JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY
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2025
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IF 6.2
Xin Huang,Hong Shen,Zirui Li,Tingting Fu,Xin Wei,Sainan Qiu
The purpose of the present study was to evaluate the effect of isochlorogenic acid A (IAA) on periodontitis and explore its potential mechanism. A ligature/LPS procedure was employed to induce periodontitis in rats. LPS-induced HPDLF was used as the in vitro model. Bioinformatic analyses indicated that angiotensin-converting enzyme (ACE) might be the target of IAA in periodontitis. PGK1/STAT1 might be the related molecules of ACE. Treatment with IAA inhibited inflammatory cytokines, inflammatory molecule transcriptions in gingival tissues and HPDLFs. MicroCT, H&E, TRAP and Runx2 staining showed that IAA relieved periodontitis. Immunofluorescence observation and WB revealed that IAA inhibited ACE/PGK1/STAT1 in dental papilla, parodontium, gingival tissues and HPDLFs. IAA suppressed glycolysis, mitochondrial fission, oxidative stress and promoted oxidative phosphorylation, mitochondrial fusion. The application of the ACE-overexpression plasmid, PGK1 SiRNA, the ACE inhibitor captopril, the PGK1 inhibitor NG52 suggested that ACE and PGK1 were involved in IAA-mediated anti-inflammatory response. Molecular docking, molecular dynamics, DARTS and CETSA indicated that IAA might combine with ACE. It was also found that MYC governed ACE transcription. The Y195 residue of PGK1 was conservative and critical for the combination between PGK1 and ACE. ACE and PGK1 were also upregulated in gingival tissues of periodontitis patients. In conclusion, IAA ameliorated periodontitis by inhibiting inflammation via ACE/PGK1/STAT1 signaling.
研究领域:
药理学
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口腔医学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
ATHEROSCLEROSIS
·
2024
·
IF 4.9
Yanhua Zhen,Jiaqi Yang,Ji Song,Zeyu Xing,Jiahe Zheng
Background and aims Atherosclerosis (AS), an arterial vasculature disease, is characterized by abnormal lipid accumulation and inflammatory response. ADP ribosylation factor like GTPase 11 (ARL11) is linked to multifarious processes in cells. This study aims to clarify the underlying mechanism of ARL11 in AS. Methods ApoE -/- mice fed with high-fat diet were used as the mouse models of AS. Gene expression in AS was determined by mRNA-sequencing. The ARL11 expression was detected by real-time PCR, western blot and immunofluorescence. The M1 polarization of macrophages was indicated by TNF-α and IL-6 levels detected by ELISA and iNOS expression determined by real-time PCR and western blot. The role of ARL11 during AS was explored through loss-of-function. Results There were 1301 upregulated and 1110 downregulated genes during AS. These differently expressed genes (DEGs) were mainly enriched in pathways and terms which are involved in inflammation. Moreover, Arl11 was highly expressed in AS models. Downregulation of Arl11 decreased the lipid deposition and atherosclerotic plaques in the aortas of AS mice, and declined inflammatory cytokines and M1 polarization of macrophages induced by IFN-γ. Furthermore, ARL11 interacted with JAK2 and p-JAK2 and modulated their degradation, thus inhibiting the activation of JAK2/STAT1 pathway. Conclusions : ARL11 promoted the development of AS via interacting with JAK2 and activating JAK2/STAT1 pathway. Thus, silencing ARL11 may prevent the process of AS and be a novel way to treat AS.
研究领域:
心血管疾病
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分子生物学
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免疫学
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DOI
PubMed
高影响因子
Molecular Medicine Reports
·
2023
·Vol. 27
·期 2
·1-10
·
IF 3.4
Cunyang Gu,Feng Gao,Shiqi Zhang,Lihua Kang,Wei Zhang,Xiaojuan Feng,Jinxi Liu,Yuexin Tian,Qun Wei,Yunxia Du,Yujia Xing,Qingjuan Liu,Shuxia Liu
Tubulointerstitial fibrosis (TIF) is an important pathological change that occurs during the development of diabetic kidney disease. The epithelial‑mesenchymal transition (EMT) of renal tubular epithelial cells is a manifestation of TIF. STAT1, a member of the STAT family of transcription factors, can be modified by the small ubiquitin‑related modifier (SUMO), thus affecting the activity of STAT1. The present study investigated the role of STAT1 SUMOylation in high glucose‑induced tubular EMT by western blotting, immunocytochemistry, immunofluorescence, co‑immunoprecipitation and dual luciferase reporter analysis. The results indicated that in the process of high glucose‑induced EMT, STAT1 activation protected the cells from EMT. However, high glucose also increased the SUMOylation of STAT1, which prevented STAT1 from exerting an effective protective role by inhibiting its activity.
研究领域:
分子生物学
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细胞生物学
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糖尿病研究
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肾病学
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产品关联
DOI
PubMed
高影响因子
Cells
·
2022
·Vol. 11
·期 22
·3588
·
IF 7.666
Tuo Li,Lei Li,Ruilong Peng,Hongying Hao,Hejun Zhang,Yalong Gao,Cong Wang,Fanjian Li,Xilei Liu,Fanglian Chen,Shu Zhang,Jianning Zhang
Background and Purpose: Neuroinflammation has been shown to play a critical role in secondary craniocerebral injury, leading to poor outcomes for TBI patients. Abrocitinib, a Janus kinase1 (JAK1) selective inhibitor approved to treat atopic dermatitis (AD) by the Food and Drug Administration (FDA), possesses a novel anti-inflammatory effect. In this study, we investigated whether abrocitinib could ameliorate neuroinflammation and exert a neuroprotective effect in traumatic brain injury (TBI) models. Methods: First, next-generation sequencing (NGS) was used to select genes closely related to neuroinflammation after TBI. Then, magnetic resonance imaging (MRI) was used to dynamically observe the changes in traumatic focus on the 1st, 3rd, and 7th days after the induction of fluid percussion injury (FPI). Moreover, abrocitinib’s effects on neurobehaviors were evaluated. A routine peripheral blood test was carried out and Evans blue dye extravasation, cerebral cortical blood flow, the levels of inflammatory cytokines, and changes in the numbers of inflammatory cells were evaluated to investigate the function of abrocitinib on the 1st day post-injury. Furthermore, the JAK1/signal transducer and activator of transcription1 (STAT1)/nuclear factor kappa (NF-κB) pathway was assessed. Results: In vivo, abrocitinib treatment was found to shrink the trauma lesions. Compared to the TBI group, the abrocitinib treatment group showed better neurological function, less blood-brain barrier (BBB) leakage, improved intracranial blood flow, relieved inflammatory cell infiltration, and reduced levels of inflammatory cytokines. In vitro, abrocitinib treatment was shown to reduce the pro-inflammatory M1 microglia phenotype and shift microglial polarization toward the anti-inflammatory M2 phenotype. The WB and IHC results showed that abrocitinib played a neuroprotective role by restraining JAK1/STAT1/NF-κB levels after TBI. Conclusions: Collectively, abrocitinib treatment after TBI is accompanied by improvements in neurological function consistent with radiological, histopathological, and biochemical changes. Therefore, abrocitinib can indeed reduce excessive neuroinflammation by restraining the JAK1/STAT1/NF-κB pathway.Keywords:TBI;abrocitinib;neuroinflammation;JAK1/STAT1/NF-κB
研究领域:
神经科学
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药理学
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炎症
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创伤
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DOI
PubMed
高影响因子
INTERNATIONAL IMMUNOPHARMACOLOGY
·
2023
·
IF 5.6
Aihua Xu,Yang Yang,Yang Shao,Manyu Jiang,Yongxin Sun,Bo Feng
Neuronal apoptosis and inflammation exacerbate the secondary injury after spinal cord injury (SCI). Four and a half domains 2 (FHL2) is a multifunctional scaffold protein with tissue- and cell-type specific effects on the regulation of inflammation, but its role in SCI remains unclear. The T10 mouse spinal cord contusion model was established, and the mice were immediately injected with lentiviruses carrying FHL2 shRNA after SCI. The results showed that FHL2 expression was increased following SCI, and then gradually decreased. Moreover, FHL2 depletion aggravated functional impairment, neuronal necrosis, and enlarged lesion cavity areas in the injured spinal cord. FHL2 deficiency facilitated neuronal apoptosis by elevating cleaved caspase 3/9 expression, neuroinflammation by regulating microglia polarization, and bone loss. Indeed, FHL2 deficiency increased the secretion of TNF-α and IL-6, M1 microglia polarization, and the activation of STAT1 pathway but decreased the secretion of IL-10 and IL-4, M2 microglia polarization, and the activation of the STAT6 pathway in the spinal cord. In vitro , FHL2 silencing promoted LPS + IFN-γ-induced microglia M1 polarization through activating the STAT1 pathway and alleviated IL-4-induced microglia M2 polarization via inhibiting the STAT6 pathway. FHL2 positively regulated the expression of poly (ADP-ribose) polymerase family member 14 (PARP14) by promoting its transcription. PARP14 overexpression inhibited FHL2 silencing-induced microglia M1 polarization and relieved the inhibitory effect of FHL2 silencing on microglia M2 polarization. Collectively, the study suggests that FHL2 reduces the microglia M1/M2 polarization-mediated inflammation via PARP14-dependent STAT1/6 pathway and thereby improves functional recovery after SCI.
研究领域:
神经科学
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炎症
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细胞生物学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
BIOCHEMICAL PHARMACOLOGY
·
2025
·
IF 5.6
Yanhua Zhen,Dongdong Li,Yulu Meng,Zeyu Xing,Jiahe Zheng
Atherosclerosis is a disorder of lipid metabolism, but its pathogenesis has not yet been fully elucidated. This study aimed to clarify the roles of homeodomain interacting protein kinase 2 (HIPK2) in atherosclerosis. Atherosclerotic model was constructed by feeding apolipoprotein E knockout (ApoE -/- ) mice with a high-fat diet. Human THP-1 macrophages and mouse RAW 264.7 macrophages were stimulated with IFN-γ to establish an in vitro model. We showed an upregulation of HIPK2 in the aorta of atherosclerotic mice. HIPK2 knockdown reduced macrophage infiltration, M1 polarization, and attenuates atherosclerosis development. Downregulation of HIPK2 in macrophages led to a significant suppression in the expression of pro-inflammatory factors, which was accompanied by an enhancement in the phosphorylation and degradation of β-catenin, as well as the activation of the signal transducer and activator of transcription 1 (STAT1) signaling pathway. Silencing of HIPK2 alone in THP-1 macrophages resulted in anti-inflammatory effects and suppression of M1 macrophage polarization. However, simultaneous silencing of HIPK2 and β-catenin (CTNNB1) reversed these effects, counteracting the outcomes observed with HIPK2 silencing alone. We validated that small ubiquitin-like modifier (SUMO)-specific peptidase 1 (SENP1) regulated HIPK2 function by affecting the SUMOylation of HIPK2 at the K32 site. SENP1 knockdown promoted HIPK2 SUMOylation, impairing its protein stability. In the rescue experiments, IFN-γ-induced inflammation and M1 polarization were resumed upon restoration of HIPK2 expression in SENP1-silenced macrophages. Our work demonstrated that HIPK2 accelerated the progression of atherosclerosis by regulating β-catenin/STAT1 signaling cascade to promote macrophage infiltration and M1 polarization. HIPK2 was regulated by SENP1-mediated de-SUMOylation.
研究领域:
医学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
SKIN RESEARCH AND TECHNOLOGY
·
2024
·
IF 2
Guiyu an Chen,Yingxun Chen,Yan Zhang,Shufeng Zheng,Louying Zhu,Mingxing Ding
Background Incontinence‐associated dermatitis (IAD) is a tough problem in clinical settings, not only increasing the risk of complications like catheter‐related urinary tract infections and pressure ulcers in elderly and critically ill patients, but also prolonging hospital stays, raising hospital costs, and possibly leading to medical disputes. This study is aimed to evaluate the therapeutic effect of silicone dressing combined with topical oxygen therapy on IAD in a rat model. Methods An IAD rat model induced by synthetic urine with trypsin was established. Hematoxylin & eosin staining was carried out to examine skin histology. Using immunofluorescence, the microvessel density in the affected skin tissues was determined. ELISA was performed to measure the concentrations of inflammatory cytokines and angiogenic factors in serum. The mRNA expression of EGF, PDGF, and VEGF was detected via qRT‐PCR. Western blotting was employed to determine NF‐κB p65/STAT1 pathway‐related protein levels. Results Compared to single therapy, silicone dressing combined with topical oxygen therapy could significantly reduce the severity of IAD, improve skin histology, inhibit inflammation, and promote angiogenesis in IAD rat models. Additionally, the results showed that relatively speaking, the combined therapy suppressed the NF‐κB p65/STAT1 signaling pathway more effectively. Conclusion These findings indicated that silicone dressing combined with topical oxygen therapy can alleviate IAD through promoting wound healing and inhibiting inflammation via NF‐κB p65/STAT1 signaling pathway in a rat model, which provided a theoretical basis for the prevention and treatment of IAD in clinic.
研究领域:
皮肤科
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药理学
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分子生物学
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临床研究
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产品关联
DOI
PubMed
高影响因子
Oncotarget
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2018
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IF 0
Wenxia Bai,Shudong Wang,Shanshan An,Mengjie Guo,Guangming Gong,Wenya Liu,Shaoxin Ma,Xin Li,Jihua Fu,Wenbing Yao
This study aimed to investigate the effect of single and combination therapy using chitosan (K), gynostemma (J), and motherwort (Y) on an experimental rat model of chronic renal failure (CRF) induced by adenine and the underlying mechanisms. CRF rats were treated with individual or combinational therapy with two or three of these agents. Biochemical indicators showed that the levels of blood urea nitrogen, creatinine and uric acid decreased and the levels of albumin and hemoglobin increased by single or combination therapy of these drugs. Drug treatment also decreased oxidative stress damage of renal tissues in CRF rats. Histopathological lesions were attenuated in each drug treatment group by various degrees. Additionally, drug treatment affected the expression of extracellular matrix (ECM) proteins including plasminogen activator inhibitor 1, collagen I, matrix metalloprotease-1, and tissue inhibitor of metalloproteinases 1. In particular, the combination therapy of K, J, and Y was superior to the respective monotherapy, which supported the prescription of KJY combination. We further studied the inhibitory effect of KJY on LPS-induced inflammation in RAW264.7 macrophages. The results showed that KJY inhibited LPS-induced secretion of inflammatory cytokines (Interferon-gamma, Interleukin-1 Beta, chemokine (C-X-C motif) ligand 10, cyclooxygenase-2 and Tumor necrosis factor-α in RAW264.7 macrophages. Combination therapy of KJY suppressed the protein expression of Cyclooxygenase-2 and inducible nitric oxide synthase in vivo and in vitro . Further study indicated that KJY inhibited STAT1 activation by down regulating p-STAT1 to exert anti-inflammatory effect and improve renal function in rats with chronic renal failure.
研究领域:
药理学
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肾病学
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免疫学
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产品关联
DOI
PubMed
PHYTOMEDICINE
·
2025
·
IF 8.3
Tong Chen,Lijun Ai,Ruonan Shuang,Jichen Diao,Xinyi Yuan,Weiwei Tao,Ling He,Chang Chen
Background Cognitive impairment is the common complication of diabetes, while its etiology remains not fully understood. Gardenia jasminoides is used in traditional Chinese medicine for clearing heat and detoxification. Its effective components Geniposide and Genipin have been found to show protective effect on diabetic cognitive impairment in our previous study. Whereas the effect and mechanism of Shanzhiside methyl ester (SME), another major component of Gardenia jasminoides , on cognitive impairment has been scarcely reported. Purpose The present study was conducted to evaluate the effect of SME on cognitive impairment symptom in diabetic mice. Methods Diabetes was induced by HFD/STZ. HG/PA induced BV2 cells were used as the in vitro model. Results Network pharmacology and bioinformatic analyses showed that HSP90AA1 might be the target of SME. As a result, SME attenuated cognitive impairment-related behavior in Morris water maze and passive avoidance tests. The treatment with SME inhibited inflammation, glycolysis via HSP90AA1/HIF1A/STAT1 signaling both in vivo and in vitro. SME regulated the transcriptions of inflammation, glycolysis, oxidative phosphorylation, oxidative stress, lipid metabolism, and mitochondrial stress related genes. The transfection with HSP90AA1 SiRNA or overexpression plasmid, the treatment with HIF1A inhibitor PX478, STAT1 inhibitor Fludarabine suggested that HSP90AA1/HIF1A/STAT1 signaling was required for the anti-inflammatory and anti-glycolytic effects of SME. The treatment with glycolysis agonist oligomycin, hexokinase inhibitor 2-DG, PKM2 activator TEPP46, PKM2 inhibitor Shikonin displayed that glycolysis was critical for the anti-inflammatory effect of SME. It was found that SME might combine with HSP90AA1. Conclusion SME attenuated cognitive impairment symptom of diabetic mice possibly via HSP90AA1/HIF1A/STAT1 mediated anti-inflammatory and anti-glycolytic effects.
研究领域:
药理学
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神经科学
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分子生物学
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生物信息学
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内分泌学
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中医药学
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细胞生物学
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产品关联
DOI
PubMed
高影响因子
Cell Death & Disease
·
2025
·Vol. 16
·期 1
·1-14
·
IF 9.6
Liu Min,Li Yuanyuan,Deng Zhilin,Zhang Ke,Huang Shuying,Xia Jiamin,Feng Yi,Liang Yundan,Sun Chengfu,Liu Xindong,Li Shurong,Su Bingyin,dong Yong,Huang Sizhou
Mutation in genes involved in DNA replication continuously disrupt DNA replication and give rise to genomic instability, a critical driver of oncogenesis. To prevent leukemia, immature T lymphocytes with genomic instability often undergo rapid cell death during development. However, the mechanism by which immature T lymphocytes undergo rapid cell death upon genomic instability has been enigmatic. Here we show that zebrafish mcm5 mutation leads to DNA damage in immature T lymphocytes and the immature T cells sensitively undergo rapid cell death. Detailed analyses demonstrated that the immature T lymphocytes undergo rapid apoptosis via upregulation of tp53 and downregulation of bcl2 transcription in mcm5 mutants. Mechanistically, Mcm5 directly binds to Stat1a and facilitates its phosphorylation to enhance bcl2a expression under the conditions of DNA replication stress. However, in mcm5 mutants, the absence of the Mcm5-Stat1 complex decreases Stat1 phosphorylation and subsequent bcl2a transcription, accelerating apoptosis of immature T lymphocytes with genomic instability. Furthermore, our study shows that the role of Mcm5 in T-cell development is conserved in mice. In conclusion, our work identifies a role of Mcm5 in regulating T cell development via Stat1-Bcl2 cascade besides its role in DNA replication, providing a kind of mechanism by which immature T cells with gene mutation-induced DNA damage are rapidly cleared during T lymphocyte development.
研究领域:
免疫学
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遗传学
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肿瘤学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
INTERNATIONAL IMMUNOPHARMACOLOGY
·
2024
·
IF 4.8
Pan Su,Liming Liu,Yuhang Gong,Shuaijun Peng,Xiangli Yan,Ming Bai,Erping Xu,Yucheng Li
Background The pathogenesis of depression is largely influenced by dyshomeostasis of neuroinflammation regulated by microglia M1/M2 polarization, and NLRP3 inflammasome acts critical roles in shifting microglia polarization. Kaempferol (Kae), a major flavonoid in edible plants, possesses anti-inflammation and anti-depression capacity, but its underlying cellular and molecular mechanisms of antidepressive effect have not yet fully explored. Methods In vivo studies with lipopolysaccharide (LPS)-induced depressive mice were carried out to evaluate antidepressant effect of Kae. In vitro, BV2 microglia cell line stimulated by LPS along with IFN-γ to detect pharmacological effects of Kae on microglia polarization and NLRP3. Based on two depression-related GEO datasets (GSE54570 and GSE54568) and the potential targets of Kae obtained from GeneCards database, enrichment analysis and protein–protein interaction (PPI) network construction reveal potential therapeutic targets of Kae for depression. Then the precise antidepressant mechanisms of Kae were verified by western blot and immunofluorescent staining in vivo and vitro . Results Our results showed that Kae significantly improves LPS-induced depressive behaviors and alleviates neuroinflammation in prefrontal cortex. Moreover, Kae obviously shifted microglia polarization to M2 phenotype, and also suppressed NLRP3 in prefrontal cortex and BV2. Enrichment analysis and PPI network construction suggested PPARγ and STAT1 signaling are related to regulation of NLRP3 in depression. Furtherly, Kae remarkably enhanced PPARγ activation and inhibited nuclear translocation of p-STAT1 in microglia of prefrontal cortex and BV2. Importantly, pre-incubation with PPARγ antagonist T0070907 or overexpression with CA STAT1 (constitutively active STAT1) both prevented pharmacologic effects of Kae on shifting microglia polarization and suppressing NLRP3 in BV2. Noteworthily, T0070907 significantly blocked the inhibitory effect of Kae on STAT1 while overexpression with CA STAT1 abolished the effect of Kae on PPARγ activation in BV2. Above results suggested that pharmacologic effects of Kae on microglia polarization and NLRP3 are dependent on the balance of counter-regulatory PPARγ and STAT1 signaling. Conclusion Our results indicated that the shifting microglia polarization and suppression of NLRP3 via tilting the balance of PPARγ and STAT1 signaling may be the antidepressant mechanism of Kae, which provides a novel perspective for elucidating antidepressive effect of Kae.
研究领域:
药理学
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神经科学
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免疫学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
Neural Regeneration Research
·
2022
·Vol. 18
·期 8
·1809
·
IF 6.058
Xu Ai-Hua,Yang Yang,Shao Yang,Jiang Man-Yu,Sun Yong-Xin
Poly(ADP-ribose)polymerase family member 14 ( PARP14 ), which is an intracellular mono(ADP-ribosyl) transferase, has been reported to promote post-stroke functional recovery, but its role in spinal cord injury (SCI) remains unclear. To investigate this, a T10 spinal cord contusion model was established in C57BL/6 mice, and immediately after the injury PARP14 shRNA-carrying lentivirus was injected 1 mm from the injury site to silence PARP14 expression. We found that PARP14 was up-regulated in the injured spinal cord and that lentivirus-mediated downregulation of PARP14 aggravated functional impairment after injury, accompanied by obvious neuronal apoptosis , severe neuroinflammation , and slight bone loss. Furthermore, PARP14 levels were elevated in microglia after SCI, PARP14 knockdown activated microglia in the spinal cord and promoted a shift from M2-polarized microglia (anti-inflammatory phenotype) to M1-polarized microglia (pro-inflammatory phenotype) that may have been mediated by the signal transducers and activators of transcription (STAT) 1/6 pathway. Next, microglia M1 and M2 polarization were induced in vitro using lipopolysaccharide/interferon-γ and interleukin-4, respectively. The results showed that PARP14 knockdown promoted microglia M1 polarization , accompanied by activation of the STAT1 pathway . In addition, PARP14 overexpression made microglia more prone to M2 polarization and further activated the STAT6 pathway . In conclusion, these findings suggest that PARP14 may improve functional recovery after SCI by regulating the phenotypic transformation of microglia via the STAT1/6 pathway.
研究领域:
神经科学
·
分子生物学
·
细胞生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
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