bims-amsmem 2022-06-19 papers

bims-amsmem

Biomed News

on AMPK signaling mechanism in energy metabolism

Issue of 2022–06–19
fiveteen papers selected by
Dipsikha Biswas, Københavns Universitet

The importance of AMPK in obesity and chronic diseases and the relationship of AMPK with nutrition: a literature review.
Chlorogenic acid improves anti-lipogenic activity of metformin by positive regulating of AMPK signaling in HepG2 cells.
β-Boswellic Acid Suppresses Breast Precancerous Lesions via GLUT1 Targeting-Mediated Glycolysis Inhibition and AMPK Pathway Activation.
Pharmacological and exercise-induced activation of AMPK as emerging therapies for myotonic dystrophy type 1 patients.
Geniposide suppresses NLRP3 inflammasome-mediated pyroptosis via the AMPK signaling pathway to mitigate myocardial ischemia/reperfusion injury.
Increasing SnRK1 activity with the AMPK activator A-769662 accelerates seed germination in rice.
Metformin Ameliorates Senescence of Adipose-Derived Mesenchymal Stem Cells and Attenuates Osteoarthritis Progression via the AMPK-Dependent Autophagy Pathway.
Sulforaphane alleviates high fat diet-induced insulin resistance via AMPK/Nrf2/GPx4 axis.
Polystyrene microplastics-induced cardiotoxicity in chickens via the ROS-driven NF-κB-NLRP3-GSDMD and AMPK-PGC-1α axes.
Modeling of mitochondrial bioenergetics and autophagy impairment in MELAS-mutant iPSC-derived retinal pigment epithelial cells.
Protective Effect of XinJiaCongRongTuSiZiWan on the Reproductive Toxicity of Female Rats Induced by Triptolide.
Effects of short-term food deprivation on catecholamine and metabolic-sensory biomarker gene expression in hindbrain A2 noradrenergic neurons projecting to the forebrain rostral preoptic area: Impact of negative versus positive estradiol feedback.
D-chiro-Inositol facilitates adiponectin biosynthesis and activates the AMPKα/PPARs pathway to inhibit high-fat diet-induced obesity and liver lipid deposition.
PLIN2 promotes HCC cells proliferation by inhibiting the degradation of HIF1α.
lncRNA NBR2 attenuates angiotensin II-induced myocardial hypertrophy through repressing ER stress via activating LKB1/AMPK/Sirt1 pathway.

Crit Rev Food Sci Nutr. 2022 Jun 16. 1-8

The importance of AMPK in obesity and chronic diseases and the relationship of AMPK with nutrition: a literature review.

Eren Canbolat, Funda Pınar Cakıroglu.

  This review will examine the role of 5'-adenosine monophosphate-activated protein kinase (AMPK) in the treatment of obesity, medical nutrition and chronic diseases, and its relationship with nutrition. In the literature, the number of studies examining the direct relationship of AMPK with nutrition is negligible. For this reason, information on the subject has been compiled from all the studies that can be accessed by searching the terms AMPK and disease, AMPK and health, AMPK and exercise, AMPK and nutrition. It can be stated that AMPK is inhibited in many pathological conditions such as inflammation, diabetes, aging and cancer, and AMPK activation has positive effects in many diseases such as insulin resistance, diabetes, obesity, cancer and Alzheimer's. When the relationship between nutrition and AMPK is examined, it is seen that food intake inhibits AMPK, but especially high-carbohydrate and fatty diets are more effective at this point. In addition, high fructose corn sirup and long chain saturated fatty acids increased by consumption of industrial foods and frequent meals appear to be an inactivator for AMPK. For AMPK activation in medical nutrition therapy, it is recommended to use methods such as evening fasting and intermittent fasting, taking into account the human circadian rhythm.

Keywords:  Adiposity; circadian nutrition; healthy eating; intermittent fasting; medical nutrition therapy; new dietary approaches; nutritional biochemistry

DOI:  https://doi.org/10.1080/10408398.2022.2087595
Cell Biochem Biophys. 2022 Jun 15.

Chlorogenic acid improves anti-lipogenic activity of metformin by positive regulating of AMPK signaling in HepG2 cells.

Fatemeh Namvarjah, Hajar Shokri-Afra, Hemen Moradi-Sardareh, Reyhaneh Babaei Khorzoughi, Parvin Pasalar, Ghodratollah Panahi, Reza Meshkani.

  Metformin improves lipid profile, however, combination therapy is developing to increase its effectiveness and reduce the deleterious effects of metformin. Chlorogenic acid (CGA) has exhibited lipid-lowering effects. This study aimed to investigate the combined effect of metformin and CGA on lipid accumulation, as well as to elucidate the engaged mechanism in HepG2 cells. To find the non-lethal doses of metformin and CGA, MTT assay was performed. High Glucose (HG) at 33 mM was used to induce lipogenesis in HepG2 cells. Following treatment with different concentrations of metformin and CGA, total lipid content (Oil Red O-staining), triglyceride level, the genes expression of SREBP-1c and FAS, and phosphorylation of AMPK and ACC were measured. Both Metformin and CGA decreased HG-induced lipid accumulation individually, by decreasing total lipid content and triglyceride level. The lowest effective doses of metformin and CGA were 0.25 mM and 5 μM, respectively, which significantly reduced SREBP-1c and FAS genes expression. The combination of these concentrations reinforced these effects. The phosphorylation of AMPK and ACC were more increased by metformin in combination with CGA than both individually. Our findings suggest that CGA synergistically enhances metformin lipid reducing action via the regulating of involved factors in fatty acid synthesis. Therefore, co-administration of metformin with CGA may have further medical value in treating lipid metabolism disorders.

Keywords:  AMP-Activated protein kinases; Chlorogenic acid; Combined therapy; Lipid metabolism; Metformin

DOI:  https://doi.org/10.1007/s12013-022-01077-1
Front Oncol. 2022 ;12 896904

β-Boswellic Acid Suppresses Breast Precancerous Lesions via GLUT1 Targeting-Mediated Glycolysis Inhibition and AMPK Pathway Activation.

Fengjie Bie, Guijuan Zhang, Xianxin Yan, Xinyi Ma, Sha Zhan, Yebei Qiu, Jingyu Cao, Yi Ma, Min Ma.

  Breast carcinoma is a multistep progressive disease. Precancerous prevention seems to be crucial. β-Boswellic acid (β-BA), the main component of the folk medicine Boswellia serrata (B. serrata), has been reported to be effective in various diseases including tumors. In this work, we demonstrated that β-BA could inhibit breast precancerous lesions in rat disease models. Consistently, β-BA could suppress proliferation and induce apoptosis on MCF-10AT without significantly influencing MCF-10A. Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis suggested that β-BA may interfere with the metabolic pathway. Metabolism-related assays showed that β-BA suppressed glycolysis and reduced ATP production, which then activated the AMPK pathway and inhibited the mTOR pathway to limit MCF-10AT proliferation. Further molecular docking analysis suggested that GLUT1 might be the target of β-BA. Forced expression of GLUT1 could rescue the glycolysis suppression and survival limitation induced by β-BA on MCF-10AT. Taken together, β-BA could relieve precancerous lesions in vivo and in vitro through GLUT1 targeting-induced glycolysis suppression and AMPK/mTOR pathway alterations. Here, we offered a molecular basis for β-BA to be developed as a promising drug candidate for the prevention of breast precancerous lesions.

Keywords:  AMPK; GLUT1; breast precancerous lesions; glycolysis; β-boswellic acid

DOI:  https://doi.org/10.3389/fonc.2022.896904
J Physiol. 2022 Jun 13.

Pharmacological and exercise-induced activation of AMPK as emerging therapies for myotonic dystrophy type 1 patients.

Aymeric Ravel-Chapuis, Elise Duchesne, Bernard J Jasmin.

  Myotonic dystrophy type 1 (DM1) is a multisystemic disorder with variable clinical features. Currently, there is no cure or effective treatment for DM1. The disease is caused by an expansion of CUG repeats in the 3'UTR of DMPK mRNAs. Mutant DMPK mRNAs accumulate in nuclei as RNA foci and trigger an imbalance in the level and localization of RNA-binding proteins causing the characteristic missplicing events which account for the varied DM1 symptoms, a disease mechanism referred to as RNA toxicity. In recent years, multiple signaling pathways have been identified as being aberrantly regulated in skeletal muscle in response to the CUG expansion, including AMPK, a sensor of energy status and a master regulator of cellular energy homeostasis. Converging lines of evidence highlight the benefits of activating AMPK signaling pharmacologically on RNA toxicity as well as on muscle histology and function in preclinical DM1 models. Importantly, a clinical trial with metformin, an activator of AMPK, resulted in functional benefits in DM1 patients. In addition, exercise, a known AMPK activator, has shown promising effects on RNA toxicity and muscle function in DM1 mice. Finally, clinical trials involving moderate-intensity exercise also induced functional benefits for DM1 patients. Taken together, these studies clearly demonstrate the molecular, histological and functional benefits of AMPK activation and exercise-based interventions on the DM1 phenotype. Despite these advances, several key questions remain and in particular, the extent of the true implication of AMPK in the observed beneficial improvements and how, mechanistically, activation of AMPK signaling improves the DM1 pathophysiology. This article is protected by copyright. All rights reserved.

Keywords:  AMPK; exercise; myotonic dystrophy type 1; skeletal muscle; therapy

DOI:  https://doi.org/10.1113/JP282725
Chin Med. 2022 Jun 17. 17(1): 73

Geniposide suppresses NLRP3 inflammasome-mediated pyroptosis via the AMPK signaling pathway to mitigate myocardial ischemia/reperfusion injury.

Haiyan Li, Dong-Hua Yang, Yanmei Zhang, Fuchun Zheng, Fenfei Gao, Jiajia Sun, Ganggang Shi.

   BACKGROUND: NLRP3 inflammasome activation and pyroptosis play a significant role in myocardial ischemia reperfusion injury (MI/RI). Geniposide was reported to show potential therapeutic use for MI/RI with its anti-inflammatory and anti-oxidative properties. However, research on the specific mechanism of geniposide has not been reported.
METHODS: The MIRI model of animal was created in male C57BL/6J mice and the hypoxia reoxygenation (H/R) model was established for the in vitro experiments. Neonatal rat ventricular myocytes (NRVMs) and H9c2 cells with knockdown of TXNIP or NLRP3 were used. Geniposide was administered to mice before vascular ligation. HE staining, 2,3,5-triphenyltetrazolium chloride (TTC) staining, echocardiography, oxidative stress and myocardial enzyme detection were used to evaluate the cardioprotective effect of geniposide. Meanwhile, pharmacological approaches of agonist and inhibitor were used to observe potential pathway for geniposide cardioprotective in vitro and in vivo. Moreover, ELISA kits were adopted to detect the levels of inflammatory factors, such as IL-1β and IL-18. The gene and protein expression of NLRP3 and pyroptosis-related factors in heart tissue were performed by RT-PCR, western blotting and immunofluorescence in vivo and in vitro, respectively.
RESULTS: Our results indicate that geniposide can reduce the area of myocardial infarction, improve heart function, and inhibit the inflammatory response in mice after MI/RI. In addition, RT-PCR and western blotting shown geniposide promoting AMPK phosphorylation to activate myocardium energy metabolism and reducing the levels of genes and proteins expression of NLRP3, ASC, N-GSDMD and cleaved caspase-1, IL-1β, IL-18. Meanwhile, geniposide improved NRVMs energy metabolism, which decreased ROS levels and the protein expression of TXNIP and thus suppressed the expression of NLRP3. AMPK antagonist or agonist and siRNA downregulation of TXNIP or NLRP3 were also verify the effect of geniposide against H/R injury. Further research found that geniposide promoted the translocation of TXNIP and reduce the binding of TXNIP and NLRP3.
CONCLUSIONS: In our study, geniposide can significantly inhibit NLRP3 inflammasome activation via the AMPK signaling pathway and inhibit pyroptosis of cardiomyocytes in myocardial tissues.

Keywords:  AMPK; Geniposide; Myocardial ischemia reperfusion; NLRP3 inflammasome; Pyroptosis

DOI:  https://doi.org/10.1186/s13020-022-00616-5
Plant Physiol Biochem. 2022 Jun 07. pii: S0981-9428(22)00277-7. [Epub ahead of print]185 155-166

Increasing SnRK1 activity with the AMPK activator A-769662 accelerates seed germination in rice.

Yuxiang Hu, Jiaqi Bai, Yongqing Xia, Yan Lin, Li Ma, Xuemei Xu, Yanfeng Ding, Lin Chen.

  Sucrose non-fermenting-1-related protein kinase 1 (SnRK1) plays a key role in rice germination. The small molecule drug, A-769662, activates AMP-activated protein kinase, a mammalian homolog of SnRK1. However, it is unknown whether A-769662 activates SnRK1, thereby affecting germination. SnRK1 in desalted extracts from germinating rice seeds was strongly activated by adding A-769662 in vitro. Applying 50 or 100 μM A-769662 accelerated germination and increased the root length, shoot length, and seedling fresh weight. 50 μM A-769662 treatment increased the catalytic activity and phosphorylation of SnRK1 during germination. Transcriptome analysis and biochemical validation were performed to investigate the mechanism whereby A-769662 treatment promoted rice germination. A-769662 treatment promoted starch hydrolysis by increasing the expression and activity of amylase and inhibited starch biosynthesis by decreasing the expression of OsAGPL2, OsAGPS2a, Wx, and SSIIa. The abscisic acid (ABA) level and gene expression of ABA-induced transcription factors, including OsNF-YC9, OsNF-YC12, OsWRKY24, OsPYL8, OsMKKK62, and OsMKKK63, which reduced the inhibition of germination by ABA were decreased under 50 μM A-769662 treatment. The increased expression of the OsACO3 and OsACO5 genes and increased ethylene levels under A-769662 treatment, which counteracted the inhibition of ABA on germination and, thus, promoted germination. These results demonstrate the activation of A-769662 on SnRK1 and further reveal the regulatory mechanism of A-769662 in rice seed germination and nutrient remobilization.

Keywords:  ABA signal; AMPK activator; Germination; Rice; SnRK1; Starch metabolism

DOI:  https://doi.org/10.1016/j.plaphy.2022.06.005
Oxid Med Cell Longev. 2022 ;2022 4620254

Metformin Ameliorates Senescence of Adipose-Derived Mesenchymal Stem Cells and Attenuates Osteoarthritis Progression via the AMPK-Dependent Autophagy Pathway.

Zheng Li, Lin Liu, Yanni Yang, Haishi Zheng, Yongsong Cai, Yao Ma, Ruiying Gu, Ke Xu, Rui Zhang, Peng Xu.

Osteoarthritis (OA) is one of the most serious age-related diseases worldwide that drastically affects the quality of life of patients. Despite advancements in the treatment of arthritis, especially with adipose-derived mesenchymal stem cells (ADSCs), senescence-induced alterations in ADSCs negatively affect the treatment outcomes. This study was aimed at mechanistically exploring whether metformin could ameliorate the senescence of ADSCs and at exploring the effect of metformin-preconditioned ADSCs in an experimental OA mouse model. In this study, an H2O2-induced mouse ADSC senescent model was established. Cell proliferation, senescence, and autophagy were investigated in vitro. Moreover, the effects of intra-articular injection of metformin-preconditioned ADSCs were investigated in vivo. Metformin could promote autophagy and activate the AMPK/mTOR pathway in ADSCs. The metformin-enhanced autophagy could improve the survival and reduce the senescence of ADSCs. The protective effects of metformin against senescence were partially blocked by 3-methyladenine and compound C. Injection of metformin-preconditioned ADSCs slowed OA progression and reduced OA pain in mice. The results suggest that metformin activates the AMPK/mTOR-dependent autophagy pathway in ADSCs against H2O2-induced senescence, while metformin-preconditioned ADSCs can potentially inhibit OA progression.

DOI: https://doi.org/10.1155/2022/4620254
Biomed Pharmacother. 2022 Jun 14. pii: S0753-3322(22)00662-X. [Epub ahead of print]152 113273

Sulforaphane alleviates high fat diet-induced insulin resistance via AMPK/Nrf2/GPx4 axis.

Ya Zhang, Qifang Wu, Jian Liu, Zhongshan Zhang, Xiaojing Ma, Yaoyue Zhang, Jiawen Zhu, Ronald W Thring, Mingjiang Wu, Yitian Gao, Haibin Tong.

  Insulin resistance is a characteristic feature of type 2 diabetes. Sulforaphane (SFN) is a natural antioxidant extracted from the cruciferous vegetables. Recent study reported that SFN exhibits excellent anti-diabetic effects, however, the underlying mechanism is still unclear. This study aimed to investigate the therapeutic effects of SFN on a high-fat diet (HFD)-induced insulin resistance and potential mechanism. SFN was found to effectively reduce body weight, fasting blood glucose and hyperlipidemia, and improve liver function in HFD-fed mice. Furthermore, SFN effectively increased glucose uptake and improved insulin signaling in palmitic acid (PA)-induced HepG2 cells. SFN also led to increased expression of antioxidant genes downstream of Nrf2 and decreased accumulation of lipid peroxides MDA and 4-HNE, both in vivo and in vitro. Further studies revealed that SFN significantly reduced glutathione peroxidase 4 (GPx4) inactivation-mediated oxidative stress by activating the AMPK and Nrf2 signaling pathways. In PA-induced HepG2 cells and flies, the alleviation of insulin resistance by SFN was diminished by GPx4 inhibitor. Taken together, SFN ameliorated HFD-induced insulin resistance by activating the AMPK-Nrf2-GPx4 pathway, providing new insights into SFN as a therapeutic compound for the alleviation of insulin resistance.

Keywords:  AMPK; GPx4; Insulin resistance; Nrf2; Oxidative stress; Sulforaphane

DOI:  https://doi.org/10.1016/j.biopha.2022.113273
Sci Total Environ. 2022 Jun 14. pii: S0048-9697(22)03824-4. [Epub ahead of print] 156727

Polystyrene microplastics-induced cardiotoxicity in chickens via the ROS-driven NF-κB-NLRP3-GSDMD and AMPK-PGC-1α axes.

Yue Zhang, Kai Yin, Dongxu Wang, Yu Wang, Hongmin Lu, Hongjing Zhao, Mingwei Xing.

  Microplastics (MPs) pollution is getting increasingly prominent, and its dangers have attracted widespread attention. The heart is the central hub of the organism's survival, and the mechanism of MPs-induced heart injury in chickens is unknown. Here, we investigated the effects of 5 μm polystyrene microplastics (PS-MPs) on the heart and primary cardiomyocytes of chickens at varied concentrations. We observed that PS-MPs caused severe pathological damage and ultrastructural changes in heart, induced myocardial pyroptosis, inflammatory cell infiltration and mitochondrial lesions. PS-MPs evoked abnormal antioxidant enzyme content and ROS overproduction. Detailed mechanistic investigation indicated that PS-MPs triggered pyroptosis via NF-κB-NLRP3-GSDMD axis and exacerbated myocardial inflammation (NLRP3, Caspase-1, IL-1β, IL-18, ASC, GSDMD, NF-κB, COX-2, iNOS and IL-6 overexpression). Additionally, PS-MPs induced mitochondrial damage (TFAM, OPA1, MFN1 and MFN2 down-expression, DRP1 and Fis1 overexpression) and energy metabolism disorders (HK2, PKM2, PDHX and LDH up-regulation) by inhibiting AMPK-PGC-1α pathway. Interestingly, NAC alleviated these aberrant manifestations in vitro. We suggested that PS-MPs driven alterations in NF-κB-NLRP3-GSDMD and AMPK-PGC-1α pathways via ROS overload, which in turn triggered oxidative stress, myocardial pyroptosis, inflammation, mitochondrial and energy metabolism dysfunction. This provided theoretical bases for protecting chickens from toxic injury by MPs.

Keywords:  AMPK-PGC-1α pathway; Cardiotoxicity; Chickens; Microplastic; NF-κB-NLRP3-GSDMD axis; Reactive oxygen species

DOI:  https://doi.org/10.1016/j.scitotenv.2022.156727
Stem Cell Res Ther. 2022 Jun 17. 13(1): 260

Modeling of mitochondrial bioenergetics and autophagy impairment in MELAS-mutant iPSC-derived retinal pigment epithelial cells.

Sujoy Bhattacharya, Jinggang Yin, Weihong Huo, Edward Chaum.

   BACKGROUND: Mitochondrial dysfunction and mitochondrial DNA (mtDNA) damage in the retinal pigment epithelium (RPE) have been implicated in the pathogenesis of age-related macular degeneration (AMD). However, a deeper understanding is required to determine the contribution of mitochondrial dysfunction and impaired mitochondrial autophagy (mitophagy) to RPE damage and AMD pathobiology. In this study, we model the impact of a prototypical systemic mitochondrial defect, mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS), in RPE health and homeostasis as an in vitro model for impaired mitochondrial bioenergetics.
METHODS: We used induced pluripotent stem cells (iPSCs) derived from skin biopsies of MELAS patients (m.3243A > G tRNA leu mutation) with different levels of mtDNA heteroplasmy and differentiated them into RPE cells. Mitochondrial depletion of ARPE-19 cells (p0 cells) was also performed using 50 ng/mL ethidium bromide (EtBr) and 50 mg/ml uridine. Cell fusion of the human platelets with the p0 cells performed using polyethylene glycol (PEG)/suspension essential medium (SMEM) mixture to generate platelet/RPE "cybrids." Confocal microscopy, FLowSight Imaging cytometry, and Seahorse XF Mito Stress test were used to analyze mitochondrial function. Western Blotting was used to analyze expression of autophagy and mitophagy proteins.
RESULTS: We found that MELAS iPSC-derived RPE cells exhibited key characteristics of native RPE. We observed heteroplasmy-dependent impairment of mitochondrial bioenergetics and reliance on glycolysis for generating energy in the MELAS iPSC-derived RPE. The degree of heteroplasmy was directly associated with increased activation of signal transducer and activator of transcription 3 (STAT3), reduced adenosine monophosphate-activated protein kinase α (AMPKα) activation, and decreased autophagic activity. In addition, impaired autophagy was associated with aberrant lysosomal function, and failure of mitochondrial recycling. The mitochondria-depleted p0 cells replicated the effects on autophagy impairment and aberrant STAT3/AMPKα signaling and showed reduced mitochondrial respiration, demonstrating phenotypic similarities between p0 and MELAS iPSC-derived RPE cells.
CONCLUSIONS: Our studies demonstrate that the MELAS iPSC-derived disease models are powerful tools for dissecting the molecular mechanisms by which mitochondrial DNA alterations influence RPE function in aging and macular degeneration, and for testing novel therapeutics in patients harboring the MELAS genotype.

Keywords:  AMPKα; Age-related macular degeneration; Autophagy flux; MELAS; Mitochondrial heteroplasmy; Mitophagy; PGC-1α; Prom1/CD133; Regenerative medicine; iPSC-derived retinal pigment epithelium

DOI:  https://doi.org/10.1186/s13287-022-02937-6
Evid Based Complement Alternat Med. 2022 ;2022 3642349

Protective Effect of XinJiaCongRongTuSiZiWan on the Reproductive Toxicity of Female Rats Induced by Triptolide.

Disi Deng, Jin Yan, Wanjing Li, Yeke Wu, Keming Wu.

Background: Although triptolide (TP) has been widely used for the treatment of inflammatory, autoimmune diseases, and various kinds of tumors, the long experimental and clinical applications have exhibited severe reproductive system toxicity in TP-treated animals and patients. More importantly, the underlying molecular mechanism involved in TP-induced reproductive system toxicity still needs more research.
Methods: Adult female Sprague Dawley rats and human ovarian granulosa cell lines were treated with TP and then treated with XinJiaCongRongTuSiZiWan (XJCRTSZW). Histological analysis and follicle count were executed using H&E staining. Hormone (E2, AMH, FSH, LH, and INH B) concentrations, inflammation indicators (IL-1β, IL-6, and TNF-α), oxidative stress indicators (SOD, GSH-Px, and MDA), apoptosis rate, protein distribution and expression (SIRT1, AMPK, and 8-OhdG), cell viability, relative protein levels (beclin-1, LC3-II/LC3-I, p62, procaspase-3, cleaved caspase-3, p-SIRT1, SIRT1, p-AMPKα-1, AMPKα-1, Akt, and p-Akt), autophagosome were detected by ELISA, commercial biochemical detection kits, flow cytometry, immunohistochemistry, CCK-8, western blotting, and transmission electron microscope, respectively.
Results: XJCRTSZW administration notably improved the TP-treated pathological symptoms, including few mature follicles in the ovary and less granular cell layer, and disordered the arrangement of the follicle, lymphocytes and plasma cells infiltration, and necrosis, shedding, and follicular cystic dilatation of the granular layer follicle cells in the ovarian stroma. Furthermore, XJCRTSZW treatment observably enhanced the TP-induced reduction of primary follicles and secondary follicles numbers and decreased the TP-induced elevation of atretic follicle numbers and the expression of AMPK, SIRT1, and 8-OhdG in GCs in vivo. Moreover, XJCRTSZW application significantly increased the TP-induced diminishment of E2, AMH, and LNH-B concentrations, apoptosis rate, SOD and GSH-Px concentrations, and p62 protein level; however, it declined the TP-induced augmentation of MDA level, the levels of IL-1β, IL-6, and TNF-α, autophagosome, beclin-1, LC3-II/LC3-I, cleaved-caspase-3, p-AMPKα-1, and p-SIRT1 protein levels both in vivo and in vitro. Besides, XJCRTSZW treatment prominently enhanced the TP-induced decrease of cell viability in vitro.
Conclusion: XJCRTSZW can alleviate TP-induced reproductive toxicity via apoptosis, inflammation, and oxidative stress both in vivo and in vitro. Moreover, XJCRTSZW ameliorates TP-induced reproductive toxicity through AMPK/SIRT and Akt signaling axis mediated autophagy both in vivo and in vitro.

DOI: https://doi.org/10.1155/2022/3642349
IBRO Neurosci Rep. 2022 Dec;13 38-46

Effects of short-term food deprivation on catecholamine and metabolic-sensory biomarker gene expression in hindbrain A2 noradrenergic neurons projecting to the forebrain rostral preoptic area: Impact of negative versus positive estradiol feedback.

Ayed A Alshamrani, Mostafa M H Ibrahim, Karen P Briski.

  Hindbrain A2 noradrenergic neurons assimilate estrogenic and metabolic cues. In female mammals, negative- versus positive-feedback patterns of estradiol (E) secretion impose divergent regulation of the gonadotropin-releasing hormone (GnRH)-pituitary-gonadal (HPG) neuroendocrine axis. Current research used retrograde tracing, dual-label immunocytochemistry, single-cell laser-microdissection, and multiplex qPCR methods to address the premise that E feedback modes uniquely affect metabolic regulation of A2 neurons involved in HPG control. Ovariectomized female rats were given E replacement to replicate plasma hormone levels characteristic of positive (high-E dose) or negative (low-E dose) feedback. Animals were either full-fed (FF) or subjected to short-term, e.g., 18-h food deprivation (FD). After FF or FD, rostral preoptic area (rPO)-projecting A2 neurons were characterized by the presence or absence of nuclear glucokinase regulatory protein (nGKRP) immunostaining. FD augmented or suppressed mRNAs encoding the catecholamine enzyme dopamine-beta-hydroxylase (DβH) and the metabolic-sensory biomarker glucokinase (GCK), relative to FF controls, in nGKRP-immunoreactive (ir)-positive A2 neurons from low-E or high-E animals, respectively. Yet, these transcript profiles were unaffected by FD in nGKRP-ir-negative A2 neurons at either E dosage level. FD altered estrogen receptor (ER)-alpha and ATP-sensitive potassium channel subunit sulfonylurea receptor-1 gene expression in nGKRP-ir-positive neurons from low-E, but not high-E animals. Results provide novel evidence that distinct hindbrain A2 neuron populations exhibit altered versus unaffected transmission to the rPO during FD-associated metabolic imbalance, and that the direction of change in this noradrenergic input is controlled by E feedback mode. These A2 cell types are correspondingly distinguished by FD-sensitive or -insensitive GCK, which correlates with the presence versus absence of nGKRP-ir. Further studies are needed to determine how E signal volume regulates neurotransmitter and metabolic sensor responses to FD in GKRP-expressing A2 neurons.

Keywords:  AMPK, adenosine 5′-monophosphate-activated protein kinase; DVC, dorsal vagal complex; Dopamine-beta-hydroxylase; DβH, dopamine-beta-hydroxylase; E, estradiol; ERα, estrogen receptor-alpha; ERβ, estrogen receptor-beta; Estradiol; FD, food-deprivation; FF, full-fed; Food deprivation; GCK, glucokinase; GKRP, glucokinase regulatory protein; Glucokinase; Glucokinase regulatory protein; GnRH, gonadotropin-releasing hormone; HPG, hypothalamic-pituitary-gonadal; KATP, ATP-sensitive potassium channel; LH, luteinizing hormone; NE, norepinephrine; O.D., optical density; OVX, ovariectomy; SUR-1, sulfonylurea receptor-1; Single-cell quantitative multiplex PCR; TH, tyrosine hydroxylase; pAMPK, phospho-AMPK; rPO, rostral preoptic area

DOI:  https://doi.org/10.1016/j.ibneur.2022.06.001
Food Funct. 2022 Jun 16.

D-chiro-Inositol facilitates adiponectin biosynthesis and activates the AMPKα/PPARs pathway to inhibit high-fat diet-induced obesity and liver lipid deposition.

Qiong Yang, Yao Zhang, Luqi Li, Jia Li, Yunlong Li, Lin Han, Min Wang.

D-chiro-Inositol (DCI) is a natural cyclohexanol isomer that widely exists in all living beings, which can effectively prevent glucose and lipid metabolism disorders in mammals. This study revealed the DCI elevated adiponectin levels to reduce obesity and hepatic lipid deposition in high-fat diet (HFD) fed mice. Twelve weeks of DCI supplementation (50 and 100 mg per kg body weight per day) lowered body weight and serum triglyceride, total cholesterol, insulin, and fasting glucose levels. Histopathology analysis revealed that DCI inhibited hepatic steatosis and adipocyte expansion. Remarkably, DCI significantly increased serum adiponectin levels and upgraded the expressions of adiponectin receptors (AdipoR1 and AdipoR2) in the liver. The results of western blot and qRT-PCR showed that DCI impeded the inhibitory effect of HFD on liver AMPKα and PPARs activities through activating AdipoRs and regulated downstream fatty acid metabolism. In addition, we analyzed the concentration difference of DCI in mouse liver and adipose tissue by the HRLC-MS/MS technology, indicating the preference of DCI in different tissues. Therefore, DCI relieved liver lipid deposition and hyperlipidemia potentially by promoting adiponectin synthesis in white adipose tissue and activating the AdipoR-AMPKα/PPARs pathway in the liver.

DOI: https://doi.org/10.1039/d2fo00869f
Exp Cell Res. 2022 Jun 10. pii: S0014-4827(22)00237-3. [Epub ahead of print] 113244

PLIN2 promotes HCC cells proliferation by inhibiting the degradation of HIF1α.

Wuguang Liu, Xiaolong Liu, Ying Liu, Ting Ling, Di Chen, Wuxiyar Otkur, Hailong Zhao, Ming Ma, Kexin Ma, Bing Dong, Zexuan Yang, Hai-Long Piao, Rui Liang, Chengyong Dong.

  PLIN2 has been found to be dysregulated in several human malignancies, which influences cancer progression. However, the roles of PLIN2 in regulating hepatocellular carcinoma (HCC) progression are still unclear. Here, we revealed that PLIN2 was frequently upregulated in HCC cells and tissues, and increased PLIN2 expression was associated with poor prognosis outcomes in HCC. In HCC cells, overexpressing PLIN2 promoted cell proliferation, PLIN2-deficiency inhibited cell vitality. Mechanistically, silencing of PLIN2 expression downregulated hypoxia inducible factor 1-α (HIF1α) expression and this downregulation in turn inhibited the targeting genes of HIF1α. Furthermore, we found that PLIN2 stabilized and retarded the degradation of the HIF1α through autophagy-lysosomal pathway by inhibiting AMPK/ULK1. Collectively, we clarified the carcinogenic role of PLIN2 in HCC and suggested a prognostic biomarker for diagnosis and clinical therapy in the future.

Keywords:  AMPKα; Autophagy; HCC; HIF1α; PLIN2

DOI:  https://doi.org/10.1016/j.yexcr.2022.113244
Bioengineered. 2022 05;13(5): 13667-13679

lncRNA NBR2 attenuates angiotensin II-induced myocardial hypertrophy through repressing ER stress via activating LKB1/AMPK/Sirt1 pathway.

Cansheng Zhu, Min Wang, Xianguan Yu, Xing Shui, Leile Tang, Zefeng Chen, Zhaojun Xiong.

  Myocardial hypertrophy leads to heart failure (HF), and emerging researchers have illustrated that long noncoding RNAs (lncRNAs) modulate myocardial hypertrophy. Here, we explored the role and mechanism of a novel lncRNA, NBR2, in modulating angiotensin II (Ang II)-induced myocardial hypertrophy. First, we examined plasma NBR2 levels in 25 patients with HF and myocardial hypertrophy and ten healthy donors and analyzed the correlation between NBR2 profiles and patients' clinical indicators. In addition, the overexpression experiment of NBR2 was carried out to probe the influence of NBR2 on myocardial hypertrophy. lncRNA NBR2 was down-regulated in plasma of patients with HF and myocardial hypertrophy (vs. healthy controls), and its level was negatively correlated with cardiac function (represented by left ventricular end-diastolic diameter and left ventricular ejection fraction) and degree of myocardial hypertrophy. Besides, Ang II treatment intensified the hypertrophy of human myocardial cell lines (HCM and AC16) and curbed the NBR2 expression. Overexpressing lncRNA NBR2 alleviated Angiotension II-induced myocardial hypertrophy and declined the profiles of hypertrophic markers. Moreover, up-regulating lncRNA NBR2 weakened Ang II-mediated endoplasmic reticulum (ER) stress and activated the LKB1/AMPK/Sirt1 pathway. Interfering with the LKB1/AMPK/Sirt1 axis abated the lncRNA NBR2-mediated inhibitory effect on myocardial hypertrophy and ER stress. This study confirmed that lncRNA NBR2 dampened myocardial hypertrophy and ER stress by modulating the LKB1/AMPK/Sirt1 pathway. Our study provides the first evidence that lncRNA NBR2 is positively associated with myocardial hypertrophy.

Keywords:  Endoplasmic reticulum stress; angiotensin II; lncRNA NBR2; myocardial hypertrophy

DOI:  https://doi.org/10.1080/21655979.2022.2062527