bims-amsmem 2023-03-05 papers

bims-amsmem

Biomed News

on AMPK signaling mechanism in energy metabolism

Issue of 2023–03–05
fourteen papers selected by
Dipsikha Biswas, Københavns Universitet

AMPK-like proteins and their function in female reproduction and gynecologic cancer.
Isoform-specific effects of neuronal repression of the AMPK catalytic subunit on cognitive function in aged mice.
The pleiotropic AMPK-CncC signaling pathway regulates the trade-off between detoxification and reproduction.
Cantharidin induces senescence via inhibition of AMP-activated protein kinase and activation of NLRP3 inflammasome in H9c2 cardiomyocytes.
Astragalin ameliorates renal injury in diabetic mice by modulating mitochondrial quality control via AMPK-dependent PGC1α pathway.
Running title: AMPK contributes to liver injury.
UBE3A deficiency-induced autophagy is associated with activation of AMPK-ULK1 and p53 pathways.
Tissue-specific metabolic profile drives iNKT cell function during obesity and liver injury.
Inhibition of VDAC1 prevents oxidative stress and apoptosis induced by bisphenol A in spermatogonia via AMPK/mTOR signaling pathway.
FNDC5 and AKR1B10 inhibit the proliferation and metastasis of adrenocortical carcinoma cells by regulating AMPK/mTOR pathway.
AdipoRon mitigates tau pathology and restores mitochondrial dynamics via AMPK-related pathway in a mouse model of Alzheimer's disease.
Jian Pi Sheng Sui Gao (JPSSG) alleviation of skeletal myoblast cell apoptosis, oxidative stress, and mitochondrial dysfunction to improve cancer-related fatigue in an AMPK-SIRT1- and HIF-1-dependent manner.
Sleeve gastrectomy decreased hepatic lipid accumulation by inducing autophagy via AMPK/mTOR pathway.
Curcumin Ameliorates Age-Induced Tight Junction Impaired in Porcine Sertoli Cells by Inactivating the NLRP3 Inflammasome through the AMPK/SIRT3/SOD2/mtROS Signaling Pathway.

Adv Protein Chem Struct Biol. 2023 ;pii: S1876-1623(22)00105-5. [Epub ahead of print]134 245-270

AMPK-like proteins and their function in female reproduction and gynecologic cancer.

Claire Baumgartner, Anil Kumar Yadav, Ilana Chefetz.

  Serine-threonine kinase (STK11), also known as liver kinase B1 (LKB1), is a regulator of cellular homeostasis through regulating the cellular ATP-to-ADP ratio. LKB1 is classified as a tumor suppressor and functions as the key activator of AMP-activated protein kinase (AMPK) and a family of serine-threonine kinases called AMPK-like proteins. These proteins include novel (nua) kinase family 1 (NUAK1 and 2), salt inducible kinase (SIK1), QIK (known as SIK2), QSK (known as SIK3 kinase), and maternal embryonic leuzine zipper kinase (MELK) on tightly controlled and specific residual sites. LKB1 also regulates brain selective kinases 1 and 2 (BRSK1 and 2), additional members of AMPK-like protein family, which functions are probably less studied. AMPK-like proteins play a role in variety of reproductive physiology functions such as follicular maturation, menopause, embryogenesis, oocyte maturation, and preimplantation development. In addition, dysfunctional activity of AMPK-like proteins contributes to apoptosis blockade in cancer cells and induction of the epithelial-mesenchymal transition required for metastasis. Dysregulation of these proteins occurs in ovarian, endometrial, and cervical cancers. AMPK-like proteins are still undergoing further classification and may represent novel targets for targeted gynecologic cancer therapies. In this chapter, we describe the AMPK-like family of proteins and their roles in reproductive physiology and gynecologic cancers.

Keywords:  AMPK-related kinases; AMPKα; Cervical cancer; Endometrial cancer; Gynecologic cancer; LKB1; Menopause; Menstruation; Ovarian cancer; Ovary; Ovulation; Ovum development

DOI:  https://doi.org/10.1016/bs.apcsb.2022.11.016
Aging (Albany NY). 2023 Feb 26. 15

Isoform-specific effects of neuronal repression of the AMPK catalytic subunit on cognitive function in aged mice.

Xueyan Zhou, Wenzhong Yang, Xin Wang, Tao Ma.

  AMP-activated protein kinase (AMPK) functions as a molecular sensor that plays a critical role in maintaining cellular energy homeostasis. Dysregulation of the AMPK signaling has been linked to synaptic failure and cognitive impairments. Our recent study demonstrates abnormally increased AMPK activity in the hippocampus of aged mice. The kinase catalytic subunit of AMPK exists in two isoforms α1 and α2, and their specific roles in aging-related cognitive deficits are unknown. Taking advantage of the unique transgenic mice (AMPKα1/α2 cKO) recently developed by our group, we investigated how isoform-specific suppression of the neuronal AMPKα may contribute to the regulation of cognitive and synaptic function associated with aging. We found that aging-related impairment of long-term object recognition memory was improved with suppression of AMPKα1 but not AMPKα2 isoform. Moreover, aging-related spatial memory deficits were unaltered with suppression of either AMPKα isoform. Biochemical experiments showed that the phosphorylation levels of the eukaryotic initiation factor 2 α subunit (eIF2α) were specifically decreased in the hippocampus of the AMPKα1 cKO mice. We further performed large-scale unbiased proteomics analysis and revealed identities of proteins whose expression is differentially regulated with AMPKα isoform suppression. These novel findings may provide insights into the roles of AMPK signaling pathway in cognitive aging.

Keywords:  AMPK; aging; learning and memory; protein synthesis; proteomics

DOI:  https://doi.org/10.18632/aging.204554
Proc Natl Acad Sci U S A. 2023 Mar 07. 120(10): e2214038120

The pleiotropic AMPK-CncC signaling pathway regulates the trade-off between detoxification and reproduction.

Heng Jiang, Xiangkun Meng, Nan Zhang, Huichen Ge, Jiaping Wei, Kun Qian, Yang Zheng, Yoonseong Park, Subba Reddy Palli, Jianjun Wang.

  The association of decreased fecundity with insecticide resistance and the negative sublethal effects of insecticides on insect reproduction indicates the typical trade-off between two highly energy-demanding processes, detoxification and reproduction. However, the underlying mechanisms are poorly understood. The energy sensor adenosine monophosphate-activated protein kinase (AMPK) and the transcription factor Cap "n" collar isoform C (CncC) are important regulators of energy metabolism and xenobiotic response, respectively. In this study, using the beetle Tribolium castaneum as a model organism, we found that deltamethrin-induced oxidative stress activated AMPK, which promoted the nuclear translocation of CncC through its phosphorylation. The CncC not only acts as a transcription activator of cytochrome P450 genes but also regulates the expression of genes coding for ecdysteroid biosynthesis and juvenile hormone (JH) degradation enzymes, resulting in increased ecdysteroid levels as well as decreased JH titer and vitellogenin (Vg) gene expression. These data show that in response to xenobiotic stress, the pleiotropic AMPK-CncC signaling pathway mediates the trade-off between detoxification and reproduction by up-regulating detoxification genes and disturbing hormonal homeostasis.

Keywords:  AMPK; CncC; detoxification; reproduction; xenobiotic stress

DOI:  https://doi.org/10.1073/pnas.2214038120
Pak J Pharm Sci. 2022 Nov;35(6(Special)): 1827-1834

Cantharidin induces senescence via inhibition of AMP-activated protein kinase and activation of NLRP3 inflammasome in H9c2 cardiomyocytes.

Yujing Shi, Yi Lv, Qi You, Weidong Qian.

Cantharidin is a natural compound with cardiotoxicity. Cellular senescence and senescence-associated secretory phenotype (SASP) are implicated in chemotherapy-associated cardiotoxicity. We here investigated how cantharidin induced cardiomyocyte senescence. H9c2 cells were treated with cantharidin. Senescence, mitochondrial functions, SASP, NOD-like receptor thermal protein domain associated protein 3 (NLRP3) signaling and AMP-activated protein kinase (AMPK) phosphorylation were examined. Cantharidin inhibited viability and increased expression of senescence-associated β--galactosidase (SA-β-Gal), p16 and p21 in H9c2 cells, suggesting occurrence of senescence. Cantharidin impaired mitochondrial functions evidenced by reduction in basal respiration, ATP levels and spare respiratory capacity. Cantharidin also decreased mitochondrial DNA copy number and down-regulated mRNA levels of cytochrome c oxidase-I, -II and -III. Moreover, cantharidin suppressed activity of mitochondria complex-I and -II. Examinations of SASP showed that cantharidin promoted expression and secretion of SASP cytokines interleukin-1β-, -6 and -8 and tumor necrosis factor-α, associated with activation of NLRP3/caspase-1 pathway. Finally, cantharidin suppressed AMPK phosphorylation. AMPK activator GSK621 abrogated the up-regulation of SA-β--Gal, p16 and p21 and counteracted the activation of NLRP3 and caspase-1 in cantharidin-challenged H9c2 cells. In conclusion, cantharidin stimulated senescence and SASP in cardiomyocytes through activation of NLRP3 inflammasome and inhibition of AMPK, providing novel molecular insights into cantharidin-induced cardiotoxicity.
Acta Pharmacol Sin. 2023 Mar 01.

Astragalin ameliorates renal injury in diabetic mice by modulating mitochondrial quality control via AMPK-dependent PGC1α pathway.

Meng-Yao Sun, Hui-Jing Ye, Chen Zheng, Zi-Jie Jin, Yan Yuan, Hong-Bo Weng.

  Diabetic kidney disease (DKD) is a common microvascular complication of diabetes mellitus, and oxidative stress and mitochondrial dysfunction play an important role in this process. It has been shown that aldose reductase (ALR2) catalyzes NADPH-dependent reduction of glucose to sorbitol, resulting in oxidative stress and mitochondrial dysfunction in diabetic patients. Astragalin (AG), a flavonoid extracted from Thesium chinense Turcz., shows an inhibitory activity on ALR2. In this study, we investigated the therapeutic effects of AG against renal injury in streptozocin (STZ)-induced diabetic mouse model. Diabetic mice were orally administered AG (5, 10 mg·kg-1·d-1) for 4 weeks. We showed that AG treatment greatly improved the proteinuria and ameliorated renal pathological damage without affecting the elevated blood glucose in diabetic mice. Furthermore, AG treatment significantly suppressed highly activated ALR2, and reduced oxidative stress in the kidney of diabetic mice and in high glucose and lipids-stimulated HK2 cells in vitro. We demonstrated that AG treatment modulated mitochondrial quality control and ameliorated apoptosis, boosting mitochondrial biogenesis, maintaining mitochondrial dynamic homeostasis, and improving energy metabolism disorder in vivo and in vitro. In high glucose and lipids-stimulated HK2 cells, we found that AG (20 μM) restored the phosphorylation level of AMPK, and upregulated the expression and transcriptional activity of PGC1α, whereas treatment with H2O2, blockade of AMPK with Compound C or knockdown of AMPKα with siRNA abolished the protective effect of AG on mitochondrial function, suggesting that antioxidant effects and activation of AMPK-dependent PGC1α pathway might be the molecular mechanisms underlying the protective effects of AG on mitochondrial quality control. We conclude that AG could be a promising drug candidate for the treatment of diabetic renal injury through activating AMPK.

Keywords:  AMPK; Astragalin; PGC1α; aldose reductase; diabetic kidney disease; mitochondrial quality control

DOI:  https://doi.org/10.1038/s41401-023-01064-z
J Appl Toxicol. 2023 Feb 27.

Running title: AMPK contributes to liver injury.

Jianxiang Huang, Songjie Liao, Xiaolong Fu, Yi Wang, Shaoyu Zhou, Yuanfu Lu.

  Natural pentacyclic triterpenoid oleanolic acid (OA) is used as an over-the-counter drug for acute and chronic hepatitis. However, clinical use of OA-containing herbal medicines has been reported to cause cholestasis, and the specific mechanism is unknown. The purpose of this study was to explore how OA causes cholestatic liver injury via the AMP-activated protein kinase (AMPK)-farnesoid X receptor (FXR) pathway. In animal experiments, it was found that OA treatment activated AMPK and decreased FXR and bile acid efflux transport proteins expression. When intervened with the specific inhibitor Compound C (CC), it was observed that AMPK activation was inhibited, the reduction of FXR and bile acid efflux transport protein expression was effectively alleviated, serum biochemical indicators were significantly reduced, and liver pathological damage brought about by OA was effectively ameliorated. In addition, OA was found to downregulate the expression of FXR and bile acid efflux transport proteins by activating the ERK1/2-LKB1-AMPK pathway in cellular experiments. The ERK1/2 inhibitor U0126 was used to pre-treat primary hepatocytes, and this drastically reduced the phosphorylation levels of LKB1 and AMPK. The inhibition effects of OA on FXR and bile acid efflux transport proteins were also effectively alleviated after pretreatment with CC. In addition, OA-induced downregulation of FXR gene and protein expression levels was significantly prevented after silencing AMPKα1 expression in AML12 cells. Our study demonstrated that OA inhibits FXR and bile acid efflux transporters through activation of AMPK, thus leading to cholestatic liver injury.

Keywords:  AMPK; Bile acids; Cholestatic liver injury; FXR; Oleanolic acid

DOI:  https://doi.org/10.1002/jat.4456
Exp Neurol. 2023 Feb 26. pii: S0014-4886(23)00042-0. [Epub ahead of print]363 114358

UBE3A deficiency-induced autophagy is associated with activation of AMPK-ULK1 and p53 pathways.

Xiaoning Hao, Jiandong Sun, Li Zhong, Michel Baudry, Xiaoning Bi.

  Angelman Syndrome (AS) is a neurodevelopmental disorder caused by deficiency of the maternally expressed UBE3A gene. The UBE3A proteins functions both as an E3 ligase in the ubiquitin-proteasome system (UPS), and as a transcriptional co-activator for steroid hormone receptors. Here we investigated the effects of UBE3A deficiency on autophagy in the cerebellum of AS mice and in COS1 cells. Numbers and size of LC3- and LAMP2-immunopositive puncta were increased in cerebellar Purkinje cells of AS mice, as compared to wildtype mice. Western blot analysis showed an increase in the conversion of LC3I to LC3II in AS mice, as expected from increased autophagy. Levels of active AMPK and of one of its substrates, ULK1, a factor involved in autophagy initiation, were also increased. Colocalization of LC3 with LAMP2 was increased and p62 levels were decreased, indicating an increase in autophagy flux. UBE3A deficiency was also associated with reduced levels of phosphorylated p53 in the cytosol and increased levels in nuclei, which favors autophagy induction. UBE3A siRNA knockdown in COS-1 cells resulted in increased size and intensity of LC3-immunopositive puncta and increased the LC3 II/I ratio, as compared to control siRNA-treated cells, confirming the results found in the cerebellum of AS mice. These results indicate that UBE3A deficiency enhances autophagic activity through activation of the AMPK-ULK1 pathway and alterations in p53.

Keywords:  Angelman syndrome; COS-1 cells; Cerebellum; LC3; Lysosome; TFEB; mTOR; p62; siRNA

DOI:  https://doi.org/10.1016/j.expneurol.2023.114358
Cell Rep. 2023 Jan 31. pii: S2211-1247(23)00046-3. [Epub ahead of print]42(1): 112035

Tissue-specific metabolic profile drives iNKT cell function during obesity and liver injury.

Cristhiane Favero Aguiar, Felipe Corrêa-da-Silva, Michelangelo Bauwelz Gonzatti, Monara Kaelle Angelim, Marco Antonio Pretti, Gustavo Gastão Davanzo, Bianca Gazieri Castelucci, Lauar Brito Monteiro, Gisele Castro, João Victor Virgilio-da-Silva, Guilherme Ribeiro, Vitor Jaccomo, Mirella C Pereira Andrade, Webster Leonardo Costa, Victor Gambarini, Fernanda Fernandes Terra, José Carlos Alves-Filho, Niels Olsen Saraiva Câmara, Mariana Boroni, Alexandre Castro Keller, Pedro M Moraes-Vieira.

  Invariant natural killer T (iNKT) cells are a distinct population of lymphocytes characterized by their reactivity to glycolipids presented by CD1d. iNKT cells are found throughout the body, and little is known about their tissue-specific metabolic regulation. Here, we show that splenic and hepatic iNKT cells are metabolically comparable and rely on glycolytic metabolism to support their activation. Deletion of the pyruvate kinase M2 (Pkm2) gene in splenic and hepatic iNKT cells impairs their response to specific stimulation and their ability to mitigate acute liver injury. In contrast, adipose tissue (AT) iNKT cells exhibit a distinctive immunometabolic profile, with AMP-activated protein kinase (AMPK) being necessary for their function. AMPK deficiency impairs AT-iNKT physiology, blocking their capacity to maintain AT homeostasis and their ability to regulate AT inflammation during obesity. Our work deepens our understanding on the tissue-specific immunometabolic regulation of iNKT cells, which directly impacts the course of liver injury and obesity-induced inflammation.

Keywords:  AMPK; CP: Immunology; CP: Metabolism; PKM2; adipose tissue; iNKT cells; immunometabolism; liver injury; metabolism; obesity

DOI:  https://doi.org/10.1016/j.celrep.2023.112035
J Toxicol Sci. 2023 ;48(3): 109-119

Inhibition of VDAC1 prevents oxidative stress and apoptosis induced by bisphenol A in spermatogonia via AMPK/mTOR signaling pathway.

Haixu Wang, Yan Li, Chuang Liu, Tianxiang Lu, Qian Zhai, Hongna Wang, Jianfang Zhang.

  Bisphenol A (BPA), one of the main components of industrial products, is clinically associated with the increased male infertility rate. However, the underlying molecular mechanism of the BPA-resulted reproductive toxicity is not fully elucidated. Voltage-dependent anion channel 1 (VDAC1) is a pore protein and located at the outer mitochondrial membrane. As a mitochondrial gatekeeper, VDAC1 controls the release of reactive oxygen species (ROS) and the metabolic and energetic functions of mitochondria, and serves as a critical player in mitochondrial-mediated apoptosis. Herein, we explored the role of VDAC1 in BPA-induced apoptosis of spermatogonia. The results showed that BPA increased spermatogonia cell line GC-1 spg cell apoptosis and intracellular ROS level, and suppressed AMPK/mTOR signaling pathway at a dose of 80 μM for 48 hr. Lentivirus-mediated short hairpin RNA targeting VDAC1 (Lv-shVDAC1) silenced VDAC1 expression and enhanced BPA-restricted cell viability. Knockdown of VDAC1 inhibited the apoptosis of BPA-treated GC-1 spg cells determined by with changes of the expressions of pro-apoptotic and anti-apoptotic proteins. Knockdown of VDAC1 also alleviated the BPA-triggered intracellular ROS generation and oxidative stress. Moreover, silence of VDAC1 increased AMPKα1/2 phosphorylation and suppressed mTOR phosphorylation under BPA exposure. Dorsomorphin, an AMPK inhibitor, partially abolished the effects of VDAC1 gene silencing on BPA-stimulated GC-1 spg cells. In conclusion, inhibition of VDAC1 attenuated the BPA-induced oxidative stress and apoptosis and promoted the cell viability in spermatogonia through modulating AMPK/mTOR signaling pathway.

Keywords:  AMPK/mTOR signaling pathway; Apoptosis; Oxidative stress; Spermatogonia; Voltage-dependent anion channel 1

DOI:  https://doi.org/10.2131/jts.48.109
Exp Ther Med. 2023 Mar;25(3): 136

FNDC5 and AKR1B10 inhibit the proliferation and metastasis of adrenocortical carcinoma cells by regulating AMPK/mTOR pathway.

Danyan Chen, Rongxi Huang, Fang Ren, Hongman Wang, Chengjian Wang, Yu Zhang.

  Being a rare malignancy, adrenocortical carcinoma (ACC) exhibits aggressiveness and poor prognosis. Fibronectin type III domain-containing protein 5 (FNDC5) is a transmembrane protein involved in multiple types of cancer. Aldo-keto reductase family 1 member B10 (AKR1B10) has a suppressive role in ACC. The present study aimed to investigate the role of FNDC5 in ACC cells as well as its mechanisms related to AKR1B10. The Gene Expression Profiling Interactive Analysis database predicted FNDC5 expression in tumour tissue of patients suffering from ACC and the overall survival rate. Western blotting as well as reverse transcription-quantitative PCR were used for the examination of the transfection efficiency of FNDC5-overexpression vector (Oe-FNDC5) and small interfering (si)RNA against AKR1B10. Cell Counting Kit-8 was employed for the assessment of cell viability. The proliferation, migration and invasion of the transfected cells were assessed by 5-ethynyl-2'-deoxyuridine staining, wound healing and Transwell assays. Additionally, cell apoptosis was evaluated by flow cytometry and caspase-3 activity was determined by ELISA. The levels of epithelial-mesenchymal transition- and 5'-AMP-activated protein kinase (AMPK)/mTOR signalling pathway-associated proteins were assessed by western blotting. The interaction between FNDC5 and AKR1B10 was confirmed by co-immunoprecipitation. FNDC5 levels in ACC tissue were reduced compared with normal tissue. After overexpressing FNDC5, proliferation, migration and invasion of NCI-H295R cells were suppressed, while cell apoptosis was promoted. FNDC5 interacted with AKR1B10 and AKR1B10 knockdown promoted proliferation, migration and invasion while inhibiting the apoptosis of NCI-H295R cells transfected with si-AKR1B10. The AMPK/mTOR signalling pathway was activated by FNDC5 overexpression, which was subsequently suppressed by AKR1B10 knockdown. Collectively, FNDC5 overexpression inhibited proliferation, migration and invasion while promoting apoptosis of NCI-H295R cells via triggering the AMPK/mTOR signalling pathway. These effects were counteracted by AKR1B10 knockdown.

Keywords:  AMPK/mTOR pathway; adrenocortical carcinoma; aldo-keto reductase family 1 member B10; fibronectin type III domain-containing protein 5

DOI:  https://doi.org/10.3892/etm.2023.11835
Exp Neurol. 2023 Mar 01. pii: S0014-4886(23)00039-0. [Epub ahead of print] 114355

AdipoRon mitigates tau pathology and restores mitochondrial dynamics via AMPK-related pathway in a mouse model of Alzheimer's disease.

Cailin Wang, Yanmin Chang, Jiahui Zhu, Yanqing Wu, Xingjun Jiang, Siyi Zheng, Gang Li, Rong Ma.

   BACKGROUND: Alzheimer's disease (AD) is a complicated and refractory neurodegenerative disease that is typically characterized by memory loss and multiple cognitive impairments. Multiple neuropathology including hyperphosphorylated tau formation and accumulation, dysregulated mitochondrial dynamics, and synaptic damage have been well implicated in the progression of AD. So far, there are few valid and effective therapeutic modalities for treatment. AdipoRon, a specific adiponectin (APN) receptor agonist, is reported to be associated with cognitive deficits improvement. In the present study, we attempt to explore the potential therapeutic effects of AdipoRon on tauopathy and related molecular mechanisms.
METHODS: In this study, P301S tau transgenic mice were used. The plasma level of APN was detected by ELISA. The level of APN receptors was qualified by western blot and immunofluorescence. 6-month-old mice were treated with AdipoRon or vehicle by oral administration daily for 4 months. The benefits of AdipoRon on tau hyperphosphorylation, mitochondrial dynamics, and synaptic function were detected by western blot, immunohistochemistry, immunofluorescence, Golgi staining and transmission electron microscopy. Morris water maze test and novel object recognition test were conducted to explore memory impairments.
RESULTS: Compared with wild-type mice, the expression of APN in plasma in 10-month-old P301S mice was obviously decreased. APN receptors in the hippocampus were increased in the hippocampus. AdipoRon treatment significantly rescued memory deficits in P301S mice. Besides, AdipoRon treatment was also detected to improve synaptic function, enhance mitochondrial fusion, and mitigate hyperphosphorylated tau accumulation in P301S mice and SY5Y cells. Mechanistically, AMPK/SIRT3 and AMPK/GSK3β signaling pathways are demonstrated to be involved in AdipoRon-mediated benefits on mitochondrial dynamics and tau accumulation, respectively, and inhibition of AMPK related pathways showed counteracted effects.
CONCLUSION: Our results demonstrated that AdipoRon treatment could significantly mitigate tau pathology, improve synaptic damage, and restore mitochondrial dynamics via the AMPK-related pathway, which provides a novel potential therapeutic approach to retard the progression of AD and other tauopathies diseases.

Keywords:  AMPK pathway; AdipoRon; Alzheimer's disease; Mitochondrial dynamics; Tau pathology

DOI:  https://doi.org/10.1016/j.expneurol.2023.114355
Ann Transl Med. 2023 Feb 15. 11(3): 156

Jian Pi Sheng Sui Gao (JPSSG) alleviation of skeletal myoblast cell apoptosis, oxidative stress, and mitochondrial dysfunction to improve cancer-related fatigue in an AMPK-SIRT1- and HIF-1-dependent manner.

Min Xiao, Wei Guo, Chi Zhang, Yukun Zhu, Zhiling Li, Cui Shao, Jiling Jiang, Zhenjiang Yang, Jianyong Zhang, Lizhu Lin.

   Background: Jian Pi Sheng Sui Gao (JPSSG), a Chinese traditional herbal paste, possesses certain efficacy in patients with cancer-related fatigue (CRF); however, its related mechanism remains unclear. Hence, network pharmacology analysis, followed by in vivo and in vitro experiments were conducted in this study with the aim to evaluate the effect of JPSSG on CRF and clarify its potential mechanism.
Methods: Network pharmacology analysis was performed. Subsequently, 12 mice were injected with CT26 cells to establish CRF mouse models and randomly divided into a model group (n=6) and JPSSG group (n=6); meanwhile, another 6 normal mice served as a control group. Then, 3.0 g/kg JPSSG was given to mice in JPSSG group for 15 days, while mice in the n control and model groups received phosphate-buffered saline (PBS) of the same volume for 15 days. For the in vitro experiment, CT26 conditioned medium (CM) was established; meanwhile, the mitochondrial damage model was constructed through C2C12 myotubes stimulated with H2O2. C2C12 myotubes were divided into 5 groups: control group (without treatment), CM group, CM + JPSSG group, H2O2 group, and H2O2 + JGSSP group.
Results: Network pharmacology analysis identified 87 bioactive compounds and 132 JPSSG-CRF interaction targets. Moreover, according to the Kyoto Encyclopedia of Genes and Genomes enrichment analysis and the subsequent in vivo and in vitro experiments, JPSSG activated adenosine 5'-monophosphate-activated protein kinase-silent-information-regulator factor 2-related-enzyme 1 (AMPK-SIRT1) and hypoxia-inducible factor-1 (HIF-1) signaling pathways during CRF. Moreover, the in vivo experiment showed that JPSSG attenuated CRF in mice, reflected by increased distance traveled, mobile time in open field test, and swimming time in exhaustive swimming test, and decreased absolute rest time and tail suspension test in the JPSSG group (vs. model group). Furthermore, JPSSG upregulated gastrocnemius weight, adenosine triphosphate (ATP), superoxide dismutase (SOD), and the cross-sectional area of the gastrocnemius. With regard to in vitro study, JPSSG elevated cell viability, B-cell lymphoma-2, ATP, SOD, and mitochondrial membrane potential, while it decreased apoptosis rate, cleaved-caspase3, malondialdehyde, and reactive oxygen species in C2C12 myotubes.
Conclusions: JPSSG ameliorates CRF via alleviating skeletal myoblast cell apoptosis, oxidative stress, and mitochondrial dysfunction in an AMPK-SIRT1- and HIF-1-dependent manner.

Keywords:  Jian Pi Sheng Sui Gao (JPSSG); cancer-related fatigue (CRF); molecular mechanism; network pharmacology; oxidative stress

DOI:  https://doi.org/10.21037/atm-22-6611
Biochem Biophys Res Commun. 2023 Feb 26. pii: S0006-291X(23)00257-7. [Epub ahead of print]653 115-125

Sleeve gastrectomy decreased hepatic lipid accumulation by inducing autophagy via AMPK/mTOR pathway.

Runzhi Zeng, Yijia Zeng, Qi Wang, Xinzhang Li, Jize Liu, Bingjun Li, Guangyong Zhang, Sanyuan Hu.

  This study was designed to investigate the roles of autophagy in the attenuation of hepatic lipid accumulation after sleeve gastrectomy (SG). Thirty-two rats were divided into normal control, obesity group, sham group, and SG group. Then serum glucagon-like polypeptide-1 (GLP-1) and lipid accumulation were determined, followed by measuring the activity of autophagy based on immunohistochemistry (IHC) and Western blot analysis. Our data showed significant decrease in the lipid accumulation after SG compared with sham group. GLP-1 and autophagy showed significant increase in rats underwent SG compared with the sham group (P < 0.05). In vitro experiments were conducted to analyze the roles of GLP-1 in autophagy. We knock-downed the expression of Beclin-1 in HepG2, and then analyzed the expression of autophagy-related protein (i.e. LC3BII and LC3BI) and lipid droplet accumulation. In HepG2 cells, GLP-1 analog reduced lipid accumulation by activating autophagy through modulating the AMPK/mTOR signaling pathway. All these concluded that SG decreased hepatic lipid accumulation by inducing autophagy through modulating AMPK/mTOR pathway.

Keywords:  Autophagy; Glucagon-like polypeptide-1; HepG2 cells; Sleeve gastrectomy; mTOR

DOI:  https://doi.org/10.1016/j.bbrc.2023.02.071
Oxid Med Cell Longev. 2023 ;2023 1708251

Curcumin Ameliorates Age-Induced Tight Junction Impaired in Porcine Sertoli Cells by Inactivating the NLRP3 Inflammasome through the AMPK/SIRT3/SOD2/mtROS Signaling Pathway.

Longfei Xiao, Zihao Fang, Qian Wang, Xihui Sheng, Xiaolong Qi, Kai Xing, Yong Guo, Hemin Ni, Xiangguo Wang, Yong Zhang.

Blood-testis barrier (BTB) made of concomitant junction apparatus between Sertoli cells (SCs) is crucial for spermatogenesis. The tight junction (TJ) function is impaired in SCs with age, exhibiting an intimate relationship to testicular dysfunction induced by age. In this study, compared with those in young boars, TJ proteins (i.e., Occludin, ZO-1, and plus Claudin-11) were discovered to have reduced expressions in testes, and spermatogenesis ability declined in old boars. An in vitro age model for D-gal-treated porcine SCs was established, the performance of Curcumin as a natural antioxidant and anti-inflammatory compound in affecting the TJ function of SCs was appraised, and related molecular mechanisms were exploited. The results manifested that 40 g/L D-gal downregulated ZO-1, Claudin-11, and Occludin in terms of the expression in SCs, whereas Curcumin restored such expressions in D-gal-treated SCs. Using the AMPK and SIRT3 inhibiters demonstrated that activation of the AMPK/SIRT3 pathway was associated with Curcumin, which not only rescued the expression of ZO-1, Occludin, Claudin-11, and SOD2 but also inhibited the production of mtROS and ROS and the activation of NLRP3 inflammasome and release of IL-1β in D-gal-treated SCs. Furthermore, with mtROS scavenger (mito-TEMPO), NLRP3 inhibitor (MCC950) plus IL-1Ra treatment ameliorated D-gal-caused TJ protein decline in SCs. In vivo data also showed that Curcumin alleviated TJ impairment in murine testes, improved D-gal-triggered spermatogenesis ability, and inactivated the NLRP3 inflammasome by virtue of the AMPK/SIRT3/mtROS/SOD2 signal transduction pathway. Given the above findings, a novel mechanism where Curcumin modulates BTB function to improve spermatogenesis ability in age-related male reproductive disorder is characterized.

DOI: https://doi.org/10.1155/2023/1708251