查找使用阿拉丁产品的科研文献

New Insights into Baicalein’s Effect on Chlorpyrifos-Induced Liver Injury in Carp: Involving Macrophage Polarization and Pyropto sis

Jing Liu,Wenyue Zhang,Xiaojing Li,Shiwen Xu

Chlorpyrifos (CPF) is widely used in agriculture, plants, and buildings to kill pests and worms. Excessive environmental residues of CPF will result in soil and ecological contamination and toxicity to animals and humans. Baicalein (Bai), derived from the root of natural Scutellaria baicalensis, is a potent anti-inflammatory, antioxidant, and antitumor agent. The objective of this paper is to investigate the molecular mechanism by which Bai prevents CPF-induced hepatotoxic injury. Carp were kept in water containing CPF (23.2 μg/L) and/or fed diets containing Bai (0.15 g/kg). We found that Bai attenuated liver tissue damage and vacuolization caused by CPF. We confirmed that CPF causes M1/M2 polarization imbalance in macrophages and hepatocyte pyroptosis, which ultimately leads to liver injury. Further exploration of the internal mechanism shows that CPF participates in liver toxicity damage by destroying the AMPK/SIRT1/pGC-1α pathway and causing mitochondrial biogenesis and mitochondrial dynamics imbalance. Notably, Bai significantly attenuated CPF-induced inhibition of the AMPK/SIRT1/pGC-1α pathway. In summary, our results suggest that Bai alleviates CPF exposure-induced inhibition of the AMPK/SIRT1/pGC-1α pathway, thereby attenuating macrophage M1 hyperpolarization and pyroptosis by inhibiting the NF-κB pathway. These results may provide new insights into the detoxification mechanism of Bai on the same type of organophosphorus pesticides.

Dioscin alleviates BDL- and DMN-induced hepatic fibrosis via Sirt1/Nrf2-mediated inhibition of p38 MAPK pathway

Lina Gu,Xufeng Tao,Youwei Xu,Xu Han,Yan Qi,Lina Xu,Lianhong Yin,Jinyong Peng

Oxidative stress is involved in hepatic stellate cells (HSCs) activation and extracellular matrix overproduction. We previously reported the promising effects of dioscin against CCl 4 -induced liver fibrosis, but its effects and mechanisms on BDL- and DMN-induced liver fibrosis remain unknown. The results in the present study indicated that dioscin significantly inhibited HSCs activation and attenuated hepatic fibrosis in rats. Furthermore, dioscin markedly up-regulated the levels of sirtuin 1 (Sirt1), HO-1, GST , GCLC and GCLM via increasing the nuclear translocation of nuclear erythroid factor 2-related factor 2 (Nrf2), which in turn inhibited mitogen-activated protein kinase 14 (p38 MAPK) phosphorylation and reduced the levels of COL1A1, COL3A1, α-SMA and fibronectin . These results were further validated by knockdown of Sirt1 and Nrf2 using siRNAs silencing, and abrogation of p38 MAPK using SB-203580 (a p38 MAPK inhibitor) in HSC-T6 and LX-2 cells. Collectively, our findings confirmed the potent effects of dioscin against liver fibrosis and also provided novel insights into the mechanisms of this compound as a candidate for the prevention of liver fibrosis in the future.

Amarogentin has protective effects against sepsis-induced brain injury via modulating the AMPK/SIRT1/NF-κB pathway

Bihui Song,Wenhao Zhou

Amarogentin (AMA), a secoiridoid glycoside that is mainly derived from SwertiaandGentiana roots, has been confirmed to exhibit antioxidative, tumor-suppressive and anti-diabetic properties. This research intends to investigate the protective effect of AMA against sepsis-induced brain injury and its mechanism. NSC-34 and HT22 cells were treated with lipopolysaccharide (LPS) to induce an in-vitro sepsis model and then treated with varying concentrations (1, 5, 10 µM) of AMA. Cell proliferation and apoptosis were evaluated. The intensity of inflammation and oxidative stress were assessed by different methods. The AMPK/SIRT1/NF-κB pathway expression was determined by WB . An in-vitro sepsis model was set up with cecal ligation and puncture (CLP) in adult C57/BL6J mice, and different concentrations (25, 50, 100 mg/kg) of AMA were applied for treatment. Neurological function was evaluated using the modified neurological severity scores (mNSS), and the brain tissue damage was measured using hematoxylin-eosin (H&E) staining and Nissl staining. Tissue apoptosis was tested using terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining. Then, the AMPK inhibitor Compound C (CC) was administered to confirm AMA-mediated mechanism. Our finding illustrated that AMA mitigated LPS-induced neuronal damage, inflammation and oxidative stress, activated the AMPK/SIRT1 pathway and choked NF-κB phosphorylation. Furthermore, AMA improved neurological functions of sepsis mice by reliving neuroinflammation and oxidative stress. Inhibition of AMPK attenuated the protective effect of AMA on neurons or the mice’s brain tissues. In conclusion, AMA protected against sepsis-induced brain injury by modulating the AMPK/SIRT1/NF-κB pathway.

Dihydromyricetin Inhibits M1 Macrophage Polarization in Atherosclerosis by Modulating miR-9-Mediated SIRT1/NF-κB Signaling Pathway

Zhousheng Yang,Tianyu Li,Chunyan Wang,Mingyu Meng,Shenglan Tan,Lei Chen

Dihydromyricetin (DMY), a natural flavonoid compound extracted from the stems and leaves of Ampelopsis grossedentata, has been found as a potential therapeutic chemical for treating atherosclerosis. This study explores the underlying mechanism of DMY repressing M1 macrophage polarization in atherosclerosis. We showed that DMY treatment markedly decreased M1 macrophage markers (e.g., Tnf-α and IL-1β) and p65-positive macrophage numbers in the vessel wall of Apoe-deficient (Apoe–/–) mice. Overexpression of miR-9 or knockdown of SIRT1 in macrophages reversed the effect of DMY on M1 macrophage polarization. The data we presented in the study indicate that the miR-9-mediated SIRT1/NF-κB pathway plays a pivotal role in M1 macrophage polarization and is one of the molecular mechanisms underlying the anti-atherosclerosis effects of DMY. We provide new solid evidence that DMY may be explored as a potential therapeutic adjuvant for treating atherosclerosis.

Attenuation of Pb-induced Aβ generation and autophagic dysfunction via activation of SIRT1: Neuroprotective properties of resveratrol

Lin Bai,Rundong Liu,Ruike Wang,Yongjuan Xin,Zuntao Wu,Yue Ba,Huizhen Zhang,Xuemin Cheng,Guoyu Zhou,Hui Huang

This study examined the neuroprotective properties of resveratrol (Res) and its target sirtuin1 (SIRT1) against lead (Pb)-mediated toxicity and discovered that both resveratrol treatment and SIRT1 overexpression restored blocked autophagic flux as well as reduced β-amyloid (Aβ) contents. Four-week-old male C57BL/6 mice were employed to consumed 0.2% Pb(Ac) 2 solution or deionized water for 3 months followed by 12 months of Res (50 mg/kg BW) or vehicle gavage. In in vitro study, SH-SY5Y cells were pretreated with the SIRT1 activator SRT1720 (2 μM) or the inhibitor EX527 (2 μM) for 2 h, then 25 μM of Pb(Ac) 2 was added and incubated for 48 h. Western blotting, RT-qPCR, enzyme-linked immunosorbent assay (ELISA), and Lyso-Tracker Red Staining were next used to estimate the potential alterations of the autophagic pathway as well as BACE1-mediated amyloid processing in response to Pb exposure, respectively. Our data revealed that Res treatment or SIRT1 activation resisted the induction of autophagy by Pb exposure through inhibition of LC3 and Beclin-1 expression and promoted the degradation of Aβ and Tau phosphorylation. Besides, the SIRT1 activator (SRT1720) downregulated the expression of BACE1, the rate-limiting enzyme for Aβ production, by inhibiting the activation of nuclear factor-κB (NF-κB) in Pb-treated SH-SY5Y cells, which resulted in reduced Aβ production. Collectively, we verified the role of Res-SIRT1-autophagy as well as the SIRT1-NF-κB-BACE1 pathway in Pb-induced neuronal cell injury by in vivo or in vitro models. Our findings further elucidate the important role of SIRT1 and Res in counteracting Pb neurotoxicity, which may provide new interventions and targets for the subsequent treatment of neurodegenerative diseases.

Early-Life Exposure to Lead Induces Cognitive Impairment in Elder Mice Targeting SIRT1 Phosphorylation and Oxidative Alterations

Zhang Lijie,Tu Runqi,Wang Yawei,Hu Yazhen,Li Xing,Cheng Xuemin,Yin Yanyan,Li Wenjie,Huang Hui

Pb is a potential risk factor for cognition, mainly mediated by enhanced oxidative stress. Resveratrol, a natural polyphenol with crucial anti-oxidative property, is recently implicated in preventing cognitive deficits in normal aging and neurodegenerative disorders. Its beneficial effects have been linked to sirtuin 1(SIRT1) activation. The aim of this work is to investigate the possible linkage between alterations in Pb-induced oxidative damage and cognitive impairment by prolonged treatment of resveratrol. Male C57BL/6 mice were given Pb(Ac)2 treatment or deionized H2O for 12 weeks, and subjected to resveratrol gavage at the dose of 50 mg/kgBw•d or vehicle after Pb exposure. Results from biochemical analysis and immunohistofluorescence showed that Pb induced oxidative DNA damage and decreased cortical antioxidant biomarker. As expected, these abnormalities were improved by resveratrol treatment. Morris water maze test, Western blotting, immunohistofluorescence staining and RT-qPCR indicated that resveratrol ameliorated spatial learning and memory deficits with alterations in hippocampal BDNF-TrkB signaling, promoted nuclear localization and phosphorylation of hippocampal SIRT1, partly increased protein levels of AMPK and PGC-1α involving in modulation of antioxidant response in Pb-exposed mice. Our results support the hypothesis that resveratrol could attenuate Pb-induced cognitive impairment which was associated with activating SIRT1 via modulation of oxidative stress. Additionally, resveratrol also repressed the Pb-induce amyloidogenic processing with resultant decline in cortical Aβ1−−40. Noteworthy, such effects were not mediated by resveratrol treatment alone. These findings emphasize the potential of SIRT1 activator as an efficacious dietary intervention to downgrade the Pb-induced neurotoxic lesion.

Role of SIRT1 in Hepatic Encephalopathy: In Vivo and In Vitro Studies Focusing on the NLRP3 Inflammasome

Fangzhou Jiao,Yao Wang,Qian Chen,Pan Cao,Chunxia Shi,Maohua Pei,Luwen Wang,Zuojiong Gong

Hepatic encephalopathy (HE) is a neuropsychiatric disorder resulting from acute or chronic liver failure. This study is aimed at investigating the therapeutic effects and mechanisms of SIRT1 in thioacetamide- (TAA-) induced rat HE models. A selective activator (CAY10602) and inhibitor (EX527) of SIRT1 were used in this study. All male rats were separated into control, TAA, CAY10602+TAA, and EX527+TAA groups. Histological damage, liver function, serum ammonia, behavioral changes, and brain oxidative stress were measured in each group. Western blotting was used to measure SIRT1, NLRP3, ASC, and IL-1β protein expression. The results showed that CAY10602 alleviated liver injury, improved neurological decline, reduced microglial activation and brain oxidative stress, and improved the survival rates of HE rats. Moreover, CAY10602 inhibited activation of the NLRP3 inflammasome in microglia of the brain cortex in HE rats. Next, cell experiments confirmed that CAY10602 inhibited activation of the NLRP3 inflammasome in BV2 microglial cells. However, inhibition of SIRT1 by EX527 or lentivirus could enhance activation of the NLRP3 inflammasome in this process. Finally, CAY10602 reduced the neurotoxicity induced by high levels of ammonia in HT22 cells. Taken together, CAY10602 alleviates TAA-induced HE by suppressing microglial activation and the NLRP3 inflammasome and reducing the neurotoxicity of NH4Cl in HT22 cells. A pharmacologic activator of SIRT1 may be a promising approach for the treatment of HE.

Isolinderalactone alleviates hepatic ischemia-reperfusion injury by inhibiting endoplasmic reticulum stress through the SIRT1/IRE1α signaling pathway

Hao Li,Zhenyu Guan,Wendong Li,Xiaodan Zhang,Hongwei Tang,Jianjun Yang,Wenzhi Guo,Mingjie Ding

Background Hepatic ischemia-reperfusion injury (HIRI) remains a clinical challenge during liver surgery and transplantation, largely due to the lack of effective pharmacological interventions. Isolinderalactone (ILL), a sesquiterpene lactone, exhibits potent antioxidant and anti-inflammatory properties. However, its therapeutic potential for HIRI and its precise molecular targets, particularly regarding the SIRT1/IRE1α-mediated endoplasmic reticulum stress (ERS) pathway, remain to be elucidated. Objective This study aimed to determine the hepatoprotective effects of ILL against HIRI and investigate its regulatory mechanism centered on the SIRT1/IRE1α signaling axis. Methods HIRI was modeled in mice via ischemia/reperfusion (I/R) and in AML12 cells via hypoxia/reoxygenation (H/R). Cellular injury, oxidative stress, endoplasmic reticulum stress (ERS), apoptosis, and inflammatory responses were assessed using biochemical, histological, molecular, and cellular imaging techniques. The physical and functional interaction between ILL and SIRT1 was characterized through molecular docking, dynamics simulations, surface plasmon resonance, and enzymatic activity assays. The role of SIRT1 was further validated using genetic knockdown and pharmacological inhibition (EX527). Results ILL treatment significantly attenuated liver tissue damage, restored intracellular redox homeostasis, and mitigated ERS-induced inflammation and apoptosis. Mechanistically, ILL not only upregulated SIRT1 expression but also directly bound to SIRT1 to enhance its deacetylase activity, thereby suppressing the downstream IRE1α/TRAF2/JNK signaling cascade. Notably, SIRT1 silencing or pharmacological blockade with EX527 significantly blunted, albeit did not completely abolish, the protective effects of ILL, indicating that the SIRT1/IRE1α axis serves as a primary, though not exclusive, mediator of ILL's hepatoprotective activity. Conclusion ILL attenuates HIRI by simultaneously elevating SIRT1 expression and activating its deacetylase function, thereby restraining IRE1α-dependent ERS and subsequent hepatic injury. These findings highlight ILL as a promising therapeutic candidate for the management of perioperative HIRI.

Evodiamine alleviates IL-1β-induced chondrocyte damage by regulating mitochondrial dysfunction via the SIRT1/PGC-1α pathway

Wang Pu,Sun Congcong,Shi Chao,Gao Yong,Luan Chunyu,Yan Chao

Osteoarthritis (OA) is a degenerative joint disease characterized by pathological changes such as articular cartilage degeneration and bone hyperplasia. Mitochondrial dysfunction in chondrocytes has been identified as a critical factor contributing to the progression of OA. Although Evodiamine (Evo) has been demonstrated effeicacy in inhibiting inflammatory responses and matrix degradation in OA chondrocytes, its effects and underlying mechanisms regarding mitochondrial dysfunction in these cells remain to be elucidated. IL-1β was utilized to stimulate chondrocytes in order to establish an in vitro OA model. Subsequently, the proliferation, lactate dehydrogenase (LDH) release, and apoptosis of chondrocytes were systematically evaluated. Mitochondrial function in chondrocytes was evaluated by quantifying of ATP content, ROS level, mitochondrial DNA (mtDNA) copy number, activities of mitochondrial respiratory chain Complexes I and III, as well as mitochondrial membrane potential change. Furthermore, the protein expression levels of the SIRT1/PGC-1α signaling pathway were examined, and an intervention involving the SIRT1 inhibitor EX527 was conducted to elucidate the potential mechanisms underlying the effects of Evo on chondrocytes. Evo treatment significantly elevated the proliferation activity of IL-1β-stimulated chondrocytes, inhibited LDH release and apoptosis, increased mtDNA copy number and ATP content, enhanced the enzymatic activities of Complexes I and III, and suppressed ROS production as well as mitochondrial membrane potential loss. Furthermore, Evo treatment activated the SIRT1/PGC-1α signaling pathway. However, the addition of the SIRT1 inhibitor EX-527 partially attenuated the protective effects of Evo against IL-1β-induced chondrocyte injury by exacerbating mitochondrial dysfunction. Evo promotes mitochondrial biosynthesis, reduces ROS production and improves mitochondrial function by activating SIRT1/PGC-1α pathway, thereby inhibiting IL-1β-induced chondrocyte injury.

β-Nicotinamide mononucleotide activates the SIRT1/NF-κB pathway to alleviate ischemia reperfusion injury after lung transplantation

Zhu Ganggui,Li Qiaxuan,Yao Qifeng,Zhao Jin,Ding Shuo,Mai Shixiong,Yue Bingqin,Chen Jingyu,Huang Man

Background Lung ischemia-reperfusion injury (LIRI) is associated with a variety of postoperative complications and affects patient prognosis. β-Nicotinamide mononucleotide (NMN) has attracted much attention due to its potential role in cellular energy metabolism and antioxidant properties. Exploring the mitigating role of NMN in ischemia-reperfusion injury after lung transplantation is crucial for improving lung transplantation success and patient quality of life. Methods A LIRI model was established using the mouse left lung portal clamp method, and the cold ischemia-reperfusion (CI/R) model with BEAS-2B cells in vitro was used to simulate the lung transplantation environment. The protective effect of NMN against lung ischemia-reperfusion injury was analyzed by histopathology, ELISA, immunofluorescence, Western blot and RT-PCR. Combined multi-omics profiling were used to study the mechanisms by which NMN attenuated lung ischemia-reperfusion injury. Results NMN significantly attenuated ischemia-reperfusion-induced structural abnormalities, pulmonary edema, inflammatory infiltration and oxidative stress injury in mouse lung tissue. Similarly, NMN attenuated CI/R-induced oxidative stress and inflammatory responses in BEAS-2B cells. Based on multi-omics analysis, we found that NMN ameliorated the apoptosis after ischemia/reperfusion through down-regulation of cleaved Caspase 3, BAX and up-regulation of BCL-2. Moreover, NMN also affected mitochondrial metabolic processes, including promoting mitochondrial oxidative phosphorylation, increasing ATP synthesis, enhancing mitochondrial complex activity, decreasing ROS generation, slowing down the decrease of mitochondrial membrane potential, and inhibiting the opening of the mitochondrial membrane permeability transition pore. Mechanistically, we found that NMN attenuates inflammation and oxidative damage through activation of the SIRT1 and NF-κB signaling pathways, and that SIRT1-specific inhibition of EX527 reversed these protective effects of NMN against inflammation and oxidative damage in vivo and in vitro. Conclusion NMN has a protective effect on inflammation and oxidative damage induced by ischemia-reperfusion injury after lung transplantation, and the SIRT1/NF-κB pathway may be involved in one of the mechanisms of the protective effect.

B7-H3 suppresses doxorubicin-induced senescence-like growth arrest in colorectal cancer through the AKT/TM4SF1/SIRT1 pathway

Wang Ruoqin,Sun Linqing,Xia Suhua,Wu Hongya,Ma Yanchao,Zhan Shenghua,Zhang Guangbo,Zhang Xueguang,Shi Tongguo,Chen Weichang

Emerging evidence suggests that cellular senescence induced by chemotherapy has been recognized as a new weapon for cancer therapy. This study aimed to research novel functions of B7-H3 in cellular senescence induced by a low dose of doxorubicin (DOX) in colorectal cancer (CRC). Here, our results demonstrated that B7-H3 knockdown promoted, while B7-H3 overexpression inhibited, DOX-induced cellular senescence. B7-H3 knockdown dramatically enhanced the growth arrest of CRC cells after low-dose DOX treatment, but B7-H3 overexpression had the opposite effect. By RNA-seq analysis and western blot, we showed that B7-H3 prevented cellular senescence and growth arrest through the AKT/TM4SF1/SIRT1 pathway. Blocking the AKT/TM4SF1/SIRT1 pathway dramatically reversed B7-H3-induced resistance to cellular senescence. More importantly, B7-H3 inhibited DOX-induced cellular senescence of CRC cells in vivo. Therefore, targeting B7-H3 or the B7-H3/AKT/TM4SF1/SIRT1 pathway might be a new strategy for promoting cellular senescence-like growth arrest during drug treatment in CRC.

Dapagliflozin Alleviates Non-Alcoholic Fatty Liver Disease in Mice by Inhibiting Ferroptosis through Activating the SIRT1/Nrf2 Pathway

Min Liu,BiYing Meng,Jing Dong,Lin Xiang