Asian Pacific Journal of Tropical Medicine
·
2015
·
IF 1.062
Chong Shi,Guo-Bin Zhang,Shu-Wang Yin
Objective To explore the effect of bortezomib on migration and invasion of cervical carcinoma HeLa cell and specific molecular mechanism. Methods The effect of bortezomib on the viability of HeLa cell was measured by MTT assay. The effect of bortezomib on cell migration and invasion was measured by Transwell assay and invasion experiment respectively. The activation of Akt/mTOR signaling pathway and expression level of MMP2, MMP9 were assayed by western blot. Results MTT assay indicated bortezomib (2.5 μM, 5 μM, 10 μM) could inhibit HeLa cell viability, and the inhibitory rate was highest at 48 h. Transwell assay and invasion experiment results showed that bortezomib inhibited HeLa cell migration and invasion. Western blotting assays presented bortezomib could suppress the phosphorylation of Akt and mTOR, and down-regulate the expression of MMP2 and MMP9. Conclusions These results suggested bortezomib could inhibit migration and invasion in cervical carcinoma HeLa cell, which might be related to Akt/mTOR signal pathway.
研究领域:
肿瘤学
·
细胞生物学
·
药理学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
JOURNAL OF ETHNOPHARMACOLOGY
·
2020
·
IF 3.69
Li-Juan Deng,Yu-He Lei,Jing-Yu Quan,Bao-Jing Li,Dong-Mei Zhang,Hai-Yan Tian,Ye Chen,En-Xin Zhang,Lei Chen,Wen-Cai Ye,Wei-Min Ning,Lin-Zhong Yu,Jun-Shan Liu
Ethnopharmacological relevance Chansu, dried secretions from Bufonidae , has long been used for cancer treatment as a traditional Chinese medicine . In searching for effective anti-hepatoma agents from Chansu, our preliminary drug screening found that a bufadienolide , namely 1β-hydroxyl-arenobufagin (1β–OH–ABF), displays anti-hepatoma activities. However, the anti-hepatoma effects and molecular mechanisms of 1β–OH–ABF have not been defined. Aim of the study To evaluate the anti-hepatoma activity of 1β–OH–ABF against liver cancer Hep3B and HepG2 cells in vitro and in vivo , as well as explore the underlying mechanisms. Materials and methods The anti-proliferative effects of 1β–OH–ABF on liver cancer Hep3B, HepG2, HuH7, SK-HEP-1 and normal hepatocyte LO2 cells were examined by MTT assay and colony formation assay. Hoechst 33258 staining and Annexin V-FITC/PI staining assay were used to analyze apoptosis induced by 1β–OH–ABF. The collapse of the mitochondrial membrane potential (ΔΨm) was detected by JC-1 staining assay. Western blotting was used to examine the expression levels of targeted proteins. The role of mTOR in 1β–OH–ABF-induced apoptosis was investigated using small interfering RNA (siRNA) transfection. Zebrafish xenograft model was established to evaluate the anti-hepatoma effects of 1β–OH–ABF in vivo . Results We found that 1β–OH–ABF inhibits the proliferation of Hep3B, HepG2, HuH7, SK-HEP-1 cells but has little cytotoxicity towards LO2 cells. 1β–OH–ABF induces mitochondria dysfunction and triggers mitochondria apoptotic pathway, which is accompanied by the loss of ΔΨm, upregulation and translocation of Bax, as well as cleavages of caspase-9, caspase-3 and PARP. Mechanistically, 1β–OH–ABF markedly decreases the expression level of p-AKT/AKT and p-mTOR (Ser2248 and Ser2481)/mTOR in a time-dependent manner. Inhibition of mTOR by siRNA strengthens 1β–OH–ABF-mediated apoptosis. Critically, 1β–OH–ABF shows a marked in vivo anti-hepatoma effect on human Hep3B cell xenografts in zebrafish model. Conclusion 1β–OH–ABF induces mitochondrial apoptosis through the suppression of mTOR signaling in vitro and in vivo , indicating that 1β–OH–ABF may serve as a potential agent for the treatment of liver cancer.
研究领域:
药理学
·
肿瘤学
·
细胞生物学
·
分子生物学
✓ 已验证
DOI
PubMed
高影响因子
BMC Pharmacology & Toxicology
·
2022
·Vol. 23
·期 1
·1-14
·
IF 2.605
Chen Weisin,Yasen Miersalijiang,Wang Hanquan,Zhuang Chenyang,Wang Zixiang,Lu Shunyi,Jiang Libo,Lin Hong
Background Intervertebral disc degeneration results from a variety of etiologies, including inflammation and aging. Degenerated intervertebral discs feature down-regulated extracellular matrix synthesis, resulting in losing their ability to retain water and absorb compression. Celecoxib is a well-known selective cyclooxygenase-2 inhibitor for treating arthritis and relieving pain. Nevertheless, the mechanism of Celecoxib for treating inflammation-related intervertebral disc degeneration has not yet been clarified.MethodProtein synthesis was analyzed by western blot. Fluorescent probes DCFH-DA and MitoSox Red detected reactive oxygen species and were measured by flow cytometry. The activity of the kinase pathway was evaluated by protein phosphorylation. Autophagy was monitored by mRFP-GFP-LC3 transfection and LC3 analysis. Mitochondrial apoptotic proteins were analyzed by western blot and cell membrane integrity was measured by flow cytometry. The autophagic gene was silenced by siRNA.Results In this study, interleukin-1β stimulation reduced the synthesis of aggrecan, type I and II collagen and caused excessive production of reactive oxygen species. We looked for a therapeutic window of Celecoxib for nucleus pulposus cells to regain extracellular matrix synthesis and reduce oxidative stress. To look into nucleus pulposus cells in response to stimuli, enhancement of autophagy was achieved by Celecoxib, confirmed by mRFP-GFP-LC3 transfection and LC3 analysis. The mammalian target of rapamycin and a panel of downstream proteins responded to Celecoxib and propelled autophagy machinery to stabilize homeostasis. Ultimately, inhibition of autophagy by silencing autophagy protein 5 disrupted the protective effects of Celecoxib, culminating in apoptosis.Conclusion In summary, we have demonstrated a new use for the old drug Celecoxib that treats intervertebral disc degeneration by enhancing autophagy in nucleus pulposus cells and opening a door for treating other degenerative diseases.
研究领域:
药理学
·
细胞生物学
·
骨科
·
分子生物学
✓ 已验证
DOI
PubMed
高影响因子
Scientific Reports
·
2026
·
IF 4.9
Da Binlin,Guo Lei,Li Liming,Zhu Feng,Zhang Juanjuan,Wang Zhiming,Guo Feilong
Hyperammonemia is frequently encountered in cirrhosis; nevertheless, its direct hepatotoxic effects remain poorly characterized. In this study, we aimed to delineate the hepatotoxic effects of chronic hyperammonemia and and explore the related mechanisms of liver injury. Thirty male C57BL/6 mice were randomly divided into three groups ( n = 10 per group): a control group, a hyperammonemia group, and a rifaximin-treated group. Starting on day 0, the hyperammonemia and rifaximin-treated groups were fed a diet supplemented with an amino acid (AA) mixture at a 1:2 ratio to normal powdered (NP) diet for 14 consecutive days to establish chronic hyperammonemia, while the control group received NP diet. From day 8 onward, mice in the rifaximin-treated group received rifaximin by gavage at 100 mg/kg once daily for 7 days; the control and hyperammonemia groups received an equivalent volume of 0.9% saline. Twenty-four hours after the final administration, blood was collected; serum was separated by centrifugation and analyzed on an automatic biochemical analyzer for blood ammonia, serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST). Immediately after blood sampling, mice were euthanized; whole brain and liver were rapidly excised, blotted dry, weighed, and used to calculate brain weight and liver index values. Tissue specimens were fixed for hematoxylin–eosin (H&E) staining to evaluate histopathological damage. Commercial kits were used to measure superoxide dismutase (SOD) activity, malondialdehyde (MDA) content, urea content and glutamine synthetase (GS) activity in the liver tissue. Take paraffin sections of liver tissue and use Terminal Deoxynucleotide Transferase dUTP Nick End Labeling (TUNEL) method to detect the apoptosis level of liver cells. Finally, quantitative real-time polymerase chain reaction (qRT-PCR) and Western blot (WB) were performed on liver samples to measure the mRNA and protein expression levels, respectively. Hyperammonemia significantly increased brain weight index, liver index, blood ammonia, serum ALT and AST ( p < 0.001); rifaximin reversed these changes ( p < 0.001). Liver urea content was significantly lower in the hyperammonemia group (0.245 ± 0.008 mmol/g, p < 0.01) than in the control group (0.281 ± 0.004 mmol/g), and rifaximin obviously rescued this reduction and raised hepatic urea to 0.300 ± 0.014 mmol/g ( p < 0.01). Hepatic GS activity declined remarkably in the hyperammonemia group (8.37 ± 0.50, p < 0.05) compared with the control group (8.87 ± 0.41), and rifaximin treatment effectively increased GS activity (9.42 ± 0.27, p < 0.05). Histologically, H&E-stained brain sections from hyperammonemia mice displayed pronounced cytotoxic edema, while liver sections showed disordered hepatocellular cords, and marked inflammatory infiltration, both of which were mitigated by rifaximin. Compared with the control group, the liver tissue SOD activity in the hyperammonemia model group was significantly reduced, and the MDA content was significantly increased ( p < 0.01); After intervention with rifaximin, SOD activity increased and MDA content decreased ( p < 0.01). TUNEL staining further showed that the apoptosis level of liver cells in the model group mice was significantly increased compared to the control group, while treatment with rifaximin significantly reduced the number of apoptotic cells ( p < 0.0001). Mechanically, hyperammonemia-induced hepatic injury are underpinned by its ability to upregulate MAPK/mTOR signaling and downregulate ULK1 activity, thereby impairing autophagic flux. Hyperammonemia may negatively regulate ULK1 activity through the MAPK/mTOR pathway, impair autophagic flux, promote liver oxidative stress and hepatocyte apoptosis, and lead to liver injury.
✓ 已验证
DOI
高影响因子
International Journal of Ophthalmology
·
2026
·Vol. 19
·期 9
·1657
·
IF 2
Wen-Xue Guan,Yue Guo,Si-Tong Chen,Zhi-Ming Liu,Yao-Yao Sun,Ming-Wei Zhao
AIM To investigate whether excessive glucocorticoid (GC) exposure disrupts retinal pigment epithelial (RPE) homeostasis through glucocorticoid receptor (GR)-dependent autophagy hyperactivation. METHODS Human retinal pigment epithelial cell line (ARPE-19 cells) were exposed to GC (0–100 µmol/L, 48h). GR subcellular localization was analyzed via mitochondrial fractionation and immunofluorescence. Functional assessments included barrier integrity [zonula occludens-1 (ZO-1) immunostaining], phagocytic capacity (FluoSpheres™-labeled photoreceptor outer segment uptake), and ultrastructural analysis (transmission electron microscopy, TEM). Autophagic flux was quantified using mCherry-green fluorescent protein-microtubule-associated protein 1A/1B-light chain 3 (LC3) B reporters. Molecular mechanisms were probed through AMP-activated protein kinase (AMPK)/mammalian target of rapamycin (mTOR) pathway activity and autophagic flux assessed by LC3-II levels. GR dependency was confirmed using the antagonist RU486, and cell-type specificity was assessed using mouse photoreceptor (661W) cells. RESULTS GC induced GR upregulation and mitochondrial translocation in a dose- and time-dependent manner, correlating with pathological autophagy activation. Key findings included: 1) tight junction disruption, evidenced by ZO-1 fragmentation, 2) reduction in phagocytic uptake efficiency, 3) mitochondrial shrinkage and autolysosome accumulation (TEM), 4) altered AMPK/mTOR signaling (p-AMPK up, p-mTOR down) associated with autophagosome formation, 5) elevated LC3-II levels confirming excessive autophagic flux. Critically, all GC-induced effects, including GR upregulation, signaling changes, and increased autophagy, were abolished by GR antagonism with RU486. CONCLUSION This study shows that GR-dependent GC exposure induces autophagic flux with ultrastructural evidence suggestive of mitochondria-targeted autophagy and alters AMPK/mTOR signaling, correlating with RPE barrier collapse and phagocytic failure, a possible link to steroid-associated central serous chorioretinopathy (CSC).
✓ 已验证
DOI
PubMed
高影响因子
JOURNAL OF ETHNOPHARMACOLOGY
·
2026
·
IF 6.8
Xiaoli Cui,Di Yang,Zhihong Zhang,Chunmei Wang,He Li,Jinghui Sun,Tianyu Zhang,Mengyang Wang
Ethnopharmacological relevance Forsythiae Fructus, a classic heat-clearing and detoxifying herb in traditional Chinese medicine (TCM), is widely used for inflammatory conditions. Its primary bioactive component, Forsythoside A (FTA), exhibits potent anti-inflammatory and antioxidant activities. Given that hypertensive nephropathy is characterized by chronic inflammation, oxidative stress, and fibrosis-hallmarks that correspond to “heat” and “toxin” pathologies in TCM theory-Forsythiae Fructus represents a rational candidate for HN therapy. However, the precise mechanisms by which FTA inhibits HN progression remain incompletely elucidated. Aim of the study This study aims to investigate the protective effects of FTA against Ang II-induced HN and to elucidate the underlying signaling mechanisms. Materials and methods We established HN models in C57BL/6 mice and NRK-52E cells using Ang II. The effects of FTA on renal injury were investigated through renal dysfunction indicators and tissue staining. RNA sequencing, molecular docking, CETSA and SPR technologies were employed to explore potential target sites and mechanisms of FTA in renal injury. Results FTA mitigated Ang II-induced renal injury by reducing renal dysfunction markers (Cr, BUN and Alb/Cr), restoring renal tissue architecture, and decreasing inflammatory markers ( Ilb, Il6, Tnf ), without exerting antihypertensive effects. RNA sequencing revealed associations with mTOR and ASCL1.Taken together, our in vivo and in vitro data reveal that FTA binds to ASCL1 and inhibits its activity, subsequently blocking the downstream CCNB1/mTOR pathway to confer renal protection. This inhibition promotes mitophagy and inhibits ferroptosis, ultimately alleviating renal injury. Conclusions This study confirmed that FTA can bind to ASCL1, targeting the ASCL1-CCNB1/mTOR pathway to protect the kidney from Ang II-induced injury, offering broad therapeutic prospects for the treatment of HN.
✓ 已验证
产品关联
DOI
PubMed
高影响因子
INTERNATIONAL IMMUNOPHARMACOLOGY
·
2025
·
IF 4.7
Xinyi Li,Hui Song,Yiwen Yuan,Na Jiang,Wei Duan,Tianzhao Xu,Chang Liu,Xinghui Liu
Cardiovascular diseases have long posed a significant threat to public health. Among them, myocarditis is a major category of cardiovascular disorders that is characterized by high mortality during its acute phase, necessitating urgent medical attention. This study aims to explore the therapeutic effects and underlying mechanisms of Spi1-mediated gene regulation in chemotherapy induced cardiomyopathy. To validate our findings, we employed bioinformatics analysis methods and established myocarditis models using the chemotherapeutic drug doxorubicin in both cellular and animal models. Our results demonstrated that the inhibition of Spi1 significantly suppressed inflammatory factor expression in H9C2 rat cardiomyocytes. Furthermore, in C57BL/6 mouse model, Spi1 inhibition was shown to improve cardiac function and alleviate both myocardial inflammation and fibrosis in mice with doxorubicin-induced myocarditis. Mechanistic investigations revealed that Spi1 suppression altered the expression of genes associated with immune response, cell differentiation and proliferation. Notably, Spi1 modulates the expression of YTHDF2, thereby influencing the PI3K/AKT/mTOR signaling pathway and subsequently regulating the inflammatory response. Collectively, these findings suggest that Spi1 plays a pivotal role in doxorubicin-induced myocarditis by mitigating inflammatory responses and myocardial injury through the regulation of YTHDF2 and the PI3K/AKT/mTOR signaling pathways, offering a promising therapeutic target for the treatment of myocarditis.
研究领域:
心血管研究
·
分子生物学
·
药理学
·
肿瘤学
·
信号转导
✓ 已验证
产品关联
DOI
PubMed
高影响因子
PHYTOTHERAPY RESEARCH
·
2025
·
IF 6.3
Bingqing Liang,Fengxian Shi,Can Jin,Min Chen,Yuxiao Niu,Anhong Li,Weihua Xu,Zhongping Ning,Fengfeng Xue,Xinming Li,Yuzhong Yan
Curcumin, a highly hydrophobic phenolic compound, has demonstrated potent anticancer activity. However, poor water solubility and a short biological half-life hinder its clinical application. We developed Curcumin-loaded Pluronic F-127 nanoparticles to enhance the bioavailability of Curcumin. It has been reported that excessive autophagy is considered to be the main mechanism of death of various cancer cells. The aim of this study is to investigate whether the Curcumin-loaded Pluronic F-127 nanoparticles exert anti-colon cancer effects by modulating autophagy and explore the specific regulatory mechanism. The proliferative, migratory and apoptotic activity of CT26 cells was assessed by CCK-8 assay, wound healing assay and flow cytometry, respectively. In addition, levels of reactive oxygen species (ROS) were examined by DCFH-DA assay in vitro. ATP levels were detected by the ELISA. The expression levels of autophagy-related proteins and apoptosis-related proteins were visualized by western blotting. Curcumin-loaded Pluronic F-127 nanoparticle inhibited the proliferation of CT26 cells and the growth of colon tumours by promoting cellular autophagy. In addition, Curcumin-loaded Pluronic F-127 nanoparticle reduced mitochondrial membrane potential and impaired mitochondrial function by increasing ROS levels, disrupting ATP biosynthesis. Then the decreased ATP/AMP ratio activated the AMPK/mTOR/ULK1 autophagy signalling pathway and induced autophagy-dependent apoptosis in CT26 cells. Intriguingly, the apoptosis and excessive autophagy induced by Curcumin-loaded Pluronic F-127 nanoparticle were reversed after pretreatment with the antioxidant N-acetyl-L-cysteine. Curcumin-loaded Pluronic F-127 nanoparticle induced autophagy-dependent apoptosis through ROS-AMPK/mTOR/ULK1 signalling in colon cancer cells. Our study offers new insights for colon cancer treatment advancement.
研究领域:
肿瘤学
·
纳米医学
·
分子生物学
·
药理学
·
细胞信号转导
✓ 已验证
产品关联
DOI
PubMed
高影响因子
MOLECULES
·
2023
·Vol. 28
·期 8
·3482
·
IF 4.6
Xingru Chen,Xiaolan Zhou,Xiaoqing Cheng,Liting Lin,Qi Wang,Ruoting Zhan,Qingguang Wu,Sijun Liu
In neurodegenerative diseases, microglial activation and neuroinflammation are essential for the control and progression of neurodegenerative diseases. Mitigating microglium-induced inflammation is one strategy for hindering the progression of neurodegenerative diseases. Ferulic acid (FA) is an effective anti-inflammatory agent, but its potential role and regulation mechanism in neuroinflammatory reactions have not been fully studied. In this study, the neuroinflammation model was established by lipopolysaccharide (LPS), and the inhibitory effect of FA on neuroinflammation of BV2 microglia was studied. The results showed that FA significantly reduced the production and expression of reactive oxygen species (ROS), tumor necrosis factor-α (TNF-α), leukocyte-6 (IL-6) and interleukin-1β (IL-1β). We further studied the mechanism of FA’s regulation of LPS-induced BV2 neuroinflammation and found that FA can significantly reduce the expression of mTOR in BV2 microglia induced by LPS, and significantly increase the expression of AMPK, indicating that FA may have an anti-inflammatory effect by activating the AMPK/mTOR signaling pathway to regulate the release of inflammatory mediators (such as NLRP3, caspase-1 p20 and IL-1β). We further added an autophagy inhibitor (3-MA) and an AMPK inhibitor (compound C, CC) for reverse verification. The results showed that FA’s inhibitory effects on TNF-α, IL-6 and IL-1β and its regulatory effect on AMPK/mTOR were destroyed by 3-MA and CC, which further indicated that FA’s inhibitory effect on neuroinflammation is related to its activation of the AMPK/mTOR autophagy signaling pathway. In a word, our experimental results show that FA can inhibit LPS-induced neuroinflammation of BV2 microglia by activating the AMPK/mTOR signaling pathway, and FA may be a potential drug for treating neuroinflammatory diseases.Keywords:BV2 microglia;ferulic acid;autophagy;AMPK/mTOR signaling pathway;NLRP3 inflammasome;neuroinflammation
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Cell Death & Disease
·
2023
·Vol. 14
·期 1
·1-12
·
IF 9
Yuan Baoshi,Shi Kexin,Zha Juanmin,Cai Yujia,Gu Yue,Huang Kai,Yue Wenchang,Zhai Qiaocheng,Ding Ning,Ren Wenyan,He Weiqi,Xu Ying,Wang Tao
Osteosarcoma is the most common primary malignant bone tumour in children and adolescents. Chemoresistance leads to poor responses to conventional therapy in patients with osteosarcoma. The discovery of novel effective therapeutic targets and drugs is still the main focus of osteosarcoma research. Nuclear receptors (NRs) have shown substantial promise as novel therapeutic targets for various cancers. In the present study, we performed a drug screen using 29 chemicals that specifically target 17 NRs in several different human osteosarcoma and osteoblast cell lines. The retinoic acid receptor beta (RARb) antagonist LE135, peroxisome proliferator activated receptor gamma (PPARg) antagonist T0070907, liver X receptor (LXR) agonist T0901317 and Rev-Erba agonist SR9011 significantly inhibited the proliferation of malignant osteosarcoma cells (U2OS, HOS-MNNG and Saos-2 cells) but did not inhibit the growth of normal osteoblasts. The effects of these NR modulators on osteosarcoma cells occurred in a dose-dependent manner and were not observed in NR-knockout osteosarcoma cells. These NR modulators also significantly inhibited osteosarcoma growth in vivo and enhanced the antitumour effect of doxorubicin (DOX). Transcriptomic and immunoblotting results showed that these NR modulators may inhibit the growth of osteosarcoma cells by regulating the PI3K/AKT/mTOR and ERK/mTOR pathways. DDIT4, which blocks mTOR activation, was identified as one of the common downstream target genes of these NRs. DDIT4 knockout significantly attenuated the inhibitory effects of these NR modulators on osteosarcoma cell growth. Together, our results revealed that modulators of RARb, PPARg, LXRs and Rev-Erba inhibit osteosarcoma growth both in vitro and in vivo through the mTOR signaling pathway, suggesting that treatment with these NR modulators is a novel potential therapeutic strategy.
✓ 已验证
产品关联
DOI
PubMed
高影响因子
NAUNYN-SCHMIEDEBERGS ARCHIVES OF PHARMACOLOGY
·
2022
·Vol. 396
·期 4
·683-692
·
IF 3.195
Huang Hui,Xue Jie,Xie Tao,Xie Mei-Lin
Osthole is a natural coumarin substance that has an inhibitory effect on hepatic cancer, but its radiosensitization effect on hepatoma cells has not been reported. This study aimed to investigate the effect of osthole. Human HCC-LM3 and SK-Hep-1 hepatoma cells were used and treated with or without osthole, irradiation, or their combination; the cell survival, migration, colony formation, DNA damage repair, intracellular lactic acid content, and glycolysis-related glycogen synthase kinase-3β (GSK-3β), p-GSK-3β, AMP-activated protein kinase (AMPK), p-AMPK, mammalian target of rapamycin (mTOR), p-mTOR, glucose transporter-1 (GLUT-1), GLUT-3, and pyruvate kinase isozyme type M2 (PKM2) protein expressions were determined. Compared with the irradiation group, the osthole plus irradiation group could further decrease the survival rate, migration, colony formation, and DNA damage repair of both hepatoma cells, indicating a synergistic effect of the combination treatment. Moreover, the combination of osthole and irradiation could decrease the content of intracellular lactic acid, ratios of intracellular p-GSK-3β/GSK-3β and p-mTOR/mTOR proteins, and expressions of intracellular GLUT-1/3 and PKM2 proteins, and increase the ratio of intracellular p-AMPK/AMPK proteins. Osthole can increase the radiosensitivity of hepatoma cells, and its radiosensitization mechanisms may be related to glycolytic inhibition by attenuating the GSK-3β/AMPK/mTOR pathway.
✓ 已验证
产品关联
DOI
PubMed
高影响因子
MOLECULAR NEUROBIOLOGY
·
2022
·Vol. 59
·期 11
·6903-6917
·
IF 5.682
Zhao Maofang,Cheng Yuan,Wang Xiaoxuan,Cui Xiaoying,Cheng Xiaojing,Fu Qian,Song Yilin,Yu Peiquan,Liu Yi,Yu Yinghua
Obesity has become a public health epidemic worldwide and is associated with many diseases with high mortality including hypertension, diabetes, and heart disease. High-fat diet (HFD)-induced energy imbalance is one of the primary causes of obesity, but the underlying mechanisms are not fully elucidated. Our study showed that HFD reduced the level of hydrogen sulfide (H 2 S) and its catalytic enzyme cystathionine β-synthase (CBS) in mouse hypothalamus and plasma. We found that HFD activated mTOR, IKK/NF-κB, the main pathway regulating inflammation. Activation of inflammatory pathway promoted the production of pro-inflammatory cytokines including IL-6, IL-1β, and TNF-α, which caused cell damage and loss in the hypothalamus. The disturbance of the hypothalamic neuron circuits resulted in body weight gain in HFD-induced mice. Importantly, we also showed that restoration of H 2 S level with NaHS or activation of CBS with SAMe attenuated HFD-induced activation of mTOR, IKK/NF-κB signaling, which reduced the inflammation and the neuronal cell loss in the hypothalamus, and also inhibited body weight gain in mice. The same effects were obtained by inhibiting mTOR or NF-κB, which suggested that mTOR and NF-κB were the critical molecular factors involved in hypothalamic inflammation. Taken together, this study identified that HFD-induced hypothalamus inflammation plays a critical role in the development of obesity. Moreover, the inhibition of hypothalamic inflammation by regaining H 2 S level could be a potential therapeutic to prevent the development of obesity. Graphical abstract
✓ 已验证
DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）