bims-amsmem 2022-05-01 papers

bims-amsmem

Biomed News

on AMPK signaling mechanism in energy metabolism

Issue of 2022‒05‒01
24 papers selected by
Dipsikha Biswas, Københavns Universitet

Caffeic acid dimethyl ether alleviates alcohol-induced hepatic steatosis via microRNA-378b-mediated CaMKK2-AMPK pathway.
Tumor metabolism destruction via metformin-based glycolysis inhibition and glucose oxidase-mediated glucose deprivation for enhanced cancer therapy.
4.8% sevoflurane induces activation of autophagy in human neuroblastoma SH-SY5Y cells by the AMPK/mTOR signaling pathway.
Claudin-1 mediates progression by regulating EMT through AMPK/TGF-β signaling in head and neck squamous cell carcinoma.
Metformin in nucleus accumbens core reduces cue-induced cocaine seeking in male and female rats.
The role of ER stress and ATP/AMPK in oxidative stress meditated hepatotoxicity induced by citrinin.
AMPK Signaling Regulates Mitophagy and Mitochondrial ATP Production in Human Trophoblast Cell Line BeWo.
Glucose-Dependent miR-125b is a Negative Regulator of β-Cell Function.
Adenosine mono-phosphate-activated protein kinase-mammalian target of rapamycin signaling participates in the protective effect of chronic intermittent hypobaric hypoxia on vascular endothelium of metabolic syndrome rats.
Glutamine, MTOR and autophagy: a multiconnection relationship.
Puerarin protects against sepsis-induced myocardial injury through AMPK-mediated ferroptosis signaling.
Midkine noncanonically suppresses AMPK activation through disrupting the LKB1-STRAD-Mo25 complex.
EGCG and ECG induce apoptosis and decrease autophagy via the AMPK/mTOR and PI3K/AKT/mTOR pathway in human melanoma cells.
Sulforaphane induces lipophagy through the activation of AMPK-mTOR-ULK1 pathway signaling in adipocytes.
Amyloid-β activates NLRP3 inflammasomes by affecting microglial immunometabolism through the Syk-AMPK pathway.
Gandi Capsule Improved Podocyte Lipid Metabolism of Diabetic Nephropathy Mice through SIRT1/AMPK/HNF4A Pathway.
Enhancement of anaerobic glycolysis - a role of PGC-1α4 in resistance exercise.
Immunotherapy Mechanism of Esophageal Squamous Cell Carcinoma with the Effect of STK11/AMPK Signaling Pathway.
Metformin Regulates TET2 Expression to Inhibit Endometrial Carcinoma Proliferation: A New Mechanism.
The paradoxical role of inositol in cancer: a consequence of the metabolic state of a tumor.
Preventive effect of salicin ether against type-2 diabetes mellitus through targeting PPARγ-regulated gene expression.
Asteltoxin inhibits extracellular vesicle production through AMPK/mTOR-mediated activation of lysosome function.
The effect of metformin on the metabolism of human vascular smooth muscle cells in high glucose conditions.
Lupeol triggers oxidative stress, ferroptosis, apoptosis and restrains inflammation in nasopharyngeal carcinoma via AMPK/NF-κB pathway.

Bioengineered. 2022 Apr;13(4): 11122-11136

Caffeic acid dimethyl ether alleviates alcohol-induced hepatic steatosis via microRNA-378b-mediated CaMKK2-AMPK pathway.

Jun Lu, Yan Zhang, Ying-Zhao Wang, Yuan-Yuan Li, Rui Wang, Yu-Juan Zhong, Li Chen, Meng-Wei Song, Lin Shi, Li Li, Yong-Wen Li.

  Alcoholic liver disease (ALD), with its increasing morbidity and mortality, has seriously and extensively affected the health of people worldwide. Caffeic Acid Dimethyl Ether (CADE) significantly inhibits alcohol-induced hepatic steatosis in vivo through AMP-activated protein kinase (AMPK) pathway, but its in-depth mechanism remains unclear. This work aimed to clarify further mechanism of CADE in improving hepatic lipid accumulation in ALD through the microRNA-378b (miR-378b)-mediated Ca2+/calmodulin-dependent protein kinase kinase 2 (CaMKK2)-AMPK signaling pathway. Here, we reported that the hepatic or serum triglyceride (TG), total cholesterol (TC), alanine aminotransferase (ALT), and aspartate transaminase (AST) levels were sharply escalated by ethanol while prominently decreased by CADE. Ethanol sharply up-regulated miR-378b expression while CADE effectively prevented the elevation of miR-378b in vivo. And treatment of CADE surely increased mRNA and protein expression of CaMKK2 as a kinase of AMPK and reduced lipid accumulation in the livers of alcohol-fed C57BL/6 mice. MiR-378b escalation exacerbated hepatic steatosis and inhibited CaMKK2-AMPK signaling, while miR-378b deficiency alleviated lipid accumulation and activated the CaMKK2 cascade. Furthermore, CADE alleviated the lipid deposition and reversed the disorder of CaMKK2-AMPK signaling pathway induced by miR-378b over-expression. However, knockdown of miR-378b eliminated the beneficial effect of CADE on lipid metabolism. In brief, our results showed that CADE ultimately improved hepatic lipid deposition by regulating the CaMKK2-AMPK signaling pathway through miR-378b.

Keywords:  ALD; CADE; CaMKK2; hepatic lipid accumulation; miR-378b

DOI:  https://doi.org/10.1080/21655979.2022.2060586
Acta Biomater. 2022 Apr 20. pii: S1742-7061(22)00231-8. [Epub ahead of print]

Tumor metabolism destruction via metformin-based glycolysis inhibition and glucose oxidase-mediated glucose deprivation for enhanced cancer therapy.

Xiangyu Meng, Zhuoxuan Lu, Qingyu Lv, Yongqiang Jiang, Liming Zhang, Zhifei Wang.

  Cancer cells rely on glycolysis to support a high proliferation rate. Metformin (Met) is a promising drug for tumor treatment that targets hexokinase 2 (HK2) to block the glycolytic process, thereby further disrupting the metabolism of cancer cells. Herein, an intelligent nanomedicine based on glucose deprivation and glycolysis inhibition is creatively constructed for enhanced cancer synergistic treatment. In brief, Met and glucose oxidase (GOx) was encapsulated into histidine/zeolitic imidazolate framework-8 (His/ZIF-8), which was followed by coating with Arg-Gly-Asp (RGD) peptides to obtain the desired nanomedicine (Met/GOx@His/ZIF-8∼RGD). This smart nanomedicine presents the controllable Met and GOx release behavior in an acidic responsive manner. The liberated Met blocks the glycolysis process via suppressing the activity of HK2 and impairing ATP production, which activates the AMP-activated protein kinase (AMPK) pathway and p53 pathway and damages the Warburg effect, eventually leading to cells apoptosis. And the GOx boosts the glucose shortage for starvation therapy by depleting accumulated glucose. According to in vitro and in vivo assays, the combination of glycolysis inhibition and starvation therapy demonstrates efficient cancer cells growth suppression and superior antitumor properties compared to the Met-based or GOx-mediated monotherapy. This work provides an advanced therapeutic strategy via disrupting cellular metabolism against cancer. STATEMENT OF SIGNIFICANCE: The obtained nanomedicine (Met/GOx@His/ZIF-8∼RGD) presents the controllable Met and glucose oxidase (GOx) release behavior in an acidic responsive manner. The liberated Met blocks the glycolysis process via suppressing the activity of HK2 and impairing ATP production, which activates the AMP-activated protein kinase (AMPK) pathway and p53 pathway and damages the Warburg effect, eventually leading to cells apoptosis. And the GOx boosts the glucose shortage for starvation therapy by depleting accumulated glucose. The combination of glycolysis inhibition and starvation therapy demonstrate the efficient suppression of cancer cells growth and the superior antitumor properties when compared to the Met-based or GOx-mediated monotherapy.

Keywords:  Metformin; glycolysis inhibition; modified zeolitic imidazolate framework-8; starvation therapy; tumor metabolism

DOI:  https://doi.org/10.1016/j.actbio.2022.04.022
Neurotoxicology. 2022 Apr 23. pii: S0161-813X(22)00056-0. [Epub ahead of print]

4.8% sevoflurane induces activation of autophagy in human neuroblastoma SH-SY5Y cells by the AMPK/mTOR signaling pathway.

Jingjing Lv, Hao Cheng, Weidong Yao, Can Liu, Yongquan Chen, Xiaoju Jin, Zeyong Yang, Yuanhai Li.

  Prolonged sevoflurane exposure leads to neurotoxicity. Autophagy plays an important role in promoting cell survival in different conditions. However, the role and mechanism of autophagy in sevoflurane-induced neurotoxicity were not fully elucidated. We attempted to indicate whether sevoflurane could activate the AMP-activated protein kinase (AMPK)/mechanistic target of rapamycin (mTOR)-mediated autophagy to attenuate anesthetics-induced neuronal injury in this study. Sevoflurane treatment significantly decreased the cell viability and induced apoptosis of SH-SY5Y cells. The expression level of Bcl-2 decreased, while that of Bax remarkably increased. Meanwhile, autophagy was activated by sevoflurane exposure as evidenced by increased expression levels of autophagy-related proteins (LC3-II and Atg5), decreased expression level of autophagic substrate P62, and increased autophagosomes and autolysosomes. Further autophagosomes and fewer autolysosomes were observed in the presence of Bafilomycin A1, an autolysosomes degradation inhibitor, suggesting that sevoflurane induced autophagic flux rather than inhibiting degradation of autophagy. Activation of autophagy by rapamycin partly reversed the sevoflurane-decreased cell viability. In contrast, inhibition of autophagy by 3-Methyladenine (3-MA) or Atg5-targeted small interfering RNA (siRNA) aggravated the sevoflurane-induced neurotoxicity. Further examination revealed that sevoflurane-induced autophagy was mediated by the AMPK/mTOR signaling pathway, with increased p-AMPK expression and decreased p-mTOR expression. Collectively, these results indicated that sevoflurane activates autophagy by regulating the AMPK/mTOR signaling pathway, which is protective against sevoflurane-induced damage in SH-SY5Y cells. Our results may assist clinicians to develop further promising therapeutic strategies for the neurotoxicity induced by inhaled anesthetics.

Keywords:  AMPK/mTOR signaling pathway; Apoptosis; Autophagy; SH-SY5Y cells; Sevoflurane

DOI:  https://doi.org/10.1016/j.neuro.2022.04.008
Transl Res. 2022 Apr 21. pii: S1931-5244(22)00071-8. [Epub ahead of print]

Claudin-1 mediates progression by regulating EMT through AMPK/TGF-β signaling in head and neck squamous cell carcinoma.

Jae Won Chang, Sung Tae Seo, Mi Ae Im, Ho-Ryun Won, Lihua Liu, Chan Oh, Yan Li Jin, Yudan Piao, Hae Jong Kim, Jung Tae Kim, Seung-Nam Jung, Bon Seok Koo.

  Claudin-1 (CLDN1), a major component of tight junction complexes in the epithelium, maintains cellular polarity and plays a critical role in cell-to-cell communication as well as epithelial cell homeostasis. Although the role of CLDN1 has been widely studied in cancer, its role in the progression and the exact regulatory mechanisms, remain controversial. Using next-generation sequencing, we first analyzed the expression profiles of tumor/non-tumor paired tissue in patients with head and neck squamous cell carcinoma (HNSC) from public and local cohorts and found out that CLDN1 is upregulated in tumors compared to normal tissues. Next, its correlation with lymph node metastasis and poor prognosis was validated in the retrospective cohort, which collectively suggests CLDN1 as an oncogene in HNSC. As expected, the knockdown of CLDN1 inhibited invasive phenotypes by downregulating epithelial-to-mesenchymal transition (EMT) in vitro. To ascertain the regulatory mechanism of CLDN1 in HNSC analysis of GO term enrichment, KEGG pathways, and curated gene sets were used. As a result, CLDN1 was negatively associated with AMP-activated protein kinase (AMPK) and positively associated with transforming growth factor-β (TGF-β) signaling. In vitro mechanistic assay showed that CLDN1 inhibited AMPK phosphorylation by regulating AMPK upstream phosphatases, which led to inhibition of Smad2 activity. Intriguingly, the invasive phenotype of cancer cells increased by CLDN1 overexpression was rescued by AMPK activation, indicating a role of the CLDN1/AMPK/TGF-β/EMT cascade in HNSC. Consistently in vivo, CLDN1 suppression significantly inhibited the tumor growth, with elevated AMPK expression, suggesting the novel observation of oncogenic CLDN1-AMPK signaling in HNSC.

Keywords:  AMP-activated protein kinase; Claudin 1; Epithelial-mesenchymal transition; Head and neck squamous cell carcinoma; RNA sequencing; Transforming growth factor-β; Tumor invasion

DOI:  https://doi.org/10.1016/j.trsl.2022.04.003
Addict Biol. 2022 May;27(3): e13165

Metformin in nucleus accumbens core reduces cue-induced cocaine seeking in male and female rats.

Amy Chan, Alexis Willard, Sarah Mulloy, Noor Ibrahim, Allegra Sciaccotta, Mark Schonfeld, Sade M Spencer.

  This study investigated the potential therapeutic effects of the FDA-approved drug metformin on cue-induced reinstatement of cocaine seeking. Metformin (dimethyl-biguanide) is a first-line treatment for type II diabetes that, among other mechanisms, is involved in the activation of adenosine monophosphate activated protein kinase (AMPK). Cocaine self-administration and extinction is associated with decreased levels of phosphorylated AMPK within the nucleus accumbens core (NAcore). Previously, it was shown that increasing AMPK activity in the NAcore decreased cue-induced reinstatement of cocaine seeking. Decreasing AMPK activity produced the opposite effect. The goal of the present study was to determine if metformin in the NAcore reduces cue-induced cocaine seeking in adult male and female Sprague Dawley rats. Rats were trained to self-administer cocaine followed by extinction prior to cue-induced reinstatement trials. Metformin microinjected in the NAcore attenuated cue-induced reinstatement in male and female rats. Importantly, metformin's effects on cocaine seeking were not due to a general depression of spontaneous locomotor activity. In female rats, metformin's effects did generalize to a reduction in cue-induced reinstatement of sucrose seeking. These data support a potential role for metformin as a pharmacotherapy for cocaine use disorder but warrant caution given the potential for metformin's effects to generalize to a natural reward in female rats.

Keywords:  cocaine; metformin; nucleus accumbens; reinstatement; self-administration

DOI:  https://doi.org/10.1111/adb.13165
Ecotoxicol Environ Saf. 2022 Apr 25. pii: S0147-6513(22)00371-2. [Epub ahead of print]237 113531

The role of ER stress and ATP/AMPK in oxidative stress meditated hepatotoxicity induced by citrinin.

Jing Wu, Chenglin Yang, Mengran Yang, Zengenni Liang, You Wu, Xiangyi Kong, Hui Fan, Siqi Wang, Can Ning, Wenguang Xiao, Ye Jin, Jine Yi, Zhihang Yuan.

  Citrinin, a secondary metabolite, can pose serious risks to the environment and organisms, but its hepatotoxic mechanisms are still unclear. Histopathological and ultrastructural results showed that citrinin-induced liver injury in Kunming mice, and the mechanism of citrinin-induced hepatotoxicity was studied in L02 cells. Firstly, citrinin mades L02 cell cycle arrest in G2/M phase by inhibition of cyclin B1, cyclin D1, cyclin-dependent kinases 2 (CDK2), and CDK4 expression. Secondly, citrinin inhibits proliferation and promotes apoptosis of L02 cells via disruption of mitochondria membrane potential, increase Bax/Bcl-2 ration, activation of caspase-3, 9, and enhance lactate dehydrogenase (LDH) release. Then, citrinin inhibits superoxide dismutase (SOD) activity and increases the accumulation of malondialdehyde (MDA) and reactive oxygen species (ROS), resulting oxidative damage in L02 cells; upregulates the protein expression of binding immunoglobulin protein (Bip), C/EBP homologous protein (CHOP), PKR-like ER kinase (PERK) and activating transcription factor6 (ATF6), inducing ER stress in L02 cells; increases the phosphorylation of AMP-activated protein kinase (AMPK) and decreases the content of adenosine-triphosphate (ATP), activating AMPK pathway in L02 cells. Eventually, pretreatment with NAC, an ROS inhibitor, alleviates citrinin-induced cell cycle G2/M arrest and apoptosis by inhibiting ROS-mediated ER stress; pretreatment with 4-PBA, an ER stress inhibitor, reversed ER stress and p-AMPK; pretreatment with dorsomorphin, an AMPK inhibitor, decreases citrinin-induced cell cycle G2/M arrest and apoptosis. In summary, citrinin induces cell cycle arrest and apoptosis to aggravate liver injury by activating ROS-ER stress-AMPK signaling pathway.

Keywords:  AMPK; Apoptosis; Cell cycle arrest; Citrinin; ER stress; ROS

DOI:  https://doi.org/10.1016/j.ecoenv.2022.113531
Front Biosci (Landmark Ed). 2022 Apr 01. 27(4): 118

AMPK Signaling Regulates Mitophagy and Mitochondrial ATP Production in Human Trophoblast Cell Line BeWo.

Bin Wu, Yun Chen, Robert Clarke, Emmanuel Akala, Peixin Yang, Bin He, Haijun Gao.

  INTRODUCTION: Accumulating evidence suggests that mitochondrial structural and functional defects are present in human placentas affected by pregnancy related disorders, but mitophagy pathways in human trophoblast cells/placental tissues have not been investigated.METHODS: In this study, we investigated three major mitophagy pathways mediated by PRKN, FUNDC1, and BNIP3/BNIP3L in response to AMPK activation by AICAR and knockdown of PRKAA1/2 (AKD) in human trophoblast cell line BeWo and the effect of AKD on mitochondrial membrane potential and ATP production.
RESULTS: Autophagy flux assay demonstrated that AMPK signaling activation stimulates autophagy, evidenced increased LC3II and SQSTM1 protein abundance in the whole cell lysates and mitochondrial fractions, and mitophagy flux assay demonstrated that the activation of AMPK signaling stimulates mitophagy via PRKN and FUNDC1 mediated but not BNIP3/BNIP3L mediated pathways. The stimulatory regulation of AMPK signaling on mitophagy was confirmed by AKD which reduced the abundance of LC3II, SQSTM1, PRKN, and FUNDC1 proteins, but increased the abundance of BNIP3/BNIP3L proteins. Coincidently, AKD resulted in elevated mitochondrial membrane potential and reduced mitochondrial ATP production, compared to control BeWo cells.
CONCLUSIONS: In summary, AMPK signaling stimulates mitophagy in human trophoblast cells via PRKN and FUNDC1 mediated mitophagy pathways and AMPK regulated mitophagy contributes to the maintenance of mitochondrial membrane potential and mitochondrial ATP production.

Keywords:  AMPK; ATP production; BeWo; human; mitochondria; mitophagy; trophoblast

DOI:  https://doi.org/10.31083/j.fbl2704118
Diabetes. 2022 Apr 27. pii: db210803. [Epub ahead of print]

Glucose-Dependent miR-125b is a Negative Regulator of β-Cell Function.

Rebecca Cheung, Grazia Pizza, Pauline Chabosseau, Delphine Rolando, Alejandra Tomas, Thomas Burgoyne, Zhiyi Wu, Anna Salowka, Anusha Tapa, Annabel Macklin, Yufei Cao, Marie-Sophie Nguyen-Tu, Matthew T Dickerson, David A Jacobson, Piero Marchetti, James Shapiro, Lorenzo Piemonti, Eelco de Koning, Isabelle Leclerc, Karim Bouzakri, Kei Sakamoto, David M Smith, Guy A Rutter, Aida Martinez-Sanchez.

Impaired pancreatic β-cell function and insulin secretion are hallmarks of type 2 diabetes. MicroRNAs are short non-coding RNAs that silence gene expression, vital for the development and function of β-cells. We have previously shown that β-cell specific deletion of the important energy sensor AMP-activated protein kinase (AMPK) results in increased miR-125b-5p levels. Nevertheless, the function of this miRNA in β-cells is unclear. We hypothesized that miR125b-5p expression is regulated by glucose and that this miRNA mediates some of the deleterious effects of hyperglycaemia in β-cells. Here we show that islet miR-125b-5p expression is up-regulated by glucose in an AMPK-dependent manner and that short-term miR125b-5p overexpression impairs glucose stimulated insulin secretion (GSIS) in the mouse insulinoma MIN6 cells and in human islets. An unbiased high-throughput screen in MIN6 cells identified multiple miR-125b-5p targets, including the transporter of lysosomal hydrolases M6pr and the mitochondrial fission regulator Mtfp1. Inactivation of miR-125b-5p in the human β-cell line EndoCβ-H1 shortened mitochondria and enhanced GSIS, whilst mice overexpressing miR-125b-5p selectively in β-cells (MIR125B-Tg) were hyperglycaemic and glucose intolerant. MIR125B-Tg β-cells contained enlarged lysosomal structures and showed reduced insulin content and secretion. Collectively, we identify miR-125b as a glucosecontrolled regulator of organelle dynamics that modulates insulin secretion.

DOI: https://doi.org/10.2337/db21-0803
Chin J Physiol. 2022 Mar-Apr;65(2):65(2): 53-63

Adenosine mono-phosphate-activated protein kinase-mammalian target of rapamycin signaling participates in the protective effect of chronic intermittent hypobaric hypoxia on vascular endothelium of metabolic syndrome rats.

Fang Cui, Min Shi, Hao-Fei Hu, Yan-Ming Tian, Chen-Ming Zhou, Hai-Chao Mi, Shuo Gu, Zan Guo, Xiang-Jian Zhang, Yi Zhang.

  Our previous study demonstrated that chronic intermittent hypobaric hypoxia (CIHH) protects vascular endothelium function through ameliorating autophagy in mesenteric arteries of metabolic syndrome (MS) rats. This study aimed to investigate the role of adenosine mono-phosphate-activated protein kinase-mammalian target of rapamycin (AMPK-mTOR) signaling in CIHH effect. Six-week-old male Sprague-Dawley rats were divided into control (CON), MS model, CIHH treatment (CIHH), and MS + CIHH groups. Serum pro-inflammatory cytokines were measured. The endothelium dependent relaxation (EDR), endothelial ultrastructure and autophagosomes were observed in mesenteric arteries. The expression of phosphor (p)-AMPKα, p-mTOR, autophagy-related and endoplasmic reticulum stress-related proteins, p-endothelial nitric oxide synthase, and cathepsin D were assayed. In MS rats, pro-inflammatory cytokines were increased, EDR was attenuated, and endothelial integrity was impaired. In addition, the expression level of p-AMPKα and cathepsin D was down-regulated, but the level of p-mTOR was up-regulated. While in MS + CIHH rats, all aforementioned abnormalities were ameliorated, and the beneficial effect of CIHH was cancelled by AMPKα inhibitor. In conclusion, AMPK-mTOR signaling pathway participates in the protection of CIHH on vascular endothelium of MS rats.

Keywords:  AMPK-mTOR signaling pathway; autophagy; chronic intermittent hypobaric hypoxia; endothelium dependent relaxation; metabolic syndrome

DOI:  https://doi.org/10.4103/cjp.cjp_84_21
Autophagy. 2022 Apr 26. 1-2

Glutamine, MTOR and autophagy: a multiconnection relationship.

Clément Bodineau, Mercedes Tomé, Piedad Del Socorro Murdoch, Raúl V Durán.

  Cancer cells metabolize glutamine mostly through glutaminolysis, a metabolic pathway that activates MTORC1. The AMPK-MTORC1 signaling axis is a key regulator of cell growth and proliferation. Our recent investigation identified that the connection between glutamine and AMPK is not restricted to glutaminolysis. Rather, we demonstrated the crucial role of ASNS (asparagine synthetase (glutamine-hydrolyzing)) and the GABA shunt for the metabolic control of the AMPK-MTORC1 axis during glutamine sufficiency. Our results elucidated a metabolic network by which glutamine metabolism regulates the MTORC1-macroautophagy/autophagy pathway through two independent branches involving glutaminolysis and ASNS-GABA shunt.

Keywords:  ASNS; GABA-shunt; MTORC1; glutamine; glutamoptosis

DOI:  https://doi.org/10.1080/15548627.2022.2062875
Aging (Albany NY). 2022 Apr 28. 14(undefined):

Puerarin protects against sepsis-induced myocardial injury through AMPK-mediated ferroptosis signaling.

Bin Zhou, Jing Zhang, Yixuan Chen, Yang Liu, Xiaoyi Tang, Panpan Xia, Peng Yu, Shuchun Yu.

  OBJECTIVE: Research suggests that Puerarin may protect against sepsis-induced myocardial damage. However, the mechanisms responsible for Puerarin's cardioprotective effect remain largely unclear. In this study, our objective is to investigate the role of Puerarin-induced AMPK-mediated ferroptosis signaling in protecting myocardial injury.METHODS: 48 male Sprague-Dawley rats were randomly divided into four groups: control group, LPS group, LPS + Pue group, LPS + Pue + Era (Erastin, ferroptosis activator) group, or LPS + Pue + CC (compound C, AMPK inhibitor) group. During the experiment, cardiac systolic function indexes and myocardial histopathological changes were monitored. The serum levels of myocardial injury marker enzyme, inflammatory response related marker enzyme, and oxidative stress related-marker enzyme were measured with ELISA. Apoptotic cardiomyocytes, the iron content in myocardial tissue, apoptosis-related proteins, AMPK, and ferroptosis-related proteins were determined.
RESULTS: Puerarin inhibited the myocardial injury induced by LPS. The cardioprotective effects of Puerarin decreased after adding ferroptosis-activating compound Erastin. The protein expression levels of GPX4 and ferritin were down-regulated, whereas ACSL4, TFR, and heart iron content were up-regulated in LPS + Pue + Era group compared with LPS+Pue group. A significant difference was identified between LPS + Pue + Era group and LPS + Pue group in P-AMPK and T-AMPK levels. Meanwhile, after providing CC, P-AMPK/T-AMPK was significantly reduced, the protein expression levels of GPX4 and ferritin were down-regulated. ACSL4, TFR, and the heart iron content were up-regulated in LPS + Pue + CC group compared to LPS + Pue group.
CONCLUSIONS: Puerarin protected against sepsis-induced myocardial injury, and AMPK-mediated ferroptosis signaling played a crucial role in its cardioprotective effect.

Keywords:  AMPK; LPS; Puerarin; ferroptosis; myocardial injury

DOI:  https://doi.org/10.18632/aging.204033
Cell Death Dis. 2022 Apr 29. 13(4): 414

Midkine noncanonically suppresses AMPK activation through disrupting the LKB1-STRAD-Mo25 complex.

Tian Xia, Di Chen, Xiaolong Liu, Huan Qi, Wen Wang, Huan Chen, Ting Ling, Wuxiyar Otkur, Chen-Song Zhang, Jongchan Kim, Sheng-Cai Lin, Hai-Long Piao.

Midkine (MDK), a secreted growth factor, regulates signal transduction and cancer progression by interacting with receptors, and it can be internalized into the cytoplasm by endocytosis. However, its intracellular function and signaling regulation remain unclear. Here, we show that intracellular MDK interacts with LKB1 and STRAD to disrupt the LKB1-STRAD-Mo25 complex. Consequently, MDK decreases the activity of LKB1 to dampen both the basal and stress-induced activation of AMPK by glucose starvation or treatment of 2-DG. We also found that MDK accelerates cancer cell proliferation by inhibiting the activation of the LKB1-AMPK axis. In human cancers, compared to other well-known growth factors, MDK expression is most significantly upregulated in cancers, especially in liver, kidney and breast cancers, correlating with clinical outcomes and inversely correlating with phosphorylated AMPK levels. Our study elucidates an inhibitory mechanism for AMPK activation, which is mediated by the intracellular MDK through disrupting the LKB1-STRAD-Mo25 complex.

DOI: https://doi.org/10.1038/s41419-022-04801-0
Chin J Nat Med. 2022 Apr;pii: S1875-5364(22)60166-3. [Epub ahead of print]20(4): 290-300

EGCG and ECG induce apoptosis and decrease autophagy via the AMPK/mTOR and PI3K/AKT/mTOR pathway in human melanoma cells.

Bing-Xin DU, Pei Lin, Jun Lin.

  Catechins have been proven to exert antitumor effects in different kinds of cancers. However, the underlying mechanisms have not been completely clarified yet. This study aimed to assess the effects and mechanisms of (-)-epigallocatechin-3-gallate (EGCG) and (-)-epicatechin-3-gallate (ECG) on human melanoma skin A375 cells. Results showed that EGCG and ECG inhibited the proliferation of A375 cells and ECG showed better inhibitory effect. Flow cytometry analysis had shown that EGCG and ECG induced apoptosis and led to cell cycle arrest. EGCG and ECG decreased Bcl-2 expression and upregulated Caspase-3 protein level, indicating the development of apoptosis. Furthermore, EGCG and ECG could decreased mitochondrial membrane potential of A375 cells. In addition, the expression of Beclin-1, LC3 and Sirt3 were downregulated at protein levels, which known to be associated with autophagy. After autophagy was increased by rapamycin, the apoptotic trend was not change, indicating that apoptosis and autophagy are independent. Mechanistically, EGCG and ECG treatments decreased phosphorylated-AMPK (p-AMPK) and increased the ratios of p-PI3K, p-AKT and p-mTOR in melanoma cells. Conclusively, EGCG and ECG induced apoptosis via mitochondrial signaling pathway, downregulated autophagy through modulating the AMPK/mTOR and PI3K/AKT/mTOR signaling pathway. It indicated that EGCG and ECG may be utilized in human melanoma treatment.

Keywords:  Apoptosis; Autophagy; ECG; EGCG; PI3K/AKT/mTOR

DOI:  https://doi.org/10.1016/S1875-5364(22)60166-3
J Nutr Biochem. 2022 Apr 21. pii: S0955-2863(22)00088-2. [Epub ahead of print] 109017

Sulforaphane induces lipophagy through the activation of AMPK-mTOR-ULK1 pathway signaling in adipocytes.

Masashi Masuda, Risa Yoshida-Shimizu, Yuki Mori, Kohta Ohnishi, Yuichiro Adachi, Maiko Sakai, Serina Kabutoya, Hirokazu Ohminami, Hisami Yamanaka-Okumura, Hironori Yamamoto, Makoto Miyazaki, Yutaka Taketani.

  Lipophagy, a form of selective autophagy, degrades lipid droplet (LD) in adipose tissue and the liver. The chemotherapeutic isothiocyanate sulforaphane (SFN) contributes to lipolysis through the activation of hormone-sensitive lipase and the browning of white adipocytes. However, the details concerning the regulation of lipolysis in adipocytes by SFN-mediated autophagy remain unclear. In this study, we investigated the effects of SFN on autophagy in the epididymal fat of mice fed a high-fat diet (HFD) or control-fat diet (CFD) and on the molecular mechanisms of autophagy in differentiated 3T3-L1 cells. Western blotting revealed that the protein expression of lipidated LC3 (LC3-II), an autophagic substrate, was induced after 3T3-L1 adipocytes treatment with SFN. In addition, SFN increased the LC3-II protein expression in the epididymal fat of mice fed an HFD. Immunofluorescence showed that the SFN-induced LC3 expression was co-localized with LDs in 3T3-L1 adipocytes and with perilipin, the most abundant adipocyte-specific protein, in adipocytes of mice fed an HFD. Next, we confirmed that SFN activates autophagy flux in differentiated 3T3-L1 cells using the mCherry-EGFP-LC3 and GFP-LC3-RFP-LC3DG probe. Furthermore, we examined the induction mechanisms of autophagy by SFN in 3T3-L1 adipocytes using western blotting. ATG5 knockdown partially blocked the SFN-induced release of fatty acids from LDs in mature 3T3-L1 adipocytes. SFN time-dependently elicited the phosphorylation of AMPK, the dephosphorylation of mTOR, and the phosphorylation of ULK1 in differentiated 3T3-L1 cells. Taken together, these results suggest that SFN may provoke lipophagy through AMPK-mTOR-ULK1 pathway signaling, resulting in partial lipolysis of adipocytes. (246/250 words).

Keywords:  Lipid droplets; adipose; autophagy; cell biology; dietary factors; obesity

DOI:  https://doi.org/10.1016/j.jnutbio.2022.109017
Aging Cell. 2022 Apr 27. e13623

Amyloid-β activates NLRP3 inflammasomes by affecting microglial immunometabolism through the Syk-AMPK pathway.

Eun Sun Jung, Kyujin Suh, Jihui Han, Heyyoung Kim, Hyung-Sik Kang, Won-Seok Choi, Inhee Mook-Jung.

  Neuroinflammation is considered one of major factors in the pathogenesis of Alzheimer's disease (AD). In particular, inflammasome activation, including NLRP3 inflammasome in microglia, is regarded as fundamental for the pro-inflammatory response of immune cells. However, the precise molecular mechanism through which the NLRP3 inflammasome is associated with AD pathologies remains unclear. Here, we show that amyloid-β activates the NLRP3 inflammasome in microglia by activating Syk and inhibiting AMPK. Deactivated AMPK induces metabolic dysregulation, mitochondrial fragmentation, and reactive oxygen species formation, leading to the activation of the NLRP3 inflammasome. In addition, flufenamic acid (FA), a member of non-steroidal anti-inflammatory drugs, was found to effectively inhibit activation of the microglial NLRP3 inflammasome by regulating Syk and AMPK. Importantly, FA has marked therapeutic effects on major AD pathologies and memory function in vivo in microglia-dependent way. All together, these findings demonstrate the molecular mechanism of microglial NLRP3 inflammasome activation by amyloid-β, which acts as an important mediator of neuroinflammation. Also, we suggest that repurposing of FA for inhibiting microglial activation of the NLRP3 inflammasome is a potential treatment for AD.

Keywords:  Alzheimer's disease; inflammasome; microglia

DOI:  https://doi.org/10.1111/acel.13623
Oxid Med Cell Longev. 2022 ;2022 6275505

Gandi Capsule Improved Podocyte Lipid Metabolism of Diabetic Nephropathy Mice through SIRT1/AMPK/HNF4A Pathway.

Ying Zhang, Huijuan Yao, Chao Li, Wei Sun, Xiaofei Chen, Yan Cao, Yue Liu, Yan Liu, Jihui Chen, Jia Qi, Qiqiang Zhang, Hai Zhang, Ajing Xu, Jian Zhang.

Podocyte lipid accumulation is a potential therapeutic target for diabetic nephropathy (DN). This study was aimed at clarifying the mechanism of Gandi capsule (GDC) ameliorating DN by regulating the lipid metabolism of podocytes. Network pharmacology methods were performed to screen the key molecules and potential targets of GDC for constructing the molecular-protein interaction network of GDC and conducting signal pathway enrichment analysis. GDC was predicted to ameliorate DN through SIRT1/AMPK/HNF4A pathway. Our results showed that GDC improved renal function in db/db mice. Besides, GDC exhibited effectiveness in relieving kidney tissue damage and renal lipid accumulation in db/db mice, and same effects were present in GDC-active ingredient baicalin. We further proved the new role of HNF4A in the lipid metabolism of DN mediated by SIRT1 and AMPK signaling pathways. The results suggested decreased expression of SIRT1 and p-AMPKα in the kidney tissue and increased expression of HNF4A of db/db mice compared with the control group. GDC and baicalin could reverse these expression changes. Furthermore, similar expression changes were observed in the murine podocyte cell line (MPC-5) treated with different concentrations of GDC and baicalin. Our research suggested that GDC and its active ingredient baicalin could alleviate the abnormal lipid metabolism in the kidney of db/db mice and might exert renal protection through the SIRT1/AMPK/HNF4A pathway.

DOI: https://doi.org/10.1155/2022/6275505
Nat Commun. 2022 Apr 28. 13(1): 2324

Enhancement of anaerobic glycolysis - a role of PGC-1α4 in resistance exercise.

Jin-Ho Koh, Mark W Pataky, Surendra Dasari, Katherine A Klaus, Ivan Vuckovic, Gregory N Ruegsegger, Arathi Prabha Kumar, Matthew M Robinson, K Sreekumaran Nair.

Resistance exercise training (RET) is an effective countermeasure to sarcopenia, related frailty and metabolic disorders. Here, we show that an RET-induced increase in PGC-1α4 (an isoform of the transcriptional co-activator PGC-1α) expression not only promotes muscle hypertrophy but also enhances glycolysis, providing a rapid supply of ATP for muscle contractions. In human skeletal muscle, PGC-1α4 binds to the nuclear receptor PPARβ following RET, resulting in downstream effects on the expressions of key glycolytic genes. In myotubes, we show that PGC-1α4 overexpression increases anaerobic glycolysis in a PPARβ-dependent manner and promotes muscle glucose uptake and fat oxidation. In contrast, we found that an acute resistance exercise bout activates glycolysis in an AMPK-dependent manner. These results provide a mechanistic link between RET and improved glucose metabolism, offering an important therapeutic target to counteract aging and inactivity-induced metabolic diseases benefitting those who cannot exercise due to many reasons.

DOI: https://doi.org/10.1038/s41467-022-30056-6
Biomed Res Int. 2022 ;2022 8636527

Immunotherapy Mechanism of Esophageal Squamous Cell Carcinoma with the Effect of STK11/AMPK Signaling Pathway.

Yang Xia, Peng Wang, Yunyao Ye, Sihui Zhang, Guangzhi Sun, Jie Xu, Gaohua Han.

This study was aimed at exploring the mechanism of serine threonine protein kinase 11 (STK11)/Adenosine 5'-monophosphate-activated protein kinase (AMPK) signaling pathway after immunotherapy for esophageal squamous cell carcinoma (ESCC), providing basic information for the clinical treatment of ESCC. In this study, tissue specimens from 100 patients with ESCC who underwent surgical treatment in Taizhou People's Hospital (group A) and 20 patients with recurrent or metastatic ESCC who received second-line immunotherapy (group B) were collected. The real-time fluorescent quantitative polymerase chain reaction (PCR) (RT-qPCR) technology was used to detect the expression levels of STK11, interferon-γ (IFN-γ), interleukin 6 (IL-6), and vascular endothelial growth factor (VEGF) in the tissues. The immunohistochemical staining was used to detect the positive expression levels (PELs) of STK11 and AMPKα in the tissues, and immunofluorescence staining was used to detect the PELs Teff cells (CD3 and CD8), Treg cells (CD4 and FOXP3), and neutrophils (CD68 and CD163). RT-qPCR results showed that the expression levels of STK11 and IFN-γ in group A were obviously lower, and those of IL-6 and VEGF were much higher in contrast to group B (P < 0.05). The results of immunohistochemical staining showed that the number of STK11- and AMPKα-positive staining cells in group A was dramatically less than that in group B (P <0.05). The results of immunofluorescence staining revealed that the number of positive staining cells for Teff cells, Treg cells, and neutrophils in group A was also less dramatically than that in group B (P <0.05). In summary, immunotherapy can play a therapeutic effect on ESCC by regulating STK11/AMPK pathway and immune cell infiltration.

DOI: https://doi.org/10.1155/2022/8636527
Front Oncol. 2022 ;12 856707

Metformin Regulates TET2 Expression to Inhibit Endometrial Carcinoma Proliferation: A New Mechanism.

Jingbo Zhang, Lei Kuang, Yanyu Li, Qing Wang, Hui Xu, Jianwei Liu, Xueyan Zhou, Yang Li, Bei Zhang.

  Objectives: To investigate the relationship between TET2 expression and endometrial cancer's clinicopathological features and prognosis, and the effect of metformin on TET2 and 5hmC levels in endometrial cancer cells.Methods: The clinical significance of TET2 expression in endometrial carcinoma was analyzed from TCGA public database. Eighty-eight patients with endometrial cancer and 20 patients with normal proliferative endometrium were enrolled in this study. TET2 and 5hmC were respectively detected by Immunohistochemistry and ELISA in endometrial tissues. Kaplan-Meier and Cox proportional hazard regression models were used to analyze relationships between TET2 and 5hmC and the overall survival of EC patients. Endometrial cell proliferation was assessed after TET2 gene knockdown. Western blotting and real-time PCR were used to detect the effect of metformin on TET2 expression and to explore whether AMPK is involved in metformin-mediated TET2 regulation.
Results: The clinical significance of expression of TET2 in endometrial cancer from TCGA public database confirmed that TET2 expression was significantly down-regulated in cancer samples and TET2 expression was also significantly different among different histopathological samples and TET2 is down-regulated in advanced, high-grade, and relapsed endometrial carcinoma tissues(P<0.05). Immunohistochemical analysis showed that TET2 and 5hmC levels were significantly lower in endometrial adenocarcinoma(P<0.05). TET2 expression was correlated with the degree of EC differentiation (P < 0.05). 5hmC levels were associated with clinical stage, differentiation, the depth of myometrial invasion, and lymph node metastasis (P < 0.05). The mean survival time of patients with negative staining for TET2 and 5hmC was shorter than that of patients with positive staining for both markers (P<0.05). Multivariate Cox regression analysis showed that TET2 expression was an independent risk factor for prognosis in patients with endometrial adenocarcinoma (HR = 14.520, 95% CI was 1.From 060 to 198.843, P = 0.045). siRNA-mediated TET2 knockdown increased the proliferation of EC cells. Metformin increased the levels of TET2 and 5hmC in EC cells. AMPK was involved in the regulation of TET2 by metformin.
Conclusions: TET2 may play an important role in EC development and may be a prognostic marker. Moreover, TET2 may be involved in a novel mechanism by which metformin inhibits EC cell proliferation.

Keywords:  5hmC; AMPK; TET2; endometrial cancer; metformin

DOI:  https://doi.org/10.3389/fonc.2022.856707
Cancer Metastasis Rev. 2022 Apr 25.

The paradoxical role of inositol in cancer: a consequence of the metabolic state of a tumor.

Kendall C Case, Michael W Schmidtke, Miriam L Greenberg.

  Inositol is an essential nutrient, obtained either by uptake from the environment or by de novo synthesis from glucose. Inositol and its derivatives exhibit tumor-suppressive effects, potentially mediated by inhibition of the ERK-MAPK or PI3K-Akt pathways. Accordingly, many cancers have been documented to silence expression of the ISYNA1 gene, which encodes the rate-limiting enzyme of inositol synthesis. Paradoxically, recent studies have also reported upregulation of ISYNA1 in some cancers. Upregulation may reflect a compensatory response brought about by defective inositol uptake or oncogenic mutations that preclude its tumor-suppressive effects. In these scenarios, de novo synthesis of inositol may be upregulated to promote cell proliferation. The role of inositol in cancer is further complicated by its ability to inhibit the master metabolic regulator AMPK, which upon activation can either decrease cell proliferation and metastasis or promote cell survival. Due to its potential dual role in cancer, inositol homeostasis must be tightly regulated in tumor cells. Thus, whether inositol acts to suppress or promote tumor progression is determined by the metabolic profile and oncogenic background of the cancer.

Keywords:  AMPK; Cancer; ISYNA1; Inositol; Metabolism; PI3K-Akt

DOI:  https://doi.org/10.1007/s10555-022-10032-8
Acta Biochim Pol. 2022 Apr 28.

Preventive effect of salicin ether against type-2 diabetes mellitus through targeting PPARγ-regulated gene expression.

Guangping Zhu, Junxia Zhang, Ling Yue, Guangda Xiang.

Diabetes mellitus is the syndrome associated with metabolism having complicated pathogenesis and its morbidity rate is rapidly increasing every year. The present study investigated the preventive effect of salicin ether against type-2 diabetes and explored the underlying mechanism. Salicin ether reduced PPARγ-LBD level and transcriptional property of RXRα-PPARγ in 293T cells. The rosiglitazone significantly (p<0.01) increased grease droplet accumulation in adipocytes in comparison to control adipocytes. Increased grease droplet accumulation by rosiglitazone in adipocytes was reversed on treatment with salicin ether in dose-dependent manner. Salicin ether treatment of the adipocytes effectively suppressed rosiglitazone induced expression of FAS, C/EBPα, aP2, and HMG-CoA genes. Treatment of the adipocytes with salicin ether led to a prominent decrease in rosiglitazone mediated increase in aP2, CHIP, and C/EBPα protein expression. The inhibitory effect of rosiglitazone on expression of p-Akt/t-Akt, PPARa, p-FoxO1/t-FoxO1, and p-AMPK/t-AMPK was significantly (p<0.01) alleviated in the adipocytes by salicin ether. In summary, the present study demonstrated that salicin ether suppressed PPARγ activity and adipocyte differentiation. Moreover, the activation of FoxO1/Akt/AMPK was up-regulated and FAS/EBPα/aP2/HMG-CoA level inhibited by salicin ether in the adipocytes. Thus, salicin ether may be studied further for possible role in the treatment of diabetes.

DOI: https://doi.org/10.18388/abp.2020_5983
Sci Rep. 2022 Apr 23. 12(1): 6674

Asteltoxin inhibits extracellular vesicle production through AMPK/mTOR-mediated activation of lysosome function.

Fumie Mitani, Jianyu Lin, Tatsuya Sakamoto, Ryo Uehara, Tomoya Hikita, Takuya Yoshida, Andi Setiawan, Masayoshi Arai, Chitose Oneyama.

Cancer cells secrete aberrantly large amounts of extracellular vesicles (EVs) including exosomes, which originate from multivesicular bodies (MVBs). Because EVs potentially contribute to tumor progression, EV inhibitors are of interest as novel therapeutics. We screened a fungal natural product library. Using cancer cells engineered to secrete luciferase-labeled EVs, we identified asteltoxin, which inhibits mitochondrial ATP synthase, as an EV inhibitor. Low concentrations of asteltoxin inhibited EV secretion without inducing mitochondrial damage. Asteltoxin attenuated cellular ATP levels and induced AMPK-mediated mTORC1 inactivation. Consequently, MiT/TFE transcription factors are translocated into the nucleus, promoting transcription of lysosomal genes and lysosome activation. Electron microscopy analysis revealed that the number of lysosomes increased relative to that of MVBs and the level of EVs decreased after treatment with asteltoxin or rapamycin, an mTORC1 inhibitor. These findings suggest that asteltoxin represents a new type of EV inhibitor that controls MVB fate.

DOI: https://doi.org/10.1038/s41598-022-10692-0
J Basic Clin Physiol Pharmacol. 2022 Apr 28.

The effect of metformin on the metabolism of human vascular smooth muscle cells in high glucose conditions.

Ali Akbar Soleimani, Borhan Rahimi Abkenar, Nafiseh Shokri, Ghasem Ghasempour, Mohammad Najafi.

  OBJECTIVES: Metformin is widely used in type 2 diabetic patients as an antihyperglycemic drug. The aim of this study was to investigate the effect of metformin on the metabolism of vascular smooth muscle cells in high glucose conditions.MATERIALS AND METHODS: The vascular smooth muscle cells were cultured in DMEM F12 containing glucose as high as 25 mM. The preconditioned cells were then treated with metformin in doses of 1, 5, and 7 mM for 24 h. MTT method was used to determine cell viability. Biochemical parameters including lactate, glucose, total protein, creatinine, and triglyceride were measured in the cell culture after the treatment with metformin. Oil Red O staining method was used to stain the lipids in the cells.
RESULTS: Metformin reduced significantly (p<0.001) VSMC proliferation in a concentration-dependent manner. With the increase of glucose uptake by VSMCs, the cell lipid deposition was not changed. Other biochemical parameters such as lactate, triglyceride, total protein, and creatinine were significantly changed in the cell culture (p<0.05).
CONCLUSIONS: Metformin increased the glucose uptake impacting metabolic pathways in VSMCs. It also increased the lactate efflux and protein metabolism without the change in cellular lipid deposition in high glucose conditions.

Keywords:  high-glucose; metabolism; metformin; vascular smooth muscle cell

DOI:  https://doi.org/10.1515/jbcpp-2022-0018
Immunopharmacol Immunotoxicol. 2022 Apr 29. 1-13

Lupeol triggers oxidative stress, ferroptosis, apoptosis and restrains inflammation in nasopharyngeal carcinoma via AMPK/NF-κB pathway.

Jing-Chun Zhou, Bin Wu, Jing-Jing Zhang, Wei Zhang.

  OBJECTIVE: Nasopharyngeal carcinoma is a malignant tumor with high incidence in Asia. This study investigated the anti-tumor capacities of lupeol in nasopharyngeal carcinoma.METHODS: CCK-8 assay was employed to select the suitable concentration and intervention time of lupeol in 5-8F and CNE1 cells. The anti-cancer impacts of lupeol were evaluated by flow cytometry, ROS generation, western blotting, ELISA, iron assay, lipid peroxidation, mitochondrial membrane potential (MMP), TUNEL, and immunohistochemistry assays. Additionally, levels of AMPK/NF-κB pathway-related proteins were tested by western blotting.
RESULTS: Cell viability was notably decreased after administration of lupeol ≧ 20 μM. 20 μM and 40 μM lupeol induced cell apoptosis, enhanced oxidative stress and restrained immune response in nasopharyngeal carcinoma cells to some extent, as evidenced by the elevation of apoptotic rate, Bax and cleaved caspase-3 expression, ROS production and malondialdehyde level, and reduction of levels of Bcl-2, MMP, superoxide dismutase, TNF-α, IL-6 and IL-1β. Also, lupeol promoted the iron secretion and lipid peroxidation, the effects of which were reversed by ferroptosis inhibitor (Fer-1). The inhibitory impacts of lupeol at the doses of 20 μM and 40 μM on glutathione and GPX4 levels were observed. Importantly, lupeol significantly elevated AMPKα phosphorylation, and reduced the levels of p-IκBα and nuclear NF-κB p65. Rescue assay stated that siAMPK could neutralize the above impacts of lupeol. Moreover, lupeol suppressed tumorigenesis of xenografts in nude mice.
CONCLUSION: Lupeol exerted the anti-cancer impacts by inducing oxidative stress, ferroptosis and apoptosis, and suppressing inflammation via the AMPK/NF-κB pathway in nasopharyngeal carcinoma.

Keywords:  AMPK/NF-κB pathway; Apoptosis; Ferroptosis; Lupeol; Nasopharyngeal carcinoma; Oxidative stress

DOI:  https://doi.org/10.1080/08923973.2022.2072328