bims-amsmem 2023-04-02 papers

bims-amsmem

Biomed News

on AMPK signaling mechanism in energy metabolism

Issue of 2023–04–02
sixteen papers selected by
Dipsikha Biswas, Københavns Universitet

Resveratrol downregulates ENaCs through the activation of AMPK in human colon cancer cells.
AMPK Phosphorylation Impacts Apoptosis in Differentiating Myoblasts Isolated from Atrophied Rat Soleus Muscle.
AMPK activators have compound and concentration-specific effects on brain metabolism.
Globular adiponectin ameliorates insulin resistance in skeletal muscle by enhancing the LKB1-mediated AMPK activation via SESN2.
Muscle Cell Insulin Resistance Is Attenuated by Rosmarinic Acid: Elucidating the Mechanisms Involved.
AMPK activation attenuates cancer-induced bone pain by reducing mitochondrial dysfunction-mediated neuroinflammation.
Ameliorative effects of mangiferin derivative TPX on insulin resistance via PI3K/AKT and AMPK signaling pathways in human HepG2 and HL-7702 hepatocytes.
Ethanol Extract of Rosa laevigata Michx. Fruit Inhibits Inflammatory Responses through NF-κB/MAPK Signaling Pathways via AMPK Activation in RAW 264.7 Macrophages.
Diminishing acetyl-CoA carboxylase 1 attenuates CCA migration via AMPK-NF-κB-snail axis.
Metformin Suppresses Thioacetamide-Induced Chronic Kidney Disease in Association with the Upregulation of AMPK and Downregulation of Oxidative Stress and Inflammation as Well as Dyslipidemia and Hypertension.
Naringenin Attenuates Isoprenaline-Induced Cardiac Hypertrophy by Suppressing Oxidative Stress through the AMPK/NOX2/MAPK Signaling Pathway.
Metformin mitigates renal dysfunction in obese insulin-resistant rats via activation of the AMPK/PPARα pathway.
Distinct Plasma Immune Profile in ALS Implicates sTNFR-II in pAMPK/Leptin Homeostasis.
The N6-methyladenine DNA demethylase ALKBH1 promotes gastric carcinogenesis by disrupting NRF1 binding capacity.
Rosiglitazone Mitigates Dexamethasone-Induced Depression in Mice via Modulating Brain Glucose Metabolism and AMPK/mTOR Signaling Pathway.
Activation of AMPK Entails the Protective Effect of Royal Jelly against High-Fat-Diet-Induced Hyperglycemia, Hyperlipidemia, and Non-Alcoholic Fatty Liver Disease in Rats.

Tissue Cell. 2023 Mar 13. pii: S0040-8166(23)00059-9. [Epub ahead of print]82 102071

Resveratrol downregulates ENaCs through the activation of AMPK in human colon cancer cells.

Ayşe Çakır Gündoğdu, Rumeysa Özyurt.

  Epithelial sodium channels (ENaCs) are critically engaged in a number of hallmarks of cancer progression, including proliferation, migration, invasion and apoptosis. Thus, the inhibition of ENaCs possesses therapeutic potential in cancer. Resveratrol, a natural polyphenol with anti-carcinogenic activity, is a potent activator of 5' AMP-activated protein kinase (AMPK) which reduces the abundance of ENaCs in the cell membrane by causing the internalization of the β subunit. However, the effect of resveratrol on ENaCs in cancer cells is unknown. Therefore, in this study, we aimed to investigate the effects of resveratrol on ENaCs in human colon cancer cells HCT116 and HT29. The influences of resveratrol either alone or together with AMPK inhibitor compound C (CC), and ENaC inhibitor amiloride on cell viability were examined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. The expression levels of phospho-AMPK Thr172 and βENaC in cells were determined by immunofluorescence staining, and the expression of apoptotic markers Caspase-3 and Caspase-9 were analyzed by qRT-PCR. Resveratrol was found to activate AMPK in a dose-dependent manner. Both AMPK activation by resveratrol and ENaC inhibition by amiloride decreased cell viability and increased apoptosis significantly. AMPK activation also reduced βENaC expression in cells. Our results suggest that ENaC inhibition through AMPK activation might be a potential mechanism underlying the anti-cancer effects of resveratrol.

Keywords:  AMPK; Apoptosis; Colon cancer; ENaC; Proliferation; Resveratrol

DOI:  https://doi.org/10.1016/j.tice.2023.102071
Cells. 2023 Mar 16. pii: 920. [Epub ahead of print]12(6):

AMPK Phosphorylation Impacts Apoptosis in Differentiating Myoblasts Isolated from Atrophied Rat Soleus Muscle.

Natalia A Vilchinskaya, Sergey V Rozhkov, Olga V Turtikova, Timur M Mirzoev, Boris S Shenkman.

  Regrowth of atrophied myofibers depends on muscle satellite cells (SCs) that exist outside the plasma membrane. Muscle atrophy appears to result in reduced number of SCs due to apoptosis. Given reduced AMP-activated protein kinase (AMPK) activity during differentiation of primary myoblasts derived from atrophic muscle, we hypothesized that there may be a potential link between AMPK and susceptibility of differentiating myoblasts to apoptosis. The aim of this study was to estimate the effect of AMPK activation (via AICAR treatment) on apoptosis in differentiating myoblasts derived from atrophied rat soleus muscle. Thirty rats were randomly assigned to the following two groups: control (C, n = 10) and 7-day hindlimb suspension (HS, n = 20). Myoblasts derived from the soleus muscles of HS rats were divided into two parts: AICAR-treated cells and non-treated cells. Apoptotic processes were evaluated by using TUNEL assay, RT-PCR and WB. In differentiating myoblasts derived from the atrophied soleus, there was a significant decrease (p < 0.05) in AMPK and ACC phosphorylation in parallel with increased number of apoptotic nuclei and a significant upregulation of pro-apoptotic markers (caspase-3, -9, BAX, p53) compared to the cells derived from control muscles. AICAR treatment of atrophic muscle-derived myoblasts during differentiation prevented reductions in AMPK and ACC phosphorylation as well as maintained the number of apoptotic nuclei and the expression of pro-apoptotic markers at the control levels. Thus, the maintenance of AMPK activity can suppress enhanced apoptosis in differentiating myoblasts derived from atrophied rat soleus muscle.

Keywords:  AICAR; AMPK; TUNEL; apoptosis; caspase-3; hindlimb suspension; primary myoblasts

DOI:  https://doi.org/10.3390/cells12060920
J Neurochem. 2023 Mar 28.

AMPK activators have compound and concentration-specific effects on brain metabolism.

Lavanya B Achanta, Donald S Thomas, Gary D Housley, Caroline D Rae.

AMP-activated protein kinase (AMPK) is a key sensor of energy balance playing important roles in the balancing of anabolic and catabolic activities. The high energy demands of the brain and its limited capacity to store energy indicate that AMPK may play a significant role in brain metabolism. Here, we activated AMPK in guinea pig cortical tissue slices, both directly with A769662 and PF 06409577, and indirectly, using AICAR and metformin. We studied the resultant metabolism of [1-13 C]glucose and [1,2-13 C]acetate using NMR spectroscopy. We found distinct activator concentration dependent effects on metabolism which ranged from decreased metabolic pool sizes at EC50 activator concentrations with no expected stimulation in glycolytic flux, to increased aerobic glycolysis and decreased pyruvate metabolism with certain activators. Further, activation with direct vs indirect activators produced distinct metabolic outcomes at both low (EC50 ) and higher (EC50 x 10) concentrations. Specific direct activation of β1-containing AMPK isoforms with PF 06409577 resulted in increased Krebs cycle activity, restoring pyruvate metabolism while A769662 increased lactate and alanine production as well as labelling of citrate and glutamine. These results reveal a complex metabolic response to AMPK activators in brain beyond increased aerobic glycolysis and indicate that further research is warranted into their concentration and mechanism-dependent impact.

DOI: https://doi.org/10.1111/jnc.15815
Sports Med Health Sci. 2023 Mar;5(1): 34-41

Globular adiponectin ameliorates insulin resistance in skeletal muscle by enhancing the LKB1-mediated AMPK activation via SESN2.

Xinmeng Liu, Yang Yang, Heng Shao, Sujuan Liu, Yanmei Niu, Li Fu.

  Adiponectin has been demonstrated to be a mediator of insulin sensitivity; however, the underlined mechanisms remain unclear. SESN2 is a stress-inducible protein that phosphorylates AMPK in different tissues. In this study, we aimed to validate the amelioration of insulin resistance by globular adiponectin (gAd) and to reveal the role of SESN2 in the improvement of glucose metabolism by gAd. We used a high-fat diet-induced wild-type and SESN2-/- C57BL/6J insulin resistance mice model to study the effects of six-week aerobic exercise or gAd administration on insulin resistance. In vitro study, C2C12 myotubes were used to determine the potential mechanism by overexpressing or inhibiting SESN2. Similar to exercise, six-week gAd administration decreased fasting glucose, triglyceride and insulin levels, reduced lipid deposition in skeletal muscle and reversed whole-body insulin resistance in mice fed on a high-fat diet. Moreover, gAd enhanced skeletal muscle glucose uptake by activating insulin signaling. However, these effects were diminished in SESN2-/- mice. We found that gAd administration increased the expression of SESN2 and Liver kinase B1 (LKB1) and increased AMPK-T172 phosphorylation in skeletal muscle of wild-type mice, while in SESN2-/- mice, LKB1 expression was also increased but the pAMPK-T172 was unchanged. At the cellular level, gAd increased cellular SESN2 and pAMPK-T172 expression. Immunoprecipitation experiment suggested that SESN2 promoted the formation of complexes of AMPK and LKB1 and hence phosphorylated AMPK. In conclusion, our results revealed that SESN2 played a critical role in gAd-induced AMPK phosphorylation, activation of insulin signaling and skeletal muscle insulin sensitization in mice with insulin resistance.

Keywords:  AMP-Activated protein kinase; Adiponectin; Exercise training; Glucose homeostasis; Sestrins

DOI:  https://doi.org/10.1016/j.smhs.2022.08.001
Int J Mol Sci. 2023 Mar 07. pii: 5094. [Epub ahead of print]24(6):

Muscle Cell Insulin Resistance Is Attenuated by Rosmarinic Acid: Elucidating the Mechanisms Involved.

Danja J Den Hartogh, Filip Vlavcheski, Evangelia Tsiani.

  Obesity and elevated blood free fatty acid (FFA) levels lead to impaired insulin action causing insulin resistance in skeletal muscle, and contributing to the development of type 2 diabetes mellitus (T2DM). Mechanistically, insulin resistance is associated with increased serine phosphorylation of the insulin receptor substrate (IRS) mediated by serine/threonine kinases including mTOR and p70S6K. Evidence demonstrated that activation of the energy sensor AMP-activated protein kinase (AMPK) may be an attractive target to counteract insulin resistance. We reported previously that rosemary extract (RE) and the RE polyphenol carnosic acid (CA) activated AMPK and counteracted the FFA-induced insulin resistance in muscle cells. The effect of rosmarinic acid (RA), another polyphenolic constituent of RE, on FFA-induced muscle insulin resistance has never been examined and is the focus of the current study. Muscle cell (L6) exposure to FFA palmitate resulted in increased serine phosphorylation of IRS-1 and reduced insulin-mediated (i) Akt activation, (ii) GLUT4 glucose transporter translocation, and (iii) glucose uptake. Notably, RA treatment abolished these effects, and restored the insulin-stimulated glucose uptake. Palmitate treatment increased the phosphorylation/activation of mTOR and p70S6K, kinases known to be involved in insulin resistance and RA significantly reduced these effects. RA increased the phosphorylation of AMPK, even in the presence of palmitate. Our data indicate that RA has the potential to counteract the palmitate-induced insulin resistance in muscle cells, and further studies are required to explore its antidiabetic properties.

Keywords:  AMPK; GLUT4; IRS-1; free fatty acid; insulin resistance; muscle; palmitate; rosmarinic acid

DOI:  https://doi.org/10.3390/ijms24065094
Acta Biochim Biophys Sin (Shanghai). 2023 Mar 25.

AMPK activation attenuates cancer-induced bone pain by reducing mitochondrial dysfunction-mediated neuroinflammation.

Heyu Yang, Yujia Wang, Shuqing Zhen, Banghua Wang, Ming Jiao, Ling Liu, Dai Li, Haili Zhu, Min Xie.

  Bone metastasis of cancer cells leads to severe pain by disrupting bone structure and inducing central sensitization. Neuroinflammation in the spinal cord plays a decisive role in the maintenance and development of pain. In the current study, male Sprague-Dawley (SD) rats are used to establish a cancer-induced bone pain (CIBP) model by intratibial injection of MRMT-1 rat breast carcinoma cells. Morphological and behavioral analyses verify the establishment of the CIBP model, which represents bone destruction, spontaneous pain and mechanical hyperalgesia in CIBP rats. Activation of astrocytes marked by upregulated glial fibrillary acidic protein (GFAP) and enhanced production of the proinflammatory cytokine interleukin-1β (IL-1β) are accompanied by increased inflammatory infiltration in the spinal cord of CIBP rats. Furthermore, activation of the NOD-like receptor pyrin domain-containing protein 3 (NLRP3) inflammasome is consistent with increased neuroinflammation. Adenosine monophosphate-activated protein kinase (AMPK) activation is involved in attenuating inflammatory pain and neuropathic pain. Intrathecal injection of the AMPK activator AICAR in the lumbar spinal cord reduces dynamin-related protein 1 (Drp1) GTPase activity and suppresses NLRP3 inflammasome activation. This effect consequently alleviates pain behaviors in CIBP rats. Cell research on C6 rat glioma cells indicates that AICAR treatment restores IL-1β-induced impairment of mitochondrial membrane potential and elevation of mitochondrial reactive oxygen species (ROS). In summary, our findings indicate that AMPK activation attenuates cancer-induced bone pain by reducing mitochondrial dysfunction-mediated neuroinflammation in the spinal cord.

Keywords:  AICAR; AMPK; NLRP3-mediated inflammatory signal; cancer-induced bone pain; mitochondrial dysfunction; spinal inflammation

DOI:  https://doi.org/10.3724/abbs.2023039
Phytomedicine. 2023 Mar 11. pii: S0944-7113(23)00098-3. [Epub ahead of print]114 154740

Ameliorative effects of mangiferin derivative TPX on insulin resistance via PI3K/AKT and AMPK signaling pathways in human HepG2 and HL-7702 hepatocytes.

Xiangcheng Fan, Guangyang Jiao, Tao Pang, Tao Wen, Zhiqing He, Jun Han, Feng Zhang, Wansheng Chen.

   BACKGROUND: As a multifaceted metabolic disorder, insulin resistance is accompanied by the preceding onset of type 2 diabetes mellitus, hyperinsulinemia, metabolic dysfunction-associated fatty liver disease (MAFLD) and other metabolic syndromes. Currently, the number of existing drugs and mechanism-based strategies is limited to alleviate insulin resistance in clinics. As a natural polyphenol product derivative, 1,3,6,7-tetrapropylene acyloxy-ketone (TPX) showed a significant hypoglycemic effect in our previous studies. However, whether TPX could improve hepatic insulin sensitivity was unknown.
PURPOSE: To explore whether insulin sensitivity can be improved by the treatment with TPX and further investigate its mechanism(s) of activity.
METHODS: To mimic hyperglycemia and insulin resistance in vitro, human HepG2 and HL-7702 hepatocytes were exposed to high glucose. Cellular glucose uptake, glucose consumption, glycogen synthesis, and glucose production were quantified after TPX treatment. The effects of TPX on AMP-activated protein kinase (AMPK) phosphorylation, glucose metabolism, and insulin signal transduction were evaluated by western blotting and network pharmacology analysis. The eGFP-membrane of glucose transporter type 4 (GLUT4) lentivirus transfected cells were constructed to investigate the effects of TPX on GLUT4 mobilization. Reactive oxygen species activity in high glucose-induced insulin-resistant cells was measured by DCFH-DA to show oxidative stress.
RESULTS: Treatment with TPX improved glycogen synthesis and inhibited gluconeogenesis by regulating GSK3β, G6Pase, and PEPCK. Furthermore, high glucose-induced inhibition of glucose consumption, glucose uptake, and GLUT4-mediated membrane translocation were reverted by TPX. Accordingly, mechanistic investigations revealed that TPX interacted with AMPK protein and activated the phosphorylation of AKT, thereby improving energy homeostasis and further ameliorating hepatic insulin resistance. Network pharmacology analysis and molecular docking further confirmed AMPK as an active target of TPX. Concordantly, the pharmacological activity of TPX was reversed by the AMPK inhibitor compound C when hepatocytes were exposed to high glucose stimulation.
CONCLUSION: In summary, our study confirmed TPX contributions to insulin resistance improvements by targeting AMPK and PI3K/AKT to restore the insulin signaling pathway, which may be an important potential treatment strategy for insulin-resistance-related diseases, including MAFLD and diabetes.

Keywords:  1, 3, 6, 7-tetrapropylene acyloxy-ketone; AMPK; Insulin resistance; Mangiferin

DOI:  https://doi.org/10.1016/j.phymed.2023.154740
Molecules. 2023 Mar 20. pii: 2813. [Epub ahead of print]28(6):

Ethanol Extract of Rosa laevigata Michx. Fruit Inhibits Inflammatory Responses through NF-κB/MAPK Signaling Pathways via AMPK Activation in RAW 264.7 Macrophages.

Hongtan Wu, Tingting Lin, Yupei Chen, Fangfang Chen, Shudi Zhang, Haiyue Pang, Lisen Huang, Chihli Yu, Gueyhorng Wang, Chun Wu.

  The fruit of Rosa laevigata Michx. (FR), a traditional Chinese herb utilized for the treatment of a variety diseases, has notably diverse pharmacological activities including hepatoprotective, anti-oxidant, and anti-inflammatory effects. Despite ongoing research on illustrating the underlying anti-inflammatory mechanism of FR, the principal mechanism remained inadequately understood. In this study, we investigated in depth the molecular mechanism of the anti-inflammatory actions of the ethanol extract of FR (EFR) and its potential targets using lipopolysaccharide (LPS)-stimulated RAW 264.7 macrophages in vitro. We showed that EFR effectively ameliorated the overproduction of inflammatory mediators and cytokines, as well as the expression of related genes. It was further demonstrated that LPS-induced activation of nuclear factor kappa B (NF-κB) and mitogen-activated protein kinases (MAPKs) were significantly inhibited by pretreatment with EFR, accompanied by a concomitant decrease in the nuclear translocation of the p65 subunit of NF-κB and activator protein 1 (AP-1). In addition, EFR pretreatment potently prevented LPS-induced decreased phosphorylation of adenosine monophosphate-activated protein kinase (AMPK). Our data also revealed that the activation of AMPK and subsequent inhibition of the mammalian target of the rapamycin (mTOR) signaling pathway was probably responsible for the inhibitory effect of EFR on LPS-induced inflammatory responses, evidenced by reverse changes observed under the condition of AMPK inactivation following co-treatment with the AMPK-specific inhibitor Compound C. Finally, the main components with an anti-inflammatory effect in EFR were identified as madecassic acid, ellagic acid, quinic acid, and procyanidin C1 by LC-MS and testified based on the inhibition of NO production and inflammatory mediator expression. Taken together, our results indicated that EFR was able to ameliorate inflammatory responses via the suppression of MAPKs/NF-κB signaling pathways following AMPK activation, suggesting the therapeutic potential of EFR for inflammatory diseases.

Keywords:  AMPK/MAPK/NF-κB cascade; EFR; LPS; anti-inflammatory

DOI:  https://doi.org/10.3390/molecules28062813
Biochim Biophys Acta Mol Basis Dis. 2023 Mar 25. pii: S0925-4439(23)00060-1. [Epub ahead of print] 166694

Diminishing acetyl-CoA carboxylase 1 attenuates CCA migration via AMPK-NF-κB-snail axis.

Saowaluk Saisomboon, Ryusho Kariya, Piyanard Boonnate, Kanlayanee Sawanyawisuth, Ubon Cha'on, Vor Luvira, Yaovalux Chamgramol, Chawalit Pairojkul, Wunchana Seubwai, Atit Silsirivanit, Sopit Wongkham, Seiji Okada, Sarawut Jitrapakdee, Kulthida Vaeteewoottacharn.

  Cholangiocarcinoma (CCA), a cancer of the biliary tract, is a significant health problem in Thailand. Reprogramming of cellular metabolism and upregulation of lipogenic enzymes have been revealed in CCA, but the mechanism is unclear. The current study highlighted the importance of acetyl-CoA carboxylase 1 (ACC1), a rate-limiting enzyme in de novo lipogenesis, on CCA migration. ACC1 expression in human CCA tissues was determined by immunohistochemistry. The results demonstrated that increased ACC1 was related to the shorter survival of CCA patients. Herein, ACC1-deficient cell lines (ACC1-KD) were generated by the clustered regularly interspaced short palindromic repeats (CRISPR)-CRISPR-associated protein 9 (cas9) system and were used for the comparative study. The ACC1 levels were 80-90 % lower than in parental cells. Suppression of ACC1 significantly reduced intracellular malonyl-CoA and neutral lipid contents. Two-fold growth retardation and 60-80 % reduced CCA cell migration and invasion were observed in ACC1-KD cells. The reduced 20-40 % of intracellular ATP levels, AMPK activation, lowered NF-κB p65 nuclear translocation, and snail expression were emphasized. Migration of ACC1-KD cells was restored by supplementation with palmitic acid and malonyl-CoA. Altogether, the importance of rate-limiting enzyme in de novo fatty acid synthesis, ACC1, and AMPK-NF-κB-snail axis on CCA progression was suggested herein. These might be the novel targets for CCA drug design. (ACC1, AMPK, Cholangiocarcinoma, De novo lipogenesis, NF-κB, Palmitic acid) (208/250 words).

Keywords:  ACC1; AMPK; Cholangiocarcinoma; De novo lipogenesis; NF-κB; Palmitic acid

DOI:  https://doi.org/10.1016/j.bbadis.2023.166694
Molecules. 2023 Mar 18. pii: 2756. [Epub ahead of print]28(6):

Metformin Suppresses Thioacetamide-Induced Chronic Kidney Disease in Association with the Upregulation of AMPK and Downregulation of Oxidative Stress and Inflammation as Well as Dyslipidemia and Hypertension.

Mohammad Y Alshahrani, Hasnaa A Ebrahim, Saeed M Alqahtani, Nervana M Bayoumy, Samaa S Kamar, Asmaa M ShamsEldeen, Mohamed A Haidara, Bahjat Al-Ani, Alia Albawardi.

  Toxic chemicals such as carbon tetrachloride and thioacetamide (TAA) are reported to induce hepato-nephrotoxicity. The potential protective outcome of the antidiabetic and pleiotropic drug metformin against TAA-induced chronic kidney disease in association with the modulation of AMP-activated protein kinase (AMPK), oxidative stress, inflammation, dyslipidemia, and systemic hypertension has not been investigated before. Therefore, 200 mg/kg TAA was injected (via the intraperitoneal route) in a model group of rats twice a week starting at week 3 for 8 weeks. The control rats were injected with the vehicle for the same period. The metformin-treated group received 200 mg/kg metformin daily for 10 weeks, beginning week 1, and received TAA injections with dosage and timing similar to those of the model group. All rats were culled at week 10. It was observed that TAA induced substantial renal injury, as demonstrated by significant kidney tissue damage and fibrosis, as well as augmented blood and kidney tissue levels of urea, creatinine, inflammation, oxidative stress, dyslipidemia, tissue inhibitor of metalloproteinases-1 (TIMP-1), and hypertension. TAA nephrotoxicity substantially inhibited the renal expression of phosphorylated AMPK. All these markers were significantly protected by metformin administration. In addition, a link between kidney fibrosis and these parameters was observed. Thus, metformin provides profound protection against TAA-induced kidney damage and fibrosis associated with the augmentation of the tissue protective enzyme AMPK and inhibition of oxidative stress, inflammation, the profibrogenic gene TIMP-1, dyslipidemia, and hypertension for a period of 10 weeks in rats.

Keywords:  AMPK; TIMP-1; chronic kidney disease; dyslipidemia; hypertension; inflammation; metformin; oxidative stress; renal fibrosis; thioacetamide

DOI:  https://doi.org/10.3390/molecules28062756
Nutrients. 2023 Mar 09. pii: 1340. [Epub ahead of print]15(6):

Naringenin Attenuates Isoprenaline-Induced Cardiac Hypertrophy by Suppressing Oxidative Stress through the AMPK/NOX2/MAPK Signaling Pathway.

Yu Li, Bo He, Chao Zhang, Yanji He, Tianyang Xia, Chunyu Zeng.

  Cardiac hypertrophy is accompanied by increased myocardial oxidative stress, and whether naringenin, a natural antioxidant, is effective in the therapy of cardiac hypertrophy remains unknown. In the present study, different dosage regimens (25, 50, and 100 mg/kg/d for three weeks) of naringenin (NAR) were orally gavaged in an isoprenaline (ISO) (7.5mg/kg)-induced cardiac hypertrophic C57BL/6J mouse model. The administration of ISO led to significant cardiac hypertrophy, which was alleviated by pretreatment with naringenin in both in vivo and in vitro experiments. Naringenin inhibited ISO-induced oxidative stress, as demonstrated by the increased SOD activity, decreased MDA level and NOX2 expression, and inhibited MAPK signaling. Meanwhile, after the pretreatment with compound C (a selective AMPK inhibitor), the anti-hypertrophic and anti-oxidative stress effects of naringenin were blocked, suggesting the protective effect of naringenin on cardiac hypertrophy. Our present study indicated that naringenin attenuated ISO-induced cardiac hypertrophy by regulating the AMPK/NOX2/MAPK signaling pathway.

Keywords:  AMPK; NOX2; cardiac hypertrophy; naringenin; oxidative stress

DOI:  https://doi.org/10.3390/nu15061340
Arch Pharm Res. 2023 Mar 26.

Metformin mitigates renal dysfunction in obese insulin-resistant rats via activation of the AMPK/PPARα pathway.

Laongdao Thongnak, Nattavadee Pengrattanachot, Sasivimon Promsan, Nichakorn Phengpol, Prempree Sutthasupha, Krit Jaikumkao, Anusorn Lungkaphin.

  Insulin signaling and lipid metabolism are disrupted by long-term consumption of a high-fat diet (HFD). This disruption can lead to insulin resistance, dyslipidemia and subsequently renal dysfunction as a consequence of the inactivation of the AMP-activated protein kinase (AMPK) and peroxisome proliferator-activated receptor-α (PPARα) or AMPK/PPARα pathways. We investigated the impact of metformin on the prevention of renal dysfunction through the modulation of AMPK-regulated PPARα-dependent pathways in insulin-resistant rats induced by a HFD. Male Wistar rats were fed a HFD for 16 weeks to induce insulin resistance. After insulin resistance had been confirmed, metformin (30 mg/kg) or gemfibrozil (50 mg/kg) was given orally for 8 weeks. Evidence of insulin resistance, dyslipidemia, lipid accumulation and kidney injury were observed in HF rats. Impairment of lipid oxidation, energy metabolism and renal organic anion transporter 3 (Oat3) expression and function were demonstrated in HF rats. Metformin can stimulate the AMPK/PPARα pathways and suppress sterol regulatory element-binding transcription factor 1 (SREBP1) and fatty acid synthase (FAS) signaling (SREBP1/FAS) to enable the regulation of lipid metabolism. Renal inflammatory markers and renal fibrosis expression induced by a HFD were more effectively reduced after metformin treatment than after gemfibrozil treatment. Interestingly, renal Oat3 function and expression and kidney injury were improved following metformin and gemfibrozil treatment. Renal cluster of differentiation 36 (CD36) or sodium glucose cotransporter type 2 (SGLT2) expression did not differ after treatment with metformin or gemfibrozil. Metformin and gemfibrozil could reduce the impairment of renal injury in obese conditions induced by a HFD through the AMPK/PPARα-dependent pathway. Interestingly, metformin demonstrated greater efficacy than gemfibrozil in attenuating renal lipotoxicity through the AMPK-regulated SREBP1/FAS signaling pathway.

Keywords:  AMPK/PPARα; Insulin resistance; Metformin; Oat3; Renal function

DOI:  https://doi.org/10.1007/s12272-023-01439-0
Int J Mol Sci. 2023 Mar 07. pii: 5065. [Epub ahead of print]24(6):

Distinct Plasma Immune Profile in ALS Implicates sTNFR-II in pAMPK/Leptin Homeostasis.

Vincent Picher-Martel, Hejer Boutej, Alexandre Vézina, Pierre Cordeau, Hannah Kaneb, Jean-Pierre Julien, Angela Genge, Nicolas Dupré, Jasna Kriz.

  Amyotrophic lateral sclerosis (ALS) is a clinically highly heterogeneous disease with a survival rate ranging from months to decades. Evidence suggests that a systemic deregulation of immune response may play a role and affect disease progression. Here, we measured 62 different immune/metabolic mediators in plasma of sporadic ALS (sALS) patients. We show that, at the protein level, the majority of immune mediators including a metabolic sensor, leptin, were significantly decreased in the plasma of sALS patients and in two animal models of the disease. Next, we found that a subset of patients with rapidly progressing ALS develop a distinct plasma assess immune-metabolic molecular signature characterized by a differential increase in soluble tumor necrosis factor receptor II (sTNF-RII) and chemokine (C-C motif) ligand 16 (CCL16) and further decrease in the levels of leptin, mostly dysregulated in male patients. Consistent with in vivo findings, exposure of human adipocytes to sALS plasma and/or sTNF-RII alone, induced a significant deregulation in leptin production/homeostasis and was associated with a robust increase in AMP-activated protein kinase (AMPK) phosphorylation. Conversely, treatment with an AMPK inhibitor restored leptin production in human adipocytes. Together, this study provides evidence of a distinct plasma immune profile in sALS which affects adipocyte function and leptin signaling. Furthermore, our results suggest that targeting the sTNF-RII/AMPK/leptin pathway in adipocytes may help restore assess immune-metabolic homeostasis in ALS.

Keywords:  AMPK; adipocytes; fast progressors; leptin; plasma; sALS; sTNF-RII

DOI:  https://doi.org/10.3390/ijms24065065
Cell Rep. 2023 Mar 22. pii: S2211-1247(23)00290-5. [Epub ahead of print]42(3): 112279

The N6-methyladenine DNA demethylase ALKBH1 promotes gastric carcinogenesis by disrupting NRF1 binding capacity.

Xiaohong Wang, Chi Chun Wong, Huarong Chen, Kaili Fu, Lingxue Shi, Hao Su, Shang Guo, Hongyan Gou, Xiaoxu Hu, Lianhai Zhang, Jiafu Ji, Jun Yu.

  DNA N6-methyladenine (6mA) is an epigenetic modification that regulates various biological processes. Here, we show that gastric cancer (GC) cells and tumors display a marked reduction in 6mA levels compared with normal gastric tissues and cells. 6mA is abundant in the surrounding transcription start sites and occurs at consensus motifs. Among the 6mA regulators, ALKBH1, a demethylase, is significantly overexpressed in GC tissues compared with adjacent normal tissues. Moreover, high ALKBH1 expression is associated with poor survival of patients with GC. ALKBH1 knockout in mice impairs chemically induced gastric carcinogenesis. Mechanistically, ALKBH1 mediates DNA 6mA demethylation to repress gene expression. In particular, the 6mA sites are enriched in NRF1 binding sequences and targeted for demethylation by ALKBH1. ALKBH1-induced 6mA demethylation inhibits NRF1-driven transcription of downstream targets, including multiple genes involved in the AMP-activated protein kinase (AMPK) signaling pathway. Accordingly, ALKBH1 suppresses AMPK signaling, causing a metabolic shift toward the Warburg effect, which facilitates tumorigenesis.

Keywords:  6mA; ALKBH1; AMPK signaling; CP: Cancer; CP: Molecular biology; NRF1; gastric cancer

DOI:  https://doi.org/10.1016/j.celrep.2023.112279
Biomedicines. 2023 Mar 11. pii: 860. [Epub ahead of print]11(3):

Rosiglitazone Mitigates Dexamethasone-Induced Depression in Mice via Modulating Brain Glucose Metabolism and AMPK/mTOR Signaling Pathway.

Aisha Alhaddad, Asmaa Radwan, Noha A Mohamed, Eman T Mehanna, Yasser M Mostafa, Norhan M El-Sayed, Shaimaa A Fattah.

  Major depressive disorder (MDD) is a common, complex disease with poorly understood pathogenesis. Disruption of glucose metabolism is implicated in the pathogenesis of depression. AMP-activated protein kinase (AMPK) has been shown to regulate the activity of several kinases, including pAKT, p38MAPK, and mTOR, which are important signaling pathways in the treatment of depression. This study tested the hypothesis that rosiglitazone (RGZ) has an antidepressant impact on dexamethasone (DEXA)-induced depression by analyzing the function of the pAKT/p38MAPK/mTOR pathway and NGF through regulation of AMPK. MDD-like pathology was induced by subcutaneous administration of DEXA (20 mg/kg) for 21 days in all groups except in the normal control group, which received saline. To investigate the possible mechanism of RGZ, the protein expression of pAMPK, pAKT, p38MAPK, and 4EBP1 as well as the levels of hexokinase, pyruvate kinase, and NGF were assessed in prefrontal cortex and hippocampal samples. The activities of pAMPK and NGF increased after treatment with RGZ. The administration of RGZ also decreased the activity of mTOR as well as downregulating the downstream signaling pathways pAKT, p38MAPK, and 4EBP1. Here, we show that RGZ exerts a potent inhibitory effect on the pAKT/p38MAPK/mTOR/4EBP1 pathway and causes activation of NGF in brain cells. This study has provided sufficient evidence of the potential for RGZ to ameliorate DEXA-induced depression. A new insight has been introduced into the critical role of NGF activation in brain cells in depression. These results suggest that RGZ is a promising antidepressant for the treatment of MDD.

Keywords:  AMP-activated protein kinase; NGF; dexamethasone; glucose metabolism; hexokinase; mTOR protein; major depressive disorder; mitogen-activated protein kinases; pyruvate kinase; rosiglitazone

DOI:  https://doi.org/10.3390/biomedicines11030860
Nutrients. 2023 Mar 18. pii: 1471. [Epub ahead of print]15(6):

Activation of AMPK Entails the Protective Effect of Royal Jelly against High-Fat-Diet-Induced Hyperglycemia, Hyperlipidemia, and Non-Alcoholic Fatty Liver Disease in Rats.

Alaa Hasanain Felemban, Ghedeir M Alshammari, Abu ElGasim Ahmed Yagoub, Laila Naif Al-Harbi, Maha H Alhussain, Mohammed Abdo Yahya.

  This study examined the mechanism underlying the protective effect of royal jelly (RJ) against high-fat-diet (HFD)-mediated non-alcoholic liver disease (NAFLD) in rats. Adult male rats were divided into five groups (n = 8 each): control fed a standard diet, control + RJ (300 mg/kg), HFD, HFD + RJ (300 mg/kg), and HFD + RJ + CC (0.2 mg/kg). The treatment with RJ reduced weight gain, increased fat pads, and attenuated fasting hyperglycemia, hyperinsulinemia, and glucose tolerance in the HFD-fed rats. It also reduced the serum levels of liver function enzymes, interleukin 6 (IL-6), tumor necrosis factor-α (TNF-α), and leptin but significantly increased the serum levels of adiponectin. In addition, and with no effect on lipid excretion in stool, RJ significantly decreased the hepatic mRNA expression of SREBP1, serum, hepatic cholesterol, and triglycerides but increased hepatic mRNA levels of PPARα. Furthermore, RJ reduced the hepatic levels of TNF-α, IL-6, and malondialdehyde (MDA) in the livers of these rats. Of note, with no effect on the mRNA levels of AMPK, RJ stimulated the phosphorylation of AMPK and increased the levels of superoxide dismutase (SOD) and total glutathione (GSH) in the livers of the control and HFD-fed rats. In conclusion, RJ attenuates NAFLD via its antioxidant potential and adiponectin-independent activation of liver AMPK.

Keywords:  AMPK; NAFLD; hyperglycemia; hyperlipidemia; royal jelly

DOI:  https://doi.org/10.3390/nu15061471