bims-amsmem 2023-01-22 papers

bims-amsmem

Biomed News

on AMPK signaling mechanism in energy metabolism

Issue of 2023–01–22
fourteen papers selected by
Dipsikha Biswas, Københavns Universitet

New Insights into the Basic and Translational Aspects of AMPK Signaling.
A new AMPK isoform mediates glucose-restriction induced longevity non-cell autonomously by promoting membrane fluidity.
Tschimganidine reduces lipid accumulation through AMPK activation and alleviates high-fat diet-induced metabolic diseases.
Targeting de novo lipid synthesis induces lipotoxicity and impairs DNA damage repair in glioblastoma mouse models.
In-silico identification of Tyr232 in AMPKα2 as a dephosphorylation site for the protein tyrosine phosphatase PTP-PEST.
Ginsenoside Rd promotes omentin secretion in adipose through TBK1-AMPK to improve mitochondrial biogenesis via WNT5A/Ca2+ pathways in heart failure.
The Novel Inhibitory Effect of YM976 on Adipocyte Differentiation.
Undaria pinnatifida (Wakame) Intake Ameliorates High-Fat Diet-Induced Glucose Intolerance via Promoting GLUT4 Expression and Membrane Translocation in Muscle.
Lycorine protects against septic myocardial injury by activating AMPK-related pathways.
Impact of AMPK on cervical carcinoma progression and metastasis.
AMPK-Regulated Autophagy Contributes to Ursolic Acid Supplementation-Alleviated Hepatic Steatosis and Liver Injury in Chronic Alcohol-Fed Mice.
Astaxanthin promotes mitochondrial biogenesis and antioxidant capacity in chronic high-intensity interval training.
New Treatment for Type 2 Diabetes Mellitus Using a Novel Bipyrazole Compound.
Rhinacanthin C Ameliorates Insulin Resistance and Lipid Accumulation in NAFLD Mice via the AMPK/SIRT1 and SREBP-1c/FAS/ACC Signaling Pathways.

Cells. 2023 Jan 04. pii: 206. [Epub ahead of print]12(2):

New Insights into the Basic and Translational Aspects of AMPK Signaling.

Yury Ladilov, Muhammad Aslam.

5'-adenosine monophosphate (AMP)-activated protein kinase (AMPK) is an enzyme regulating numerous cellular processes involved in cell survival as well as health- and lifespan [...].

DOI: https://doi.org/10.3390/cells12020206
Nat Commun. 2023 Jan 18. 14(1): 288

A new AMPK isoform mediates glucose-restriction induced longevity non-cell autonomously by promoting membrane fluidity.

Jin-Hyuck Jeong, Jun-Seok Han, Youngae Jung, Seung-Min Lee, So-Hyun Park, Mooncheol Park, Min-Gi Shin, Nami Kim, Mi Sun Kang, Seokho Kim, Kwang-Pyo Lee, Ki-Sun Kwon, Chun-A Kim, Yong Ryoul Yang, Geum-Sook Hwang, Eun-Soo Kwon.

Dietary restriction (DR) delays aging and the onset of age-associated diseases. However, it is yet to be determined whether and how restriction of specific nutrients promote longevity. Previous genome-wide screens isolated several Escherichia coli mutants that extended lifespan of Caenorhabditis elegans. Here, using 1H-NMR metabolite analyses and inter-species genetics, we demonstrate that E. coli mutants depleted of intracellular glucose extend C. elegans lifespans, serving as bona fide glucose-restricted (GR) diets. Unlike general DR, GR diets don't reduce the fecundity of animals, while still improving stress resistance and ameliorating neuro-degenerative pathologies of Aβ42. Interestingly, AAK-2a, a new AMPK isoform, is necessary and sufficient for GR-induced longevity. AAK-2a functions exclusively in neurons to modulate GR-mediated longevity via neuropeptide signaling. Last, we find that GR/AAK-2a prolongs longevity through PAQR-2/NHR-49/Δ9 desaturases by promoting membrane fluidity in peripheral tissues. Together, our studies identify the molecular mechanisms underlying prolonged longevity by glucose specific restriction in the context of whole animals.

DOI: https://doi.org/10.1038/s41467-023-35952-z
BMB Rep. 2023 Jan 17. pii: 5831. [Epub ahead of print]

Tschimganidine reduces lipid accumulation through AMPK activation and alleviates high-fat diet-induced metabolic diseases.

Min-Seon Hwang, Jung-Hwan Baek, Jun-Kyu Song, In Hye Lee, Kyung-Hee Chun.

Obesity increases the risk of mortality and morbidity because it results in hypertension, heart disease, and type 2 diabetes. Therefore, there is an urgent need for pharmacotherapeutic drugs to treat obesity. We performed a screening assay using natural products with anti-adipogenic properties in 3T3-L1 cells and determined that tschimganidine, a terpenoid from the Umbelliferae family, inhibited adipogenesis. To evaluate the anti-obesity effects of tschimganidine in vivo. Mice were fed either a normal chow diet (NFD) or a high-fat chow diet (HFD) with or without tschimganidine for 12 weeks. Treatment with tschimganidine decreased lipid accumulation and adipogenesis, accompanied by reduced expression of adipogenesis and lipid accumulation-related factors. Tschimganidine significantly increased the phosphorylation of AMP-activated protein kinase (AMPK) and decreased that of AKT. Depletion of AMPK relieved the reduction in lipid accumulation resulting from tschimganidine treatment. Moreover, tschimganidine administration drastically reduced the weight and size of both gonadal white adipose tissue (WAT) and blood glucose levels in high-fat diet-induced obese mice. We suggest that tschimganidine is a potent anti-obesity agent, which impedes adipogenesis and improves glucose homeostasis. Tschimganidine can then be evaluated for clinical application as a therapeutic agent.
Sci Transl Med. 2023 Jan 18. 15(679): eabq6288

Targeting de novo lipid synthesis induces lipotoxicity and impairs DNA damage repair in glioblastoma mouse models.

Katharina M Eyme, Alessandro Sammarco, Roshani Jha, Hayk Mnatsakanyan, Caline Pechdimaljian, Litia Carvalho, Rudolph Neustadt, Charlotte Moses, Ahmad Alnasser, Daniel F Tardiff, Baolong Su, Kevin J Williams, Steven J Bensinger, Chee Yeun Chung, Christian E Badr.

Deregulated de novo lipid synthesis (DNLS) is a potential druggable vulnerability in glioblastoma (GBM), a highly lethal and incurable cancer. Yet the molecular mechanisms that determine susceptibility to DNLS-targeted therapies remain unknown, and the lack of brain-penetrant inhibitors of DNLS has prevented their clinical evaluation as GBM therapeutics. Here, we report that YTX-7739, a clinical-stage inhibitor of stearoyl CoA desaturase (SCD), triggers lipotoxicity in patient-derived GBM stem-like cells (GSCs) and inhibits fatty acid desaturation in GSCs orthotopically implanted in mice. When administered as a single agent, or in combination with temozolomide (TMZ), YTX-7739 showed therapeutic efficacy in orthotopic GSC mouse models owing to its lipotoxicity and ability to impair DNA damage repair. Leveraging genetic, pharmacological, and physiological manipulation of key signaling nodes in gliomagenesis complemented with shotgun lipidomics, we show that aberrant MEK/ERK signaling and its repression of the energy sensor AMP-activated protein kinase (AMPK) primarily drive therapeutic vulnerability to SCD and other DNLS inhibitors. Conversely, AMPK activation mitigates lipotoxicity and renders GSCs resistant to the loss of DNLS, both in culture and in vivo, by decreasing the saturation state of phospholipids and diverting toxic lipids into lipid droplets. Together, our findings reveal mechanisms of metabolic plasticity in GSCs and provide a framework for the rational integration of DNLS-targeted GBM therapies.

DOI: https://doi.org/10.1126/scitranslmed.abq6288
Proteins. 2023 Jan 16.

In-silico identification of Tyr232 in AMPKα2 as a dephosphorylation site for the protein tyrosine phosphatase PTP-PEST.

Amrutha Manikandan, T S Sreevidya, Narayanan Manoj, Satyavani Vemparala, Madhulika Dixit.

  The AMP-activated protein kinase (AMPK) is known to be activated by the protein tyrosine phosphatase non-receptor type 12 (PTP-PEST) under hypoxic conditions. This activation is mediated by tyrosine dephosphorylation of the AMPKα subunit. However, the identity of the phosphotyrosine residues that PTP-PEST dephosphorylates remains unknown. In this study, we first predicted the structure of the complex of the AMPKα2 subunit and PTP-PEST catalytic domain using bioinformatics tools and further confirmed the stability of the complex using molecular dynamics simulations. Evaluation of the protein-protein interfaces indicated that residue Tyr232 is the most likely dephosphorylation site on AMPKα2. In addition, we explored the effect of phosphorylation of PTP-PEST residue Tyr64 on the stability of the complex. Phosphorylation of the highly conserved Tyr64, an interface residue, enhances the stability of the complex via the rearrangement of a network of electrostatic interactions in conjunction with conformational changes in the catalytic WPD loop. We generated a phosphomimetic (PTP-PEST-Y64D) mutant and used co-immunoprecipitation to study the effect of PTP-PEST phosphorylation on AMPKα2 binding. The mutant exhibited an increased affinity for AMPKα2 and corroborated the in-silico predictions. Together, our findings present a plausible structural basis of AMPK regulation by PTP-PEST and show how phosphorylation of PTP-PEST affects its interaction with AMPKα2. This article is protected by copyright. All rights reserved.

Keywords:  AMP-Activated Protein Kinase; Molecular docking analysis; Molecular dynamics simulation; Phosphorylation sites; Protein Tyrosine Phosphatase

DOI:  https://doi.org/10.1002/prot.26470
Redox Biol. 2023 Jan 14. pii: S2213-2317(23)00011-3. [Epub ahead of print]60 102610

Ginsenoside Rd promotes omentin secretion in adipose through TBK1-AMPK to improve mitochondrial biogenesis via WNT5A/Ca2+ pathways in heart failure.

Shiyao Wan, ZeKun Cui, Lingling Wu, Fan Zhang, Tao Liu, Jingui Hu, Jiangwei Tian, Boyang Yu, Fuming Liu, Junping Kou, Fang Li.

  Ginsenoside Rd is an active ingredient in Panax ginseng CA Mey and can be absorbed into the adipose tissue. Adipokines play an important role in the treatment of cardiovascular diseases. However, the potential benefit of Rd on heart failure (HF) and the underlying mechanism associated with the crosstalk between adipocytes and cardiomyocytes remains to be illustrated. Here, the results identified that Rd improved cardiac function and inhibited cardiac pathological changes in transverse aortic constriction (TAC), coronary ligation (CAL) and isoproterenol (ISO)-induced HF mice. And Rd promoted the release of omentin from the adipose tissue and up-regulated omentin expression in lipopolysaccharide (LPS)-induced 3T3-L1 adipocytes. Further, Rd could increase TBK1 and AMPK phosphorylation in adipocytes. And also, the TBK1-AMPK signaling pathway regulated the expression of omentin in LPS-induced adipocytes. Moreover, the omentin mRNA expression was significantly decreased by TBK1 knockdown in LPS-induced 3T3-L1 adipocytes. Additionally, molecular docking and SPR analysis confirmed that Rd had a certain binding ability with TBK1, and co-treatment with TBK1 inhibitors or TBK1 knockdown partially abolished the effect of Rd on increasing the omentin expression and the ratio of p-AMPK to AMPK in adipocytes. Moreover, we found that circulating omentin level diminished in the HF patients compared with healthy subjects. Meanwhile, the adipose tissue-specific overexpression of omentin improved cardiac function, reduced myocardial infarct size and ameliorated cardiac pathological features in CAL-induced HF mice. Consistently, exogenous omentin reduced mtROS levels and restored ΔψM to improve oxygen and glucose deprivation (OGD)-induced cardiomyocytes injury. Further, omentin inhibited the WNT5A/Ca2+ signaling pathway and promoted mitochondrial biogenesis function to ameliorate myocardial ischemia injury. However, WNT5A knockdown inhibited the impairment of mitochondrial biogenesis and partially counteracted the cardioprotective effect of omentin in vitro. Therefore, this study indicated that Rd promoted omentin secretion from adipocytes through the TBK1-AMPK pathway to improve mitochondrial biogenesis function via WNT5A/Ca2+ signaling pathway to ameliorate myocardial ischemia injury, which provided a new therapeutic mechanism and potential drugs for the treatment of HF.

Keywords:  Adipose-myocardium crosstalk; Ginsenoside Rd; Heart failure; Mitochondrial biogenesis; Omentin; WNT5A

DOI:  https://doi.org/10.1016/j.redox.2023.102610
Cells. 2023 Jan 04. pii: 205. [Epub ahead of print]12(2):

The Novel Inhibitory Effect of YM976 on Adipocyte Differentiation.

Hee Jung Kim, Dong-Hoon Kim, Sung Hee Um.

  The pyrimidine derivative YM976 (4-(3-chlorophenyl)-1,7-diethylpyrido(2,3-d)-pyrimidin-2(1H)-one) exerts anti-inflammatory and anti-asthmatic effects. Considering that accumulation of lipids in adipose tissue is accompanied by inflammation, we investigated whether YM976 affects adipocyte differentiation. We found that YM976 significantly decreased lipid accumulation without cytotoxicity and reduced the expression levels of peroxisome proliferator-activated receptor γ (PPARγ) and CCAAT/enhancer-binding protein α (C/EBPα) as well as their lipogenic regulators including fatty acid synthase (FASN) and fatty acid-binding protein 4 (FABP4) in 3T3-L1 cells induced for differentiation. YM976 mainly inhibited the early stage of adipocyte differentiation. Furthermore, intracellular cAMP level was elevated by YM976 resulting in increased phosphorylation of adenosine monophosphate-activated protein kinase (AMPK). Conversely, decreasing the levels of AMPK or treatment with Compound C, an AMPK inhibitor, lessened the suppressive effects of YM976 on PPARγ transcriptional activity and adipogenesis. Thus, our results suggest YM976 as a novel potential compound for controlling lipid accumulation and formation of adipocytes in obesity.

Keywords:  AMPK; YM976; adipocyte differentiation; lipid metabolism; obesity

DOI:  https://doi.org/10.3390/cells12020205
J Nutr Metab. 2023 ;2023 9774157

Undaria pinnatifida (Wakame) Intake Ameliorates High-Fat Diet-Induced Glucose Intolerance via Promoting GLUT4 Expression and Membrane Translocation in Muscle.

Motoki Imai, Fumitaka Kawakami, Mutsumi Chiba, Makoto Kanzaki, Hiroko Maruyama.

Type 2 diabetes mellitus (T2DM), a lifestyle-related disease, is developed due to eating habits and decreased physical activity. Diabetes also increases the risk of cancer and major neurodegenerative diseases; controlling the onset of diabetes helps prevent various illnesses. Eating seaweed, such as Undaria pinnatifida (wakame), is a part of the Asian food culture. Therefore, we analyzed the antidiabetic effect of wakame intake using the high-fat diet-induced diabetes mouse model. Furthermore, we analyzed the effect of wakame extract on the cell membrane translocation of glucose transporter-4 (GLUT4) and activation of insulin signal molecules, such as AKT and AMPK, in insulin-sensitive tissues. Differentiated C2C12 cells were incubated with wakame components. The membrane translocation of GLUT4 and phosphorylation of AKT and AMPK were investigated with immunofluorescence staining and Western blotting, respectively. Also, male C57BL/6J mice were fed the normal diet (ND), high-fat diet (HFD), ND with 1% wakame powder (ND + W), or HFD with 1% wakame powder (HFD + W). We evaluated the effect of wakame intake on high-fat diet-induced glucose intolerance using an oral glucose tolerance test. Moreover, we analyzed insulin signaling molecules, such as GLUT4, AKT, and AMPK, in muscle using Western blotting. GLUT4 membrane translocation was promoted by wakame components. Also, GLUT4 levels and AKT and AMPK phosphorylation were significantly elevated by wakame components in C2C12 cells. In addition, the area under the curve (AUC) of the HFD + W group was significantly smaller than that of the HFD group. Furthermore, the level of GLUT4 in the muscle was increased in the wakame intake group. This study revealed that various wakame components exerted antidiabetic effects on the mice on a high-fat diet by promoting glucose uptake in the skeletal muscle, enhancing GLUT4 levels, and activating AKT and AMPK.

DOI: https://doi.org/10.1155/2023/9774157
Free Radic Biol Med. 2023 Jan 17. pii: S0891-5849(23)00011-4. [Epub ahead of print]

Lycorine protects against septic myocardial injury by activating AMPK-related pathways.

Huadong Zhao, Ying Chen, Lu Qian, Luyang Du, Xue Wu, Ye Tian, Chao Deng, Shuai Liu, Wenwen Yang, Chenxi Lu, Yan Zhang, Jun Ren, Yang Yang.

  Cardiac dysfunction is a common complication in patients with sepsis triggering high morbidity and mortality. Lycorine (LYC), the main effective monomer component extracted from Lycoris bulbs, possesses antiviral, anti-inflammatory, analgesic, liver protection properties. In this study, the effect of LYC pre- and post-treatment as well as the underlying mechanism were evaluated in the cecal ligation and puncture (CLP) model of BALB/c mice. The survival rate, anal temperature, sepsis score, blood biochemical/routine indicators, cardiac function and structure, sepsis-related pathophysiological processes, and AMPK signaling in septic mice were observed by echocardiography, histological staining, western blot, qPCR, and etc. LYC pretreatment attenuated myocardial injury in septic mice by reducing inflammation, inhibiting oxidative stress, improving mitochondrial function, modulating endoplasmic reticulum (ER) stress, and activating AMPK pathway. In particular, AMPK deficiency and AMPK inhibitor (Compound C) partially reversed the protective effects of LYC in septic mice. In addition, LYC posttreatment also has slight protective phenotypes on septic myocardial injury, but the effect is not as ideal as pretreatment. Taken together, these findings suggest that LYC may be a potential drug for the treatment of sepsis.

Keywords:  AMPK; Lycorine; Sepsis; Septic myocardial injury

DOI:  https://doi.org/10.1016/j.freeradbiomed.2023.01.010
Cell Death Dis. 2023 Jan 19. 14(1): 43

Impact of AMPK on cervical carcinoma progression and metastasis.

Paweł Konieczny, Tomasz Adamus, Maciej Sułkowski, Klaudia Skrzypek, Marcin Majka.

Cervical cancer (CC) is the fourth most common malignant neoplasm among women. Late diagnosis is directly associated with the incidence of metastatic disease and remarkably limits the effectiveness of conventional anticancer therapies at the advanced tumor stage. In this study, we investigated the role of 5'AMP-activated kinase (AMPK) in the metastatic progression of cervical cancer. Since the epithelial mesenchymal transition (EMT) is known as major mechanism enabling cancer cell metastasis, cell lines, which accurately represent this process, have been used as a research model. We used C-4I and HTB-35 cervical cancer cell lines representing distant stages of the disease, in which we genetically modified the expression of the AMPK catalytic subunit α. We have shown that tumor progression leads to metabolic deregulation which results in reduced expression and activity of AMPK. We also demonstrated that AMPK is related to the ability of cells to acquire invasive phenotype and potential for in vivo metastases, and its activity may inhibit these processes. Our findings support the hypothesis that AMPK is a promising therapeutic target and modulation of its expression and activity may improve the efficacy of cervical cancer treatment.

DOI: https://doi.org/10.1038/s41419-023-05583-9
ACS Omega. 2023 Jan 10. 8(1): 907-914

AMPK-Regulated Autophagy Contributes to Ursolic Acid Supplementation-Alleviated Hepatic Steatosis and Liver Injury in Chronic Alcohol-Fed Mice.

Yue Ma, Qinchao Ding, Qianyu Qian, Luyan Feng, Qin Zhu, Caijuan Si, Xiaobing Dou, Songtao Li.

Alcoholic liver disease (ALD) is a chronic liver disease caused by long-term heavy consumption of alcohol. The pathogenesis of ALD is complex, and there is no effective clinical treatment at present. Ursolic acid (UA), a general triterpenoid with multiple biological roles, is widely distributed in plants. This study aims to explore the therapeutic effect and potential mechanisms of UA that protect against liver injury and hepatic steatosis in an ALD mouse model. In this study, we analyzed the lipid accumulation and the effect of UA treatment in a mouse model of ALD; AML12 and HepG2 cells were used to study the biological effect and potential mechanisms of UA on ethanol-induced hepatotoxicity. The morphologic and histological detections showed that UA significantly reduced alcohol-induced liver injury and hepatic steatosis. In addition, UA dramatically ameliorated alcohol-induced metabolic disorders, oxidative stress, and inflammation. Furthermore, UA treatment activated autophagy via the AMPK-ACC pathway to protect hepatocytes from lipotoxicity. Thus, these findings demonstrate that UA treatment alleviates alcoholic-induced liver injury by activating autophagy through the AMPK-ACC pathway. Therefore, UA may represent a promising candidate for the treatment of ALD.

DOI: https://doi.org/10.1021/acsomega.2c06252
Eur J Nutr. 2023 Jan 17.

Astaxanthin promotes mitochondrial biogenesis and antioxidant capacity in chronic high-intensity interval training.

Yang Wang, Xiaoping Chen, Julien S Baker, Gareth W Davison, Shujun Xu, Yingsong Zhou, Xiaoming Bao.

   PURPOSE: Reactive oxygen and nitrogen species are required for exercise-induced molecular adaptations; however, excessive exercise may cause cellular oxidative distress. We postulate that astaxanthin (ASX) can neutralize oxidative distress and stimulate mitochondrial biogenesis in high-intensity exercise-trained mice.
METHODS: Six-week-old mice (n = 8/group) were treated with ASX (10 mg/kg BW) or placebo. Training groups participated in 30 min/day high-intensity interval training (HIIT) for 6 weeks. Gastrocnemius muscle was collected and assayed following the exercise training period.
RESULTS: Compared to the HIIT control mice, the ASX-treated HIIT mice reduced malonaldehyde levels and upregulated the expression of Nrf2 and FOXO3a. Meanwhile, the genes NQO1 and GCLC, modulated by Nrf2, and SOD2, regulated by FOXO3a, and GPx4, were transcriptionally upregulated in the ASX-treated HIIT group. Meanwhile, the expression of energy sensors, AMPK, SIRT1, and SIRT3, increased in the ASX-treated HIIT group compared to the HIIT control group. Additionally, PGC-1α, regulated by AMPK and SIRT1, was upregulated in the ASX-treated HIIT group. Further, the increased PGC-1α stimulated the transcript of NRF1 and Tfam and mitochondrial proteins IDH2 and ATP50. Finally, the ASX-treated HIIT mice had upregulations in the transcript level of mitochondrial fusion factors, including Mfn1, Mfn2, and OPA1. However, the protein level of AMPK, SIRT1, and FOXO3a, and the transcript level of Nrf2, NQO1, PGC-1α, NRF1, Mfn1, Mfn2, and OPA1 decreased in the HIIT control group compared to the sedentary control group.
CONCLUSION: Supplementation with ASX can reduce oxidative stress and promote antioxidant capacity and mitochondrial biogenesis during strenuous HIIT exercise in mice.

Keywords:  Astaxanthin; High-intensity interval training; Mitochondrial biogenesis; Nrf2; Oxidative stress; PGC-1α; RONS

DOI:  https://doi.org/10.1007/s00394-023-03083-2
Cells. 2023 Jan 09. pii: 267. [Epub ahead of print]12(2):

New Treatment for Type 2 Diabetes Mellitus Using a Novel Bipyrazole Compound.

Abdelrahim Alqudah, Esam Y Qnais, Mohammed A Wedyan, Sara Altaber, Rawan Abudalo, Omar Gammoh, Hakam Alkhateeb, Sajeda Bataineh, Rabaa Y Athamneh, Muna Oqal, Kayed Abu-Safieh, Lana McClements.

  2',3,3,5'-Tetramethyl-4'-nitro-2'H-1,3'-bipyrazole (TMNB) is a novel bipyrazole compound with unknown therapeutic potential in diabetes mellitus. This study aims to investigate the anti-diabetic effects of TMNB in a high-fat diet and streptozotocin-(HFD/STZ)-induced rat model of type 2 diabetes mellitus (T2D). Rats were fed HFD, followed by a single low dose of STZ (40 mg/kg). HFD/STZ diabetic rats were treated orally with TMNB (10 mg/kg) or (200 mg/kg) metformin for 10 days before terminating the experiment and collecting plasma, soleus muscle, adipose tissue, and liver for further downstream analysis. TMNB reduced the elevated levels of serum glucose in diabetic rats compared to the vehicle control group (p < 0.001). TMNB abrogated the increase in serum insulin in the treated diabetic group compared to the vehicle control rats (p < 0.001). The homeostasis model assessment of insulin resistance (HOMA-IR) was decreased in the diabetic rats treated with TMNB compared to the vehicle controls. The skeletal muscle and adipose tissue protein contents of GLUT4 and AMPK were upregulated following treatment with TMNB (p < 0.001, < 0.01, respectively). TMNB was able to upregulate GLUT2 and AMPK protein expression in liver (p < 0.001, < 0.001, respectively). LDL, triglyceride, and cholesterol were reduced in diabetic rats treated with TMNB compared to the vehicle controls (p < 0.001, 0.01, respectively). TMNB reduced MDA and IL-6 levels (p < 0.001), and increased GSH level (p < 0.05) in diabetic rats compared to the vehicle controls. Conclusion: TMNB ameliorates insulin resistance, oxidative stress, and inflammation in a T2D model. TMNB could represent a promising therapeutic agent to treat T2D.

Keywords:  2′,3,3,5′-tetramethyl-4′-nitro-2′H-1,3′-bipyrazole; diabetes; inflammation; insulin resistance; oxidative stress

DOI:  https://doi.org/10.3390/cells12020267
Evid Based Complement Alternat Med. 2023 ;2023 6603522

Rhinacanthin C Ameliorates Insulin Resistance and Lipid Accumulation in NAFLD Mice via the AMPK/SIRT1 and SREBP-1c/FAS/ACC Signaling Pathways.

Zhiqiang Gong, Sha Han, Chenlin Li, Tianxiu Meng, Yu Huo, Xianfu Liu, Yanhong Huang, Lifang Yang.

Rhinacanthin C (RC) is a naphthoquinone ester with an anti-inflammatory activity extracted from Rhinacanthus nasutus (L.) Kurz (Rn). It has been proven to improve hyperglycemia and hyperlipidemia, but the prevention and mechanism of RC in nonalcoholic fatty liver disease (NAFLD) are not clear. In the current study, we first extracted RC from Rn using ethyl acetate and identified it by HPLC, MS, and NMR. At the same time, molecular docking analysis of RC with AMPK and SREBP-1c was performed using AutoDock software. In addition, the mouse model of NAFLD was induced by a high-fat diet in vivo, and low, medium, and high concentrations of RC were used for intervention. The results showed that RC significantly reduced the body mass and liver body coefficient of NAFLD mice, inhibited liver inflammation and fat accumulation, and improved insulin resistance. Further studies showed that RC significantly reduced the levels of serum leptin and resistin, upregulated the expression levels of adiponectin and adiponectin receptor in the liver, and inhibited the expression levels of MCP-1, TNF-α, and IL-6. In terms of mechanism, RC upregulates the expression of p-AMPK and SIRT1 and downregulates the expression of p-p65, SREBP-1c, Fas, Acc-α, PPAR-γ, and SCD1. These studies suggest that RC improves insulin resistance and lipid accumulation in NAFLD by activating the AMPK/SIRT1 and SREBP-1c/Fas/ACC pathways, respectively.

DOI: https://doi.org/10.1155/2023/6603522