bims-amsmem 2023-06-04 papers

bims-amsmem

Biomed News

on AMPK signaling mechanism in energy metabolism

Issue of 2023‒06‒04
eight papers selected by
Dipsikha Biswas, Københavns Universitet

Natural activators of AMPK signaling: potential role in the management of type-2 diabetes.
Metformin protects fibroblasts from patients with GNE myopathy by restoring autophagic flux via an AMPK/mTOR-independent pathway.
Canagliflozin mitigates carfilzomib-induced endothelial apoptosis via an AMPK-dependent pathway.
Metformin protects against retinal ischemia/reperfusion injury through AMPK-mediated mitochondrial fusion.
Editorial: Phytochemicals targeting autophagy in treatment of bacterial infection and malignancies.
Effect of Oleanolic acid administration on hepatic AMPK, SIRT-1, IL-6 and NF-κB levels in experimental diabetes.
Exercise-Induced Autophagy Ameliorates Motor Symptoms Progressivity in Parkinson's Disease Through Alpha-Synuclein Degradation: A Review.
Energy stress modulation of AMPK/FoxO3 signaling inhibits mitochondria-associated ferroptosis.

J Diabetes Metab Disord. 2023 Jun;22(1): 47-59

Natural activators of AMPK signaling: potential role in the management of type-2 diabetes.

Sanyogita Chauhan, Aakash Partap Singh, Avtar Chand Rana, Sunil Kumar, Ravi Kumar, Jitender Singh, Ashok Jangra, Dinesh Kumar.

  Adenosine 5'-monophosphate-activated protein kinase (AMPK) is an evolutionarily conserved serine/threonine kinase involved in the homeostasis of cellular energy. AMPK has developed as an appealing clinical target for the diagnosis of multiple metabolic diseases such as diabetes mellitus, obesity, inflammation, and cancer. Genetic and pharmacological studies indicate that AMPK is needed in response to glucose deficiency, dietary restriction, and increased physical activity for preserving glucose homeostasis. After activation, AMPK influences metabolic mechanisms contributing to enhanced ATP production, thus growing processes that absorb ATP simultaneously. In this review, several natural products have been discussed which enhance the sensitivity of AMPK and alleviate sub complications or different pathways by which such AMPK triggers can be addressed. AMPK Natural products as potential AMPK activators can be developed as alternate pharmacological intervention to reverse metabolic disorders including type 2 diabetes.

Keywords:  AMPK activators; Insulin; Natural products; Type 2 diabetes

DOI:  https://doi.org/10.1007/s40200-022-01155-4
Biomed Pharmacother. 2023 May 29. pii: S0753-3322(23)00748-5. [Epub ahead of print]164 114958

Metformin protects fibroblasts from patients with GNE myopathy by restoring autophagic flux via an AMPK/mTOR-independent pathway.

Tongtong Zhang, Xiang Yin, Xuefan Yu, Ren Shang, Liuzhe Lu, Jing Miao.

  UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase (GNE) myopathy is an autosomal recessive disease characterized by rimmed vacuoles (RVs). Previous studies have shown that metformin protects against several neuromuscular disorders. In the present study, we summarize the clinical features of three GNE patients with the p.D207V mutation. The pathogenesis of GNE myopathy is described, and the significance of metformin in this disease is observed. Skin biopsy-derived fibroblasts from patients with GNE myopathy, carrying a D207V mutation in GNE, were cultured. GNE fibroblasts and control fibroblasts were treated under normal culture conditions, serum starvation conditions, or serum starvation + metformin conditions. Histopathological and immunohistochemical analyses of muscle samples showed that autophagy was involved in the formation of RVs in the muscle of patients. Starved GNE fibroblasts showed decreased autophagy-related proteins and impaired autophagic flow (p < 0.05). The mRFP-GFP-LC3 assay showed that the fusion of autophagosomes with lysosomes was partially blocked in GNE cells. Notably, metformin treatment upregulated the expression of autophagy proteins, increased the number of autolysosomes (p < 0.001), and influenced the viability of GNE cells (p < 0.001). Furthermore, adenosine 5'-monophosphate (AMP)-activated protein kinase (AMPK) and phosphorylated (p)-AMPK expression levels were upregulated in serum-starved GNE fibroblasts, while the mammalian target of rapamycin (mTOR) and p-mTOR expression levels were downregulated in both groups. Metformin treatment inhibited the AMPK-mTOR signaling pathway. Our results suggest that metformin plays a protective role in the GNE fibroblast by restoring autophagic flux and through the AMPK/mTOR-independent pathway.

Keywords:  AMPK; Autophagy; GNE myopathy; Metformin

DOI:  https://doi.org/10.1016/j.biopha.2023.114958
Biomed Pharmacother. 2023 May 27. pii: S0753-3322(23)00697-2. [Epub ahead of print]164 114907

Canagliflozin mitigates carfilzomib-induced endothelial apoptosis via an AMPK-dependent pathway.

Mohamed S Dabour, Ibrahim Y Abdelgawad, Marianne K O Grant, Engie S El-Sawaf, Beshay N Zordoky.

  Carfilzomib (CFZ) is a proteasome inhibitor approved for relapsed/refractory multiple myeloma (MM) but its clinical use is limited by cardiovascular toxicity. The mechanisms of CFZ-induced cardiovascular toxicity are not fully understood but endothelial dysfunction may be a common denominator. Here, we first characterized the direct toxic effects of CFZ on endothelial cells (HUVECs and EA.hy926 cells) and tested whether SGLT2 inhibitors, known to have cardioprotective effects, can protect against CFZ-induced toxicity. To determine the chemotherapeutic effect of CFZ in the presence of SGLT2 inhibitors, MM and lymphoma cells were treated with CFZ with or without canagliflozin. CFZ decreased cell viability and induced apoptotic cell death in endothelial cells in a concentration-dependent manner. CFZ also upregulated ICAM-1 and VCAM-1 and downregulated VEGFR-2. These effects were associated with the activation of Akt and MAPK pathways, inhibition of p70s6k, and downregulation of AMPK. Canagliflozin, but not empagliflozin or dapagliflozin, protected endothelial cells from CFZ-induced apoptosis. Mechanistically, canagliflozin abrogated CFZ-induced JNK activation and AMPK inhibition. AICAR (an AMPK activator) protected from CFZ-induced apoptosis, and compound C (an AMPK inhibitor) abrogated the protective effect of canagliflozin, strongly suggesting that AMPK mediates these effects. Canagliflozin did not interfere with the anticancer effect of CFZ in cancer cells. In conclusion, our findings demonstrate for the first time the direct toxic effects of CFZ in endothelial cells and the associated signaling changes. Canagliflozin abrogated the apoptotic effects of CFZ in endothelial cells in an AMPK-dependent mechanism, without interfering with its cytotoxicity in cancer cells.

Keywords:  AMPK; Canagliflozin; Carfilzomib; Endothelial Cells; SGLT2 inhibitors

DOI:  https://doi.org/10.1016/j.biopha.2023.114907
Free Radic Biol Med. 2023 May 28. pii: S0891-5849(23)00435-5. [Epub ahead of print]

Metformin protects against retinal ischemia/reperfusion injury through AMPK-mediated mitochondrial fusion.

Kun Zhang, Tao Wang, Gui-Feng Sun, Jin-Xing Xiao, Li-Ping Jiang, Fang-Fang Tou, Xin-Hui Qu, Xiao-Jian Han.

  Retinal ischemia/reperfusion (I/R) injury is a common pathological process responsible for cellular damage in glaucoma, diabetic retinopathy and hypertensive retinopathy. Metformin is a biguanide drug that exerts strong effects on multiple diseases. This study aims to evaluate the protective effect of metformin against retinal I/R injury and its underlying mechanism. I/R induced reduction in retina thickness and cell number in ganglion cell layer, and metformin alleviated I/R-induced retinal injury. Both retinal I/R and simulated ischemia/reperfusion (SIR) in R28 cells down-regulated expression of mitochondrial fusion protein Mfn2 and OPA1, which led to mitochondrial fission. Metformin also alleviated damage in R28 cells, and reversed the alteration in Mfn2 and OPA1, mitochondrial fission and mitochondrial membrane potential (MMP) disruption-induced by I/R or SIR as well. Intriguingly, inhibition of AMPK by compound C or siRNA prevented metformin-mediated up-regulation of Mfn2 and OPA1. Compound C and knockdown of Mfn2 or OPA1 dramatically alleviated the protective effect of metformin against intracellular ROS generation, MMP disruption, mitochondrial fission and loss of RGCs in ganglion cell layer-induced by SIR or I/R. Moreover, scavenging mitochondrial ROS (mito-ROS) by mito-TEMPO exerted the similar protection against I/R-induced retinal injury or SIR-induced damage in R28 cells as metformin. Our data show for the first time that metformin protects against retinal I/R injury through AMPK-mediated mitochondrial fusion and the decreased mito-ROS generation. These findings might also repurpose metformin as a therapeutic agent for retinal I/R injury.

Keywords:  AMPK; Metformin; Mitochondrial dynamics; Reactive oxygen species; Retinal ischemia/reperfusion injury

DOI:  https://doi.org/10.1016/j.freeradbiomed.2023.05.019
Front Pharmacol. 2023 ;14 1205764

Editorial: Phytochemicals targeting autophagy in treatment of bacterial infection and malignancies.

Xiaoxue Bai, Lei Song.



Keywords:  AMP-activated protein kinase (AMPK); apoptosis; cancer; chemotherapy; mammalian target of rapamycin (mTOR)

DOI:  https://doi.org/10.3389/fphar.2023.1205764
J Diabetes Metab Disord. 2023 Jun;22(1): 581-590

Effect of Oleanolic acid administration on hepatic AMPK, SIRT-1, IL-6 and NF-κB levels in experimental diabetes.

Hatice Iskender, Eda Dokumacioglu, Kubra Asena Terim Kapakin, Ismail Bolat, Behzat Mokhtare, Armagan Hayirli, Guler Yenice.

  Objectives: Diabetes mellitus (DM) is an important public health problem all over the world, considering its complications and increasing prevalence. Oleanolic acid (OA) has anti-diabetic property via modulating glucose metabolism and acting as 5'-adenosine monophosphate (AMP)-activated protein kinase (AMPK) / Sirtuin-1 (SIRT-1) activator and Interleukin 6 (IL-6) / Nuclear factor kappa B (NF-κB) inhibitor. This research questioned if the OA treatment amliorates the hepatic inflammatory profile in the diabetic rats.Methods: Twenty-eight male Sprague Dawley rats were first subjected to either no diabetes induction (healthy) or diabetes induction by i.p. injection of 50 mg/kg streptozotocin. Then rats in both groups were treated with either tap water or OA (5 mg/kg) within 1 ml tap water by oral gavage for 21 days.
Results: The diabetic rats had higher hepatic MDA (2.88x) and serum AST (2.01x), ALP (2.22x), and ALT (4.27x) levels and 50% lower hepatic SOD level than the healthy rats. The OA treatment significantly reversed these antioxidant parameters in the diabetic rats. The diabetic rats had lower AMPK (85%) and hepatic SIRT-1 (47%) levels and higher hepatic NF-κB (53%) and IL-6 (34%) levels than the healthy rats. Comparing with the health rats, the OA treatment increased hepatic SIRT-1 level, but tended to increase hepatic AMPK level and decrease hepatic NF-κB and IL-6 levels in the diabetic rats. It was also partially effective to ameliorate degenerative changes and necrosis in the diabetic rats.
Conclusion: The OA treatment can be considered to alleviate oxidative stress and reduce severity of inflammation in hepatocytes in the diabetic subjects.

Keywords:  AMPK; Diabetes; Inflammation; Oleanolic acid; SIRT-1

DOI:  https://doi.org/10.1007/s40200-022-01178-x
Neuropsychiatr Dis Treat. 2023 ;19 1253-1262

Exercise-Induced Autophagy Ameliorates Motor Symptoms Progressivity in Parkinson's Disease Through Alpha-Synuclein Degradation: A Review.

Hanna Goenawan, Shabrina Kiasati, Nova Sylviana, Imam Megantara, Ronny Lesmana.

  This study reviews the molecular mechanism of exercise-induced autophagy/mitophagy and its possible mechanism in delaying motor symptoms progressivity in Parkinson's disease (PD). Relevant articles obtained from PubMed and EBSCOhost were reviewed. After analyzing the articles, it was found that autophagy can be induced by exercise and can possibly be activated through the AMPK-ULK1 pathway. Mitophagy can also be induced by exercise and can possibly be activated through PINK1/Parkin pathway and AMPK-dependent pathway. Moreover, exercise-induced autophagy can decrease the accumulation of toxic α-synuclein aggregates in PD and therefore can delay motor symptoms progressivity.

Keywords:  Parkinson’s disease; alpha-synuclein; autophagy; exercise

DOI:  https://doi.org/10.2147/NDT.S401416
Redox Biol. 2023 May 24. pii: S2213-2317(23)00161-1. [Epub ahead of print]63 102760

Energy stress modulation of AMPK/FoxO3 signaling inhibits mitochondria-associated ferroptosis.

Sufang Zhong, Wenjin Chen, Bocheng Wang, Chao Gao, Xiamin Liu, Yonggui Song, Hui Qi, Hongbing Liu, Tao Wu, Rikang Wang, Baodong Chen.

  Cancer cells and ischemic diseases exhibit unique metabolic responses and adaptations to energy stress. Forkhead box O 3a (FoxO3a) is a transcription factor that plays an important role in cell metabolism, mitochondrial dysfunction and oxidative stress response. Although the AMP-activated protein kinase (AMPK)/FoxO3a signaling pathway plays a pivotal role in maintaining energy homeostasis under conditions of energy stress, the role of AMPK/FoxO3a signaling in mitochondria-associated ferroptosis has not yet been fully elucidated. We show that glucose starvation induced AMPK/FoxO3a activation and inhibited ferroptosis induced by erastin. Inhibition of AMPK or loss of FoxO3a in cancer cells under the glucose starvation condition can sensitize these cells to ferroptosis. Glucose deprivation inhibited mitochondria-related gene expression, reduced mitochondrial DNA(mtDNA) copy number, decreased expression of mitochondrial proteins and lowered the levels of respiratory complexes by inducing FoxO3a. Loss of FoxO3a promoted mitochondrial membrane potential hyperpolarization, oxygen consumption, lipid peroxide accumulation and abolished the protective effects of energy stress on ferroptosis in vitro. In addition, we identified a FDA-approved antipsychotic agent, the potent FoxO3a agonist trifluoperazine, which largely reduced ferroptosis-associated cerebral ischemia-reperfusion (CIR) injuries in rats through AMPK/FoxO3a/HIF-1α signaling and mitochondria-dependent mechanisms. We found that FoxO3a binds to the promoters of SLC7A11 and reduces CIR-mediated glutamate excitotoxicity through inhibiting the expression of SLC7A11. Collectively, these results suggest that energy stress modulation of AMPK/FoxO3a signaling regulates mitochondrial activity and alters the ferroptosis response. The regulation of FoxO3a by AMPK may play a crucial role in mitochondrial gene expression that controls energy balance and confers resistance to mitochondria-associated ferroptosis and CIR injuries.

Keywords:  AMPK; Energy stress; Ferroptosis; FoxO3a; Lipid peroxidation

DOI:  https://doi.org/10.1016/j.redox.2023.102760