TNF) production. Conversely, E. rectale treatment reduced TNF levels and the incidence of lymphoma in sensitized Eμ-Myc mice. Moreover, lipopolysaccharide from the resident microbiota of lymphoma patients and mice synergizes with TNF signaling and reinforces the NF-κB pathway via the MyD88-dependent TLR4 signaling, amalgamating in enhanced intestinal B cell survival and proliferation. These findings reveal a mechanism of inflammation-associated lymphomagenesis and a potential clinical rationale for therapeutic targeting of gut microbiota.
研究领域:
肿瘤学
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免疫学
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微生物学
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分子生物学
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DOI
PubMed
高影响因子
MOLECULAR THERAPY
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2024
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IF 12.1
Xiaozhen Kang,Yifeng Han,Mengdi Wu,Yuxin Li,Peng Qian,Chuning Xu,Zhengyun Zou,Jie Dong,Jiwu Wei
Tumor necrosis factor (TNF) has been recognized as an immune activation factor in tumor immunotherapy. Our study demonstrated that TNF blockade markedly enhanced the antitumor efficacy of oncolytic adenovirus (AdV) therapy. To minimize systemic side effects, we engineered a recombinant oncolytic AdV encoding a TNF inhibitor (AdV-TNFi) to confine TNF blockade within the tumor microenvironment (TME). AdV-TNFi significantly improved therapeutic outcomes across various solid tumor models, including four murine and two golden hamster cancers. Immune cell profiling identified CD8 + T cells as the primary mediators of AdV-TNFi-induced antitumor effects, rather than CD4 + T or NK cells. Additionally, AdV-TNFi significantly decreased the infiltration of suppressive myeloid-derived immune cells within the TME and promoted long-term antitumor immune surveillance. Further investigation indicated that TNFR2, more than TNFR1, is pertinent to the immunosuppressive TME, with a recombinant AdV-encoding anti-TNFR2 demonstrating comparable antitumor efficacy to AdV-TNFi. Moreover, AdV-TNFi enhanced the antitumor efficacy of gemcitabine and immune checkpoint blockades (ICBs), such as anti-PD-L1 and anti-TIGIT antibodies, in pancreatic carcinoma and the anti-EGFR antibody in colon carcinoma. In conclusion, intratumoral blockade of the TNF/TNFR2 axis using AdV augments cancer immunotherapy efficacy while mitigating the risks associated with systemic TNF or TNFR2 suppression, warranting further clinical investigation.
研究领域:
肿瘤学
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免疫学
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分子生物学
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癌症治疗
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DOI
PubMed
高影响因子
JOURNAL OF APPLIED TOXICOLOGY
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2020
·Vol. 40
·期 11
·1526-1533
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IF 2.997
Yalei Yu,Youyou Zhang,Jie Zhang,Chuhuai Guan,Liang Liu,Liang Ren
Cantharidin is of high medicinal value but has strong toxicity. Nowadays, multiple research has focused on the mechanism of its antitumor activity while research on toxicological profiles associated with cantharidin poisoning is still limited. Its hepatotoxicity has attracted attention recently for the crucial role of the liver in detoxification. Here, we aim to find a potential mechanism for cantharidin-induced acute hepatotoxicity with a view to assisting subsequent research or clinical use or detoxification. Twenty-one male Sprague-Dawley rats were randomly divided into control, low-dose (1.34 mg/kg) and high-dose (2.67 mg/kg) cantharidin exposure groups. We used hematoxylin-eosin to observe pathological changes and used immunofluorescent staining, western blotting and real-time quantitative polymerase chain reaction to detect the expression of the markers. The main pathological changes in livers of cantharidin-treated rats were necrosis, inflammatory infiltration and hemorrhage. We found coexpression of tumor necrosis factor alpha (TNF-α), IkappaB kinase-alpha (IKK-α) and caspase3 by immunofluorescent staining in livers of cantharidin-treated rats. Compared with the control, the levels of TNF-α, IKK-α and caspase3 increased significantly in the experimental groups ( P < .05). The ratio of B-cell lymphoma-2 (Bcl-2)/Bax increased in the low-dose group but decreased in the high-dose group ( P < .05). Cantharidin exposure raised IKK-α mRNA and caspase3 mRNA levels ( P < .05). In conclusion, the participation of TNF-α, IKK-α, Bcl-2, Bax and caspase3 uncovered a novel mechanism underlying cantharidin-induced acute hepatotoxicity, and the mechanism needs to be studied further.
研究领域:
药理学
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毒理学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
COLLOIDS AND SURFACES B-BIOINTERFACES
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2024
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IF 5.4
Qingling Nie,Peipei Xu,Jiajia Liu,Yanhanzhuo Wang,Qian Huang,Ruiyun You,Yunzhen Liu,Lizhi Li,Yudong Lu
To improve the sensitivity, accuracy and specificity of the assay, a two-dimensional silver substrate with EF=5.85×10 8 was first synthesized as a SERS substrate, on the surface of which DSP molecules were modified to form a DSP-antibody coupling through the activation of two N-hydroxy succinimide (NHS) esters to capture TNF-α. Subsequently, aptamerized silver-coated gold nanospheres (Au@TFMBA@Ag) were synthesized as Surface-Enhanced Raman Scattering (SERS) recognition probes. These probes were employed to create a sandwich structure for the quantitative detection of Tumor Necrosis Factor-alpha (TNF-α), utilizing the SERS signal intensity at 1374 cm −1 . Quantitative detection of TNF-α was successfully accomplished within the concentration range of 10 −4 to 10 −10 mg·mL −1 . Clinical serum samples were collected and subjected to testing. Significance analysis, conducted through the T-test (p < 0.0001), unequivocally showed the method's ability to differentiate between sera from normal individuals and those diagnosed with colon cancer.
研究领域:
生物医学
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癌症检测
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纳米技术
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产品关联
DOI
PubMed
高影响因子
CELLULAR SIGNALLING
·
2023
·
IF 4.8
Liqun Chen,Wei Fang,Weizhi Chen,Yiliu Wei,Jinwang Ding,Jiafeng Li,Jun Lin,Qiaoyi Wu
Glioma stem cells (GSCs) are thought to be responsible for the initiation and progression of glioblastoma (GBM). GBM presents highly invasive growth with a very high recurrence rate, so it has become a clinical problem to be solved urgently. RNAseq demonstrates that thrombospondin 1 (THBS1) acts not only in the angiogenic core of glioma but also with a high degree of invasiveness and infiltration. Nevertheless, defects in the signaling pathway research lead to a poor prognosis in glioma patients. To investigate the relevant molecular mechanism and signal pathway of glioma stem cell behavior mediated by THBS1 , U251 astroglioma cells and GSCs were taken as model cells for in vitro experiments. The biological effects of THBS1 on glioma proliferation, migration, and adhesion were evaluated using Cell Counting Kit-8(CCK8) assays, EdU incorporation assays, migration assays, Transwell assays, Western blotting , and RNAseq. We found that the knockout of the THBS1 gene by CRISPR/Cas9 promoted proliferation and migration in U251 cells and GSCs, as well as influencing cell cycle progression by regulating the TNF/MAPK/NF-κB and TGF-β/Smad signaling pathways. Moreover, U251 cells and GSCs showed different responses to THBS1 knockout, suggesting specific and potential targets for GSCs in signaling pathways mediated by THBS1 .
研究领域:
肿瘤学
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分子生物学
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细胞生物学
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癌症研究
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DOI
PubMed
高影响因子
Antioxidants
·
2026
·Vol. 15
·期 2
·223
·
IF 8.2
Xiaoyao Ma,Jiali Rao,Xuefei Li,Zibin Li,Xuan Lu,Yujie Lu,Juan Guo,Baomin Feng
Acetaminophen (APAP) overdose is a major global cause of drug-induced liver injury (DILI), and the rising incidence of APAP-induced hepatotoxicity has raised substantial concern in the medical community, highlighting an urgent need for effective therapeutic approaches. Coptidis Rhizoma alkaloids (CRAs) have shown hepatoprotective effects in multiple hepatic disease models. This study aimed to investigate the therapeutic efficacy and the underlying mechanisms of CRA in acetaminophen (APAP)-induced acute liver injury. After identifying 18 alkaloid components in CRA, we employed an integrated strategy of untargeted metabolomics and network pharmacological analysis to investigate the underlying mechanisms. The potential mechanisms were subsequently validated through histopathological examination and molecular biology assays. Our results showed that CRA exerted dose-dependent protection against APAP-induced liver injury in vitro and in vivo. This protective effect was mediated by enhanced hepatic glutathione (GSH) biosynthesis via increased intracellular cysteine (Cys) availability. In the mouse model, hepatic Cys and GSH levels were increased by 2.2-fold and 1.8-fold, respectively, relative to the model group, which consequently attenuated oxidative stress damage. Furthermore, CRA suppressed APAP-induced activation of ERK and NF-κB, reducing the phosphorylation levels by 39.2% and 38.0%, respectively. Accordingly, it also downregulated the subsequent expression of inflammatory mediators in the TNF signaling pathway. These findings provide crucial mechanistic insights into the hepatoprotective role of CRA against APAP-induced toxicity, establishing a valuable foundation for developing novel therapeutic or preventive strategies for APAP-induced liver injury.
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DOI
PubMed
高影响因子
CHEMICAL ENGINEERING JOURNAL
·
2026
·
IF 12.5
Jianan Chen,Tong Xing,Jialei Song,Hang Zhang,Shaotian Fu,Lizhi Jiang,Yiqi Xu,Lei He,Huatao Liu,Hailong Ma,Xin Wang,Tangjun Zhou,An Qin,Peixiang Ma,Jie Zhao
The inflammatory environment mediated by TNF-α in the intervertebral disc can reduce the transfection efficiency of LNPs. • Engineered fibroblasts overexpressing TNF-α antibodies exhibit resistance to the decline in proliferation ability and activity induced by the inflammatory microenvironment. • Engineered fibroblasts rescue the inflammatory phenotype and ameliorate ECM homeostasis of degenerated nucleus pulposus cells in IVDD models in vitro and in vivo. Lumbar intervertebral disc degeneration (IVDD) is a prevalent degenerative condition lacking effective early-stage treatments. While fibroblast cell therapy and mRNA therapeutics represent promising approaches, their efficacy is limited by the inflammatory microenvironment of degenerated discs, which affects the delivery efficiency and compromises cell viability and gene delivery. To overcome these challenges, we developed an LNP-mRNA-engineered fibroblast strategy, utilizing fibroblasts as a “Trojan horse” for targeted mRNA delivery. In IVDD progression, inflammatory factors, particularly TNF-α, accumulate and exacerbate degeneration. Engineered fibroblasts mitigates TNF-α-induced senescence and proliferation arrest in inflammatory conditions, counteracts nucleus pulposus inflammation, and restores extracellular matrix production. In a rat IVDD model, engineered fibroblasts significantly improved disc height and showed superior therapeutic effects compared to naive fibroblasts. These results highlight the dual therapeutic mechanism of our approach, i.e. combining cell therapy with mRNA delivery, and its clinical potential in the treatment of IVDD. Download: Download high-res image (105KB) Download: Download full-size image
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高影响因子
International Journal of Pharmaceutics-X
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2026
·
IF 7.9
Sai Gao,Ruili Yin,Jingxuan Shi,Zhuang Miao,Longyan Yang,Dong Zhao
Psoriasis is a chronic immune-mediated inflammatory skin disease characterized by keratinocyte hyperproliferation and cytokine-driven immune activation, in which TNF-α plays a central pathogenic role. We developed a layered hydrated silk fibroin (SF) microneedle system (ETA@Hyd MN) with SF tips loaded with etanercept (ETA, a TNF-α inhibitor for psoriasis), for local cutaneous delivery to reduce systemic exposure and rapidly dissolving polyvinyl alcohol (PVA) bases that facilitate retention of the SF tips within the skin. Hydration markedly slowed ETA release, with approximately 80% released at 48 h compared with approximately 75% released within 1 h from microneedles without hydration. In HaCaT cell scratch assays, release media from ETA@Hyd MN attenuated the accelerated wound closure response, resulting in a greater remaining scratch width than that in the model group at 48 h. In an IMQ-induced psoriasis-like mouse model, ETA@Hyd MN improved clinical symptoms, reduced PASI scores, alleviated spleen enlargement, and suppressed epidermal hyperplasia and TNF-α/IL-6 expression. These results demonstrate that ETA@Hyd MN enables sustained ETA release and effectively suppresses inflammation, highlighting its potential for treating inflammatory skin diseases. Download: Download high-res image (190KB) Download: Download full-size image
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高影响因子
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