bims-amsmem 2022-09-25 papers

bims-amsmem

Biomed News

on AMPK signaling mechanism in energy metabolism

Issue of 2022–09–25
25 papers selected by
Dipsikha Biswas, Københavns Universitet

Obesity-induced miR-802 directly targets AMPK and promotes nonalcoholic steatohepatitis in mice.
AMPK: The key to ischemia-reperfusion injury.
Activation of AMPK-PGC-1α pathway ameliorates peritoneal dialysis related peritoneal fibrosis in mice by enhancing mitochondrial biogenesis.
Downregulation of LKB1/AMPK Signaling in Blood Mononuclear Cells Is Associated with the Severity of Guillain-Barre Syndrome.
Farnesoid X Receptor Overexpression Decreases the Migration, Invasion and Angiogenesis of Human Bladder Cancers via AMPK Activation and Cholesterol Biosynthesis Inhibition.
PM2.5 inhibits system Xc- activity to induce ferroptosis by activating the AMPK-Beclin1 pathway in acute lung injury.
Inhibition of Hepatic AMPK Pathway Contributes to Free Fatty Acids-Induced Fatty Liver Disease in Laying Hen.
Dihydromyricetin alters myosin heavy chain expression via AMPK signaling pathway in porcine myotubes.
Biochanin A ameliorated oleate-induced steatosis in HepG2 cells by activating the SIRT3/AMPK/ULK-1 signaling pathway.
Effects of the peripheral CB1 receptor antagonist JD5037 in mono- and polytherapy with the AMPK activator metformin in a monocrotaline-induced rat model of pulmonary hypertension.
AMPK-Nrf2 Signaling Pathway in Phrenic Motoneurons following Cervical Spinal Cord Injury.
A Botanical Mixture Consisting of Inula japonica and Potentilla chinensis Relieves Obesity via the AMPK Signaling Pathway in 3T3-L1 Adipocytes and HFD-Fed Obese Mice.
Nuak kinase signaling in development and disease of the central nervous system.
Empagliflozin activates Sestrin2-mediated AMPK/mTOR pathway and ameliorates lipid accumulation in obesity-related nonalcoholic fatty liver disease.
Is metformin a possible treatment for diabetic neuropathy?
Liquorice root extract and isoliquiritigenin attenuate high-fat diet-induced hepatic steatosis and damage in rats by regulating AMPK.
Exercise and Metformin Intervention Prevents Lipotoxicity-Induced Hepatocyte Apoptosis by Alleviating Oxidative and ER Stress and Activating the AMPK/Nrf2/HO-1 Signaling Pathway in db/db Mice.
Melatonin ameliorates lung cell inflammation and apoptosis caused by Klebsiella pneumoniae via AMP-activated protein kinase.
Quercetin induces autophagy-associated death in HL-60 cells through CaMKKβ/AMPK/mTOR signal pathway.
Schaftoside improves cerebral ischemia-reperfusion injury by enhancing autophagy and reducing apoptosis and inflammation through the AMPK/mTOR pathway.
Knocking on GDF15's door for the treatment of type 2 diabetes mellitus.
The ABA-LANCL1/2 Hormone-Receptors System Protects H9c2 Cardiomyocytes from Hypoxia-Induced Mitochondrial Injury via an AMPK- and NO-Mediated Mechanism.
PIM3-AMPK-HDAC4/5 axis restricts MuERVL-marked 2-cell-like state in embryonic stem cells.
Laminin-α4 negatively regulates adipocyte beiging through the suppression of AMPKα in male mice.
Britannin mediates apoptosis and glycolysis of T-cell lymphoblastic lymphoma cells by AMPK-dependent autophagy.

Mol Metab. 2022 Sep 17. pii: S2212-8778(22)00172-7. [Epub ahead of print] 101603

Obesity-induced miR-802 directly targets AMPK and promotes nonalcoholic steatohepatitis in mice.

Hao Sun, Sunmi Seok, Hyunkyung Jung, Byron Kemper, Jongsook Kim Kemper.

   OBJECTIVE: Obesity-associated non-alcoholic fatty liver disease (NAFLD) is a leading cause of liver failure and death. However, the pathogenesis of NAFLD and its severe form, non-alcoholic steatohepatitis (NASH), is poorly understood. The energy sensor, AMP-activated protein kinase (AMPK), has decreased activity in obesity and NAFLD, but the mechanisms are unclear. Here, we examined whether obesity-induced miR-802 has a role in promoting NASH by targeting AMPK. We also investigated whether miR-802 and AMPK have roles in modulating beneficial therapeutic effects mediated by obeticholic acid (OCA), a promising clinical agent for NASH.
METHODS: Immunoblotting, luciferase assays, and RNA-protein interaction studies were performed to test whether miR-802 directly targets AMPK. The roles of miR-802 and AMPK in NASH were examined in mice fed a NASH-promoting diet.
RESULTS: Hepatic miR-802 and AMPK levels were inversely correlated in both NAFLD patients and obese mice. MicroRNA in silico analysis, together with biochemical studies in hepatic cells, suggested that miR-802 inhibits hepatic expression of AMPK by binding to the 3' untranslated regions of both human AMPKα1 and mouse Ampkβ1. In diet-induced NASH mice, OCA treatment reduced hepatic miR-802 levels and improved AMPK activity, ameliorating steatosis, inflammation, and apoptosis, but these OCA-mediated beneficial effects on NASH pathologies, particularly reducing apoptosis, were reversed by overexpression of miR-802 or downregulation of AMPK.
CONCLUSIONS: These results indicate that miR-802 inhibits AMPK by directly targeting Ampkβ1, promoting NAFLD/NASH in mice. The miR-802-AMPK axis that modulates OCA-mediated beneficial effects on NASH may represent a new therapeutic target.

Keywords:  FXR; Hepatocellular apoptosis; Inflammation; NAFLD; NASH; OCA

DOI:  https://doi.org/10.1016/j.molmet.2022.101603
J Cell Physiol. 2022 Sep 22.

AMPK: The key to ischemia-reperfusion injury.

Jie Cai, Xinyue Chen, Xingyu Liu, Zhangwang Li, Ao Shi, Xiaoyi Tang, Panpan Xia, Jing Zhang, Peng Yu.

  Ischemia-reperfusion injury (IRI) refers to a syndrome in which tissue damage is further aggravated and organ function further deteriorates when blood flow is restored after a period of tissue ischemia. Acute myocardial infarction, stress ulcer, pancreatitis, intestinal ischemia, intermittent claudication, acute tubular necrosis, postshock liver failure, and multisystem organ failure are all related to reperfusion injury. AMP-activated protein kinase (AMPK) has been identified in multiple catabolic and anabolic signaling pathways. The functions of AMPK during health and diseases are intriguing but still need further research. Except for its conventional roles as an intracellular energy switch, emerging evidence reveals the critical role of AMPK in IRI as an energy-sensing signal molecule by regulating metabolism, autophagy, oxidative stress, inflammation, and other progressions. At the same time, drugs based on AMPK for the treatment of IRI are constantly being researched and applied in clinics. In this review, we summarize the mechanisms underlying the effects of AMPK in IRI and describe the AMPK-targeting drugs in treatment, hoping to increase the understanding of AMPK in IRI and provide new insights into future clinical treatment.

Keywords:  AMPK; glycolysis and glycogen synthesis; ischemia-reperfusion injury; lipid metabolism; programmed cell death

DOI:  https://doi.org/10.1002/jcp.30875
Ren Fail. 2022 Dec;44(1): 1545-1557

Activation of AMPK-PGC-1α pathway ameliorates peritoneal dialysis related peritoneal fibrosis in mice by enhancing mitochondrial biogenesis.

Jun Wu, Jushuang Li, Baohong Feng, Zhimin Bi, Geli Zhu, Yanxia Zhang, Xiangyou Li.

   BACKGROUND: The pathogenesis of peritoneal dialysis (PD)-related peritoneal fibrosis (PF) is not clearly understood, and current treatment options are limited.
METHODS: In this study, the effect of PD-related PF on mitochondrial biogenesis was investigated, and the effect of activation of the adenosine monophosphate-activated protein kinase (AMPK)-PGC-1α (peroxisome proliferator-activated receptor γ coactivator-1α) pathway on PF was evaluated in mice.
RESULTS: In a mouse model of PD-related PF, AMPK-PGC-1α signaling (phospho-AMPK, PGC-1α, NRF-1, NRF-2 and TFAM expression) was downregulated, mitochondrial DNA (mtDNA) levels were reduced, and mitochondrial structure was damaged in the peritoneum. In addition, TdT-mediated dUTP nick-end labeling (TUNEL) staining showed typical apoptosis characteristics in peritoneal mesothelial cells (PMCs). Activation of the AMPK-PGC-1α pathway (PGC-1α overexpression or metformin, which is an agonist of AMPK) upregulated phospho-AMPK, PGC-1α, nuclear respiratory factors 1 (NRF-1) and 2 (NRF-2), and mitochondrial transcription factor A (TFAM) expression and mtDNA content, improved mitochondrial morphological manifestations, inhibited apoptosis of PMCs and alleviated PF.
CONCLUSION: Our study may suggest that activation of the AMPK-PGC-1α pathway ameliorates PD-related PF by enhancing mitochondrial biogenesis.

Keywords:  AMPK; PGC-1α; Peritoneal dialysis; mitochondrial biogenesis; peritoneal fibrosis

DOI:  https://doi.org/10.1080/0886022X.2022.2126789
Cells. 2022 Sep 16. pii: 2897. [Epub ahead of print]11(18):

Downregulation of LKB1/AMPK Signaling in Blood Mononuclear Cells Is Associated with the Severity of Guillain-Barre Syndrome.

Verica Paunovic, Stojan Peric, Irena Vukovic, Marina Stamenkovic, Emina Milosevic, Danijela Stevanovic, Milos Mandic, Ivana Basta, Ivana Berisavac, Mirjana Arsenijevic, Ivo Bozovic, Marko Nikolic, Zorica Stevic, Vladimir Trajkovic.

  AMP-activated protein kinase (AMPK) is an intracellular energy sensor that regulates metabolic and immune functions mainly through the inhibition of the mechanistic target of rapamycin (mTOR)-dependent anabolic pathways and the activation of catabolic processes such as autophagy. The AMPK/mTOR signaling pathway and autophagy markers were analyzed by immunoblotting in blood mononuclear cells of 20 healthy control subjects and 23 patients with an acute demyelinating form of Guillain-Barré syndrome (GBS). The activation of the liver kinase B1 (LKB1)/AMPK/Raptor signaling axis was significantly reduced in GBS compared to control subjects. In contrast, the phosphorylated forms of mTOR activator AKT and mTOR substrate 4EBP1, as well as the levels of autophagy markers LC3-II, beclin-1, ATG5, p62/sequestosome 1, and NBR1 were similar between the two groups. The downregulation of LKB1/AMPK signaling, but not the activation status of the AKT/mTOR/4EBP1 pathway or the levels of autophagy markers, correlated with higher clinical activity and worse outcomes of GBS. A retrospective study in a diabetic cohort of GBS patients demonstrated that treatment with AMPK activator metformin was associated with milder GBS compared to insulin/sulphonylurea therapy. In conclusion, the impairment of the LKB1/AMPK pathway might contribute to the development/progression of GBS, thus representing a potential therapeutic target in this immune-mediated peripheral polyneuropathy.

Keywords:  AMP-activated protein kinase; Guillain–Barré syndrome; autophagy; mTOR; metformin; peripheral blood mononuclear cells

DOI:  https://doi.org/10.3390/cells11182897
Cancers (Basel). 2022 Sep 09. pii: 4398. [Epub ahead of print]14(18):

Farnesoid X Receptor Overexpression Decreases the Migration, Invasion and Angiogenesis of Human Bladder Cancers via AMPK Activation and Cholesterol Biosynthesis Inhibition.

Chien-Rui Lai, Yu-Ling Tsai, Wen-Chiuan Tsai, Tzu-Min Chen, Hsin-Han Chang, Chih-Ying Changchien, Sheng-Tang Wu, Hisao-Hsien Wang, Ying Chen, Yu-Huei Lin.

  Bladder cancer is one of the most prevailing cancers worldwide. Although treatments for urothelial carcinoma have improved, the rate of recurrence observed in the clinic is still high. The aim of this study was to evaluate whether cholesterol biosynthesis is involved in the effect of Farnesoid X Receptor (FXR) on bladder cancers. FXR overexpression contributed to activation of 5' AMP-activated protein kinase (AMPK) and decreased cholesterol levels. FXR overexpression reduced cholesterol biosynthesis and secretion by downregulating Sterol Regulatory Element Binding Protein 2 (SREBP2) and 3-Hydroxy-3-Methylglutaryl-CoA Reductase (HMGCR) expression. In addition, an AMPK inhibitor, dorsomorphin, reversed the inhibition of migration, invasion and angiogenesis by FXR overexpression. In a metastatic xenograft animal study, FXR overexpression suppressed bladder cancer lung metastasis by decreasing matrix metalloproteinase-2 (MMP2), SREBP2 and HMGCR expression. Moreover, FXR overexpression combined with atorvastatin treatment further enhanced the downregulation of the migratory, adhesive, invasive and angiogenic properties in human urothelial carcinoma. In clinical observations, statin administration was associated with better survival rates of early-stage bladder cancer patients. Our results may provide guidance for improving therapeutic strategies for the treatment of urothelial carcinoma.

Keywords:  AMPK; FXR; angiogenesis; atorvastatin; bladder cancer; cholesterol; invasion; migration

DOI:  https://doi.org/10.3390/cancers14184398
Ecotoxicol Environ Saf. 2022 Sep 19. pii: S0147-6513(22)00923-X. [Epub ahead of print]245 114083

PM2.5 inhibits system Xc- activity to induce ferroptosis by activating the AMPK-Beclin1 pathway in acute lung injury.

Kun Yan, Tianhua Hou, Laiyu Zhu, Xinxin Ci, Liping Peng.

  Urban airborne fine particulate matter (PM2.5) is a global pollution source that has been strongly related to multiple respiratory diseases involving various types of regulated cell death (RCD). However, the role of ferroptosis, a novel form of RCD, in PM2.5-induced acute lung injury (ALI), has not been elucidated. Herein, we define the role and mechanism of ferroptosis in a PM2.5-induced ALI model. First, we demonstrated that lipid peroxidation and iron accumulation were significantly enhanced in ALI models and were accompanied by activation of the AMP-activated protein kinase (AMPK)-Beclin1 signaling pathway and inhibition of the key subunit SLC7A11 of System Xc-. However, these abnormalities were partially reversed by ferroptosis inhibitors. We further revealed that Beclin1 knockdown or overexpression ameliorated or exacerbated PM2.5-induced ferroptosis, respectively. Mechanistically, we verified that Beclin1 blocks System Xc- activity to trigger ferroptosis by directly binding to SLC7A11. Finally, knockdown of Beclin1 by AAV-shRNA or inhibition of AMPK, an upstream activator of Beclin1, ameliorated PM2.5-induced ferroptosis and ALI. Taken together, our results revealed that ferroptosis plays a novel role in PM2.5-induced ALI and elucidated the specific mechanism involving the AMPK-Beclin1 pathway and System Xc-, which may provide new insight into the toxicological effects of PM2.5 on respiratory problems.

Keywords:  Acute lung injury; Beclin1; Ferroptosis; PM2.5; System X(c)-

DOI:  https://doi.org/10.1016/j.ecoenv.2022.114083
Metabolites. 2022 Sep 01. pii: 825. [Epub ahead of print]12(9):

Inhibition of Hepatic AMPK Pathway Contributes to Free Fatty Acids-Induced Fatty Liver Disease in Laying Hen.

Cheng Huang, Xiaona Gao, Yan Shi, Lianying Guo, Changming Zhou, Ning Li, Wei Chen, Fan Yang, Guyue Li, Yu Zhuang, Ping Liu, Guoliang Hu, Xiaoquan Guo.

  Metabolism-associated fatty liver disease (MAFLD) is one of the most common causes of liver disease; however, the underlying processes remain unknown. This study aimed to investigate the changes of free fatty acids (FFA) on the expression of genes related to the AMP-activated protein kinase (AMPK) signaling pathway in the primary hepatocytes of laying hens. The primary hepatocytes of laying hens were treated with FFA (containing a 2:1 ratio of oleic and palmitic acids) for 24 h. FFA significantly increased lipid droplet accumulation, decreased glycogen synthesis, increased the levels of triglycerides (TG), total cholesterol (TC), reactive oxygen species (ROS), malondialdehyde (MDA), and glucose content in the supernatant (GLU) in the primary hepatocytes of laying hens, and decreased the levels of total antioxidant capacity (T-AOC) and superoxide dismutase (SOD), as well as mitochondrial membrane potential (MMP). The results of the PCR array combined with Western blotting experiments showed that the activity of AMPK was inhibited. Inhibition of AMPK signaling pathway decreases the expression of genes involved in fatty acid oxidation, increases the expression of genes involved in lipid synthesis, decreases the expression of genes involved in glycogen synthesis, increases the expression of genes involved in glycolysis, increases the expression of genes involved in oxidative stress, and increases the expression of genes involved in cell proliferation and apoptosis. Taken together, our results suggest that FFA can affect the homeostasis of the AMPK signaling pathway by altering energy metabolic homeostasis, inducing oxidative stress, and adjusting the onset of cell proliferation and apoptosis.

Keywords:  AMPK signaling pathway; FFA; MAFLD; PCR array; primary hepatocytes

DOI:  https://doi.org/10.3390/metabo12090825
Food Funct. 2022 Sep 23.

Dihydromyricetin alters myosin heavy chain expression via AMPK signaling pathway in porcine myotubes.

Zhongyang Guo, Xiaoling Chen, Daiwen Chen, Bing Yu, Jun He, Ping Zheng, Yuheng Luo, Hong Chen, Hui Yan, Zhiqing Huang.

Dihydromyricetin (DHM) has attracted wide concern for its excellent biological function and pharmacological activities and was reported to have a positive effect on skeletal muscle insulin resistance, slow-twitch fibers expression and AMPK signaling. Thus, we took porcine myotubes derived from skeletal muscle satellite cells as the object to investigate the effects of DHM on myosin heavy chain (MyHC) expression and its mechanism in this study. Data showed that DHM up-regulated protein expression of MyHC I and down-regulated the protein expression of MyHC IIb, accompanied by an increase of MyHC I mRNA level and a decrease of MyHC IIb mRNA level. Besides, DHM increased the activities of malate dehydrogenase and succinic dehydrogenase and reduced lactate dehydrogenase activity. AMP-activated protein kinase (AMPK) was phosphorylated and AMPKα1 mRNA level was increased by DHM. The AMPK signaling-related factors including peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α), sirtuin1 (Sirt1), nuclear respiratory factor 1 (NRF1), and phospho-calmodulin-dependent protein kinase kinase-β (p-CaMKKβ) were increased by DHM. Inhibition of the AMPK signaling by compound C and AMPKα1 siRNA significantly attenuated the effects of DHM on expressions of MyHC I, MyHC IIb, PGC-1α and Sirt1. As a whole, DHM increased MyHC I expression and decreased MyHC IIb expression by the AMPK signaling.

DOI: https://doi.org/10.1039/d2fo02173k
J Food Biochem. 2022 Sep 20. e14428

Biochanin A ameliorated oleate-induced steatosis in HepG2 cells by activating the SIRT3/AMPK/ULK-1 signaling pathway.

Guo-En Wang, Xiao-Ting Liu, Fan Yang, Ruo-Hong Wang, Xin-Yu Liu, Xi-Ting Lv, Xiao-Li Lin, Yan-Fen Chen.

  Biochanin A (Bio-A), an isoflavone abundant in chickpeas, possesses hypoglycemic, hypolipidemic, and anti-inflammatory effects. However, whether Bio-A has antihepatosteatosis effect remains unclear. This study aimed to evaluate the antihepatosteatosis effect of Bio-A on oleate (OA)-treated hepatocytes, and explore the underlying mechanism. When incubated with OA for 24 h, HepG2 cells were treated with various concentrations of Bio-A for 24 h to obtain an optimal antihepatosteatosis dose. HepG2 cells were treated with the AMP-activated protein kinase (AMPK) inhibitor Compound C, or the sirtuin-3 (SIRT3) inhibitor 3-TYP, and incubated with 50 μM Bio-A. The results indicated that 12.6% of lipid content, particularly 11.0% of triglyceride content, and the expression of adipocyte differentiation-related protein were significantly decreased in Bio-A-treated hepatosteatosis cells, followed by an increase in the expression of Beclin 1, phosphorylation of Unc-51-like kinase 1 (ULK-1), the microtubule-associated protein 1 light chain 3 (LC3)-II/LC3-I ratio, and a decrease in expression of p62. The results indicated that Bio-A upregulated autophagosome formation and autophagy flux. In addition, Bio-A increased SIRT3 expression and AMPK phosphorylation in OA-treated HepG2 cells. Blockade of AMPK and SIRT3 blocked the antihepatosteatosis effect and ULK-1 activation by Bio-A. AMPK inhibition did not eliminate the activation of SIRT3 by Bio-A. AutoDock analysis demonstrated that interaction might exist between Bio-A and SIRT3. In conclusion, Bio-A reduced fat accumulation in OA-treated HepG2 cells by activating SIRT3/AMPK/ULK-1-mediated autophagy. The findings provide a theoretical basis for the effect of Bio-A on hepatic steatosis-related diseases. PRACTICAL APPLICATIONS: This study highlights the antihepatosteatosis effects of biochanin A (Bio-A) on oleate (OA)-treated hepatocytes. Bio-A, one of the isoflavones in Cicer arietinum Linn., possesses multiple bioactivities such as antiobesity, anti-inflammation, and hypoglycemic and hypolipidemic effects. This study provides a new application of Bio-A to treat hepatic steatosis, and revealed the underlying mechanism of Bio-A involved in the activation of the SIRT3/AMPK/ULK-1-mediated autophagy. The findings provide a theoretical basis for the application of Bio-A to hepatic steatosis-related diseases.

Keywords:  LC3; adipocyte differentiation-related protein; autophagy; chickpea; hepatic steatosis; p62

DOI:  https://doi.org/10.1111/jfbc.14428
Front Pharmacol. 2022 ;13 965613

Effects of the peripheral CB1 receptor antagonist JD5037 in mono- and polytherapy with the AMPK activator metformin in a monocrotaline-induced rat model of pulmonary hypertension.

Patryk Remiszewski, Anna Pędzińska-Betiuk, Krzysztof Mińczuk, Eberhard Schlicker, Justyna Klimek, Janusz Dzięcioł, Barbara Malinowska.

  Pulmonary hypertension (PH) is a disease leading to increased pressure in the pulmonary artery and right heart failure. The adenosine monophosphate-activated protein kinase (AMPK) activator, metformin, has a protective effect against PH. CB1 receptor blockade reduces the number of pathological alterations in experimental lung fibrosis. The current study evaluates the effect of the peripheral cannabinoid CB1 receptor antagonist JD5037 in mono- and polytherapy with metformin in rat monocrotaline-induced mild PH. Animals received metformin (100 mg/kg), JD5037 (3 mg/kg), or a combination of both once daily for 21 days. Monocrotaline (60 mg/kg) increased right ventricular (RV) systolic pressure (RVSP), led to RV and lung hypertrophy and remodeling, and decreased oxygen saturation. Metformin partially restored the monocrotaline-induced effects, i.e., decreased RVSP, increased oxygen saturation, and counteracted cardiac fibrotic, hypertrophic, and inflammatory changes. JD5037 modified parameters related to inflammation and/or fibrosis. Only polytherapy with metformin and JD5037 improved Fulton's index and coronary artery hypertrophy and tended to be more effective than monotherapy against alterations in RVSP, oxygen saturation and coronary artery tunica media vacuolization. In conclusion, monotherapy with JD5037 does not markedly influence the PH-related changes. However, polytherapy with metformin tends to be more efficient than any of these compounds alone.

Keywords:  AMP-activated protein kinase; JD5037; cannabinoid 1 receptor; metformin; monocrotaline; polytherapy; pulmonary arterial hypertension

DOI:  https://doi.org/10.3389/fphar.2022.965613
Antioxidants (Basel). 2022 Aug 26. pii: 1665. [Epub ahead of print]11(9):

AMPK-Nrf2 Signaling Pathway in Phrenic Motoneurons following Cervical Spinal Cord Injury.

Pauline Michel-Flutot, Laurie Efthimiadi, Lynda Djerbal, Therese B Deramaudt, Marcel Bonay, Stéphane Vinit.

  High spinal cord injuries (SCI) induce the deafferentation of phrenic motoneurons, leading to permanent diaphragm paralysis. This involves secondary injury associated with pathologic and inflammatory processes at the site of injury, and at the level of phrenic motoneurons. In the present study, we evaluated the antioxidant response in phrenic motoneurons involving the AMPK-Nrf2 signaling pathway following C2 spinal cord lateral hemi-section in rats. We showed that there is an abrupt reduction in the expression of phosphorylated AMPK and Nrf2 at one hour post-injury in phrenic motoneurons. A rebound is then observed at one day post-injury, reflecting a return to homeostasis condition. In the total spinal cord around phrenic motoneurons, the increase in phosphorylated AMPK and Nrf2 occurred at three days post-injury, showing the differential antioxidant response between phrenic motoneurons and other cell types. Taken together, our results display the implication of the AMPK-Nrf2 signaling pathway in phrenic motoneurons' response to oxidative stress following high SCI. Harnessing this AMPK-Nrf2 signaling pathway could improve the antioxidant response and help in spinal rewiring to these deafferented phrenic motoneurons to improve diaphragm activity in patients suffering high SCI.

Keywords:  AMPK; Nrf2; antioxidant; neuroinflammation; phrenic motoneuron; rat; spinal cord injury

DOI:  https://doi.org/10.3390/antiox11091665
Nutrients. 2022 Sep 06. pii: 3685. [Epub ahead of print]14(18):

A Botanical Mixture Consisting of Inula japonica and Potentilla chinensis Relieves Obesity via the AMPK Signaling Pathway in 3T3-L1 Adipocytes and HFD-Fed Obese Mice.

Su-Yeon Lee, Kyung-Sook Chung, So-Ri Son, So Young Lee, Dae Sik Jang, Jong-Kil Lee, Hyun-Jae Kim, Chang-Seon Na, Sun-Hee Lee, Kyung-Tae Lee.

  Excessive lipid accumulation in white adipose tissue (WAT) is the major cause of obesity. Herein, we investigated the anti-obesity effect and molecular mechanism of a botanical mixture of 30% EtOH extract from the leaves of Inula japonica and Potentilla chinensis (EEIP) in 3T3-L1 preadipocytes and high-fat diet (HFD)-fed obese mice. In vitro, EEIP prevented lipid accumulation by downregulating the expression of lipogenesis-related transcription factors such as CCAAT/enhancer binding protein (C/EBP)α, peroxisome proliferator-activated receptor (PPAR)γ, and sterol regulatory element binding protein (SREBP)-1 via AMP-activated protein kinase (AMPK) activation and G0/G1 cell cycle arrest by regulating the Akt-mTOR pathways without inducing cytotoxicity. In vivo, EEIP significantly reduced body weight gain and body fat mass in the group administered concurrently with HFD (pre-) or administered during the maintenance of HFD (post-) including subcutaneous, gonadal, renal, and mesenteric fats, and improved blood lipid profiles and metabolic hormones. EEIP pre-administration also alleviated WAT hypertrophy and liver lipid accumulation by reducing C/EBPα, PPARγ, and SREBP-1 expression via AMPK activation. In the brown adipose tissue, EEIP pre-administration upregulated the expression of thermogenic factors. Furthermore, EEIP improved the HFD-induced altered gut microbiota in mice. Taken together, our data indicated that EEIP improves HFD-induced obesity through adipogenesis inhibition in the WAT and liver and is a promising dietary natural material for improving obesity.

Keywords:  AMPK; Inula japonica; Potentilla chinensis; high-fat diet; microbiota

DOI:  https://doi.org/10.3390/nu14183685
Cell Signal. 2022 Sep 16. pii: S0898-6568(22)00234-0. [Epub ahead of print] 110472

Nuak kinase signaling in development and disease of the central nervous system.

Sarah A Bennison, Xiaonan Liu, Kazuhito Toyo-Oka.

  Protein kinases represent important signaling hubs for a variety of biological functions. Many kinases are traditionally studied for their roles in cancer cell biology, but recent advances in neuroscience research show repurposed kinase function to be important for nervous system development and function. Two members of the AMP-activated protein kinase (AMPK) related family, Nuak1 and Nuak2, have drawn attention in neuroscience due to their mutations in autism spectrum disorder (ASD), attention deficit hyperactivity disorder (ADHD), schizophrenia, and intellectual disability (ID). Furthermore, Nuak kinases have also been implicated in tauopathy and other disorders of aging. This review highlights what is known about the Nuak kinases in nervous system development and disease and explores the possibility of Nuak kinases as targets for therapeutic innovation.

Keywords:  AMPK; Aging; Autism; Neurite formation; Neurodevelopment; Nuak

DOI:  https://doi.org/10.1016/j.cellsig.2022.110472
Front Pharmacol. 2022 ;13 944886

Empagliflozin activates Sestrin2-mediated AMPK/mTOR pathway and ameliorates lipid accumulation in obesity-related nonalcoholic fatty liver disease.

Yuting Ma, Guangdong Zhang, Zenggguang Kuang, Qian Xu, Tongtong Ye, Xue Li, Na Qu, Fang Han, Chengxia Kan, Xiaodong Sun.

  Empagliflozin (EMPA) therapy has led to improvements in patients with non-alcoholic fatty liver disease (NAFLD). Sestrin2 is a stress-inducible protein that controls the AMPK-mTOR pathway and inhibits oxidative damage in cells. This study investigated the functional implications of EMPA on the multifactorial pathogenesis of NAFLD and potential underlying molecular mechanisms of pathogenesis. An in vitro model of NAFLD was established by treating HepG2 cells with palmitic acid (PA); an in vivo model of NAFLD was generated by feeding C57BL/6 mice a high-fat diet. Investigations of morphology and lipid deposition in liver tissue were performed. Expression patterns of Sestrin2 and genes related to lipogenesis and inflammation were assessed by reverse transcription polymerase chain reaction. Protein levels of Sestrin2 and AMPK/mTOR pathway components were detected by Western blotting. NAFLD liver tissues and PA-stimulated HepG2 cells exhibited excessive lipid production and triglyceride secretion, along with upregulation of Sestrin2 and increased expression of lipogenesis-related genes. EMPA treatment reversed liver damage by upregulating Sestrin2 and activating the AMPK-mTOR pathway. Knockdown of Sestrin2 effectively increased lipogenesis and enhanced the mRNA expression levels of lipogenic and pro-inflammatory genes in PA-stimulated HepG2 cells; EMPA treatment did not affect these changes. Furthermore, Sestrin2 knockdown inhibited AMPK-mTOR signaling pathway activity. The upregulation of Sestrin2 after treatment with EMPA protects against lipid deposition-related metabolic disorders; it also inhibits lipogenesis and inflammation through activation of the AMPK-mTOR signaling pathway. These results suggest that Sestrin2 can be targeted by EMPA therapy to alleviate lipogenesis and inflammation in obesity-related NAFLD.

Keywords:  AMPK-mTOR; empagliflozin; free fatty acids; inflammation; nonalcoholic fatty liver disease

DOI:  https://doi.org/10.3389/fphar.2022.944886
J Diabetes. 2022 Sep 18.

Is metformin a possible treatment for diabetic neuropathy?

Juechun Wei, Yanling Wei, Meiyan Huang, Peng Wang, Shushan Jia.

  Metformin is a hypoglycemic drug widely used in the treatment of type 2 diabetes. It has been proven to have analgesic and neuroprotective effects. Metformin can reverse pain in rodents, such as diabetic neuropathic pain, neuropathic pain caused by chemotherapy drugs, inflammatory pain and pain caused by surgical incision. In clinical use, however, metformin is associated with reduced plasma vitamin B12 levels, which can further neuropathy. In rodent diabetes models, metformin plays a neuroprotective and analgesic role by activating adenosine monophosphate-activated protein kinase, clearing methylgloxal, reducing insulin resistance, and neuroinflammation. This paper also summarized the neurological adverse reactions of metformin in diabetic patients. In addition, whether metformin has sexual dimorphism needs further study.

Keywords:  adenosine monophosphate-activated protein kinase (AMPK); diabetic neuropathy; metformin; pain; vitamin B12

DOI:  https://doi.org/10.1111/1753-0407.13310
Arch Physiol Biochem. 2022 Sep 19. 1-16

Liquorice root extract and isoliquiritigenin attenuate high-fat diet-induced hepatic steatosis and damage in rats by regulating AMPK.

Mohammed Abdo Yahya, Ghedeir M Alshammari, Magdi A Osman, Laila Naif Al-Harbi, Abu ElGasim A Yagoub, Sahar Abdulaziz AlSedairy.

  Objective: This study compared the ability of Liquorice roots aqueous extract (LRE) and its ingredient, isoliquiritigenin (ISL), in alleviating high-fat diet (HFD)-induced hepatic steatosis and examined if this effect involves activation of AMPK.Materials and methods: Control or HFD-fed rats were treated with the vehicle, LRE (200 mg/kg), or ISL (30 mg/kg) for 8 weeks orally.Results: ISL and LRE reduced HFD-induced hyperglycaemia, improved liver structure, lowered serum and hepatic lipids, and attenuated hepatic oxidative stress and inflammation. In the control and HFD-fed rats, ISL and LRE significantly stimulated the muscular and hepatic mRNA and protein levels of AMPK, improved oral glucose tolerance, reduced hepatic mRNA levels of SREBP1/2, and upregulated hepatic levels of PPARα and Bcl2. These effects were comparable for ISL and LRE and were prevented by co-administration of compound C, an AMPK inhibitor.Discussion and conclusion: ISL and LRE provide an effective theory to alleviate hepatic steatosis through activating AMPK.

Keywords:  AMPK; HFD; ISL; Liquorice; hepatic steatosis

DOI:  https://doi.org/10.1080/13813455.2022.2102654
Oxid Med Cell Longev. 2022 ;2022 2297268

Exercise and Metformin Intervention Prevents Lipotoxicity-Induced Hepatocyte Apoptosis by Alleviating Oxidative and ER Stress and Activating the AMPK/Nrf2/HO-1 Signaling Pathway in db/db Mice.

Yuan Zhang, Yuting Liu, Xiaowei Liu, Xinmeng Yuan, Mengqi Xiang, Jingjing Liu, Liumei Zhang, Shouqian Zhu, Jiao Lu, Qiang Tang, Sulin Cheng.

Objective: Nonalcoholic fatty liver disease (NAFLD) and type 2 diabetes (T2DM) commonly coexist and act synergistically to drive adverse clinical outcomes. This study is aimed at investigating the effects of exercise intervention and oral hypoglycaemic drug of metformin (MET) alone or combined on hepatic lipid accumulation. To investigate if oxidative stress and endoplasmic reticulum stress (ERS) are involved in lipotoxicity-induced hepatocyte apoptosis in diabetic mice and whether exercise and/or MET alleviated oxidative stress or ERS-apoptosis by AMPK-Nrf2-HO-1 signaling pathway.
Methods: Forty db/db mice with diabetes (random blood glucose ≥ 250 mg/dL) were randomly allocated into four groups: control (CON), exercise training alone (EX), metformin treatment alone (MET), and exercise combined with metformin (EM) groups. Hematoxylin-eosin and oil red O staining were carried out to observe hepatic lipid accumulation. Immunohistochemical and TUNEL methods were used to detect the protein expression of the binding immunoglobulin protein (BiP) and superoxide dismutase-1 (SOD1) and the apoptosis level of hepatocytes. ERS-related gene expression and the AMPK-Nrf2-HO-1 signaling pathway were tested by western blotting.
Results: Our data showed that db/db mice exhibited increased liver lipid accumulation, which induced oxidative and ER stress of the PERK-eIF2α-ATF4 pathway, and hepatocyte apoptosis. MET combined with exercise training significantly alleviated hepatic lipid accumulation by suppressing BiP expression, the central regulator of ER homeostasis, and its downstream PERK-eIF2α-ATF4 pathway, as well as upregulated the AMPK-Nrf2-HO-1 signaling pathway. Moreover, the combination of exercise and MET displayed protective effects on hepatocyte apoptosis by downregulating Bax expression and TUNEL-positive staining, restoring the balance of cleaved-caspase-3 and caspase-3, and improving the antioxidant defense system to prevent oxidative damage in db/db mice.
Conclusion: Compared to MET or exercise intervention alone, the combined exercise and metformin exhibited significant effect on ameliorating hepatic steatosis, inhibiting oxidative and ER stress-induced hepatocyte apoptosis via improving the capacity of the antioxidant defense system and suppression of the PERK-eIF2α-ATF4 pathway. Furthermore, upregulation of AMPK-Nrf2-HO-1 signaling pathway might be a key crosstalk between MET and exercise, which may have additive effects on alleviating hepatic lipid accumulation.

DOI: https://doi.org/10.1155/2022/2297268
Inflammopharmacology. 2022 Sep 21.

Melatonin ameliorates lung cell inflammation and apoptosis caused by Klebsiella pneumoniae via AMP-activated protein kinase.

Wei Jiang, Jun Liu, Xuequn Zhao, Wenjie Yang.

  Klebsiella pneumoniae is a Gram-negative bacterium and the causative agent of several life-threatening nosocomial infections, including pneumonia. K. pneumoniae induces acute lung injury and inflammation in humans that require immediate hospitalization and treatment. Therefore, attenuation of K. pneumoniae-induced inflammation is necessary for the survival of patients. This study investigated the mechanisms by which melatonin abrogated K. pneumoniae-induced inflammation and apoptosis of lung cell lines, HLF-1 and BEAS-2B. Our results showed that in vitro infection of HLF-1 and BEAS-2B cells by K. pneumoniae significantly induced inflammation and apoptosis increased elevated levels of IL-6, CXCL1, CXCL2, and caspase-9 mRNA. However, these effects were abrogated by melatonin treatment. Infection with K. pneumoniae significantly increased the expression of AMP-induced protein kinase (AMPK). Furthermore, AMPK silencing significantly abrogated the suppression of inflammation and apoptosis in melatonin-infected K. pneumoniae lung cells. Melatonin could alleviate K. pneumoniae infection-induced inflammation in three-dimensional lung spheroids. In conclusion, our study demonstrated that melatonin abrogated K. pneumoniae-induced inflammation and apoptosis in lung cells through AMPK. Our study demonstrated the potential of melatonin for therapy against K. pneumoniae infections including pneumonia.

Keywords:  AMPK; Cell death; Inflammation; Klebsiella pneumoniae; Melatonin

DOI:  https://doi.org/10.1007/s10787-022-01073-0
Acta Biochim Biophys Sin (Shanghai). 2022 Aug 25.

Quercetin induces autophagy-associated death in HL-60 cells through CaMKKβ/AMPK/mTOR signal pathway.

Jie Xiao, Ben Zhang, Songmei Yin, Shuangfeng Xie, Kezhi Huang, Jieyu Wang, Wenjuan Yang, Hongyun Liu, Guoyang Zhang, Xiaoyan Liu, Yiqing Li, Danian Nie.

  Acute myeloid leukemia (AML) is one of the most common malignancies of the hematopoietic progenitor cell in adults. Quercetin has gained recognition over the years because of its anti-cancer effect with minimal toxicity. Herein, we aim to investigate the anti-leukemia mechanism of quercetin and to decipher the signaling pathway of quercetin in HL-60 leukemic cells. We observed that quercetin induces apoptosis and autophagic cell death, in which both pathways play an important role in suppressing the viability of leukemia cells. Phosphorylated AMPK (p-AMPK) protein expressions are lower in primary AML cells, HL-60 cells, KG-1 and THP-1 cells than in peripheral blood monocular cells. After quercetin treatment, the expression of p-AMPK is increased while the expression of p-mTOR is decreased in a dose-dependent manner. Mechanistically, compound C, an AMPK phosphorylation inhibitor, upregulates the phosphorylation of mTOR and inhibits autophagy and apoptosis in quercetin-induced HL-60 cells, while silencing of CaMKKβ inhibits the quercetin-induced phosphorylation of AMPK, resulting in increased mTOR phosphorylation. Furthermore, silencing of CaMKKβ inhibits the autophagy in HL-60 cells. Taken together, our data delineate that quercetin plays its anti-leukemia role by inhibiting cell viability and inducing apoptosis and autophagy in leukemia cells. Quercetin inhibits the phosphorylation of mTOR by regulating the activity of AMPK, thus playing a role in the regulation of autophagy and apoptosis. CaMKKβ is a potential upstream molecule for AMPK/mTOR signaling pathway, through which quercetin induces autophagy in HL-60 cells.

Keywords:  AMP-activated protein kinase; acute myeloid leukemia; autophagy; mammalian rapamycin target protein; quercetin

DOI:  https://doi.org/10.3724/abbs.2022117
Adv Clin Exp Med. 2022 Sep 22.

Schaftoside improves cerebral ischemia-reperfusion injury by enhancing autophagy and reducing apoptosis and inflammation through the AMPK/mTOR pathway.

Lin Zhang, Minghua Wu, Zhaoyao Chen.

   BACKGROUND: As a flavonoid compound, schaftoside (SS) possesses a wide range of pharmaceutical activities. Nonetheless, it is unclear whether SS has a neuroprotective effect in cerebral ischemia-reperfusion injury (CI/RI).
OBJECTIVES: To examine the neuroprotective effect of SS in CI/RI and explore the underlying mechanism.
MATERIAL AND METHODS: An in vivo middle cerebral artery occlusion (MCAO) was used to simulate CI/RI in rats. Oxygen glucose deprivation/reperfusion (OGD/R) of HT22 cells was used to establish a cellular model of CI/RI in vitro. Pathological changes were evaluated with hematoxylin and eosin (H&E) staining, apoptosis was measured using terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining and flow cytometry, and inflammatory factors were assessed using enzyme-linked immunosorbent assay (ELISA). Protein expression was detected using western blot or immunofluorescence.
RESULTS: Our results indicated that SS attenuated CI/RI by improving neurologic deficits and reducing brain edema. Moreover, SS treatment blocked apoptosis and inflammation and enhanced autophagy in MCAO rats. Schaftoside was found to amplify the activation of adenosine monophosphate-activated protein kinase (AMPK)/mammalian target of rapamycin (mTOR) pathway induced by MCAO. Similarly, SS pretreatment increased cell viability and autophagy, and reduced apoptosis and inflammation in OGD/R-induced HT22 cells. The OGD/R enlarges the p-AMPK/AMPK ratio while restricting the p-mTOR/mTOR ratio, and it was found that SS further enhanced the effect of OGD/R on the AMPK/mTOR pathway. Rapamycin promoted the effect of SS on OGD/R-induced HT22 cells, while compound C produced the opposite results. Mechanistically, SS promoted autophagy and reduced apoptosis and inflammation through the regulation of the AMPK/mTOR signaling pathway.
CONCLUSIONS: The obtained results showed that SS protected against CI/RI through an autophagy-mediated AMPK/mTOR pathway when accessed in vitro and in vivo.

Keywords:  apoptosis; autophagy; cerebral ischemia-reperfusion injury; inflammation; schaftoside

DOI:  https://doi.org/10.17219/acem/152207
Trends Endocrinol Metab. 2022 Sep 20. pii: S1043-2760(22)00163-1. [Epub ahead of print]

Knocking on GDF15's door for the treatment of type 2 diabetes mellitus.

David Aguilar-Recarte, Emma Barroso, Xavier Palomer, Walter Wahli, Manuel Vázquez-Carrera.

  Although a large number of drugs are available for the treatment of type 2 diabetes mellitus (T2DM), many patients do not achieve adequate disease control despite adhering to medication. Recent findings indicate that the pharmacological modulation of the stress-induced cytokine growth differentiation factor 15 (GDF15) shows promise for the treatment of T2DM. GDF15 suppresses appetite and reduces inflammation, increases thermogenesis and lipid catabolism, sustains AMP-activated protein kinase (AMPK) activity, and ameliorates insulin resistance and hepatic steatosis. In addition, circulating GDF15 levels are elevated in response to several antidiabetic drugs, including metformin, with GDF15 mediating some of their effects. Here, we review the mechanistic insights into the beneficial effects of recently explored therapeutic approaches that target GDF15 for the treatment of T2DM.

Keywords:  AMPK; GFRAL; NAFLD; inflammation; insulin resistance; myokine

DOI:  https://doi.org/10.1016/j.tem.2022.08.004
Cells. 2022 Sep 15. pii: 2888. [Epub ahead of print]11(18):

The ABA-LANCL1/2 Hormone-Receptors System Protects H9c2 Cardiomyocytes from Hypoxia-Induced Mitochondrial Injury via an AMPK- and NO-Mediated Mechanism.

Sonia Spinelli, Lucrezia Guida, Tiziana Vigliarolo, Mario Passalacqua, Giulia Begani, Mirko Magnone, Laura Sturla, Andrea Benzi, Pietro Ameri, Edoardo Lazzarini, Claudia Bearzi, Roberto Rizzi, Elena Zocchi.

  Abscisic acid (ABA) regulates plant responses to stress, partly via NO. In mammals, ABA stimulates NO production by innate immune cells and keratinocytes, glucose uptake and mitochondrial respiration by skeletal myocytes and improves blood glucose homeostasis through its receptors LANCL1 and LANCL2. We hypothesized a role for the ABA-LANCL1/2 system in cardiomyocyte protection from hypoxia via NO. The effect of ABA and of the silencing or overexpression of LANCL1 and LANCL2 were investigated in H9c2 rat cardiomyoblasts under normoxia or hypoxia/reoxygenation. In H9c2, hypoxia induced ABA release, and ABA stimulated NO production. ABA increased the survival of H9c2 to hypoxia, and L-NAME, an inhibitor of NO synthase (NOS), abrogated this effect. ABA also increased glucose uptake and NADPH levels and increased phosphorylation of Akt, AMPK and eNOS. Overexpression or silencing of LANCL1/2 significantly increased or decreased, respectively, transcription, expression and phosphorylation of AMPK, Akt and eNOS; transcription of NAMPT, Sirt1 and the arginine transporter. The mitochondrial proton gradient and cell vitality increased in LANCL1/2-overexpressing vs. -silenced cells after hypoxia/reoxygenation, and L-NAME abrogated this difference. These results implicate the ABA-LANCL1/2 hormone-receptor system in NO-mediated cardiomyocyte protection against hypoxia.

Keywords:  ABA; AMPK; LANCL1/2; NO; PGC-1α; Sirt1; cardiomyocyte; eNOS; mitochondrial proton gradient

DOI:  https://doi.org/10.3390/cells11182888
Stem Cell Reports. 2022 Sep 08. pii: S2213-6711(22)00418-0. [Epub ahead of print]

PIM3-AMPK-HDAC4/5 axis restricts MuERVL-marked 2-cell-like state in embryonic stem cells.

Xin Zhao, Jian Shen, Xuan Zhao, Miao Zhang, Xiao Feng, Weiyu Zhang, Xinyi Lu.

  A minority of embryonic stem cells (ESCs) marked by endogenous retrovirus MuERVL are totipotent 2-cell-like cells. However, the majority of ESCs repress MuERVL. Currently, it is still unclear regarding the signaling pathway(s) repressing the MuERVL-associated 2-cell-like state of ESCs. Here, we identify the PIM3-downstream signaling axis as a key route to repress MuERVL and 2-cell-like state. Downregulation, deletion, or inhibition of PIM3 activated MuERVL, 2-cell genes, and trophectodermal genes in ESCs. By screening PIM3-regulated pathways, we discovered AMPK as its key target. The loss of Pim3 caused an increase in AMPK phosphorylation, which phosphorylated HDAC4/5 and triggered their transfer out of the nucleus in Pim3-/- ESCs. The reduction of nuclear HDAC4/5 caused increased H3K9ac and reduced H3K9me1/2 enrichment on MuERVL, thus activating MuERVL and 2-cell-like state. In summary, our study uncovers a novel axis by which PIM3 suppresses 2-cell marker MuERVL and totipotent state in ESCs.

Keywords:  2-cell-like cell; AMPK; HDAC4/5; MuERVL; Pim3; embryonic stem cells; endogenous retrovirus; totipotency

DOI:  https://doi.org/10.1016/j.stemcr.2022.08.009
Endocrinology. 2022 Sep 19. pii: bqac154. [Epub ahead of print]

Laminin-α4 negatively regulates adipocyte beiging through the suppression of AMPKα in male mice.

Anna Goddi, Alanis Carmona, Soo Young Park, Gokhan Dalgin, Maria A Gonzalez Porras, Eric M Brey, Ronald N Cohen.

  Laminin-α4 (LAMA4) is an extracellular matrix protein implicated in the regulation of adipocyte differentiation and function. Prior research describes a role for LAMA4 in modulating adipocyte thermogenesis and uncoupling protein-1 (UCP1) expression in white adipose; however, the mechanisms involved are poorly understood. Here, we describe that Lama4 knockout mice (Lama4-/-) exhibit heightened mitochondrial biogenesis and peroxisome proliferator-activated receptor gamma coactivator-1 (PGC-1) expression in subcutaneous white adipose tissue (sWAT). Furthermore, the acute silencing of LAMA4 with siRNA in primary murine adipocytes was sufficient to upregulate the expression of thermogenic markers UCP1 and PR domain containing 16 (PRDM16). Silencing also resulted in an upregulation of PGC1-α and AMP-activated protein kinase (AMPK)-α expression. Subsequently, we show that integrin linked kinase (ILK) is downregulated in the sWAT of Lama4-/- mice, and its silencing in adipocytes similarly resulted in elevated expression of UCP1 and AMPKα. Lastly, we demonstrate that treatment of human induced pluripotent stem cell (hiPSC)-derived thermogenic adipocytes with LAMA4 (LN411) inhibited the expression of thermogenic markers and AMPKα. Overall, our results indicate that LAMA4 negatively regulates a thermogenic phenotype and pathways involving mitochondrial biogenesis in adipocytes through the suppression of AMPKα.

Keywords:  Laminins; adipocyte; adipose tissue; beige; extracellular matrix; thermogenesis

DOI:  https://doi.org/10.1210/endocr/bqac154
J Biochem Mol Toxicol. 2022 Sep 19. e23211

Britannin mediates apoptosis and glycolysis of T-cell lymphoblastic lymphoma cells by AMPK-dependent autophagy.

Haoyuan Hong, Bin Luo, Zucheng Xie, Meiwei Li, Qingyuan Xu, Zhendong He, Zhigang Peng.

  Britannin is a natural pseudoguaiacane sesquiterpene lactone, which is reported to possess a significant anticancer function. However, its anticancer effects in T-cell lymphoblastic lymphoma (T-LBL) have not been studied. We investigated the molecular mechanisms of britannin's effective anticancer activity in T-LBL cells. We detected the proliferation, apoptosis, glucose consumption, and lactate production in T-LBL cells treated with or without britannin. We applied a mouse xenograft for in vivo study. The results showed that the IC50 for britannin in SUP-T1 and MOLT4 cells were 5.661 and 6.043 μM, respectively. Britannin inhibited the growth of T-LBL cells in vitro and in vivo. Besides this, britannin enhanced LC3 puncta formation, as well as LC3II and beclin1 expression in SUP-T1 and MOLT4 cells, while decreased p62 expression, indicating that britannin promoted the autophagy of T-LBL cells in vitro. Moreover, britannin promoted apoptosis and reduced glycolysis of T-LBL cells, which was reversed by the typical autophagic inhibitor chloroquine. Britannin increased the phosphorylation of AMPK, while decreasing the phosphorylation of mTOR and S6K1 in T-LBL cells. Moreover, the induction of autophagy in T-LBL cells by britannin was restrained by Compound C, the inhibitor of AMPK. Taken together, britannin mediated apoptosis and glycolysis of T-LBL cells in an autophagy-dependent manner, which was achieved by regulating AMPK/mTOR/S6K1 signaling, demonstrating its therapeutic potential against T-LBL.

Keywords:  T-cell lymphoblastic lymphoma; apoptosis; autophagy; britannin; glycolysis

DOI:  https://doi.org/10.1002/jbt.23211