bims-amsmem 2022-12-18 papers

bims-amsmem

Biomed News

on AMPK signaling mechanism in energy metabolism

Issue of 2022‒12‒18
fourteen papers selected by
Dipsikha Biswas, Københavns Universitet

Role of AMPK in autophagy.
Singular versus combinatory glucose-sensitive signal control of metabolic sensor protein profiles in hypothalamic astrocyte cultures from each sex.
Macrophagic AMPKα1 orchestrates regenerative inflammation induced by glucocorticoids.
Adiponectin Stimulates Apolipoprotein A-1 Gene Expression in HepG2 Cells via AMPK, PPARα, and LXRs Signaling Mechanisms.
Roles of Ghrelin and Leptin in Body Mass Regulation under Food Restriction Based on the AMPK Pathway in the Red-Backed Vole, Eothenomys miletus, from Kunming and Dali Regions.
AMP-activated protein kinase inhibition in fibro-adipogenic progenitors impairs muscle regeneration and increases fibrosis.
AMPKα2 controls the anti-atherosclerotic effects of fish oils by modulating the SUMOylation of GPR120.
Targeting AMPK signaling by polyphenols: a novel strategy for tackling aging.
Osthole Suppresses Knee Osteoarthritis Development by Enhancing Autophagy Activated via the AMPK/ULK1 Pathway.
AMP kinase activation by Omega-3 polyunsaturated fatty acid protects the retina against ischemic insult: An in vitro and in vivo study.
Sex Differences in Neuropathy: The Paradigmatic Case of MetFormin.
Coordination of the AMPK, Akt, mTOR, and p53 Pathways under Glucose Starvation.
Electroacupuncture alleviates traumatic brain injury by inhibiting autophagy via increasing IL-10 production and blocking the AMPK/mTOR signaling pathway in rats.
A Hydrodistillate of Gynostemma pentaphyllum and Damulin B Prevent Cisplatin-Induced Nephrotoxicity In Vitro and In Vivo via Regulation of AMPKα1 Transcription.

Front Physiol. 2022 ;13 1015500

Role of AMPK in autophagy.

Shengyuan Wang, Hongyan Li, Minghao Yuan, Haixia Fan, Zhiyou Cai.

  Adenosine monophosphate-activated protein kinase (AMPK) is a significant energy sensor in the maintenance of cellular energy homeostasis. Autophagy is a highly conserved catabolic process that involves an intracellular degradation system in which cytoplasmic components, such as protein aggregates, organelles, and other macromolecules, are directed to the lysosome through the self-degradative process to maintain cellular homeostasis. Given the triggered autophagy process in various situations including the nutrient deficit, AMPK is potentially linked with different stages of autophagy. Above all, AMPK increases ULK1 activity by directly phosphorylating Ser467, Ser555, Thr574, and Ser637 at least four sites, which increases the recruitment of autophagy-relevant proteins (ATG proteins) to the membrane domains which affects autophagy at the initiation stage. Secondly, AMPK inhibits VPS34 complexes that do not contain pro-autophagic factors and are thus involved in isolation membrane forming processes, by direct phosphorylation of VPS34 on Thr163 and Ser165. After phosphorylation, AMPK can govern autophagosome formation through recruiting downstream autophagy-related proteins to the autophagosome formation site. Finally, the AMPK-SIRT1 signaling pathway can be activated by upregulating the transcription of autophagy-related genes, thereby enhancing autophagosome-lysosome fusion. This review provides an introduction to the role of AMPK in different stages of autophagy.

Keywords:  AMPK; autophagosome autophagosome; autophagy autophagy; lysosome; mTOR

DOI:  https://doi.org/10.3389/fphys.2022.1015500
Transl Neurosci. 2022 Jan 01. 13(1): 408-420

Singular versus combinatory glucose-sensitive signal control of metabolic sensor protein profiles in hypothalamic astrocyte cultures from each sex.

Abdulrahman Alhamyani, Prabhat R Napit, Khaggeswar Bheemanapally, Paul W Sylvester, Karen P Briski.

  Brain metabolic-sensory targets for modulatory glucose-sensitive endocrine and neurochemical signals remain unidentified. A hypothalamic astrocyte primary culture model was here used to investigate whether glucocorticoid receptor (GR) and noradrenergic signals regulate astrocyte glucose (glucose transporter-2 [GLUT2], glucokinase) and/or energy (5'-AMP-activated protein kinase [AMPK]) sensor reactivity to glucoprivation by sex. Glucose-supplied astrocytes of each sex showed increased GLUT2 expression after incubation with the GR agonist dexamethasone (DEX) or norepinephrine (NE); DEX plus NE (DEX/NE) augmented GLUT2 in the female, but not in male. Glucoprivation did not alter GLUT2 expression, but eliminated NE regulation of this protein in both sexes. Male and female astrocyte glucokinase profiles were refractory to all drug treatments, but were down-regulated by glucoprivation. Glucoprivation altered AMPK expression in male only, and caused divergent sex-specific changes in activated, i.e., phosphoAMPK (pAMPK) levels. DEX or DEX/NE inhibited (male) or stimulated (female) AMPK and pAMPK proteins in both glucose-supplied and -deprived astrocytes. In male, NE coincidently up-regulated AMPK and inhibited pAMPK profiles in glucose-supplied astrocytes; these effects were abolished by glucoprivation. In female, AMPK profiles were unaffected by NE irrespective of glucose status, whereas pAMPK expression was up-regulated by NE only during glucoprivation. Present outcomes document, for each sex, effects of glucose status on hypothalamic astrocyte glucokinase, AMPK, and pAMPK protein expression and on noradrenergic control of these profiles. Data also show that DEX and NE regulation of GLUT2 is sex-monomorphic, but both stimuli impose divergent sex-specific effects on AMPK and pAMPK. Further effort is warranted to characterize mechanisms responsible for sex-dimorphic GR and noradrenergic governance of hypothalamic astrocyte energy sensory function.

Keywords:  AMPK; GLUT2; dexamethasone; glucocorticoid receptor; glucokinase; norepinephrine

DOI:  https://doi.org/10.1515/tnsci-2022-0259
EMBO Rep. 2022 Dec 15. e55363

Macrophagic AMPKα1 orchestrates regenerative inflammation induced by glucocorticoids.

Giorgio Caratti, Thibaut Desgeorges, Gaëtan Juban, Ulrich Stiffel, Aurélie Fessard, Mascha Koenen, Bozhena Caratti, Marine Théret, Carsten Skurk, Bénédicte Chazaud, Jan P Tuckermann, Rémi Mounier.

  Macrophages are key cells after tissue damage since they mediate both acute inflammatory phase and regenerative inflammation by shifting from pro-inflammatory to restorative cells. Glucocorticoids (GCs) are the most potent anti-inflammatory hormone in clinical use, still their actions on macrophages are not fully understood. We show that the metabolic sensor AMP-activated protein kinase (AMPK) is required for GCs to induce restorative macrophages. GC Dexamethasone activates AMPK in macrophages and GC receptor (GR) phosphorylation is decreased in AMPK-deficient macrophages. Loss of AMPK in macrophages abrogates the GC-induced acquisition of their repair phenotype and impairs GC-induced resolution of inflammation in vivo during post-injury muscle regeneration and acute lung injury. Mechanistically, two categories of genes are impacted by GC treatment in macrophages. Firstly, canonical cytokine regulation by GCs is not affected by AMPK loss. Secondly, AMPK-dependent GC-induced genes required for the phenotypic transition of macrophages are co-regulated by the transcription factor FOXO3, an AMPK substrate. Thus, beyond cytokine regulation, GR requires AMPK-FOXO3 for immunomodulatory actions in macrophages, linking their metabolic status to transcriptional control in regenerative inflammation.

Keywords:  acute lung injury; glucocorticoids; macrophages; regenerative inflammation; skeletal muscle regeneration

DOI:  https://doi.org/10.15252/embr.202255363
Biochemistry (Mosc). 2022 Nov;87(11): 1252-1259

Adiponectin Stimulates Apolipoprotein A-1 Gene Expression in HepG2 Cells via AMPK, PPARα, and LXRs Signaling Mechanisms.

Dmitry A Tanyanskiy, Vladimir S Shavva, Ella B Dizhe, Galina N Oleinikova, Alexey V Lizunov, Ekaterina V Nekrasova, Denis A Mogilenko, Ekaterina E Larionova, Sergey V Orlov, Alexander D Denisenko.

  Adiponectin is an adipose tissue hormone, participating in energy metabolism and involved in atherogenesis. Previously, it was found that adiponectin increases expression of the APOA1 (apolipoprotein A-1) gene in hepatocytes, but the mechanisms of this effect remained unexplored. Our aim was to investigate the role of adiponectin receptors AdipoR1/R2, AMP-activated protein kinase (AMPK), nuclear peroxisome proliferator-activated receptor alpha (PPARα) and liver X receptors (LXRs) in mediating the action of adiponectin on hepatic APOA1 expression in human hepatoma HepG2 cells. The level of APOA1 expression was determined by RT-qPCR and ELISA. We showed that the siRNA-mediated knockdown of genes coding for AdipoR1, AdipoR2, AMPK, PPARα, and LXRα and β prevented adiponectin-induced APOA1 expression in HepG2 cells and demonstrated that interaction of PPARα and LXRs with the APOA1 gene hepatic enhancer is important for the adiponectin-dependent APOA1 transcription. The results of this study point out to the involvement of both types of adiponectin receptors, AMPK, PPARα, and LXRs in the adiponectin-dependent upregulation of the APOA1 expression.

Keywords:  AMPK; adiponectin; apolipoprotein A-1; hepatocytes; nuclear receptors

DOI:  https://doi.org/10.1134/S0006297922110049
Animals (Basel). 2022 Nov 28. pii: 3333. [Epub ahead of print]12(23):

Roles of Ghrelin and Leptin in Body Mass Regulation under Food Restriction Based on the AMPK Pathway in the Red-Backed Vole, Eothenomys miletus, from Kunming and Dali Regions.

Yuting Liu, Ting Jia, Yue Ren, Zhengkun Wang, Wanlong Zhu.

  The phenotype plasticity of animals' physiological characteristics is an important survival strategy to cope with environmental changes, especially the change in climate factors. Small mammals that inhabit seasonally changing environments often face the stress of food shortage in winter. This study measured and compared the thermogenic characteristics and related physiological indicators in the adenosine-5'-monophosphate-activated protein kinase (AMPK) pathway in Eothenomys miletus between Kunming (KM, n = 18) and Dali (DL, n = 18) under food restriction and refeeding. The results showed that food restriction and the region have significant effects on body mass, the resting metabolic rate (RMR), hypothalamic neuropeptide gene expression, ghrelin levels in the stomach and serum, serum leptin level and the activity of AMPK, and malonyl CoA and carnitine palmitoyltransferase 1 (CPT-1) activity. Food restriction reduced the body mass, the gene expression of neuropeptide proopiomelanocortin (POMC), cocaine- and amphetamine-regulated transcription peptide (CART), and leptin level. However, the ghrelin concentration and AMPK activity increased. After refeeding, there was no difference in these physiological indexes between the food restriction and control groups. Moreover, the physiological indicators also showed regional differences, such as the body mass, POMC and CART gene expression, ghrelin concentration in the stomach and serum, and AMPK activity in DL changed more significantly. All these results showed that food restriction reduces energy metabolism in E. miletus. After refeeding, most of the relevant physiological indicators can return to the control level, indicating that E. miletus has strong phenotypic plasticity. Ghrelin, leptin, and the AMPK pathway play an important role in the energy metabolism of E. miletus under food restriction. Moreover, regional differences in physiological indicators under food restriction may be related to the different temperatures or food resources in different regions.

Keywords:  AMPK pathway; Eothenomys miletus; food restriction; ghrelin; leptin

DOI:  https://doi.org/10.3390/ani12233333
J Cachexia Sarcopenia Muscle. 2022 Dec 13.

AMP-activated protein kinase inhibition in fibro-adipogenic progenitors impairs muscle regeneration and increases fibrosis.

Xiangdong Liu, Liang Zhao, Yao Gao, Yanting Chen, Qiyu Tian, Jun Seok Son, Song Ah Chae, Jeanene Marie de Avila, Mei-Jun Zhu, Min Du.

  BACKGROUND: Following muscle injury, fibro-adipogenic progenitors (FAPs) are rapidly activated and undergo apoptosis at the resolution stage, which is required for proper muscle regeneration. When excessive FAPs remain, it contributes to fibrotic and fatty infiltration, impairing muscle recovery. Mechanisms controlling FAP apoptosis remain poorly defined. We hypothesized that AMP-activated protein kinase (AMPK) in FAPs mediates their apoptosis during the muscle regeneration.METHODS: To test, AMPKα1fl/fl PDGFRαCre mice were used to knock out AMPKα1 in FAPs. Following AMPKα1 knockout, the mice were injected with phosphate-buffered saline or glycerol to induce muscle injury. Tibialis anterior muscle and FAPs were collected at 3, 7 and 14 days post-injury (dpi) for further analysis.
RESULTS: We found that AMPKα1 deletion in FAPs enhanced p65 translocation to the nuclei by 110% (n = 3; P < 0.01). AMPKα1 knockout group had a higher gene expression of MMP-9 (matrix metalloproteinase-9) by 470% (n = 3; P < 0.05) and protein level by 39% (n = 3; P < 0.05). Loss of AMPKα1 up-regulated the active TGF-β1 (transforming growth factor-β1) levels by 21% (n = 3; P < 0.05). TGF-β promoted apoptotic resistance, because AMPKα1-deficient group had 36% lower cleaved Caspase 3 (cCAS3) content (n = 3; P < 0.05). Fibrotic differentiation of FAPs was promoted, with increased collagen protein level by 54% (n = 3; P < 0.05). Moreover, obesity decreased phosphorylation of AMPK by 54% (n = 3; P < 0.05), which decreased cCAS3 in FAPs by 44% (n = 3; P < 0.05) and elevated collagen accumulation (52%; n = 3; P < 0.05) during muscle regeneration.
CONCLUSIONS: These data suggest that AMPK is a key mediator of FAPs apoptosis, and its inhibition due to obesity results in fibrosis of regenerated muscle.

Keywords:  AMPK; FAPs; MMP-9; TGF-β; fibrosis; obesity

DOI:  https://doi.org/10.1002/jcsm.13150
Nat Commun. 2022 Dec 13. 13(1): 7721

AMPKα2 controls the anti-atherosclerotic effects of fish oils by modulating the SUMOylation of GPR120.

Cheng-Hui Yan, Hai-Wei Liu, Xiao-Xiang Tian, Jiayin Li, Ye Ding, Yi Li, Zhu Mei, Ming-Hui Zou, Ya-Ling Han.

Consuming fish oils (FO) is linked to reduced risk of cardiovascular disease in certain populations. However, FO failed to exhibit therapeutic effects in some patients with cardiovascular disease. This study aimed to determine the possible reasons for the inconsistent effects of FO. AMP-activated protein kinase (AMPK) α2 is an important energy metabolic sensor, which was reported to involve in FO mediated regulation of lipid and glucose metabolism. In an in vivo study, FO administration significantly reduced the aortic lesions and inflammation in the Ldlr-/- mouse model of atherosclerosis, but not in Ldlr-/-/Prkaa2-/-and Ldlr-/-/Prkaa2-/-Sm22Cre mice. Mechanistically, inactivation of AMPKα2 increased the SUMOylation of the fatty acid receptor GPR120 to block FO-induced internalization and binding to β-arrestin. In contrast, activation of AMPKα2 can phosphorylate the C-MYC at Serine 67 to inhibit its trans-localization into the nuclei and transcription of SUMO-conjugating E2 enzyme UBC9 and SUMO2/3 in vascular smooth muscle cells (VSMCs), which result in GPR120 SUMOylation. In human arteries, AMPKα2 levels were inversely correlated with UBC9 expression. In a cohort of patients with atherosclerosis, FO concentrations did not correlate with atherosclerotic severity, however, in a subgroup analysis a negative correlation between FO concentrations and atherosclerotic severity was found in patients with higher AMPKα2 levels. These data indicate that AMPKα2 is required for the anti-inflammatory and anti-atherosclerotic effects of FO.

DOI: https://doi.org/10.1038/s41467-022-34996-x
Food Funct. 2022 Dec 16.

Targeting AMPK signaling by polyphenols: a novel strategy for tackling aging.

Wei Xu, Yi Luo, Jiaxin Yin, Mengzhen Huang, Feijun Luo.

Aging is an inevitable biological process and is accompanied by a gradual decline of physiological functions, such as the incidence of age-related diseases. Aging becomes a major burden and challenge for society to prevent or delay the occurrence and development of these age-related diseases. AMPK is a key regulator of intracellular energy and participates in the adaptation of calorie restriction. It is also an important mediator of nutritionally sensitive pathways that regulate the biological effects of nutrient active ingredients. AMPK can limit proliferation and activate autophagy. Recent studies have shown that nutritional intervention can delay aging and lessen age-related diseases in many animal and even human models. Polyphenols function as a natural antidote and are important anti-inflammatory and antioxidant agents in human diets. Polyphenols can prevent age-related diseases because they regulate complex networks of cellular processes such as oxidative damage, inflammation, cellular aging, and autophagy, and have also attracted wide attention as a potential beneficial substance for longevity. In this review, we systemically summarized the progress of targeting AMPK signaling by dietary polyphenols in aging prevention. Polyphenols can reduce oxidative stress and inflammatory response, and maintain the steady state of energy. Polyphenols can also modulate sirtuins/NAD+, nutrient-sensing, proteostasis, mitochondrial function, autophagy and senescence via targeting AMPK signaling. Therefore, targeting the AMPK signaling pathway by dietary polyphenols may be a novel anti-aging strategy.

DOI: https://doi.org/10.1039/d2fo02688k
Molecules. 2022 Dec 06. pii: 8624. [Epub ahead of print]27(23):

Osthole Suppresses Knee Osteoarthritis Development by Enhancing Autophagy Activated via the AMPK/ULK1 Pathway.

Teng Ma, Xiangpeng Wang, Wenjing Qu, Lingsen Yang, Cheng Jing, Bingrui Zhu, Yongkui Zhang, Wenpeng Xie.

  Knee osteoarthritis (KOA) is an increasingly prevalent heterogeneous disease characterized by cartilage erosion and inflammation. As the main chemical constituent of Angelicae Pubescentis Radix (APR), an anti-inflammatory herbal medicine, the potential biological effects and underlying mechanism of osthole on chondrocytes and KOA progression remain elusive. In this study, the potential effect and mechanism of osthole on KOA were investigated in vitro and in vivo. We found that osthole inhibited IL-1β-induced apoptosis and cartilage matrix degeneration by activating autophagy in rat chondrocytes. In addition, osthole could activate autophagy through phosphorylation of AMPK/ULK1, and AMPK serves as a positive upstream regulator of ULK1. Furthermore, KOA rats treated with osthole showed phosphorylation of the AMPK/ULK1 pathway and autophagy activation, as well as cartilage protection. Collectively, the AMPK/ULK1 signaling pathway can be activated by osthole to enhance autophagy, thereby suppressing KOA development. Osthole may be a novel and effective therapeutic agent for the clinical treatment of KOA.

Keywords:  AMPK/ULK1; autophagy; degeneration; knee osteoarthritis; osthole

DOI:  https://doi.org/10.3390/molecules27238624
Exp Eye Res. 2022 Dec 09. pii: S0014-4835(22)00426-2. [Epub ahead of print] 109345

AMP kinase activation by Omega-3 polyunsaturated fatty acid protects the retina against ischemic insult: An in vitro and in vivo study.

Marcella N Dátilo, Guilherme P Formigari, José B Lopes de Faria, Jacqueline M Lopes de Faria.

  PURPOSE: To investigate the possible beneficial effects of omega-3 polyunsaturated fatty acids (ω3-PUFAs) in ischemic retinal angiogenesis and whether AMP-activated protein kinase (AMPK) is involved.METHODS: Human retinal microvascular endothelial cells (hRMECs) were exposed to dimethyloxalylglycine (DMOG), a hypoxia-inducible factor hydroxylase inhibitor, in the presence or absence of docosahexaenoic acid (DHA) and small interfering RNA (siRNA) for AMPKα for 24 h. Ischemic factors, endothelial mesenchymal transition marker, endothelial barrier integrity, cell migration, and tube formation were evaluated. Neonatal AMPKα2-/- and control wild-type (WT) mice were submitted to an oxygen-induced retinopathy (OIR) protocol; their nursing mother mice were either fed ω3-PUFAs or not. In the end, ischemic markers and endothelial cell proliferation were evaluated in neonatal mouse retinal tissue through immunohistochemical or immunofluorescent assays among all studied groups.
RESULTS: Cells exposed to DMOG displayed increased expressions of hypoxic and endothelial mesenchymal transition (vimentin) markers and barrier disarrangement of Zonula Occludens-1 compared to the control, accompanied by increased cellular migration and tube formation (p < 0.05). AMPK activity was significantly decreased. Supplementation with DHA restored the mentioned alterations compared to DMOG (p<0.05). In siRNAAMPKα-treated cells, the beneficial effects observed with DHA were abolished. DHA upregulated G-protein receptor-120 (GPR120), which promptly increased intracellular levels of calcium (p ≤ 0.001), which consequently increased Calcium/calmodulin-dependent protein kinase kinase β expression (CaMKKβ) thus phosphorylating AMPKThr172. AMPKα2-/- and wild-type (WT) OIR mice exhibited similar retinal ischemic changes, and the oral supplementation with ω3-PUFA efficiently prevented the noticed ischemic alterations only in WT mice, suggesting that AMPKα2 is pivotal in the protective effects of ω3-PUFA.
CONCLUSIONS: ω3-PUFAs protect the retina from the effects of ischemic conditions, and this effect occurs via the GPR120-CaMKKβ-AMPK axis. A better understanding of this mechanism might improve the control of pathological angiogenesis in retinal ischemic diseases.

Keywords:  AMPK; Angiogenesis; Docosahexaenoic acid; Oxygen-induced retinopathy; Retinal ischemia

DOI:  https://doi.org/10.1016/j.exer.2022.109345
Int J Mol Sci. 2022 Nov 22. pii: 14503. [Epub ahead of print]23(23):

Sex Differences in Neuropathy: The Paradigmatic Case of MetFormin.

Federica De Angelis, Valentina Vacca, Jessica Tofanicchio, Georgios Strimpakos, Giacomo Giacovazzo, Flaminia Pavone, Roberto Coccurello, Sara Marinelli.

  As a widely prescribed anti-diabetic drug, metformin has been receiving novel attention for its analgesic potential. In the study of the complex etiology of neuropathic pain (NeP), male and female individuals exhibit quite different responses characterized by higher pain sensitivity and greater NeP incidence in women. This "gender gap" in our knowledge of sex differences in pain processing strongly limits the sex-oriented treatment of patients suffering from NeP. Besides, the current investigation of the analgesic potential of metformin has not addressed the "gender gap" problem. Hence, this study focuses on metformin and sex-dependent analgesia in a murine model of NeP induced by chronic constriction injury of the sciatic nerve. We investigated sexual dimorphism in signaling pathways involved by 7 days of metformin administration, such as changes in AMP-activated protein kinase and the positive regulation of autophagy machinery, discovering that metformin affected in a sexually dimorphic manner the immunological and inflammatory response to nerve lesion. These effects were complemented by morphological and adaptive changes occurring after peripheral nerve injury. Altogether these data can contribute to explaining a number of potential mechanisms responsible for the complete recovery from NeP found in male mice, as opposed to the failure of long-lasting recovery in female animals.

Keywords:  AMPK; TNFα; allodynia; autophagy; leptin; macrophages; metformin; neurofilaments; neuropathic pain; sex differences

DOI:  https://doi.org/10.3390/ijms232314503
Int J Mol Sci. 2022 Nov 29. pii: 14945. [Epub ahead of print]23(23):

Coordination of the AMPK, Akt, mTOR, and p53 Pathways under Glucose Starvation.

Yifan Zhou, Feng Liu.

  Glucose is a direct energy source for eukaryotic cells, and its deficiency elicits complex stress responses and diverse cellular outcomes. Although several signaling pathways involved have been identified, how they coordinately dictate the cell fate remains obscure. We propose a minimal network model for the cellular response to glucose restriction, characterizing the glucose uptake and signaling of the AMPK, Akt, mTOR, and p53 pathways. We demonstrate that in the presence of sufficient growth factors and amino acids, cells may undergo proliferation, senescence, or apoptosis, depending on the extracellular glucose level. AMPK is first activated upon glucose limitation, activating p53 to induce cell-cycle arrest; possibly, cells resume proliferation after timely glucose restoration. For long-term energy stress, cell senescence is maintained by low/intermediate levels of p53 and persistent activation of mTOR and Akt, or cells commit apoptosis when the proteins undergo biphasic dynamics, e.g., p53 switches from intermediate levels to high levels while mTOR and Akt become inactivated in the later phase. The biphasic dynamics of p53 are associated with flipping of two bistable switches. Appropriate mTOR levels are required for optimal cell-fate decision. This work suggests that senescence and apoptosis occur sequentially in glucose-depleted cells, and a theoretical framework is provided for exploring the cellular response to energy stress.

Keywords:  apoptosis; biphasic dynamics; cell-fate decision; glucose starvation; network modeling; senescence

DOI:  https://doi.org/10.3390/ijms232314945
Metab Brain Dis. 2022 Dec 15.

Electroacupuncture alleviates traumatic brain injury by inhibiting autophagy via increasing IL-10 production and blocking the AMPK/mTOR signaling pathway in rats.

Tao Wu, Jiushe Kou, Xuemei Li, Yongchang Diwu, Yuanyuan Li, Dong-Yuan Cao, Ruihui Wang.

  Autophagy, switched by the AMPK/mTOR signaling, has been revealed to contribute greatly to traumatic brain injury (TBI). Electroacupuncture (EA) is a promising therapeutic method for TBI, however, the underlying mechanism is still unclear. Herein, we hypothesize that the therapeutic effect of EA on TBI is associated with its inhibition on AMPK/mTOR-mediated autophagy. Sprague-Dawley rats were randomly divided into three groups: sham, TBI, and TBI + EA. TBI model was established by using an electronic controlled cortical impactor. Rats were treated with EA at 12 h after modeling, 15 min daily for 14 consecutive days. EA was applied at the acupuncture points Quchi (LI 11), Hegu (LI4), Baihui (GV20), Guanyuan (CV4), Zusanli (ST36) and Yongquan (KI1), using dense-sparse wave, at frequencies of 1 Hz, and an amplitude of 1 mA. After 3, 7 and 14 days of modeling, the modified neurological severity scale (mNSS), rota rod system, and Morris Water Maze (MWM) test showed that EA treatment promoted neurological function recovery in TBI rats. Moreover, EA treatment alleviated brain edema, pathological damage, neuronal apoptosis in TBI rats. EA improved abnormal ultrastructure, including abnormal mitochondrial morphology and increased autophagosomes, in the brain neurons of TBI rats, as measured by transmission electron microscopy, and the concentration of adenosine triphosphate (ATP), adenosine diphosphate (ADP), and adenosine monophosphate (AMP). Western blot and immunohistochemistry (IHC) assays were performed to measure the protein levels of interleukin 10 (IL-10), autophagy-related proteins and key proteins in the AMPK/mTOR signaling pathway. EA treatment increased IL-10 production, inhibited the AMPK/mTOR signaling, and inhibited excessive autophagy in TBI rats. Additionally, AMPK inhibitor Compound C treatment had similar effects to EA. Both AMPK agonist AICAR and IL-10 neutralizing antibody treatments reversed the effects of EA on the related protein levels of autophagy and the AMPK/mTOR signaling pathway, and abolished the protective effects of EA on TBI rats. In conclusion, EA treatment promoted neurological function recovery and alleviated pathological damage and neuronal apoptosis in TBI rats through inhibiting excessive autophagy via increasing IL-10 production and blocking the AMPK/mTOR signaling pathway.

Keywords:  AMPK/mTOR pathway; Autophagy; Electroacupuncture; Traumatic brain injury

DOI:  https://doi.org/10.1007/s11011-022-01133-y
Nutrients. 2022 Nov 24. pii: 4997. [Epub ahead of print]14(23):

A Hydrodistillate of Gynostemma pentaphyllum and Damulin B Prevent Cisplatin-Induced Nephrotoxicity In Vitro and In Vivo via Regulation of AMPKα1 Transcription.

Minhyeok Song, Minseok Kim, Dang Hieu Hoang, Lochana Mangesh Kovale, Jihyun Lee, Youngjoo Kim, Changhyun Lee, Jongki Hong, Sungchul Park, Wonchae Choe, Insug Kang, Sung Soo Kim, Joohun Ha.

  The clinical application of cisplatin, one of the most effective chemotherapeutic agents used to treat various cancers, has been limited by the risk of adverse effects, notably nephrotoxicity. Despite intensive research for decades, there are no effective approaches for alleviating cisplatin nephrotoxicity. This study aimed to investigate the protective effects and potential mechanisms of a Gynostemma pentaphyllum leaves hydrodistillate (GPHD) and its major component, damulin B, against cisplatin-induced nephrotoxicity in vitro and in vivo. A hydro-distillation method can extract large amounts of components within a short period of time using non-toxic, environmentally friendly solvent. We found that the levels of AMP-activated protein kinase α1 (AMPKα1), reactive oxygen species (ROS), and apoptosis were tightly associated with each other in HEK293 cells treated with cisplatin. We demonstrated that AMPKα1 acted as an anti-oxidant factor and that ROS generated by cisplatin suppressed the expression of AMPKα1 at the transcriptional level, thereby resulting in induction of apoptosis. Treatment with GPHD or damulin B effectively prevented cisplatin-induced apoptosis of HEK293 cells and cisplatin-induced acute kidney injury in mice by suppressing oxidative stress and maintaining AMPKα1 levels. Therefore, our study suggests that GPHD and damulin B may serve as prospective adjuvant agents against cisplatin-induced nephrotoxicity.

Keywords:  AMPKα1; Gynostemma pentaphyllum; cisplatin; damulin B; nephrotoxicity

DOI:  https://doi.org/10.3390/nu14234997