Adenosine Monophosphate-activated Protein Kinase Activation Research Articles

Hippocampal and gut AMPK activation attenuates enterocolitis-like symptoms and co-occurring depressive-like behavior in ulcerative colitis model mice: Involvement of brain-gut autophagy

Patients with inflammatory bowel disease, including ulcerative colitis (UC) and Crohn's disease, have a high incidence of psychiatric disorders, including depression and anxiety. However, the underlying pathogenic mechanism remains unknown. Dextran sulfate sodium (DSS)-treated mice, a model of UC, exhibit depressive-like behavior and reduced adenosine monophosphate-activated protein kinase (AMPK) activity, which regulates various physiological functions in the brain and gut. However, comprehensive studies on UC pathophysiology with co-occurring depression focused on brain-gut AMPK activity are lacking. Therefore, we aimed to investigate whether resveratrol (RES), an AMPK activator, prevented DSS-induced UC-like symptoms and depressive-like behavior. DSS treatment induced UC-like pathology and depressive-like behavior, as assessed via the tail suspension test. Moreover, western blotting and immunohistochemical studies revealed that DSS increased p-p70S6 kinase (Thr389), p62, tumor necrosis factor-α, interleukin (IL)-1β, IL-18, NLR family pyrin domain containing 3 (NLRP3), cleaved caspase-1, cleaved Gasdermin-D (GSDMD), and cleaved caspase-3 expression levels in the rectum and hippocampus, and increased CD40, iNOS, and Kelch-like ECH-associated protein 1 expression levels, and the number of Iba1-positive cells in the hippocampus, and decreased p-AMPK and LC3II/I expression levels, and the number of NF-E2-related factor 2 (Nrf2)-positive cells, and reduced neurogenesis in the hippocampus. These changes were reversed by the RES administration. RES also enhanced PGC1α and SOD1 expression in the hippocampus of DSS-treated male mice. Moreover, NLRP3 staining was observed in the neurons and microglia, and cleaved GSDMD staining in neurons in the hippocampus of DSS-treated mice. Notably, RES prevented UC-like pathology and depressive-like behavior and enhancement of autophagy, decreased rectal and hippocampal inflammatory cytokines and inflammasome, and induced the Nrf2-PGC1α-SOD1 pathway in the hippocampus, resulting in neurogenesis in the hippocampal dentate gyrus. Our findings suggest that brain-gut AMPK activation may be an important therapeutic strategy in patients with UC and depression.

Antiproliferative Activity of Gibbosic Acid H through Induction of G0/G1 Cell Cycle Arrest and Apoptosis in Human Lung Cancer Cells.

Lung cancer is one of the most common causative cancers worldwide. Particularly, non-small cell lung cancer (NSCLC) accounts for approximately 85% of all lung cancer cases. NSCLC is a serious form of lung cancer that requires prompt diagnosis, and the 5-year survival rate for patients with this disease is only 24%. Gibbosic acid H (GaH), a natural lanostanoid obtained from the Ganoderma species (Ganodermataceae), has antiproliferative activities against colon and lung cancer cells. The aim of the present study was to evaluate the antiproliferative activity of GaH in NSCLC cells and to elucidate the underlying molecular mechanisms. GaH was found to induce G0/G1 cell cycle arrest and autophagy by activating adenosine monophosphate-activated protein kinase in A549 and H1299 cells. The induction of this cell cycle arrest was associated with the downregulation of cyclin E1 and CDK2. Additionally, the induction of autophagy by GaH was correlated with the upregulation of LC3B, beclin-1, and p53 expression. GaH also induced apoptosis by upregulating cleaved caspase-3 and Bax in the lung cancer cells. These findings suggest that GaH has a potential in the growth inhibition of human lung cancer cells.

Ezetimibe ameliorates cisplatin-induced nephrotoxicity: A novel therapeutic approach via modulating AMPK/Nrf2/TXNIP signaling.

Cisplatin (Cis) is among the most powerful antineoplastic medications, nevertheless, its serious side effects; particularly nephrotoxicity designates a major concern. Previous studies reported that ezetimibe (Eze), a well-known antihyperlipidemic drug, exerts additional trivial pharmacological effects. In this work, we displayed Eze as an intriguing protective candidate in a cisplatin-induced nephrotoxicity rat model through AMPK activation. Eze (10 mg/kg, p.o.) was administered for two weeks and Cis (10 mg/kg, i.p.) was administered on the 10th day to induce nephrotoxicity in male Wistar rats. Treatment with Eze greatly augmented the phosphorylation of adenosine 5'-monophosphate-activated protein kinase (AMPK) and the antioxidant regulator; nuclear factor erythroid 2-related factor 2 (Nrf2), thus, mitigating oxidative injury through induction of the antioxidant enzymes, such as heme oxygenase-1 (HO-1) and glutathione reductase (GR). As well, Eze relieved inflammation by reducing protein expression of thioredoxin-interacting protein (TXNIP) and nucleotide-binding domain-like receptor protein 3 (NLRP3), which led to a decrease in the release of caspase-1, in addition to, the inflammatory markers IL-18and IL-1 β. Besides, Eze ameliorated apoptosis in the renal cells through inhibiting the phosphorylated Apoptosis signal-regulating kinase-1(p-ASK1), caspase-3 and reducing Bax/Bcl2ratio. Correspondingly, histopathological examination corroborated the previous biochemical findings. Collectively, Eze exerts significant renal protection against Cis-induced nephrotoxicity via antioxidant, anti-inflammatory and anti-apoptotic pathways that are probably mediated, at least partly, via activating AMPK/Nrf2/HO-1 pathway and conquering both TXNIP/NLRP3 inflammasome and TXNIP/ASK1 signaling pathways. To confirm the protective effect of Eze via AMPK-activation, an AMPK-inhibitor, dorsomorphin (Dors), when co-administered with Eze abolished its protective effect.

Berberine Induces Mitophagy through Adenosine Monophosphate-Activated Protein Kinase and Ameliorates Mitochondrial Dysfunction in PINK1 Knockout Mouse Embryonic Fibroblasts.

Mitophagy stimulation has been shown to have a therapeutic effect on various neurodegenerative diseases. However, nontoxic mitophagy inducers are still very limited. In this study, we found that the natural alkaloid berberine exhibited mitophagy stimulation activity in various human cells. Berberine did not interfere with mitochondrial function, unlike the well-known mitophagy inducer carbonyl cyanide m-chlorophenyl hydrazone (CCCP), and subsequently induced mitochondrial biogenesis. Berberine treatment induced the activation of adenosine monophosphate-activated protein kinase (AMPK), and the AMPK inhibitor compound C abolished berberine-induced mitophagy, suggesting that AMPK activation is essential for berberine-induced mitophagy. Notably, berberine treatment reversed mitochondrial dysfunction in PINK1 knockout mouse embryonic fibroblasts. Our results suggest that berberine is a mitophagy-specific inducer and can be used as a therapeutic treatment for neurodegenerative diseases, including Parkinson's disease, and that natural alkaloids are potential sources of mitophagy inducers.

Drynaria rhizome water extract alleviates high‑fat diet‑induced obesity in mice.

Drynaria rhizome is a herbal medicine used for strengthening bones and treating bone diseases in East Asia. Although obesity is considered to benefit bone formation, it has been revealed that visceral fat accumulation can promote osteoporosis. Given the complex relationship between bone metabolism and obesity, bone‑strengthening medicines should be evaluated while considering the effects of obesity. The present study investigated the effects of Drynaria rhizome extract (DRE) on high‑fat diet (HFD)‑induced obese mice. DRE was supplemented with the HFD. Body weight, food intake, the expression levels of lipogenesis transcription factors, including sterol regulatory element binding protein (SREBP)‑1, peroxisome proliferator‑activated receptor (PPAR)‑γ and adenosine monophosphate‑activated protein kinase (AMPK)‑α, and AMPK activation were evaluated. Mice fed DRE and a HFD exhibited reduced body weight without differences in food intake compared with those in the HFD group. Furthermore, DRE; upregulated AMPK‑α of epididymal one; down‑regulated SREBP‑1 and PPAR‑γ, as determined using western blotting and quantitative polymerase chain reaction, respectively. Decreased lipid accumulation were observed in both fat pad and liver of HFD‑fed mice, which were suppressed by DRE treatment. These results demonstrated the potential of DRE as a dietary natural product for strengthening bones and managing obesity.

Metformin Prevents Cocaine Sensitization: Involvement of Adenosine Monophosphate-Activated Protein Kinase Trafficking between Subcellular Compartments in the Corticostriatal Reward Circuit

Repeated cocaine exposure produces an enhanced locomotor response (sensitization) paralleled by biological adaptations in the brain. Previous studies demonstrated region-specific responsivity of adenosine monophosphate-activated protein kinase (AMPK) to repeated cocaine exposure. AMPK maintains cellular energy homeostasis at the organismal and cellular levels. Here, our objective was to quantify changes in phosphorylated (active) and total AMPK in the cytosol and synaptosome of the medial prefrontal cortex, nucleus accumbens, and dorsal striatum following acute or sensitizing cocaine injections. Brain region and cellular compartment selective changes in AMPK and pAMPK were found with some differences associated with acute withdrawal versus ongoing cocaine treatment. Our additional goal was to determine the behavioral and molecular effects of pretreatment with the indirect AMPK activator metformin. Metformin potentiated the locomotor activating effects of acute cocaine but blocked the development of sensitization. Sex differences largely obscured any protein-level treatment group effects, although pAMPK in the NAc shell cytosol was surprisingly reduced by metformin in rats receiving repeated cocaine. The rationale for these studies was to inform our understanding of AMPK activation dynamics in subcellular compartments and provide additional support for repurposing metformin for treating cocaine use disorder.

Clearance of β-amyloid mediated by autophagy is enhanced by MTORC1 inhibition but not AMPK activation in APP/PSEN1 astrocytes.

Proteostasis mechanisms mediated by macroautophagy/autophagy are altered in neurodegenerative diseases such as Alzheimer disease (AD) and their recovery/enhancement has been proposed as a therapeutic approach. From the two central nodes in the anabolism-catabolism balance, it is generally accepted that mechanistic target of rapamycin kinase complex 1 (MTORC1)_ activation leads to the inhibition of autophagy, whereas adenosine 5'-monophosphate (AMP)-activated protein kinase (AMPK) has the opposite role. In AD, amyloid beta (Aβ) production disturbs the optimal neuronal/glial proteostasis. As astrocytes are essential for brain homeostasis, the purpose of this work was to analyze if the upregulation of autophagy in this cell type, either by MTORC1 inhibition or AMPK activation, could modulate the generation/degradation of β-amyloid. By using primary astrocytes from amyloid beta precursor protein (APP)/Presenilin 1 (PSEN1) mouse model of AD, we confirmed that MTORC1 inhibition reduced Aβ secretion through moderate autophagy induction. Surprisingly, pharmacologically increased activity of AMPK did not enhance autophagy but had different effects on Aβ secretion. Conversely, AMPK inhibition did not affect autophagy but reduced Aβ secretion. These puzzling data were confirmed through the overexpression of different mutant AMPK isoforms: while only the constitutively active AMPK increased autophagy, all versions augmented Aβ secretion. We conclude that AMPK has a significantly different role in primary astrocytes than in other reported cells, similar to our previous findings in neurons. Our data support that perhaps only a basal AMPK activity is needed to maintain autophagy whereas the increased activity, either physiologically or pharmacologically, has no direct effect on autophagy-dependent amyloidosis. These results shed light on the controversy about the therapeutic effect of AMPK activation on autophagy induction.

Extracellular Superoxide Dismutase Attenuates Hepatic Oxidative Stress in Nonalcoholic Fatty Liver Disease through the Adenosine Monophosphate-Activated Protein Kinase Activation.

Oxidative stress is key in type 2 diabetes-associated nonalcoholic fatty liver disease (NAFLD). We explored whether extracellular superoxide dismutase (EC-SOD) activates adenosine monophosphate-activated protein kinase (AMPK) to enhance antioxidant synthesis and lipid metabolism in NAFLD. Human recombinant EC-SOD (hEC-SOD) was administered to 8-week-old male C57BLKS/J db/db mice through intraperitoneal injection once a week for 8 weeks. Target molecules involved in oxidative stress and lipid metabolism were investigated. hEC-SOD improved insulin resistance and systemic and hepatic oxidative stress characterized by increases in urinary 8-hydroxy-deoxyguanosine and 8-isoprostane levels in db/db mice and a decrease in DHE expression in the liver, respectively. Hepatic SOD3 expression in db/db mice was reversed by hEC-SOD, which improved hepatic steatosis, inflammation with M2 polarization, apoptosis, autophagy, fibrosis and lipid metabolism in db/db mice, as reflected by the changes in serum and hepatic markers, monocyte chemoattractant protein-1, tumor necrosis factor-α, TUNEL-positive cells, Bcl-2/BAX ratio, beclin1 and LC3-II/LC3-1. At the molecular level, hEC-SOD increased phosphorylated-AMPK related to CaMKKß, activation of peroxisome proliferative-activated receptor-gamma coactivator (PGC)-1α and dephosphorylation of forkhead box O (FoxO)1 and their subsequent downstream signaling. In HepG2Cs cells using AMPKα1 and AMPKα2 siRNA, hEC-SOD demonstrated a protective effect via the direct activation of both AMPK-PGC-1α and AMPK-FoxO1. EC-SOD might be a potential therapeutic agent for NAFLD through the activation of AMPK-PGC-1α and AMPK-FoxO1 signaling in hepatocytes, which modulates lipid metabolism, leading to anti-inflammatory, antioxidative and antiapoptotic effects and improving autophagy in the liver.

METFORMIN MITIGATES SEPSIS-ASSOCIATED PULMONARY FIBROSIS BY PROMOTING AMPK ACTIVATION AND INHIBITING HIF-1α-INDUCED AEROBIC GLYCOLYSIS.

Recent research has revealed that aerobic glycolysis has a strong correlation with sepsis-associated pulmonary fibrosis (PF). However, at present, the mechanism and pathogenesis remain unclear. We aimed to test the hypothesis that the adenosine monophosphate-activated protein kinase (AMPK) activation and suppression of hypoxia-inducible factor 1α (HIF-1α)-induced aerobic glycolysis play a central role in septic pulmonary fibrogenesis. Cellular experiments demonstrated that lipopolysaccharide increased fibroblast activation through AMPK inactivation, HIF-1α induction, alongside an augmentation of aerobic glycolysis. By contrast, the effects were reversed by AMPK activation or HIF-1α inhibition. In addition, pretreatment with metformin, which is an AMPK activator, suppresses HIF-1α expression and alleviates PF associated with sepsis, which is caused by aerobic glycolysis, in mice. Hypoxia-inducible factor 1α knockdown demonstrated similar protective effects in vivo . Our research implies that targeting AMPK activation and HIF-1α-induced aerobic glycolysis with metformin might be a practical and useful therapeutic alternative for sepsis-associated PF.

Si-Ni-San inhibits hepatic Fasn expression and lipid accumulation in MAFLD mice through AMPK/p300/SREBP-1c axis

BackgroundSoothing the liver and regulating qi is one of the core ideas of traditional Chinese medicine (TCM) in the treatment of fatty liver. Si-Ni-San (SNS) is a well-known herbal formula in TCM for liver soothing and qi regulation in fatty liver treatment. However, its efficacy lacks modern scientific evidence. PurposeThis study was aimed to investigate the impact of SNS on metabolic associated fatty liver disease (MAFLD) in mice and explore the underlying molecular mechanisms, particularly its effects on lipid metabolism in hepatocytes. MethodsThe therapeutic effect of SNS was evaluated using in vivo and in vitro models of high-fat/high-cholesterol (HFHC) diet-induced mice and palmitic acid (PA)-induced hepatocytes, respectively. Molecular biological techniques such as RNA-sequencing (RNA-seq), co-immunoprecipitation (co-IP), and western blotting were employed to elucidate the molecular mechanism of SNS in regulating lipid metabolism in hepatocytes. ResultsOur findings revealed that SNS effectively reduced lipid accumulation in the livers of HFHC diet-induced mice and PA-induced hepatocytes. RNA-seq analysis demonstrated that SNS significantly down-regulated the expression of fatty acid synthase (Fasn) in the livers of HFHC-fed mice. Mechanistically, SNS inhibited Fasn expression and lipid accumulation by activating adenosine monophosphate (AMP)-activated protein kinase (AMPK). Activation of AMPK suppressed the activity of the transcriptional coactivator p300 and modulated the protein stability of sterol regulatory element-binding protein-1c (SREBP-1c). Importantly, p300 was required for the inhibition of Fasn expression and lipid accumulation by SNS. Furthermore, SNS activated AMPK by decreasing adenosine triphosphate (ATP) production in hepatocytes. ConclusionThis study provided novel evidence on the regulatory mechanisms underlying the effects of SNS on Fasn expression. Our findings demonstrate, for the first time, that SNS exerts suppressive effects on Fasn expression through modulation of the AMPK/p300/SREBP-1c axis. Consequently, this regulatory pathway mitigates excessive lipid accumulation and ameliorates MAFLD in mice.

1,5-anhydro-D-fructose induces anti-aging effects on aging-associated brain diseases by increasing 5'-adenosine monophosphate-activated protein kinase activity via the peroxisome proliferator-activated receptor-γ co-activator-1α/brain-derived neurotrophic factor pathway.

5'-Adenosine monophosphate-activated protein kinase (AMPK) is a metabolic sensor that serves as a cellular housekeeper; it also controls energy homeostasis and stress resistance. Thus, correct regulation of this factor can enhance health and survival. AMPK signaling may have a critical role in aging-associated brain diseases. Some in vitro studies have shown that 1,5-anhydro-D-fructose (1,5-AF) induces AMPK activation. In the present study, we experimentally evaluated the effects of 1,5-AF on aging-associated brain diseases in vivo using an animal model of acute ischemic stroke (AIS), stroke-prone spontaneously hypertensive rats (SHRSPs), and the spontaneous senescence-accelerated mouse-prone 8 (SAMP8) model. In the AIS model, intraperitoneal injection of 1,5-AF reduced cerebral infarct volume, neurological deficits, and mortality. In SHRSPs, oral administration of 1,5-AF reduced blood pressure and prolonged survival. In the SAMP8 model, oral administration of 1,5-AF alleviated aging-related decline in motor cognitive function. Although aging reduced the expression levels of peroxisome proliferator-activated receptor-γ co-activator-1α (PGC-1α) and brain-derived neurotrophic factor (BDNF), we found that 1,5-AF activated AMPK, which led to upregulation of the PGC-1α/BDNF pathway. Our results suggest that 1,5-AF can induce endogenous neurovascular protection, potentially preventing aging-associated brain diseases. Clinical studies are needed to determine whether 1,5-AF can prevent aging-associated brain diseases.

Exercise attenuates polyglutamine-mediated neuromuscular degeneration in a mouse model of spinal and bulbar muscular atrophy.

Spinal and bulbar muscular atrophy (SBMA) is a hereditary neuromuscular disorder caused by the expansion of trinucleotide cytosine-adenine-guanine (CAG) repeats, which encodes a polyglutamine (polyQ) tract in the androgen receptor (AR) gene. Recent evidence suggests that, in addition to motor neuron degeneration, defective skeletal muscles are also the primary contributors to the pathogenesis in SBMA. While benefits of physical exercise have been suggested in SBMA, underlying mechanism remains elusive. We investigated the effect of running exercise in a transgenic mouse model of SBMA carrying human AR with 97 expanded CAGs (AR97Q). We assigned AR97Q mice to exercise and sedentary control groups, and mice in the exercise group received 1-h forced running wheel (5m/min) 5days a week for 4weeks during the early stage of the disease. Motor function (grip strength and rotarod performance) and survival of each group were analysed, and histopathological and biological features in skeletal muscles and motor neurons were evaluated. AR97Q mice in the exercise group showed improvement in motor function (~40% and ~50% increase in grip strength and rotarod performance, respectively, P<0.05) and survival (median survival 23.6 vs. 16.7weeks, P<0.05) with amelioration of neuronal and muscular histopathology (~1.4-fold and ~2.8-fold increase in motor neuron and muscle fibre size, respectively, P<0.001) compared to those in the sedentary group. Nuclear accumulation of polyQ-expanded AR in skeletal muscles and motor neurons was suppressed in the mice with exercise compared to the sedentary mice (~50% and ~30% reduction in 1C2-positive cells in skeletal muscles and motor neurons, respectively, P<0.05). We found that the exercise activated 5'-adenosine monophosphate-activated protein kinase (AMPK) signalling and inhibited mammalian target of rapamycin pathway that regulates protein synthesis in skeletal muscles of SBMA mice. Pharmacological activation of AMPK inhibited protein synthesis and reduced polyQ-expanded AR proteins in C2C12 muscle cells. Our findings suggest the therapeutic potential of exercise-induced effect via AMPK activation in SBMA.

Metformin reduces hepatocarcinogenesis by inducing downregulation of Cyp26a1 and CD8+ T cells.

Hepatocellular carcinoma (HCC) is a highly heterogeneous cancer with major challenges in both prevention and therapy. Metformin, adenosine monophosphate-activated protein kinase (AMPK) activator, has been suggested to reduce the incidence of HCC when used for patients with diabetes in preclinical and clinical studies. However, the possible effects of metformin and their mechanisms of action in non-diabetic HCC have not been adequately investigated. Fah-/- mice were used to construct a liver-injury-induced non-diabetic HCC model for exploring hepatocarcinogenesis and therapeutic potential of metformin. Changes in relevant tumour and biochemical indicators were measured. Bulk and single-cell RNA-sequencing analyses were performed to validate the crucial role of proinflammatory/pro-tumour CD8+ T cells. In vitro and in vivo experiments were performed to confirm Cyp26a1-related antitumour mechanisms of metformin. RNA-sequencing analysis showed that chronic liver injury led to significant changes in AMPK-, glucose- and retinol metabolism-related pathways in Fah-/- mice. Metformin prevented the formation of non-diabetic HCC in Fah-/- mice with chronic liver injury. Cyp26a1 ddexpression in hepatocytes was significantly suppressed after metformin treatment. Moreover, downregulation of Cyp26a1 occurred in conjunction with increased levels of all-trans-retinoic acid (atRA), which is involved in the activation of metformin-suppressed hepatocarcinogenesis in Fah-/- mice. In contrast, both CD8+ T-cell infiltration and proinflammatory/pro-tumour cytokines in the liver were significantly upregulated in Fah-/- mice during chronic liver injury, which was notably reversed by either metformin or atRA treatment. Regarding mechanisms, metformin regulated the decrease in Cyp26a1 enzyme expression and increased atRA expression via the AMPK/STAT3/Gadd45β/JNK/c-Jun pathway. Metformin inhibits non-diabetic HCC by upregulating atRA levels and downregulating CD8+ T cells. This is the first reporting that the traditional drug metformin regulates the metabolite atRA via the Cyp26a1-involved pathway. The present study provides a potential application of metformin and atRA in non-diabetic HCC.

Interferon-stimulated gene TDRD7 interacts with AMPK and inhibits its activation to suppress viral replication and pathogenesis.

Virus infection triggers induction of interferon (IFN)-stimulated genes (ISGs), which ironically inhibit viruses themselves. We identified Tudor domain-containing 7 (TDRD7) as a novel antiviral ISG, which inhibits viral replication by interfering with autophagy pathway. Here, we present a molecular basis for autophagy inhibitory function of TDRD7. TDRD7 interacted with adenosine monophosphate (AMP)-activated protein kinase (AMPK), the kinase that initiates autophagy, to inhibit its activation. We identified domains required for the interaction; deleting AMPK-interacting domain blocked antiAMPK and antiviral activities of TDRD7. We used primary cells and mice to evaluate the TDRD7-AMPK antiviral pathway. TDRD7-deficient primary mouse cells exhibited enhanced AMPK activation and viral replication. Finally, TDRD7 knockout mice showed increased susceptibility to respiratory virus infection. Therefore, our study revealed a new antiviral pathway of IFN and its contribution to host response. Our results have therapeutic potential; a TDRD7-derived peptide may be an effective AMPK inhibitor with application as antiviral agent.

Host cell sensing and restoration of mitochondrial function and metabolism within Helicobacter pylori VacA intoxicated cells.

Persistent human gastric infection with Helicobacter pylori is the single most important risk factor for development of gastric malignancy, which is one of the leading causes of cancer-related deaths worldwide. An important virulence factor for Hp colonization and severity of gastric disease is the protein exotoxin VacA, which is secreted by the bacterium and modulates functional properties of gastric cells. VacA acts by damaging mitochondria, which impairs host cell metabolism through impairment of energy production. Here, we demonstrate that intoxicated cells have the capacity to detect VacA-mediated damage, and orchestrate the repair of mitochondrial function, thereby restoring cellular health and vitality. This study provides new insights into cellular recognition and responses to intracellular-acting toxin modulation of host cell function, which could be relevant for the growing list of pathogenic microbes and viruses identified that target mitochondria as part of their virulence strategies.

The onset of adenosine monophosphate-activated protein kinase activity on orthodontic tooth movement in rats with type 2 diabetes.

Adenosine monophosphate-activated protein kinase (AMPK) plays pivotal roles in metabolic diseases including type 2 diabetes. However, the specific role of AMPK for orthodontic tooth movement in type 2 diabetes is unclear. In this study, a diabetic rat model was established through dietary manipulation and streptozocin injection. Examinations were conducted to select qualified type 2 diabetic rats. Then, an orthodontic device was applied to these rats for 0, 3, 7, or 14 days. The distance of orthodontic tooth movement and parameters of alveolar bone were analyzed by micro-computed tomography. Periodontal osteoclastic activity, inflammatory status, and AMPK activity were measured via histological analyses. Next, we repeated the establishment of diabetic rats to investigate whether change of AMPK activity was associated with orthodontic tooth movement under type 2 diabetes. The results showed that diabetic rats exhibited an exacerbated alveolar bone resorption, overactive inflammation, and decreased periodontal AMPK activity during orthodontic tooth movement. Injection of the AMPK agonist alleviated type 2 diabetes-induced periodontal inflammation and alveolar bone resorption, thus normalizing distance of orthodontic tooth movement. Our study indicates that type 2 diabetes decreases periodontal AMPK activity, leading to excessive inflammation elevating osteoclast formation and alveolar bone resorption, which could be reversed by AMPK activation.

Effects of Quercetin Nanoemulsion on Cholesterol Efflux and MicroRNA-33/34a Expression in the Liver of Mice Fed with a High-Cholesterol Diet.

Quercetin is a flavonoid widely present in plants; despite its beneficial physiological activity, it exhibits considerably low bioavailability. Nanoemulsion technology is used for improving the bioavailability of lipophilic phenolic compounds. This study aimed to investigate the potential effects of quercetin nanoemulsion (QN) on regulating the microRNA (miR)-33/34a pathway involved in cholesterol efflux in the liver of mice fed with a high-cholesterol (HC) diet. Subsequently, C57BL/6J mice were divided into four groups and fed a normal chow diet, HC diet supplemented with 1% cholesterol and 0.5% cholic acid, or HC diet supplemented with 0.05% QN or 0.1% QN for 6 weeks. Serum and hepatic lipid profiles were assayed using commercial enzymatic kits. Gene expression and miR levels were quantified using real-time quantitative reverse transcription polymerase chain reaction, and adenosine monophosphate-activated protein kinase (AMPK) activity was measured using an AMPK Kinase Assay kit. QN supplementation improved serum and liver lipid profiles. QN upregulated the mRNA levels of adenosine triphosphate (ATP)-binding cassette subfamily A1, ATP-binding cassette subfamily G1, and scavenger receptor class B type 1, which are related to cholesterol efflux. In the QN group, the hepatic AMPK activity increased, whereas miR-33, and miR-34a expression levels decreased. These results suggest that QN may enhance cholesterol efflux, at least partly through modulating AMPK activity and miR-33/34a expression in the liver.

Erratum: Activating adenosine monophosphate-activated protein kinase mediates fibroblast growth factor 1 protection from nonalcoholic fatty liver disease in mice.

Erratum: Activating adenosine monophosphate-activated protein kinase mediates fibroblast growth factor 1 protection from nonalcoholic fatty liver disease in mice.

Sesamol Alleviates High-Fat Diet-Induced Hepatic Insulin Resistance in C57BL/6J Mice Through AMPK Activation Mediated by Adipose Adiponectin.

Sesamol is the major bioactive constituent isolated from sesame seeds and has a variety of bioactivities. However, its role and mechanism in liver insulin resistance remain unknown. The current study was designed to investigate the underlying adipose-liver crosstalk mechanism of sesamol ameliorating hepatic insulin sensitivity. The therapeutic effect of sesamol was evaluated in high-fat diet (HFD)-fed C57BL/6J mice (100mg/kg for 8weeks, XYGW-2021-75) and the mechanism was further explored in HepG2 cells with/without adiponectin and adenosine 5 '-monophosphate-activated protein kinase (AMPK) inhibitor administration. Our in vivo data showed that sesamol reduced hepatic insulin resistance in HFD-induced mice with obesity by modulating protein expression levels of glycogen synthase (GS), phosphoenolpyruvate carboxykinase (PEPCK) and protein kinase B (AKT). Moreover, sesamol not only increased the serum and adipose tissue adiponectin concentrations but also activated the phosphorylation of AMPK in the liver. Furthermore, in vitro studies using recombinant human adiponectin and an AMPK inhibitor revealed that adiponectin and sesamol have a synergic impact on increasing glycogenesis and reducing gluconeogenesis, of which the effects could be attenuated by the AMPK inhibitor. Taken together, our results suggested that sesamol stimulated adiponectin secretion from adipocytes, whereby exhibited a co-effect on activating the downstream signal of hepatic AMPK, resulting in the alleviation of hepatic insulin resistance. The novel findings of sesamol on hepatic effects provides prospective therapeutic approaches to treat insulin resistance.

Pretreatment with Lovastatin Improves Depression-Like Behavior After Traumatic Brain Injury Through Activation of the AMPK Pathway

The beneficial effect of pretreatment with statins on traumatic brain injury (TBI)-induced depression and anxiety and its mechanism of action remain unclear. In this study, we combined epidemiological and experimental animal data to clarify this issue. We used the Taiwan National Health Insurance database to identify patients who were diagnosed with TBI from 2000 to 2013 and compared patients with and without statin treatment matched by age, sex, and underlying comorbidities in a 1:1 ratio. The risk of developing depression and/or anxiety was compared between patients with and without a statin using Cox proportional hazards regression. We also used a rat model to assess the effect of lovastatin pretreatment on neurobehavioral and neuropathological changes following TBI. The risk of developing depression was lower in the 41,803 patients in the statin cohort than nonstatin cohort (adjusted hazard ratio, 0.91 [95% confidence interval, 0.83-0.99]). In animal models, the lovastatin group had significantly reduced infarct volume, decreased immobility time and latency to eat, a reduced number of Fluoro- Jade-positive cells and levels of glial fibrillary acidic protein and tumor necrosis factor-alpha, and increased adenosine monophosphate -activated protein kinase (AMPK) and its upstream kinase liver kinase B1 in the hippocampal dentate gyrus. These effects were blocked in AMPK inhibitor-pretreated TBI rats. Our epidemiological data showed that a decreased risk of depression was associated with statin pretreatment, which was supported by an animal study. The underlying mechanism for this appears to involve AMPK activation in the statin pretreatment-induced alleviation of TBI.