bims-amsmem 2022-05-22 papers

bims-amsmem

Biomed News

on AMPK signaling mechanism in energy metabolism

Issue of 2022–05–22
twenty-one papers selected by
Dipsikha Biswas, Københavns Universitet

Hypothalamic AMPK as a possible target for energy balance-related diseases.
Transcriptional control of energy metabolism by nuclear receptors.
The Tumor Suppressor Kinase LKB1: Metabolic Nexus.
AMPK activation enhances neutrophil's fungicidal activity in vitro and improves the clinical outcome of Fusarium solani keratitis in vivo.
Docosahexaenoic acid ester of phloridzin reduces inflammation and insulin resistance via AMPK.
LKB1 Is Physiologically Required for Sleep from Drosophila melanogaster to the Mus musculus.
Translation initiation factor eIF3a regulates glucose metabolism and cell proliferation via promoting small GTPase Rheb synthesis and AMPK activation.
6'-O-Galloylpaeoniflorin Exerts Inhibitory Bioactivities in Human Neuroblastoma Cells via Modulating AMPK/miR-489/XIAP Pathway.
Dapagliflozin Ameliorates Lipopolysaccharide Related Acute Kidney Injury in Mice with Streptozotocin-induced Diabetes Mellitus.
Protective effects of Radix Isatidis polysaccharide ameliorates obesity via promotion AMPK pathway in high-fat-diet-induced obese rats and 3T3-L1 adipocyte cells.
Metformin-ROS-Nrf2 connection in the host defense mechanism against oxidative stress, apoptosis, cancers, and ageing.
cPKCγ Deficiency Exacerbates Autophagy Impairment and Hyperphosphorylated Tau Buildup through the AMPK/mTOR Pathway in Mice with Type 1 Diabetes Mellitus.
AMPK controls sucrose taste sensitization in Drosophila.
Aerobic Exercise Improves Type 2 Diabetes Mellitus-Related Cognitive Impairment by Inhibiting JAK2/STAT3 and Enhancing AMPK/SIRT1 Pathways in Mice.
Trifolirhizin regulates the balance of Th17/Treg cells and inflammation in the ulcerative colitis mice through inhibiting the TXNIP-mediated activation of NLRP3 inflammasome.
Metformin Improves the Prognosis of Adult Mice with Sepsis-Associated Encephalopathy Better than That of Aged Mice.
Liquiritin Attenuates Pathological Cardiac Hypertrophy by Activating the PKA/LKB1/AMPK Pathway.
Upregulation of 4-Hydroxynonenal Contributes to the Negative Effect of n-6 Polyunsaturated Fatty Acid on Alcohol-Induced Liver Injury and Hepatic Steatosis.
A Double-blind, Randomized Controlled Trial on Glucose-lowering Effects and Safety of Adding 0.25 or 0.5 mg Lobeglitazone in Type 2 Diabetes Patients with Inadequate Control on Metformin and DPP-4 Inhibitor Therapy: REFIND Study.
Controversial molecular functions of CBS versus non-CBS domain variants of PRKAG2 in arrhythmia and cardiomyopathy: A case report and literature review.
MicroRNA-206 inhibition and activation of the AMPK/Nampt signalling pathway enhance sevoflurane post-conditioning-induced amelioration of myocardial ischaemia/reperfusion injury.

Trends Pharmacol Sci. 2022 May 12. pii: S0165-6147(22)00087-6. [Epub ahead of print]

Hypothalamic AMPK as a possible target for energy balance-related diseases.

Miguel López.

  Hypothalamic AMP-activated protein kinase (AMPK) is a canonical regulator of energy balance and metabolism at the whole-body level. This makes this enzyme an attractive target for treating energy balance-related diseases. However, targeting AMPK within the hypothalamus presents a challenge related to the specific cellular biodistribution of the enzyme and the need to use clinically safe methods of administration. Current evidence has shown that targeting based on small extracellular vesicles (sEVs) might offer a realistic approach for regulating hypothalamic AMPK. This would allow modulation of both sides of the energy-balance equation, namely food intake and energy expenditure, and therefore of overall metabolism. Moreover, this strategy could provide treatment options not only for obesity but also for catabolic/wasting diseases such as hyperthyroidism, rheumatoid arthritis, and even cancer cachexia.

Keywords:  AMPK; cancer cachexia; food intake; hyperthyroidism; hypothalamus; obesity; rheumatoid arthritis; thermogenesis

DOI:  https://doi.org/10.1016/j.tips.2022.04.007
Nat Rev Mol Cell Biol. 2022 May 16.

Transcriptional control of energy metabolism by nuclear receptors.

Charlotte Scholtes, Vincent Giguère.

Transcriptional regulation of catabolic pathways is a central mechanism by which cells respond to physiological cues to generate the energy required for anabolic pathways, transport of molecules and mechanical work. Nuclear receptors are members of a superfamily of transcription factors that transduce hormonal, nutrient, metabolite and redox signals into specific metabolic gene programmes, and thus hold a major status as regulators of cellular energy generation. Nuclear receptors also regulate the expression of genes involved in cellular processes that are implicated in energy production, including mitochondrial biogenesis and autophagy. Recent advances in genome-wide approaches have considerably expanded the repertoire of both nuclear receptors and metabolic genes under their direct transcriptional control. To fine-tune the expression of their target genes, nuclear receptors must act cooperatively with other transcription factors and coregulator proteins, integrate signals from key metabolic sensory systems such as the AMP-activated protein kinase (AMPK) and mechanistic target of rapamycin (mTOR) complexes and synchronize their activities with the biological clock. Therefore, nuclear receptors must function as more than molecular switches for small lipophilic ligands - as initially ascribed - but rather must be capable of orchestrating a large ensemble of input signals. Therefore, a primary role for several nuclear receptors is to serve as the focal point of transcriptional hubs in energy metabolism: their molecular task is to receive and transduce multiple systemic and intracellular metabolic signals to maintain energy homeostasis from individual cells to the whole organism.

DOI: https://doi.org/10.1038/s41580-022-00486-7
Front Cell Dev Biol. 2022 ;10 881297

The Tumor Suppressor Kinase LKB1: Metabolic Nexus.

Mohammed Bourouh, Paola A Marignani.

  Liver kinase B1 (LKB1) is a multitasking tumor suppressor kinase that is implicated in multiple malignancies such as lung, gastrointestinal, pancreatic, and breast. LKB1 was first identified as the gene responsible for Peutz-Jeghers syndrome (PJS) characterized by hamartomatous polyps and oral mucotaneous pigmentation. LKB1 functions to activate AMP-activated protein kinase (AMPK) during energy stress to shift metabolic processes from active anabolic pathways to active catabolic pathways to generate ATP. Genetic loss or inactivation of LKB1 promotes metabolic reprogramming and metabolic adaptations of cancer cells that fuel increased growth and division rates. As a result, LKB1 loss is associated with increased aggressiveness and treatment options for patients with LKB1 mutant tumors are limited. Recently, there has been new insights into the role LKB1 has on metabolic regulation and the identification of potential vulnerabilities in LKB1 mutant tumors. In this review, we discuss the tumor suppressive role of LKB1 and the impact LKB1 loss has on metabolic reprograming in cancer cells, with a focus on lung cancer. We also discuss potential therapeutic avenues to treat malignancies associated with LKB1 loss by targeting aberrant metabolic pathways associated with LKB1 loss.

Keywords:  AMPK; LKB1; cancer metabolism; glycolysis; lung cancer; mTOR; tumor suppressor

DOI:  https://doi.org/10.3389/fcell.2022.881297
Curr Eye Res. 2022 May 14. 1-42

AMPK activation enhances neutrophil's fungicidal activity in vitro and improves the clinical outcome of Fusarium solani keratitis in vivo.

Wei Si, Yanting Xie, Junlu Dong, Chunmei Wang, Fenfen Zhang, Juan Yue, Shoujun Jian, Jingjing Wei, Susu Liu, Liya Wang, Hongmin Zhang.

   PURPOSE: To determine whether Activated 5'-AMP-activated protein kinase (AMPK) activation enhances Fusarium solani (F.solani) fungicidal capacity of neutrophils.
METHODS: The expression of AMPK and phosphorylated-AMPK (p-AMPK) proteins was tested using Western Blot. Plate counting studied the effects of the fungicidal capacity of neutrophils enhanced by AMPK activation. Phagocytized spores by neutrophils were assessed by immunostaining, and inhibited hyphal growth images were captured by JULI Stage real-time cell history recorder. Flow cytometry assay tested Reactive Oxygen Species (ROS) production and the percentage of apoptosis neutrophils. ROS Assay Kit also tested ROS production at different time points. The F.solani keratitis murine model was established, and slit-lamp microscopy captured corneal photographs.
RESULTS: Our experiments were divided into the following groups. Neutrophils (N), neutrophils + spores (N + S), neutrophils + spores+ 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR) (N + S+A), neutrophils + spores + Compound C (N + S+C). AMPK activator AICAR significantly increased the expression of p-AMPK in neutrophils. The plate counting experiment showed that the number of colonies in the N + S+A was significantly less than in the N + S group. Immunostaining results showed phagocytized spores were significantly increased in the N + S+A group compared with the N + S group. Captured photographs by real-time cell history recorder camera showed F.solani hyphal growth in the N + S+A group was significantly inhibited than in the N + S group. ROS release in the N + S+A group was significantly higher in the N + S+A group than in other groups. The percentage of apoptosis neutrophils in the N + S+A group was decreased than in the N + S group. Captured photographs by slit-lamp showed AICAR eye drop treatment alleviated the severity and decreased clinical score at 12 and 24 hours post-infection (h.p.i).
CONCLUSION: AMPK activation enhances the efficacy of neutrophils in killing F.solani in vitro and in vivo.

Keywords:  AMPK; Fungal keratitis; Fusarium solani ; ROS; neutrophils; phagocytosis

DOI:  https://doi.org/10.1080/02713683.2022.2078494
Curr Pharm Des. 2022 May 18.

Docosahexaenoic acid ester of phloridzin reduces inflammation and insulin resistance via AMPK.

Jingqing Chen, Zhenlong Wu, Jin Wang, Xuemeng Si, Rui Zhang, Tianqi Sun, Qiaoyan Dong, Wenqing Wu, Yefeng Qiu.

   BACKGROUND: Docosahexaenoic acid-acylated phloridzin (PZ-DHA), a novel polyphenol fatty acid ester derivative, is synthesized through an acylation reaction of phloridzin (PZ) and docosahexaenoic acid (DHA). PZ-DHA is more stable than DHA and exhibits higher cellular uptake and bioavailability than PZ.
OBJECTIVE: To investigate the effects of PZ-DHA on insulin resistance in the skeletal muscle and the related mechanisms, we used palmitic acid (PA)-treated C2C12 myotubes as an insulin resistance model.
RESULTS: We found that PZ-DHA increased the activity of AMP-activated protein kinase (AMPK) and improved glucose uptake and mitochondrial function in an AMPK-dependent manner in untreated C2C12 myotubes. PZ-DHA treatment of the myotubes reversed PA-induced insulin resistance; this was indicated by increases in glucose uptake and the expression of membrane glucose transporter 4 (Glut4) and phosphorylated Akt. Moreover, PZ-DHA treatment reversed PA-induced inflammation and oxidative stress. These effects of PZ-DHA were mediated by AMPK. Furthermore, the increase in AMPK activity, improvement in insulin resistance, and decrease in inflammatory and oxidative responses after PZ-DHA treatment diminished upon co-treatment with a liver kinase B1 (LKB1) inhibitor, suggesting that PZ-DHA improved AMPK activity by regulating its upstream kinase, LKB1.
CONCLUSION: The effects of PZ-DHA on insulin resistance in C2C12 myotubes may be mediated by the LKB1-AMPK signaling pathway. Hence, PZ-DHA is a promising therapeutic agent for insulin resistance in type 2 diabetes.

Keywords:  Docosahexaenoic acid; glucose uptake; insulin resistance; myotubes; phloridzin

DOI:  https://doi.org/10.2174/1381612828666220518102440
Genetics. 2022 May 17. pii: iyac082. [Epub ahead of print]

LKB1 Is Physiologically Required for Sleep from Drosophila melanogaster to the Mus musculus.

Ziyi Liu, Lifen Jiang, Chaoyi Li, Chengang Li, Jingqun Yang, Jianjun Yu, Renbo Mao, Yi Rao.

  Liver Kinase B1 (LKB1) is known as a master kinase for 14 kinases related to the adenosine monophosphate (AMP)-activated protein kinase (AMPK). Two of them salt inducible kinase 3 (SIK3) and AMPKα have previously been implicated in sleep regulation. We generated loss-of-function (LOF) mutants for Lkb1 in both Drosophila and mice. Sleep, but not circadian rhythms, was reduced in Lkb1-mutant flies and in flies with neuronal deletion of Lkb1. Genetic interactions between Lkb1 and Threonine to Alanine mutation at residue 184 of AMPK in Drosophila sleep or those between Lkb1 and Threonine to Glutamic Acid mutation at residue 196 of SIK3 in Drosophila viability have been observed. Sleep was reduced in mice after virally mediated reduction of Lkb1 in the brain. Electroencephalography (EEG) analysis showed that non-rapid eye movement (NREM) sleep and sleep need were both reduced in Lkb1-mutant mice. These results indicate that LKB1 plays a physiological role in sleep regulation conserved from flies to mice.

Keywords:  Flies; LKB1; Mice; Sleep

DOI:  https://doi.org/10.1093/genetics/iyac082
J Biol Chem. 2022 May 17. pii: S0021-9258(22)00484-7. [Epub ahead of print] 102044

Translation initiation factor eIF3a regulates glucose metabolism and cell proliferation via promoting small GTPase Rheb synthesis and AMPK activation.

Shijie Ma, Zizheng Dong, Yanfei Huang, Jing-Yuan Liu, Jian-Ting Zhang.

  eIF3a, the largest subunit of eukaryotic initiation factor 3 (eIF3) complex, has been shown to be overexpressed in malignant cancer cells, potentially making it a proto-oncogene. eIF3a overexpression can drive cancer cell proliferation but contributes to better prognosis. While its contribution to prognosis was previously shown to be due to its function in suppressing synthesis of DNA damage repair proteins, it remains unclear how eIF3a regulates cancer cell proliferation. In this study, we show using genetic approaches that eIF3a controls cell proliferation by regulating glucose metabolism via the phosphorylation and activation of AMPKα at Thr172 in its kinase activation loop. We demonstrate that eIF3a regulates AMPK activation mainly by controlling synthesis of the small GTPase Rheb, largely independent of the well-known AMPK upstream kinases LKB1 and CaMKK2, and also independent of mTOR signaling and glucose levels. Our findings suggest that glucose metabolism in and proliferation of cancer cells may be translationally regulated via a novel eIF3a-Rheb-AMPK signaling axis.

Keywords:  AMPK; Rheb; cell proliferation; eIF3a; glucose metabolism; protein synthesis

DOI:  https://doi.org/10.1016/j.jbc.2022.102044
Biomed Res Int. 2022 ;2022 1327835

6'-O-Galloylpaeoniflorin Exerts Inhibitory Bioactivities in Human Neuroblastoma Cells via Modulating AMPK/miR-489/XIAP Pathway.

Lijun Zhou, Aiwu Li, Qiangye Zhang.

Although therapies against neuroblastoma (NBM) have advanced, the patients still suffer from poor prognoses due to distal metastasis or the occurrence of multidrug resistance. Accumulating evidence has proved that chemicals derived from natural products possess potent anti-NBM properties or can be used as adjuvants for chemotherapy. In the present study, we demonstrated that 6'-O-galloylpaeoniflorin (GPF), a galloylated derivative of paeoniflorin isolated from the roots of Paeonia lactiflora Pall, exerted significant inhibitory effects on proliferation and invasion of SH-SY5Y cells (an NBM cell line) and enhanced the sensitivity of SH-SY5Y cells to cisplatin in vitro. Further studies showed that GPF treatment upregulated miR-489 in NBM cells via activating AMP-activated protein kinase (AMPK). We also demonstrated that similar to GPF treatment, miR-489 exhibited a significant anti-NBM capacity. Further studies showed that miR-489 directly targeted the X-linked inhibitor of apoptosis protein (XIAP). Overall, our results indicated that GPF possessed an evident anti-NBM capacity dependent on AMPK/miR-489/XIAP pathway, providing an emerging strategy for clinical treatment of NBM.

DOI: https://doi.org/10.1155/2022/1327835
Int J Med Sci. 2022 ;19(4): 729-739

Dapagliflozin Ameliorates Lipopolysaccharide Related Acute Kidney Injury in Mice with Streptozotocin-induced Diabetes Mellitus.

Po-Jui Chi, Chung-Jen Lee, Yi-Jen Hsieh, Chia-Wen Lu, Bang-Gee Hsu.

  Sepsis, which is a serious medical condition induced by infection, has been the most common cause of acute kidney injury (AKI) and is associated with high mortality and morbidity. Sodium-glucose cotransporter 2 (SGLT2) inhibitor is a new oral antidiabetic drug that has greatly improved the cardiovascular and renal outcomes in patients with type 2 diabetes independent of its sugar lowering effect, possibly by attenuation of the inflammatory process. We investigated the effect of the SGLT2 inhibitor dapagliflozin on lipopolysaccharide (LPS)-induced endotoxic shock with AKI in streptozotocin-induced diabetic mice. Endotoxin shock with AKI was induced by intravenous injection of 10 mg/kg LPS in C57BL6 mice with streptozotocin-induced diabetic mellitus with or without dapagliflozin treatment. Observation was done for 48 hours thereafter. In addition, NRK-52E cells incubated with LPS or dapagliflozin were evaluated for the possible mechanism. Treatment with dapagliflozin attenuated LPS-induced endotoxic shock associated AKI and decreased the inflammatory cytokines in diabetic mice. In the in vitro study, dapagliflozin decreased the expression of inflammatory cytokines and reactive oxygen species and increased the expressions of AMP-activated protein kinase (AMPK), nuclear factor erythroid-2-related factor, and heme oxygenase 1. These results demonstrated that dapagliflozin can attenuate LPS-induced endotoxic shock associated with AKI; this was possibly mediated by activation of the AMPK pathway.

Keywords:  acute kidney injury; dapagliflozin; diabetes; inflammatory cytokines; lipopolysaccharide; reactive oxygen species

DOI:  https://doi.org/10.7150/ijms.69031
J Pharm Pharmacol. 2022 May 17. pii: rgac027. [Epub ahead of print]

Protective effects of Radix Isatidis polysaccharide ameliorates obesity via promotion AMPK pathway in high-fat-diet-induced obese rats and 3T3-L1 adipocyte cells.

Ye Yuan, Dong-Ni Wang, Wen-You Zhang, Ting-Ting Sun, Yi-Ting Feng, Mo-Xiang Liu, Ji-Ping Li.

   OBJECTIVES: The purpose of this paper is to ascertain the effect and mechanism of Radix Isatidis polysaccharide (RIP) on obesity.
METHODS: High fat diet (HFD)-induced obese rats and the MDI-induced 3T3-L1 adipocyte cells were established to evaluate the ameliorated obesity effect and mechanism from RIP.
KEY FINDINGS: Experiments in vivo show that oral administration of RIP has significant preventive effects on HFD-induced obesity and metabolic disorders in rats. With treatment of RIP (20, 40 and 80 mg/kg BW), the body weight, fat accumulation, adipocyte cell size, serum lipid levels and antioxidant enzyme activity were progressively improved. On the other hand, the treatment of 3T3-L1 cells with RIP (25, 50 and 100 mg/L) led to a decrease in lipid accumulation and glucose consumption. In addition, during adipogenesis in 3T3-L1 cells, RIP remarkably down-regulated mRNA levels of peroxisome proliferator-activated receptor-γ (PPARγ), CCAAT/enhancer binding protein-α (C/EBPα), sterol regulatory element-binding protein-1c (SREBP-1c), fatty acid synthase (FAS), acetyl-CoA carboxylase and glycerol-3-phosphate dehydrogenase. Furthermore, after RIP treatment, the protein expression of PPARγ, C/EBPα, FAS, HMG-CoA reductase and acetyl-CoA synthetase-1 (AceCS1) were significantly decreased and the expression of p-AMPK was increased.
CONCLUSION: These results highlight the potential of RIP for obesity interventions and suggest that RIP inhibited adipocyte differentiation and lipid synthesis by activating adenosine 5'-monophosphate (AMP)-activated protein kinase (AMPK) signalling pathway and down-regulating the expression of major adipogenic transcription factors, PPARγ, C/EBPα, etc.

Keywords:  3T3-L1 adipocytes; AMPK; C/EBPα; PPARγ; Radix Isatidis polysaccharide; obesity

DOI:  https://doi.org/10.1093/jpp/rgac027
Biochim Biophys Acta Gen Subj. 2022 May 16. pii: S0304-4165(22)00089-7. [Epub ahead of print] 130171

Metformin-ROS-Nrf2 connection in the host defense mechanism against oxidative stress, apoptosis, cancers, and ageing.

Heiichiro Udono, Mikako Nishida.

  Reactive oxygen species (ROS) acts as a second messenger to trigger biological responses in low concentrations, while it is implicated to be toxic to biomolecules in high concentrations. Mild inhibition of respiratory chain Complex I by metformin at physiologically relevant concentrations stimulates production of low-level mitochondrial ROS. The ROS seems to induce anti-oxidative stress response via activation of nuclear factor erythroid 2- related factor 2 (Nrf2) and glutathione peroxidase (GPx), which results in not only elimination of ROS but also activation of cellular responses including resistance to apoptosis, metabolic changes, cell proliferation, senescence prevention, lifespan extension, and immune T cell activation against cancers, regardless of its effect controlling blood glucose level and T2DM. Although metformin's effect against T2DM, cancers, and ageing, are believed mostly attributed to the activation of AMP-activated protein kinase (AMPK), the cellular responses involving metformin-ROS-Nrf2 axis might be another natural asset to improve healthspan and lifespan. (150 word).

Keywords:  Ageing; Apoptosis; Mitochondrial ROS; Nrf2; Oxidative stress

DOI:  https://doi.org/10.1016/j.bbagen.2022.130171
Neurosci Bull. 2022 May 21.

cPKCγ Deficiency Exacerbates Autophagy Impairment and Hyperphosphorylated Tau Buildup through the AMPK/mTOR Pathway in Mice with Type 1 Diabetes Mellitus.

Jiayin Zheng, Yue Wang, Yue Liu, Song Han, Ying Zhang, Yanlin Luo, Yi Yan, Junfa Li, Li Zhao.

  Type 1 diabetes mellitus (T1DM)-induced cognitive dysfunction is common, but its underlying mechanisms are still poorly understood. In this study, we found that knockout of conventional protein kinase C (cPKC)γ significantly increased the phosphorylation of Tau at Ser214 and neurofibrillary tangles, but did not affect the activities of GSK-3β and PP2A in the hippocampal neurons of T1DM mice. cPKCγ deficiency significantly decreased the level of autophagy in the hippocampal neurons of T1DM mice. Activation of autophagy greatly alleviated the cognitive impairment induced by cPKCγ deficiency in T1DM mice. Moreover, cPKCγ deficiency reduced the AMPK phosphorylation levels and increased the phosphorylation levels of mTOR in vivo and in vitro. The high glucose-induced Tau phosphorylation at Ser214 was further increased by the autophagy inhibitor and was significantly decreased by an mTOR inhibitor. In conclusion, these results indicated that cPKCγ promotes autophagy through the AMPK/mTOR signaling pathway, thus reducing the level of phosphorylated Tau at Ser214 and neurofibrillary tangles.

Keywords:  AMPK/mTOR signaling pathway; Autophagy; Conventional protein kinase C (cPKC)γ; Phosphorylated Tau; Tau

DOI:  https://doi.org/10.1007/s12264-022-00863-4
J Genet Genomics. 2022 May 13. pii: S1673-8527(22)00135-7. [Epub ahead of print]

AMPK controls sucrose taste sensitization in Drosophila.

Yun Hu, Zhi-Ying Liu, Sha-Sha Li, An-Qi Li, Qiao-Ping Wang.

DOI: https://doi.org/10.1016/j.jgg.2022.04.015
Dis Markers. 2022 ;2022 6010504

Aerobic Exercise Improves Type 2 Diabetes Mellitus-Related Cognitive Impairment by Inhibiting JAK2/STAT3 and Enhancing AMPK/SIRT1 Pathways in Mice.

Lili Lin, Yonghua Wang, Wenli Xu, Chaolu Huang, Jinrong Hu, Xixi Chen, Xinhuang Lv, Yuelin Qin, Xiaoyong Zhao, Haiyan Li.

Type 2 diabetes mellitus (T2DM) is a prevalent risk factor for cognitive impairment. Aerobic exercise can improve T2DM-related cognitive impairment; however, the possible mechanisms remain elusive. Thus, we assessed db/m mice and leptin receptor-deficient (db/db) mice that did or did not perform aerobic exercise (8 m/min, 60 min/day, and 5 days/week for 12 weeks). In this study, cognitive function was significantly impaired in the T2DM mice; aerobic exercise improved cognitive impairment through activating the AMPK/SIRT1 signalling pathway and inhibiting the JAK2/STAT3 signalling pathway in T2DM mice. However, after the application of RO8191 (JAK2 activator) or Compound C (AMPK inhibitor), the positive improvement of the exercise was evidently suppressed. Taken together, our data indicated that long-term aerobic exercise improves type 2 diabetes mellitus-related cognitive impairment by inhibiting JAK2/STAT3 and enhancing AMPK/SIRT1 pathways in mice.

DOI: https://doi.org/10.1155/2022/6010504
Clin Exp Pharmacol Physiol. 2022 May 16.

Trifolirhizin regulates the balance of Th17/Treg cells and inflammation in the ulcerative colitis mice through inhibiting the TXNIP-mediated activation of NLRP3 inflammasome.

Qing Zhang, Shufang Wang, Shanyun Ji.

  Ulcerative colitis (UC) is a chronic and recurrent autoimmune disease, characterized by recurrence and remission of mucosal inflammation. Although the understanding of the pathogenesis of UC has been improved, effective therapeutic drugs are required for treating patients with UC. In current work, the mouse model of colitis was established. Trifolirhizin was demonstrated to improve symptom in dextran sulfate sodium (DSS)-induced colitis mice. The body weight of mice was elevated, while the disease activity index (DAI) was reduced. Moreover, Trifolirhizin was involved in inhibition of inflammation and regulation of Th17/Treg cell balance in DSS-induced colitis mice. Further, the activation NLRP3 inflammasome was suppressed by Trifolirhizin in DSS-induced colitis mice. Trifolirhizin was also identified to regulate AMPK-TXNIP pathway. The Trifolirhizin-mediated anti-inflammatory effect was inhibited by suppressing AMPK in DSS-induced UC mice. In summary, the research suggested that administration of Trifolirhizin significantly improved the symptoms and the pathological damage in DSS-induced UC mice. Trifolirhizin regulated the balance of Th17/Treg cells and inflammation in the UC mice through inhibiting the TXNIP-mediated activation of NLRP3 inflammasome. This article is protected by copyright. All rights reserved.

Keywords:  Th17/Treg balance; Trifolirhizin; Ulcerative colitis; inflammation

DOI:  https://doi.org/10.1111/1440-1681.13654
J Immunol Res. 2022 ;2022 3218452

Metformin Improves the Prognosis of Adult Mice with Sepsis-Associated Encephalopathy Better than That of Aged Mice.

Gaofei Song, Huoyan Liang, Heng Song, Xianfei Ding, Dong Wang, Xiaojuan Zhang, Tongwen Sun.

Sepsis-associated encephalopathy (SAE) is often associated with increased ICU occupancy and hospital mortality and poor long-term outcomes, with currently no specific treatment. Pathophysiological mechanisms of SAE are complex and may involve activation of microglia, multiple intracranial inflammatory factors, and inflammatory pathways. We hypothesized that metformin may have an effect on microglia, which affects the prognosis of SAE. In this study, metformin treatment of mice with SAE induced by lipopolysaccharide (LPS) reduced the expression of microglia protein and related inflammatory factors. Poor prognosis of SAE is related to increased expression of tumor necrosis factor-α (TNF-α) and interleukin-1 beta (IL-1β) in brain tissues. Levels of inflammatory cytokines produced by LPS-induced SAE mouse microglia were significantly increased compared with those in the sham group. In addition, ionized calcium-binding adapter molecule 1 (Iba-1) was significantly reduced in metformin-treated SAE mice compared with untreated SAE mice, suggesting that metformin can reduce microgliosis and inhibit central nervous system inflammation, thereby improving patient outcomes. In conclusion, our results stipulate that metformin inhibits inflammation through the adenosine 5'-monophosphate (AMP-) activated protein kinase pathway by inhibiting nuclear factor kappa beta (NF-κB). Metformin can partially reverse the severe prognosis caused by sepsis by blocking microglial proliferation and inhibiting the production of inflammatory factors.

DOI: https://doi.org/10.1155/2022/3218452
Front Pharmacol. 2022 ;13 870699

Liquiritin Attenuates Pathological Cardiac Hypertrophy by Activating the PKA/LKB1/AMPK Pathway.

Xiahenazi Aiyasiding, Hai-Han Liao, Hong Feng, Nan Zhang, Zheng Lin, Wen Ding, Han Yan, Zi-Ying Zhou, Qi-Zhu Tang.

  Background: Liquiritin (LQ) is one of the main flavonoids extracted from the roots of Glycyrrhiza spp., which are widely used in traditional Chinese medicine. Studies in both cellular and animal disease models have shown that LQ attenuates or prevents oxidative stress, inflammation, and apoptosis. However, the potential therapeutic effects of LQ on pressure overload-induced cardiac hypertrophy have not been so far explored. Therefore, we investigated the cardioprotective role of LQ and its underlying mechanisms in the aortic banding (AB)-induced cardiac hypertrophy mouse model. Methods and Results: Starting 3 days after AB surgery, LQ (80 mg/kg/day) was administered daily over 4 weeks. Echocardiography and pressure-volume loop analysis indicated that LQ treatment markedly improved hypertrophy-related cardiac dysfunction. Moreover, hematoxylin and eosin, picrosirius red, and TUNEL staining showed that LQ significantly inhibited cardiomyocyte hypertrophy, interstitial fibrosis, and apoptosis. Western blot assays further showed that LQ activated LKB1/AMPKα2/ACC signaling and inhibited mTORC1 phosphorylation in cardiomyocytes. Notably, LQ treatment failed to prevent cardiac dysfunction, hypertrophy, and fibrosis in AMPKα2 knockout (AMPKα2-/-) mice. However, LQ still induced LKB1 phosphorylation in AMPKα2-/- mouse hearts. In vitro experiments further demonstrated that LQ inhibited Ang II-induced hypertrophy in neonatal rat cardiomyocytes (NRCMs) by increasing cAMP levels and PKA activity. Supporting the central involvement of the cAMP/PKA/LKB1/AMPKα2 signaling pathway in the cardioprotective effects of LQ, inhibition of Ang II-induced hypertrophy and induction of LKB1 and AMPKα phosphorylation were no longer observed after inhibiting PKA activity. Conclusion: This study revealed that LQ alleviates pressure overload-induced cardiac hypertrophy in vivo and inhibits Ang II-induced cardiomyocyte hypertrophy in vitro via activating cAMP/PKA/LKB1/AMPKα2 signaling. These findings suggest that LQ might be a valuable adjunct to therapeutic approaches for treating pathological cardiac remodeling.

Keywords:  AMPKα2; PKA; cAMP; cardiac hypertrophy; heart; liquiritin

DOI:  https://doi.org/10.3389/fphar.2022.870699
J Agric Food Chem. 2022 May 19.

Upregulation of 4-Hydroxynonenal Contributes to the Negative Effect of n-6 Polyunsaturated Fatty Acid on Alcohol-Induced Liver Injury and Hepatic Steatosis.

Ai Fu, Jiaomei Li, Qinchao Ding, Rui Guo, Aiwen Pi, Wenwen Yang, Yanli Chen, Xiaobing Dou, Zhenyuan Song, Songtao Li.

  The present study aimed to investigate the effects of saturated fatty acids (SFA) and n-6 polyunsaturated fatty acids (PUFA) on alcoholic liver disease (ALD) and the underlying mechanisms. C57BL/6J male mice were randomly fed a corn oil or palm oil diet (rich in n-6 PUFA and SFA, respectively) with or without ethanol for four weeks (n = 10/group). A series of experiments in vitro with AML-12 hepatocyte were conducted to better elucidate the potential mechanisms underlying the phenomenon observed in animals. Compared with palm oil, corn oil aggravated alcohol-induced liver injury and hepatic steatosis, indicated by a histological analysis and significant elevations of plasma alanine aminotransferase and hepatic triacylglycerol (TG) level. Apoptosis-associated proteins in the ASK1-JNK pathway were significantly enhanced in the liver of mice from the corn oil + ethanol group than in the palm oil + ethanol group. The corn oil + ethanol diet also inhibited the activation of both AMPK and downstream protein acetyl-CoA carboxylase (ACC) and promoted the SREBP-1c expression, subsequently accelerating lipid synthesis. In addition, 4-hydroxynonenal (4-HNE) levels in plasma and liver were significantly upregulated in response to corn oil + ethanol feeding. Interestingly, the in vitro study showed that 4-HNE significantly attenuated cell viability, elevated the expression of cleaved-caspase 3 protein and TG level, and regulated key molecules in ASK1-JNK and AMPK pathways in a dose-dependent manner. In conclusion, the n-6 PUFA diet showed a negative effect on alcohol-induced liver injury and steatosis. It might be related to the upregulation of 4-HNE and subsequent changes of proteins, namely, ASK1, JNK, AMPK, ACC, and SREBP-1c.

Keywords:  4-HNE; alcoholic liver diseases; corn oil; n-6 PUFA; palm oil

DOI:  https://doi.org/10.1021/acs.jafc.2c00852
Diabetes Obes Metab. 2022 May 17.

A Double-blind, Randomized Controlled Trial on Glucose-lowering Effects and Safety of Adding 0.25 or 0.5 mg Lobeglitazone in Type 2 Diabetes Patients with Inadequate Control on Metformin and DPP-4 Inhibitor Therapy: REFIND Study.

Soree Ryang, Sang Soo Kim, Ji Cheol Bae, Ji Min Han, Su Kyoung Kwon, Young Il Kim, Il Sung Nam-Goong, Eun Sook Kim, Mi-Kyung Kim, Chang Won Lee, Soyeon Yoo, Gwanpyo Koh, Min Jeong Kwon, Jeong Hyun Park, In Joo Kim.

   AIMS: To compare the efficacy and safety of adding low-dose lobeglitazone (0.25 mg/day) or standard-dose lobeglitazone (0.5 mg/day) to type 2 diabetes mellitus (T2DM) patients with inadequate glucose control on metformin and dipeptidyl peptidase (DPP4) inhibitor therapy.
MATERIALS AND METHODS: In this phase 4, multi-center, double-blind, randomized controlled, non-inferiority trial, patients with T2DM insufficiently controlled by metformin and DPP4 inhibitor combination therapy were randomized to receive either low-dose or standard-dose lobeglitazone. The primary endpoint was non-inferiority of low-dose lobeglitazone in terms of glycemic control, expressed as the difference in mean glycated hemoglobin (HbA1c) levels at week 24 relative to baseline values and compared with standard-dose lobeglitazone, using 0.5% non-inferiority margin.
RESULTS: At week 24, the mean HbA1c levels were 6.87±0.54% and 6.68±0.46% in low-dose and standard-dose lobeglitazone groups, respectively (P=0.031). The between-group difference was 0.18% (95% confidence interval [CI] 0.017-0.345), showing non-inferiority of the low-dose lobeglitazone. Mean body weight changes were significantly greater in the standard-dose group (1.36±2.23 kg) than in the low-dose group (0.50±1.85 kg) at week 24. The changes in HOMA-IR, lipid profile, and liver enzyme levels showed no significant difference between the groups. Overall treatment-emergent adverse events (including weight gain, edema, and hypoglycemia) occurred more frequently in the standard-dose group.
CONCLUSIONS: Adding low-dose lobeglitazone to metformin and DPP4 inhibitor combination resulted in a non-inferior glucose-lowering outcome and fewer adverse events compared with standard-dose lobeglitazone. Therefore, low-dose lobeglitazone might be one option for individualized strategy in T2DM patients. This article is protected by copyright. All rights reserved.

Keywords:  antidiabetic drugs; beta-cell function; glycemic control; thiazolidinediones; type 2 diabetes

DOI:  https://doi.org/10.1111/dom.14766
Mol Genet Genomic Med. 2022 May 19. e1962

Controversial molecular functions of CBS versus non-CBS domain variants of PRKAG2 in arrhythmia and cardiomyopathy: A case report and literature review.

Xue Gong, Peiyu Yu, Ting Wu, Yunru He, Kaiyu Zhou, Yimin Hua, Sha Lin, Tao Wang, He Huang, Yifei Li.

   BACKGROUND: PRKAG2 cardiac syndrome is a rare autosomal dominant genetic disorder caused by a PRKAG2 gene variant. There are several major adverse cardiac presentations, including hypertrophic cardiomyopathy (HCM) and life-threatening arrhythmia. Two cases with pathogenic variants in the PRKAG2 gene are reported here who presents different cardiac phenotypes.
METHODS: Exome sequencing and variant analysis of PRKAG2 were performed to obtain genetic data, and clinical characteristics were determined.
RESULTS: The first proband was a 9-month-old female infant (Case 1), and was identified with severe DCM and resistant heart failure. The second proband was a 10-year-old female infant (Case 2), and presented with HCM and ventricular preexcitation. Exome sequencing identified a de novo c.425C > T (p.T142I) heterozygous variant in the PRKAG2 gene for Case 1, and a c.869A > T (p.K290I) for Case 2. The mutated sites in the protein were labeled and identified as p.K290 in the CBS domain and p.T142 in the non-CBS domain. Differences in the molecular functions of CBS and non-CBS domains have not been resolved, and variants might lead to the different cardiomyopathy phenotypes. Single-cell RNA analysis demonstrated similar expression levels of PRKAG2 in cardiomyocytes and conductive tissues. These results suggest that the arrhythmia induced by the PRKAG2 variant was the primary change, and not secondary to cardiomyopathy.
CONCLUSION: In summary, this is the first case report to describe a DCM phenotype with early onset in patients possessing a PRKAG2 c.425C > T (p.T142I) pathogenic variant. Our results aid in understanding the molecular function of non-CBS variants in terms of the disordered sequence of transcripts. Moreover, we used scRNA-seq to show that electrically conductive cells express a higher level of PRKAG2 than do cardiomyocytes. Therefore, variants in PRKAG2 are expected to also alter the biological function of the conduction system.

Keywords:  AMPK signaling; PRKAG2 cardiac syndrome; case report; genomic sequence; scRNA-seq

DOI:  https://doi.org/10.1002/mgg3.1962
J Drug Target. 2022 May 19. 1

MicroRNA-206 inhibition and activation of the AMPK/Nampt signalling pathway enhance sevoflurane post-conditioning-induced amelioration of myocardial ischaemia/reperfusion injury.

DOI: https://doi.org/10.1080/1061186X.2022.2078565