INTERNATIONAL IMMUNOPHARMACOLOGY
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2022
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IF 5.714
Jie-Fang Gao,Liu Tang,Fei Luo,Yi-Yuan Zhang,Lu Chen,Hong Ding,Zu-Dong Meng
Background and purpose Atopic dermatitis (AD) is a chronic inflammatory skin disease, characterized by pruritus and impaired skin barrier function. The pathology of AD involves in immune dysfunction and epidermal barrier disruption. Reactive oxygen species (ROS) are found to be associated with AD, and play a role in the immunological abnormalities and dysfunctional skin barrier. Nicotinamide mononucleotide (NMN) plays an important role in oxidative stress related diseases, but its role in AD is unclear. Methods KM mice were treated with DNFB to induce AD-like lesion and typical applied with NMN for two weeks. The dermatitis score, the degree of itching and TEWL were evaluated during modeling. Epidermal thickness of skin lesions and histopathological changes were detected. Further, inflammatory factors, epidermal differentiation-related genes, oxidative stress indicators and JAK2/STAT5 signaling pathway were evaluated. NHEK cells were stimulated by TNF-α/IFN-γ after pre-treatment with NMN, then ROS levels, inflammatory factors and JAK2/STAT5 signaling pathway were detected. Results NMN exhibited potent anti-atopic activities, shown by alleviated AD-like symptoms, inhibited the increased expression of inflammatory cytokines and restored proteins and mRNA level of skin barrier genes. In addition, NMN inhibited TNF-α/IFN-γ-stimulated elevation of inflammatory chemokines, which was associated with blocking the activation of ROS-mediated JAK2/STAT5 pathway. Conclusion NMN may have a positive effect on relieving symptoms of AD.
研究领域:
皮肤病学
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免疫学
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药理学
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分子生物学
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DOI
PubMed
高影响因子
ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY
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2019
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IF 4.527
Yuezhu Zhang,Shuyue Wang,Tianyang Zhao,Liwei Yang,Shuangyu Guo,Yanbin Shi,Xueting Zhang,Liting Zhou,Lin Ye
Mono-2-ethylhexyl phthalate (MEHP), as the major metabolite of Di-(2-ethylhexyl) phthalate (DEHP), can induce lipid accumulation in hepatocytes and further leads to non-alcoholic fatty liver disease (NAFLD), while the underlying mechanism is unclear. We aim to clarify the effects of JAK2/STAT5 pathway on lipid accumulation induced by MEHP and the role of oxidation stress in NAFLD. BRL-3A hepatocytes were exposed to MEHP (0, 10, 50, 100 and 200 μM) for 24 h and 48 h. Then the lipid droplets in cells were observed by Oil-Red-O staining and quantified by isopropyl alcohol . The levels of TG, SOD, TBARS, AST and ALT were all detected by commercial kits. RT-PCR was used to detect mRNA expression, and western blotting was used to detect the expression of proteins encoded by JAK2/STAT5 pathway genes and lipid metabolism-related genes. As a result, MEHP promoted the lipid synthesis and accumulation in BRL-3A cells. MEHP down-regulated the expression and inhibited the activation of JAK2/STAT5. Moreover, the lipid metabolism-related kinases levels were elevated after MEHP exposure. In addition, the SOD levels were gradually decreased and the TBARS levels were increased in MEHP-treated groups. The lipid metabolism-related proteins levels were correlated with the oxidation stress levels. Furthermore, the ALT and AST levels were elevated after MEHP exposure. Therefore, we concluded that MEHP led to lipid accumulation through inhibiting JAK2/STAT5 pathway, resulted in damaging liver parenchyma and NAFLD by aggravating oxidation stress.
研究领域:
毒理学
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细胞生物学
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肝病学
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DOI
PubMed
高影响因子
JOURNAL OF IMMUNOLOGY
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2026
·Vol. 215
·期 4
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IF 4
Xu Shujuan,Jiang Yixiang,Wang Shengtao,Chen Beili,Lin Wenyuan,Jiang Fang,Wu Xianyi,Tang Rongfang,Nie Yuwei,Chen Tongtong,Wang Xiaotao
Myelodysplastic syndrome (MDS) is a heterogeneous group of myeloid neoplasms characterized by treatment difficulties and a propensity to progress to acute myeloid leukemia. Impaired natural killer (NK) cell surveillance is a hallmark of MDS, yet the underlying molecular mechanisms remain poorly understood. This study aims to elucidate the mechanism by which HIF-1α regulates NK cell differentiation disorders and its impact on NK cell cytotoxicity in MDS. Flow cytometry was employed to compare HIF-1α expression and NK cell differentiation between wild-type and NUP98/HOXD13 (NHD13) mice. Our results demonstrated a significant increase in HIF-1α expression in the bone marrow and peripheral blood of MDS mice, accompanied by a notable decrease in immature NK cell subsets and activating receptors (NKG2D, NKp44, and DNAM-1). Overexpression of HIF-1α in human NK cells or pharmacological stabilization with CoCl2 inhibits the differentiation into mature NK cells, suppresses the expression of degranulation molecules such as Granzyme B, and impairs NK cell cytotoxicity. Western blot analysis indicated that HIF-1α regulates NK cell differentiation and function via the JAK1/STAT5/SOCS2 signaling pathway. Collectively, these findings suggest that the hypoxic microenvironment in MDS enhances HIF-1α expression, which subsequently impairs NK cell maturation and inhibits their cytotoxicity. Targeting HIF-1α may delay MDS progression by enhancing NK cell function via the JAK1/STAT5/SOCS2 signaling pathway.
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DOI
PubMed
高影响因子
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
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2024
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IF 6
Qingqing Zhang,Yuying Liu,Jie Zhang,Yanchen Li,Jin Wang,Nanxin Liu,Jie Zhang,Xiaoyan Pan
Proteolysis targeting chimeras (PROTAC) are bifunctional chimeric molecules capable of directly degrading binding proteins through the ubiquitin-proteasome pathway. PROTACs have demonstrated significant potential in overcoming drug resistance and targeting previously untreatable targets. However, several limitations still need to be addressed, including their high molecular weight resulting in poor membrane permeability and bioavailability. In this study, we proposed that cancer-targeted penetrating peptides could enhance the cell permeability of PROTACs. We developed 26 novel targeted penetrating peptides for leukemia and lymphoma cells, among which C9C-f(3Bta) and Cyclo-C9C–R exhibited superior membrane permeability, targetability, and stability. By combining C9C-f(3Bta) and Cyclo-C9C–R with IMA-PROTAC, we effectively enhanced the anti-proliferative activity of IMA-PROTAC, facilitated degradation of Bcr-Abl protein in K562 cells, and reduced downstream STAT5 phosphorylation. Furthermore, the combined application promoted cell apoptosis while blocking G1 phase progression. HPLC-MRM-MS revealed that the combination of C9C-f(3Bta) or Cyclo-C9C–R with IMA-PROTAC significantly enhanced intracellular IMA-PROTAC content. In summary, our proof-of-concept study validated the hypothesis that combining PROTACs with targeted penetrating peptides can improve protein degradation efficiency as well as anti-proliferative capabilities.
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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DOI
PubMed
高影响因子
Marine Drugs
·
2025
·Vol. 23
·期 7
·289
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IF 5.4
Shijie Bi,Yating Cao,Shiyuan Fang,Yanyan Chu,Zixuan Zhang,Meng Li,Rilei Yu,Jinbo Yang,Yu Tang,Peiju Qiu
The internal tandem duplication mutation of FMS-like tyrosine kinase 3 (FLT3-ITD) is associated with high recurrence and mortality rates in acute myeloid leukemia (AML), making it a critical target for anti-AML therapies. Plinabulin is a diketopiperazines derivative that exhibits extensive anti-cancer potency by targeting β-tubulin. We designed and synthesized a novel FLT3 inhibitor, namely5-3, based on the structure of plinabulin and evaluated its effect on FLT3-ITD mutant AML cells. The results indicated that5-3potently and selectively inhibits the growth of mutant FLT3-expressingleukemia cells, and had no effect on FLT3 wide-type cancer cells, suggesting the antiproliferative activity of5-3depends highly on FLT3-ITD expression. Mechanically,5-3significantly suppressed the phosphorylation of FLT3 signaling pathway, including STAT5, Erk and Akt. Moreover, the efficiency of compound5-3is not associated with Plinabulin’s typical target, β-tubulin. In conclusion, the study identified diketopiperazine derivative as a novel FLT3-ITD selective inhibitor. These results demonstrated that5-3might be a drug candidate for the treatment of FLT3-ITD-positive AML.
研究领域:
肿瘤学
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药物化学
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分子生物学
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血液学
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药理学
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产品关联
DOI
PubMed
高影响因子
Environmental Sciences Europe
·
2019
·Vol. 31
·期 1
·1-14
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IF 5.878
Tang Huaqiao,Xu Min,Luo Jie,Zhao Ling,Ye Gang,Shi Fei,Lv Cheng,Chen Helin,Wang Yanyan,Li Yinglun
The widespread use of nano-copper as a feed additive in the absence of toxicological studies has potential risks to humans and animals. Toxicity studies on nano-copper in animals usually exposure from the respiratory tract, however, it is necessary to study the oral exposure toxicity of nano-copper to understand its risks as a feed additive.Currently the hepatotoxicity and mechanism of nano-copper after sub-choronic oral exposure at equivalent doses of 50, 100, and 200 mg/kg/day were evaluated in rats; micro-copper and Cu ions were used as controls. Nano-copper (200 mg/kg) increased serum alanine aminotransferase and aspartate aminotransferase significantly, further promoting hepatic oxidative stress, inflammation, and corresponding histopathological changes, and exhibited significant dose-dependent changes. Nano-copper also decreased the level of nuclear receptors, resulting in significant reductions in mRNA, protein, and activity of hepatic CYP450 enzymes. The molecular mechanisms responsible for these toxic effects involved the signaling pathway of NF-κB, MAPK, and STAT5.Nano-copper caused strong hepatic toxicity by inducing oxidative stress and inflammation. The decreased drug metabolism enzymes lead to nano-copper–drug interaction that provoked the concerns on animal-derived food safety.
研究领域:
毒理学
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药理学
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兽医学
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环境健康
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DOI
高影响因子
COMPARATIVE BIOCHEMISTRY AND PHYSIOLOGY B-BIOCHEMISTRY & MOLECULAR BIOLOGY
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2020
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IF 2.219
Xi Yuan,Yuxin Lin,Jingkai Qin,Yazhou Zhang,Guokun Yang,Ruijian Cai,Zongzhen Liao,Caiyun Sun,Wensheng Li
Red-spotted grouper ( Epinephelus akaara ) is one of the high economic value grouper species, however, the knowledge regarding its growth is limited. In this study, full-length cDNAs of growth hormone ( gh ) and its receptors ( ghr1 and ghr2 ) were cloned from the pituitary and liver of red-spotted grouper, respectively. Tissue distribution analysis showed that gh mRNA was predominantly expressed in the pituitary. ghr1 mRNA was highly expressed in the liver, muscle, fat and gonad, while ghr2 mRNA expression was ubiquitously high in the peripheral tissues. However, the mRNA expression of both ghr isoforms was relatively low in the central nervous system. Secretory recombinant grouper GH (rgGH) was expressed in yeast Pichia pastoris and verified. HEK293T cells transiently transfected with the GHR isoforms were used to elucidate the receptor-mediated signaling pathways related to growth regulation. rgGH activated rapid phosphorylation of Janus kinase 2, signal transducer and activator of transcription 5 (STAT5) and extracellular signal-regulated protein kinase 1/2 through GHR1, but only STAT5 was phosphorylated via GHR2. rgGH strongly activated STAT5 phosphorylation and significantly stimulated ghr1 , ghr2 and insulin-like growth factor ( igf1 , igf2 ) mRNA expression in primary cultured hepatocytes. Data showed that the recombinant protein rgGH played effects on igf1 / 2 mRNA expression via GHR-mediated signaling pathways. Our findings provide essential information about GH and GHRs characteristics in red-spotted grouper.
研究领域:
水产养殖
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分子生物学
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内分泌学
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DOI
PubMed
高影响因子
Stem Cell Research & Therapy
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2022
·Vol. 13
·期 1
·1-19
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IF 8.079
Lin Yifeng,Dong Shunni,Ye Xiaohang,Liu Juan,Li Jiaqun,Zhang Yanye,Tu Mixue,Wang Siwen,Ying Yanyun,Chen Ruixue,Wang Feixia,Ni Feida,Chen Jianpeng,Du Binyang,Zhang Dan
Background Thin endometrium is a primary cause of defective endometrial receptivity, resulting in infertility or recurrent miscarriage. Much effort has been devoted toward regenerating thin endometrium by stem cell-based therapies. The human placenta-derived mesenchymal stem cells (HP-MSCs) are emerging alternative sources of MSCs with various advantages. To maximize their retention inside the uterus, we loaded HP-MSCs with cross-linked hyaluronic acid hydrogel (HA hydrogel) to investigate their therapeutic efficacy and possible underlying mechanisms.
Methods Ethanol was injected into the mice uterus to establish the endometrium-injured model. The retention time of HP-MSCs and HA hydrogel was detected by in vivo imaging, while the distribution of HP-MSCs was detected by immunofluorescence staining. Functional restoration of the uterus was assessed by testing embryo implantation rates. The endometrial morphological alteration was observed by H&E staining, Masson staining, and immunohistochemistry. In vitro studies were further conducted using EdU, transwell, tube formation, and western blot assays. Results Instilled HP-MSCs with HA hydrogel (HP-MSCs-HA) exhibited a prolonged retention time in mouse uteri than normal HP-MSCs. In vivo studies showed that the HP-MSCs-HA could significantly increase the gland number and endometrial thickness ( P < 0.001, P < 0.05), decrease fibrous area ( P < 0.0001), and promote the proliferation and angiogenesis of endometrial cells (as indicated by Ki67 and VEGF, P < 0.05, P < 0.05, respectively) in mice injured endometrium. HP-MSCs-HA could also significantly improve the embryo implantation rate ( P < 0.01) compared with the ethanol group. Further mechanistic study showed the paracrine effects of HP-MSCs. They could not only promote the proliferation and migration of human endometrial stromal cells via the JNK/Erk1/2-Stat3-VEGF pathway but also facilitate the proliferation of glandular cells via Jak2-Stat5 and c-Fos-VEGF pathway. In turn, the increased VEGF in the endometrium promoted the angiogenesis of endothelial cells. Conclusion Our study suggested the potential therapeutic effects and the underlying mechanisms of HP-MSCs-HA on treating thin endometrium. HA hydrogel could be a preferable delivery method for HP-MSCs, and the strategy represents a promising therapeutic approach against endometrial injury in clinical settings. Graphical abstract
研究领域:
生殖医学
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干细胞治疗
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组织工程
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再生医学
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DOI
PubMed
高影响因子
FOOD CHEMISTRY
·
2021
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IF 7.514
Wen Jing Zhu,Li Ping Lin,Dan Liu,Jia Cheng Qian,Bei Bei Zhou,Dan Dan Yuan,Ren Xiang Tan
Globally consumed kimchi is manufactured through fermenting cruciferous vegetables containing indole glucosinolates (IG). But few reports describe the IG metabolism during the fermentation. Here, we show that indole-3-carbinol (I3C), a breakdown product of IG, is transformed during the kimchi fermentation into 3,3′-diindolylmethane (DIM) and 2-(indol-3-ylmethyl)-3,3′-diindolylmethane (LTr1). LTr1 was found to kill the acute myeloid leukemia (AML) cells with FMS-like tyrosine kinase 3 (FLT3) receptor mutations, by inhibiting the FLT3 phosphorylation and the expression of downstream proteins (STAT5, ERK, and AKT). In the immune-depleted mice xenografted with human MV4-11 cells, LTr1 was demonstrated to reduce the tumor growth and synergize with sorafenib, an anti-AML agent in clinic. The work updates the chemical and biological knowledge about kimchi, and in particular establishes LTr1 as an FLT3 inhibitor that is effective and synergistic with sorafenib in treating AML.
研究领域:
肿瘤学
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药理学
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生物化学
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发酵科学
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分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
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