Fatigue is a serious disturbance to human health, especially in people who have a severe disease such as cancer, or have been infected with COVID-19. Our research objective is to evaluate the anti-fatigue effect and mechanism of icariin through a mouse experimental model. Mice were treated with icariin for 30 days and anti-fatigue effects were evaluated by the weight-bearing swimming test, serum urea nitrogen test, lactic acid accumulation and clearance test in blood and the amount of liver glycogen. The protein expression levels of adenosine monophosphate-activated protein kinase (AMPK) and peroxisome proliferator-activated receptor-gamma coactivator-1alpha (PGC1-α) in the skeletal muscle of mice in each group were measured by western blotting. Results showed that icariin prolonged the weight-bearing swimming time of animals, reduced the serum urea nitrogen level after exercise, decreased the blood lactic acid concentration after exercise and increased the liver glycogen content observably. Compared to that in the control group, icariin upregulated AMPK and PGC1-α expression in skeletal muscle. Icariin can improve fatigue resistance in mice and its mechanism may be through improving the AMPK/PGC-1α pathway in skeletal muscle to enhance energy synthesis, decreasing the accumulation of metabolites and slowing glycogen consumption and decomposition.

BACKGROUND: Mitochondria dysfunction is one of the major causes of insulin resistance, and other countless complications of obesity. PGC-1α, and UCP-2 play key roles in energy expenditure regulation in the mitochondrial thermogenesis. However, the effects of bariatric surgery on the level of PGC-1α and UCP-2 and their relationships are unclear.
OBJECTIVE: This study aimed to investigate the effect of bariatric surgery on key pathways in energy, and to assess the potential predictive role of body composition and metabolic parameters in this regard.
METHODS: Hazrat-e Rasool General Hospital, Center of Excellence of International Federation for Surgery of Obesity.
METHODS: This prospective cohort study was carried out on 45 patients with morbid obesity who underwent Roux-en-Y gastric bypass surgery. The patients have evaluated three-time points at baseline, three, and six months after the surgery. Body composition components, the levels of PGC-1α, UCP-2, and metabolic parameters were measured three times during this study.
RESULTS: Significant changes in TWL%, EBMIL%, and metabolic lab tests were observed at three- and six months post-surgery (P < 0.001). The PGC-1α and UCP-2 had a significant increase three and then six-month post-operation compared with the baseline (P < 0.001). Moreover, multivariate linear regression analysis identified that the changing trend of PGC-1α was associated with insulin, uric Acid, HOMA-IR, fat mass and trunk fat mass. UCP-2 was associated with TSH, AST, fat mass and FFM.
CONCLUSIONS: Bariatric surgery has been shown to have a positive effect on UCP-2 and PGC-1α levels, as well as body composition and metabolic parameters. As a result, it is believed that bariatric surgery could improve thermogenesis and energy expenditure by enhancing mitochondrial biogenesis and function. However, further studies are needed to fully understand the precise mechanisms and possible causal relationship.

We tested the hypothesis that AMPK activation and peroxisome proliferator gamma coactivator 1 alpha (PGC-1α) expression are not augmented as exercise intensity (power output) increases from maximal to supramaximal intensities and conducted an exploratory analysis comparing AMPK activation and PGC-1α expression in males and females. Seventeen (n = 9 males; n = 8 females) recreationally active, healthy, young individuals volunteered to participate in the current study. Participants completed work matched interval exercise at 100% (Max) and 133% (Supra) of peak work rate (WRpeak). Intervals were 1 min in duration and participants were prescribed 6 and 8 intervals of Max and Supra, respectively, to equate external work across protocols. PGC-1α mRNA expression and activation of AMPK (p-ACC) were examined in muscle biopsy samples. Interval WR (watts; W), intensity (%WRpeak) and average HR (bpm), blood lactate (mmol/L) and rating of perceived exertion were all higher (all p < 0.05) in Supra. Fatigue was greater (p < 0.05) in Supra. PGC-1α mRNA expression significantly increased after exercise in Max (p < 0.01) and Supra (p < 0.01), but was not significantly different (p = 0.71) between intensities. A main effect of time (Pre - 0 h) (p < 0.01) was observed for p-ACC; however, no effect of intensity (p = 0.08) or interaction (p = 0.97) was observed. No significant effects of time (p = 0.05) intensity (p = 0.42), or interaction (p = 0.97) were observed for p-AMPK (Thr172). Exploratory sex analysis demonstrated a main effect of sex for p-ACC (greater p-ACC in males; p < 0.05) but not for p-AMPK or PGC-1α expression. Our results confirm that AMPK-PGC-1α signalling is not augmented following supramaximal exercise and provide novel data demonstrating a decrease in AMPK activation (p-ACC) in females compared to men. Trial registration: https://doi.org/10.17605/OSF.IO/U7PX9.

BACKGROUND: Hepatocellular carcinoma (HCC) is the most common primary malignancy. Peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PPARGC1A) plays a crucial role in regulating the biogenesis of mitochondria. We aimed to assess the association between PPARGC1A polymorphisms and HCC risk in a Moroccan population.
METHODS: In this case-control study, 147 patients with HCC and 147 controls without pre-existing liver disease were matched for ethnicity. TaqMan SNP allelic discrimination assays were used for genotyping of PPARGC1A rs8192678 and rs12640088 polymorphisms.
RESULTS: The result revealed that individuals with the GA/AA genotypes for rs8192678 had a significantly higher risk of HCC compared to those with the GG genotype (OR=6.68; P<0.0001, and OR=9.78; P<0.0001, respectively). In particular, the A allele of rs8192678 was over-represented in HCC patients compared to controls (40% versus 12%, P<0.0001, respectively). With respect to PPARGC1A rs12640088 variant, two genetic models (codominant and dominant) were tested to explore any potential variations in the distribution of SNP A>C among HCC cases and control subjects group. Overall, no significant association between rs12640088 and HCC was found (P>0.05). Interestingly, a significantly higher level of aspartate aminotransferase was observed in HCC patients with GG-GA genotypes (280 IU/L) compared to those with GG genotype (164 IU/L) at rs8192678 (P=0.0019).
CONCLUSIONS: Our results suggest that the PPARGC1A rs8192678 polymorphism is associated with an increased risk of HCC in Moroccan population and may serve as a prognostic marker for liver cancer.

The effect of interactions between perfluorooctanesulfonic (PFOS)/perfluorooctanoic acid (PFOA) levels and nuclear receptor genotypes on fatty acid (FA) levels, including those of triglycerides, is not clear understood. Therefore, in the present study, we aimed to analyse the association of PFOS/PFOA levels and single-nucleotide polymorphisms (SNPs) in nuclear receptors with FA levels in pregnant women. We analysed 504 mothers in a birth cohort between 2002 and 2005 in Japan. Serum PFOS/PFOA and FA levels were measured using liquid chromatography-tandem mass spectrometry and gas chromatography-mass spectrometry. Maternal genotypes in PPARA (rs1800234; rs135561), PPARG (rs3856806), PPARGC1A (rs2970847; rs8192678), PPARD (rs1053049; rs2267668), CAR (rs2307424; rs2501873), LXRA (rs2279238) and LXRB (rs1405655; rs2303044; rs4802703) were analysed. When gene-environment interaction was considered, PFOS exposure (log10 scale) decreased palmitic, palmitoleic, and oleic acid levels (log10 scale), with the observed β in the range of - 0.452 to - 0.244; PPARGC1A (rs8192678) and PPARD (rs1053049; rs2267668) genotypes decreased triglyceride, palmitic, palmitoleic, and oleic acid levels, with the observed β in the range of - 0.266 to - 0.176. Interactions between PFOS exposure and SNPs were significant for palmitic acid (Pint = 0.004 to 0.017). In conclusion, the interactions between maternal PFOS levels and PPARGC1A or PPARD may modify maternal FA levels.

BACKGROUND: Leptin (LEP), leptin receptor (LEPR) and peroxisome proliferator-activated receptor gamma co-activator 1-alpha (PGC1A) are involved in the pathogenesis of multiple sclerosis (MS) by affecting the inflammatory response and reactive oxygen species production. LEP rs7799039 and LEPR rs1137101 genetic variants modify the serum LEP levels and PGC1A rs8192678 alters the PGC1A activity. The study objective was to explore the associations of these variants with susceptibility to MS, disease course/clinical parameters and also with peripheral blood mononuclear cell expression of the target genes and plasma LEP concentrations, in the study subjects.
METHODS: The study groups included 528 patients with MS and 429 controls. TaqMan® assays were used for genotyping and gene expression quantification. The Chi-square, parametric and nonparametric tests and simple/multiple logistic regression were performed for the statistical analysis of data.
RESULTS: A multiple logistic regression model including all three investigated variants, applied to patients (RRMS + SPMS) and controls, showed that PGC1A rs8192678 minor allele had an increased risk for the occurrence of disease, with OR (95%CI) = 1,32 (1,01-1,73), P = 0,04. Between-effect of gender and LEPR variant on the multiple sclerosis severity score (MSSS) was identified (P = 0,005). In male patients (relapsing-remitting and secondary progressive), LEPR minor allele carriers had increased MSSS (GG + AG vs AA, median (minimum-maximum) = 5,38 (0,64-9,88) vs 4,27 (0,78-9,63); P = 0,01, Padj = 0,03). In relapsing-remitting patients LEP rs7799039 affected the LEP gene expression (P = 0,006; Padj = 0,04).
CONCLUSIONS: The current findings implicate an impact of investigated genetic variants on the pathogenesis of MS.

To date, there are limited and incomplete data on possible sex-based differences in fiber-types of skeletal muscle and their response to physical exercise. Adult healthy male and female mice completed a single bout of endurance exercise to examine the sex-based differences of the peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC1α), heat shock protein 60 (Hsp60), interleukin 6 (IL-6) expression, as well as the Myosin Heavy Chain (MHC) fiber-type distribution in soleus and extensor digitorum longus (EDL) muscles. Our results showed for the first time that in male soleus, a muscle rich of type IIa fibers, endurance exercise activates specifically genes involved in mitochondrial biogenesis such as PGC1 α1 isoform, Hsp60 and IL-6, whereas the expression of PGC1 α2 and α3 was significantly upregulated in EDL muscle, a fast-twitch skeletal muscle, independently from the gender. Moreover, we found that the acute response of different PGC1α isoforms was muscle and gender dependent. These findings add a new piece to the huge puzzle of muscle response to physical exercise. Given the importance of these genes in the physiological response of the muscle to exercise, we strongly believe that our data could support future research studies to personalize a specific and sex-based exercise training protocol.

OBJECTIVE: 20-hydroxyeicosatetraenoic acid (20-HETE) is a metabolite of arachidonic acid catalysed by cytochrome P450 enzymes and plays an important role in cell death and proliferation. We hypothesized that 20-HETE synthesis inhibition may have protective effects in traumatic brain injury (TBI) and investigated possible underlying molecular mechanisms.
METHODS: Neurologic deficits, and lesion volume, reactive oxygen species (ROS) levels and cell death as assessed using immunofluorescence staining, transmission electron microscopy and Western blotting were used to determine post-TBI effects of HET0016, an inhibitor of 20-HETE synthesis, and their underlying mechanisms.
RESULTS: The level of 20-HETE was found to be increased significantly after TBI in mice. 20-HETE synthesis inhibition reduced neuronal apoptosis, ROS production and damage to mitochondrial structures after TBI. Mechanistically, HET0016 decreased the Drp1 level and increased the expression of Mfn1 and Mfn2 after TBI, indicating a reversal of the abnormal post-TBI mitochondrial dynamics. HET0016 also promoted the restoration of SIRT1 and PGC-1α in vivo, and a SIRT1 activator (SRT1720) reversed the downregulation of SIRT1 and PGC-1α and the abnormal mitochondrial dynamics induced by 20-HETE in vitro. Furthermore, plasma 20-HETE levels were found to be higher in TBI patients with unfavourable neurological outcomes and were correlated with the GOS score.
CONCLUSIONS: The inhibition of 20-HETE synthesis represents a novel strategy to mitigate TBI-induced mitochondrial dysfunction and neuronal apoptosis by regulating the SIRT1/PGC-1α pathway.

Previous studies suggested that alterations in the energy metabolism might be underlying cancer initiation and progression. Polymorphisms of genes involved in energy metabolism regulation, such as peroxisome proliferator-activated receptor gamma coactivator 1α (PPARGC1A), -β (PPARGC1B), and paraoxonase 1 (PON1), might confer susceptibility to esophageal squamous cell carcinoma (ESCC) and partially explain its pathogenesis. We investigated the effects of several single nucleotide polymorphisms (SNPs) in three metabolic-related genes (e.g., PPARGC1A, PPARGC1B, and PON1) on ESCC susceptibility. In total, 829 patients with sporadic ESCC and 1522 nontumor controls were enrolled in the study. SNPs were genotyped using PCR-ligase detection reaction. Our study revealed that the PPARGC1A rs3736265 G/A SNP significantly increased the risk for ESCC (GA vs. GG: adjusted odds ratio [OR] = 1.25, 95% confidence interval [95% CI] = 1.02-1.54, p = 0.034; GA+AA vs. GG: adjusted OR = 1.25, 95% CI = 1.03-1.52, p = 0.027]. In addition, a stratified analysis revealed that the PPARGC1A rs3736265 SNP was correlated with the development of ESCC in male and nondrinking subgroups. We also confirmed that the PPARGC1B rs17572019 G/A SNP promoted the risk of ESCC in subgroup with high alcohol intake. The PPARGC1A rs8192678 C/T polymorphism decreased the susceptibility of ESCC in men. These findings highlight that polymorphisms in PPARGC1A and PPARGC1B may contribute to ESCC susceptibility. In the future, further well-designed epidemiological studies are needed to confirm our findings.

The molecular mechanism for worsening left ventricular (LV) function after mitral valve (MV) repair for chronic mitral regurgitation remains unknown. We wished to assess the LV transcriptome and identify determinants associated with worsening LV function post-MV repair. A total of 13 patients who underwent MV repair for chronic primary mitral regurgitation were divided into two groups, preserved LV function (N = 8) and worsening LV function (N = 5), for the study. Specimens of LV from the patients taken during surgery were used for the gene microarray study. Cardiomyocyte cell line HL-1 cells were transfected with gene-containing plasmids and further evaluated for mRNA and protein expression, apoptosis, and contractile protein degradation. Of 67,258 expressed sequence tags, microarrays identified 718 genes to be differentially expressed between preserved-LVF and worsening-LVF, including genes related to the protein ubiquitination pathway, bone morphogenetic protein (BMP) receptors, and regulation of eIF4 and p70S6K signaling. In addition, worsening-LVF was associated with altered expressions of genes pathologically relevant to heart failure, such asdownregulated apelin receptors and upregulated peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PPARGC1A). HL-1 cardiomyocyte cells transfected with ubiquitination-related genes demonstrated activation of the protein ubiquitination pathwaywith an increase in the ubiquitin activating enzyme E1 (UAE-E1). It also led to increased apoptosis, downregulated and ubiquitinated X-linked inhibitor of apoptosis protein (XIAP), and reduced cell viability. Overexpression of ubiquitination-related genes also resulted in degradation and increased ubiquitination of α-smooth muscle actin (SMA). In conclusion, worsening-LVF presented differential gene expression profiles from preserved-LVF after MV repair. Upregulation of protein ubiquitination-related genes associated with worsening-LVF after MV repair may exert adverse effects on LV through increased apoptosis and contractile protein degradation.