bims-amsmem 2022-10-02 papers

bims-amsmem

Biomed News

on AMPK signaling mechanism in energy metabolism

Issue of 2022–10–02
thirteen papers selected by
Dipsikha Biswas, Københavns Universitet

Irisin inhibits PCSK9 expression through activating AMPK-SREBP2 pathway.
Enhancement of cGMP-dependent pathway activity ameliorates hyperglycemia-induced decrease in SIRT1-AMPK activity in podocytes: Impact on glucose uptake and podocyte function.
AMPK-dependent autophagy activation and alpha-Synuclein clearance: a putative mechanism behind alpha-mangostin's neuroprotection in a rotenone-induced mouse model of Parkinson's disease.
A non-mitogenic FGF4 analog alleviates non-alcoholic steatohepatitis through an AMPK-dependent pathway.
Gender difference in hepatic AMPK pathway activated lipid metabolism induced by aged polystyrene microplastics exposure.
Hepatic AMPK signaling activation in response to dynamic REDOX balance is a biomarker of exercise to improve blood glucose control.
Sex Dimorphic Glucose Transporter-2 Regulation of Hypothalamic Astrocyte Glucose and Energy Sensor Expression and Glycogen Metabolism.
Photobiomodulation promotes repair following spinal cord injury by restoring neuronal mitochondrial bioenergetics via AMPK/PGC-1α/TFAM pathway.
5-Methoxyflavone-induced AMPKα activation inhibits NF-κB and P38 MAPK signaling to attenuate influenza A virus-mediated inflammation and lung injury in vitro and in vivo.
Metformin suppresses foam cell formation, inflammation and ferroptosis via the AMPK/ERK signaling pathway in ox‑LDL‑induced THP‑1 monocytes.
AdipoRon induces AMPK activation and ameliorates Alzheimer's like pathologies and associated cognitive impairment in APP/PS1 mice.
Negative Cross-Talk between TLR2/4-Independent AMPKα1 and TLR2/4-Dependent JNK Regulates S. pneumoniae-Induced Mucosal Innate Immune Response.
Riboflavin ameliorates mitochondrial dysfunction via the AMPK/PGC1α/HO‑1 signaling pathway and attenuates carbon tetrachloride‑induced liver fibrosis in rats.

Biochem Biophys Res Commun. 2022 Sep 16. pii: S0006-291X(22)01284-0. [Epub ahead of print]630 77-83

Irisin inhibits PCSK9 expression through activating AMPK-SREBP2 pathway.

Runqiu Xu, Qi Liu, Xiaoxue Ma, Jingbo Hou.

   AIMS: Previous studies found that irisin attenuated the vascular wall inflammation caused by Oxidized low-density lipoprotein (ox-LDL), and recent experiments have shown that proprotein convertase subtilisin/kexin type 9 (PCSK9) can act on various cells in the vascular wall to induce inflammatory responses. But, the relationship between irisin and PCSK9 has not been reported. The aim of this study was to investigate the effect of irisin on PSCK9 in endothelial cells and hepatocytes under the induction of ox-LDL.
METHODS: Experiments were performed using human umbilical vein endothelial cells and Hep G2, and cells were treated with irisin and (or) ox-LDL for evaluating expression of PCSK9 and downstream inflammatory proteins, while the expression levels of AMP-dependent protein kinase (AMPK) and sterol-regulatory element binding protein 2 (SREBP2) were also examined. Then Compound C was used to inhibit AMPK activation and SiAMPK for silencing of AMPK mRNA, and the above assays were also performed to deeply validate the role of the AMPK-SREBP2 pathway.
RESULTS: Irisin treatment significantly downregulated the expression of PCSK9 and inflammation-related proteins induced by ox-LDL, also restored the content of p-AMPK and reduced the SREBP2 content. After the use of Compound C or SiAMPK, the content of p-AMPK was obviously decreased, and the positive effect of irisin was greatly weakened.
CONCLUSIONS: This study demonstrates that irisin suppresses PCSK9 expression through the AMPK-SREBP2 pathway and ameliorates ox-LDL-induced endothelial cells inflammation.

Keywords:  atherosclerosis, irisin, PCSK9, AMPK, SREBP2

DOI:  https://doi.org/10.1016/j.bbrc.2022.09.034
Biochim Biophys Acta Mol Cell Res. 2022 Sep 21. pii: S0167-4889(22)00154-9. [Epub ahead of print]1869(12): 119362

Enhancement of cGMP-dependent pathway activity ameliorates hyperglycemia-induced decrease in SIRT1-AMPK activity in podocytes: Impact on glucose uptake and podocyte function.

Dorota Rogacka, Patrycja Rachubik, Irena Audzeyenka, Maria Szrejder, Tomasz Kulesza, Dorota Myślińska, Stefan Angielski, Agnieszka Piwkowska.

  Hyperglycemia significantly decreases 3',5'-cyclic guanosine monophosphate (cGMP)-dependent pathway activity in the kidney. A well-characterized downstream signaling effector of cGMP is cGMP-dependent protein kinase G (PKG), exerting a wide range of downstream effects, including vasodilation and vascular smooth muscle cells relaxation. In podocytes that are exposed to high glucose concentrations, crosstalk between the protein deacetylase sirtuin 1 (SIRT1) and adenosine monophosphate-dependent protein kinase (AMPK) decreased, attenuating insulin responsiveness and impairing podocyte function. The present study examined the effect of enhancing cGMP-dependent pathway activity on SIRT1-AMPK crosstalk in podocytes under hyperglycemic conditions. We found that enhancing cGMP-dependent pathway activity using a cGMP analog was associated with increases in SIRT1 protein levels and activity, with a concomitant increase in the degree of AMPK phosphorylation. The beneficial effects of enhancing cGMP-dependent pathway activity on SIRT1-AMPK crosstalk also included improvements in podocyte function. Based on our findings, we postulate an important role for SIRT1-AMPK crosstalk in the regulation of albumin permeability in hyperglycemia that is strongly associated with activity of the cGMP-dependent pathway.

Keywords:  AMPK; Albumin permeability; Glucose uptake; Podocyte; SIRT1; cGMP

DOI:  https://doi.org/10.1016/j.bbamcr.2022.119362
Metab Brain Dis. 2022 Sep 30.

AMPK-dependent autophagy activation and alpha-Synuclein clearance: a putative mechanism behind alpha-mangostin's neuroprotection in a rotenone-induced mouse model of Parkinson's disease.

Pathik Parekh, Nishant Sharma, Monika Sharma, Anagha Gadepalli, Adil Ali Sayyed, Sayan Chatterjee, Abhijeet Kate, Amit Khairnar.

  Alpha-Synuclein (α-Syn) accumulation is central to the pathogenesis of Parkinson's disease (PD), hence the quest for finding potential therapeutics that may promote the α-Syn clearance is the need of the hour. To this, activation of the evolutionarily conserved protein and key regulator of the autophagy, 5'AMP-activated protein kinase (AMPK) is well-known to induce autophagy and subsequently the clearance of α-Syn aggregates. Alpha-mangostin (AM) a polyphenolic xanthone obtained from Garcinia Mangostana L. was previously reported to activate AMPK-dependent autophagy in various pre-clinical cancer models. However, no studies evidenced the effect of AM on AMPK-dependent autophagy activation in the PD. Therefore, the present study aimed to investigate the neuroprotective activity of AM in the chronic rotenone mouse model of PD against rotenone-induced α-Syn accumulation and to dissect molecular mechanisms underlying the observed neuroprotection. The findings showed that AM exerts neuroprotection against rotenone-induced α-Syn accumulation in the striatum and cortex by activating AMPK, upregulating autophagy (LC3II/I, Beclin-1), and lysosomal (TFEB) markers. Of note, an in-vitro study utilizing rat pheochromocytoma cells verified that AM conferred the neuroprotection only through AMPK activation, as the presence of inhibitors of AMPK (dorsomorphin) and autophagy (3-methyl adenine) failed to mitigate rotenone-induced α-Syn accumulation. Moreover, AM also counteracted rotenone-induced behavioral deficits, oxidative stress, and degeneration of nigro-striatal dopaminergic neurons. In conclusion, AM provided neuroprotection by ameliorating the rotenone-induced α-Syn accumulation through AMPK-dependent autophagy activation and it can be considered as a therapeutic agent which might be having a higher translational value in the treatment of PD.

Keywords:  AMPK; Alpha-mangostin; Autophagy; Chronic rotenone mouse model; Neurodegeneration; Parkinson’s disease

DOI:  https://doi.org/10.1007/s11011-022-01087-1
Biochim Biophys Acta Mol Basis Dis. 2022 Sep 24. pii: S0925-4439(22)00231-9. [Epub ahead of print]1868(12): 166560

A non-mitogenic FGF4 analog alleviates non-alcoholic steatohepatitis through an AMPK-dependent pathway.

Luyao Wang, Wenliya Dong, Huan Gao, Chuchu Chen, Siyu Liang, Xianxi Ye, Yi Liu, Yushu Hou, Lei Fan, Tongtong Pan, Zengshou Wang, Yongping Chen, Yongde Luo, Lintao Song.

   BACKGROUND & AIMS: Non-alcoholic fatty liver disease (NAFLD) has emerged as a major liver disease increasingly in association with non-alcoholic steatohepatitis (NASH), cirrhosis and hepatocellular carcinoma (HCC). However, there are currently no approved therapies for treating NAFLD and NASH. Fibroblast growth factor 4 (FGF4) has recently been shown as a promising drug candidate for several metabolic diseases.
METHODS: Mice fed a high-fat diet with high fructose/glucose drinking water (HF/HFG, Western-like diet) for 21 weeks were intraperitoneally injected with non-mitogenic recombinant FGF4△NT (rFGF4△NT, 1.0 mg/kg body weight) every other day for 8 weeks. Primary mouse hepatocytes cultured in medium containing high glucose/palmitic acid (HG/PA) or TNFα/cyclohexane (TNFα/CHX) were treated with 1.0 μg/ml rFGF4△NT. Changes in parameters for histopathology, lipid metabolism, inflammation, hepatocellular apoptosis and fibrosis were determined. The Caspase6 activity and AMPK pathway were assessed.
RESULTS: Administration of rFGF4△NT significantly attenuated the Western-like diet-induced hepatic steatosis, inflammation, liver injury and fibrosis in mice. rFGF4△NT treatment reduced fatty acid-induced lipid accumulation and lipotoxicity-induced hepatocyte apoptosis, which were associated with inhibition of Caspase6 cleavage and activation. Inhibition of AMP-activated protein kinase (AMPK) by Compound C or deficiency of Ampk abrogated rFGF4△NT-induced hepatoprotection in primary hepatocytes and in mice with NASH.
CONCLUSION: rFGF4△NT exerts significant protective effects on NASH via an AMPK-dependent signaling pathway. Our study indicates that FGF4 analogs may have therapeutic potential for the Western-like diet induced NASH.

Keywords:  AMP-activated protein kinase; Apoptosis; Fibrosis; Inflammation; NASH; Non-mitogenic fibroblast growth factor 4

DOI:  https://doi.org/10.1016/j.bbadis.2022.166560
Ecotoxicol Environ Saf. 2022 Sep 22. pii: S0147-6513(22)00945-9. [Epub ahead of print]245 114105

Gender difference in hepatic AMPK pathway activated lipid metabolism induced by aged polystyrene microplastics exposure.

Xiaona Yang, Jin Jiang, Qing Wang, Jiawei Duan, Na Chen, Di Wu, Yankai Xia.

  Microplastics (MPs) pollution becomes an increasing concern and researchers keep exploring the health effects caused by MPs exposure. The ageing process in the environment significantly alters the physicochemical characteristics of MPs and subsequently affects their toxicities. The health effects of aged MPs exposure and the mechanism underlying are worthy of exploration. Polystyrene microplastics (PS-MPs) (with size less than 50 µm) were obtained by grinding and screening polystyrene materials. PS-MPs continued to be aged by ozone treatment (0.4 mg/min, 9 h). Both male and female C57BL/6 mice were orally exposed to 0 or 2 mg/kg/d aged PS-MPs for 28 days. Results showed that PS-MPs were found in liver, ovary and spleen of females and liver, testis and spleen of males in the aged PS-MPs group. Exposure to aged PS-MPs significantly decreased abdominal fat/body coefficient, the adipocyte size and the serum LDL-C level in females. Compared to the control, serum estradiol (E2) level, the mRNA expression levels of genes regulating E2 production (17β-hsd, 3β-hsd and Star) in ovary and the protein expression levels of E2 receptors (ERα, ERβ), AMPKα and p-AMPKα1 in liver increased significantly, and the mRNA expression levels of AMP-activated protein kinase (AMPK) downstream genes (Srebp-1c, Fas and Scd1) in liver decreased significantly in the female aged PS-MPs group. Liver metabolomic profiling showed that differential metabolites between female aged PS-MPs group and female control group were enriched in biotin metabolism and the level of biotin increased significantly in the female aged PS-MPs group. However, no significant changes were detected in males. These results indicated that aged PS-MPs exposure increased ovarian E2 production and activated the AMPK pathway in the liver which might inhibit liver lipid synthesis only in females. Our findings provide new insights into the potential sex-specific health effects of environmental MPs pollution.

Keywords:  AMPK; Estradiol; Lipid metabolism; Liver; Ovary; Polystyrene microplastics

DOI:  https://doi.org/10.1016/j.ecoenv.2022.114105
Elife. 2022 Sep 26. pii: e79939. [Epub ahead of print]11

Hepatic AMPK signaling activation in response to dynamic REDOX balance is a biomarker of exercise to improve blood glucose control.

Meiling Wu, Anda Zhao, Xingchen Yan, Hongyang Gao, Chunwang Zhang, Xiaomin Liu, Qiwen Luo, Feizhou Xie, Shanlin Liu, Dongyun Shi.

  Antioxidant intervention is considered to inhibit reactive oxygen species (ROS) and alleviates hyperglycemia. Paradoxically, moderate exercise can produce ROS to improve diabetes. The exact redox mechanism of these two different approaches remains largely unclear. Here, by comparing exercise and antioxidants intervention on type 2 diabetic rats, we found moderate exercise upregulated compensatory antioxidant capability and reached a higher level of redox balance in the liver. In contrast, antioxidant intervention achieved a low-level redox balance by inhibiting oxidative stress. Both of these two interventions could promote glucose catabolism and inhibit gluconeogenesis through activation of hepatic AMPK signaling, therefore ameliorating diabetes. During exercise, different levels of ROS generated by exercise have differential regulations on the activity and expression of hepatic AMPK. Moderate exercise-derived ROS promoted hepatic AMPK glutathionylation activation. However, excessive exercise increased oxidative damage and inhibited the activity and expression of AMPK. Overall, our results illustrate that both exercise and antioxidant intervention improve blood glucose in diabetes by promoting redox balance, despite different levels of redox balance. These results indicate that the AMPK signaling activation, combined with oxidative damage markers, could act as a sensitive biomarker, reflecting the threshold of redox balance defining effective treatment in diabetes. These findings provide theoretical evidence for the precise treatment of diabetes by antioxidants and exercise.

Keywords:  biochemistry; chemical biology; rat

DOI:  https://doi.org/10.7554/eLife.79939
Neurochem Res. 2022 Sep 29.

Sex Dimorphic Glucose Transporter-2 Regulation of Hypothalamic Astrocyte Glucose and Energy Sensor Expression and Glycogen Metabolism.

Madhu Babu Pasula, Prabhat R Napit, Abdulrahman Alhamyani, Sagor C Roy, Paul W Sylvester, Khaggeswar Bheemanapally, Karen P Briski.

  The plasma membrane glucose transporter-2 (GLUT2) monitors brain cell uptake of the critical nutrient glucose, and functions within astrocytes of as-yet-unknown location to control glucose counter-regulation. Hypothalamic astrocyte-neuron metabolic coupling provides vital cues to the neural glucostatic network. Current research utilized an established hypothalamic primary astrocyte culture model along with gene knockdown tools to investigate whether GLUT2 imposes sex-specific regulation of glucose/energy sensor function and glycogen metabolism in this cell population. Data show that GLUT2 stimulates or inhibits glucokinase (GCK) expression in glucose-supplied versus -deprived male astrocytes, but does not control this protein in female. Astrocyte 5'-AMP-activated protein kinaseα1/2 (AMPK) protein is augmented by GLUT2 in each sex, but phosphoAMPKα1/2 is coincidently up- (male) or down- (female) regulated. GLUT2 effects on glycogen synthase (GS) diverges in the two sexes, but direction of this control is reversed by glucoprivation in each sex. GLUT2 increases (male) or decreases (female) glycogen phosphorylase-brain type (GPbb) protein during glucoprivation, yet simultaneously inhibits (male) or stimulates (female) GP-muscle type (GPmm) expression. Astrocyte glycogen accumulation is restrained by GLUT2 when glucose is present (male) or absent (both sexes). Outcomes disclose sex-dependent GLUT2 control of the astrocyte glycolytic pathway sensor GCK. Data show that glucose status determines GLUT2 regulation of GS (both sexes), GPbb (female), and GPmm (male), and that GLUT2 imposes opposite control of GS, GPbb, and GPmm profiles between sexes during glucoprivation. Ongoing studies aim to investigate molecular mechanisms underlying sex-dimorphic GLUT2 regulation of hypothalamic astrocyte metabolic-sensory and glycogen metabolic proteins, and to characterize effects of sex-specific astrocyte target protein responses to GLUT2 on glucose regulation.

Keywords:  AMPK; GLUT2; Glycogen; Glycogen phosphorylase; Sex differences; glucokinase

DOI:  https://doi.org/10.1007/s11064-022-03757-z
Front Pharmacol. 2022 ;13 991421

Photobiomodulation promotes repair following spinal cord injury by restoring neuronal mitochondrial bioenergetics via AMPK/PGC-1α/TFAM pathway.

Zhijie Zhu, Xuankang Wang, Zhiwen Song, Xiaoshuang Zuo, Yangguang Ma, Zhihao Zhang, Cheng Ju, Zhuowen Liang, Kun Li, Xueyu Hu, Zhe Wang.

  Background: Insufficient neuronal mitochondrial bioenergetics supply occurs after spinal cord injury (SCI), leading to neuronal apoptosis and impaired motor function. Previous reports have shown that photobiomodulation (PBM) could reduce neuronal apoptosis and promote functional recovery, but the underlying mechanism remains unclear. Therefore, we aimed to investigate whether PBM improved prognosis by promoting neuronal mitochondrial bioenergetics after SCI. Methods: Sprague Dawley rats were randomly divided into four groups: a Sham group, an SCI group, an SCI + PBM group and an SCI + PBM + Compound C group. After SCI model was established, PBM and Compound C (an AMPK inhibitor) injection were carried out. The level of neuron apoptosis, the recovery of motor function and mitochondrial function were observed at different times (7, 14, and 28 days). The AMPK/PGC-1α/TFAM pathway was hypothesized to be a potential target through which PBM could affect neuronal mitochondrial bioenergetics. In vitro, ventral spinal cord 4.1 (VSC4.1) cells were irradiated with PBM and cotreated with Compound C after oxygen and glucose deprivation (OGD). Results: PBM promoted the recovery of mitochondrial respiratory chain complex activity, increased ATP production, alleviated neuronal apoptosis and reversed motor dysfunction after SCI. The activation of the AMPK/PGC-1α/TFAM pathway after SCI were facilitated by PBM but inhibited by Compound C. Equally important, PBM could inhibit OGD-induced VSC4.1 cell apoptosis by increasing ATP production whereas these changes could be abolished by Compound C. Conclusion: PBM activated AMPK/PGC-1α/TFAM pathway to restore mitochondrial bioenergetics and exerted neuroprotective effects after SCI.

Keywords:  AMPK; PGC-1α; TFAM; mitochondria; neuron; photobiomodulation; spinal cord injury

DOI:  https://doi.org/10.3389/fphar.2022.991421
Cell Mol Biol Lett. 2022 Sep 30. 27(1): 82

5-Methoxyflavone-induced AMPKα activation inhibits NF-κB and P38 MAPK signaling to attenuate influenza A virus-mediated inflammation and lung injury in vitro and in vivo.

Sushan Yang, Linxin Wang, Xiping Pan, Yueyun Liang, Yuehan Zhang, Jing Li, Beixian Zhou.

  Influenza-related acute lung injury (ALI) is a life-threatening condition that results mostly from uncontrolled replication of influenza virus (IV) and severe proinflammatory responses. The methoxy flavonoid compound 5-methoxyflavone (5-MF) is believed to have superior biological activity in the treatment of cancer. However, the effects and underlying mechanism of 5-MF on IV-mediated ALI are still unclear. Here, we showed that 5-MF significantly improved the survival of mice with lethal IV infection and ameliorated IV-mediated lung edema, lung histological changes, and inflammatory cell lung recruitment. We found that 5-MF has antiviral activity against influenza A virus (IAV), which was probably associated with increased expression of radical S-adenosyl methionine domain containing 2 (RSAD2) and suppression of endosomal acidification. Moreover, IV-infected A549 cells with 5-MF treatment markedly reduced proinflammatory mediator expression (IL-6, CXCL8, TNF-α, CXCL10, CCL2, CCL3, CCL4, GM-CSF, COX-2, and PGE2) and prevented P-IKBα, P-P65, and P-P38 activation. Interestingly, we demonstrated that 5-MF treatment could trigger activation of AMP-activated protein kinase (AMPK)α in IV-infected A549 cells, as evidenced by activation of the AMPKα downstream molecule P53. Importantly, the addition of AMPKα blocker compound C dramatically abolished 5-MF-mediated increased levels of RSAD2, the inhibitory effects on H1N1 virus-elicited endosomal acidification, and the suppression expression of proinflammatory mediators (IL-6, TNF-α, CXCL10, COX-2 and PGE2), as well as the inactivation of P-IKBα, P-P65, and P-P38 MAPK signaling pathways. Furthermore, inhibition of AMPKα abrogated the protective effects of 5-MF on H1N1 virus-mediated lung injury and excessive inflammation in vivo. Taken together, these results indicate that 5-MF alleviated IV-mediated ALI and suppressed excessive inflammatory responses through activation of AMPKα signaling.

Keywords:  5-Methoxyflavone; AMPKα; Anti-inflammatory; Antiviral; Influenza A virus

DOI:  https://doi.org/10.1186/s11658-022-00381-1
Exp Ther Med. 2022 Oct;24(4): 636

Metformin suppresses foam cell formation, inflammation and ferroptosis via the AMPK/ERK signaling pathway in ox‑LDL‑induced THP‑1 monocytes.

Yihan Zhao, Yizhen Zhao, Yuan Tian, Yang Zhou.

  Numerous studies have shown that the formation of foam cells is of vital importance in the process of atherosclerosis. The aim of the present study was to assess the effects of metformin on foam cell formation in oxidized low-density lipoprotein (ox-LDL)-treated THP-1 cells and explore its associated mechanism of action. Human monocytic THP-1 cells were pretreated with metformin for 2 h and subsequently treated with ox-LDL for 24 h. The data indicated that metformin significantly inhibited lipid accumulation in ox-LDL-treated THP-1 cells by decreasing the expression of scavenger receptor A, cluster of differentiation 36 and adipocyte enhancer-binding protein 1. In addition, metformin increased the expression levels of scavenger receptor B1 and ATP binding cassette transporter G1 and suppresses the esterification of free cholesterol. Furthermore, it markedly inhibited ferroptosis (reflected by the upregulation of glutathione peroxidase glutathione peroxidase 4 and the downregulation of Heme oxygenase-1). In addition, it caused a marked suppression in the expression levels of cysteinyl aspartate specific proteinase-1, IL-1β, NOD-like receptor protein 3, IL-18 secretion and in the levels of oxidative stress. Metformin attenuated the activation of ERK and facilitated the phosphorylation of 5' adenosine monophosphate-activated protein kinase (AMPK). Treatment of THP-1 cells with an ERK inhibitor reversed these effects, while inhibition of AMPK activity exacerbated the effects noted in ox-LDL-treated THP-1 cells. In conclusion, the present study suggested that metformin suppressed foam cell formation, inflammatory responses and inhibited ferroptosis in ox-LDL-treated macrophages via the AMPK/ERK signaling pathway.

Keywords:  atherosclerosis; ferroptosis; foam cells; inflammation; metformin; oxidized low-density lipoprotein

DOI:  https://doi.org/10.3892/etm.2022.11573
Neurobiol Dis. 2022 Sep 23. pii: S0969-9961(22)00268-6. [Epub ahead of print]174 105876

AdipoRon induces AMPK activation and ameliorates Alzheimer's like pathologies and associated cognitive impairment in APP/PS1 mice.

Mayuri Khandelwal, Kapil Manglani, Prabhat Upadhyay, Mohammad Azad, Sarika Gupta.

  Alzheimer's disease (AD) is a progressive devastating neurodegenerative disorder characterized by extracellular amyloid beta (Aβ42) plaque formation, hyperphosphorylation of tau protein leading to intracellular neurofibrillary tangle formation. Recently discovered hallmark features responsible for AD pathogenesis are neuronal insulin resistance, dysregulation in adiponectin and AMPK signaling. The presence of adiponectin and its receptor in the brain with its unique anti-diabetic effects and association with neurodegenerative diseases has raised our interest in exploring orally active small molecule adiponectin receptor agonist, AdipoRon. To date, all the available drugs for the treatment of AD provides symptomatic relief and do not stall the progression of the disease. Indeed, it is becoming increasingly apparent to find appropriate targets. Here, we attempt to shed lights on adiponectin receptor agonist, AdipoRon and its downstream molecular targets in reducing disease pathogenesis and insulin resistance. In brain, AdipoRon induced AMPK activation, increased insulin sensitivity, reduced amyloid beta plaque deposition and improved cognitive impairment. Levels of BACE were also downregulated while LDLR, APOE and neprilysin were upregulated promoting amyloid beta clearance from brain. AdipoRon further reduced the chronic inflammatory marker, GFAP and improved synaptic markers PSD-95 and synaptophysin in APP/PS1 mice. Our in-vitro studies further confirmed the potential role of AdipoRon in improving insulin sensitivity by increasing GLUT 4 translocation, glucose uptake and insulin signaling under hyperinsulinemic condition. Our findings suggest that AdipoRon could be a promising lead in the future treatment strategies in the development of effective AD treatment.

Keywords:  APP/PS1 mice; Adiponectin receptor agonist; Alzheimer's disease; Brain insulin resistance; Type III diabetes

DOI:  https://doi.org/10.1016/j.nbd.2022.105876
J Immunol. 2022 Sep 02. pii: ji2100901. [Epub ahead of print]

Negative Cross-Talk between TLR2/4-Independent AMPKα1 and TLR2/4-Dependent JNK Regulates S. pneumoniae-Induced Mucosal Innate Immune Response.

Shingo Matsuyama, Kensei Komatsu, Byung-Cheol Lee, Yukihiro Tasaki, Masanori Miyata, Haidong Xu, Tsuyoshi Shuto, Hirofumi Kai, Jian-Dong Li.

Streptococcus pneumoniae is major cause of otitis media (OM) and life-threatening pneumonia. Overproduction of mucin, the major component of mucus, plays a critical role in the pathogenesis of both OM and pneumonia. However, the molecular mechanisms underlying the tight regulation of mucin upregulation in the mucosal epithelium by S. pneumoniae infection remain largely unknown. In this study, we show that S. pneumoniae pneumolysin (PLY) activates AMP-activated protein kinase α1 (AMPKα1), the master regulator of energy homeostasis, which is required for S. pneumoniae-induced mucin MUC5AC upregulation in vitro and in vivo. Moreover, we found that PLY activates AMPKα1 via cholesterol-dependent membrane binding of PLY and subsequent activation of the Ca2+- Ca2+/calmodulin-dependent kinase kinase β (CaMKKβ) and Cdc42-mixed-lineage protein kinase 3 (MLK3) signaling axis in a TLR2/4-independent manner. AMPKα1 positively regulates PLY-induced MUC5AC expression via negative cross-talk with TLR2/4-dependent activation of MAPK JNK, the negative regulator of MUC5AC expression. Moreover, pharmacological inhibition of AMPKα1 suppressed MUC5AC induction in the S. pneumoniae-induced OM mouse model, thereby demonstrating its therapeutic potential in suppressing mucus overproduction in OM. Taken together, our data unveil a novel mechanism by which negative cross-talk between TLR2/4-independent activation of AMPKα1 and TLR2/4-dependent activation of JNK tightly regulates the S. pneumoniae PLY-induced host mucosal innate immune response.

DOI: https://doi.org/10.4049/jimmunol.2100901
Exp Ther Med. 2022 Oct;24(4): 608

Riboflavin ameliorates mitochondrial dysfunction via the AMPK/PGC1α/HO‑1 signaling pathway and attenuates carbon tetrachloride‑induced liver fibrosis in rats.

Ning Tang, Feng Hong, Wei Hao, Ting-Ting Yu, Guo-Guang Wang, Wei Li.

  Hepatic fibrosis is a global health problem, with increasing evidence demonstrating that oxidative stress serves a pivotal role in fibrogenesis. Riboflavin is a vital nutrient in the human and animal diet, which enhances the activity of antioxidant enzymes and ameliorates oxidative stress. The present study evaluated the effect of riboflavin on liver fibrosis and the mechanisms underlying this process. Rats were subcutaneously injected with carbon tetrachloride (CCl4) dissolved in sterile olive oil twice per week to induce hepatic fibrosis. The effect of riboflavin on CCl4-induced liver fibrosis was then assessed. Blood samples and liver tissues were collected and analyzed. The liver tissue morphological changes, immunohistochemical analysis, levels of malondialdehyde (MDA) and superoxide dismutase (SOD) in the mitochondria, and the protein expression levels of α-smooth muscle actin (α-SMA), transforming growth factor-β1 (TGF-β1), extracellular signal-regulated kinase (ERK), p38, c-Jun N-terminal kinase (JNK), AMP-activated protein kinase (AMPK), peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α) and heme oxygenase 1 (HO-1) in the liver were also analyzed. The results demonstrated that riboflavin treatment significantly decreased the levels of alanine transaminase and aspartate transaminase in the serum, increased SOD activity and modulated the MDA level in the mitochondria. Furthermore, riboflavin significantly inhibited the CCl4-induced, upregulated protein expression levels of phosphorylated (p)-ERK, p-p38, p-JNK, TGF-β1 and α-SMA. Moreover, riboflavin significantly increased the expression of p-AMPK, PGC-1α and HO-1 in the liver tissue. These results suggested that riboflavin delays CCl4-induced hepatic fibrosis by enhancing the mitochondrial function via the AMPK/PGC-1α/HO-1 and mitogen-activated protein kinase signaling pathways.

Keywords:  AMPK/PGC-1α/HO-1 signaling; CCL4; liver fibrosis; mitochondria; riboflavin

DOI:  https://doi.org/10.3892/etm.2022.11545