bims-amsmem 2022-07-24 papers

bims-amsmem

Biomed News

on AMPK signaling mechanism in energy metabolism

Issue of 2022–07–24
25 papers selected by
Dipsikha Biswas, Københavns Universitet

AMPK Activation Alleviates Myocardial Ischemia-Reperfusion Injury by Regulating Drp1-Mediated Mitochondrial Dynamics.
Nutrient Condition in the Microenvironment Determines Essential Metabolisms of CD8+ T Cells for Enhanced IFNγ Production by Metformin.
High Glucose Accelerates Tumor Progression by Regulating MEDAG-Mediated Autophagy Levels in Breast Cancer.
Metformin mitigates stress-induced premature senescence by upregulating AMPKα at Ser485 phosphorylation induced SIRT3 expression and inactivating mitochondrial oxidants.
Salt-inducible kinases: new players in pulmonary arterial hypertension?
Naringenin promoted spinal microglia M2 polarization in rat model of cancer-induced bone pain via regulating AMPK/PGC-1α signaling axis.
Ameliorated effects of a lipopeptide surfactin on insulin resistance in vitro and in vivo.
The Effect of PRKAA2 Variation on Type 2 Diabetes Mellitus in the Asian Population: A Systematic Review and Meta-Analysis.
[Protective effect of salidroside on high fat-induced apoptosis in H9c2 cardiomyocytes through AMPK/mTOR/p70S6K pathway].
Role of AMPK/mTOR, mitochondria, and ROS in the pathogenesis of endometriosis.
Retraction notice to "Vitexin alleviates ox-LDL-mediated endothelial injury by inducingautophagy via AMPK signaling activation" [Mol. Immunol. 85 (2017) 214-221].
Metformin Alleviates Delayed Hydrocephalus after Intraventricular Hemorrhage by Inhibiting Inflammation and Fibrosis.
Impaired AMP-Activated Protein Kinase Signaling in Heart Failure With Preserved Ejection Fraction-Associated Atrial Fibrillation.
Anisomycin inhibits angiogenesis, growth, and survival of triple-negative breast cancer through mitochondrial dysfunction, AMPK activation, and mTOR inhibition.
AMPK-PPARγ-Cidec Axis Drives the Fasting-Induced Lipid Droplet Aggregation in the Liver of Obese Mice.
Notch-activated mesenchymal stromal/stem cells enhance the protective effect against acetaminophen-induced acute liver injury by activating AMPK/SIRT1 pathway.
[Hyperinsulinemia and age-related diseases: interrelations and approaches to treatment].
Periplocin Induces Apoptosis of Pancreatic Cancer Cells through Autophagy via the AMPK/mTOR Pathway.
Baicalin Induced Apoptosis of Human Cholangiocarcinoma Cell through Activating AMPK/mTORC1/p70S6K Signaling Pathway.
Nootkatone, a Sesquiterpene Ketone From Alpiniae oxyphyllae Fructus, Ameliorates Metabolic-Associated Fatty Liver by Regulating AMPK and MAPK Signaling.
Ketamine Promotes LPS-Induced Pulmonary Autophagy and Reduces Apoptosis through the AMPK/mTOR Pathway.
Inhibition of AMPK/PFKFB3 mediated glycolysis synergizes with penfluridol to suppress gallbladder cancer growth.
Mitochondrial function and nutrient sensing pathways in ageing: enhancing longevity through dietary interventions.
The autophagy inducer trehalose stimulates macropinocytosis in NF1-deficient glioblastoma cells.
New insights into anti-diabetes effects and molecular mechanisms of dietary saponins.

Front Pharmacol. 2022 ;13 862204

AMPK Activation Alleviates Myocardial Ischemia-Reperfusion Injury by Regulating Drp1-Mediated Mitochondrial Dynamics.

Jingxia Du, Hongchao Li, Jingjing Song, Tingting Wang, Yibo Dong, An Zhan, Yan Li, Gaofeng Liang.

  Mitochondrial dysfunction is a salient feature of myocardial ischemia/reperfusion injury (MIRI), while the potential mechanism of mitochondrial dynamics disorder remains unclear. This study sought to explore whether activation of Adenosine monophosphate-activated protein kinase (AMPK) could alleviate MIRI by regulating GTPase dynamin-related protein 1 (Drp1)-mediated mitochondrial dynamics. Isolated mouse hearts in a Langendorff perfusion system were subjected to ischemia/reperfusion (I/R) treatment, and H9C2 cells were subjected to hypoxia /reoxygenation (H/R) treatment in vitro. The results showed that AICAR, the AMPK activator, could significantly improve the function of left ventricular, decrease arrhythmia incidence and myocardial infarction area of isolated hearts. Meanwhile, AICAR increased superoxide dismutase (SOD) activity and decreased malondialdehyde (MDA) content in myocardial homogenate. Mechanistically, AICAR inhibited the phosphorylation of Drp1 at Ser 616 while enhanced phosphorylation of Drp1 at Ser 637. In addition, AICAR reduced the expression of inflammatory cytokines including TNF-ɑ, IL-6, and IL-1β, as well as mitochondrial fission genes Mff and Fis1, while improved the expression of mitochondrial fusion genes Mfn1 and Mfn2. Similar results were also observed in H9C2 cells. AICAR improved mitochondrial membrane potential (MMP), reduced reactive oxygen species (ROS) production, and inhibited mitochondrial damage. To further prove if Drp1 regulated mitochondrial dynamics mediated AMPK protection effect, the mitochondrial fission inhibitor Mdivi-1 was utilized. We found that Mdivi-1 significantly improved MMP, inhibited ROS production, reduced the expression of TNF-a, IL-6, IL-1β, Fis1, and Mff, and improved the expression of Mfn1 and Mfn2. However, the protection effect of Mdivi-1 was not reversed by AMPK inhibitor Compound C. In conclusion, this study confirmed that activation of AMPK exerted the protective effects on MIRI, which were largely dependent on the inhibition of Drp1-mediated mitochondrial fission.

Keywords:  AMPK; DRP1; ROS; inflammatory factors; mitochondrial dynamics; myocardial ischemia/reperfusion injury

DOI:  https://doi.org/10.3389/fphar.2022.862204
Front Immunol. 2022 ;13 864225

Nutrient Condition in the Microenvironment Determines Essential Metabolisms of CD8+ T Cells for Enhanced IFNγ Production by Metformin.

Ruoyu Chao, Mikako Nishida, Nahoko Yamashita, Miho Tokumasu, Weiyang Zhao, Ikuru Kudo, Heiichiro Udono.

  Metformin (Met), a first-line drug for type 2 diabetes, lowers blood glucose levels by suppressing gluconeogenesis in the liver, presumably through the liver kinase B1-dependent activation of AMP-activated protein kinase (AMPK) after inhibiting respiratory chain complex I. Met is also implicated as a drug to be repurposed for cancers; its mechanism is believed identical to that of gluconeogenesis inhibition. However, AMPK activation requires high Met concentrations at more than 1 mM, which are unachievable in vivo. The immune-mediated antitumor response might be the case in a low dose Met. Thus, we proposed activating or expanding tumor-infiltrating CD8+ T cells (CD8TILs) in a mouse model by orally administering Met in free drinking water. Here we showed that Met, at around 10 μM and a physiologically relevant concentration, enhanced production of IFNγ,TNFα and expression of CD25 of CD8+ T cells upon TCR stimulation. Under a glucose-rich condition, glycolysis was exclusively involved in enhancing IFNγ production. Under a low-glucose condition, fatty acid oxidation or autophagy-dependent glutaminolysis, or both, was also involved. Moreover, phosphoenolpyruvate carboxykinase 1 (PCK1), converting oxaloacetate to phosphoenolpyruvate, became essential. Importantly, the enhanced IFNγ production was blocked by a mitochondrial ROS scavenger and not by an inhibitor of AMPK. In addition, IFNγ production by CD8TILs relied on pyruvate translocation to the mitochondria and PCK1. Our results revealed a direct effect of Met on IFNγ production of CD8+ T cells that was dependent on differential metabolic pathways and determined by nutrient conditions in the microenvironment.

Keywords:  CD8+ T lymphocytes; FAO; IFNg; autophagy +T; glutaminolysis; glycolysis; metformin

DOI:  https://doi.org/10.3389/fimmu.2022.864225
Int J Biol Sci. 2022 ;18(11): 4289-4300

High Glucose Accelerates Tumor Progression by Regulating MEDAG-Mediated Autophagy Levels in Breast Cancer.

Chenyuan Li, Si Sun, Yi Tu, Hanpu Zhang, Feng Yao, Shichong Liao, Shengrong Sun, Zhiyu Li, Zhong Wang.

  Recent studies have shown that diabetes is a major risk factor for breast cancer (BC), but the mechanism is incompletely understood. Mesenteric estrogen-dependent adipogenesis (MEDAG) plays a significant role in both glucose uptake and BC development. However, the relationship between MEDAG and BC under high glucose (HG) conditions remains unclear. In our study, MEDAG expression was higher in BC tissue from diabetic patients than in BC tissue from nondiabetic patients. HG promoted BC progression in vitro and in vivo by upregulating MEDAG expression. Furthermore, MEDAG deficiency increased the autophagosome number and autophagic flux. Moreover, inhibition of autophagy partially reversed MEDAG knockdown (MEDAGKD)-induced suppression of tumorigenic biological behaviors and epithelial-mesenchymal transition (EMT) progression. Finally, MEDAG significantly suppressed AMPK phosphorylation. Additionally, the AMPK inhibitor Compound C markedly reduced autophagosome accumulation and antitumor effects in MEDAGKD cells. Treatment with the AMPK activator AICAR exhibited similar effects in MEDAG-overexpressing (MEDAGOE) cells. In conclusion, the MEDAG-AMPK-autophagy axis is vital to BC progression in diabetic patients. Our findings provide a novel treatment target for BC in patients with diabetes.

Keywords:  AMPK signaling; EMT; MEDAG; breast cancer; diabetes

DOI:  https://doi.org/10.7150/ijbs.70002
Mech Ageing Dev. 2022 Jul 18. pii: S0047-6374(22)00090-2. [Epub ahead of print] 111708

Metformin mitigates stress-induced premature senescence by upregulating AMPKα at Ser485 phosphorylation induced SIRT3 expression and inactivating mitochondrial oxidants.

Jin Young Sung, Seul Gi Kim, Young Jin Kang, Hyoung Chul Choi.

  The senescence of vascular smooth muscle cells (VSMCs) is an important cause of cardiovascular disease such as atherosclerosis and hypertension. These senescence may be triggered by many factors, such as oxidative stress, inflammation, DNA damage, and senescence-associated secretory phenotypes (SASPs). Mitochondrial oxidative stress induces cellular senescence, but the mechanisms by which mitochondrial reactive oxygen species (mtROS) regulates cellular senescence are still largely unknown. Here, we investigated the mechanism responsible for the anti-aging effect of metformin by examining links between VSMC senescence and mtROS in in vitro and in vivo. Metformin was found to increase p-AMPK (Ser485), but to decrease senescence-associated phenotypes and protein levels of senescence markers during ADR-induced VSMC senescence. Importantly, metformin decreased mtROS by inducing the deacetylation of superoxide dismutase 2 (SOD2) by increasing SIRT3 expression. Moreover, AMPK depletion reduced the expression of SIRT3 and increased the expression of acetylated SOD2 despite metformin treatment, suggesting AMPK activation by metformin is required to protect against mitochondrial oxidative stress by SIRT3. This study provides mechanistic evidence that metformin acts as an anti-aging agent and alleviates VSMC senescence by upregulating mitochondrial antioxidant induced p-AMPK (Ser485)-dependent SIRT3 expression, which suggests metformin has therapeutic potential for the treatment of age-associated vascular disease.

Keywords:  Metformin; SIRT3; SOD2 acetylation; VSMC senescence; mitochondrial ROS; p-AMPK (Ser485)

DOI:  https://doi.org/10.1016/j.mad.2022.111708
Trends Pharmacol Sci. 2022 Jul 15. pii: S0165-6147(22)00135-3. [Epub ahead of print]

Salt-inducible kinases: new players in pulmonary arterial hypertension?

Tatiana António, Patrício Soares-da-Silva, Nuno M Pires, Pedro Gomes.

  Salt-inducible kinases (SIKs) are serine/threonine kinases belonging to the AMP-activated protein kinase (AMPK) family. Accumulating evidence indicates that SIKs phosphorylate multiple targets, including histone deacetylases (HDACs) and cAMP response element-binding protein (CREB)-regulated transcriptional coactivators (CRTCs), to coordinate signaling pathways implicated in metabolism, cell growth, proliferation, apoptosis, and inflammation. These pathways downstream of SIKs are altered not only in pathologies like cancer, systemic hypertension, and inflammatory diseases, but also in pulmonary arterial hypertension (PAH), a multifactorial disease characterized by pulmonary vasoconstriction, inflammation and remodeling of pulmonary arteries owing to endothelial dysfunction and aberrant proliferation of smooth muscle cells (SMCs). In this opinion article, we present evidence of SIKs as modulators of key signaling pathways involved in PAH pathophysiology and discuss the potential of SIKs as therapeutic targets for PAH, emphasizing the need for deeper molecular insights on PAH.

Keywords:  AMPK; cancer; inflammation; pulmonary arterial hypertension; salt-inducible kinases; signaling pathways

DOI:  https://doi.org/10.1016/j.tips.2022.06.008
Biomed Pharmacother. 2022 May;pii: S0753-3322(22)00301-8. [Epub ahead of print]149 112912

Naringenin promoted spinal microglia M2 polarization in rat model of cancer-induced bone pain via regulating AMPK/PGC-1α signaling axis.

Meng-Meng Ge, Dan-Yang Li, Lu Wang, Long-Qing Zhang, Dai-Qiang Liu, Yu-Ke Tian, Da-Wei Ye, Zhi-Heng Liu, Ya-Qun Zhou, Hui Yang.

  Cancer-induced bone pain (CIBP) treatment remains a clinical challenge because the pathophysiological mechanisms are not fully understood. Recently, it was verified that shifting microglial polarization toward the M2 phenotype reveals a potential strategy for CIBP treatment. Naringenin, a natural flavone flavonoid, has been reported to have antioxidant, anti-inflammatory and neuroprotective properties. However, the role of naringenin on regulating microglial polarization in CIBP rats and the molecular mechanisms participating in this process have not been fully clarified. Herein, we investigated the potential effect of naringenin on M1/M2 microglial polarization and further explored the potential mechanisms of this action. Our study demonstrated that intraperitoneal administration of naringenin could upregulate the antioxidative molecule glutathione peroxidase 4 (GPx4) level in the spinal cord, as well as bone cancer-induced mechanical allodynia in rats. Moreover, naringenin treatment also suppressed microglia-mediated neuroinflammation by downregulating the phosphorylation of nuclear factor κB (NF-κB) p65 expression and promoting microglial polarization toward the M2 phenotype in CIBP rats. The promoting effects mediated by naringenin on M1/M2 microglial polarization are dependent on the serine/threonine protein kinase adenosine monophosphate-activated protein kinase (AMPK)/proliferator-activated receptor γ coactivator-1α (PGC-1α) signaling pathway. Inhibition of AMPK activation with the classical AMPK inhibitor Compound C attenuated this effect of naringenin. These results improved the understanding of the anti-inflammatory property of naringenin on microglial polarization, which might provide new alternative avenues for CIBP treatment.

Keywords:  Cancer-induced bone pain; Microglial polarization; Naringenin; Oxidative stress

DOI:  https://doi.org/10.1016/j.biopha.2022.112912
Food Sci Nutr. 2022 Jul;10(7): 2455-2469

Ameliorated effects of a lipopeptide surfactin on insulin resistance in vitro and in vivo.

Xiaoyu Chen, Hongyuan Zhao, Fanqiang Meng, Libang Zhou, Xinyi Pang, Zhaoxin Lu, Yingjian Lu.

  Surfactin, produced by Bacillus amyloliquefaciens fmb50, was used to treat insulin-resistant (IR) hepatocyte. It was found that surfactin increased glucose consumption in insulin-resistant HepG2 (IR-HepG2) cells and ameliorated IR by increasing glucose transporter 4 (GLUT4) protein expression and AMP-activated protein kinase (AMPK) mRNA expression, promoting GLUT4 translocation and activating phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt) in IR-HepG2 cells. Meanwhile, surfactin downregulated protein expression of phosphoenolpyruvate carboxy kinase (PEPCK) and glucose-6-phosphatase (G6Pase), further inhibiting hepatic gluconeogenesis. In addition, surfactin played important roles in eliminating reactive oxygen species (ROS), improving mitochondrial dysfunction, and inhibiting proinflammatory mediators. We observed that surfactin promoted glucose consumption, meanwhile increased translocation and protein expression of GLUT4 in Caco-2 cells. These results confirmed the conclusion in hepatic cells. Furthermore, surfactin supplement decreased body weight, food intake, and fasting blood glucose of type 2 diabetes mellitus (T2DM) mice induced by streptozotocin (STZ)/high-fat diet (HFD). Our data indicated that surfactin ameliorated insulin resistance and lowered blood glucose in intro and in vivo.

Keywords:  GLUT4; PI3K/Akt pathway; inflammation; insulin resistance; oxidative stress; surfactin

DOI:  https://doi.org/10.1002/fsn3.2852
Malays J Med Sci. 2022 Jun;29(3): 5-16

The Effect of PRKAA2 Variation on Type 2 Diabetes Mellitus in the Asian Population: A Systematic Review and Meta-Analysis.

Dita Maria Virginia, Iwan Dwiprahasto, Mae Sri Hartati Wahyuningsih, Dwi Aris Agung Nugrahaningsih.

  The prevalence of type 2 diabetes mellitus (T2DM) is increasing among Asians. The adenosine monophosphate-activated protein kinase (AMPK) increases T2DM risk through insulin resistance. Glucose levels are related to AMPK subunit α2 encoded by PRKAA2. This systematic review and meta-analysis aimed to analyse the association between PRKAA2 variation and T2DM risk. Publication search related to PRKAA2 and T2DM used PubMed, ProQuest, and ScienceDirect databases. Article selection based on inclusion and exclusion criteria only included Japanese and Chinese populations. This meta-analysis used five genotype models to estimate the effect of PRKAA2 variation and T2DM risk. Additionally, a fixed-effect model was selected to measure the pooled size effect if P > 0.05 or I2 < 50%. Qualitative analysis included four eligible studies, and meta-analysis included only two studies because both showed data concerning rs2746342 variation. Patients with G allele are 1.45 times more likely to have T2DM than patients with T allele (95% confidence interval [CI]: 1.20, 1.76; P: 0.0001). Notably, patients who had GG genotype have 1.96 times higher risk of T2DM compared with those with TT genotype (95% CI: 1.34, 2.87; P: 0.0005), dominant model (odds ratio [OR]: 1.75; 95% CI: 1.32, 2.31; P: 0.001), and recessive model (OR: 1.43; 95% CI: 1.01, 2.01; P: 0.04). PRKAA2 variation, especially in rs2746342, has an association with T2DM risk in the G allele, additive, dominant, and recessive models. G allele might be the most contributable factor in increasing T2DM susceptibility.

Keywords:  AMP-activated protein kinase; Asian; genetic variation; risk factor; type 2 diabetes mellitus

DOI:  https://doi.org/10.21315/mjms2022.29.3.2
Zhongguo Zhong Yao Za Zhi. 2022 Jul;47(14): 3837-3843

[Protective effect of salidroside on high fat-induced apoptosis in H9c2 cardiomyocytes through AMPK/mTOR/p70S6K pathway].

Mei-Zhu Wu, Yun Xiang, Cui-Yu Bao, Tao Liu.

  The study explored the effect of salidroside(SAL) on high fat-induced apoptosis in H9 c2 cardiomyocytes based on AMPK/mTOR/p70 S6 K pathway.H9 c2 cardiomyocytes were cultured in vitro and the lipotoxicity model of H9 c2 cardiomyocytes was constructed by 0.2 mmol·L~(-1) palmitic acid(PA) treatment for 24 hours.The cells were divided into control group, PA group, and SAL group(20 μmol·L~(-1)).Cell proliferation was detected with cell proliferation kit I(MTT) assay after SAL and PA treatment.Dihydroethidium(DHE) probe, Annexin V-FITC/PI kit, and JC-1 probe were used to estimate reactive oxygen species(ROS) level, cell apoptosis, and mitochondrial membrane potential(MMP) change, respectively.The expression levels of p-AMPK/AMPK, p-mTOR/mTOR, p-p70 S6 K/p70 S6 K and apoptosis-related proteins Bax, Bcl-2, and cleaved caspase-3 were investigated with Western blot.The mRNA levels of AMPK, mTOR and p70 S6 K were determined by quantitative reverse transcription-polymerase chain reaction(qRT-PCR).RESULTS:: showed that compared with control group, PA group had decreased cell proliferation ability, MMP, Bcl-2 protein expression and AMPK protein and mRNA expression, while increased ROS level, Bax and cleaved caspase-3 protein expression, and mTOR and p70 S6 K mRNA and protein expression, and the difference was statistically significant(P<0.05, P<0.01).Compared with PA group, SAL improved cell proliferation ability, MMP level, Bcl-2 protein expression, and AMPK mRNA and protein expression, while down-regulated ROS level, cell apoptosis, Bax and cleaved caspase-3 protein expression, and mTOR and p70 S6 K mRNA and protein expression, and the difference was statistically significant(P<0.05, P<0.01).In conclusion, SAL exerted protective effects on high fat-induced lipotoxicity of H9 c2 cardiomyocytes, alleviated the oxidative stress injury and reduced cell apoptosis via regulating AMPK/mTOR/p70 S6 K signaling pathway.

Keywords:  AMPK; H9c2 cardiomyocyte; high fat; mTOR; p70S6K; salidroside(SAL)

DOI:  https://doi.org/10.19540/j.cnki.cjcmm.20220224.401
Life Sci. 2022 Jul 15. pii: S0024-3205(22)00505-7. [Epub ahead of print] 120805

Role of AMPK/mTOR, mitochondria, and ROS in the pathogenesis of endometriosis.

Lama Assaf, Assaad A Eid, Joseph Nassif.

  Endometriosis is the presence of endometrial tissue outside the uterine cavity usually in the ovaries, fallopian tube, and pelvic cavity. It's a chronic enigmatic gynecological condition associated with dysmenorrhea, dyspareunia, pelvic pain, and infertility. Endometriosis lesions exist in a unique microenvironment characterized by increased concentrations of hormones, inflammation, and oxidative stress. This environment promotes cell survival through the binding of membrane receptors and subsequent cascading activation of intracellular kinases that stimulate a cellular response. In endometriosis, well-established signaling pathways, mTOR and AMPK, are altered via steroid hormones and other factors to promote cell growth, migration, and proliferation. This is accompanied by dysfunction in the mitochondria that increase energy production to sustain proliferation demands consequently leading to reactive oxygen species overproduction. This review aims to summarize the role of altered mTOR/AMPK signaling pathway, mitochondrial dysfunction, and reactive oxygen species overproduction along with providing therapeutic and diagnostic approaches. Highlighting these factors would provide a better understanding to reach a coherent theory for the pathogenesis of endometriosis.

Keywords:  AMPK; Endometriosis; Inflammation; Mitochondrial dysfunction; Reactive oxygen species; mTOR

DOI:  https://doi.org/10.1016/j.lfs.2022.120805
Mol Immunol. 2022 Jul 19. pii: S0161-5890(22)00377-7. [Epub ahead of print]

Retraction notice to "Vitexin alleviates ox-LDL-mediated endothelial injury by inducingautophagy via AMPK signaling activation" [Mol. Immunol. 85 (2017) 214-221].

Shaoli Zhang, Changlei Guo, Zhigang Chen, Peiyong Zhang, Jianhua Li, Yan Li.

DOI: https://doi.org/10.1016/j.molimm.2022.06.012
Transl Stroke Res. 2022 Jul 19.

Metformin Alleviates Delayed Hydrocephalus after Intraventricular Hemorrhage by Inhibiting Inflammation and Fibrosis.

Yi Cao, Chang Liu, Gaowei Li, Weina Gao, Hui Tang, Shuanmin Fan, Xin Tang, Long Zhao, Haoxiang Wang, Aijun Peng, Chao You, Aiping Tong, Liangxue Zhou.

  Intraventricular hemorrhage (IVH) is a subtype of intracerebral hemorrhage (ICH) with high morbidity and mortality. Posthemorrhagic hydrocephalus (PHH) is a common and major complication that affects prognosis, but the mechanism is still unclear. Inflammation and fibrosis have been well established as the major causes of PHH after IVH. In this study, we aimed to investigate the effects of metformin on IVH in adult male mice and further explored the underlying molecular mechanisms of these effects. In the acute phase, metformin treatment exerted dose-dependent neuroprotective effects by reducing periependymal apoptosis and neuronal degeneration and decreasing brain edema. Moreover, high-dose metformin reduced inflammatory cell infiltration and the release of proinflammatory factors, thus protecting ependymal structure integrity and subependymal neurons. In the chronic phase, metformin administration improved neurocognitive function and reduced delayed hydrocephalus. Additionally, metformin significantly inhibited basal subarachnoid fibrosis and ependymal glial scarring. The ependymal structures partially restored. Mechanically, IVH reduced phospho-AMPK (p-AMPK) and SIRT1 expression and activated the phospho-NF-κB (p-NF-κB) inflammatory signaling pathway. However, metformin treatment increased AMPK/SIRT1 expression and lowered the protein expression of p-NF-κB and its downstream inflammation. Compound C and EX527 administration reversed the anti-inflammatory effect of metformin. In conclusion, metformin attenuated neuroinflammation and subsequent fibrosis after IVH by regulating AMPK /SIRT1/ NF-κB pathways, thereby reducing delayed hydrocephalus. Metformin may be a promising therapeutic agent to prevent delayed hydrocephalus following IVH.

Keywords:  Fibrosis; Inflammation; Intraventricular hemorrhage; Metformin; Post-hemorrhage hydrocephalus

DOI:  https://doi.org/10.1007/s12975-022-01026-3
Circulation. 2022 Jul 05. 146(1): 73-76

Impaired AMP-Activated Protein Kinase Signaling in Heart Failure With Preserved Ejection Fraction-Associated Atrial Fibrillation.

Dan Tong, Gabriele G Schiattarella, Nan Jiang, Daniel Daou, Yuxuan Luo, Mark S Link, Sergio Lavandero, Thomas G Gillette, Joseph A Hill.



Keywords:  atrial fibrillation; heart failure, diastolic

DOI:  https://doi.org/10.1161/CIRCULATIONAHA.121.058301
Can J Physiol Pharmacol. 2022 Jul 19.

Anisomycin inhibits angiogenesis, growth, and survival of triple-negative breast cancer through mitochondrial dysfunction, AMPK activation, and mTOR inhibition.

Wenjuan Yang, Cuiling Zhou, Qiushi Sun, Gege Guan.

  Aberrant upregulation of mitochondrial biogenesis is observed in breast cancer and holds potential therapeutic option. In our work, we showed that inhibition of mitochondrial function by anisomycin is effective against triple-negative breast cancer (TNBC). Anisomycin inhibits growth and induces caspase-dependent apoptosis in a panel of TNBC cell lines. Of note, anisomycin at a tolerable dose remarkably suppresses growth of TNBC in mice. In addition, anisomycin effectively targets breast cancer angiogenesis through inhibiting capillary network formation, migration, proliferation, and survival. Mechanistic studies show that although anisomycin activates p38 and JNK, their activations are not required for anisomycin's action. In contrast, anisomycin inhibits mitochondrial respiration, and decreases mitochondrial membrane potential and adenosine triphosphate (ATP) level. The inhibitory effect of anisomycin is significantly reversed in mitochondria respiration-deficient ρ0 cells. As a consequence, anisomycin activates AMPK and inhibits mammalian target-of-rapamycin signaling pathways. Our work demonstrated that anisomycin is a useful addition to the treatment armamentarium for TNBC.

Keywords:  AMPK/mTOR; TNBC; angiogenesis; angiogenèse; anisomycin; anisomycine; mitochondrial respiration; respiration mitochondriale

DOI:  https://doi.org/10.1139/cjpp-2021-0577
Front Nutr. 2022 ;9 917801

AMPK-PPARγ-Cidec Axis Drives the Fasting-Induced Lipid Droplet Aggregation in the Liver of Obese Mice.

Hongqiang Li, Jian Sun, Bojiang Li, Aiwen Jiang, Jingli Tao, Caibo Ning, Rongyang Li, Honglin Liu.

  Intermittent fasting is one of the most common clinical treatments for the obesity, a main risk factor of the metabolic syndrome which can lead to a variety of diseases. Fasting-induced fat mobilization alters the metabolic state of lipid in the liver, predisposing to increase the hepatic lipid droplet aggregation and triglyceride levels. However, the underlying mechanisms regarding the lipid droplet aggregation in the liver after fasting remains elusive. Here, we report that a lipid droplet surface binding protein Cidec (cell death inducing DFFA like effector C) is activated by AMPK to regulate the hepatic lipid droplet fusion following fasting in obese mice. Specifically, we found that lipid droplets were significantly aggregated in the liver of high-fat-diet and ob/ob mice after 16 and 24 h of fasting, accompanied by the dramatically up-regulated expression of Cidec. Consistently, overexpression of Cidec in the AML12 cells resulted in the intracellular lipid droplet aggregation. Furthermore, we showed that fasting caused the up-regulated expression of AMPK, which in turn activated the transcription of Cidec through the transcription factor PPARγ. Altogether, our observations reveal that fasting-induced hepatic lipid droplet aggregation is mediated by the AMPK-activated expression of Cidec via PPARγ, extending our understanding about the molecular mechanism of the impact of fasting on the obesity and providing potential targets for the treatment of human obesity.

Keywords:  AMPK; Cidec; PPARγ; fasting; lipid droplet; obesity

DOI:  https://doi.org/10.3389/fnut.2022.917801
Stem Cell Res Ther. 2022 Jul 16. 13(1): 318

Notch-activated mesenchymal stromal/stem cells enhance the protective effect against acetaminophen-induced acute liver injury by activating AMPK/SIRT1 pathway.

Mengxue Yu, Min Zhou, Jiahui Li, Ruobin Zong, Yufei Yan, Liangyi Kong, Qiang Zhu, Changyong Li.

   BACKGROUND: Notch signaling plays important roles in regulating innate immunity. However, little is known about the role of Notch in mesenchymal stromal/stem cell (MSC)-mediated immunomodulation during liver inflammatory response.
METHODS: Notch activation in human umbilical cord-derived MSCs was performed by a tissue culture plate coated with Notch ligand, recombinant human Jagged1 (JAG1). Mice were given intravenous injection of Notch-activated MSCs after acetaminophen (APAP)-induced acute liver injury. Liver tissues were collected and analyzed by histology and immunohistochemistry.
RESULTS: MSC administration reduced APAP-induced hepatocellular damage, as manifested by decreased serum ALT levels, intrahepatic macrophage/neutrophil infiltration, hepatocellular apoptosis and proinflammatory mediators. The anti-inflammatory activity and therapeutic effects of MSCs were greatly enhanced by Notch activation via its ligand JAG1. However, Notch2 disruption in MSCs markedly diminished the protective effect of MSCs against APAP-induced acute liver injury, even in the presence of JAG1 pretreatment. Strikingly, Notch-activated MSCs promoted AMP-activated protein kinase (AMPKα) phosphorylation, increased the sirtuins 1 (SIRT1) deacetylase expression, but downregulated spliced X-box-binding protein 1 (XBP1s) expression and consequently reduced NLR family pyrin domain-containing 3 (NLRP3) inflammasome activation. Furthermore, SIRT1 disruption or XBP1s overexpression in macrophages exacerbated APAP-triggered liver inflammation and augmented NLRP3/caspase-1 activity in MSC-administrated mice. Mechanistic studies further demonstrated that JAG1-pretreated MSCs activated Notch2/COX2/PGE2 signaling, which in turn induced macrophage AMPK/SIRT1 activation, leading to XBP1s deacetylation and inhibition of NLRP3 activity.
CONCLUSIONS: Activation of Notch2 is required for the ability of MSCs to reduce the severity of APAP-induced liver damage in mice. Our findings underscore a novel molecular insights into MSCs-mediated immunomodulation by activating Notch2/COX2/AMPK/SIRT1 pathway and thus provide a new strategy for the treatment of liver inflammatory diseases.

Keywords:  Acute liver injury; Mesenchymal stromal/stem cell; Notch signaling; SIRT1; XBP1

DOI:  https://doi.org/10.1186/s13287-022-02999-6
Vopr Pitan. 2022 ;91(3): 21-31

[Hyperinsulinemia and age-related diseases: interrelations and approaches to treatment].

A V Martyushev-Poklad, D S Yankevich, M V Petrova, N G Savitskaya.

  Hyperinsulinemia is closely related with insulin resistance, that is the key mechanism for the progression of age-related diseases. A lot of aspects of hyperinsulinemia and interrelations between the mentioned conditions are very scarcely covered in Russian publications. The present review is designed to fill the gaps in understanding the causal relationships between hyperinsulinemia, insulin resistance, age-related diseases and lifestyle factors. Material and methods. Based on sources from PubMed and Google Scholar, using the keywords "hyperinsulinemia" + "chronic disease" OR "age-related disease" the authors analyzed the causes of hyperinsulinemia, the mechanisms of its influence on various aspects of insulin resistance, and the role of hyperinsulinemia in pathogenesis of a wide range of clinical syndromes and age-related diseases. Consideration of the effects that lifestyle factors produce on hyperinsulinemia opens up opportunities for its correction. Results. The major causes of hyperinslinemia are improper diet and nutrition regime (frequent meals and excess of highly glycemic food, too short fasting window), along with other factors causing hyperreactivity of pancreatic beta-cells (fructose, systemic inflammation, oxidative stress, low vitamin D level, etc.). Hyperinsulinemia affects cellular energy balance (primarily, in liver, muscle, brain and adipose tissue); a major factor is suppression of 5'AMP-activated protein kinase (AMPK) along with stimulation of mitogen-activated protein kinase. Insulin resistance is a consequence of AMPK inhibition, an adaptive response designed to preserve cellular homeostasis. Conclusion. Obesity, metabolic syndrome, chronic systemic inflammation, age-related syndromes and diseases (including arterial hypertension, atherosclerosis, neurodegenerative diseases, tumors, osteoarthritis, sarcopenia, etc.) can be considered as clinical manifestations of the body's systemic adaptation to hyperinsulinemia in the form of insulin resistance. Available approach to reduce insulin resistance is correction of lifestyle factors to mitigate hyperinsulinemia and restore AMPK activity. The revealed causal relationships can provide background for personalized strategy of prevention and treatment for age-related diseases through reduction of insulin resistance and correction of energy homeostasis.

Keywords:  AMP-activated protein kinase; age-related diseases; hyperinsulinemia; inflammaging; insulin resistance; metabolic syndrome; obesity

DOI:  https://doi.org/10.33029/0042-8833-2022-91-3-21-31
J Oncol. 2022 ;2022 8055004

Periplocin Induces Apoptosis of Pancreatic Cancer Cells through Autophagy via the AMPK/mTOR Pathway.

Hewei Zhang, Yongqiang Wang, Yan Zhang, Beishi Zheng, Xiaowu Wang, Jiawei Chen, Bicheng Chen, Gangyin Xie, Lihong Yang.

Periplocin, a natural compound, has been shown to induce apoptosis in a variety of cancer cells. However, no research has been conducted to demonstrate that Periplocin has a regulatory effect on autophagy. This study is aimed to determine the effect of Periplocin treatment on autophagy in human pancreatic cancer cells, as well as the underlying mechanisms. Pancreatic cancer cells were treated with different concentrations of Periplocin, and real-time cell analysis (RTCA), colony formation assay, and Ki67 immunofluorescence detection were used to determine cell proliferation. Autophagy protein was detected by immunofluorescence and western blotting. Western blotting was also used to detect the caspase family of apoptotic proteins. Flow cytometry and TUNEL staining were used to detect cell apoptosis. Following treatment with Periplocin, the expression of autophagy genes was detected using RNA-seq. In vivo examination of the effect of Periplocin on autophagy in pancreatic was performed using a xenograft model. Periplocin inhibits the proliferation of CFPAC1 and PANC1 cells and induces autophagy by regulating the AMPK/mTOR pathway. Using the AMPK inhibitor Compound C(CC), both the Periplocin-induced inhibition of cell proliferation and autophagy activation was reduced, which further verified this conclusion. Periplocin inhibits CFPAC1 xenograft tumor growth in nude mice and increases tumor cell autophagy. Collectively, these results have shown that Periplocin promotes autophagy in human pancreatic cancer cells by regulating the AMPK/mTOR pathway.

DOI: https://doi.org/10.1155/2022/8055004
Bull Exp Biol Med. 2022 Jul 20.

Baicalin Induced Apoptosis of Human Cholangiocarcinoma Cell through Activating AMPK/mTORC1/p70S6K Signaling Pathway.

M Jia, F Yang, Y Xu, Q Xu, Y Zeng, R Dai, Y Xiang.

  Baicalin (naturally bioactive flavone compound isolated from Scutellaria baicalensis) has been demonstrated to exert strong anticancer activity against various tumor cells. However, the possibility of using baicalin for the treatment of cholangiocarcinoma and its effectiveness remain unstudied. The effect of baicalin on QBC939 cholangiocarcinoma cell culture was studied by assessing cell viability (CCK-8 test) and expression of the key proteins (Western blotting). Baicalin induced apoptosis of QBC939 cells in culture in a dose- and time-dependent manner. The proapoptotic effect was attributed to inhibition of the mTORC1-p70S6K signaling pathway resulting from baicalin-induced AMPK activation. These findings provide a new approach for cholangiocarcinoma treatment and serve as a basis for developing baicalin-based combination cancer therapy strategies.

Keywords:  AMPK; apoptosis; baicalin; cholangiocarcinoma; mTOR

DOI:  https://doi.org/10.1007/s10517-022-05550-y
Front Pharmacol. 2022 ;13 909280

Nootkatone, a Sesquiterpene Ketone From Alpiniae oxyphyllae Fructus, Ameliorates Metabolic-Associated Fatty Liver by Regulating AMPK and MAPK Signaling.

Zhang Yong, Huang Zibao, Zhou Zhi, Ma Ning, Wang Ruiqi, Chen Mimi, He Xiaowen, Dong Lin, Xia Zhixuan, Liu Qiang, Lu Weiying, Zhang Xiaopo.

  Metabolic-associated fatty liver disease (MAFLD) is becoming more common due to lifestyle changes. A long-term high-fat and high-glucose diet induces glycolipid metabolism disorders in the liver, which results in the development of MAFLD. To date, there is no specific clinically useful therapeutics for this disease. Natural products or synthetic compounds were screened and investigated to find effective agents for treating MAFLD. In this study, nootkatone (Nok), a natural sesquiterpene ketone isolated from Alpiniae oxyphyllae fructus, was explored for its potential to treat MAFLD, and underlying mechanisms were studied. Our results show that Nok dramatically ameliorated the disordered lipid and glucose metabolism in MAFLD mice, decreased fat accumulation in hepatic tissue, and improved liver injury. Inflammation, metabolic disorder, and oxidative stress were ameliorated in liver tissue based on RNA-seq transcriptome comparison between a Nok-treated group and an MAFLD model group. Furthermore, Nok significantly activated AMPK activity and inhibited MAPK activity, especially the p38 and JNK signaling pathways, in vivo based on western blot analysis. The pharmaceutical effects and potential signaling pathways impacted by Nok were also investigated in L02 cells. Nok significantly promoted the consumption of glucose and decreased the deposition of triglycerides in vitro. The p-AMPKα level was notably upregulated by Nok, indicating dramatic AMPK activation. In addition, Nok decreased the levels of p-ERK1/2, p-p38, and p-JNK. Nok also inhibited the activation of MAPK signaling and, thus, alleviated MAFLD development. Our results suggest that Nok may be useful in treating MAFLD. Nok may ameliorate MAFLD by regulating glycolipid metabolism disorders by activating AMPK and inhibiting MAPK activity. Collectively, this study suggests that Nok is an effective compound for the treatment of MAFLD.

Keywords:  AMPK; Alpiniae oxyphyllae Fructus; MAFLD (metabolic-associated fatty liver disease); MAPK; nootkatone

DOI:  https://doi.org/10.3389/fphar.2022.909280
Contrast Media Mol Imaging. 2022 ;2022 8713701

Ketamine Promotes LPS-Induced Pulmonary Autophagy and Reduces Apoptosis through the AMPK/mTOR Pathway.

Jianwei Cao, Huiqiang Mai, Yanfen Chen, Ruilin Yuan, Erbin Fang, Meiling Liu, Chunlai Fu.

To explore the protective effect of ketamine on acute lung injury (ALI) in sepsis mice regarding the autophagy and apoptosis, lipopolysaccharide (LPS) was used to construct a sepsis-induced ALI model. In in vivo experiments, ketamine at a concentration of 20 mg/kg was injected before modeling. The serum levels of inflammatory factors IL-1β, IL-6, and TNF-α were detected by enzyme-linked immunosorbent assay (ELISA) kit. At the same time, quantitative real-time polymerase chain reaction (qRT-PCR) was used to detect apoptosis-related factors Bax and Bcl-2 and autophagy-related factors Beclin-1 and P62. In in vitro experiment, firstly, Cell Counting Kit-8 (CCK8) assay was used to detect the cell viability and identify optimal concentration of ketamine. TUNEL staining, Western blotting (WB), and qRT-PCR were used to detect alveolar type II epithelial cells (AEC II) AEC II cell apoptosis. The content of inflammatory factors in the cell supernatant was detected by kits and the autophagy intensity of AEC II cells was detected by PCR and WB. At the same time, the expression changes of AMPK/mTOR pathway were detected by WB technology. Compared with the Sham group, the dry-wet ratio of the lung tissue in the LPS group was obviously increased, the expression of inflammatory factors in the serum was upregulated, and apoptosis and autophagy activation occurred. In the LPS + ketamine group, ketamine significantly promoted autophagy intensity and inhibited inflammatory response, thereby reducing apoptosis. In vitro, 1 mmol/L ketamine can effectively improve the viability of AEC II cells after LPS treatment, promote autophagy, and decrease cell apoptosis. And we found that the above-mentioned effect of ketamine was by regulating the activation of AMPK/mTOR pathway. In this study, we demonstrated that LPS treatment can induce inflammation and autophagy and induce apoptosis in lung cells. In contrast, AMPK expression was activated after ketamine treatment, inhibiting the mTOR pathway and promoting autophagy, thereby alleviating the apoptosis of AEC II cells.

DOI: https://doi.org/10.1155/2022/8713701
Cell Commun Signal. 2022 Jul 16. 20(1): 105

Inhibition of AMPK/PFKFB3 mediated glycolysis synergizes with penfluridol to suppress gallbladder cancer growth.

Jiahao Hu, Jiasheng Cao, Ren'an Jin, Bin Zhang, Win Topatana, Sarun Juengpanich, Shijie Li, Tian'en Chen, Ziyi Lu, Xiujun Cai, Mingyu Chen.

   BACKGROUND: Penfluridol (PF) is an FDA-approved antipsychotic drug that has recently been shown to have anticancer activity. However, the anticancer effects and underlying mechanisms of PF are not well-established in gallbladder cancer (GBC).
METHODS: The anticancer efficacy of PF on GBC was investigated via a series of cell functions experiments, including cell viability, colony formation, apoptosis assays, and so on. The corresponding signaling changes after PF treatment were explored by western blotting. Then, nude mice were utilized to study and test the anticancer activity of PF in vivo. Besides, glucose consumption and lactic production assays were used to detect the glycolysis alteration.
RESULTS: In this study, we discovered that PF greatly inhibited the proliferation and invasion ability of GBC cells (GBCs). The glucose consumption and lactic generation ability of GBCs were dramatically elevated following PF treatment. Additionally, we discovered that inhibiting glycolysis could improve PF's anticancer efficacy. Further studies established that the activation of the AMPK/PFKFB3 signaling pathway medicated glycolysis after PF treatment. We proved mechanistically that inhibition of AMPK/PFKFB3 singling pathway mediated glycolysis was a potential synergetic strategy to improve the anticancer efficacy of PF on GBC.
CONCLUSIONS: By inhibiting AMPK, the anticancer effects of PF on GBCs were amplified. As a result, our investigations shed new light on the possibility of repurposing PF as an anticancer drug for GBC, and AMPK inhibition in combination with PF may represent a novel therapeutic strategy for GBC. Video abstract.

Keywords:  AMPK/PFKFB3; Apoptosis; Gallbladder cancer; Glycolysis; Penfluridol

DOI:  https://doi.org/10.1186/s12964-022-00882-8
Biogerontology. 2022 Jul 16.

Mitochondrial function and nutrient sensing pathways in ageing: enhancing longevity through dietary interventions.

Elangbam Tomtheelnganbee, Puja Sah, R Sharma.

  Ageing is accompanied by alterations in several biochemical processes, highly influenced by its environment. It is controlled by the interactions at various levels of biological hierarchy. To maintain homeostasis, a number of nutrient sensors respond to the nutritional status of the cell and control its energy metabolism. Mitochondrial physiology is influenced by the energy status of the cell. The alterations in mitochondrial physiology and the network of nutrient sensors result in mitochondrial damage leading to age related metabolic degeneration and diseases. Calorie restriction (CR) has proved to be as the most successful intervention to achieve the goal of longevity and healthspan. CR elicits a hormetic response and regulates metabolism by modulating these networks. In this review, the authors summarize the interdependent relationship between mitochondrial physiology and nutrient sensors during the ageing process and their role in regulating metabolism.

Keywords:  AMPK; Ageing; Dietary restriction; Mitochondria; Sirtuins; mTOR

DOI:  https://doi.org/10.1007/s10522-022-09978-7
Cancer Cell Int. 2022 Jul 21. 22(1): 232

The autophagy inducer trehalose stimulates macropinocytosis in NF1-deficient glioblastoma cells.

Barbara Del Bello, Alessandra Gamberucci, Paola Marcolongo, Emilia Maellaro.

   BACKGROUND: Glioblastoma is a highly aggressive brain tumor. A big effort is required to find novel molecules which can cross the blood-brain barrier and efficiently kill these tumor cells. In this perspective, trehalose (α-glucopyranosyl-[1→1]-α-D-glucopyranoside), found in various dietary sources and used as a safe nutrient supplement, attracted our attention for its pleiotropic effects against tumor cells.
METHODS: Human glioblastoma cell lines U373-MG and T98G were exposed to trehalose and analyzed at different time points. Cell proliferation was evaluated at medium term, and clonogenic capacity and cell morphology were evaluated at long term. Western blot was used to evaluate biochemical markers of autophagy (also measured in cells co-treated with EIPA or chloroquine), and mTOR, AMPK and ERK 1/2 signalling. Macropinocytosis was evaluated morphologically by bright-field microscopy; in cells loaded with the fluorescein-conjugated fluid-phase tracer dextran, macropinocytic vacuoles were also visualized by fluorescence microscopy, and the extent of macropinocytosis was quantified by flow cytometry.
RESULTS: The long-term effect of trehalose on U373-MG and T98G cell lines was impressive, as indicated by a dramatic reduction in clonogenic efficiency. Mechanistically, trehalose proved to be an efficient autophagy inducer in macropinocytosis-deficient T98G cells and an efficient inducer of macropinocytosis and eventual cell death by methuosis in U373-MG glioblastoma cells, proved to be poorly responsive to induction of autophagy. These two processes appeared to act in a mutually exclusive manner; indeed, co-treatment of U373-MG cells with the macropinocytosis inhibitor, EIPA, significantly increased the autophagic response. mTOR activation and AMPK inhibition occurred in a similar way in the two trehalose-treated cell lines. Interestingly, ERK 1/2 was activated only in macropinocytosis-proficient U373-MG cells harbouring loss-of-function mutations in the negative RAS regulator, NF1, suggesting a key role of RAS signalling.
CONCLUSIONS: Our results indicate that trehalose is worthy of further study as a candidate molecule for glioblastoma therapy, due to its capacity to induce a sustained autophagic response, ultimately leading to loss of clonogenic potential, and more interestingly, to force macropinocytosis, eventually leading to cell death by methuosis, particularly in tumor cells with RAS hyperactivity. As a further anticancer strategy, stimulation of macropinocytosis may be exploited to increase intracellular delivery of anticancer drugs.

Keywords:  Autophagy; ERK 1/2; Glioblastoma cells; Macropinocytosis; Methuosis; NF1; Trehalose

DOI:  https://doi.org/10.1186/s12935-022-02652-5
Crit Rev Food Sci Nutr. 2022 Jul 22. 1-26

New insights into anti-diabetes effects and molecular mechanisms of dietary saponins.

Yifan Zhou, Baojun Xu.

  Diabetes mellitus (DM) is a long-term metabolic disorder that manifests as chronic hyperglycemia and impaired insulin, bringing a heavy load on the global health care system. Considering the inevitable side effects of conventional anti-diabetic drugs, saponins-rich natural products exert promising therapeutic properties to serve as safer and more cost-effective alternatives for DM management. Herein, this review systematically summarized the research progress on the anti-diabetic properties of dietary saponins and their underlying molecular mechanisms in the past 20 years. Dietary saponins possessed the multidirectional anti-diabetic capabilities by concurrent regulation of various signaling pathways, such as IRS-1/PI3K/Akt, AMPK, Nrf2/ARE, NF-κB-NLRP3, SREBP-1c, and PPARγ, in liver, pancreas, gut, and skeletal muscle. However, the industrialization and commercialization of dietary saponin-based drugs are confronted with a significant challenge due to the low bioavailability and lack of the standardization. Hence, in-depth evaluations in pharmacological profile, function-structure interaction, drug-signal pathway interrelation are essential for developing dietary saponins-based anti-diabetic treatments in the future.

Keywords:  AMPK; Dietary saponin; PI3K/Akt; anti-diabetes; anti-inflammation; intracellular signaling pathways

DOI:  https://doi.org/10.1080/10408398.2022.2101425