Proliferator-activated Receptor Gamma Coactivator 1-alpha Research Articles

Inhibitory Effect of Styrylpyrone Extract of Phellinus linteus on Hepatic Steatosis in HepG2 Cells.

The prevalence of nonalcoholic fatty liver disease (NAFLD) is estimated to be approximately about 25.24% of the population worldwide. NAFLD is a complex syndrome and is characterized by a simple benign hepatocyte steatosis to more severe steatohepatitis in the liver pathology. Phellinus linteus (PL) is traditionally used as a hepatoprotective supplement. Styrylpyrone-enriched extract (SPEE) obtained from the PL mycelia has been shown to have potential inhibition effects on high-fat- and high-fructose-diet-induced NAFLD. In the continuous study, we aimed to explore the inhibitory effects of SPEE on free fatty acid mixture O/P [oleic acid (OA): palmitic acid (PA); 2:1, molar ratio]-induced lipid accumulation in HepG2 cells. Results showed that SPEE presented the highest free radical scavenging ability on DPPH and ABTS, and reducing power on ferric ions, better than that of partitions obtained from n-hexane, n-butanol and distilled water. In free-fatty-acid-induced lipid accumulation in HepG2 cells, SPEE showed an inhibition effect on O/P-induced lipid accumulation of 27% at a dosage of 500 μg/mL. As compared to the O/P induction group, the antioxidant activities of superoxide dismutase, glutathione peroxidase and catalase were enhanced by 73%, 67% and 35%, respectively, in the SPEE group. In addition, the inflammatory factors (TNF-α, IL-6 and IL-1β) were significantly down-regulated by the SPEE treatment. The expressions of anti-adipogenic genes involved in hepatic lipid metabolism of 5' adenosine monophosphate (AMP)-activated protein kinase (AMPK), sirtuin 1 (SIRT1) and peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) were enhanced in the SPEE supplemented HepG2 cells. In the protein expression study, p-AMPK, SIRT1 and PGC1-α were significantly increased to 121, 72 and 62%, respectively, after the treatment of SPEE. Conclusively, the styrylpyrone-enriched extract SPEE can ameliorate lipid accumulation and decrease inflammation and oxidative stress through the activation of SIRT1/AMPK/PGC1-α pathways.

Design and Development of Novel Glitazones for Activation of PGC-1α Signaling Via PPAR-γ Agonism: A Promising Therapeutic Approach against Parkinson's Disease.

Herein, we rationally designed and developed two novel glitazones (G1 and G2) to target peroxisome proliferator-activated receptor-gamma coactivator 1-alpha (PGC-1α) signaling through peroxisome proliferator-activated receptors (PPAR)-γ agonism as a therapeutic for Parkinson's disease (PD). The synthesized molecules were analyzed by mass spectrometry and NMR spectroscopy. The neuroprotective functionality of the synthesized molecules was assessed by a cell viability assay in lipopolysaccharide-intoxicated SHSY5Y neuroblastoma cell lines. The ability of these new glitazones to scavenge free radicals was further ascertained via a lipid peroxide assay, and pharmacokinetic properties were verified using in silico absorption, distribution, metabolism, excretion, and toxicity analyses. The molecular docking reports recognized the mode of interaction of the glitazones with PPAR-γ. The G1 and G2 exhibited a noticeable neuroprotective effect in lipopolysaccharide-intoxicated SHSY5Y neuroblastoma cells with the half-maximal inhibitory concentration value of 2.247 and 4.509 μM, respectively. Both test compounds prevented 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced motor impairment in mice, as demonstrated by the beam walk test. Further, treating the diseased mice with G1 and G2 resulted in significant restoration of antioxidant enzymes glutathione and superoxide and reduced the intensity of lipid peroxidation inside the brain tissues. Histopathological analysis of the glitazones-treated mice brain revealed a reduced apoptotic region and a rise in the number of viable pyramidal neurons and oligodendrocytes. The study concluded that G1 and G2 showed promising results in treating PD by activating PGC-1α signaling in brain via PPAR-γ agonism. However, more extensive research is necessary for a better understanding of functional targets and signaling pathways.

Hydropersulfides (RSSH) attenuate doxorubicin-induced cardiotoxicity while boosting its anticancer action

Cardiotoxicity is a frequent and often lethal complication of doxorubicin (DOX)-based chemotherapy. Here, we report that hydropersulfides (RSSH) are the most effective reactive sulfur species in conferring protection against DOX-induced toxicity in H9c2 cardiac cells. Mechanistically, RSSH supplementation alleviates the DOX-evoked surge in reactive oxygen species (ROS), activating nuclear factor erythroid 2-related factor 2 (Nrf2)-dependent pathways, thus boosting endogenous antioxidant defenses. Simultaneously, RSSH turns on peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α), a master regulator of mitochondrial function, while decreasing caspase-3 activity to inhibit apoptosis. Of note, we find that RSSH potentiate anticancer DOX effects in three different cancer cell lines, with evidence that suggests this occurs via induction of reductive stress. Indeed, cancer cells already exhibit much higher basal hydrogen sulfide (H2S), sulfane sulfur, and reducing equivalents compared to cardiac cells. Thus, RSSH may represent a new promising avenue to fend off DOX-induced cardiotoxicity while boosting its anticancer effects.

NAD+ DEPLETION IN THE INTESTINAL EPITHELIUM RESULTS IN MITOCHONDRIAL DYSFUNCTION AND INFLUENCES THE PATHOGENESIS OF EXPERIMENTAL COLITIS

Abstract We have previously shown that mitochondrial dysfunction and disruption of mitochondrial biogenesis contribute to the pathogenesis of IBD. Peroxisome Proliferator-activated Receptor–gamma Coactivator 1-alpha (PGC1α) is the primary regulator of mitochondrial biogenesis. In patients with ulcerative colitis (UC) and mice undergoing experimental colitis, the transcript and protein levels of PGC1α are reduced, which is concomitant with a decrease in mitochondrial function, derangement of mitochondrial structure, and an increase in oxidative stress. Further, mice lacking PGC1α in the intestinal epithelium develop severe disease during acute and chronic colitis models. PGC1α is primarily activated via deacetylation by the nicotinamide adenine dinucleotide (NAD+)-dependent Sirtuin 1 (SIRT1). Thus, we hypothesized that decreased NAD+ in the intestinal epithelium during inflammation renders SIRT1 unable to activate PGC1α, resulting in decreased mitochondrial biogenesis and subsequent mitochondrial dysfunction. Here, we show that levels of deacetylated PGC1α (active) are decreased within the intestinal epithelium of patients with UC (n=4), implying that Sirt1 may be inactivated within diseased tissue. We also found a decrease in the intestional NAD+ levels in UC patients (n=10; p<0.001)). Similar to findings in humans, we show that not only are the levels of deacetylated PGC1α (active) decreased within the intestinal epithelium during murine models of DSS colitis (n=10; p<0.001) and infectious (Citrobacter rodentium-induced) colitis (n=10; p<0.001), but both the transcript and protein levels of Sirt1 are also decreased in mice undergoing experimental colitis (n=10 per group per model). We further found a decrease in intestinal NAD+ levels in colitic mice (n=8; p<0.0001). Although we found no significant decrease in the mRNA levels of NAD+-synthesizing enzymes in diseased intestinal tissue (p>0.05), there was a 1.5-fold increase in the intestinal mRNA levels of the NAD+-consuming DNA-repair enzyme Poly(ADP-ribose) polymerase-1 (PARP1) in mice undergoing experimental colitis (n=8; p<0.001), as well as a dramatic increase in the enzymatic activity of PARP1 in DSS-subjected intestinal tissue relative to controls. Treatment of mice undergoing experimental colitis with an NAD+precursor [nicotinamide riboside (NR), 500 mg/kg/day] decreased the severity of colitis (n=10; p<0.001), restored mitochondrial function (p<0.001), and increased active PGC1α levels (p<0.05). NR treatment did not benefit villincre;PGCfl/flmice (mice that lack PGC1α specifically in the intestinal epithelium; n=10; p>0.05) undergoing experimental colitis, suggesting that the therapeutic effects of NR require active PGC1α. Thus, future therapeutic approaches targeting the activity of PGC1α, and in turn mitochondrial health, may complement the treatment for IBD and improve outcomes in patients.

Klotho, Oxidative Stress, and Mitochondrial Damage in Kidney Disease.

Reducing oxidative stress stands at the center of a prevention and control strategy for mitigating cellular senescence and aging. Kidney disease is characterized by a premature aging syndrome, and to find a modulator targeting against oxidative stress, mitochondrial dysfunction, and cellular senescence in kidney cells could be of great significance to prevent and control the progression of this disease. This review focuses on the pathogenic mechanisms related to the appearance of oxidative stress damage and mitochondrial dysfunction in kidney disease. In this scenario, the anti-aging Klotho protein plays a crucial role by modulating signaling pathways involving the manganese-containing superoxide dismutase (Mn-SOD) and the transcription factors FoxO and Nrf2, known antioxidant systems, and other known mitochondrial function regulators, such as mitochondrial uncoupling protein 1 (UCP1), B-cell lymphoma-2 (BCL-2), Wnt/β-catenin, peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1 alpha), transcription factor EB, (TFEB), and peroxisome proliferator-activated receptor gamma (PPAR-gamma). Therefore, Klotho is postulated as a very promising new target for future therapeutic strategies against oxidative stress, mitochondria abnormalities, and cellular senescence in kidney disease patients.

Bavachin and Corylifol A Improve Muscle Atrophy by Enhancing Mitochondria Quality Control in Type 2 Diabetic Mice.

Type 2 diabetes reduces muscle mass and function. Chronic inflammation and mitochondrial dysfunction play critical roles in muscle atrophy pathogenesis. Here, we investigated the effects of bavachin and corylifol A from Psoralea corylifolia L. seeds on muscle atrophy in dexamethasone-treated mice and in db/db mice. Bavachin and corylifol A enhanced muscle strength and muscle mass in dexamethasone-treated mice. In diabetic mice, they enhanced muscle strength and cross-sectional areas. Bavachin and corylifol A suppressed inflammatory cytokine (interleukin-6 and tumor necrosis factor-α) expression levels by downregulating nuclear factor-κB phosphorylation. They decreased the muscle atrophic factor (myostatin, atrogin-1, and muscle RING finger-1) expression levels. They activated the AKT synthetic signaling pathway and induced a switch from fast-type glycolytic fibers (type 2B) to slow-type oxidative fibers (types I and 2A). They increased mitochondrial biogenesis and dynamic factor (optic atrophy-1, mitofusin-1/2, fission, mitochondrial 1, and dynamin 1-like) expression levels via the AMP-activated protein kinase-peroxisome proliferator-activated receptor gamma coactivator 1-alpha signaling pathway. They also improved mitochondrial quality by upregulating the mitophagy factor (p62, parkin, PTEN-induced kinase-1, and BCL2-interacting protein-3) expression levels. Therefore, bavachin and corylifol A exert potential therapeutic effects on muscle atrophy by suppressing inflammation and improving mitochondrial function.

Молекулярно-генетический анализ генов ADRB2, NOS3 и PPARGC1A у единоборцев города Перми

The study of genetic predisposition to certain types of sports activities will make it possible to sci-entifically select the most promising athletes and adjust their training process, since these data influence the formation of the physical qualities of athletes. The purpose of this study is to identify the relationship between pol-ymorphic variants of the ADRB2 (Adrenoceptor Beta 2), NOS3 (Nitric Oxide Synthase 3) и PPARGC1A (Peroxi-some Proliferator-Activated Receptor Gamma Coactivator 1-Alpha) genes associated with endurance in judo and freestyle wrestling athletes with different sports qualifications. The sample for the study included 50 ath-letes, of which 27 were athletes involved in judo at the «Vityaz» sports school, and 23 athletes involved in free-style wrestling at the «Planeta» sports and health club in the city of Perm. Depending on their sporting success, the combatants were distributed into Group I with high qualifications and into Group II with low qualifications. In 50 martial artists aged 10 to 16 years, laboratory research was carried out using real-time polymerase chain reaction (PCR-RT) and polymorphisms of three genes were identified: G/T polymorphism of the NOS3 gene (rs1799983), G/A polymorphism of the PPARGC1A gene (rs8192678) and A/G polymorphism of the ADRB2 gene (rs1042713). An analysis of the relationship between allelic variants of genes in martial artists and their sports qualifications was carried out. An analysis of the relationship between allelic variants of genes in martial artists and their sports qualifications was carried out; significant differences were established between Group I and Group II for genotype A/A (Fexp 2.98>1.96 at p=0.05) and genotype G/G (Fexp 2.60>1.96 at p=0.05) of the ADRB2 gene, and also for the G/A genotype of the PPARGC1A gene (Fexp 2.43>1.96 at p=0.05). The frequency of occurrence of TGS, calculated for the physical quality “endurance”, based on the polymorphism of the ADRB2, NOS3 and PPARGC1A genes in 50 martial artists, ranged from 33 to 100. Combatants with the greatest TGS are highly qualified. The relationship between the two samples (Group I with high qualifications and Group II with low qualifications) and TGS, established based on the analysis of polymorphic positions of three genes (ADRB2, NOS3 and PPARGC1A) is statistically insignificant.

Beneficial Mitochondrial Biogenesis in Gastrocnemius Muscle Promoted by High-Intensity Interval Training in Elderly Female Rats.

Exercise can attenuate mitochondrial dysfunction caused by aging. Our study aimed to compare 12 weeks of high-intensity interval training (HIIT) and moderate-intensity continuous training (MICT) on the expression of mitochondria proteins [e.g., AMP-activated protein kinase (AMPK), Estrogen-related receptor alpha (ERRα), p38 mitogen-activated protein kinase (P38MAPK), and Peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1-α)] in gastrocnemius muscle of old female rats. In this experimental study, thirty six old female Wistar rats (18-month-old and 270-310 g) were divided into three groups: i. HIIT, ii. MICT, and iii. Control group (C). The HIIT protocol was performed for 12 weeks with 16-28 minutes (2 minutes training with 85-90% VO2max in high intensity and 2 minutes training with 45-75% VO2max low intensity). The MICT was performed for 30-60 minutes with the intensity of 65-70% VO2max. The gastrocnemius muscle expression of AMPK, ERRα, P38MAPK, and PGC1α proteins were determined by Western blotting. The expression of AMPK (P=0.004), P38MAPK (P=0.003), PGC-1α (P=0.028), and ERRα (P=0.006) in HIIT was higher than C group. AMPK (P=0.03), P38MAPK (P=0.032), PGC-1α (P=0.015), and ERRα (P=0.028) in MICT was higher than the C group. Also expression of AMPK (P=0.008), P38MAPK (P=0.009), PGC-1α (P=0.020) and ERRα (P=0.014) in MICT was higher than MICT group. It seems that exercise training has beneficial effects on mitochondrial biogenesis, but the HIIT training method is more effective than MICT in improving mitochondrial function in aging.

Taurine promotes axonal sprouting via Shh-mediated mitochondrial improvement in stroke.

Motor function is restored by axonal sprouting in ischemic stroke. Mitochondria play a crucial role in axonal sprouting. Taurine (TAU) is known to protect the brain against experimental stroke, but its role in axonal sprouting and the underlying mechanism are unclear. We evaluated the motor function of stroke mice using the rotarod test on days 7, 14, and 28. Immunocytochemistry with biotinylated dextran amine was used to detect axonal sprouting. We observed neurite outgrowth and cell apoptosis in cortical neurons under oxygen and glucose deprivation (OGD), respectively. Furthermore, we evaluated the mitochondrial function, adenosine triphosphate (ATP), mitochondrial DNA (mtDNA), peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PCG-1α), transcription factor A of mitochondria (TFAM), protein patched homolog 1 (PTCH1), and cellular myelocytomatosis oncogene (c-Myc). TAU recovered the motor function and promoted axonal sprouting in ischemic mice. TAU restored the neuritogenesis ability of cortical neurons and reduced OGD-induced cell apoptosis. TAU also reduced reactive oxygen species, stabilized mitochondrial membrane potential, enhanced ATP and mtDNA content, increased the levels of PGC-1α, and TFAM, and restored the impaired levels of PTCH1, and c-Myc. Furthermore, these TAU-related effects could be blocked using an Shh inhibitor (cyclopamine). Taurine promoted axonal sprouting via Shh-mediated mitochondrial improvement in ischemic stroke.

SIRT3 regulates mitochondrial biogenesis in aging-related diseases.

Sirtuin 3 (SIRT3), the main family member of mitochondrial deacetylase, targets the majority of substrates controlling mitochondrial biogenesis via lysine deacetylation and modulates important cellular functions such as energy metabolism, reactive oxygen species production and clearance, oxidative stress, and aging. Deletion of SIRT3 has a deleterious effect on mitochondrial biogenesis, thus leading to the defect in mitochondrial function and insufficient ATP production. Imbalance of mitochondrial dynamics leads to excessive mitochondrial biogenesis, dampening mitochondrial function. Mitochondrial dysfunction plays an important role in several diseases related to aging, such as cardiovascular disease, cancer and neurodegenerative diseases. Peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1α) launches mitochondrial biogenesis through activating nuclear respiratory factors. These factors act on genes, transcribing and translating mitochondrial DNA to generate new mitochondria. PGC1α builds a bridge between SIRT3 and mitochondrial biogenesis. This review described the involvement of SIRT3 and mitochondrial dynamics, particularly mitochondrial biogenesis in aging-related diseases, and further illustrated the role of the signaling events between SIRT3 and mitochondrial biogenesis in the pathological process of aging-related diseases.

Thioredoxin-1 Promotes Mitochondrial Biogenesis Through Regulating AMPK/Sirt1/PGC1α Pathway in Alzheimer's Disease.

Alzheimer's disease (AD) is the most common neurodegenerative disease. Increasing studies suggest that mitochondrial dysfunction is closely related to the pathogenesis of AD. Thioredoxin-1 (Trx-1), one of the major redox proteins in mammalian cells, plays neuroprotection in AD. However, whether Trx-1 could regulate the mitochondrial biogenesis in AD is largely unknown. In the present study, we found that Aβ25-35 treatment not only markedly induced excessive production of reactive oxygen species and apoptosis, but also significantly decreased the number of mitochondria with biological activity and the adenosine triphosphate content in mitochondria, suggesting mitochondrial biogenesis was impaired in AD cells. These changes were reversed by Lentivirus-mediated stable overexpression of Trx-1 or exogenous administration of recombinant human Trx-1. What's more, adeno-associated virus-mediated specific overexpression of Trx-1 in the hippocampus of β-amyloid precursor protein/presenilin 1 (APP/PS1) mice ameliorated the learning and memory and attenuated hippocampal Aβ deposition. Importantly, overexpression of Trx-1 in APP/PS1 mice restored the decrease in mitochondrial biogenesis-associated proteins, including adenosine monophosphate -activated protein kinase (AMPK), silent information regulator factor 2-related enzyme 1 (Sirt1) and peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1α). In addition, Lentivirus-mediated overexpression of Trx-1 in rat adrenal pheochromocytoma (PC12) cells also restored the decrease of AMPK, Sirt1, and PGC1α by Aβ25-35 treatment. Pharmacological inhibition of AMPK activity significantly abolished the effect of Trx-1 on mitochondrial biogenesis. Taken together, our data provide evidence that Trx-1 promoted mitochondrial biogenesis via restoring AMPK/Sirt1/PGC1α pathway in AD.

Sodium Butyrate Ameliorates Type 2 Diabetes-Related Sarcopenia Through IL-33-Independent ILC2s/IL-13/STAT3 Signaling Pathway.

Sarcopenia has been described as a new complication of type 2 diabetes mellitus (T2DM). T2DM and sarcopenia impact each other, resulting in a variety of adverse outcomes such as frailty, disability, poor quality of life and increased mortality. Sodium butyrate (NaB) is reported to play a protective role against T2DM. The present study aimed to investigate whether NaB could ameliorate T2DM-related sarcopenia and the underlying mechanisms. The male db/db mice at 7-weeks were used as T2DM-related sarcopenia animal model with C57BL/6J mice as control. Mice were grouped according to whether they received NaB orally as follows: C57BL/6J+water group, C57BL/6J+NaB group, db/db+water group, and db/db+NaB group. Then, db/db mice receiving NaB orally were administered with inhibitors of group 2 innate lymphocytes (ILC2s), anti-CD90.2 by intraperitoneal injection divided into db/db+NaB+PBS group and db/db+NaB+anti-CD90.2 group. NaB dissolved in water at 150 mM. The skeletal muscle mass was measured by dural X-ray (DXA) test. ILC2s in spleen and skeletal muscle were evaluated by flow cytometry. The expressions of IL-33, IL-13, STAT3, P-STAT3, GATA-3 and peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1α) were assessed by ELISA or WB. The morphology of skeletal muscle fibers was assessed by immunofluorescence staining. The proportion of ILC2s and the expressions of ILC2s markers IL-13 and GATA-3 were all significantly decreased in db/db mice, and these changes were improved by NaB. NaB increased the proportion of slow-twitch fibers in gastrocnemius, thus partially reversing the reduced exercise capacity of db/db mice. The expression of slow-twitch fibers marker PGC-1α induced by NaB was increased via activation of ILC2s/IL-13/STAT3 pathway. On the other way, IL-33 was not necessary for the activation of ILC2s/IL-13/STAT3 pathway. After depletion of ILC2s by anti-CD90.2, the ameliorating effect of NaB on T2DM-related sarcopenia was partially antagonized. These results indicated that NaB could ameliorate type 2 diabetes-related sarcopenia by activating IL-33-independent ILC2s/IL-13/STAT3 signaling pathway.

PGC-1α/NRF1-dependent cardiac mitochondrial biogenesis: A druggable pathway of calycosin against triptolide cardiotoxicity.

Mitochondrion-related cardiotoxicity due to cardiotoxin stimuli is closely linked to abnormal activities of peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1α), followed by co-inactivation of nuclear respiratory factor-1(NRF1). Pharmacological interventions targeting mitochondria may be effective for developing agents against cardiotoxicity. Herein, in triptolide-treated H9C2 cardiomyocytes, we observed defective mitochondrial biogenesis and respiration, characterized by depletion of mitochondrial mass and mitochondrial DNA copy number, downregulation of mitochondrial respiratory chain complexes subunits, and disorders of mitochondrial membrane potential and mitochondrial oxidative phosphorylation. Dysregulation of mitochondria led to cardiac pathological features, such as myocardial fiber fracture, intercellular space enlargement, and elevation of serum aspartate aminotransferase, creatine kinase isoenzyme, lactate dehydrogenase, and cardiac troponin I. However, following calycosin treatment, an active compound from Astragali Radix, the mitochondrion-related disorders at both cell and tissue levels were significantly ameliorated, which was facilitated by the activation of PGC-1α via deacetylation, followed by NRF1 co-activation. Calycosin-enhanced PGC-1α deacetylation is impelled by increasing sirtuin-1 expression and NAD+/NADH ratio. PGC-1α/NRF1 signaling in calycosin-mediated mitochondrial biogenesis protection was further confirmed by NRF1 knockdown and PGC-1α inhibition with SR18292. We conclude that calycosin ameliorated triptolide-induced cardiotoxicity by protecting PGC-1α/NRF1-dependent cardiac mitochondrial biogenesis and respiration, which is the druggable pathway for cardiotoxicity mitigation.

Peroxisome Proliferator-Activated Receptor Gamma Coactivator-1Alpha (PGC-1α): A Transcriptional Regulator at the Interface of Aging and Age-Related Macular Degeneration?

Human age-related macular degeneration (AMD) is a prevalent age-related disease which causes retinal dysfunction and disability. Genetic and cell culture studies from AMD patients have implicated impaired activity of peroxisome proliferator-activated receptor gamma coactivator-1alpha (PGC-1α). PGC-1α is a transcriptional co-regulator that acts to control a plethora of metabolic processes relevant to AMD pathophysiology including gluconeogenesis, oxidative phosphorylation, and response to oxidative injury. Perturbation of PGC-1α activity in mice causes AMD-like RPE and retinal pathology. There is potential for therapeutic modulation of the PGC-1α pathway in AMD treatment.

Liraglutide ameliorates gentamicin-induced acute kidney injury in rats via PGC-1α- mediated mitochondrial biogenesis: Involvement of PKA/CREB and Notch/Hes-1 signaling pathways.

Acute kidney injury (AKI) is a challenging side effect which may clinically impede the use of gentamicin (GM). The present study explored the impact of liraglutide (Lir) on GM-induced kidney injury in rats. Lir (0.2 and 0.4mg/kg, s.c) was given for 10days (a dose/day) starting 3days before giving GM (100mg/kg, i.p) once daily for 7days. Interestingly, Lir notably ameliorated GM-induced elevated levels of renal injury markers; urea and creatinine. Moreover, Lir remarkably mitigated malondialdehyde (MDA) level and elevated glutathione (GSH) level as well as superoxide dismutase (SOD) activity. Also, Lir pre-treatment notably diminished inflammatory markers levels; interleukin-1β (IL-1β), tumor necrosis factor alpha (TNF-α), vascular cell adhesion molecule (VCAM), monocyte chemoattractant protein 1 (MCP-1) and interferon gamma (INF-γ). In addition, Lir significantly replenished expression of Peroxisome proliferator-activated receptor gamma coactivator-1alpha (PGC-1α), Protein kinase A (PKA), cAMP response element-binding protein (CREB), nuclear Nuclear factor erythroid 2-related factor 2 (Nrf2), heme Oxygenase-1 (HO-1), B-cell lymphoma 2 (Bcl-2), and remarkably attenuated expression of Notch homolog 1 (Notch1), Hairy and enhancer of split-1 (Hes-1), Bcl-2-associatedX(Bax), cleaved caspase 3 and nuclear Nuclear factor Kappa B (NF-κB (p65)). The nephroprotective activity of Lir was further confirmed by histopathological examination as well as transmission electron microscopy (TEM). In conclusion Lir achieved its nephroprotective effects through the amelioration of oxidative stress, inflammatory and apoptotic manifestations. It is worth-mentioning that the current study is the first to focus on the involvement of mitochondrial biogenesis and its upstream regulators, PKA/CREB and Notch/Hes-1 signaling pathways in the nephroprotective potentials of Lir. The attenuation of the aforementioned injurious aspects is partially attributed to the improvement of the mitochondrial status as demonstrated by elevated PGC-1α expression via acceleration of PKA/CREB and abatement of Notch/Hes-1 signaling pathways.

Synergic effect of exogenous lactate and caffeine on fat oxidation and hepatic glycogen concentration in resting rats.

Although several physiological roles of lactate have been revealed in the last decades, its effects on energy metabolism and substrate oxidation remain unknown. Therefore, we investigated the effects of lactate on the energy metabolism of resting rats. Male rats were divided into control (Con; distilled water), caffeine (Caf; 10 mg/kg), L-lactate (Lac; 2 g/kg), and lactate-plus-caffeine (Lac+Caf; 2 g/ kg + 10 mg) groups. Following oral administration of supplements, resting energy expenditure (study 1), biochemical blood parameters, and mRNA expression involved in energy metabolism in the soleus muscle were measured at different time points within 120 minutes of administration (study 2). Moreover, glycogen level and Pyruvate dehydrogenase (PDH) activity were measured. Groups did not differ in total energy expenditure throughout the 6 hour post-treatment evaluation. Within the first 4 hours, the Lac and Lac+Caf groups showed higher fat oxidation rates than the Con group (p<0.05). Lactate treatment decreased blood free fatty acid levels (p<0.05) and increased the mRNA expression of fatty acid translocase (FAT/CD36) (p<0.05) and peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) (p<0.05) in the skeletal muscle. Hepatic glycogen level in the Lac+Caf group was significantly increased (p<0.05). Moreover, after 30 and 120 minutes, PDH activity was significantly higher in lactate-supplemented groups compared to Con group (p<0.05). Our findings showed that Lac+Caf enhanced fat metabolism in the whole body and skeletal muscle while increasing hepatic glycogen concentration and PDH activity. This indicates Lac+Caf can be used as a potential post-workout supplement.

Quercetin alleviates cyclophosphamide-induced premature ovarian insufficiency in mice by reducing mitochondrial oxidative stress and pyroptosis in granulosa cells

BackgroundExposure to cyclophosphamide (CTX) induces premature ovarian insufficiency (POI). Quercetin is a natural flavonoid that exhibits anti-inflammatory and antioxidant properties, and its antioxidant activity is correlated with POI. However, the mechanism underlying its protective role in CTX-induced ovarian dysfunction is unclear. This study aimed to explore whether quercetin can protect ovarian reserves by activating mitochondrial biogenesis and inhibiting pyroptosis.MethodsThirty-six female C57BL/6 mice were randomly subdivided into six groups. Except for the control group, all groups were injected with 90 mg/kg CTX to establish a POI model and further treated with coenzyme 10 or various doses of quercetin. The mice were sacrificed 48 h after 10 IU pregnant mare serum gonadotropin was injected four weeks after treatments. We used enzyme-linked immunosorbent assays to detect serum hormone expression and light and transmission electron microscopy to assess ovarian tissue morphology and mitochondria. Additionally, we tested oxidant and antioxidant levels in ovarian tissues and mitochondrial function in granulosa cells (GCs). The expression of mitochondrial biogenesis and pyroptosis-related proteins and mRNA was analyzed using western blotting and RT-qPCR.ResultsQuercetin elevated serum anti-Müllerian hormone, estradiol, and progesterone levels, decreased serum follicle-stimulating hormone and luteinizing hormone levels, and alleviated ovarian pathology. It reduced the mitochondrial DNA content and mitochondrial membrane potential. Furthermore, it upregulated ATP levels and the mRNA and protein expression of peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1α), mitochondrial transcription factor A, and superoxide dismutase 2. In addition, it suppressed NOD-like receptor pyrin domain containing 3, caspase-1, interleukin-1β, and gasdermin D levels in the GCs of POI mice.ConclusionsQuercetin protected the ovarian reserve from CTX-induced ovarian damage by reversing mitochondrial dysfunction and activating mitochondrial biogenesis via the PGC1-α pathway. Moreover, quercetin may improve ovarian functions by downregulating pyroptosis in the CTX-induced POI model. Thus, quercetin can be considered a potential agent for treating POI.

CRISPR-Cas9 mediated genome editing of Huntington's disease neurospheres.

Huntington's disease (HD) is a fatal genetic disease caused by polyglutamine aggregation encoded by an expanded CAG repeat in the huntingtin gene (HTT). In this study, we cultured neurospheres derived from R6/2 mice, a representative animal model of HD, as an in vitro model. GuideRNAs were designed to induce large deletion or frameshift indel mutation of CAG expansion. These gRNAs and Cas9 were delivered to the R6/2 neurospheres and disease-related phenotypes were observed. Deletion or indel mutation of the CAG repeat was confirmed by PCR, T7E1 assay and sequencing of the edited neurospheres. Edited neurospheres showed decreased polyglutamine aggregation compared with control HD neurospheres. In the edited neurosphere, we confirmed the upregulation of peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1α) and brain-derived neurotrophic factor (BDNF), whose reduced expressions are closely involved in the disease progression. In addition, flow cytometry result showed an increase in cell viability with an overall decrease in necrotic and apoptotic populations among edited R6/2 neurospheres. Additional siRNA experiments confirmed that the increased viability was decreased through inhibition of PGC-1α or BDNF. Our study confirmed that CAG repeat of R6/2 mouse-derived neurospheres can be edited through CRISPR-Cas9. Editing of CAG repeat sequence decreases polyglutamine aggregation and cellular apoptosis of HD neurospheres, which may be related to the increased expressions of PGC-1α and BDNF.Our data provide the evidence that CRISPR-Cas9 mediated genome editing has therapeutic potential on HD neuronal cells.

Stepwise Coordination-Driven Metal-Phenolic Nanoparticle as a Neuroprotection Enhancer for Alzheimer's Disease Therapy.

Current therapeutic strategies for Alzheimer's disease (AD) mainly focus on inhibition of aberrant amyloid-β peptide (Aβ) aggregation. However, these strategies cannot repair the side symptoms (e.g., high neuronal oxidative stress) triggered by Aβ accumulation and thus show limited effects on suppressing Aβ-induced neuronal apoptosis. Herein, we develop a stepwise metal-phenolic coordination approach for the rational design of a neuroprotection enhancer, K8@Fe-Rh/Pda NPs, in which rhein and polydopamine are effectively coupled to enhance the treatment of AD in APPswe/PSEN1dE9 transgenic (APP/PS1) mice. We discover that the polydopamine inhibits the aggregation of Aβ oligomers, and rhein helps repair damage to neurons triggered by Aβ aggregation. Based on molecular docking, we demonstrate that the polydopamine has a strong interaction with Aβ monomers/fibrils through its multiple recognition sites (e.g., catechol groups, imine groups, and indolic/catecholic π-systems), thereby reducing Aβ burden. Further investigation of the antioxidant mechanisms suggests that K8@Fe-Rh/Pda NPs promote the mitochondrial biogenesis via activating the sirtuin 1 (SIRT1)/peroxisome proliferator-activated receptor gamma coactivator 1-alpha pathway. This finally inhibits neuronal apoptosis. Moreover, an intravenous injection of these nanoparticles potently improves the cognitive function in APP/PS1 mice without adverse effects. Overall, our work provides a promising approach to develop advanced nanomaterials for multi-target treatment of AD.

Protective effect of Qingluotongbi formula against Tripterygium wilfordii induced liver injury in mice by improving fatty acid β-oxidation and mitochondrial biosynthesis

Context Qingluotongbi formula (QLT) is a Chinese medicine compound consisting of Tripterygium wilfordii Hook. f. (Celastraceae, TW), Panax notoginseng (Burkill) F.H.Chen (Araliaceae, PN), Rehmannia glutinosa (Gaertn.) DC. (Orobanchaceae, RG), Sinomenium acutum (Thunb.) Rehder & E.H. Wilson (Menispermaceae, SA), and Bombyx mori L. (Bombycidae, BM). Objective This study investigated the protective effect and possible mechanism of QLT against TW-induced liver injury in mice. Materials and methods To establish the model of TW-induced liver injury in mice, C57BL/6J mice were randomly divided into 4 groups: control group, low-dose TW group, middle-dose TW group, and high-dose TW group. To observe the effects of QLT and its individual ingredients against TW-induced liver injury, C57BL/6J mice were randomly divided into 7 groups: control group, TW group, QLT group, PN group, RG group, SA group, BM group. After administration for 7 days, C57BL/6J mice were tested for biochemical indicators and liver pathological changes. Then, we evaluated the mitochondrial function and analysed the gene and protein expression related to the peroxisome proliferator-activated receptor alpha (PPARα)/peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1α) pathway by quantitative real-time PCR (qRT-PCR) and Western blotting. Results Compared with the control group (0.30 ± 0.35), TW significantly increased mice liver histological score (L, 0.95 ± 1.14; M, 1.25 ± 1.16; H, 4.00 ± 1.13). QLT and its ingredients significantly improved the pathology scores (CON, 0.63 ± 0.74; TW, 4.19 ± 1.53; QLT, 1.56 ± 0.62; PN, 1.94 ± 0.68; RG, 2.75 ± 1.39; SA, 4.13 ± 0.99; BM, 4.13 ± 0.99). Western blot and qRT-PCR analysis revealed that QLT and its ingredients reversed TW-induced suppression of PPARα/PGC1-α pathway. Discussion and conclusions: These findings provide valuable information for compound compatibility studies and TW clinical applications.