bims-amsmem Biomed News
on AMPK signaling mechanism in energy metabolism
Issue of 2022–07–31
forty-five papers selected by
Dipsikha Biswas, Københavns Universitet
  1. Epithelial-Mesenchymal Transition Suppresses AMPK and Sensitizes Cancer Cells to Pyroptosis under Energy Stress.
  2. The Marine-Derived Macrolactone Mandelalide A Is an Indirect Activator of AMPK.
  3. The role of liver kinase B1 in tumor progression through regulation of lipid metabolism.
  4. A critical role of AMP-activated protein kinase in regulating intestinal nutrient absorption, barrier function, and intestinal diseases.
  5. Rationed and satiated growth hormone transgenic Coho Salmon (Oncorhynchus kisutch) show tissue specific differences in energy stores.
  6. An AMPK biosensor for Caenorhabditis elegans.
  7. Therapeutic vs. Suprapharmacological Metformin Concentrations: Different Effects on Energy Metabolism and Mitochondrial Function in Skeletal Muscle Cells in vitro.
  8. Combination of chronic stress with fructose diet increases AMP-activated protein kinase phosphorylation and affects agouti-related protein and proopiomelanocortin expression in the hypothalamus of male Wistar rats.
  9. Astragalus polysaccharide alleviates transport stress-induced heart injury in newly hatched chicks via ERS-UPR-autophagy dependent pathway.
  10. Stress-responsive AMP Kinase like protein regulates encystation of Entamoeba invadens.
  11. 3,4',5-Trimethoxy-trans-stilbene Alleviates Endothelial Dysfunction in Diabetic and Obese Mice via Activation of the AMPK/SIRT1/eNOS Pathway.
  12. Comparative Analysis of Policosanols Related to Growth Times from the Seedlings of Various Korean Oat (Avena sativa L.) Cultivars and Screening for Adenosine 5'-Monophosphate-Activated Protein Kinase (AMPK) Activation.
  13. Puerarin attenuates hepatic steatosis via G-protein-coupled estrogen receptor-mediated calcium and SIRT1 signaling pathways.
  14. Adenine Combined with Cisplatin Promotes Anticancer Activity against Hepatocellular Cancer Cells through AMPK-Mediated p53/p21 and p38 MAPK Cascades.
  15. Thymol Alleviates LPS-Induced Liver Inflammation and Apoptosis by Inhibiting NLRP3 Inflammasome Activation and the AMPK-mTOR-Autophagy Pathway.
  16. AMP-activated protein kinase β1 or β2 deletion enhances colon cancer cell growth and tumorigenesis.
  17. Amorphigenin from Amorpha fruticosa L. Root Extract Induces Autophagy-Mediated Melanosome Degradation in mTOR-Independent- and AMPK-Dependent Manner.
  18. TRPV1 Protects Against Pressure Overload-Induced Cardiac Hypertrophy by Promoting Mitochondria-Associated Endoplasmic Reticulum Membranes.
  19. LC3B, mTOR, AMPK Are Molecular Targets for Neoadjuvant Chemotherapy in Gastric Cancers.
  20. Seabuckthorn Reverses High-Fat-Diet-Induced Obesity and Enhances Fat Browning via Activation of AMPK/SIRT1 Pathway.
  21. Adipokines in Sleep Disturbance and Metabolic Dysfunction: Insights from Network Analysis.
  22. Metabolic Action of Metformin.
  23. The Role of Mitochondrial Metabolism, AMPK-SIRT Mediated Pathway, LncRNA and MicroRNA in Osteoarthritis.
  24. Alginate Oligosaccharides Ameliorate DSS-Induced Colitis through Modulation of AMPK/NF-κB Pathway and Intestinal Microbiota.
  25. Astragaloside IV Protects Detrusor from Partial Bladder Outlet Obstruction-Induced Oxidative Stress by Activating Mitophagy through AMPK-ULK1 Pathway.
  26. Beneficial Effects of Theaflavins on Metabolic Syndrome: From Molecular Evidence to Gut Microbiome.
  27. Investigating the effect of Sulforaphane on AMPK/AKT/NRF2 pathway in human granulosa-lutein cells under H2O2-induced oxidative stress.
  28. Renoprotective Effect of Pediococcus acidilactici GKA4 on Cisplatin-Induced Acute Kidney Injury by Mitigating Inflammation and Oxidative Stress and Regulating the MAPK, AMPK/SIRT1/NF-κB, and PI3K/AKT Pathways.
  29. The ameliorating effects of metformin on disarrangement ongoing in gastrocnemius muscle of sarcopenic and obese sarcopenic mice.
  30. Metformin induces mitochondrial remodeling and differentiation of pancreatic progenitor cells into beta-cells by a potential mechanism including suppression of the T1R3, PLCβ2, cytoplasmic Ca+2, and AKT.
  31. Effect of Coffee on Lipopolysaccharide-Induced Immortalized Human Oral Keratinocytes.
  32. Atherosclerosis Plaque Reduction by Lycopene Is Mediated by Increased Energy Expenditure through AMPK and PPARα in ApoE KO Mice Fed with a High Fat Diet.
  33. Immunomodulatory and Antiaging Mechanisms of Resveratrol, Rapamycin, and Metformin: Focus on mTOR and AMPK Signaling Networks.
  34. Curcumin Alleviates D-Galactose-Induced Cardiomyocyte Senescence by Promoting Autophagy via the SIRT1/AMPK/mTOR Pathway.
  35. The Effect of Laminaria japonica on Metabolic Syndrome: A Systematic Review of Its Efficacy and Mechanism of Action.
  36. Effect of 3-caffeoyl, 4-dihydrocaffeoylquinic acid from Salicornia herbacea on endothelial nitric oxide synthase activation via calcium signaling pathway.
  37. The CARM1 transcriptome and arginine methylproteome mediate skeletal muscle integrative biology.
  38. Puerarin Attenuates Oxidative Stress and Ferroptosis via AMPK/PGC1α/Nrf2 Pathway after Subarachnoid Hemorrhage in Rats.
  39. Phosphoproteomics of three exercise modalities identifies canonical signaling and C18ORF25 as an AMPK substrate regulating skeletal muscle function.
  40. Bioactive Peptides and Exercise Modulate the AMPK/SIRT1/PGC-1α/FOXO3 Pathway as a Therapeutic Approach for Hypertensive Rats.
  41. Resistance to Obesity in SOD1 Deficient Mice with a High-Fat/High-Sucrose Diet.
  42. Xiaoyao San, a Chinese herbal formula, ameliorates depression-like behavior in mice through the AdipoR1/AMPK/ACC pathway in hypothalamus.
  43. Elecampane (Inula helenium) Root Extract and Its Major Sesquiterpene Lactone, Alantolactone, Inhibit Adipogenesis of 3T3-L1 Preadipocytes.
  44. Effect of Taurine on the Regulation of Glucose Uptake in the Skeletal Muscle.
  45. Evidence for a neuromuscular circuit involving hypothalamic interleukin-6 in the control of skeletal muscle metabolism.
  1. Cells. 2022 Jul 15. pii: 2208. [Epub ahead of print]11(14):
    Epithelial-Mesenchymal Transition Suppresses AMPK and Sensitizes Cancer Cells to Pyroptosis under Energy Stress.
    Mingwei Liang, Jennifer W Li, Huacheng Luo, Sarah Lulu, Ozlem Calbay, Anitha Shenoy, Ming Tan, Brian K Law, Shuang Huang, Tsan Sam Xiao, Hao Chen, Lizi Wu, Jia Chang, Jianrong Lu.
      Epithelial-mesenchymal transition (EMT) is implicated in tumor metastasis and therapeutic resistance. It remains a challenge to target cancer cells that have undergone EMT. The Snail family of key EMT-inducing transcription factors directly binds to and transcriptionally represses not only epithelial genes but also a myriad of additional genomic targets that may carry out significant biological functions. Therefore, we reasoned that EMT inherently causes various concomitant phenotypes, some of which may create targetable vulnerabilities for cancer treatment. In the present study, we found that Snail transcription factors bind to the promoters of multiple genes encoding subunits of the AMP-activated protein kinase (AMPK) complex, and expression of AMPK genes was markedly downregulated by EMT. Accordingly, high AMPK expression in tumors correlated with epithelial cell markers and low AMPK expression in tumors was strongly associated with adverse prognosis. AMPK is the principal sensor of cellular energy status. In response to energy stress, AMPK is activated and critically reprograms cellular metabolism to restore energy homeostasis and maintain cell survival. We showed that activation of AMPK by energy stress was severely impaired by EMT. Consequently, EMT cancer cells became hypersensitive to a variety of energy stress conditions and primarily underwent pyroptosis, a regulated form of necrotic cell death. Collectively, the study suggests that EMT impedes the activation of AMPK signaling induced by energy stress and sensitizes cancer cells to pyroptotic cell death under energy stress conditions. Therefore, while EMT promotes malignant progression, it concurrently induces collateral vulnerabilities that may be therapeutically exploited.
    Keywords:  AMPK; EMT; cancer; energy stress; metformin; pyroptosis
    DOI:  https://doi.org/10.3390/cells11142208
  2. Mar Drugs. 2022 Jun 27. pii: 418. [Epub ahead of print]20(7):
    The Marine-Derived Macrolactone Mandelalide A Is an Indirect Activator of AMPK.
    Daphne R Mattos, Xuemei Wan, Jeffrey D Serrill, Minh H Nguyen, Ian R Humphreys, Benoit Viollet, Amos B Smith, Kerry L McPhail, Jane E Ishmael.
      The mandelalides are complex macrolactone natural products with distinct macrocycle motifs and a bioactivity profile that is heavily influenced by compound glycosylation. Mandelalides A and B are direct inhibitors of mitochondrial ATP synthase (complex V) and therefore more toxic to mammalian cells with an oxidative metabolic phenotype. To provide further insight into the pharmacology of the mandelalides, we studied the AMP-activated protein kinase (AMPK) energy stress pathway and report that mandelalide A is an indirect activator of AMPK. Wild-type mouse embryonic fibroblasts (MEFs) and representative human non-small cell lung cancer (NSCLC) cells showed statistically significant increases in phospho-AMPK (Thr172) and phospho-ACC (Ser79) in response to mandelalide A. Mandelalide L, which also harbors an A-type macrocycle, induced similar increases in phospho-AMPK (Thr172) and phospho-ACC (Ser79) in U87-MG glioblastoma cells. In contrast, MEFs co-treated with an AMPK inhibitor (dorsomorphin), AMPKα-null MEFs, or NSCLC cells lacking liver kinase B1 (LKB1) lacked this activity. Mandelalide A was significantly more cytotoxic to AMPKα-null MEFs than wild-type cells, suggesting that AMPK activation serves as a protective response to mandelalide-induced depletion of cellular ATP. However, LKB1 status alone was not predictive of the antiproliferative effects of mandelalide A against NSCLC cells. When EGFR status was considered, erlotinib and mandelalide A showed strong cytotoxic synergy in combination against erlotinib-resistant 11-18 NSCLC cells but not against erlotinib-sensitive PC-9 cells. Finally, prolonged exposures rendered mandelalide A, a potent and efficacious cytotoxin, against a panel of human glioblastoma cell types regardless of the underlying metabolic phenotype of the cell. These results add biological relevance to the mandelalide series and provide the basis for their further pre-clinical evaluation as ATP synthase inhibitors and secondary activators of AMPK.
    Keywords:  AMP-activated protein kinase; ATP synthase; ATPase; OXPHOS; macrolactone; oxidative phosphorylation; polyketide
    DOI:  https://doi.org/10.3390/md20070418
  3. Clin Transl Oncol. 2022 Jul 27.
    The role of liver kinase B1 in tumor progression through regulation of lipid metabolism.
    Jialu Geng, Yanghe Zhang, Qingfei Meng, Hang Yan, Yishu Wang.
      The somatic mutation of liver kinase B1 (LKB1) has been implicated in various tumors, which is reflected in the survival, proliferation, and metastasis of tumor cells. However, the regulation of LKB1 in lipid metabolism, a process that is involved in tumor progression is not completely clear. We conclude that LKB1 deficiency results in abnormal expression and activation of multiple molecules related to lipid metabolism which locate downstream of AMP-activated protein kinase (AMPK) or salt-induced kinase (SIK). Abnormal lipid metabolism induced by LKB1 deficiency contributes to the proliferation and metastasis of tumor cells through energy regulation.
    Keywords:  AMPK; LKB1; Lipid metabolism; Tumor
    DOI:  https://doi.org/10.1007/s12094-022-02863-2
  4. J Cell Physiol. 2022 Jul 26.
    A critical role of AMP-activated protein kinase in regulating intestinal nutrient absorption, barrier function, and intestinal diseases.
    Zhihui Wu, Chengfei Xu, Tenghui Zheng, Qihui Li, Siwang Yang, Jiayuan Shao, Wutai Guan, Shihai Zhang.
      As one of the most important organs in animals, the intestine is responsible for nutrient absorption and acts as a barrier between the body and the environment. Intestinal physiology and function require the participation of energy. 5'-adenosine monophosphate-activated protein kinase (AMPK), a classical and highly expressed energy regulator in intestinal cells, regulates the process of nutrient absorption and barrier function and is also involved in the therapy of intestinal diseases. Studies have yielded findings that AMPK regulates the absorption of glucose, amino acids, and fatty acids in the intestine primarily by regulating transportation systems, as we detailed here. Moreover, AMPK is involved in the regulation of the intestinal mechanical barrier and immune barrier through manipulating the expression of tight junctions, antimicrobial peptides, and secretory immunoglobulins. In addition, AMPK also participates in the regulation of intestinal diseases, which indicates that AMPK is a promising therapeutic target for intestinal diseases and cancer. In this review, we summarized the current understanding regarding how AMPK regulates intestinal nutrient absorption, barrier function, and intestinal diseases.
    Keywords:  AMPK; intestinal barrier; intestinal diseases; intestine; nutrition absorption
    DOI:  https://doi.org/10.1002/jcp.30841
  5. Comp Biochem Physiol B Biochem Mol Biol. 2022 Jul 25. pii: S1096-4959(22)00069-0. [Epub ahead of print] 110781
    Rationed and satiated growth hormone transgenic Coho Salmon (Oncorhynchus kisutch) show tissue specific differences in energy stores.
    W A Thompson, G Y Lau, J G Richards, R H Devlin.
      Growth hormone transgenic coho salmon experience increased growth rates, driven primarily through elevated feed intake and feed conversion. However, neuropeptides that signal appetite stimulation have been shown to exhibit variable responses across fed states, suggesting a more complex system mediating growth in these fish. Studies have proposed that growth hormone may have a modulatory role on the energy reserves of fish, possibly through AMP-activated protein kinase (AMPK) activation. AMPK, an energy sensor in cells, has previously been shown to be upregulated in growth hormone transgenic salmon when compared to wild type, however, whether this effect is seen across fed states is unknown. Here, we tested the hypothesis that growth hormone induces an energetic deficit in metabolic tissues, leading to constitutive AMPK activation in growth hormone transgenic salmon. This study compared AMPK activity, ATP, and glycogen, of the liver, heart, and muscle of wild-type, and growth hormone transgenic salmon either fed to satiation or a wild-type ration. The results suggest that white muscle ATP levels in growth hormone salmon are elevated in satiation and rationed conditions. In the liver, growth hormone transgenic salmon fed a rationed wild-type diet experience reductions in ATP level and glycogen. In none of the tissues examined, did AMPK activity change. Taken together, these results indicate that growth hormone transgenic salmon experience metabolic duress when not fed to satiation.
    Keywords:  AMPK; ATP; Aquaculture; Glycogen; Growth hormone; Salmon
    DOI:  https://doi.org/10.1016/j.cbpb.2022.110781
  6. MicroPubl Biol. 2022 ;2022
    An AMPK biosensor for Caenorhabditis elegans.
    Lynly Carman, Ryan J Schuck, Edwin Li, Matthew D Nelson.
      Adenosine monophosphate-activated kinase (AMPK) functions in a broad spectrum of cellular stress response pathways. Investigation of AMPK activity has been limited to whole-organism analyses in Caenorhabditis elegans which does not allow for observations of cellular heterogeneity, temporal dynamics, or correlation with physiological states in real time. We codon adapted the genetically-coded AMPK biosensor, called AMPKAR-EV, for use in C. elegans . We report heterogeneity of activation in different tissues (intestine, neurons, muscle) and test the biosensor in the context of two missense mutations affecting residues T243 and S244 on the AMPK α subunit, AAK-2, which are predicted regulatory sites.
    DOI:  https://doi.org/10.17912/micropub.biology.000596
  7. Front Pharmacol. 2022 ;13 930308
    Therapeutic vs. Suprapharmacological Metformin Concentrations: Different Effects on Energy Metabolism and Mitochondrial Function in Skeletal Muscle Cells in vitro.
    Kasja Pavlovic, Nina Krako Jakovljevic, Andjelka M Isakovic, Tijana Ivanovic, Ivanka Markovic, Nebojsa M Lalic.
      Metformin is an oral antidiabetic agent that has been widely used in clinical practice for over 60 years, and is currently the most prescribed antidiabetic drug worldwide. However, the molecular mechanisms of metformin action in different tissues are still not completely understood. Although metformin-induced inhibition of mitochondrial respiratory chain Complex I and activation of AMP-activated protein kinase have been observed in many studies, published data is inconsistent. Furthermore, metformin concentrations used for in vitro studies and their pharmacological relevance are a common point of debate. The aim of this study was to explore the effects of different metformin concentrations on energy metabolism and activity of relevant signaling pathways in C2C12 muscle cells in vitro. In order to determine if therapeutic metformin concentrations have an effect on skeletal muscle cells, we used micromolar metformin concentrations (50 µM), and compared the effects with those of higher, millimolar concentrations (5 mM), that have already been established to affect mitochondrial function and AMPK activity. We conducted all experiments in conditions of high (25 mM) and low glucose (5.5 mM) concentration, in order to discern the role of glucose availability on metformin action. According to our results, micromolar metformin treatment did not cause Complex I inhibition nor AMPK activation. Also, cells cultured in low glucose medium were more sensitive to Complex I inhibition, mitochondrial membrane depolarization and AMPK activation by millimolar metformin, but cells cultured in high glucose medium were more prone to induction of ROS production. In conclusion, even though suprapharmacological metformin concentrations cause Complex I inhibition and AMPK activation in skeletal muscle cells in vitro, therapeutic concentrations cause no such effect. This raises the question if these mechanisms are relevant for therapeutic effects of metformin in skeletal muscle.
    Keywords:  metformin; mitochondria; respirometry; skeletal muscle; therapeutic concentration
    DOI:  https://doi.org/10.3389/fphar.2022.930308
  8. Acta Biochim Pol. 2022 Jul 25.
    Combination of chronic stress with fructose diet increases AMP-activated protein kinase phosphorylation and affects agouti-related protein and proopiomelanocortin expression in the hypothalamus of male Wistar rats.
    Abdulbaset Zidane Shirif, Sanja Kovačević, Biljana Bursać, Iva Lakić, Nataša Veličković, Tanja Jevdjovic, Ana Djordjevic.
      Appetite regulation in the hypothalamus is dependent on hormonal signals from the periphery, such as insulin and leptin, and can be modulated by both sugar-rich diet and stress. Our aim was to explore the effects of 9-week feeding with 20% fructose solution combined with 4-week chronic unpredictable stress, on appetite-regulating neuropeptides and modulatory role of leptin and insulin signalling in the hypothalamus of male Wistar rats. Energy intake, body mass and adiposity, as well as circulatory leptin and insulin concentrations were assessed. Hypothalamic insulin signalling was analysed at the level of glucose transporters, as well as at the protein level and phosphorylation of insulin receptor, insulin receptor supstrate-1, Akt and ERK. Phosphorylation of AMP-activated protein kinase (AMPK), level of protein tyrosine phosphatase 1B (PTP1B) and expression of leptin receptor (ObRb) and suppressor of cytokine signalling 3 (SOCS3) were also analysed, together with the expression of orexigenic agouti-related protein (AgRP) and anorexigenic proopiomelanocortin (POMC) neuropeptides. The results revealed that stress decreased body mass and adiposity, blood leptin level and expression of ObRb, SOCS3 and POMC, while combination with fructose diet led to marked increase of AgRP, associated with AMPK phosphorylation despite increased plasma insulin. Reduced Akt, enhanced ERK activity and elevated PTP1B were also observed in the hypothalamus of these animals. In conclusion, our results showed that joint effects of fructose diet and stress are more deleterious than the separate ones, since inappropriate appetite control in the hypothalamus may provide a setting for the disturbed energy homeostasis in the long run.
    DOI:  https://doi.org/10.18388/abp.2020_6075
  9. Poult Sci. 2022 Jun 23. pii: S0032-5791(22)00321-2. [Epub ahead of print]101(9): 102030
    Astragalus polysaccharide alleviates transport stress-induced heart injury in newly hatched chicks via ERS-UPR-autophagy dependent pathway.
    Jian Chen, Yi-Xi Tang, Jian-Xun Kang, Ya-Ru Xu, Ahmed Ibrahim Ahmed Elsherbeni, Hassan Bayoumi Ali Gharib, Jin-Long Li.
      Transport stress (TS) not only affects animal welfare but also eventually leads to higher morbidity and mortality. Moreover, TS could induce heart injury in animals, but the possible mechanism has yet to be fully explored. Astragalus polysaccharide (APS) is a main active component of Radix Astragali, which has an extensive anti-stress effect. However, the effect of APS on TS-induced heart injury has not yet been elucidated. In this study, a chick model of simulated TS was used. 240 newly hatched chicks were arranged into 4 groups: Control (Con), Transport group (T), Transport + water group (TW), and Transport + APS group (TA). Before transport, the chicks of the TW and TA groups were treated with deionized water and APS (0.25 mg/mL, 100 µL) by oral drops respectively. The histopathological analysis of myocardial tissue was assessed by hematoxylin and eosin staining. qRT-PCR and Western Blotting assays were employed to measure the expression of genes and proteins. Semiquantitative PCR was performed for the X box-binding protein-1 (XBP-1) mRNA splicing assay. The results indicated that APS significantly reduced TS-induced myocardial histopathological changes. Meanwhile, TS induced endoplasmic reticulum stress (ERS), evidenced by an activation of the unfolded protein response (UPR) signaling pathway and up-regulation of ERS-markers (P < 0.05). Moreover, TS markedly triggered autophagy induction by activating AMP-activated protein kinase (AMPK), reflected by augmented LC3-II/LC3-I, AMPK phosphorylation and autophagy-related genes (ATGs) expression (P < 0.05). Importantly, our study manifested that treatment of APS could reduce TS-induced ERS and AMPK-activated autophagy, accordingly alleviating heart injury of transported chicks. In summary, these findings indicate that TS induces heart injury in chicks via an ERS-UPR-autophagy-dependent pathway, and APS as an effective therapeutic method to alleviate it.
    Keywords:  Astragalus polysaccharide; endoplasmic reticulum stress; heart injury; newly hatched chick; transport stress
    DOI:  https://doi.org/10.1016/j.psj.2022.102030
  10. Mol Biochem Parasitol. 2022 Jul 21. pii: S0166-6851(22)00061-5. [Epub ahead of print]251 111507
    Stress-responsive AMP Kinase like protein regulates encystation of Entamoeba invadens.
    Piyali Goswami, Sintu Kumar Samanta, Tarun Agarwal, Sudip K Ghosh.
      Starvation is always accompanied by an increase in the ratio of AMP/ATP followed by activation of AMPK. It is one of the sensors for cellular energy status and is highly conserved across various species. Its role in the stage differentiation process of protozoan species like Giardia, Plasmodium, Trypanosome, and Toxoplasma has been reported. Since Entamoeba undergoes encystation in glucose-starved conditions; it intrigued us to investigate the existence and role of AMPK during the differentiation of trophozoites to the cyst. By employing in silico approaches, we have identified an AMPK homologue which is denominated here as EiAMPK (AMPK-like protein in Entamoeba invadens). Sequence and structural analysis indicate that EiAMPK is sequentially and structurally similar to the AMPK alpha subunit of other organisms. The recombinant form of EiAMPK was functionally active and in accordance, its activity was inhibited by an AMPK-specific inhibitor (eg. Compound C). The increased expression of EiAMPK during different stresses indicated that EiAMPK is a stress-responsive gene. To further investigate, whether EiAMPK has any role in encystation, we employed RNAi-mediated gene silencing that demonstrated its active involvement in encystation. It is known that Entamoeba maintains a flow of glucose from the glycolytic pathway to chitin synthesis for cyst wall formation during encystation. It is conceivable that EiAMPK might have a command over such glucose metabolism. As anticipated, the chitin synthesis was found greatly inhibited in both EiAMPK knockdown and Compound C treated cells, indicating that EiAMPK regulates the cyst wall chitin synthesis.
    Keywords:  AMP Kinase; Cell-wall chitin; Cellular stress; Encystation; Entamoeba
    DOI:  https://doi.org/10.1016/j.molbiopara.2022.111507
  11. Antioxidants (Basel). 2022 Jun 28. pii: 1286. [Epub ahead of print]11(7):
    3,4',5-Trimethoxy-trans-stilbene Alleviates Endothelial Dysfunction in Diabetic and Obese Mice via Activation of the AMPK/SIRT1/eNOS Pathway.
    Chunxiu Zhou, Yi Tan, Baojun Xu, Yitao Wang, Wai-San Cheang.
      3,4',5-trimethoxy-trans-stilbene (TMS) is a methoxylated derivative of resveratrol. Previous studies showed the vaso-protective effects of resveratrol; nevertheless, research on this derivative is scarce. The current study aimed to explore whether TMS can alleviate endothelial dysfunction in diabetic and obese mice, along with the underlying mechanisms. Thoracic aortas isolated from male C57BL/6J mice and primary cultures of rat aortic endothelial cells were treated with high glucose with or without TMS. High glucose exposure impaired acetylcholine-induced endothelium-dependent relaxations, down-regulated NO bioavailability and the AMP-activated protein kinase (AMPK)/Sirtuin 1 (SIRT1)/endothelial nitric oxide synthase (eNOS) pathway, increased endoplasmic reticulum (ER) stress and oxidative stress, which were reversed by TMS treatment. Moreover, the protective effects of TMS were abolished by Compound C (AMPK inhibitor), and EX527 (SIRT1 inhibitor). The mice were fed with high-fat diet (60% kcal% fat) for 14 weeks to establish a diabetic and obese model, and were orally administered TMS (10 mg/kg/day) in the last 4 weeks. Chronic TMS treatment alleviated endothelial dysfunction via enhancing the AMPK/SIRT1/eNOS pathway and attenuated oxidative stress and ER stress in aortas of diet-induced obese mice. In summary, our study reveals the potent vaso-protective effect of TMS and its therapeutic potential against endothelial dysfunction in metabolic disorders.
    Keywords:  3,4′,5-trimethoxy-trans-stilbene; diabetes; endoplasmic reticulum stress; endothelial dysfunction; oxidative stress
    DOI:  https://doi.org/10.3390/antiox11071286
  12. Plants (Basel). 2022 Jul 14. pii: 1844. [Epub ahead of print]11(14):
    Comparative Analysis of Policosanols Related to Growth Times from the Seedlings of Various Korean Oat (Avena sativa L.) Cultivars and Screening for Adenosine 5'-Monophosphate-Activated Protein Kinase (AMPK) Activation.
    Han-Gyeol Lee, So-Yeun Woo, Hyung-Jae Ahn, Ji-Yeong Yang, Mi-Ja Lee, Hyun-Young Kim, Seung-Yeob Song, Jin-Hwan Lee, Woo-Duck Seo.
      The objectives of this research were to evaluate the policosanol profiles and adenosine-5'-monophosphate-activated protein kinase (AMPK) properties in the seedlings of Korean oat (Avena sativa L.) cultivars at different growth times. Nine policosanols in the silylated hexane extracts were detected using GC-MS and their contents showed considerable differences; specifically, hexacosanol (6) exhibited the highest composition, constituting 88-91% of the total average content. Moreover, the average hexacosanol (6) contents showed remarkable variations of 337.8 (5 days) → 416.8 (7 days) → 458.9 (9 days) → 490.0 (11 days) → 479.2 (13 days) → 427.0 mg/100 g (15 days). The seedlings collected at 11 days showed the highest average policosanol content (541.7 mg/100 g), with the lowest content being 383.4 mg/100 g after 5 days. Interestingly, policosanols from oat seedlings grown for 11 days induced the most prevalent phenotype of AMPK activation in HepG2 cells, indicating that policosanols are an excellent AMPK activator.
    Keywords:  AMPK; GC-MS; growth times; hexacosanol; oat seedling; policosanol
    DOI:  https://doi.org/10.3390/plants11141844
  13. Phytother Res. 2022 Jul 24.
    Puerarin attenuates hepatic steatosis via G-protein-coupled estrogen receptor-mediated calcium and SIRT1 signaling pathways.
    Thi Hoa Pham, Gi Ho Lee, Sun Woo Jin, Seung Yeon Lee, Eun Hee Han, Nam Doo Kim, Hye Gwang Jeong.
      Puerarin, the major bioactive ingredient isolated from the root of Pueraria lobata (Willd.), attenuates body weight gain and reduces lipid levels in high-fat diet-induced obese mice; however, the underlying mechanism responsible for regulating lipid metabolism remains unclear. This study investigated the molecular mechanism(s) underlying the role of puerarin in regulating lipogenesis and lipolysis in human HepG2 cells. In this study, puerarin strongly inhibited the expression of fatty acid synthase (FASN) and sterol regulatory element binding protein 1c (SREBP-1c). Moreover, puerarin significantly induced the expression of adipose triglyceride lipase (ATGL), which is responsible for triacylglycerol hydrolase activity in cells. Puerarin enhanced 5' AMP-activated protein kinase (AMPK) activity, which is a central regulator of hepatic lipid metabolism. Furthermore, this AMPK activation could be mediated by sirtuin 1 (SIRT1) and calcium signaling pathways involved in G protein-coupled estrogen receptor (GPER) signaling. GPER blockage significantly reversed the effect of puerarin on lipid accumulation and the related signaling pathways. Docking studies showed that puerarin could bind in the GPER in a similar manner as GPER agonist G1. Our results suggest that puerarin can improve hepatic steatosis by activating GPER; it's signaling cascade sequentially induced calcium and SIRT1 signaling pathways. Thus, puerarin may be a potential therapeutic agent for the treatment of non-alcoholic fatty liver disease.
    Keywords:  AMPK; FASN; GPER; hepatic steatosis; puerarin
    DOI:  https://doi.org/10.1002/ptr.7526
  14. Pharmaceuticals (Basel). 2022 Jun 26. pii: 795. [Epub ahead of print]15(7):
    Adenine Combined with Cisplatin Promotes Anticancer Activity against Hepatocellular Cancer Cells through AMPK-Mediated p53/p21 and p38 MAPK Cascades.
    Jhen-Yu Huang, You-Cian Lin, Han-Min Chen, Jiun-Tsai Lin, Shao-Hsuan Kao.
      Cisplatin has been widely used in cancer treatments. Recent evidence indicates that adenine has potential anticancer activities against various types of cancers. However, the effects of the combination of adenine and cisplatin on hepatocellular carcinoma (HCC) cells remain sketchy. Here, our objective was to elucidate the anticancer activity of adenine in combination with cisplatin in HCC cells and its mechanistic pathways. Cell viability and cell cycle progression were assessed by the SRB assay and flow cytometry, respectively. Apoptosis was demonstrated by PI/annexin V staining and flow cytometric analysis. Protein expression, signaling cascade, and mRNA expression were analyzed by Western blotting and quantitative RT-PCR, respectively. Our results showed that adenine jointly potentiated the inhibitory effects of cisplatin on the cell viability of SK-Hep1 and Huh7 cells. Further investigation showed that adenine combined with cisplatin induced higher S phase arrest and apoptosis in HCC cells. Mechanically, adenine induced AMPK activation, reduced mTOR phosphorylation, and increased p53 and p21 levels. The combination of adenine and cisplatin synergistically reduced Bcl-2 and increased PUMA, cleaved caspase-3, and PARP in HCC cells. Adenine also upregulated the mRNA expression of p53, p21, PUMA, and PARP, while knockdown of AMPK reduced the increased expression of these genes. Furthermore, adenine also induced the activation of p38 MAPK through AMPK signaling, and the inhibition of p38 MAPK reduced the apoptosis of HCC cells with exposure to adenine combined with cisplatin. Collectively, these findings reveal that the combination of adenine and cisplatin synergistically enhances apoptosis of HCC cells, which may be attributed to the AMPK-mediated p53/p21 and p38 MAPK cascades. It suggests that adenine may be a potential adjuvant for the treatment of HCC in combination with cisplatin.
    Keywords:  AMP-activated protein kinase; adenine; apoptosis; cisplatin; hepatocellular carcinoma cells
    DOI:  https://doi.org/10.3390/ph15070795
  15. Nutrients. 2022 Jul 08. pii: 2809. [Epub ahead of print]14(14):
    Thymol Alleviates LPS-Induced Liver Inflammation and Apoptosis by Inhibiting NLRP3 Inflammasome Activation and the AMPK-mTOR-Autophagy Pathway.
    Xiujing Dou, Di Yan, Siqi Liu, Lujia Gao, Anshan Shan.
      Thymol is a natural antibacterial agent found in the essential oil extracted from thyme, which has been proven to be beneficial in food and medicine. Meanwhile, the NOD-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome and autophagy have been reported to play key roles in the progression of liver injury. However, the effects of thymol on the NLRP3 inflammasome and autophagy in protecting the liver remain unclear. The present study used a mouse model with liver injury induced by lipopolysaccharides (LPS) to investigate the regulatory mechanisms of thymol. We found that thymol alleviated LPS-induced liver structural damage, as judged by reduced inflammatory cell infiltration and improved structure. In addition, elevated levels of the liver damage indicators (alanine transaminase (ALT), aspartate transaminase (AST), and total bilirubin (TBIL)) dropped after thymol administration. The mRNA and protein expression of inflammatory cytokines (tumor necrosis factor (TNF)-α, interleukin (IL)-6, and IL-22), apoptosis-related genes (caspase3 and caspase9), and the activity of apoptosis-related genes (caspase3 and caspase9) were increased in LPS-treated livers, whereas the changes were alleviated after thymol administration. Thymol inhibited LPS-induced increment in lactate dehydrogenase (LDH) activity in primary hepatocytes of the mouse. In addition, thymol protected mice from liver injury by inhibiting NLRP3 inflammasome activation induced by LPS. Mechanistically, the present study indicates that thymol has liver protective activity resulting from the modulation of the AMP-activated protein kinase-mammalian target of rapamycin (AMPK-mTOR) to regulate the autophagy pathway, hence curbing inflammation.
    Keywords:  NLRP3 inflammasome; autophagy; inflammation; liver injury; mTOR; thymol
    DOI:  https://doi.org/10.3390/nu14142809
  16. Acta Biochim Biophys Sin (Shanghai). 2022 Jul 25. 54(7): 1-8
    AMP-activated protein kinase β1 or β2 deletion enhances colon cancer cell growth and tumorigenesis.
    Fuli Shi, Zhimin Tang, Shanshan Jiang, Zhijuan Xiong, Wansi Zhang, Yuanjun Li, Hui Lin, Zhijun Luo, Ying Ying.
      Abnormal metabolism is a major hallmark of cancer and has been validated as a therapeutic target. Adenine monophosphate-activated protein kinase (AMPK), an αβγ heterotrimer, performs essential functions in cancer progression due to its central role in maintaining the homeostasis of cellular energy. While the contributions of AMPKα and AMPKγ subunits to cancer development have been established, specific roles of AMPKβ1 and AMPKβ2 isoforms in cancer development are poorly understood. Here, we show the functions of AMPKβ1 and AMPKβ2 in colon cancer. Specifically, deletion of AMPKβ1 or AMPKβ2 leads to increased cell proliferation, colony formation, migration, and tumorigenesis in HCT116 and HT29 colon cancer cells. Interestingly, the AMPKβ1 and AMPKβ2 isoforms have slightly different effects on regulating cancer metabolism, as colon cancer cells with AMPKβ1 knockout showed decreased rates of glycolysis-related oxygen consumption, while AMPKβ2 deletion led to enhanced rates of oxygen consumption due to oxidative phosphorylation. These results demonstrate that functional AMPKβ1 and AMPKβ2 inhibit growth and tumorigenesis in colon cancer cells, suggesting their potential as effective targets for colon cancer therapy.
    Keywords:  AMPKβ1; AMPKβ2; Warburg effect; colon cancer; tumorigenesis
    DOI:  https://doi.org/10.3724/abbs.2022086
  17. Curr Issues Mol Biol. 2022 Jun 29. 44(7): 2856-2867
    Amorphigenin from Amorpha fruticosa L. Root Extract Induces Autophagy-Mediated Melanosome Degradation in mTOR-Independent- and AMPK-Dependent Manner.
    Ki Won Lee, Dang Thi Nguyen, Minju Kim, Si Hyeon Lee, Seyeon Lim, Jisu Kim, Ki Hun Park, Jeong Yoon Kim, Jiyun Yoo, Cheol Hwangbo, Kwang Dong Kim.
      In this study, we investigated the depigmentation effect of Amorpha fruticosa L. root extract (RE), an herbal medicine. A. fruticosa RE significantly induced depigmentation in α-MSH-treated B16F10 cells at noncytotoxic concentrations. Further, the RE decreased the protein levels of the melanosomal proteins Tyr and Pmel without decreasing their transcript levels. We found that MG132, a proteasome complex inhibitor, was unable to rescue the protein levels, but PepA/E-64D (a lysosomal enzyme inhibitor), 3-MA (a representative autophagy inhibitor), and ATG5 knockdown effectively rescued the protein levels and inhibited the depigmentation effect following RE treatment. Among rotenoids, amorphigenin composed in the RE was identified as a functional chemical that could induce depigmentation; whereas rapamycin, an mTOR inhibitor and a nonselective autophagy inducer, could not induce depigmentation, and amorphigenin effectively induced depigmentation through the degradation of melanosomal proteins. Amorphigenin activated AMPK without affecting mTOR, and knockdown of AMPK offset the whitening effect through degradation of melanosome proteins by amorphigenin. Results from this study suggested that amorphigenin can induce degradation of the melanosome through an AMPK-dependent autophagy process, and has the potential to be used as a depigmentation agent for the treatment of hyperpigmentation.
    Keywords:  AMPK; Amorpha fruticosa L.; amorphigenin; autophagy; depigmentation
    DOI:  https://doi.org/10.3390/cimb44070196
  18. J Cardiovasc Pharmacol. 2022 Jun 27.
    TRPV1 Protects Against Pressure Overload-Induced Cardiac Hypertrophy by Promoting Mitochondria-Associated Endoplasmic Reticulum Membranes.
    Yuxiang Wang, Xiuchuan Li, Xiaoli Xu, Xuemei Qu, Yongjian Yang.
       ABSTRACT: Transient receptor potential vanilloid type 1 (TRPV1) is a non-selective cation channel that mediates the relationship between mitochondrial function and pathological myocardial hypertrophy. However, its underlying mechanisms remain unclear. This study aimed to investigate whether TRPV1 activation improves the morphology and function of intracellular mitochondria to protect cardiomyocytes after pressure overload-induced myocardial hypertrophy. The myocardial hypertrophy model was established by performing transverse aortic constriction (TAC) surgery in C57BL/6J male mice. The data revealed that TRPV1 activation significantly reduced myocardial hypertrophy, promoted ejection fraction (EF) % and fractional shortening (FS) %, and decreased the left ventricular internal diameter in end-diastole (LVIDd) and left ventricular internal diameter in end-systole (LVIDs) after TAC. Moreover, in vitro experiments revealed that TRPV1 reduces cardiomyocyte area and improves mitochondrial function by promoting mitochondria-associated endoplasmic reticulum membranes (MAMs) formation in a phenylephrine (PE)-treated cardiomyocyte hypertrophy model. TRPV1 up-regulates the phosphorylation levels of AMP-activated protein kinase (AMPK) and expression of mitofusin2 (MFN2). TRPV1 function is blocked by single-stranded RNA interfering with silent interfering MFN2. And activation of TRPV1 reduced mitochondrial reactive oxygen species (ROS) caused by PE, while disruption of MAMs by siMFN2 abolished TRPV1-mediated mitochondrial protection. Our findings suggest that TRPV1 effectively protects against pressure overload-induced cardiac hypertrophy by promoting MAM formation and conserved mitochondrial function via the AMPK/MFN2 pathway in cardiomyocytes.
    DOI:  https://doi.org/10.1097/FJC.0000000000001301
  19. Curr Issues Mol Biol. 2022 Jun 26. 44(7): 2772-2782
    LC3B, mTOR, AMPK Are Molecular Targets for Neoadjuvant Chemotherapy in Gastric Cancers.
    Liudmila V Spirina, Alexandra V Avgustinovich, Olga V Bakina, Sergey G Afanas'ev, Maxim Yu Volkov, Amina Y Kebekbayeva.
      Autophagy plays a dual role in oncogenesis processes. On one hand, autophagy enhances the cell resistance to oncogenic factors, and on the other hand, it participates in the tumor progression. The aim of the study was to find the associations between the effectiveness of the FLOT regimen in resectable gastric cancers (GCs) with the key autophagy-related proteins. Materials and Methods: The study included 34 patients with morphologically verified gastric cancer. All patients had FLOT neoadjunvant chemotherapy (NACT) (fluorouracil, leucovorin, oxaliplatin, and docetaxel) followed by gastrectomy. The studied tissue material was the non-transformed and tumor tissues obtained during diagnostic video gastroscopy in patients before the start of the combined treatment and after surgical treatment, frozen after collection. The LC3B, mTOR, and AMPK expression was determined by real-time PCR. The content of the LC3B protein was determined by Western blotting analysis. Results: The mRNA level and the content of the LC3B protein were associated with the tumor stage and the presence of signet ring cells. The AMPK mRNA level was increased in patients with the T4N0-2M0 stage by 37.7 and 7.33 times, which was consequently compared with patients with the T2N0M0 and T3N0-1M0 stages. The opposite changes in the mTOR and AMPK in the GCs before anti-cancer therapy were noted. The tumor size and regional lymph node affections were associated with a decrease in the mTOR mRNA level. A decrease in the mTOR expression was accompanied by an increase in the AMPK expression in the GCs. The mTOR expression was reduced in patients with a cancer spreading; in contrast, AMPK grew with the tumor size. There was an increase in the LC3B expression, which can probably determine the response to therapy. An increase in LC3B mRNA before the start of treatment and the protein content in cancers after NACT with a decrease in therapy effectiveness was recorded. There was an increase in the protein level in patients with partial regression and stabilization by 3.65 and 5.78 times, respectively, when compared with patients with complete tumor regression was noted. Conclusions: The anticancer effectiveness in GCS is down to the LC3B, mTOR, and AMPK expression. These were found to be entire molecular targets affecting the cancer progression and metastasis as well as the NACT effectiveness.
    Keywords:  AMPK; LC3B; NACT; gastric cancer; mTOR
    DOI:  https://doi.org/10.3390/cimb44070190
  20. Nutrients. 2022 Jul 15. pii: 2903. [Epub ahead of print]14(14):
    Seabuckthorn Reverses High-Fat-Diet-Induced Obesity and Enhances Fat Browning via Activation of AMPK/SIRT1 Pathway.
    Yu Wang, Xuyang Gao, Xiaoyou Chen, Qiang Li, Xinrui Li, Junxing Zhao.
      Seabuckthorn possesses various bioactive compounds and exhibits several positive pharmacological activities. The present trial aims to determine the effect of seabuckthorn powder intake on high-fat diet (HFD)-induced obesity prevention in mice. The results suggest that seabuckthorn powder intake decreased body weight, fat mass, and circulating lipid levels, and improved insulin sensitivity in HFD-fed mice. Moreover, dietary seabuckthorn powder alleviated hepatic steatosis and hepatic lipid accumulation induced by the HFD. Furthermore, seabuckthorn exhibited obvious anti-inflammatory capacity in white adipose tissue (WAT) by regulating the abundance of inflammation-related cytokines, such as interleukins 4, 6, and 10; tumor necrosis factor α; and interferon-γ. More importantly, dietary seabuckthorn powder promoted a thermogenic program in BAT and induced beige adipocyte formation in iWAT in HFD-fed mice. Interestingly, we found that seabuckthorn powder effectively restored AMPK and SIRT1 activities in both BAT and iWAT in HFD-fed mice. Collectively, these results potentiate the application of seabuckthorn powder as a nutritional intervention strategy to prevent obesity and related metabolic diseases by promoting thermogenesis in BAT and improving beige adipocyte formation in WAT.
    Keywords:  AMPK; SIRT1; beige; brown adipose tissue; obesity; seabuckthorn
    DOI:  https://doi.org/10.3390/nu14142903
  21. Clocks Sleep. 2022 Jun 22. 4(3): 321-331
    Adipokines in Sleep Disturbance and Metabolic Dysfunction: Insights from Network Analysis.
    Zhikui Wei, You Chen, Raghu P Upender.
      Adipokines are a growing group of secreted proteins that play important roles in obesity, sleep disturbance, and metabolic derangements. Due to the complex interplay between adipokines, sleep, and metabolic regulation, an integrated approach is required to better understand the significance of adipokines in these processes. In the present study, we created and analyzed a network of six adipokines and their molecular partners involved in sleep disturbance and metabolic dysregulation. This network represents information flow from regulatory factors, adipokines, and physiologic pathways to disease processes in metabolic dysfunction. Analyses using network metrics revealed that obesity and obstructive sleep apnea were major drivers for the sleep associated metabolic dysregulation. Two adipokines, leptin and adiponectin, were found to have higher degrees than other adipokines, indicating their central roles in the network. These adipokines signal through major metabolic pathways such as insulin signaling, inflammation, food intake, and energy expenditure, and exert their functions in cardiovascular, reproductive, and autoimmune diseases. Leptin, AMP activated protein kinase (AMPK), and fatty acid oxidation were found to have global influence in the network and represent potentially important interventional targets for metabolic and sleep disorders. These findings underscore the great potential of using network based approaches to identify new insights and pharmaceutical targets in metabolic and sleep disorders.
    Keywords:  adipokine; cardiovascular disease; metabolic syndrome; network analysis; sleep disorder
    DOI:  https://doi.org/10.3390/clockssleep4030027
  22. Pharmaceuticals (Basel). 2022 Jun 30. pii: 810. [Epub ahead of print]15(7):
    Metabolic Action of Metformin.
    Izabela Szymczak-Pajor, Sylwia Wenclewska, Agnieszka Śliwińska.
      Metformin, a cheap and safe biguanide derivative, due to its ability to influence metabolism, is widely used as a first-line drug for type 2 diabetes (T2DM) treatment. Therefore, the aim of this review was to present the updated biochemical and molecular effects exerted by the drug. It has been well explored that metformin suppresses hepatic glucose production in both AMPK-independent and AMPK-dependent manners. Substantial scientific evidence also revealed that its action is related to decreased secretion of lipids from intestinal epithelial cells, as well as strengthened oxidation of fatty acids in adipose tissue and muscles. It was recognized that metformin's supra-therapeutic doses suppress mitochondrial respiration in intestinal epithelial cells, whereas its therapeutic doses elevate cellular respiration in the liver. The drug is also suggested to improve systemic insulin sensitivity as a result of alteration in gut microbiota composition, maintenance of intestinal barrier integrity, and alleviation of low-grade inflammation.
    Keywords:  glucose metabolism; hepatic gluconeogenesis; lipid metabolism; metformin
    DOI:  https://doi.org/10.3390/ph15070810
  23. Biomedicines. 2022 Jun 22. pii: 1477. [Epub ahead of print]10(7):
    The Role of Mitochondrial Metabolism, AMPK-SIRT Mediated Pathway, LncRNA and MicroRNA in Osteoarthritis.
    Hao-Yu Liu, Chi-Fen Chang, Cheng-Chang Lu, Shun-Cheng Wu, Bin Huang, Tsung-Lin Cheng, Sung-Yen Lin, Cheng-Jung Ho, Mon-Juan Lee, Chung-Da Yang, Ying-Chun Wang, Jhong-You Li, Ping-Cheng Liu, Chun-Wang Wei, Lin Kang, Chung-Hwan Chen.
      Osteoarthritis (OA) is the most common joint disease characterized by degeneration of articular cartilage and causes severe joint pain, physical disability, and impaired quality of life. Recently, it was found that mitochondria not only act as a powerhouse of cells that provide energy for cellular metabolism, but are also involved in crucial pathways responsible for maintaining chondrocyte physiology. Therefore, a growing amount of evidence emphasizes that impairment of mitochondrial function is associated with OA pathogenesis; however, the exact mechanism is not well known. Moreover, the AMP-activated protein kinase (AMPK)-Sirtuin (SIRT) signaling pathway, long non-coding RNA (lncRNA), and microRNA (miRNA) are important for regulating the physiological and pathological processes of chondrocytes, indicating that these may be targets for OA treatment. In this review, we first focus on the importance of mitochondria metabolic dysregulation related to OA. Then, we show recent evidence on the AMPK-SIRT mediated pathway associated with OA pathogenesis and potential treatment options. Finally, we discuss current research into the effects of lncRNA and miRNA on OA progression or inhibition.
    Keywords:  AMP-activated protein kinase (AMPK); long non-coding RNA (lncRNA); microRNA (miRNA); mitochondria; osteoarthritis; sirtuins (SIRT)
    DOI:  https://doi.org/10.3390/biomedicines10071477
  24. Nutrients. 2022 Jul 13. pii: 2864. [Epub ahead of print]14(14):
    Alginate Oligosaccharides Ameliorate DSS-Induced Colitis through Modulation of AMPK/NF-κB Pathway and Intestinal Microbiota.
    Yue Zhang, Congcong Guo, Yanru Li, Xianlei Han, Xuegang Luo, Liehuan Chen, Tongcun Zhang, Nan Wang, Weiming Wang.
      Alginate oligosaccharides (AOS) are shown to have various biological activities of great value to medicine, food, and agriculture. However, little information is available about their beneficial effects and mechanisms on ulcerative colitis. In this study, AOS with a polymerization degree between 2 and 4 were found to possess anti-inflammatory effects in vitro and in vivo. AOS could decrease the levels of nitric oxide (NO), IL-1β, IL-6, and TNFα, and upregulate the levels of IL-10 in both RAW 264.7 and bone-marrow-derived macrophage (BMDM) cells under lipopolysaccharide (LPS) stimulation. Additionally, oral AOS administration could significantly prevent bodyweight loss, colonic shortening, and rectal bleeding in dextran sodium sulfate (DSS)-induced colitis mice. AOS pretreatment could also reduce disease activity index scores and histopathologic scores and downregulate proinflammatory cytokine levels. Importantly, AOS administration could reverse DSS-induced AMPK deactivation and NF-κB activation in colonic tissues, as evidenced by enhanced AMPK phosphorylation and p65 phosphorylation inhibition. AOS could also upregulate AMPK phosphorylation and inhibit NF-κB activation in vitro. Moreover, 16S rRNA gene sequencing of gut microbiota indicated that supplemental doses of AOS could affect overall gut microbiota structure to a varying extent and specifically change the abundance of some bacteria. Medium-dose AOS could be superior to low- or high-dose AOS in maintaining remission in DSS-induced colitis mice. In conclusion, AOS can play a protective role in colitis through modulation of gut microbiota and the AMPK/NF-kB pathway.
    Keywords:  AMPK; NF-κB; alginate oligosaccharides; intestinal microbiota; ulcerative colitis
    DOI:  https://doi.org/10.3390/nu14142864
  25. Oxid Med Cell Longev. 2022 ;2022 5757367
    Astragaloside IV Protects Detrusor from Partial Bladder Outlet Obstruction-Induced Oxidative Stress by Activating Mitophagy through AMPK-ULK1 Pathway.
    Xiaoyu Zhu, Fangze Tao, Li Zhang, Yajie Yu, Yanchao Xu, Gang Yang, Zhifeng Wei, Yidong Cheng, Xuelai Yin, Xinyuan Zhang, Wu Wei, Anxi Wang.
       Aims: Bladder outlet obstruction (BOO) and the consequent low contractility of detrusor are the leading causes of voiding dysfunction. In this study, we aimed to evaluate the pharmacological activity of astragaloside IV (AS-IV), an antioxidant biomolecule that possess beneficial effect in many organs, on detrusor contractility and bladder wall remodeling process.
    Methods: Partial BOO (pBOO) was created by urethral occlusion in female rats, followed by oral gavage of different dose of AS-IV or vehicle. Cystometric evaluation and contractility test were performed. Bladder wall sections were used in morphology staining, and bladder tissue lysate was used for ELISA assay. Primary smooth muscle cells (SMCs) derived from detrusor were used for mechanism studies.
    Results: Seven weeks after pBOO, the bladder compensatory enlarged, and the contractility in response to electrical or chemical stimuli was reduced, while AS-IV treatment reversed this effect dose-dependently. AS-IV also showed beneficial effect on reversing the bladder wall remodeling process, as well as reducing ROS level. In mechanism study, AS-IV activated mitophagy and alleviated oxidative stress via an AMPK-dependent pathway.
    Conclusion: Out data suggested that AS-IV enhanced the contractility of detrusor and protected the bladder from obstruction induced damage, via enhancing the mitophagy and restoring mitochondria function trough an AMPK-dependent way.
    DOI:  https://doi.org/10.1155/2022/5757367
  26. Int J Mol Sci. 2022 Jul 08. pii: 7595. [Epub ahead of print]23(14):
    Beneficial Effects of Theaflavins on Metabolic Syndrome: From Molecular Evidence to Gut Microbiome.
    Meng Shi, Yuting Lu, Junling Wu, Zhibing Zheng, Chenghao Lv, Jianhui Ye, Si Qin, Chaoxi Zeng.
      In recent years, many natural foods and herbs rich in phytochemicals have been proposed as health supplements for patients with metabolic syndrome (MetS). Theaflavins (TFs) are a polyphenol hydroxyl substance with the structure of diphenol ketone, and they have the potential to prevent and treat a wide range of MetS. However, the stability and bioavailability of TFs are poor. TFs have the marvelous ability to alleviate MetS through antiobesity and lipid-lowering (AMPK-FoxO3A-MnSOD, PPAR, AMPK, PI3K/Akt), hypoglycemic (IRS-1/Akt/GLUT4, Ca2+/CaMKK2-AMPK, SGLT1), and uric-acid-lowering (XO, GLUT9, OAT) effects, and the modulation of the gut microbiota (increasing beneficial gut microbiota such as Akkermansia and Prevotella). This paper summarizes and updates the bioavailability of TFs, and the available signaling pathways and molecular evidence on the functionalities of TFs against metabolic abnormalities in vitro and in vivo, representing a promising opportunity to prevent MetS in the future with the utilization of TFs.
    Keywords:  TFs; bioavailability; gut microbiota; mechanism; metabolic syndrome
    DOI:  https://doi.org/10.3390/ijms23147595
  27. Eur J Obstet Gynecol Reprod Biol. 2022 Jul 14. pii: S0301-2115(22)00428-6. [Epub ahead of print]276 125-133
    Investigating the effect of Sulforaphane on AMPK/AKT/NRF2 pathway in human granulosa-lutein cells under H2O2-induced oxidative stress.
    Maryam Taheri, Nasim Hayati Roudbari, Fardin Amidi, Kazem Parivar.
      Excessive production of reactive oxygen species (ROS) in granulosa cells (GCs) plays a role in pathogenesis of polycystic ovarian syndrome (PCOS) by developing oxidative stress (OS). It was shown that Sulforaphane (SFN), with known antioxidant properties, can have protective effects in different diseases through affecting the nuclear factor (erythroid-derived 2)-like 2 (NRF2) signaling pathway. Thus, the purpose of the current work was to examine the protective impact of SFN through the activation of the AMPK/AKT/NRF2 pathway against OS produced by H2O2 in granulosa-lutein cells (GLCs). Individuals' GLCs were obtained during ovum retrieval in intracytoplasmic sperm injection (ICSI) cycles. First, the induced OS model was created in GLCs using H2O2 exposure. To examine the protective effect of SFN against OS, the cells were cultured for 24 h in presence or absence of SFN. Eventually, the levels of intracellular ROS and apoptosis were measured by flow cytometry, and genes and proteins expression levels of AMPK, AKT, and NRF2 were evaluated using qRT-PCR and western blotting. Compared to the control group, the levels of intracellular ROS and apoptosis rose dramatically in GLCs with enhanced OS. SFN therapy decreased ROS and apoptosis levels and increased the overexpression of AMPK, AKT, and NRF2 genes and proteins. This study's results revealed that SFN exposure results in the alleviation of ROS and apoptosis levels possibly through activating the overexpression of genes and proteins of AMPK, AKT, and NRF2, and exerts its protective effects against OS in GLCs.
    Keywords:  AMP-activated protein kinase; Granulosa cells; NF-E2-related factor 2; Oxidative stress; Sulforaphane
    DOI:  https://doi.org/10.1016/j.ejogrb.2022.07.006
  28. Nutrients. 2022 Jul 13. pii: 2877. [Epub ahead of print]14(14):
    Renoprotective Effect of Pediococcus acidilactici GKA4 on Cisplatin-Induced Acute Kidney Injury by Mitigating Inflammation and Oxidative Stress and Regulating the MAPK, AMPK/SIRT1/NF-κB, and PI3K/AKT Pathways.
    Wen-Hsin Lin, Wen-Ping Jiang, Chin-Chu Chen, Li-Ya Lee, You-Shan Tsai, Liang-Hsuan Chien, Ya-Ni Chou, Jeng-Shyan Deng, Guan-Jhong Huang.
      Acute kidney injury (AKI) describes a sudden loss of kidney function and is associated with a high mortality. Pediococcus acidilactici is a potent producer of bacteriocin and inhibits the growth of pathogens during fermentation and food storage; it has been used in the food industry for many years. In this study, the potential of P. acidilactici GKA4 (GKA4) to ameliorate AKI was investigated using a cisplatin-induced animal model. First, mice were given oral GKA4 for ten days and intraperitoneally injected with cisplatin on the seventh day to create an AKI mode. GKA4 attenuated renal histopathological alterations, serum biomarkers, the levels of inflammatory mediators, and lipid oxidation in cisplatin-induced nephrotoxicity. Moreover, GKA4 significantly decreased the expression of inflammation-related proteins and mitogen-activated protein kinase (MAPK) in kidney tissues. Eventually, GKA4 also increased the levels of related antioxidant enzymes and pathways. Consistently, sirtuin 1 (SIRT1) upregulated the level of autophagy-related proteins (LC3B, p62, and Beclin1). Further studies are needed to check our results and advance our knowledge of the mechanism whereby PI3K inhibition (wortmannin) reverses the effect of GKA4 on cisplatin-treated AKI. Taken together, GKA4 provides a therapeutic target with promising clinical potential after cisplatin treatment by reducing oxidative stress and inflammation via the MAPK, AMP-activated protein kinase (AMPK)/SIRT1/nuclear factor kappa B (NF-κB), and phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT) axes.
    Keywords:  Pediococcus acidilactici GKA4; acute kidney injury; anti-inflammation; cisplatin; oxidative stress
    DOI:  https://doi.org/10.3390/nu14142877
  29. Biochim Biophys Acta Mol Basis Dis. 2022 Jul 26. pii: S0925-4439(22)00179-X. [Epub ahead of print] 166508
    The ameliorating effects of metformin on disarrangement ongoing in gastrocnemius muscle of sarcopenic and obese sarcopenic mice.
    Qiong Lyu, Ya Wen, Bin He, Xiang Zhang, Jinliang Chen, Yue Sun, Yuxing Zhao, Lingjie Xu, Qian Xiao, Huisheng Deng.
      Sarcopenia and obese sarcopenia are increasingly prevalent chronic diseases with multifactorial pathogenesis, and no approved therapeutic drug to date. In the established sarcopenic mice models, muscle weakness, ectopic lipid deposition, and inflammatory responses in both serum and gastrocnemius muscle were observed, which were even deteriorated in obese sarcopenic models. With metformin intervention for 5 months, metformin exhibited benefits and restoring effects on gastrocnemius muscle of sarcopenic mice, but less effective on that of obese sarcopenic mice, as reflected in the increased percentage of muscle mass and enlarged fiber cross-sectional area, enhanced grip strength and exercise capacities, as well as the ameliorated ectopic lipid deposition and partially restored level of TNF-α, IL-1β, IL-6, MCP-1 and IL-1α, which may be via the activation of phospho-AMPKα (Thr172). The significant up-regulated mRNA and protein level of lipolysis related proteins like hormone-sensitive lipase (HSL) and adipose triglyceride lipase (ATGL) may contribute to the ameliorated ectopic lipid deposition with metformin intervention. The uptake of free fatty acid may be also inhibited in obese sarcopenic mice with metformin administration, as reflected in down-regulated mRNA and protein level of fatty acid transporter CD36. Furthermore, NF-κB signaling pathway was involved in the anti-inflammatory effect of metformin. These findings suggest that metformin treatment may be conducive to the prevention of age-related sarcopenia by regulating lipid metabolism in skeletal muscle, i.e. enhanced lipolysis and attenuated hyper-inflammatory responses, which may be AMPK-dependent processes. Moreover, high-fat diet would aggravate the damage to ageing in skeletal muscles and reduced their reactivity to metformin.
    Keywords:  AMPK; Ectopic lipid deposition; Inflammation; Metformin; Obese sarcopenia; Sarcopenia
    DOI:  https://doi.org/10.1016/j.bbadis.2022.166508
  30. J Physiol Biochem. 2022 Jul 30.
    Metformin induces mitochondrial remodeling and differentiation of pancreatic progenitor cells into beta-cells by a potential mechanism including suppression of the T1R3, PLCβ2, cytoplasmic Ca+2, and AKT.
    Ertan Celik, Merve Ercin, Sehnaz Bolkent, Selda Gezginci-Oktayoglu.
      The main goal of this study was to investigate the molecular changes in pancreatic progenitor cells subject to high glucose, aspartame, and metformin in vitro. This scope of work glucose, aspartame, and metformin were exposed to pancreatic islet derived progenitor cells (PID-PCs) for 10 days. GLUT1's role in beta-cell differentiation was examined by using GLUT1 inhibitor WZB117. Insulin+ cell ratio was measured by flow cytometry; the expression of beta-cell differentiation related genes was shown by RT-PCR; mitochondrial mass, mitochondrial ROS level, cytoplasmic Ca2+, glucose uptake, and metabolite analysis were made fluorometrically and spectrophotometrically; and proteins involved in related molecular pathways were determined by western blotting. Findings showed that glucose or aspartame exposed cells had similar metabolic and gene expression profile to control PID-PCs. Furthermore, relatively few insulin+ cells in aspartame treated cells were determined. Aspartame signal is transmitted through PLCβ2, CAMKK2 and LKB1 in PID-PCs. The most obvious finding of this study is that metformin significantly increased beta-cell differentiation. The mechanism involves suppression of the sweet taste signal's molecules T1R3, PLCβ2, cytoplasmic Ca+2, and AKT in addition to the direct effect of metformin on mitochondria and AMPK, and the energy metabolism of PID-PCs is remodelled in the direction of oxidative phosphorylation. These findings are very important in terms of determining that metformin stimulates the mitochondrial remodeling and the differentiation of PID-PCs to beta-cells and thus it may contribute to the compensation step, which is the first stage of diabetes development.
    Keywords:  Aspartame; Beta-cell differentiation; Glucose metabolism; Metformin; Mitochondrial remodeling; Pancreatic progenitor cells
    DOI:  https://doi.org/10.1007/s13105-022-00910-8
  31. Foods. 2022 Jul 24. pii: 2199. [Epub ahead of print]11(15):
    Effect of Coffee on Lipopolysaccharide-Induced Immortalized Human Oral Keratinocytes.
    Jianan Song, Byunggook Kim, Oksu Kim, Ying Yang, Danyang Liu, Wenqi Fu, Guowu Ma, Young Kim, Okjoon Kim.
      Periodontitis is a common inflammatory disease that is strongly influenced by dietary habits. Coffee is one of the most common dietary components; however, current research on the relationship between coffee consumption and periodontitis, as well as its underlying mechanisms, is limited. Based on a previous report, caffeine (CA) and chlorogenic acid (CGA) were formulated into artificial coffee (AC) for this experiment. Cell viability, prostaglandin E2 release, Western blotting, cellular reactive oxygen species (ROS) production, and NF-E2-related factor 2 (Nrf2) translocation analyses were performed to explore the effects of AC on lipopolysaccharide (LPS)-induced immortalized human oral keratinocytes (IHOKs) and elucidate their underlying mechanisms. AC pretreatment attenuated LPS-induced inflammatory mediator release, ROS production, and nuclear factor kappa B translocation in IHOKs. CA and CGA promoted AMP-activated protein kinase phosphorylation and down-regulated the nuclear factor-κB pathways to exert anti-inflammatory effects. Additionally, CGA promoted Nrf2 translocation and heme oxygenase-1 expression and showed anti-oxidative effects. Furthermore, AC, CA, and CGA components showed synergistic effects. Thus, we predict that coffee consumption may be beneficial for alleviating periodontitis. Moreover, the main coffee components CA and CGA seem to play a synergistic role in periodontitis.
    Keywords:  AMPK pathway; Nrf2/HO-1 pathway; artificial coffee; caffeine; chlorogenic acid; periodontitis
    DOI:  https://doi.org/10.3390/foods11152199
  32. Biomolecules. 2022 Jul 12. pii: 973. [Epub ahead of print]12(7):
    Atherosclerosis Plaque Reduction by Lycopene Is Mediated by Increased Energy Expenditure through AMPK and PPARα in ApoE KO Mice Fed with a High Fat Diet.
    Federica Mannino, Giovanni Pallio, Domenica Altavilla, Francesco Squadrito, Giovanna Vermiglio, Alessandra Bitto, Natasha Irrera.
      Lycopene is a carotenoid found in tomatoes that has potent antioxidant activity. The Mediterranean diet is particularly rich in lycopene, which has well-known beneficial effects on cardiovascular health. We tested the effects of lycopene extract in a group of 20 ApoE knockout mice, fed with a high fat western diet for 14 weeks. Starting from week 3 and up to week 14, the mice were randomly divided into two groups that received lycopene (n = 10) by oral suspension every day at the human equivalent dose of 60 mg/day (0.246 mg/mouse/day), or the vehicle solution (n = 10). The lycopene administration reduced triglycerides and cholesterol blood levels starting from week 6 and continuing through to the end of the experiment (p &lt; 0.001). This reduction was mediated by an enhanced liver expression of PPAR-α and AMPK-α and reduced SREBP levels (p &lt; 0.0001). As a histological red-out, the extent of atherosclerotic plaques and the intima-media thickness in the aorta were significantly reduced by lycopene. In this context, lycopene augmented the Nrf-2 positivity staining in the endothelium, thereby confirming that its antioxidant activity was mediated by this nuclear factor. The positive results obtained in this pre-clinical model further support the use of lycopene extracts to reduce atherosclerosis.
    Keywords:  PPARα; atherosclerosis; lycopene; nutraceuticals; oxidative stress
    DOI:  https://doi.org/10.3390/biom12070973
  33. Pharmaceuticals (Basel). 2022 Jul 23. pii: 912. [Epub ahead of print]15(8):
    Immunomodulatory and Antiaging Mechanisms of Resveratrol, Rapamycin, and Metformin: Focus on mTOR and AMPK Signaling Networks.
    Vincenzo Sorrenti, Francesca Benedetti, Alessandro Buriani, Stefano Fortinguerra, Giada Caudullo, Sergio Davinelli, Davide Zella, Giovanni Scapagnini.
      Aging results from the progressive dysregulation of several molecular pathways and mTOR and AMPK signaling have been suggested to play a role in the complex changes in key biological networks involved in cellular senescence. Moreover, multiple factors, including poor nutritional balance, drive immunosenescence progression, one of the meaningful aspects of aging. Unsurprisingly, nutraceutical and pharmacological interventions could help maintain an optimal biological response by providing essential bioactive micronutrients required for the development, maintenance, and the expression of the immune response at all stages of life. In this regard, many studies have provided evidence of potential antiaging properties of resveratrol, as well as rapamycin and metformin. Indeed, in vitro and in vivo models have demonstrated for these molecules a number of positive effects associated with healthy aging. The current review focuses on the mechanisms of action of these three important compounds and their suggested use for the clinical treatment of immunosenescence and aging.
    Keywords:  AMPK; aging; immunity; immunomodulators; immunosenescence; mTOR; metformin; rapamycin; resveratrol; signaling pathways
    DOI:  https://doi.org/10.3390/ph15080912
  34. Evid Based Complement Alternat Med. 2022 ;2022 2990843
    Curcumin Alleviates D-Galactose-Induced Cardiomyocyte Senescence by Promoting Autophagy via the SIRT1/AMPK/mTOR Pathway.
    Lei Yang, Jun Shi, Xiaowan Wang, Rong Zhang.
      Oxidative stress and impaired autophagy are the hallmarks of cardiac aging. However, there are no specific drugs available to prevent cardiac aging. Curcumin is a natural polyphenolic drug with antioxidant, antiaging, and autophagy-promoting effects. Here, we describe the preventive role of Curcumin in cardiac aging through the induction of autophagy and the restoration of autophagy via the SIRT1/AMPK/mTOR pathway. The number of cells positive for senescence-associated β-galactosidase, P53, P16, and intracellular ROS increased significantly in senescent cardiomyocytes, stimulated using D-galactose. Curcumin reversed this effect in a dose-dependent manner. Curcumin-induced autophagy increased the expression of SIRT1and phosphorylated AMPK and decreased phosphorylated mTOR in a dose-dependent manner. SIRT1-siRNA-mediated knockdown inhibited the antioxidation, antiaging, the promotion of autophagy, and the SIRT1/AMPK/mTOR pathway activation effect of curcumin. Therefore, curcumin could be an effective anticardiac aging drug.
    DOI:  https://doi.org/10.1155/2022/2990843
  35. Nutrients. 2022 Jul 25. pii: 3046. [Epub ahead of print]14(15):
    The Effect of Laminaria japonica on Metabolic Syndrome: A Systematic Review of Its Efficacy and Mechanism of Action.
    In-Seon Lee, Seok-Jae Ko, Yu Na Lee, Gahyun Lee, Hasanur Rahman, Bonglee Kim.
      Metabolic syndrome (MetS) is a medical condition characterized by abdominal obesity, insulin resistance, high blood pressure, and hyperlipidemia. An increase in the incidence of MetS provokes an escalation in health care costs and a downturn in quality of life. However, there is currently no cure for MetS, and the absence of immediate treatment for MetS has prompted the development of novel therapies. In accordance with recent studies, the brown seaweed Laminaria japonica (LJP) has anti-inflammatory and antioxidant properties, and so forth. LJP contains bioactive compounds used as food globally, and it has been used as a medicine in East Asian countries. We conducted a systematic review to examine whether LJP could potentially be a useful therapeutic drug for MetS. The following databases were searched from initiation to September 2021: PubMed, Web of Science, EMBASE, and Cochrane Central Register of Controlled Trials Library. Clinical trials and in vivo studies evaluating the effects of LJP on MetS were included. LJP reduces the oxidative stress-related lipid mechanisms, inflammatory cytokines and macrophage-related chemokines, muscle cell proliferation, and migration. Bioactive-glucosidase inhibitors reduce diabetic complications, a therapeutic target in obesity and type 2 diabetes. In obesity, LJP increases AMP-activated protein kinase and decreases acetyl-CoA carboxylase. Based on our findings, we suggest that LJP could treat MetS, as it has pharmacological effects on MetS.
    Keywords:  AMPK; Laminaria japonica; atherosclerosis; diabetes; metabolic syndrome; obesity
    DOI:  https://doi.org/10.3390/nu14153046
  36. Toxicol Res. 2022 Jul;38(3): 355-364
    Effect of 3-caffeoyl, 4-dihydrocaffeoylquinic acid from Salicornia herbacea on endothelial nitric oxide synthase activation via calcium signaling pathway.
    Gi Ho Lee, Seung Yeon Lee, Chuanfeng Zheng, Hoa Thi Pham, Chae Yeon Kim, Mi Yeon Kim, Eun Hee Han, Yong Pil Hwang, Hye Gwang Jeong.
      3-Caffeoyl-4-dicaffeoylquinic acid (CDCQ) is a natural chlorogenic acid isolated from Salicornia herbacea that protects against oxidative stress, inflammation, and cancer. Nitric oxide (NO) plays a physiologically beneficial role in the cardiovascular system, including vasodilation, protection of endothelial cell function, and anti-inflammation. However, the effect of CDCQ on NO production and eNOS phosphorylation in endothelial cells is unclear. We investigated the effect of CDCQ on eNOS phosphorylation and NO production in human endothelial cells, and the underlying signaling pathway. CDCQ significantly increased NO production and the phosphorylation of eNOS at Ser1177. Additionally, CDCQ induced phosphorylation of PKA, CaMKII, CaMKKβ, and AMPK. Interestingly, CDCQ increased the intracellular Ca2+ level, and L-type Ca2+ channel (LTCC) blockade significantly attenuated CDCQ-induced eNOS activity and NO production by inhibiting PKA, CaMKII, CaMKKβ, and AMPK phosphorylation. These results suggest that CDCQ increased eNOS phosphorylation and NO production by Ca2+-dependent phosphorylation of PKA, CaMKII, CaMKKβ, and AMPK. Our findings provide evidence that CDCQ plays a pivotal role in the activity of eNOS and NO production, which is involved in the protection of endothelial dysfunction.
    Keywords:  3-Caffeoyl-4-dicaffeoylquinic acid; Ca2+; L-type Ca2+ channel; Nitric oxide; eNOS
    DOI:  https://doi.org/10.1007/s43188-022-00121-9
  37. Mol Metab. 2022 Jul 21. pii: S2212-8778(22)00124-7. [Epub ahead of print] 101555
    The CARM1 transcriptome and arginine methylproteome mediate skeletal muscle integrative biology.
    Tiffany L vanLieshout, Derek W Stouth, Nicolas G Hartel, Goutham Vasam, Sean Y Ng, Erin K Webb, Irena A Rebalka, Andrew I Mikhail, Nicholas A Graham, Keir J Menzies, Thomas J Hawke, Vladimir Ljubicic.
       OBJECTIVE: Coactivator-associated arginine methyltransferase 1 (CARM1) catalyzes the methylation of arginine residues on target proteins to regulate critical processes in health and disease. A mechanistic understanding of the role(s) of CARM1 in skeletal muscle biology is only gradually emerging. The purpose of this study was to elucidate the function of CARM1 in regulating the maintenance and plasticity of skeletal muscle.
    METHODS: We used transcriptomic, methylproteomic, molecular, functional, and integrative physiological approaches to determine the specific impact of CARM1 in muscle homeostasis.
    RESULTS: Our data defines the occurrence of arginine methylation in skeletal muscle and demonstrates that this mark occurs on par with phosphorylation and ubiquitination. CARM1 skeletal muscle-specific knockout (mKO) mice displayed altered transcriptomic and arginine methylproteomic signatures with molecular and functional outcomes confirming remodeled skeletal muscle contractile and neuromuscular junction characteristics, which presaged decreased exercise tolerance. Moreover, CARM1 regulates AMPK-PGC-1α signalling during acute conditions of activity-induced muscle plasticity.
    CONCLUSIONS: This study uncovers the broad impact of CARM1 in the maintenance and remodelling of skeletal muscle biology.
    Keywords:  AMPK; PGC-1α; mitochondria; muscle plasticity; neuromuscular junction
    DOI:  https://doi.org/10.1016/j.molmet.2022.101555
  38. Antioxidants (Basel). 2022 Jun 27. pii: 1259. [Epub ahead of print]11(7):
    Puerarin Attenuates Oxidative Stress and Ferroptosis via AMPK/PGC1α/Nrf2 Pathway after Subarachnoid Hemorrhage in Rats.
    Yi Huang, Honggang Wu, Yongmei Hu, Chenhui Zhou, Jiawei Wu, Yiwen Wu, Haifeng Wang, Cameron Lenahan, Lei Huang, Sheng Nie, Xiang Gao, Jie Sun.
      Puerarin was shown to exert anti-oxidative and anti-ferroptosis effects in multiple diseases. The goal of this study was to explore the neuroprotective effect of puerarin on early brain injury (EBI) after subarachnoid hemorrhage (SAH) in rats. A total of 177 adult male Sprague Dawley rats were used. SAH was included via endovascular perforation. Intranasal puerarin or intracerebroventricular dorsomorphin (AMPK inhibitor) and SR18292 (PGC1α inhibitor) were administered. The protein levels of pAMPK, PGC1α, Nrf2, 4HNE, HO1, MDA, ACSL4, GSSG, and iron concentration in the ipsilateral hemisphere were significantly increased, whereas SOD, GPX4, and GSH were decreased at 24 h after SAH. Moreover, puerarin treatment significantly increased the protein levels of pAMPK, PGC1α, Nrf2, HO1, SOD, GPX4, and GSH, but decreased the levels of 4HNE, MDA, ACSL4, GSSG, and iron concentration in the ipsilateral hemisphere at 24 h after SAH. Dorsomorphin or SR18292 partially abolished the beneficial effects of puerarin exerted on neurological dysfunction, oxidative stress injury, and ferroptosis. In conclusion, puerarin improved neurobehavioral impairments and attenuated oxidative-stress-induced brain ferroptosis after SAH in rats. The neuroprotection acted through the activation of the AMPK/PGC1α/Nrf2-signaling pathway. Thus, puerarin may serve as new therapeutics against EBI in SAH patients.
    Keywords:  early brain injury; ferroptosis; oxidative stress; puerarin; subarachnoid hemorrhage
    DOI:  https://doi.org/10.3390/antiox11071259
  39. Cell Metab. 2022 Jul 19. pii: S1550-4131(22)00302-3. [Epub ahead of print]
    Phosphoproteomics of three exercise modalities identifies canonical signaling and C18ORF25 as an AMPK substrate regulating skeletal muscle function.
    Ronnie Blazev, Christian S Carl, Yaan-Kit Ng, Jeffrey Molendijk, Christian T Voldstedlund, Yuanyuan Zhao, Di Xiao, Andrew J Kueh, Paula M Miotto, Vanessa R Haynes, Justin P Hardee, Jin D Chung, James W McNamara, Hongwei Qian, Paul Gregorevic, Jonathan S Oakhill, Marco J Herold, Thomas E Jensen, Leszek Lisowski, Gordon S Lynch, Garron T Dodd, Matthew J Watt, Pengyi Yang, Bente Kiens, Erik A Richter, Benjamin L Parker.
      Exercise induces signaling networks to improve muscle function and confer health benefits. To identify divergent and common signaling networks during and after different exercise modalities, we performed a phosphoproteomic analysis of human skeletal muscle from a cross-over intervention of endurance, sprint, and resistance exercise. This identified 5,486 phosphosites regulated during or after at least one type of exercise modality and only 420 core phosphosites common to all exercise. One of these core phosphosites was S67 on the uncharacterized protein C18ORF25, which we validated as an AMPK substrate. Mice lacking C18ORF25 have reduced skeletal muscle fiber size, exercise capacity, and muscle contractile function, and this was associated with reduced phosphorylation of contractile and Ca2+ handling proteins. Expression of C18ORF25 S66/67D phospho-mimetic reversed the decreased muscle force production. This work defines the divergent and canonical exercise phosphoproteome across different modalities and identifies C18ORF25 as a regulator of exercise signaling and muscle function.
    Keywords:  AMPK; C18ORF25; exercise; phosphoproteomics; signaling; skeletal muscle
    DOI:  https://doi.org/10.1016/j.cmet.2022.07.003
  40. Pharmaceuticals (Basel). 2022 Jul 01. pii: 819. [Epub ahead of print]15(7):
    Bioactive Peptides and Exercise Modulate the AMPK/SIRT1/PGC-1α/FOXO3 Pathway as a Therapeutic Approach for Hypertensive Rats.
    Jou-Hsuan Ho, Rathinasamy Baskaran, Ming-Fu Wang, Hong-Siang Yang, Yun-Hsin Lo, Zuhair M Mohammedsaleh, Wan-Teng Lin.
      Peptides are fragments of fundamental protein sequences that may have health benefits in addition to basic dietary benefits. Recently, we have reported on the pharmacological benefits of alcalase potato protein hydrolysate (APPH) and bioactive peptides isolated from APPH. The aim was to evaluate the synergistic effect of exercise along with DIKTNKPVIF (DF) peptides in ameliorating hypertension in spontaneously hypertensive rat (SHR) rats. We examined ECG parameters, lipid profiles, cardiac markers, and histology, and quantified the proteins associated with fibrosis, hypertrophy, apoptosis, mitochondrial biogenesis, and longevity pathways. DF peptide administration, along with exercise, reduced the blood pressure and cardiac marker levels in serum. Furthermore, it also suppressed the expression of fibrosis markers COL1A1, CTGF, and uPA and downregulated cardiac-hypertrophy-associated markers such as calcineurin, NFATC3, GATA4, pGATA4 and BNP. Exercise synergistically increases the expression of IFG1, PI3K, and AKT cell-survival pathway proteins, along with DF administration. Moreover, AMPK/SIRT1/PGC-1α/FOXO3 pathway protein expression was increased with the combinatorial administration of DF and exercise. Our data suggest that exercise, along with DF peptides, act synergistically in alleviating hypertension by activating the mitochondrial biogenesis pathway.
    Keywords:  AMPK; bioactive peptide; exercise; hypertension; mitochondrial biogenesis
    DOI:  https://doi.org/10.3390/ph15070819
  41. Antioxidants (Basel). 2022 Jul 19. pii: 1403. [Epub ahead of print]11(7):
    Resistance to Obesity in SOD1 Deficient Mice with a High-Fat/High-Sucrose Diet.
    Atsushi Sato, Yasunaga Shiraishi, Toyokazu Kimura, Ayumu Osaki, Kazuki Kagami, Yasuo Ido, Takeshi Adachi.
      Metabolic syndrome (Mets) is an important condition because it may cause stroke and heart disease in the future. Reactive oxygen species (ROSs) influence the pathogenesis of Mets; however, the types of ROSs and their localization remain largely unknown. In this study, we investigated the effects of SOD1, which localize to the cytoplasm and mitochondrial intermembrane space and metabolize superoxide anion, on Mets using SOD1 deficient mice (SOD1-/-). SOD1-/- fed on a high-fat/high-sucrose diet (HFHSD) for 24 weeks showed reduced body weight gain and adipose tissue size compared to wild-type mice (WT). Insulin secretion was dramatically decreased in SOD1-/- fed on HFHSD even though blood glucose levels were similar to WT. Ambulatory oxygen consumption was accelerated in SOD1-/- with HFHSD; however, ATP levels of skeletal muscle were somewhat reduced compared to WT. Reflecting the reduced ATP, the expression of phosphorylated AMPK (Thr 172) was more robust in SOD1-/-. SOD1 is involved in the ATP production mechanism in mitochondria and may contribute to visceral fat accumulation by causing insulin secretion and insulin resistance.
    Keywords:  AMPK; ATP; SOD1; insulin secretion; metabolic syndrome; mitochondrial intermembrane space; oxygen consumption; superoxide anion
    DOI:  https://doi.org/10.3390/antiox11071403
  42. J Integr Med. 2022 Jul 25. pii: S2095-4964(22)00076-0. [Epub ahead of print]
    Xiaoyao San, a Chinese herbal formula, ameliorates depression-like behavior in mice through the AdipoR1/AMPK/ACC pathway in hypothalamus.
    Kai-Rui Tang, Xiao-Wei Mo, Xing-Yi Zhou, Yue-Yue Chen, Dong-Dong Liu, Liang-Liang He, Qing-Yu Ma, Xiao-Juan Li, Jia-Xu Chen.
       OBJECTIVE: Depression and metabolic disorders have overlapping psychosocial and pathophysiological causes. Current research is focused on the possible role of adiponectin in regulating common biological mechanisms. Xiaoyao San (XYS), a classic Chinese medicine compound, has been widely used in the treatment of depression and can alleviate metabolic disorders such as lipid or glucose metabolism disorders. However, the ability of XYS to ameliorate depression-like behavior as well as metabolic dysfunction in mice and the underlying mechanisms are unclear.
    METHODS: An in vivo animal model of depression was established by chronic social defeat stress (CSDS). XYS and fluoxetine were administered by gavage to the drug intervention group. Depression-like behaviors were analyzed by the social interaction test, open field test, forced swim test, and elevated plus maze test. Glucose levels were measured using the oral glucose tolerance test. The involvement of certain molecules was validated by immunofluorescence, histopathology, and Western blotting. In vitro, hypothalamic primary neurons were exposed to high glucose to induce neuronal damage, and the neuroprotective effect of XYS was evaluated by cell counting kit-8 assay. Immunofluorescence and Western blotting were used to evaluate the influences of XYS on adiponectin receptor 1 (AdipoR1), adenosine 5'-monophosphate-activated protein kinase (AMPK), acetyl-coenzyme A carboxylase (ACC) and other related proteins.
    RESULTS: XYS ameliorated CSDS-induced depression-like behaviors and glucose tolerance impairment in mice and increased the level of serum adiponectin. XYS also restored Nissl bodies in hypothalamic neurons in mice that exhibited depression-like behaviors and decreased the degree of neuronal morphological damage. In vivo and in vitro studies indicated that XYS increased the expression of AdipoR1 in hypothalamic neurons.
    CONCLUSION: Adiponectin may be a key regulator linking depression and metabolic disorders; regulation of the hypothalamic AdipoR1/AMPK/ACC pathway plays an important role in treatment of depression by XYS.
    Keywords:  Adiponectin; Adiponectin receptor 1; Chronic social defeat stress; Depression; Glucose metabolism disorders; Xiaoyao San
    DOI:  https://doi.org/10.1016/j.joim.2022.07.003
  43. Molecules. 2022 Jul 25. pii: 4765. [Epub ahead of print]27(15):
    Elecampane (Inula helenium) Root Extract and Its Major Sesquiterpene Lactone, Alantolactone, Inhibit Adipogenesis of 3T3-L1 Preadipocytes.
    Yeon-Seop Jung, Yun-Jeong Jeong, Joung-Hee Kim, Chang-Hwan Jeon, Syng-Ook Lee.
      Recent studies have shown that Nur77 and AMPKα play an important role in regulating adipogenesis and isoalantolactone (ISO) dual-targeting AMPKα and Nur77 inhibits adipogenesis. In this study, we hypothesized that Inula helenium (elecampane) root extract (IHE), which contains two sesquiterpene lactones, alantolactone (ALA) and ISO, as major compounds, might inhibit adipogenesis. Here, we found that ALA and IHE simultaneously target AMPKα and Nur77 and inhibited adipogenic differentiation of 3T3-L1 cells, accompanied by the decreased expression of adipocyte markers. Further mechanistic studies demonstrated that IHE shares similar mechanisms of action with ISO that reduce mitotic clonal expansion during the early phase of adipogenic differentiation and decrease expression of cell cycle regulators. These results suggest that IHE inhibits adipogenesis, in part, through co-regulation of AMPKα and Nur77, and has potential as a therapeutic option for obesity and related metabolic dysfunction.
    Keywords:  AMPKα; Inula helenium; Nur77; adipogenesis; alantolactone; elecampane
    DOI:  https://doi.org/10.3390/molecules27154765
  44. Adv Exp Med Biol. 2022 ;1370 305-309
    Effect of Taurine on the Regulation of Glucose Uptake in the Skeletal Muscle.
    Song-Gyu Ra.
      Diabetes is so common in Japan as to be called a national disease. Taurine, a free amino acid found abundantly in mammalian tissues that is also a key ingredient of many "energy drinks," has been shown to be effective in improving the hyperglycemic state caused by diabetes. Taurine administration is associated with increased insulin secretion from the pancreas, higher levels of insulin signaling-related factors, and higher expression of the glucose transporter, GLUT4. Skeletal muscle is the main target organ of insulin: Via cell surface GLUT4 molecules, myocytes take up blood glucose, enabling skeletal muscle contraction. The enhancing effect of taurine on blood glucose uptake in skeletal muscle has not been fully studied, and little is known about its mechanism. This review article summarizes what is known about the effects of taurine on insulin secretion from the pancreas and especially blood glucose uptake in skeletal muscle.
    Keywords:  AMPK; Exercise; GLUT4; TXNIP
    DOI:  https://doi.org/10.1007/978-3-030-93337-1_29
  45. Sci Adv. 2022 Jul 29. 8(30): eabm7355
    Evidence for a neuromuscular circuit involving hypothalamic interleukin-6 in the control of skeletal muscle metabolism.
    Carlos Kiyoshi Katashima, Thayana de Oliveira Micheletti, Renata Rosseto Braga, Rodrigo Stellzer Gaspar, Ludger J E Goeminne, Alexandre Moura-Assis, Barbara Moreira Crisol, Rafael S Brícola, Vagner Ramon R Silva, Camila de Oliveira Ramos, Alisson L da Rocha, Mariana Rosolen Tavares, Fernando Moreira Simabuco, Valquiria Aparecida Matheus, Lucas Buscaratti, Henrique Marques-Souza, Patricia Pazos, David Gonzalez-Touceda, Sulay Tovar, María Del Carmen García, Jose Cesar Rosa Neto, Rui Curi, Sandro Massao Hirabara, Patrícia Chakur Brum, Patrícia Oliveira Prada, Leandro P de Moura, José Rodrigo Pauli, Adelino S R da Silva, Dennys Esper Cintra, Licio A Velloso, Eduardo Rochete Ropelle.
      Hypothalamic interleukin-6 (IL6) exerts a broad metabolic control. Here, we demonstrated that IL6 activates the ERK1/2 pathway in the ventromedial hypothalamus (VMH), stimulating AMPK/ACC signaling and fatty acid oxidation in mouse skeletal muscle. Bioinformatics analysis revealed that the hypothalamic IL6/ERK1/2 axis is closely associated with fatty acid oxidation- and mitochondrial-related genes in the skeletal muscle of isogenic BXD mouse strains and humans. We showed that the hypothalamic IL6/ERK1/2 pathway requires the α2-adrenergic pathway to modify fatty acid skeletal muscle metabolism. To address the physiological relevance of these findings, we demonstrated that this neuromuscular circuit is required to underpin AMPK/ACC signaling activation and fatty acid oxidation after exercise. Last, the selective down-regulation of IL6 receptor in VMH abolished the effects of exercise to sustain AMPK and ACC phosphorylation and fatty acid oxidation in the muscle after exercise. Together, these data demonstrated that the IL6/ERK axis in VMH controls fatty acid metabolism in the skeletal muscle.
    DOI:  https://doi.org/10.1126/sciadv.abm7355
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