IMMUNITY
·
2024
·
IF 25.5
Jiping Sun,Youqin Zhang,Qingbing Zhang,Lin Hu,Linfeng Zhao,Hongdong Wang,Yue Yuan,Hongshen Niu,Dongdi Wang,Huasheng Zhang,Jianyue Liu,Xujiao Feng,Xiaohui Su,Ju Qiu,Jing Sun,Heping Xu,Catherine Zhang,Kathleen Wang,Yan Bi,Edgar G. Engleman,Lei Shen
Adipose tissue group 2 innate lymphoid cells (ILC2s) help maintain metabolic homeostasis by sustaining type 2 immunity and promoting adipose beiging. Although impairment of the ILC2 compartment contributes to obesity-associated insulin resistance, the underlying mechanisms have not been elucidated. Here, we found that ILC2s in obese mice and humans exhibited impaired liver kinase B1 (LKB1) activation. Genetic ablation of LKB1 disrupted ILC2 mitochondrial metabolism and suppressed ILC2 responses, resulting in exacerbated insulin resistance. Mechanistically, LKB1 deficiency induced aberrant PD-1 expression through activation of NFAT, which in turn enhanced mitophagy by suppressing Bcl-xL expression. Blockade of PD-1 restored the normal functions of ILC2s and reversed obesity-induced insulin resistance in mice. Collectively, these data present the LKB1-PD-1 axis as a promising therapeutic target for the treatment of metabolic disease.
研究领域:
免疫学
·
代谢生物学
·
医学
✓ 已验证
DOI
PubMed
高影响因子
PHARMACEUTICAL BIOLOGY
·
2020
·
IF 2.971
Yucheng Li,Baoying Wang,Jiduo Shen,Ming Bai,Erping Xu
Context Berberine is an alkaloid that possesses various pharmacologic effects.Objective To explore the mechanism of berberine to improve insulin sensitivity in fructose-fed mice.Materials and methods Sixty male ICR mice were randomly divided into 6 groups (10 mice in each group): control, fructose, pioglitazone (10 mg/kg) and berberine (50, 100, and 200 mg/kg). Except for the control group, the mice received 20% fructose drinking for 10 weeks. Pioglitazone and berberine were orally administered once daily during the last 4 weeks. The insulin sensitivity was evaluated using an oral glucose tolerance test (OGTT). The serum levels of fasting glucose and insulin, blood lipids, and hormones were determined. The hepatic AMP and ATP contents were detected using high performance liquid chromatography (HPLC) analysis, and the protein expression was examined by immunoblotting.Results Berberine significantly reversed the insulin resistance induced by fructose, including lowering fasting insulin levels (from 113.9 to 67.4) and area under the curve (AUC) during OGTT (from 1310 to 1073), decreasing serum leptin (from 0.28 to 0.13) and increasing serum adiponectin levels (from 1.50 to 2.80). Moreover, berberine enhanced the phosphorylation levels of protein kinase B (PKB/AKT; 2.27-fold) and glycogen synthase kinase-3β (GSK3β; 2.56-fold), and increased hepatic glycogen content (from 0.19 to 1.65). Furthermore, berberine upregulated the protein expression of peroxisome proliferator activated receptor gamma coactivator 1α (PGC1α; 2.61-fold), phospho-AMP-activated protein kinase (p-AMPK; 1.35-fold) and phospho-liver kinase B1 (p-LKB1; 1.41-fold), whereas it decreased the AMP/ATP ratio (from 4.25 to 1.82).Conclusion The present study demonstrated the protective effects of berberine against insulin resistance induced by fructose. Our findings may provide an experimental basis for the application of berberine in the treatment of insulin resistance.
研究领域:
药理学
·
代谢紊乱
·
分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
EXPERIMENTAL CELL RESEARCH
·
2022
·
IF 4.145
Xiao Li,Xiaowei Sun,Li Li,Yao Luo,Yingjie Chi,Guangying Zheng
Diabetic cataract (DC) is a common complication of diabetes mellitus. The epithelial-mesenchymal transition (EMT) of lens epithelial cells (LECs) is a crucial event in the development of DC. Murine double minute 2 (MDM2) is an E3 ubiquitin ligase that promotes EMT by regulating diverse targets. However, little is known about how MDM2 is involved in the pathogenesis of DC. We found the mRNA and protein levels of MDM2 were up-regulated in the lens of DC patients and rats. Thus, high glucose (HG)-induced human lens epithelial cells (HLECs) were constructed for further investigation. The results showed that the level of MDM2 was increased in HG-cultured HLECs, and the MDM2 knockdown alleviated HG-induced abnormal migration, EMT, and oxidative stress damage. Moreover, co-immunoprecipitation and ubiquitination assays demonstrated that MDM2 down-regulated LKB1 expression by ubiquitination degradation. LKB1 was found to be lower expressed in human and rat DC lenses, and HG-stimulated HLECs. Also, LKB1 overexpression mitigated HG-induced dysfunction of HLECs. Finally, our data showed that the changes related to EMT and oxidative stress induced by MDM2 knockdown were restored by down-regulation of LKB1. Together, MDM2 may involve in the pathogenesis of DC through down-regulating LKB1. MDM2 might be an effective therapeutical target of DC.
研究领域:
眼科学
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细胞生物学
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分子生物学
·
糖尿病
✓ 已验证
产品关联
DOI
PubMed
高影响因子
PHARMACOLOGICAL RESEARCH
·
2019
·
IF 5.574
Jin Wen,Bin Xu,Yuchao Sun,Mengqiao Lian,Yanli Li,Yuan Lin,Dapeng Chen,Yunpeng Diao,Marwan Almoiliqy,Li Wang
Intestinal ischemia-reperfusion (I/R) injury is a common pathological process with high clinical morbidity and mortality. Paeoniflorin , a monoterpene glucoside, is found to have diverse health beneficial effects including autophagy modulation, anti-inflammatory, anti-apoptotic, and anti-oxidative effects. Based on our pre-experiments, we proposed that paeoniflorin could ameliorate intestinal I/R injury and restore autophagy through activating LKB1/AMPK signal pathway. Our proposal was verified using rat intestinal I/R model in vivo and intestinal epithelial cell line (IEC-6 cells) hypoxia/reoxygenation (H/R) model in vitro. Our results showed that paeoniflorin pretreatment exerted protective effects in rat intestinal I/R injury by reducing intestinal morphological damage, inflammation, oxidative stress, and apoptosis . Paeoniflorin restored H/R-impaired autophagy flux by up-regulating autophagy-related protein p62/SQSTM1 degradation, LC3II and beclin-1 expression, and autophagosomes synthesis without significantly affecting control IEC-6 cells. Paeoniflorin pretreatment significantly activated LKB1/AMPK signaling pathway by reversing the decreased LKB1 and AMPK phosphorylation without affecting total LKB1 both in vivo and in vitro . LKB1 knockdown reduced AMPK phosphorylation, suppressed LC3II and Beclin-1 level, and decreased the degradation of SQSTM/p62, and the knockdown weakened the effects of paeoniflorin in restoring the impaired autophagy flux in H/R injured IEC-6 cells, suggesting that paeoniflorin mitigated the intestinal I/R-impaired autophagy flux by activating LKB1/AMPK signaling pathway. Our study may provide valuable information for further studies.
研究领域:
药理学
·
病理生理学
·
细胞生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
PHARMAZIE
·
2018
·Vol. 73
·期 10
·594-597
·
IF 1.016
Wu Bo,Chen Xi,Zhou Ying,Hu Pingjun,Wu Dan,Zheng Guodong,Cai Yi
Background: Andrographolide (Andro) belongs to the main bioactive ingredients of Andrographis paniculata. Many studies have shown that andro has a variety of pharmacological activities such as anti-inflammatory, anti-bacterial, anti-virus, anti-oxidant, immune regulation
and liver protective effects. Moreover andro has been reported to have anticancer activity in multiple types of cancer, including gastric cancer, breast cancer, lung cancer and so on. However, there is no report about the effect of andro on the human NPC cell line C666-1 and the molecular
mechanisms of andro-mediated apoptosis in C666-1 cells remain to be clarified. Methods: Cell proliferation was measured by a CCK8 assay, cell apoptosis rate was evaluated by flow cytometric analysis, and the protein expression of LKB1/AMPK signaling pathways was detected by Western
blotting. Results: Treatment with andro inhibited cell proliferation and induced apoptosis of C666-1 cells. Moreover, andro could activate LKB1-AMPK signaling. We also demonstrated that Ca2+/calmodulin-dependent protein kinase kinaseβ (CaMKKβ) was not involved in
the regulation of andro on AMPK activation in C666-1 Cells. Conclusions: Andro suppressed proliferation and induced apoptosis of C666-1 cells through regulating the LKB1/AMPK/mTOR signal pathway.
研究领域:
肿瘤学
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药理学
·
细胞生物学
·
分子生物学
✓ 已验证
DOI
PubMed
高影响因子
EUROPEAN JOURNAL OF PHARMACOLOGY
·
2023
·
IF 5
Ling Yang,Linzi Li,Qian Lu,Lingfeng Li,Chun Xie,Fakun Jiang,Hongbing Li,Ai Zhao,Qian Wang,Wenyong Xiong
As a global epidemic disease, obesity causes dysfunction of glucose and lipid metabolism leading to persistently high morbidity and mortality. Given the difficulty to achieve and maintain weight loss through controlling diet and physical exercise, pharmacotherapy is considered an effective treatment for obesity. This investigation revealed that alisol B, a triterpene monomer isolated from the classical Chinese medicine Alisma orientale (Sam.) Juzep, functioned in suppressing adipogenesis and reducing the mass of subcutaneous adipose tissue, resulting in the reduction of weight gain, and improvements of hyperglycemia, hyperlipidemia, and insulin resistance in HFD-induced obese mice. In consistent to the results, alisol B also significantly inhibited adipocyte differentiation and maturation in vitro . Furthermore, our data revealed that the effects of alisol B on adipogenesis were mediated by LKB1-AMPK signaling pathway. In total, alisol B could be a potential lead compound which contributes to the improvement of obesity-related metabolic disorders.
研究领域:
药理学
·
代谢学
·
内分泌学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
CELL BIOLOGY INTERNATIONAL
·
2018
·Vol. 42
·期 8
·994-1005
·
IF 1.936
Kuiyuan Song,Guanqun Zheng,Yue Zhao
Lung cancer is one of life-threatening cancers in the worldwide. Liver kinase B1 (LKB1) has been reported to be closely related to cancers; however, the underlying mechanism of LKB1 in lung cancer remains unclear. In our study, a LKB1 specific shRNA was employed to down-regulate LKB1 levels and a LKB1 over-expression plasmid was constructed to up-regulate LKB1 levels. Thereafter, growth of lung cancer cells was assessed by MTT assay and flow cytometry. Effects of LKB1 on the activation of sonic hedgehog (Shh) signaling pathway were detected by Western blot. Effects of LKB1 on lung cancer growth and Shh signaling pathway activation were also assessed in vivo. Our results showed that LKB1 inhibited proliferation of lung cancer cells and induced their apoptosis. Moreover, LKB1 inhibited Shh signaling pathway activation. Our in vivo study also showed that LKB1 inhibited lung cancer growth in vivo and modulated Shh signaling pathway. Treatment with cyclopamine, a Shh signaling pathway inhibitor, reversed the effects of LKB1 silencing and enhanced the effects of LKB1 over-expression. Results of our study demonstrate that LKB1 inhibits lung cancer growth in vitro and in vivo through Shh signaling pathway.
研究领域:
肿瘤学
·
分子生物学
·
细胞生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
BIOORGANIC CHEMISTRY
·
2026
·
IF 5.1
Yongsheng Fang,Han Liu,Fakun Jiang,Qian Lu,Bangrui Huang,Chuanjun Mao,Qian Long,Qixin Zhou,Xiaodong Yang,Jun Cao,Wenyong Xiong
Hepatic steatosis is a chronic progressive condition that leads to multiple severe liver disorders. However, current therapeutic options are limited for available drugs. Screening active natural products for curing hepatic steatosis provide novel chemical scaffolds for drug development and chemical probes to reveal novel mechanisms in the development of hepatic steatosis. Here, we established an in vitro cell model for measuring hepatic lipid content and screened a series of euphorane-type diterpenoids to identify active diterpenoids for decreasing hepatic lipids. Interestingly, among these diterpenoids, euphorbia factor L3 (EFL3) exhibited the most pronounced inhibition activity for lipid amount, both in cultured hepatocytes and in HFD-induced mice with hepatic steatosis. Mechanistic studies demonstrated that EFL3 activated the LKB1-AMPK signaling pathway in hepatocytes, leading to downregulation of the lipogenic factors SREBP-1c, ACC1, and FASN, and leading to upregulation of fatty acid oxidation-related proteins SIRT1, PGC-1α, PPARα, and CPT1A. These changes improved cellular lipid metabolism and ultimately ameliorated hepatic steatosis in mice. In summary, this study supports the key role of LKB1-AMPK pathway in regulation of hepatic steatosis and reveals that EFL3 could be considered as a novel compound for drug development against hepatic steatosis.
✓ 已验证
DOI
PubMed
高影响因子
VETERINARY RESEARCH
·
2023
·Vol. 54
·期 1
·1-12
·
IF 4.4
Fu Shaodong,Wang Zhenglei,Han Xiangan,Xu Yuanyuan,Miao Jinfeng
Macrophages play a pivotal role in the inflammatory response to the zoonotic pathogen E. coli, responsible for causing enteric infections. While considerable research has been conducted to comprehend the pathogenesis of this disease, scant attention devoted to host-derived H2S. Herein, we reported that E. coli infection enhanced the expression of CSE in macrophages, accompanied by a significantly increased inflammatory response. This process may be mediated by the involvement of excessive autophagy. Inhibition of AMPK or autophagy with pharmacological inhibitors could alleviate the inflammation. Additionally, cell model showed that the mRNA expression of classic inflammatory factors (Il-1β, Il-6), macrophage polarization markers (iNOS, Arg1) and ROS production was significantly down-regulated after employing CSE specific inhibitor PAG. And PAG is capable of inhibiting excessive autophagy through the LKB1-AMPK-ULK1 axis. Interestingly, exogenous H2S could suppress inflammation response. Our study emphasizes the importance of CSE in regulating the macrophage-mediated response to E. coli. Increased CSE in macrophages leads to excessive inflammation, which should be considered a new target for drug development to treat intestinal infection.
研究领域:
免疫学
·
微生物学
·
药理学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Nutrients
·
2018
·Vol. 10
·期 8
·1024
·
IF 4.196
Yu-Cheng Li,Jing-Yi Qiao,Bao-Ying Wang,Ming Bai,Ji-Duo Shen,Yong-Xian Cheng
The present study aimed to evaluate the effects of paeoniflorin on insulin resistance and hepatic steatosis induced by fructose. Male Sprague-Dawley rats were fed 20% fructose drink for eight weeks. The insulin sensitivity, serum lipid profiles, and hepatic lipids contents were measured. The results showed that paeoniflorin significantly decreased serum insulin and glucagon levels, improved insulin sensitivity and serum lipids profiles, and alleviated hepatic steatosis in fructose-fed rats. Moreover, paeoniflorin enhanced the phosphorylation level of AMP-activated protein kinase (AMPK) and protein kinase B (PKB/AKT) and inhibited the phosphorylation of acetyl coenzyme A carboxylase (ACC)1 in liver. Paeoniflorin also increased the hepatic carnitine palmitoyltransferase (CPT)-1 mRNA and protein expression and decreased the mRNA expression of sterol regulatory element-binding protein (SREBP)1c, stearyl coenzyme A decarboxylase (SCD)-1 and fatty acid synthetase (FAS). Furthermore, we found that paeoniflorin significantly increased the heptatic protein expression of tumor suppressor serine/threonine kinase (LKB)1 but not Ca2+/CaM-dependent protein kinase kinase (CaMKK)β. These results suggest that the protective effects of paeoniflorin might be involved in the activation of LKB1/AMPK and insulin signaling, which resulted in the inhibition of lipogenesis, as well as the activation of β-oxidation and glycogenesis, thus ameliorated the insulin resistance and hepatic steatosis. The present study may provide evidence for the beneficial effects of paeoniflorin in the treatment of insulin resistance and non-alcoholic fatty liver.Keywords:insulin resistance;hepatic steatosis;paeoniflorin;AMPK
研究领域:
药理学
·
代谢
·
肝病学
✓ 已验证
DOI
PubMed
高影响因子
STEM CELLS AND DEVELOPMENT
·
2023
·
IF 4
Mr. Genghua Xu,Ms. Nuoya Liu,Ms. Yaqing Qiu,Ms. Jiayu Qi,Prof. Danyan Zhu
The histamine H3 receptor, prominently expressed in neurons with a minor presence in glial cells, acts as both an autoreceptor and an alloreceptor, controlling the release of histamine and other neurotransmitters. The receptor impacts various essential physiological processes. Our team's initial investigations had demonstrated that the histamine H3 receptor antagonists could facilitate the nerve regeneration via promoting the histamine H1 receptors on primary neural stem cells in the traumatic brain injury mouse, which suggested the potential of histamine H3 receptor as a promising target for treating neurological disorders and promoting nerve regeneration. Pitolisant (PITO) is the only histamine H3 receptor antagonist approved by the FDA for treating narcolepsy. However, there are no reports on Pitolisant in neural development or regeneration, and it is urgent to be further studied in strong biological activity models in vitro. The embryonic stem (ES) cells were differentiated into neural cells in vitro, which replicated the neurodevelopmental processes that occur in vivo. It also provided an alternative model for studying neurodevelopmental processes and testing drugs for neurological conditions. Therefore, we aimed to elucidate the regulatory role of Pitolisant in the early differentiation of ES cells into neural cells. Our results demonstrated that Pitolisant could promote the differentiation of ES cells towards neural stem cells (NSCs) and stimulated the formation of growth cones. Furthermore, Pitolisant was capable of inducing the polarization of NSCs through the cAMP-LKB1-SAD/MARK2 pathway, but had no significant effect on later neuronal maturation. Pitolisant altered mitochondrial morphology and up-regulated the levels of mitochondrial-related proteins TOM20, Drp1, and p-Drp1, and reversed the inhibitory effect of Mdivi-1 on mitochondrial fission during the early neural differentiation of ES cells. Additionally, Pitolisant induced the increase in cytosolic Ca2+. Our study provided an experimental foundation for the potential application of histamine H3 receptor-targeted modulators in the field of neuroregeneration.
研究领域:
神经科学
·
干细胞生物学
·
药理学
·
细胞生物学
✓ 已验证
DOI
PubMed
高影响因子
JOURNAL OF EXPERIMENTAL MEDICINE
·
2024
·Vol. 221
·期 7
·e20240111
·
IF 12.6
Xue Yun,Chen Yuting,Sun Sijia,Tong Xinyuan,Chen Yujia,Tang Shijie,Wang Xue,Bi Simin,Qiu Yuqin,Zhao Qiqi,Qin Zhen,Xu Qin,Ai Yingjie,Chen Leilei,Zhang Beizhen,Liu Zhijie,Ji Minbiao,Lang Meidong,Chen Luonan,Xu Guoliang,Hu Liang,Ye Dan,Ji Hongbin
Phenotypic plasticity is a rising cancer hallmark, and lung adeno-to-squamous transition (AST) triggered by LKB1 inactivation is significantly associated with drug resistance. Mechanistic insights into AST are urgently needed to identify therapeutic vulnerability in LKB1-deficient lung cancer. Here, we find that ten-eleven translocation (TET)–mediated DNA demethylation is elevated during AST in KrasLSL-G12D/+; Lkb1L/L (KL) mice, and knockout of individual Tet genes reveals that Tet2 is required for squamous transition. TET2 promotes neutrophil infiltration through STAT3-mediated CXCL5 expression. Targeting the STAT3–CXCL5 nexus effectively inhibits squamous transition through reducing neutrophil infiltration. Interestingly, tumor-infiltrating neutrophils are laden with triglycerides and can transfer the lipid to tumor cells to promote cell proliferation and squamous transition. Pharmacological inhibition of macropinocytosis dramatically inhibits neutrophil-to–cancer cell lipid transfer and blocks squamous transition. These data uncover an epigenetic mechanism orchestrating phenotypic plasticity through regulating immune microenvironment and metabolic communication, and identify therapeutic strategies to inhibit AST.
研究领域:
肿瘤学
·
免疫学
·
分子生物学
·
癌症生物学
✓ 已验证
DOI
PubMed
高影响因子
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