Peroxisome Proliferator-activated Receptor Gamma Coactivator-1α Research Articles

Modulating gut dysbiosis and mitochondrial dysfunction in oxazolone-induced ulcerative colitis: the restorative effects of β-glucan and/or celastrol

ABSTRACT Objectives Microbiome–Mitochondria interaction is gaining a significant attention; thus, studying its mechanism emerges as a must to provide restorative lines in managing diseases. The aim is to study the mechanistic effects of β-Glucan and/or Celastrol in oxazolone-induced ulcerative colitis (UC). Methods 75 Wistar rats were allocated into 5 equal groups. Group I: control group. Group II: UC group, Group III: β-Glucan-treated UC group, Group IV: Celastrol-treated UC group & Group V: mutual treatment group. All groups were subjected to the detection of free fatty acid receptor 2 (FFAR-2) and peroxisome proliferator-activated receptor gamma co-activator1α (PGC-1α) mRNA gene expressions. Citrate synthase (CS) activity, mitochondrial membrane potential (MMP), ATP concentration, reactive oxygen species (ROS) were detected. Trimethylamine N-oxide (TMAO) concentration was measured. Results After treatment we monitored significant upregulation of FFAR-2 and PGC-1α mRNA expression. Likewise, ATP level and CS activity were significantly increased. On the contrary, there was a significant lessening in ROS and TMAO levels with improvement of MMP. Conclusion Mutual use of β- Glucan and Celastrol had a greater effect than each alone against UC, which is considered a novel finding highlighting the ameliorative effects of this combined treatment in modulating Microbiome/Mitochondria axis, thus launching promising avenues for UC.

Advanced Glycation End Products Induced Mitochondrial Dysfunction of Chondrocytes through Repression of AMPKα-SIRT1-PGC-1α Pathway

Introduction: Our previous studies have demonstrated advanced glycation end products (AGEs) was an important mediator in osteoarthritis (OA) which may induce mitochondrial dysfunction. AMP-activated protein kinase (AMPK), sirtuin 1 (SIRT1), and its downstream target peroxisome proliferator-activated receptor gamma coactivator-1α (PGC-1α) are the critical sensors that regulate mitochondrial biogenesis and have been recognized as therapeutic targets in OA. This study was designed to test whether AGEs caused mitochondrial dysfunction through modulation of AMPKα/SIRT1/PGC-1α. Methods: We knocked down or overexpressed AMPKα, SIRT1, and PGC-1α by small interfering RNA or plasmid DNA transfection, respectively. Mitochondrial membrane potential (△Ψ) was detected by tetraethylbenzimidazolyl carbocyanine iodide (JC-1) fluorescence probe. Results: The results showed that AGEs impaired △Ψ, intracellular ATP level, and mitochondrial DNA content, linked to decreased AMPKα, SIRT1, and PGC-1α expression in chondrocyte. AMPKα pharmacologic activation or overexpression of AMPKα, SIRT1, and PGC-1α reversed impairments of mitochondrial biogenesis, oxidative stress, and inflammation in AGEs-induced chondrocytes. However, AMPKα activation using AICAR had decreased capacity to increase each of those same effect readouts in AGEs-treated SIRT1-siRNA or PGC-1α-siRNA chondrocyte. Conclusion: Taken together, AGEs reduced the AMPKα/SIRT1/PGC-1α signaling in chondrocytes, leading to mitochondrial dysfunction as a result of increased oxidative stress, inflammation, and apoptosis. These results indicated that target AMPK may be as a novel therapeutic strategy for AGEs-related OA prevention.

DYRK1B-STAT3 Drives Cardiac Hypertrophy and Heart Failure by Impairing Mitochondrial Bioenergetics.

Heart failure is a global public health issue that is associated with increasing morbidity and mortality. Previous studies have suggested that mitochondrial dysfunction plays critical roles in the progression of heart failure; however, the underlying mechanisms remain unclear. Because kinases have been reported to modulate mitochondrial function, we investigated the effects of DYRK1B (dual-specificity tyrosine-regulated kinase 1B) on mitochondrial bioenergetics, cardiac hypertrophy, and heart failure. We engineered DYRK1B transgenic and knockout mice and used transverse aortic constriction to produce an in vivo model of cardiac hypertrophy. The effects of DYRK1B and its downstream mediators were subsequently elucidated using RNA-sequencing analysis and mitochondrial functional analysis. We found that DYRK1B expression was clearly upregulated in failing human myocardium and in hypertrophic murine hearts, as well. Cardiac-specific DYRK1B overexpression resulted in cardiac dysfunction accompanied by a decline in the left ventricular ejection fraction, fraction shortening, and increased cardiac fibrosis. In striking contrast to DYRK1B overexpression, the deletion of DYRK1B mitigated transverse aortic constriction-induced cardiac hypertrophy and heart failure. Mechanistically, DYRK1B was positively associated with impaired mitochondrial bioenergetics by directly binding with STAT3 to increase its phosphorylation and nuclear accumulation, ultimately contributing toward the downregulation of PGC-1α (peroxisome proliferator-activated receptor gamma coactivator-1α). Furthermore, the inhibition of DYRK1B or STAT3 activity using specific inhibitors was able to restore cardiac performance by rejuvenating mitochondrial bioenergetics. Taken together, the findings of this study provide new insights into the previously unrecognized role of DYRK1B in mitochondrial bioenergetics and the progression of cardiac hypertrophy and heart failure. Consequently, these findings may provide new therapeutic options for patients with heart failure.

LPIN1 promotes triglycerides synthesis and is transcriptionally regulated by PPARG in buffalo mammary epithelial cells

Studies on 3T3-L1 cells and HepG2 hepatocytes have shown that phosphatidic acid phosphohydrolase1 (LPIN1) plays a key role in adipogenesis, acting as a co-activator of peroxisome proliferator-activated receptor gamma coactivator 1a (PGC-1a) to regulate fatty acid metabolism. However, the functional role and regulatory mechanism of LPIN1 gene in milk fat synthesis of buffalo are still unknown. In this study, overexpression of buffalo LPIN1 gene transfected with recombinant fusion expression vector significantly increased the expression of AGPAT6, DGAT1, DGAT2, GPAM and BTN1A1 genes involved in triglyceride (TAG) synthesis and secretion, as well as PPARG and SREBF1 genes regulating fatty acid metabolism in the buffalo mammary epithelial cells (BMECs), while the lentivirus-mediated knockdown of buffalo LPIN1 dramatically decreased the relative mRNA abundance of these genes. Correspondingly, total cellular TAG content in the BMECs increased significantly after LPIN1 overexpression, but decreased significantly after LPIN1 knockdown. In addition, the overexpression or knockdown of PPARG also enhanced or reduced the expression of LPIN1 and the transcriptional activity of its promoter. The core region of buffalo LPIN1 promoter spans from − 666 bp to + 42 bp, and two PPAR response elements (PPREs: PPRE1 and PPRE2) were identified in this region. Site mutagenesis analysis showed that PPARG directly regulated the transcription of buffalo LPIN1 by binding to the PPRE1 and PPRE2 on its core promoter. The results here reveal that the LPIN1 gene is involved in the milk fat synthesis of BMECs, and one of the important pathways is to participate in this process through direct transcriptional regulation of PPARG, which in turn significantly affects the content of TAG in BMECs.

Time-dependent regulation of hepatic cytochrome P450 mRNA in male liver-specific PGC-1α knockout mice

The circadian rhythm has profound effect on the body, exerting effects on diverse events like sleep-wake patterns, eating behavior and hepatic detoxification. The cytochrome p450 s (Cyps) is the main group of enzymes responsible for detoxification. However, the underlying mechanisms behind circadian regulation of the Cyps are currently not fully clarified. Therefore, the aim of the present study was to investigate the requirement of hepatic peroxisome proliferator-activated receptor gamma coactivator-1α (PGC-1α) for the circadian regulation of the hepatic expression of Cyp1−4 using liver-specific PGC-1α knockout (LKO) mice and littermate controls. The circadian regulator genes Bmal1 and Clock displayed decreased mRNA content at zeitgeber time (ZT) 12, compared to ZT-2 and the mRNA content of Cyp2a4 and Cyp2e1 was higher at ZT-12 than at ZT-2. Moreover, the increase in Cyp2e1 mRNA content was not observed in the PGC-1α LKO mice and hepatic PGC-1α deficiency tended to blunt the rhythmic expression of Clock and Bmal1. However, no circadian regulation was evident at the protein level for the investigated Cyps except for a change in Cyp2e1 protein content in the LKO mice. Of the measured transcription factors, only, the mRNA content of peroxisome proliferator-activated receptor α, showed rhythmic expression. To further analyze the difference between the control and LKO mice, principal component analysis were executed on the mRNA data. This demonstrated a clear separation of the experimental groups with respect to ZT and genotype. Our finding provides novel insight into the role of hepatic PGC-1α for basic and circadian expression of Cyps in mouse liver. This is important for our understanding of the molecular events behind circadian Cyp regulation and hence circadian regulation of hepatic detoxification capacity.

Immature sword bean pods (Canavalia gladiata) inhibit adipogenesis in C3H10T1/2 cells and mice with high-fat diet-induced obesity.

Sword bean (SB; Canavalia gladiata) is a perennial vine used as a food and medicinal plant in Asia. SB is rich in nutrients, such as flavonoids and urease, and has various functions, including beneficial effects on dysentery, nausea, and hemorrhoids, as well as anti-inflammatory and antioxidant activity. Various plant parts are used; however, little is known about the physiological effects of SB pods (SBP). In this study, the anti-obesity effects of SBP extract were evaluated. To investigate the anti-obesity effects of SBP extract, we confirmed the SBP extract downregulated lipogenesis-related genes and upregulated genes involved in lipolysis and brown adipocyte markers in differentiated C3H10T1/2 adipocytes in vitro. Next, we use a high-fat diet (HFD)-induced obesity mouse model to determine the anti-obesity effects of SBP extract. Treatment with SBP extract significantly reduced adipocytes. The extract decreased the HFD-induced increases in body weight and plasma triglyceride levels in mice after 8 weeks. mRNA and protein levels of the adipogenesis and lipogenesis-related factors CCAAT/enhancer binding protein-β, CCAAT/enhancer binding protein-α, peroxisome proliferator-activated receptor-γ (PPARγ), and their target genes Ap2, SREBP-1c, FAS, and SCD-1 were reduced by SBP extract. In contrast, AMP-activated protein kinase and sirtuin1, involved in the thermogenic catabolism of fat, were activated by SBP extract in adipocytes and white adipose tissue, increasing the expression of peroxisome proliferator-activated receptor gamma coactivator-1α, peroxisome proliferator-activated receptor-α (PPARα), and uncoupling protein 1 and activating thermogenic activity. SBP extract exerts an anti-obesity effect by inhibiting lipogenesis-related factors and activating fat-catabolizing factors; it is, therefore, a promising functional food and natural anti-obesity agent.

The role of PGC-1α in mitochondrial transcription factors: A promising pathway in the treatments of mitochondrial diseases activated by Gynostemma pentaphyllum

The peroxisome proliferator-activated receptor-gamma coactivator 1α (PGC-1α), being a key transcription factor in mitochondrial biogenesis, interacts as a coactivator of several mitochondrial nuclear transcription factors, such as nuclear respiratory factor (NRF) 1 and 2, estrogen-related receptor α (ERRα), as well as non-nuclear receptor myocyte-enhancing factor 2 (MEF-2). Gynostemma pentaphyllum (GP) is a plant used in many countries, mainly in Asia, having strong activity in PGC-1α. A wide range of GP pharmacological properties has been reported, including anti-inflammatory and antioxidant activity, lipid metabolism modulator, and neuroprotective activity. The activation of PGC-1α by exogenous factors has become a promising strategy in the treatment of various pathologies, especially when focused on mitochondria. In our review, we found numerous benefits of GP in controlling age-associated metabolic diseases, mainly in diabetes type 2, fat liver, and obesity. Some studies have also reported that, due to the strong phosphorylation of AMP protein kinase (AMPK) exerted by GP, GP-treated mice showed a significant increase in Sirtuin 1 (SIRT1) mRNA expression, a protein that acts directly on cellular aging processes. However, further studies in humans could provide more proof of its efficiency in diseases such as metabolic syndrome as well as any other pathology that involves changes in mitochondrial functions.

Genetic Reduction of Mitochondria Complex I Subunits is Protective against Cisplatin-Induced Neurotoxicity in Drosophila.

Chemotherapy-induced peripheral neuropathy (CIPN) is a prevalent side effect of widely used platinum-based anticancer agents. There are few predictable risk factors with which to identify susceptible patients. Effective preventive measures or treatments are not available. Here, we have used a model of CIPN in Drosophila melanogaster to identify genetic changes that confer resistance to cisplatin-induced neuronal damage but not in the rapidly dividing cells of the ovary. The Drosophila strain attP40, used as a genetic background for the creation of RNAi lines, is resistant to cisplatin damage compared with the similar attP2 background strain. attP40 flies have reduced mRNA expression of ND-13A, a component of the mitochondria electron transport chain complex I. Reduction of ND-13A via neuron-specific RNAi leads to resistance to the dose-dependent climbing deficiencies and neuronal apoptosis observed in control flies. These flies are also resistant to acute oxidative stress, suggesting a mechanism for resistance to cisplatin. The mitochondria of attP40 flies function similarly to control attP2 mitochondria under normal conditions. Mitochondria are damaged by cisplatin, leading to reduced activity, but attP40 mitochondria are able to retain function and even increase basal respiration rates in response to this stress. This retained mitochondrial activity is likely mediated by Sirt1 and peroxisome proliferator-activated receptor gamma coactivator-1α, and is key to cisplatin resistance. Our findings represent the potential for both identification of susceptible patients and prevention of CIPN through the targeting of mitochondria.SIGNIFICANCE STATEMENT Chemotherapy-induced peripheral neuropathy is a major, debilitating side effect of many platinum-based cancer drugs. There are few available screening tools to identify patients at risk, and there are no effective treatments. Here, we report a novel genetic change that confers resistance to cisplatin-induced neurotoxicity in a Drosophila model while preserving the toxic effect in rapidly dividing cells. This work has the potential to influence patient susceptibility testing and development of novel CIPN preventive treatments.

Lycium barbarum Polysaccharides Promotes Mitochondrial Biogenesis and Energy Balance in a NAFLD Cell Model.

To explore the protective effect and underlying mechanism of Lycium barbarum polysaccharides (LBP) in a non-alcoholic fatty liver disease (NAFLD) cell model. Normal human hepatocyte LO2 cells were treated with 1 mmol/L free fatty acids (FFA) mixture for 24 h to induce NAFLD cell model. Cells were divided into 5 groups, including control, model, low-, medium- and high dose LBP (30,100 and 300 µg/mL) groups. The monosaccharide components of LBP were analyzed with high performance liquid chromatography. Effects of LBP on cell viability and intracellular lipid accumulation were assessed by cell counting Kit-8 assay and oil red O staining, respectively. Triglyceride (TG), alanine aminotransferase (ALT), aspartate aminotransferase (AST), adenosine triphosphate (ATP) and oxidative stress indicators were evaluated. Energy balance and mitochondrial biogenesis related mRNA and proteins were determined by quantitative real-time polymerase chain reaction and Western blot, respectively. Heteropolysaccharides with mannose and glucose are the main components of LBP. LBP treatment significantly decreased intracellular lipid accumulation as well as TG, ALT, AST and malondialdehyde levels (P<0.05 or P<0.01), increased the levels of superoxide dismutase, phospholipid hydroperoxide glutathione peroxidase, catalase, and ATP in NAFLD cell model (P<0.05). Meanwhile, the expression of uncoupling protein 2 was down-regulated and peroxisome proliferator-activated receptor gamma coactivator-1α/nuclear respiratory factor 1/mitochondrial transcription factor A pathway was up-regulated (P<0.05). LBP promotes mitochondrial biogenesis and improves energy balance in NAFLD cell model.

Gum Arabic supplementation prevents loss of learning and memory through stimulation of mitochondrial function in the hippocampus of type 2 diabetic rats

The aim was to determine whether gum Arabic (GA) supplementation prevents cognitive decline in type 2 diabetes, through stimulation of mitochondrial function in the hippocampus. Type 2 diabetic rats and controls were assigned to following groups for 16 weeks: Control + Water; Control + GA 10% w/v; Diabetes + Water; Diabetes + GA 10% w/v. Latency in water maze was shorter for Diabetes + GA compared to Diabetes + Water (P < 0.05). Diabetes + GA group had a higher expression density per cell of peroxisome proliferator-activated receptor gamma coactivator-1α (PGC-1α) compared to Diabetes + Water (P < 0.05). A similar trend was observed for ATP synthase β-subunit expression (ATPB). Number of PGC-1α positive cells was higher in diabetes compared to control groups (p < 0.05). The GA prevented learning and memory loss in type 2 diabetes. This was associated with greater expression of PGC-1a and a trend for greater ATBP protein expression in the hippocampus.

Sanse Powder Essential Oil Nanoemulsion Negatively Regulates TRPA1 by AMPK/mTOR Signaling in Synovitis: Knee Osteoarthritis Rat Model and Fibroblast-Like Synoviocyte Isolates.

Synovitis is the primary driving factor for the occurrence and development of knee osteoarthritis (KOA) and fibroblast-like synoviocytes (FLSs) and plays a crucial role during this process. Our previous works revealed that transient receptor potential ankyrin 1 (TRPA1) ion channels mediate the amplification of KOA synovitis. In recent years, essential oils have been proved to have blocking effect on transient receptor potential channels. Meanwhile, the therapeutic effect of Sanse Powder on KOA synovitis has been confirmed in clinical trials and basic studies; although, the mechanism remains unclear. In the present study, Sanse Powder essential oil nanoemulsion (SP-NEs) was prepared, and then chemical composition, physicochemical properties, and stability were investigated. Besides, both in MIA-induced KOA rats and in LPS-stimulated FLSs, we investigated whether SP-NES could alleviate KOA synovitis by interfering with AMP-activated protein kinase- (AMPK-) mammalian target of rapamycin (mTOR), an energy sensing pathway proved to negatively regulate the TRPA1. Our research shows that the top three substances in SP-NEs were tumerone, delta-cadinene, and Ar-tumerone, which accounted for 51.62% of the total, and should be considered as the main pharmacodynamic ingredient. Less inflammatory cell infiltration and type I collagen deposition were found in the synovial tissue of KOA rats treated with SP-NEs, as well as the downregulated expressions of interleukin (IL)-1β, IL-18, and TRPA1. Besides, SP-NEs increased the phosphorylation level of AMPK and decreased the phosphorylation level of mTOR in the KOA model, and SP-NEs also upregulated expressions of peroxisome proliferator-activated receptor-gamma (PPARγ) and PPARγ coactivator-1α and downstream signaling molecules of AMPK-mTOR in vivo and in vitro. To conclude, a kind of Chinese herbal medicine for external use which is effective in treating synovitis of KOA was extracted and prepared into essential oil nanoemulsion with stable properties in the present study. It may alleviate synovitis in experimental KOA through the negative regulation of TRPA1 by AMPK-mTOR signaling.

Jieduquyuziyin Prescription alleviates hepatic gluconeogenesis via PI3K/Akt/PGC-1α pathway in glucocorticoid-induced MRL/lpr mice

Ethnopharmacological relevanceJieduquyuziyin prescription (JP) is a traditional Chinese medicine (TCM) formula. According to both TCM theory and more than a decade of clinical practice, JP has been testified to be effective for systemic lupus erythematosus (SLE) treatment as an approved hospital prescription in China. Aim of the studyTo determine the effect of JP on the treatment of SLE by glucocorticoid (GC) and to further examine the molecular mechanisms. Materials and methodsWe conducted in vivo experiments to estimate the effect of JP on hepatic gluconeogenesis in MRL/lpr mice treated with GC. Additionally, isoproterenol (ISO) induced hepatic gluconeogenesis model and GC-treated MRL/lpr mouse hepatocytes were carried out in vitro experiments to verify the effect of JP on gluconeogenesis. ResultsThe results showed that JP combined with GC could effectively alleviate the lupus symptoms in MRL/lpr mice and improve the pathological changes of the kidney and liver. And the combination of JP reduced the side effects caused by GC, which was related to the inhibition of GC-induced hepatic gluconeogenesis in MRL/lpr mice. Specifically, JP up-regulated the expression of glucocorticoid receptor (GR) α, phosphoinositide-3-kinase (PI3K) and Akt restrained by GC to reduce the production of forkhead box O1 (FoxO1), peroxisome proliferator-activated receptor-gamma coactivator-1α (PGC-1α), and the gluconeogenic genes phosphoenolpyruvate carboxykinase (PEPCK) and glucose-6-phosphatase (G6Pase). In vivo, the use of JP either alone or with GC could reduce spleen enlargement, high levels of serum antibodies, aggravated urine protein and renal pathological damage in MRL/lpr mice. Furthermore, the glucose content was reduced in the liver of MRL/lpr mice treated with JP, and the liver damage and steatosis were also alleviated. In vitro, the expressions of PI3K and Akt increased and the expressions of FoxO1, PGC-1α, PEPCK and G6Pase decreased after JP treatment in ISO-treated hepatocytes. Compared with MRL/MP mice, we found that JP could significantly inhibit the expression of gluconeogenesis in the hepatocytes of MRL/lpr mice induced by GC to a greater extent. ConclusionsThe therapeutic effect of JP on GC-induced is likely related to hepatic gluconeogenesis, which provides a new perspective to reveal the positive role of JP in SLE.

Integrated Metagenomics and Metabolomics to Reveal the Effects of Policosanol on Modulating the Gut Microbiota and Lipid Metabolism in Hyperlipidemic C57BL/6 Mice.

The aim of the study was to investigate the regulatory effects of policosanol on hyperlipidemia, gut microbiota and metabolic status in a C57BL/6 mouse model. A total of 35 C57BL/6 mice were assigned to 3 groups, chow (n=12), high fat diet (HFD, n=12) and HFD+policosanol (n=11), then treated for 18 weeks. Policosanol supplementation significantly reduced serum triglycerides and total cholesterol, as well as the weight of brown adipose tissue (BAT) (p<0.05), without affecting body weight in HFD-fed mice (p>0.05). Combined 16S rRNA gene sequencing and untargeted metabolomic analysis demonstrated that policosanol had regulatory effects on gut microbiota and serum metabolism in mice. In obese mice, policosanol increased the proportion of Bacteroides, decreased the proportion of Firmicutes, and increased the ratio of Bacteroides to Firmicutes (p<0.05). Policosanol promoted lipolysis and thermogenesis process, including tricarboxylic acid (TCA) cycle and pyruvate cycle, correlated with the increasing level of Bacteroides, Parasutterella, and decreasing level of Lactobacillus and Candidatus_Saccharimonas. Moreover, policosanol decreased fatty acid synthase (FAS) in the iWAT of obese mice. Policosanol also increased peroxisome proliferators-activated receptor-γ (PPARγ), uncoupling Protein-1 (UCP-1), peroxisome proliferator-activated receptor gamma coactivator-1α (PGC-1α) and PR domain containing 16 (PRDM16) in brown adipose tissue (BAT) obese mice (p<0.05). This study presents the new insight that policosanol may inhibit the synthesis of fatty acids, and promote lipolysis, thermogenesis related gene expression and regulate gut microbiota constituents, which provides potential for policosanol as an antihyperlipidemia functional food additive and provide new evidence for whole grain food to replace refined food.

Bacillus amyloliquefaciens BLCC1-0238 Alone or in Combination with Mannan-Oligosaccharides Alleviates Subclinical Necrotic Enteritis in Broilers.

Subclinical necrotic enteritis (SNE) is a severe intestinal disease in broilers which brings huge economic losses to poultry industry. Herein, the effects of Bacillus amyloliquefaciens BLCC1-0238 (B. amyloliquefaciens BLCC1-0238) alone or in combination with mannan-oligosaccharides (MOS) on the SNE challenge model in broilers were comprehensively explored. A total of 360 broilers were randomly divided into 4 groups, including an SNE infection control (IC), an antibiotic pretreatment control (AC), a B. amyloliquefaciens BLCC1-0238 pretreatment (BP), and a B. amyloliquefaciens BLCC1-0238 + MOS pretreatment (BMP). The results showed that compared with the IC, three pretreatment groups significantly improved the growth performance, lowered the overall mortality, and reduced intestinal mucosal lesions in broilers. Additionally, the expression levels of claudin-3 and peroxisome proliferator-activated receptor-gamma coactivator-1α in the BP and BMP groups and the levels of mucin-2 and mechanistic target of rapamycin in the BMP group were significantly upregulated compared with the IC. By contrast, the expression levels of interferon-γ, interleukin-10, and secretory immunoglobulin A in the BP and BMP groups were significantly downregulated. In conclusion, these findings show that B. amyloliquefaciens BLCC1-0238 in combination with MOS can exert synergetic effects by the interplay between them on improving growth performance and combating the SNE infection in broilers.

Dulaglutide improves muscle function by attenuating inflammation through OPA-1-TLR-9 signaling in aged mice.

Dulaglutide, a glucagon-like peptide-1 receptor (GLP-1R) agonist, is widely used to treat diabetes. However, its effects on muscle wasting due to aging are poorly understood. In the current study, we investigated the therapeutic potential and underlying mechanism of dulaglutide in muscle wasting in aged mice. Dulaglutide improved muscle mass and strength in aged mice. Histological analysis revealed that the cross-sectional area of the tibialis anterior (TA) in the dulaglutide-treated group was thicker than that in the vehicle group. Moreover, dulaglutide increased the shift toward middle and large-sized fibers in both young and aged mice compared to the vehicle. Dulaglutide increased myofiber type I and type IIa in young (18.5% and 8.2%) and aged (1.8% and 19.7%) mice, respectively, compared to the vehicle group. Peroxisome proliferator-activated receptor-gamma coactivator-1α (PGC-1α), a master regulator of mitochondrial biogenesis, decreased but increased by dulaglutide in aged mice. The expression of atrophic factors such as myostatin, atrogin-1, and muscle RING-finger protein-1 was decreased in aged mice, whereas that of the myogenic factor, MyoD, was increased in both young and aged mice following dulaglutide treatment. In aged mice, optic atrophy-1 (OPA-1) protein was decreased, whereas Toll-like receptor-9 (TLR-9) and its targeting inflammatory cytokines (interleukin-6 [IL-6] and tumor necrosis factor-α [TNF-α]) were elevated in the TA and quadriceps (QD) muscles. In contrast, dulaglutide administration reversed this expression pattern, thereby significantly attenuating the expression of inflammatory cytokines in aged mice. These data suggest that dulaglutide may exert beneficial effects in the treatment of muscle wasting due to aging.

Exercise-Induced Lactate Release Mediates Mitochondrial Biogenesis in the Hippocampus of Mice via Monocarboxylate Transporters.

Regular exercise training induces mitochondrial biogenesis in the brain via activation of peroxisome proliferator-activated receptor gamma-coactivator 1α (PGC-1α). However, it remains unclear whether a single bout of exercise would increase mitochondrial biogenesis in the brain. Therefore, we first investigated whether mitochondrial biogenesis in the hippocampus is affected by a single bout of exercise in mice. A single bout of high-intensity exercise, but not low- or moderate-intensity, increased hippocampal PGC-1α mRNA and mitochondrial DNA (mtDNA) copy number at 12 and 48h. These results depended on exercise intensity, and blood lactate levels observed immediately after exercise. As lactate induces mitochondrial biogenesis in the brain, we examined the effects of acute lactate administration on blood and hippocampal extracellular lactate concentration by in vivo microdialysis. Intraperitoneal (I.P.) lactate injection increased hippocampal extracellular lactate concentration to the same as blood lactate level, promoting PGC-1α mRNA expression in the hippocampus. However, this was suppressed by administering UK5099, a lactate transporter inhibitor, before lactate injection. I.P. UK5099 administration did not affect running performance and blood lactate concentration immediately after exercise but attenuated exercise-induced hippocampal PGC-1α mRNA and mtDNA copy number. In addition, hippocampal monocarboxylate transporters (MCT)1, MCT2, and brain-derived neurotrophic factor (BDNF) mRNA expression, except MCT4, also increased after high-intensity exercise, which was abolished by UK5099 administration. Further, injection of 1,4-dideoxy-1,4-imino-D-arabinitol (glycogen phosphorylase inhibitor) into the hippocampus before high-intensity exercise suppressed glycogen consumption during exercise, but hippocampal lactate, PGC-1α, MCT1, and MCT2 mRNA concentrations were not altered after exercise. These results indicate that the increased blood lactate released from skeletal muscle may induce hippocampal mitochondrial biogenesis and BDNF expression by inducing MCT expression in mice, especially during short-term high-intensity exercise. Thus, a single bout of exercise above the lactate threshold could provide an effective strategy for increasing mitochondrial biogenesis in the hippocampus.

LncRNA HOXA-AS2 regulates microglial polarization via recruitment of PRC2 and epigenetic modification of PGC-1\u03b1 expression

BackgroundMicroglia-mediated neuroinflammation plays an important role in Parkinson’s disease (PD), and it exerts proinflammatory or anti-inflammatory effects depending on the M1/M2 polarization phenotype. Hence, promoting microglia toward the anti-inflammatory M2 phenotype is a potential therapeutic approach for PD. Long noncoding RNAs (lncRNAs) are crucial in the progression of neurodegenerative diseases, but little is known about their role in microglial polarization in PD.MethodsIn our study, we profiled the expression of lncRNAs in the peripheral blood mononuclear cells (PBMCs) of PD patients using a microarray. RT-qPCR was used to evaluate the lncRNA levels and mRNA levels of cytokines and microglial cell markers both in vitro and in vivo. RIP and ChIP assays were analyzed for the underlying mechanism of lncRNA regulating microglial polarization.ResultsWe found that HOXA-AS2 was upregulated in the PBMCs of PD patients and negatively associated with peroxisome proliferator-activated receptor gamma coactivator-1a (PGC-1α) expression. Moreover, HOXA-AS2 knockdown significantly repressed microglial M1 polarization and promoted M2 polarization by regulating PGC-1α expression. Mechanistic investigations demonstrated that HOXA-AS2 could directly interact with polycomb repressive complex 2 (PRC2) and modulate the histone methylation of the promoter of PGC-1α.ConclusionsOur findings identify the upregulated lncRNA HOXA-AS2 promotes neuroinflammation by regulating microglial polarization through interacts with the PRC2 complex and epigenetically silencing PGC-1α. HOXA-AS2 may be a potential therapeutic target for microglia-mediated neuroinflammation in patients with PD.

Effect of maternal apical periodontitis on the final step of insulin signalling and inflammatory pathway in the adult male offspring of rats.

To evaluate the final step of insulin signalling, inflammatory pathway (related to the inhibition of insulin signalling), peroxisome proliferator-activated receptor-gamma coactivator 1α (PGC-1α) protein content and DNA methylation in the Slc2a4 gene promoter region in the skeletal muscle of adult male offspring of rats with apical periodontitis (AP) in a single tooth or in four teeth. Female Wistar rats were distributed into three groups: a control group, a group with one tooth with AP and a group with four teeth with AP. Thirty days after induction of AP, female rats from all groups were mated with healthy male rats. When male offspring reached 75days of age, the following analyses were performed in the gastrocnemius muscle (GM): insulin-stimulated Akt serine and threonine phosphorylation status; NF-κB p50 and p65subunits phosphorylation status; GLUT4, TNF-α and PGC-1α protein content by Western blotting; GLUT4 and TNF-α gene expression by real-time polymerase chain reaction (PCR); and DNA methylation in the Slc2a4 gene promoter region by restriction digestion and real-time PCR. Analysis of variance was performed, followed by Tukey's post hoc test. p values <.05 were considered to be statistically significant. Maternal AP in four teeth decreased insulin-stimulated Akt serine and threonine phosphorylation status, reduced GLUT4 gene expression and its protein content, and increased NF-κB p50 and p65 subunits phosphorylation status in the GM of adult offspring. There were no alterations in the parameters analysed in the GM of adult offspring of rats with AP in a single tooth. In addition, maternal AP did not affect TNF-α gene expression and its protein content, PGC-1α protein content and DNA methylation in the Slc2a4 gene promoter region in the GM of adult offspring. Maternal AP in four teeth was associated with impairment in the final step of insulin signalling in the GM of adult male offspring in rats. An increase in NF-κB activity may be involved in this decrease in insulin signalling. This study demonstrates the impact of maternal AP on the health of offspring, demonstrating the importance of maintaining adequate maternal oral health to prevent diseases in adult offspring in rats.

The exercise-instrumental music program and irisin levels in younger non-professional athletes

A passive lifestyle and lack of exercise are triggering factors in increasing metabolic syndrome, whereas metabolic syndrome is associated with increased morbidity and mortality. This study aimed to analyse an exercise-based non-pharmacological approach combined with instrumental music to the plasma levels of irisin. The study employed a randomised pretest-posttest-only group design recruiting 30 male participants. The individuals aged between 19-21 years, body mass index (BMI) 18.5-24.9 kg/m2, normal blood pressure, normal resting heart rate (RHR), VO2max 40-50 ml/kg bodyweight/min, normal haemoglobin (Hb). The subjects were randomly divided into three groups, MIE (n=10, moderate-intensity exercise), MIEM (n=10, moderate-intensity exercise + instrumental music), and HIE (n=10, high-intensity exercise). Blood sampling was collected from pre- and 5 min post-exercise treatment. ELISA method was used to measure the circulating irisin levels. The non-parametric Kruskal-Wallis test, Mann Whitney test and Spearman correlation were chosen to analyse the data. The results showed that there is no significant difference in pre-exercise irisin levels (ng/ml) in MIE (1.58±0.89), MIEM (1.77±3.12), and HIE (1.65±0.88) with a P-value of 0.098. Importantly, the alteration of irisin levels post-exercise program revealed that the level of this peptide (ng/ml) is higher in HIE (7.28±5.11) compared to MIE (1.95±1.85) and MIEM (4.16±3.40) with a P-value of 0.019. The plasma levels of irisin significantly correlate to energy expenditure (r=0.353, P≤0.01), plasma peroxisome proliferator-activated receptor gamma coactivator-1α (r=0.597, P≤0.001), and high-density lipoprotein (r=0.513, P≤0.01). In summary, increased irisin secretion may directly contribute to the gradual alteration of energy expenditure and correlate to physical exercise intensity-related musical treatment.

Adaptive responses to air pollution in human dermal fibroblasts and their potential roles in aging.

The damaging effects of air pollution on the skin are becoming increasingly researched and the outcomes of this research are now a major influence in the selection and development of protective ingredients for skincare formulations. However, extensive research has not yet been conducted into the specific cellular defense systems that are being affected after exposure to such pollutants. Research investigating the affected systems is integral to the development of suitable interventions that are capable of augmenting the systems most impacted by air pollutant exposure. The following studies involved exposing primary human dermal fibroblasts to different concentrations of particulate matter and analyzing its effects on mitochondrial complex activity, nuclear factor erythroid 2‐related factor 2 localization using immunocytochemistry and protein expression of electron transport chain complex proteins, sirtuin‐1 (SIRT1), and peroxisome proliferator‐activated receptor gamma coactivator‐1α (PGC‐1α) using western blotting. Particulate matter‐induced alterations in both mitochondrial complex protein and activity, indicating oxidative stress, which was also complimented by increased expression of antioxidant proteins GSTP1/2 and SOD2. Particulate matter also seemed to modify expression of the proteins SIRT1 and PGC‐1α which are heavily involved in the regulation of mitochondrial biogenesis and energy metabolism. Given the reported results indicating that particulate matter induces damage through oxidative stress and has a profound effect on mitochondrial homeostasis, interventions involving targeted mitochondrial antioxidants may help to minimize the damaging downstream effects of pollutant‐induced oxidative stress originating from the mitochondria.