bims-amsmem 2023-03-12 papers

bims-amsmem

Biomed News

on AMPK signaling mechanism in energy metabolism

Issue of 2023–03–12
fourteen papers selected by
Dipsikha Biswas, Københavns Universitet

The role of AMPK in cancer metabolism and its impact on the immunomodulation of the tumor microenvironment.
Phosphorylation of PHF2 by AMPK releases the repressive H3K9me2 and inhibits cancer metastasis.
Phosphorylation of LKB1 by PDK1 Inhibits Cell Proliferation and Organ Growth by Decreased Activation of AMPK.
An AMP Kinase-pathway dependent integrated stress response regulates ageing and longevity.
Magnolol improves Alzheimer's disease-like pathologies and cognitive decline by promoting autophagy through activation of the AMPK/mTOR/ULK1 pathway.
Heat-Killed Enterococcus faecalis Inhibit FL83B Hepatic Lipid Accumulation and High Fat Diet-Induced Fatty Liver Damage in Rats by Activating Lipolysis through the Regulation the AMPK Signaling Pathway.
Homoplantaginin attenuates high glucose-induced vascular endothelial cell apoptosis through promoting autophagy via the AMPK/TFEB pathway.
Posttranslational regulation of liver kinase B1 (LKB1) in human cancer.
Low rumen degradable starch promotes the growth performance of goats by increasing protein synthesis in skeletal muscle via the AMPK-mTOR pathway.
Synergistic activation of AMPK by AdipoR1/2 agonist and inhibitor of EDPs-EBP interaction recover NAFLD through enhancing mitochondrial function in mice.
Role of SUMO-Specific Protease 2 in Leptin-Induced Fatty Acid Metabolism in White Adipocytes.
Oxymatrine and insulin resistance: Focusing on mechanistic intricacies involve in diabetes associated cardiomyopathy via SIRT1/AMPK and TGF-β signaling pathway.
High-Intensity Interval Training Ameliorates Molecular Changes in the Hippocampus of Male Rats with the Diabetic Brain: the Role of Adiponectin.
A Novel Mix of Polyphenols and Micronutrients Reduces Adipogenesis and Promotes White Adipose Tissue Browning via UCP1 Expression and AMPK Activation.

Front Immunol. 2023 ;14 1114582

The role of AMPK in cancer metabolism and its impact on the immunomodulation of the tumor microenvironment.

Chenicheri Kizhakkeveettil Keerthana, Tennyson Prakash Rayginia, Sadiq Chembothumparambil Shifana, Nikhil Ponnoor Anto, Kalishwaralal Kalimuthu, Noah Isakov, Ruby John Anto.

  Adenosine monophosphate-activated protein kinase (AMPK) is a key metabolic sensor that is pivotal for the maintenance of cellular energy homeostasis. AMPK contributes to diverse metabolic and physiological effects besides its fundamental role in glucose and lipid metabolism. Aberrancy in AMPK signaling is one of the determining factors which lead to the development of chronic diseases such as obesity, inflammation, diabetes, and cancer. The activation of AMPK and its downstream signaling cascades orchestrate dynamic changes in the tumor cellular bioenergetics. It is well documented that AMPK possesses a suppressor role in the context of tumor development and progression by modulating the inflammatory and metabolic pathways. In addition, AMPK plays a central role in potentiating the phenotypic and functional reprogramming of various classes of immune cells which reside in the tumor microenvironment (TME). Furthermore, AMPK-mediated inflammatory responses facilitate the recruitment of certain types of immune cells to the TME, which impedes the development, progression, and metastasis of cancer. Thus, AMPK appears to play an important role in the regulation of anti-tumor immune response by regulating the metabolic plasticity of various immune cells. AMPK effectuates the metabolic modulation of anti-tumor immunity via nutrient regulation in the TME and by virtue of its molecular crosstalk with major immune checkpoints. Several studies including that from our lab emphasize on the role of AMPK in regulating the anticancer effects of several phytochemicals, which are potential anticancer drug candidates. The scope of this review encompasses the significance of the AMPK signaling in cancer metabolism and its influence on the key drivers of immune responses within the TME, with a special emphasis on the potential use of phytochemicals to target AMPK and combat cancer by modulating the tumor metabolism.

Keywords:  AMPK signaling; T cells; cancer metabolism; immune checkpoints; immune response; macrophages; phytochemicals; tumor microenvironment

DOI:  https://doi.org/10.3389/fimmu.2023.1114582
Signal Transduct Target Ther. 2023 03 06. 8(1): 95

Phosphorylation of PHF2 by AMPK releases the repressive H3K9me2 and inhibits cancer metastasis.

Ying Dong, Hao Hu, Xuan Zhang, Yunkai Zhang, Xin Sun, Hanlin Wang, Weijuan Kan, Min-Jia Tan, Hong Shi, Yi Zang, Jia Li.

Epithelial to mesenchymal transition (EMT) plays a crucial role in cancer metastasis, accompanied with vast epigenetic changes. AMP-activated protein kinase (AMPK), a cellular energy sensor, plays regulatory roles in multiple biological processes. Although a few studies have shed light on AMPK regulating cancer metastasis, the inside epigenetic mechanisms remain unknown. Herein we show that AMPK activation by metformin relieves the repressive H3K9me2-mediated silencing of epithelial genes (e.g., CDH1) during EMT processes and inhibits lung cancer metastasis. PHF2, a H3K9me2 demethylase, was identified to interact with AMPKα2. Genetic deletion of PHF2 aggravates lung cancer metastasis and abolishes the H3K9me2 downregulation and anti-metastasis effect of metformin. Mechanistically, AMPK phosphorylates PHF2 at S655 site, enhancing PHF2 demethylation activity and triggering the transcription of CDH1. Furthermore, the PHF2-S655E mutant that mimics AMPK-mediated phosphorylation status further reduces H3K9me2 and suppresses lung cancer metastasis, while PHF2-S655A mutant presents opposite phenotype and reverses the anti-metastasis effect of metformin. PHF2-S655 phosphorylation strikingly reduces in lung cancer patients and the higher phosphorylation level predicts better survival. Altogether, we reveal the mechanism of AMPK inhibiting lung cancer metastasis via PHF2 mediated H3K9me2 demethylation, thereby promoting the clinical application of metformin and highlighting PHF2 as the potential epigenetic target in cancer metastasis.

DOI: https://doi.org/10.1038/s41392-022-01302-6
Cells. 2023 Mar 06. pii: 812. [Epub ahead of print]12(5):

Phosphorylation of LKB1 by PDK1 Inhibits Cell Proliferation and Organ Growth by Decreased Activation of AMPK.

Sarah Borkowsky, Maximilian Gass, Azadeh Alavizargar, Johannes Hanewinkel, Ina Hallstein, Pavel Nedvetsky, Andreas Heuer, Michael P Krahn.

  The master kinase LKB1 is a key regulator of se veral cellular processes, including cell proliferation, cell polarity and cellular metabolism. It phosphorylates and activates several downstream kinases, including AMP-dependent kinase, AMPK. Activation of AMPK by low energy supply and phosphorylation of LKB1 results in an inhibition of mTOR, thus decreasing energy-consuming processes, in particular translation and, thus, cell growth. LKB1 itself is a constitutively active kinase, which is regulated by posttranslational modifications and direct binding to phospholipids of the plasma membrane. Here, we report that LKB1 binds to Phosphoinositide-dependent kinase (PDK1) by a conserved binding motif. Furthermore, a PDK1-consensus motif is located within the kinase domain of LKB1 and LKB1 gets phosphorylated by PDK1 in vitro. In Drosophila, knockin of phosphorylation-deficient LKB1 results in normal survival of the flies, but an increased activation of LKB1, whereas a phospho-mimetic LKB1 variant displays decreased AMPK activation. As a functional consequence, cell growth as well as organism size is decreased in phosphorylation-deficient LKB1. Molecular dynamics simulations of PDK1-mediated LKB1 phosphorylation revealed changes in the ATP binding pocket, suggesting a conformational change upon phosphorylation, which in turn can alter LKB1's kinase activity. Thus, phosphorylation of LKB1 by PDK1 results in an inhibition of LKB1, decreased activation of AMPK and enhanced cell growth.

Keywords:  AMPK; LKB1; PDK1; cell proliferation; mTOR

DOI:  https://doi.org/10.3390/cells12050812
Biogerontology. 2023 Mar 06.

An AMP Kinase-pathway dependent integrated stress response regulates ageing and longevity.

H G Keizer, R Brands, W Seinen.

  The purpose of this article is to investigate the role of the AMP-kinase pathway (AMPK pathway) in the induction of a concomitant set of health benefits by exercise, numerous drugs, and health ingredients, all of which are adversely affected by ageing. Despite the AMPK pathway being frequently mentioned in relation to both these health effects and ageing, it appears challenging to understand how the activation of a single biochemical pathway by various treatments can produce such a diverse range of concurrent health benefits, involving so many organs. We discovered that the AMPK pathway functions as an integrated stress response system because of the presence of a feedback loop in it. This evolutionary conserved stress response system detects changes in AMP/ATP and NAD/NADH ratios, as well as the presence of potential toxins, and responds by activating a common protective transcriptional response that protects against aging and promotes longevity. The inactivation of the AMPK pathway with age most likely explains why ageing has a negative impact on the above-mentioned set of health benefits. We conclude that the presence of a feedback loop in the AMP-kinase pathway positions this pathway as an AMPK-ISR (AMP Kinase-dependent integrated stress response) system that responds to almost any type of (moderate) environmental stress by inducing various age-related health benefits and longevity.

Keywords:  AMPK; Ageing; Biochemistry; Feedback-loop; Longevity; Pathway

DOI:  https://doi.org/10.1007/s10522-023-10024-3
Biomed Pharmacother. 2023 Mar 06. pii: S0753-3322(23)00261-5. [Epub ahead of print]161 114473

Magnolol improves Alzheimer's disease-like pathologies and cognitive decline by promoting autophagy through activation of the AMPK/mTOR/ULK1 pathway.

Xuechu Wang, Jianping Jia.

  Alzheimer's disease (AD) is the most common neurodegenerative disease. Amyloid-β (Aβ) plaque deposition and apoptosis are main pathological features of AD. Autophagy plays an important role in clearing abnormal protein accumulation and inhibiting apoptosis; however, autophagy defects often occur from the early stages of AD. The serine/threonine AMP-activated protein kinase (AMPK)/mammalian target of rapamycin (mTOR)/unc-51-like kinase 1/2 (ULK1/2) pathway serves as an energy sensor and is involved in autophagy activation. Furthermore, magnolol is an autophagy regulator, and has potential for AD therapy. We propose that magnolol can ameliorate AD pathologies and inhibit apoptosis by regulating autophagy through the AMPK/mTOR/ULK1 pathway. We examined cognitive function and AD-related pathologies in AD transgenic mice and the protective mechanism of magnolol by western blotting, flow cytometry, and a tandem mRFP-GFP-LC3 adenovirus assay in Aβ oligomer (AβO)-induced N2a and BV2 cell models. In our study, magnolol decreased amyloid pathology and ameliorated cognitive impairment in APP/PS1 mice. Moreover, magnolol inhibited apoptosis by downregulating cleaved-caspase-9 and Bax and upregulating Bcl-2 in APP/PS1 mice and AβO-induced cell models. Magnolol promoted autophagy by degrading p62/SQSTM1, and upregulating LC3II and Beclin-1 expression. Magnolol activated the AMPK/mTOR/ULK1 pathway by increasing phosphorylation of AMPK and ULK1 and decreasing mTOR phosphorylation in in vivo and in vitro AD models. AMPK inhibitor weakened the effects of magnolol in promoting autophagy and inhibiting apoptosis, and ULK1 knockdown weakened the effect of magnolol on AβO-induced apoptosis. These results indicate that magnolol inhibits apoptosis and improves AD-related pathologies by promoting autophagy through activation of the AMPK/mTOR/ULK1 pathway.

Keywords:  Alzheimer's disease; Apoptosis; Autophagy; Magnolol

DOI:  https://doi.org/10.1016/j.biopha.2023.114473
Int J Mol Sci. 2023 Feb 24. pii: 4486. [Epub ahead of print]24(5):

Heat-Killed Enterococcus faecalis Inhibit FL83B Hepatic Lipid Accumulation and High Fat Diet-Induced Fatty Liver Damage in Rats by Activating Lipolysis through the Regulation the AMPK Signaling Pathway.

Jin-Ho Lee, Keun-Jung Woo, Joonpyo Hong, Kwon-Il Han, Han Sung Kim, Tack-Joong Kim.

  Continuous consumption of high-calorie meals causes lipid accumulation in the liver and liver damage, leading to non-alcoholic fatty liver disease (NAFLD). A case study of the hepatic lipid accumulation model is needed to identify the mechanisms underlying lipid metabolism in the liver. In this study, the prevention mechanism of lipid accumulation in the liver of Enterococcus faecalis 2001 (EF-2001) was extended using FL83B cells (FL83Bs) and high-fat diet (HFD)-induced hepatic steatosis. EF-2001 treatment inhibited the oleic acid (OA) lipid accumulation in FL83B liver cells. Furthermore, we performed lipid reduction analysis to confirm the underlying mechanism of lipolysis. The results showed that EF-2001 downregulated proteins and upregulated AMP-activated protein kinase (AMPK) phosphorylation in the sterol regulatory element-binding protein 1c (SREBP-1c) and AMPK signaling pathways, respectively. The effect of EF-2001 on OA-induced hepatic lipid accumulation in FL83Bs enhanced the phosphorylation of acetyl-CoA carboxylase and reduced the levels of lipid accumulation proteins SREBP-1c and fatty acid synthase. EF-2001 treatment increased the levels of adipose triglyceride lipase and monoacylglycerol during lipase enzyme activation, which, when increased, contributed to increased liver lipolysis. In conclusion, EF-2001 inhibits OA-induced FL83B hepatic lipid accumulation and HFD-induced hepatic steatosis in rats through the AMPK signaling pathway.

Keywords:  AMPK signaling; EF-2001; Enterococcus faecalis; high-fat diet; lipid metabolism

DOI:  https://doi.org/10.3390/ijms24054486
Phytother Res. 2023 Mar 06.

Homoplantaginin attenuates high glucose-induced vascular endothelial cell apoptosis through promoting autophagy via the AMPK/TFEB pathway.

Lili Fan, Xueying Zhang, Yihai Huang, Baobao Zhang, Wenjing Li, Qingru Shi, Yining Lin, Feihua Wu.

  Vascular endothelial cell (VEC) injury is a key factor in the development of diabetic vascular complications. Homoplantaginin (Hom), one of the main flavonoids from Salvia plebeia R. Br. has been reported to protect VEC. However, its effects and mechanisms against diabetic vascular endothelium remain unclear. Here, the effect of Hom on VEC was assessed using high glucose (HG)-treated human umbilical vein endothelial cells and db/db mice. In vitro, Hom significantly inhibited apoptosis and promoted autophagosome formation and lysosomal function such as lysosomal membrane permeability and the expression of LAMP1 and cathepsin B. The antiapoptosis effect of Hom was reversed by autophagy inhibitor chloroquine phosphate or bafilomycin A1. Furthermore, Hom promoted gene expression and nuclear translocation of transcription factor EB (TFEB). TFEB gene knockdown attenuated the effect of Hom on upregulating lysosomal function and autophagy. Moreover, Hom activated adenosine monophosphate-dependent protein kinase (AMPK) and inhibited the phosphorylation of mTOR, p70S6K, and TFEB. These effects were attenuated by AMPK inhibitor Compound C. Molecular docking showed a good interaction between Hom and AMPK protein. Animal studies indicated that Hom effectively upregulated the protein expression of p-AMPK and TFEB, enhanced autophagy, reduced apoptosis, and alleviated vascular injury. These findings revealed that Hom ameliorated HG-mediated VEC apoptosis by enhancing autophagy via the AMPK/mTORC1/TFEB pathway.

Keywords:  apoptosis; autophagy; high glucose; homoplantaginin; transcription factor EB; vascular endothelial cell

DOI:  https://doi.org/10.1002/ptr.7797
J Biol Chem. 2023 Mar 02. pii: S0021-9258(23)00212-0. [Epub ahead of print] 104570

Posttranslational regulation of liver kinase B1 (LKB1) in human cancer.

Lanlin Hu, Mingxin Liu, Bo Tang, Qiang Li, Bo-Syong Pan, Chuan Xu, Hui-Kuan Lin.

  Liver kinase B1 (LKB1) is a serine-threonine kinase that participates in multiple cellular and biological processes, including energy metabolism, cell polarity, cell proliferation, cell migration, and many others. LKB1 is initially identified as a germline-mutated causative gene in Peutz-Jeghers syndrome (PJS) and is commonly regarded as a tumor suppressor due to frequent inactivation in a variety of cancers. LKB1 directly binds and activates its downstream kinases including the AMP-activated protein kinase (AMPK) and AMPK-related kinases by phosphorylation, which has been intensively investigated for the past decades. An increasing number of studies has uncovered the posttranslational modifications (PTMs) of LKB1 and consequent changes in its localization, activity, and interaction with substrates. The alteration in LKB1 function as a consequence of genetic mutations and aberrant upstream signaling regulation leads to tumor development and progression. Here, we review current knowledge about the mechanism of LKB1 in cancer and the contributions of PTMs, such as phosphorylation, ubiquitination, SUMOylation, acetylation, prenylation, and others, to the regulation of LKB1 function, offering new insights into the therapeutic strategies in cancer.

Keywords:  AMPK; Liver kinase B1; cancer therapy; posttranslational modification

DOI:  https://doi.org/10.1016/j.jbc.2023.104570
Anim Nutr. 2023 Jun;13 1-8

Low rumen degradable starch promotes the growth performance of goats by increasing protein synthesis in skeletal muscle via the AMPK-mTOR pathway.

Ziqi Liang, Chunjia Jin, Hanxun Bai, Gaofeng Liang, Xiaodong Su, Dangdang Wang, Junhu Yao.

  Since starch digestion in the small intestine provides more energy than digestion in the rumen of ruminants, reducing dietary rumen degradable starch (RDS) content is beneficial for improving energy utilization of starch in ruminants. The present study tested whether the reduction of rumen degradable starch by restricting dietary corn processing for growing goats could improve growth performance, and further investigated the possible underlying mechanism. In this study, twenty-four 12-wk-old goats were selected and randomly allocated to receive either a high RDS diet (HRDS, crushed corn-based concentrate, the mean of particle sizes of corn grain = 1.64 mm, n = 12) or a low RDS diet (LRDS, non-processed corn-based concentrate, the mean of particle sizes of corn grain >8 mm, n = 12). Growth performance, carcass traits, plasma biochemical indices, gene expression of glucose and amino acid transporters, and protein expression of the AMPK-mTOR pathway were measured. Compared to the HRDS, LRDS tended to increase the average daily gain (ADG, P = 0.054) and decreased the feed-to-gain ratio (F/G, P < 0.05). Furthermore, LRDS increased the net lean tissue rate (P < 0.01), protein content (P < 0.05) and total free amino acids (P < 0.05) in the biceps femoris (BF) muscle of goats. LRDS increased the glucose concentration (P < 0.01), but reduced total amino acid concentration (P < 0.05) and tended to reduce blood urea nitrogen (BUN) concentration (P = 0.062) in plasma of goats. The mRNA expression of insulin receptors (INSR), glucose transporter 4 (GLUT4), L-type amino acid transporter 1 (LAT1) and 4F2 heavy chain (4F2hc) in BF muscle, and sodium-glucose cotransporters 1 (SGLT1) and glucose transporter 2 (GLUT2) in the small intestine were significantly increased (P < 0.05) in LRDS goats. LRDS also led to marked activation of p70-S6 kinase (S6K) (P < 0.05), but lower activation of AMP-activated protein kinase (AMPK) (P < 0.05) and eukaryotic initiation factor 2α (P < 0.01). Our findings suggested that reducing the content of dietary RDS enhanced postruminal starch digestion and increased plasma glucose, thereby improving amino acid utilization and promoting protein synthesis in the skeletal muscle of goats via the AMPK-mTOR pathway. These changes may contribute to improvement in growth performance and carcass traits in LRDS goats.

Keywords:  AMPK-mTOR pathway; Amino acid; Glucose; Protein synthesis; Rumen degradable starch

DOI:  https://doi.org/10.1016/j.aninu.2022.10.006
Acta Pharm Sin B. 2023 Feb;13(2): 542-558

Synergistic activation of AMPK by AdipoR1/2 agonist and inhibitor of EDPs-EBP interaction recover NAFLD through enhancing mitochondrial function in mice.

Nazi Song, Hongjiao Xu, Shuohan Wu, Suijia Luo, Jingyao Xu, Qian Zhao, Rui Wang, Xianxing Jiang.

  Nonalcoholic fatty liver disease (NAFLD), especially nonalcoholic steatohepatitis (NASH), is a common hepatic manifestation of metabolic syndrome. However, there are no effective therapy to treat this devastating disease. Accumulating evidence suggests that the generation of elastin-derived peptides (EDPs) and the inhibition of adiponectin receptors (AdipoR)1/2 plays essential roles in hepatic lipid metabolism and liver fibrosis. We recently reported that the AdipoR1/2 dual agonist JT003 significantly degraded the extracellular matrix (ECM) and ameliorated liver fibrosis. However, the degradation of the ECM lead to the generation of EDPs, which could further alter liver homeostasis negatively. Thus, in this study, we successfully combined AdipoR1/2 agonist JT003 with V14, which acted as an inhibitor of EDPs-EBP interaction to overcome the defect of ECM degradation. We found that combination of JT003 and V14 possessed excellent synergistic benefits on ameliorating NASH and liver fibrosis than either alone since they compensate the shortage of each other. These effects are induced by the enhancement of the mitochondrial antioxidant capacity, mitophagy, and mitochondrial biogenesis via AMPK pathway. Furthermore, specific suppression of AMPK could block the effects of the combination of JT003 and V14 on reduced oxidative stress, increased mitophagy and mitochondrial biogenesis. These positive results suggested that this administration of combination of AdipoR1/2 dual agonist and inhibitor of EDPs-EBP interaction can be recommended alternatively for an effective and promising therapeutic strategy for the treatment of NAFLD and NASH related fibrosis.

Keywords:  AMPK; AdipoR1/2 agonist; Combination therapy; EDPs; Liver fibrosis; Mitochondrial biogenesis; Mitochondrial function; Mitophagy; NASH

DOI:  https://doi.org/10.1016/j.apsb.2022.10.003
Diabetes Metab J. 2023 Mar 06.

Role of SUMO-Specific Protease 2 in Leptin-Induced Fatty Acid Metabolism in White Adipocytes.

Praise Chanmee Kim, Ji Seon Lee, Sung Soo Chung, Kyong Soo Park.

   Background: Leptin is a 16-kDa fat-derived hormone with a primary role in controlling adipose tissue levels. Leptin increases fatty acid oxidation (FAO) acutely through adenosine monophosphate-activated protein kinase (AMPK) and on delay through the SUMO-specific protease 2 (SENP2)-peroxisome proliferator-activated receptor δ/γ (PPARδ/γ) pathway in skeletal muscle. Leptin also directly increases FAO and decreases lipogenesis in adipocytes; however, the mechanism behind these effects remains unknown. Here, we investigated the role of SENP2 in the regulation of fatty acid metabolism by leptin in adipocytes and white adipose tissues.
Methods: The effects of leptin mediated by SENP2 on fatty acid metabolism were tested by siRNA-mediated knockdown in 3T3-L1 adipocytes. The role of SENP2 was confirmed in vivo using adipocyte-specific Senp2 knockout (Senp2-aKO) mice. We revealed the molecular mechanism involved in the leptin-induced transcriptional regulation of carnitine palmitoyl transferase 1b (Cpt1b) and long-chain acyl-coenzyme A synthetase 1 (Acsl1) using transfection/reporter assays and chromatin immunoprecipitation.
Results: SENP2 mediated the increased expression of FAO-associated enzymes, CPT1b and ACSL1, which peaked 24 hours after leptin treatment in adipocytes. In contrast, leptin stimulated FAO through AMPK during the initial several hours after treatment. In white adipose tissues, FAO and mRNA levels of Cpt1b and Acsl1 were increased by 2-fold 24 hours after leptin injection in control mice but not in Senp2-aKO mice. Leptin increased PPARα binding to the Cpt1b and Acsl1 promoters in adipocytes through SENP2.
Conclusion: These results suggest that the SENP2-PPARα pathway plays an important role in leptin-induced FAO in white adipocytes.

Keywords:  Adipocytes, white; Fatty acids; Leptin; Peroxisome proliferator-activated receptors; Senp2 protein, mouse

DOI:  https://doi.org/10.4093/dmj.2022.0156
J Biochem Mol Toxicol. 2023 Mar 08. e23330

Oxymatrine and insulin resistance: Focusing on mechanistic intricacies involve in diabetes associated cardiomyopathy via SIRT1/AMPK and TGF-β signaling pathway.

Sanket Seksaria, Sidharth Mehan, Bhaskar J Dutta, Ghanshyam D Gupta, Subrahmanya S Ganti, Amrita Singh.

  Cardiomyopathy (CDM) and related morbidity and mortality are increasing at an alarming rate, in large part because of the increase in the number of diabetes mellitus cases. The clinical consequence associated with CDM is heart failure (HF) and is considerably worse for patients with diabetes mellitus, as compared to nondiabetics. Diabetic cardiomyopathy (DCM) is characterized by structural and functional malfunctioning of the heart, which includes diastolic dysfunction followed by systolic dysfunction, myocyte hypertrophy, cardiac dysfunctional remodeling, and myocardial fibrosis. Indeed, many reports in the literature indicate that various signaling pathways, such as the AMP-activated protein kinase (AMPK), silent information regulator 1 (SIRT1), PI3K/Akt, and TGF-β/smad pathways, are involved in diabetes-related cardiomyopathy, which increases the risk of functional and structural abnormalities of the heart. Therefore, targeting these pathways augments the prevention as well as treatment of patients with DCM. Alternative pharmacotherapy, such as that using natural compounds, has been shown to have promising therapeutic effects. Thus, this article reviews the potential role of the quinazoline alkaloid, oxymatrine obtained from the Sophora flavescensin CDM associated with diabetes mellitus. Numerous studies have given a therapeutic glimpse of the role of oxymatrine in the multiple secondary complications related to diabetes, such as retinopathy, nephropathy, stroke, and cardiovascular complications via reductions in oxidative stress, inflammation, and metabolic dysregulation, which might be due to targeting signaling pathways, such as AMPK, SIRT1, PI3K/Akt, and TGF-β pathways. Thus, these pathways are considered central regulators of diabetes and its secondary complications, and targeting these pathways with oxymatrine might provide a therapeutic tool for the diagnosis and treatment of diabetes-associated cardiomyopathy.

Keywords:  AMPK; SIRT1; TGF-β; cardiomyopathy; diabetes; oxidative stress; oxymatrine

DOI:  https://doi.org/10.1002/jbt.23330
Mol Neurobiol. 2023 Mar 06.

High-Intensity Interval Training Ameliorates Molecular Changes in the Hippocampus of Male Rats with the Diabetic Brain: the Role of Adiponectin.

Kayvan Khoramipour, Mohammad Abbas Bejeshk, Mohammad Amin Rajizadeh, Hamid Najafipour, Padideh Dehghan, Fattaneh Farahmand.

  Alzheimer's disease (AD) is closely related to type 2 diabetes (T2D). This study investigated the impact of high-intensity interval training (HIIT) on diabetes-induced disturbances in AD-related factors (including AMP-activated protein kinase (AMPK), glycogen synthase kinase-3β (GSK3β), and tau protein) in the hippocampus, with the main focus on adiponectin signaling.In total, 28 male Wistar rats at the age of 8 weeks were randomly assigned to four groups (n = 7 in each group): control (Con), type 2 diabetes (T2D), HIIT (Ex), and type 2 diabetes + HIIT (T2D + Ex). T2D was induced by a high-fat diet plus a single dose of streptozotocin (STZ). Rats in Ex and T2D + Ex groups performed 8 weeks of HIIT (running at 8-95% of Vmax, 4-10 intervals). Insulin and adiponectin levels in serum and hippocampus were measured along with hippocampal expression of insulin and adiponectin receptors, phosphorylated AMPK, dephosphorylated GSK3β, and phosphorylated tau. Homeostasis model assessment for insulin resistance (HOMA-IR), homeostasis model assessment for insulin resistance beta (HOMA-β), and quantitative insulin sensitivity check index (QUICKI) were calculated to assess insulin resistance and sensitivity. T2D decreased insulin and adiponectin levels in serum and hippocampus, as well as the hippocampal levels of insulin and adiponectin receptors and AMPK, but increased GSK3β and tau in the hippocampus. HIIT reversed diabetes-induced impairments and consequently decreased tau accumulation in the hippocampus of diabetic rats. HOMA-IR, HOMA-β, and QUICKI were improved in Ex and T2D + Ex groups. Overall, our results confirmed that T2D has undesirable effects on the levels of some Alzheimer's-related factors in the hippocampus, and HIIT could ameliorate these impairments in the hippocampus.

Keywords:  Adiponectin; Alzheimer’s disease; HIIT; Hippocampus; Type 2 diabetes

DOI:  https://doi.org/10.1007/s12035-023-03285-z
Cells. 2023 Feb 24. pii: 714. [Epub ahead of print]12(5):

A Novel Mix of Polyphenols and Micronutrients Reduces Adipogenesis and Promotes White Adipose Tissue Browning via UCP1 Expression and AMPK Activation.

Francesca Pacifici, Gina Malatesta, Caterina Mammi, Donatella Pastore, Vincenzo Marzolla, Camillo Ricordi, Francesca Chiereghin, Marco Infante, Giulia Donadel, Francesco Curcio, Annalisa Noce, Valentina Rovella, Davide Lauro, Manfredi Tesauro, Nicola Di Daniele, Enrico Garaci, Massimiliano Caprio, David Della-Morte.

  Background: Obesity is a pandemic disease characterized by excessive severe body comorbidities. Reduction in fat accumulation represents a mechanism of prevention, and the replacement of white adipose tissue (WAT) with brown adipose tissue (BAT) has been proposed as one promising strategy against obesity. In the present study, we sought to investigate the ability of a natural mixture of polyphenols and micronutrients (A5+) to counteract white adipogenesis by promoting WAT browning. Methods: For this study, we employed a murine 3T3-L1 fibroblast cell line treated with A5+, or DMSO as control, during the differentiation in mature adipocytes for 10 days. Cell cycle analysis was performed using propidium iodide staining and cytofluorimetric analysis. Intracellular lipid contents were detected by Oil Red O staining. Inflammation Array, along with qRT-PCR and Western Blot analyses, served to measure the expression of the analyzed markers, such as pro-inflammatory cytokines. Results: A5+ administration significantly reduced lipids' accumulation in adipocytes when compared to control cells (p < 0.005). Similarly, A5+ inhibited cellular proliferation during the mitotic clonal expansion (MCE), the most relevant stage in adipocytes differentiation (p < 0.0001). We also found that A5+ significantly reduced the release of pro-inflammatory cytokines, such as IL-6 and Leptin (p < 0.005), and promoted fat browning and fatty acid oxidation through increasing expression levels of genes related to BAT, such as UCP1 (p < 0.05). This thermogenic process is mediated via AMPK-ATGL pathway activation. Conclusion: Overall, these results demonstrated that the synergistic effect of compounds contained in A5+ may be able to counteract adipogenesis and then obesity by inducing fat browning.

Keywords:  AMPK; UCP1; adipogenesis; browning; mitotic clonal expansion; polyphenols

DOI:  https://doi.org/10.3390/cells12050714