bims-amsmem 2023-04-30 papers

bims-amsmem

Biomed News

on AMPK signaling mechanism in energy metabolism

Issue of 2023–04–30
fourteen papers selected by
Dipsikha Biswas, Københavns Universitet

AMPK and the Endocrine Control of Metabolism.
Alpha-SNAP (M105I) mutation promotes neuronal differentiation of neural stem/progenitor cells through overactivation of AMPK.
Integrative Analysis of the AMPK subunits in Colorectal Adeno Carcinoma.
Acute Kidney Injury Induces Oxidative Stress and Hepatic Lipid Accumulation through AMPK Signaling Pathway.
Comments on 'Downregulation of hepatic ceruloplasmin ameliorates NAFLD via SCO1-AMPK-LKB1 complex'.
BMAL1 involved in autophagy and injury of thoracic aortic endothelial cells of rats induced by intermittent heat stress through the AMPK/mTOR/ULK1 pathway.
[Effects of muscle derived-IL-6 on insulin resistance of skeletal muscle cells and its mechanisms].
Blueberry Stem Extract Prevents Lacrimal Hyposecretion in Non-obese Diabetic Mice via Activation of AMPK.
Standardized Sanguisorba officinalis L. Extract Inhibits Adipogenesis and Promotes Thermogenesis via Reducing Oxidative Stress.
Icariin, the main prenylflavonoid of Epimedii Folium, ameliorated chronic kidney disease by modulating energy metabolism via AMPK activation.
Kaempferol Suppresses Carbon Tetrachloride-Induced Liver Damage in Rats via the MAPKs/NF-κB and AMPK/Nrf2 Signaling Pathways.
Oscillation of Autophagy Induction under Cellular Stress and What Lies behind It, a Systems Biology Study.
Tripeptide IRW Improves AMPK/eNOS Signaling Pathway via Activating ACE2 in the Aorta of High-Fat-Diet-Fed C57BL/6 Mice.
Protective Effect of Ferulic Acid on Lipopolysaccharide-Induced BV2 Microglia Inflammation via AMPK/mTOR Signaling Pathway.

Endocr Rev. 2023 Apr 28. pii: bnad012. [Epub ahead of print]

AMPK and the Endocrine Control of Metabolism.

Logan K Townsend, Gregory R Steinberg.

  Complex multi-cellular organisms require a coordinated response from multiple tissues to maintain whole-body homeostasis in the face of energetic stressors like fasting, cold and exercise. It is also essential that energy is stored efficiently with feeding and the chronic nutrient surplus that occurs with obesity. Mammals have adapted several endocrine signals that regulate metabolism in response to changes in nutrient availability and energy demand. These include hormones altered by fasting and refeeding including insulin, glucagon, GLP-1 (glucagon like peptide-1), catecholamines, ghrelin and FGF21 (fibroblast growth factor 21); adipokines such as leptin and adiponectin; cell stress-induced cytokines like TNFα (tumor necrosis factor alpha) and GDF15 (growth differentiating factor 15), and lastly exerkines such as IL-6 (interleukin-6) and irisin. Over the last two decades, it has become apparent that many of these endocrine factors control metabolism by regulating the activity of the AMPK (AMP-activated protein kinase). AMPK is a master regulator of nutrient homeostasis, phosphorylating over 100-distinct substrates that are critical for controlling autophagy, carbohydrate, fatty acid, cholesterol and protein metabolism. In this review we discuss how AMPK integrates endocrine signals to maintain energy balance in response to diverse homeostatic challenges. We also present some considerations with respect to experimental design which should enhance reproducibility and the fidelity of the conclusions.

Keywords:  AMPK; Exercise; Fasting; Metabolism; Obesity

DOI:  https://doi.org/10.1210/endrev/bnad012
Front Cell Dev Biol. 2023 ;11 1061777

Alpha-SNAP (M105I) mutation promotes neuronal differentiation of neural stem/progenitor cells through overactivation of AMPK.

Felipe A Bustamante-Barrientos, Maxs Méndez-Ruette, Luis Molina, Tania Koning, Pamela Ehrenfeld, Carlos B González, Ursula Wyneken, Roberto Henzi, Luis Federico Bátiz.

  Background: The M105I point mutation in α-SNAP (Soluble N-ethylmaleimide-sensitive factor attachment protein-alpha) leads in mice to a complex phenotype known as hyh (hydrocephalus with hop gait), characterized by cortical malformation and hydrocephalus, among other neuropathological features. Studies performed by our laboratory and others support that the hyh phenotype is triggered by a primary alteration in embryonic neural stem/progenitor cells (NSPCs) that leads to a disruption of the ventricular and subventricular zones (VZ/SVZ) during the neurogenic period. Besides the canonical role of α-SNAP in SNARE-mediated intracellular membrane fusion dynamics, it also negatively modulates AMP-activated protein kinase (AMPK) activity. AMPK is a conserved metabolic sensor associated with the proliferation/differentiation balance in NSPCs. Methods: Brain samples from hyh mutant mice (hydrocephalus with hop gait) (B6C3Fe-a/a-Napahyh/J) were analyzed by light microscopy, immunofluorescence, and Western blot at different developmental stages. In addition, NSPCs derived from WT and hyh mutant mice were cultured as neurospheres for in vitro characterization and pharmacological assays. BrdU labeling was used to assess proliferative activity in situ and in vitro. Pharmacological modulation of AMPK was performed using Compound C (AMPK inhibitor) and AICAR (AMPK activator). Results: α-SNAP was preferentially expressed in the brain, showing variations in the levels of α-SNAP protein in different brain regions and developmental stages. NSPCs from hyh mice (hyh-NSPCs) displayed reduced levels of α-SNAP and increased levels of phosphorylated AMPKα (pAMPKαThr172), which were associated with a reduction in their proliferative activity and a preferential commitment with the neuronal lineage. Interestingly, pharmacological inhibition of AMPK in hyh-NSPCs increased proliferative activity and completely abolished the increased generation of neurons. Conversely, AICAR-mediated activation of AMPK in WT-NSPCs reduced proliferation and boosted neuronal differentiation. Discussion: Our findings support that α-SNAP regulates AMPK signaling in NSPCs, further modulating their neurogenic capacity. The naturally occurring M105I mutation of α-SNAP provokes an AMPK overactivation in NSPCs, thus connecting the α-SNAP/AMPK axis with the etiopathogenesis and neuropathology of the hyh phenotype.

Keywords:  AMPK phosphatase; brain development; cell fate; cell metabolism; hydrocephalus with hop gait; neurogenesis; proliferation; ventricular zone

DOI:  https://doi.org/10.3389/fcell.2023.1061777
Asian Pac J Cancer Prev. 2023 Apr 01. pii: 90569. [Epub ahead of print]24(4): 1159-1171

Integrative Analysis of the AMPK subunits in Colorectal Adeno Carcinoma.

Beena T B, Jesil Mathew A, Harikumar K B, Safeeda E.

   BACKGROUND: The 5-adenosine monophosphate (AMP)-activated protein kinase (AMPK) is an emerging cancer treatment and therapeutic target. Due to the enzyme's complexity and dual nature, it is a confounding target in the treatment strategy. The study aimed to conduct an integrative analysis of the seven subunits and twelve isoforms of AMPK, which is not reported so far in colorectal adenocarcinoma patients.
METHODOLOGY: The web-based tools UALCAN, Timer 2.0, KM Plotter, cBioPortal, COSMIC, and STRING were used to investigate the differential expression of AMPK subunits, protein-level Expression, promoter methylation status, survival analyses, Enrichment analysis, and protein-protein interaction.
RESULTS: The mRNA expression of AMPK subunits are upregulated in Colorectal Adeno Carcinoma (COAD), while the protein expression is comparatively reduced in colon tumors. The protein-level expression of α2 and β2 is decreased significantly in COAD patients. The γ3 subunit in colon tumor is hypermethylated. The study also reports that Liver Kinase B1 mutation in 7% of CRC patients, which might be the reason for downregulation of the gene and the protein expression of AMPK subunits in COAD.
CONCLUSION: The Overall analysis of the subunits affirms that AMPK expression is beneficial in cancer.

Keywords:  AMPK; Protein expression; Survival Analysis; colorectal cancer; differential gene expression

DOI:  https://doi.org/10.31557/APJCP.2023.24.4.1159
Antioxidants (Basel). 2023 Apr 05. pii: 883. [Epub ahead of print]12(4):

Acute Kidney Injury Induces Oxidative Stress and Hepatic Lipid Accumulation through AMPK Signaling Pathway.

Kathy K W Au-Yeung, Yue Shang, Charith U B Wijerathne, Susara Madduma Hewage, Yaw L Siow, Karmin O.

  Acute kidney injury (AKI) often impairs the function of other organs leading to distant organ injury. The liver is the major organ that regulates metabolism and lipid homeostasis in the body. It has been reported that AKI causes liver injury with increased oxidative stress, inflammatory response and steatosis. In the present study, we investigated the mechanisms by which ischemia-reperfusion-induced AKI caused hepatic lipid accumulation. Kidney ischemia (45 min)-reperfusion (24 h) led to a significant increase in plasma creatinine and transaminase in Sprague Dawley rats, indicating kidney and liver injury. Histological and biochemical analyses revealed hepatic lipid accumulation with a significant elevation of triglyceride and cholesterol levels in the liver. This was accompanied by a decreased AMP-activated protein kinase (AMPK) phosphorylation, indicating the reduced activation of AMPK, which is an energy sensor that regulates lipid metabolism. The expression of AMPK-regulated genes that were responsible for fatty acid oxidation (CPTIα, ACOX) was significantly decreased, while the expression of lipogenesis genes (SREPB-1c, ACC1) was significantly elevated. The oxidative stress biomarker malondialdehyde was elevated in the plasma and liver. Incubation of HepG2 cells with an oxidative stress inducer hydrogen peroxide inhibited AMPK phosphorylation and caused cellular lipid accumulation. This was accompanied by decreased expression of genes responsible for fatty acid oxidation and increased expression of genes responsible for lipogenesis. These results suggest that AKI elicits hepatic lipid accumulation through decreased fatty acid metabolism and increased lipogenesis. Oxidative stress may contribute, in part, to the downregulation of the AMPK signaling pathway leading to hepatic lipid accumulation and injury.

Keywords:  AKI; AMPK; fatty liver; lipid; oxidative stress

DOI:  https://doi.org/10.3390/antiox12040883
J Mol Cell Biol. 2023 Apr 24. pii: mjad026. [Epub ahead of print]

Comments on 'Downregulation of hepatic ceruloplasmin ameliorates NAFLD via SCO1-AMPK-LKB1 complex'.

Sijia Lu, Suzhen Chen, Ji Miao, Junli Liu.

DOI: https://doi.org/10.1093/jmcb/mjad026
Biochem Biophys Res Commun. 2023 Apr 14. pii: S0006-291X(23)00444-8. [Epub ahead of print]661 34-41

BMAL1 involved in autophagy and injury of thoracic aortic endothelial cells of rats induced by intermittent heat stress through the AMPK/mTOR/ULK1 pathway.

Chunli Yang, Ziwei Deng, Qihang Zeng, Xiaoyu Chang, Xiaomin Wu, Guanghua Li.

  Physiological activities of the body exhibit an obvious biological rhythm. At the core of the circadian rhythm, BMAL1 is the only clock gene whose deletion leads to abnormal physiological functions. However, whether intermittent heat stress influences cardiovascular function by altering the circadian rhythm of clock genes has not been reported. This study aimed to investigate whether intermittent heat stress induces autophagy and apoptosis, and the effects of BMAL1 on thoracic aortic autophagy and apoptosis. An intermittent heat stress model was established in vitro, and western blotting and immunofluorescence were used to detect the expression of autophagy, apoptosis, the AMPK/mTOR/ULK1 pathway, and BMAL1. After BMAL1 silencing, RT-qPCR was performed to detect the expression levels of autophagy and apoptosis-related genes. Our results suggest that heat stress induces autophagy and apoptosis in RTAECs. In addition, intermittent heat stress increased the phosphorylation of AMPK and ULK1, but reduced the phosphorylation of mTOR, AMPK inhibitor Compound C reversed the phosphorylation of AMPK, mTOR, and ULK1, and Beclin1 and LC3-II/LC3-I were downregulated. Furthermore, BMAL1 expression was elevated in vitro and shBMAL1 decreased autophagy and apoptosis. We revealed that intermittent heat stress induces autophagy and apoptosis, and that BMAL1 may be involved in the occurrence of autophagy and apoptosis.

Keywords:  Apoptosis; Autophagy; BMAL1; Intermittent heat stress; RTAEC

DOI:  https://doi.org/10.1016/j.bbrc.2023.04.035
Zhongguo Ying Yong Sheng Li Xue Za Zhi. 2022 Sep;38(5): 530-536

[Effects of muscle derived-IL-6 on insulin resistance of skeletal muscle cells and its mechanisms].

Hui Tang, Yi-Ping Zhao, Dan Huang, Jian-Guang Cai, Yi Wang.

   OBJECTIVE: To study the effects of exogenous calcium-load on promoting muscle-derived IL-6 secretion, and regulating AMPK and p38MAPK signal pathway to improve insulin resistance.
METHODS: C2C12 cell lines and palmitic acid-induced insulin resistance C2C12 cell lines were selected as the experimental objects. Preliminary experiment was aimed to determinate the glucose concentrations of culture solutions and observe contraction status of cells under microscope following different calcium concentrations culture 24 h. In the first official experiment, cells were divided into four groups: control group (A group, normal culture solution), IR group(B group, 0.6 mmol/L palmitic acid culture cells 24 h), 1 000 ng/ml IL-6 culture IR B group cells 48 h(IL-6+IR group) and IL-6 shRNA culture A group cells (IL-6shRNA group). In the second official experiment, cells were divided into three groups: IR group(A group), 100 μmol/L CaCl2 culture IR group cells 48 h(CaCl2+IR group) and 100 μmol/L CaCl2 and IL-6shRNA co- culture IR group cells 48 h(CaCl2+IL-6shRNA+IR group). The expression levels of GLUT4 mRNA and IL-6 mRNA were measured by real-time PCR, the protein expression levels of p-AMPK, p-p38MAPK, p-IRS-1 and p-PI-3K were measured by Western blot.
RESULTS: Preliminary experiment results showed that compared with 0 μmol/L CaCl2 group, the glucose concentrations were decreased significantly after cells treated with CaCl2, at different concentrations. The cell contractions were observed under microscope and the cell contraction was most obvious treated with 100 μmol/L CaCl2. The first official experiment results showed that compared with IR group, the contents of p-AMP-activated protein kinase(p-AMPK), p-insulin receptor substrate 1(p-IRS-1), p-phosphoinositide-3 kinase(p-PI-3K), the expression level of glucose transporter 4(GLUT4) mRNA and the glucose uptake of IL-6+IR group were increased significantly(P＜0.05 or P＜0.01), the p-p38MAPK protein expression level was decreased significantly (P＜0.01) ; Compared with control group, the expression levels of p-AMPK, P-IRS-1, p-PI-3K, the expression level of GLUT4 mRNA and the glucose uptake of IL-6shRNA group were decreased significantly (P＜0.05 or P＜0.01), the p-p38MAPK protein expression level was increased significantly (P＜0.01). The second official experiment results showed that compared with IR group, the expression levels of p-AMPK, P-IRS-1, p-PI-3K, the level of GLUT4 mRNA of CaCl2+IR group were increased significantly (P＜0.05 or P＜0.01), the p-p38MAPK protein expression level was decreased significantly (P＜0.01); Compared with CaCl2+IR group, the contents of p-AMPK, P-IRS-1, p-PI-3K, the expression level of GLUT4 mRNA and the glucose uptake of CaCl2+IL-6 shRNA+IR group were decreased significantly (P＜0.05 or P＜0.01), the p-p38MAPK protein expression level was increased significantly (P＜0.01).
CONCLUSION: Exogenous Ca-load can stimulate muscle cells contraction, and exercise-induced IL-6 improves insulin resistance by activating AMPK, PI-3Kand inhibiting p38MAPK signal pathway.

Keywords:  C2C12 cell lines; Calcuim-load; insulin resistant; muscle-derived IL-6

DOI:  https://doi.org/10.12047/j.cjap.6310.2022.099
In Vivo. 2023 May-Jun;37(3):37(3): 1003-1015

Blueberry Stem Extract Prevents Lacrimal Hyposecretion in Non-obese Diabetic Mice via Activation of AMPK.

Kenjirou Ogawa, Yuta Ohno, Akane Tagashira, Karin Urata, Keitaro Satoh, Naruki Fujimoto, Hiroko Sonoda, Masahiro Ikeda, Toshiyuki Matsuzaki, Kazuo Nishiyama, Hisato Kunitake, Y O Goto, Masao Yamasaki.

   BACKGROUND/AIM: Tears secreted from the lacrimal gland are essential for preserving the ocular surface. Thus, dysfunction of the lacrimal gland in Sjögren's syndrome (SS) can lead to dry eye, resulting in a reduced quality of life. We previously reported that blueberry 'leaf' water extract prevents lacrimal hyposecretion in male non-obese diabetic (NOD) mice in a SS-like model. In this study, we investigated the effect of blueberry 'stem' water extract (BStEx) on lacrimal hyposecretion in NOD mice.
MATERIALS AND METHODS: Male NOD mice were fed 1% BStEx or control (AIN-93G) for 2, 4, or 6 weeks from 4 weeks of age. Pilocarpine-induced tear secretion was measured using a phenol red-impregnated thread. The lacrimal glands were histologically evaluated by HE staining. Inflammatory cytokine levels in the lacrimal glands were measured using ELISA. Immunostaining was performed to examine aquaporin 5 (AQP5) localization. The expression levels of autophagy-related proteins, AQP5, and phosphorylated AMPK were measured using western blotting.
RESULTS: After feeding BStEx to mice for 4 or 6 weeks, tear volume was observed to have increased in the BStEx group compared with that in the control group. There were no significant differences in inflammatory cell infiltration, autophagy-related protein expression, or the localization and expression of AQP5 in the lacrimal glands between the two groups. In contrast, AMPK phosphorylation increased in the BStEx group.
CONCLUSION: BStEx prevented lacrimal hyposecretion in the SS-like model of male NOD mice, probably by opening tight junctions via the activation of AMPK in lacrimal acinar cells.

Keywords:  AMPK phosphorylation; Blueberry Stem; NOD mice; Sjögren’s syndrome; lacrimal gland; tear secretion

DOI:  https://doi.org/10.21873/invivo.13174
Antioxidants (Basel). 2023 Apr 04. pii: 882. [Epub ahead of print]12(4):

Standardized Sanguisorba officinalis L. Extract Inhibits Adipogenesis and Promotes Thermogenesis via Reducing Oxidative Stress.

Yulong Zheng, So-Yeon Lee, Yeji Lee, Tae-Kyeong Lee, Ji Eun Kim, Tae Hyeon Kim, Il-Jun Kang.

  Obesity produces many health problems, including systemic oxidative stress. This study comprehensively investigated the effects of Sanguisorba officinalis L. extract (SO) as an antioxidant on abnormal lipid accumulation and oxidative stress in 3T3-L1 adipocytes and high-fat diet (HFD)-induced obese mice (n = 48). We evaluated the anti-adipogenic and antioxidant effects of SO on 3T3-L1 by cell viability, Oil red O staining, and NBT assays. The ameliorative effects of SO in HFD-induced C57BL/6J mice were investigated by measuring body weight, serum lipids, adipocyte size, hepatic steatosis, AMPK pathway-related proteins, and thermogenic factors. In addition, the effect of SO on oxidative stress in obese mice was evaluated by the activity of antioxidant enzymes and the production of lipid peroxidation products and ROS production in adipose tissue. We found that SO dose-dependently decreased lipid accumulation and ROS production in 3T3-L1 adipocytes. In C57BL/6J obese mice, SO (above 200 mg/kg) attenuated the HFD-induced gain in body weight and white adipose tissue (WAT) weight without affecting appetite. SO also decreased serum glucose, lipid, and leptin levels and attenuated adipocyte hypertrophy and hepatic steatosis. Furthermore, SO increased the expression of SOD1 and SOD2 in WAT, decreased ROS and lipid peroxides, and activated the AMPK pathway and thermogenic factors. In summary, SO reduces oxidative stress in adipose tissue by increasing antioxidant enzyme activity and improves obesity symptoms through AMPK-pathway-regulated energy metabolism and mitochondrial respiratory thermogenesis.

Keywords:  AMPK pathway; Sanguisorba officinalis L. extract; antioxidant enzymes; obesity; oxidative stress; reactive oxygen species; thermogenesis

DOI:  https://doi.org/10.3390/antiox12040882
J Ethnopharmacol. 2023 Apr 21. pii: S0378-8741(23)00411-7. [Epub ahead of print] 116543

Icariin, the main prenylflavonoid of Epimedii Folium, ameliorated chronic kidney disease by modulating energy metabolism via AMPK activation.

Yudan Zhao, Wanyue Yang, Xin Zhang, Chongning Lv, Jincai Lu.

   ETHNOPHARMACOLOGICAL RELEVANCE: Epimedii Folium is a famous traditional Chinese medicine (TCM) widely used in classic formulas, Chinese patent drugs and health care products for treating kidney diseases. Therefore, we speculated that icariin, its main component, might also have a good therapeutic effect on chronic kidney disease (CKD).
AIM OF STUDY: To investigate the efficacy and potential mechanism of icariin on CKD.
MATERIALS AND METHODS: A CKD model was established by intragastric administration of adenine (200 mg/kg/d) to adult male SD rats for 28 consecutive days. TGF-β1-induced fibrotic HK-2 cells were applied to establish the renal fibrosis model in vitro. Biochemical determination, pathological staining, flow cytometry and ELISA were performed to preliminarily evaluate the renoprotection of icariin. The intervention effect of icariin on renal fibrosis progression was assessed by cell stiffness determination and multiple immunological methods. The potential mechanism of icariin on CKD was revealed by means of 1H NMR metabolomics, qRT-PCR and western blotting analysis.
RESULTS: Icariin at the dosage of 100 mg/kg/d and 200 mg/kg/d markedly ameliorated rat renal function in a dose-dependent manner. Based on renal pathological features, the mechanism of icariin intervention in CKD was initially revealed by metabolomics, which was closely related to energy metabolism pathways. Furthermore, the detection results of AMPK and related factors in its mediated signaling pathways indicated that icariin exerted a therapeutic effect on CKD by attenuating inflammation and oxidative stress responses and retarding renal fibrosis progression through regulating AMPK/SIRT1/NF-κB and AMPK/ACC signaling pathways.
CONCLUSION: It was the first time to demonstrate that icariin could treat adenine-induced CKD by modulating energy metabolism via AMPK activation in a dose-dependent manner.

Keywords:  AMPK; Chronic kidney disease; Energy metabolism; Icariin; Metabolomics

DOI:  https://doi.org/10.1016/j.jep.2023.116543
Int J Mol Sci. 2023 Apr 07. pii: 6900. [Epub ahead of print]24(8):

Kaempferol Suppresses Carbon Tetrachloride-Induced Liver Damage in Rats via the MAPKs/NF-κB and AMPK/Nrf2 Signaling Pathways.

Changyong Lee, Sik Yoon, Jeon-Ok Moon.

  Oxidative stress plays a critical role in the development of liver disease, making antioxidants a promising therapeutic approach for the prevention and management of liver injuries. The aim of this study was to investigate the hepatoprotective effects of kaempferol, an antioxidant flavonoid found in various edible vegetables, and its underlying mechanism in male Sprague-Dawley rats with carbon tetrachloride (CCl4)-induced acute liver damage. Oral administration of kaempferol at doses of 5 and 10 mg/kg body weight resulted in the amelioration of CCl4-induced abnormalities in hepatic histology and serum parameters. Additionally, kaempferol decreased the levels of pro-inflammatory mediators, TNF-α and IL-1β, as well as COX-2 and iNOS. Furthermore, kaempferol suppressed nuclear factor-kappa B (NF-κB) p65 activation, as well as the phosphorylation of Akt and mitogen-activated protein kinase members (MAPKs), including extracellular signal-regulated kinase, c-Jun NH2-terminal kinase, and p38 in CCl4-intoxicated rats. In addition, kaempferol improved the imbalanced oxidative status, as evidenced by the reduction in reactive oxygen species levels and lipid peroxidation, along with increased glutathione content in the CCl4-treated rat liver. Administering kaempferol also enhanced the activation of nuclear factor-E2-related factor (Nrf2) and heme oxygenase-1 protein, as well as the phosphorylation of AMP-activated protein kinase (AMPK). Overall, these findings suggest that kaempferol exhibits antioxidative, anti-inflammatory, and hepatoprotective effects through inhibiting the MAPK/NF-κB signaling pathway and activating the AMPK/Nrf2 signaling pathway in CCl4-intoxicated rats.

Keywords:  AMPK; MAPK; NF-κB; Nrf2; anti-inflammatory; antioxidative; hepatoprotective; kaempferol

DOI:  https://doi.org/10.3390/ijms24086900
Int J Mol Sci. 2023 Apr 21. pii: 7671. [Epub ahead of print]24(8):

Oscillation of Autophagy Induction under Cellular Stress and What Lies behind It, a Systems Biology Study.

Bence Hajdú, Luca Csabai, Margita Márton, Marianna Holczer, Tamás Korcsmáros, Orsolya Kapuy.

  One of the main inducers of autophagy-dependent self-cannibalism, called ULK1, is tightly regulated by the two sensor molecules of nutrient conditions and energy status, known as mTOR and AMPK kinases, respectively. Recently, we developed a freely available mathematical model to explore the oscillatory characteristic of the AMPK-mTOR-ULK1 regulatory triangle. Here, we introduce a systems biology analysis to explain in detail the dynamical features of the essential negative and double-negative feedback loops and also the periodic repeat of autophagy induction upon cellular stress. We propose an additional regulatory molecule in the autophagy control network that delays some of AMPK's effect on the system, making the model output more consistent with experimental results. Furthermore, a network analysis on AutophagyNet was carried out to identify which proteins could be the proposed regulatory components in the system. These regulatory proteins should satisfy the following rules: (1) they are induced by AMPK; (2) they promote ULK1; (3) they down-regulate mTOR upon cellular stress. We have found 16 such regulatory components that have been experimentally proven to satisfy at least two of the given rules. Identifying such critical regulators of autophagy induction could support anti-cancer- and ageing-related therapeutic efforts.

Keywords:  autophagy; bistable switch; feedback loops; mathematical modelling; oscillation

DOI:  https://doi.org/10.3390/ijms24087671
Biology (Basel). 2023 Apr 06. pii: 556. [Epub ahead of print]12(4):

Tripeptide IRW Improves AMPK/eNOS Signaling Pathway via Activating ACE2 in the Aorta of High-Fat-Diet-Fed C57BL/6 Mice.

Fatemeh Ashkar, Khushwant S Bhullar, Xu Jiang, Jianping Wu.

  This study aims to investigate the effect of tripeptide IRW on the local renin-angiotensin system (RAS), particularly angiotensin-converting enzyme 2 (ACE2), and their association with signaling pathways in the aorta of a high-fat-diet (HFD)-induced insulin-resistant mouse model. C57BL/6 mice were fed HFD (45% of the total calories) for six weeks, and then IRW was added to the diet (45 mg/kg body weight (BW)) for another eight weeks. ACE2 mRNA expression and protein level(s) were increased (p < 0.05), while angiotensin II receptor (AT1R) and angiotensin-converting enzyme (ACE) protein abundance was significantly reduced (p < 0.05) in the aorta of HFD mice treated by IRW. IRW supplementation also improved glucose transporter 4 (GLUT4) abundance (p < 0.05) alongside AMP-activated protein kinase (AMPK) (p < 0.05), Sirtuin 1 (SIRT1) (p < 0.05), and endothelial nitric oxide synthase (eNOS) (p < 0.05) expression. IRW downregulated the levels of endothelin 1 (ET-1) and p38 mitogen-activated protein kinases (p38 MAPK, p < 0.05). Furthermore, the levels of AMPK and eNOS in vascular smooth muscle cells (VSMCs) were significantly reduced in ACE2 knockdown cells treated with or without IRW (p < 0.01). In conclusion, this study provided new evidence of the regulatory role of IRW on the aortic ACE2 against metabolic syndrome (MetS) in an HFD-induced insulin-resistant model.

Keywords:  ACE2; GLUT4; IRW; eNOS; insulin resistance; peptides

DOI:  https://doi.org/10.3390/biology12040556
Molecules. 2023 Apr 14. pii: 3482. [Epub ahead of print]28(8):

Protective Effect of Ferulic Acid on Lipopolysaccharide-Induced BV2 Microglia Inflammation via AMPK/mTOR Signaling Pathway.

Xingru Chen, Xiaolan Zhou, Xiaoqing Cheng, Liting Lin, Qi Wang, Ruoting Zhan, Qingguang Wu, Sijun Liu.

  In neurodegenerative diseases, microglial activation and neuroinflammation are essential for the control and progression of neurodegenerative diseases. Mitigating microglium-induced inflammation is one strategy for hindering the progression of neurodegenerative diseases. Ferulic acid (FA) is an effective anti-inflammatory agent, but its potential role and regulation mechanism in neuroinflammatory reactions have not been fully studied. In this study, the neuroinflammation model was established by lipopolysaccharide (LPS), and the inhibitory effect of FA on neuroinflammation of BV2 microglia was studied. The results showed that FA significantly reduced the production and expression of reactive oxygen species (ROS), tumor necrosis factor-α (TNF-α), leukocyte-6 (IL-6) and interleukin-1β (IL-1β). We further studied the mechanism of FA's regulation of LPS-induced BV2 neuroinflammation and found that FA can significantly reduce the expression of mTOR in BV2 microglia induced by LPS, and significantly increase the expression of AMPK, indicating that FA may have an anti-inflammatory effect by activating the AMPK/mTOR signaling pathway to regulate the release of inflammatory mediators (such as NLRP3, caspase-1 p20 and IL-1β). We further added an autophagy inhibitor (3-MA) and an AMPK inhibitor (compound C, CC) for reverse verification. The results showed that FA's inhibitory effects on TNF-α, IL-6 and IL-1β and its regulatory effect on AMPK/mTOR were destroyed by 3-MA and CC, which further indicated that FA's inhibitory effect on neuroinflammation is related to its activation of the AMPK/mTOR autophagy signaling pathway. In a word, our experimental results show that FA can inhibit LPS-induced neuroinflammation of BV2 microglia by activating the AMPK/mTOR signaling pathway, and FA may be a potential drug for treating neuroinflammatory diseases.

Keywords:  AMPK/mTOR signaling pathway; BV2 microglia; NLRP3 inflammasome; autophagy; ferulic acid; neuroinflammation

DOI:  https://doi.org/10.3390/molecules28083482