There is considerable support for the view that aerobic exercise may confer cognitive benefits to mild cognitively impaired elderly persons. However, the biological mechanisms mediating these effects are not entirely clear. As a preliminary step towards informing this gap in knowledge, we enrolled older adults confirmed to have mild cognitive impairment (MCI) in a 6-month exercise program. Male and female subjects were randomized into a 6-month program of either aerobic or stretch (control) exercise. Data collected from the first 10 completers, aerobic exercise (n=5) or stretch (control) exercise (n=5), were used to determine intervention-induced changes in the global gene expression profiles of the aerobic and stretch groups. Using microarray, we identified genes with altered expression (relative to baseline values) in response to the 6-month exercise intervention. Genes whose expression were altered by at least two-fold, and met the p-value cutoff of 0.01 were inputted into the Ingenuity Pathway Knowledge Base Library to generate gene-interaction networks. After a 6-month aerobic exercise-training, genes promoting inflammation became down-regulated, whereas genes having anti-inflammatory properties and those modulating immune function or promoting neuron survival and axon growth, became up-regulated (all fold change≥±2.0, p<0.01). These changes were not observed in the stretch group. Importantly, the differences in the expression profiles correlated with significant improvement in maximal oxygen uptake (VO2max) in the aerobic program as opposed to the stretch group. We conclude that three distinct cellular pathways may collectively influence the training effects of aerobic exercise in MCI subjects. We plan to confirm these effects using rt-PCR and correlate such changes with the cognitive phenotype.

Regular endurance exercise training induces beneficial functional and health effects in human skeletal muscle. The putative contribution to the training response of the epigenome as a mediator between genes and environment has not been clarified. Here we investigated the contribution of DNA methylation and associated transcriptomic changes in a well-controlled human intervention study. Training effects were mirrored by significant alterations in DNA methylation and gene expression in regions with a homogeneous muscle energetics and remodeling ontology. Moreover, a signature of DNA methylation and gene expression separated the samples based on training and gender. Differential DNA methylation was predominantly observed in enhancers, gene bodies and intergenic regions and less in CpG islands or promoters. We identified transcriptional regulator binding motifs of MRF, MEF2 and ETS proteins in the proximity of the changing sites. A transcriptional network analysis revealed modules harboring distinct ontologies and, interestingly, the overall direction of the changes of methylation within each module was inversely correlated to expression changes. In conclusion, we show that highly consistent and associated modifications in methylation and expression, concordant with observed health-enhancing phenotypic adaptations, are induced by a physiological stimulus.

Reactive oxygen species (ROS) and nitrogen species have an indispensable role in regulating cell signalling pathways, including transcriptional control via hypoxia inducible factor-1α (HIF-1α). Hyperbaric oxygenation treatment (HBO2) increases tissue oxygen content and leads to enhanced ROS production. In the present study DSS-induced colitis has been employed in BALB/c mice as an experimental model of gut mucosa inflammation to investigate the effects of HBO2 on HIF-1α, antioxidative enzyme, and proinflammatory cytokine genes during the colonic inflammation. Here we report that HBO2 significantly reduces severity of DSS-induced colitis, as evidenced by the clinical features, histological assessment, impaired immune cell expansion and mobilization, and reversal of IL-1β, IL-2, and IL-6 gene expression. Gene expression and antioxidative enzyme activity were changed by the HBO2 and the inflammatory microenvironment in the gut mucosa. Strong correlation of HIF-1α mRNA level to GPx1, SOD1, and IL-6 mRNA expression suggests involvement of HIF-1α in transcriptionalregulation of these genes during colonic inflammation and HBO2. This is further confirmed by a strong correlation of HIF-1α with known target genes VEGF and PGK1. Results demonstrate that HBO2 has an anti-inflammatory effect in DSS-induced colitis in mice, and this effect is at least partly dependent on expression of HIF-1α and antioxidative genes.

Mesenchymal stem cells (MSCs) have emerged as a promising tool for the treatment of several neurodegenerative disorders, including Alzheimer's disease (AD). The main neuropathological hallmarks of AD are senile plaques, composed of amyloid beta (Aβ), and neurofibrillary tangles, formed by hyperphosphorylated tau. However, current therapies for AD have shown limited efficacy. In this study, we evaluated whether pre-treatment with cannabidiol (CBD), at 5 μM concentration, modulated the transcriptional profile of MSCs derived from gingiva (GMSCs) in order to improve their therapeutic potential, by performing a transcriptomic analysis by the next-generation sequencing (NGS) platform. By comparing the expression profiles between GMSCs treated with CBD (CBD-GMSCs) and control GMSCs (CTR-GMSCs), we found that CBD led to the downregulation of genes linked to AD, including genes coding for the kinases responsible of tau phosphorylation and for the secretases involved in Aβ generation. In parallel, immunocytochemistry analysis has shown that CBD inhibited the expression of GSK3β, a central player in AD pathogenesis, by promoting PI3K/Akt signalling. In order to understand through which receptor CBD exerted these effects, we have performed pre-treatments with receptor antagonists for the cannabinoid receptors (SR141716A and AM630) or for the vanilloid receptor 1 (TRPVI). Here, we have proved that TRPV1 was able to mediate the modulatory effect of CBD on the PI3K/Akt/GSK3β axis. In conclusion, we have found that pre-treatment with CBD prevented the expression of proteins potentially involved in tau phosphorylation and Aβ production in GMSCs. Therefore, we suggested that GMSCs preconditioned with CBD possess a molecular profile that might be more beneficial for the treatment of AD.

We have previously reported that decaffeinated green tea extract (GTE) in combination with voluntary exercise (Ex) reduces metabolic syndrome in high fat-fed C57BL/6J mice. Here, we examined for the first time the effect of treatment with 77 mg/g GTE, Ex, or both (GTE + Ex) on genes related to the conversion of white adipose tissue (WAT) to brown fat-like adipose tissue (BLAT) in this model. GTE+Ex induced genes related to lipolysis (hormone sensitive lipase [3.0-fold] and patatin-like phospholipase domain-containing protein 2 [2-fold]), mitochondrialβ-oxidation (NADH dehydrogenase 5 [2.3-fold], cytochrome B [2.0-fold], and cytochrome C oxidase III [1.9-fold increase]), and adipose tissue browning (peroxisome proliferator-activated receptor-γ coactivator-1α [1.8-fold], bone morphogenetic protein 4 [2.6-fold], and phosphatase and tensin homolog [2.6-fold]) in visceral WAT compared to HF-fed mice. These results suggest that GTE+Ex function in part by inducing the conversion of WAT to BLAT and provides novel mechanistic insight into this combination.

Since the laser and photomodulation were discovered over 50 years, they have been used for many applications in medicine and in dentistry also. In particular, light-emitting diodes therapy (LT) achieved a great success in medical treatment and photo-therapy. In the decades, LT has been used for several therapeutic purposes. Many beneficial effects have been demonstrated in vitro and in vivo, including antibacterial, antiviral, antitumor, cell differentiation, immune potentiating and tissue repair activities. Beneficial effects of LT have also been observed in clinical settings. Although there are lots of cell culture studies in low-level laser therapy, there are only a few cell culture studies in LT that have similar characteristics. The aim of this study was to investigate the effects of LT on primary human gingival fibroblast cells (HGF) on elastin (ELN) gene activation using Real Time PCR. ELN gene activation is directly connected with elastin protein production and HGF functionality. Human gingival tissue biopsies were obtained from three healthy patients during tooth extraction. The gingival specimens were fragmented with a scalpel and transferred in culture dishes containing Dulbecco’s modified Eagle medium supplemented with 20% fetal calf serum (FBS) and antibiotics, i.e. penicillin 100U/ml and streptomycin 100μg/ml. Cells were incubated in a humidified atmosphere of 5% CO2 at 37C. The medium was changed the next day and twice a week. After 15 days, the samples of gingival tissue were removed from the culture dishes. Cells were harvested after an additional 24 h incubation. Human gingival fibroblasts at the second passage were seeded on multiple 6-well plates. The cells stimulation was performed with a light-emitting diodes (LEDs) medical device type E-Light. The LED irradiation seems to be directly correlated with the elastin (ELN) gene activation. Interestingly, ELN gene expression in the cultured human gingival fibroblasts seems to be inversely related to the patients’ age; in fact, its expression tends to decrease with aging. In summary, the result of the present study shows that LED irradiation promoted ELN gene expression more in elderly than in younger adults.

Multiple sclerosis (MS) is a neurodegenerative disease of the central nervous system. The animal model of MS, experimental autoimmune encephalomyelitis (EAE), is commonly used for studies of human inflammatory demyelinating diseases and has been shown to be suitable for studying the effects of exercise on MS pathophysiology. The present study was conducted to determine the impact of forced swimming and voluntary running wheel exercises before and after the induction of EAE on expression of Nogo-A, NgR, and ROCK genes in the brain tissue. A total of 96 C57BL/6 mice were randomly divided into two groups, namely exercises before (EXb, n = 48) and after (EXa, n = 48) induction of EAE. Each group was divided into four subgroups: Forced Swimming + EAE (n = 12), Voluntary Running Wheel + EAE (n = 12), NoEX-EAE (n = 12), and Control group (n = 12). Animals performed either swimming exercise for 30 min per day or running wheel for one hour per day, five days per week for four weeks. Results of Luxal Fast Blue (LFB) staining demonstrated that the degree of demyelination was significantly less in the experimental exercised compared to NoEX-EAE groups (P < .05). Amazingly, both modes of exercise reduced the severity of MS symptoms in mice exposed to swimming and wheel running, evaluated as body weight, clinical scores, degree of demyelination, and gene expressions, regardless of whether the exercise was performed before or after EAE induction.

PURPOSE:Exercise has been prescribed to the elderly based on its effect on increasing muscle strength and protein synthesis that prevent sense of balance and/or cognitive functions. However, a few molecular mechanism researches has been conducted on how the vestibular organs, cerebellum, and hippocampus, which are responsible for the deterioration and balance of spatial learning memory due to aging, are affected by exercise.

METHODS:The 9-week old and 84-week old C57Bl/6 were assigned randomly to Young-Control (YC), Young-Exercise (YE), Old-Control (OC) and Old-Exercise (OE) groups for 4 -week treadmill running. A Rotarod test was used to evaluate motor coordination function. Moreover, a high-throughput whole transcript expression RNA array approach was applied to the cerebellum of aged mice to explain the novel molecular mechanism of beneficial effect of exercise.

RESULTS:As results, the motor coordination function was significantly improved in exercise-aged mice. The RNA sequencing analysis showed that the expression of cerebellar genes was significantly changed by aging rather than exercise. Especially, Cers1 was up-regulated in sedentary aged mice and down-regulated in exercise aged mice. Fumonisin B1, inhibition of Cers1, mitigates neuronal cell death induced by doxorubicin.

CONCLUSION:These results provide unraveling specific transcripts and understanding of the exercise-related cerebellum transcriptome in aged mice. Well-designed exercise program might prevent the motor coordination defect in aged model, which development of the exercise protocol for elderly population based on these markers.

New therapeutic approaches are needed to treat leukemia effectively. Dietary restriction regimens, including fasting, have been considered for the prevention and treatment of certain solid tumor types. However, whether and how dietary restriction affects hematopoietic malignancies is unknown. Here we report that fasting alone robustly inhibits the initiation and reverses the leukemic progression of both B cell and T cell acute lymphoblastic leukemia (B-ALL and T-ALL, respectively), but not acute myeloid leukemia (AML), in mouse models of these tumors. Mechanistically, we found that attenuated leptin-receptor (LEPR) expression is essential for the development and maintenance of ALL, and that fasting inhibits ALL development by upregulation of LEPR and its downstream signaling through the protein PR/SET domain 1 (PRDM1). The expression of LEPR signaling-related genes correlated with the prognosis of pediatric patients with pre-B-ALL, and fasting effectively inhibited B-ALL growth in a human xenograft model. Our results indicate that the effects of fasting on tumor growth are cancer-type dependent, and they suggest new avenues for the development of treatment strategies for leukemia.

BACKGROUND:The rapid pace of life, eating habits, and environmental pollution have increased stress levels and its related disorders. The complex molecular response to stress is mediated by stress genes and a variety of regulatory pathways. Oxidative stress is internal damage caused by reactive oxygen species. Increasing evidence suggests that chronic psychosocial stress may increase oxidative stress, which in turn may contribute to aging, and etiology of coronary diseases, cancer, arthritis, etc. Psychophysiological concomitants of meditation have been extensively researched, but there are very little data available on biochemical activity leading to relieving stress by causing a relaxation response by Sudarshan Kriya (SK). SK is a breathing technique that involves breathing in three different rhythms. It is preceded by Ujjayi Pranayam (long and deep breaths with constriction at the base of throat) and Bhastrika (fast and forceful breaths through nose along with arm movements).

METHODS:Forty-two SK practitioners and 42 normal healthy controls were recruited for our study. The practitioners had practiced SK for at least 1 year. Selected normal healthy controls did not perform any conventional physical exercise or any formal stress management technique. Whole blood was used for glutathione peroxidase estimation and red blood cell lysate was used for superoxide dismutase activity assay and for glutathione estimation. White blood cells were isolated from fresh blood and assayed for gene expression using reverse transcriptase-polymerase chain reaction. The parameters studied are antioxidant enzymes, genes involved in oxidative stress, DNA damage, cell cycle control, aging, and apoptosis.

RESULTS:A better antioxidant status both at the enzyme activity and RNA level was seen in SK practitioners. This was accompanied by better stress regulation and better immune status due to prolonged life span of lymphocytes by up-regulation of antiapoptotic genes and prosurvival genes in these subjects.

CONCLUSIONS:Our pilot study provides the first evidence suggesting that SK practice may exert effects on immunity, aging, cell death, and stress regulation through transcriptional regulation.

BACKGROUND:Vitamin C (vit C) is an essential dietary nutrient, which is a potent antioxidant, a free radical scavenger and functions as a cofactor in many enzymatic reactions. Vit C is also considered to enhance the immune effector function of macrophages, which are regarded to be the first line of defence in response to any pathogen. The THP-1 cell line is widely used for studying macrophage functions and for analyzing host cell-pathogen interactions.

RESULTS:We performed a genome-wide temporal gene expression and functional enrichment analysis of THP-1 cells treated with 100 μM of vit C, a physiologically relevant concentration of the vitamin. Modulatory effects of vitamin C on THP-1 cells were revealed by differential expression of genes starting from 8 h onwards. The number of differentially expressed genes peaked at the earliest time-point i.e. 8 h followed by temporal decline till 96 h. Further, functional enrichment analysis based on statistically stringent criteria revealed a gamut of functional responses, namely, 'Regulation of gene expression', 'Signal transduction', 'Cell cycle', 'Immune system process', 'cAMP metabolic process', 'Cholesterol transport' and 'Ion homeostasis'. A comparative analysis of vit C-mediated modulation of gene expression data in THP-1cells and human skin fibroblasts disclosed an overlap in certain functional processes such as 'Regulation of transcription', 'Cell cycle' and 'Extracellular matrix organization', and THP-1specific responses, namely, 'Regulation of gene expression' and 'Ion homeostasis'. It was noteworthy that vit C modulated the 'Immune system' process throughout the time-course.

CONCLUSIONS:This study reveals the genome-wide effects of physiological levels of vit C on THP-1 gene expression. The multitude of effects impacted by vit C in macrophages highlights its role in maintaining homeostasis of several cellular functions. This study provides a rational basis for the use of the Vitamin C- THP-1 cell model, to study biochemical and cellular responses to stresses, including infection with M. tuberculosis and other intracellular pathogens.

Ganoderma lucidum (lingzhi) has been used for the general promotion of health in Asia for many centuries. The common method of consumption is to boil lingzhi in water and then drink the liquid. In this study, we examined the potential anticancer activities of G. lucidum submerged in two commonly consumed forms of alcohol in East Asia: malt whiskey and rice wine. The anticancer effect of G. lucidum, using whiskey and rice wine-based extraction methods, has not been previously reported. The growth inhibition of G. lucidum whiskey and rice wine extracts on the prostate cancer cell lines, PC3 and DU145, was determined. Using Affymetrix gene expression assays, several biologically active pathways associated with the anticancer activities of G. lucidum extracts were identified. Using gene expression analysis (real-time polymerase chain reaction [RT-PCR]) and protein analysis (Western blotting), we confirmed the expression of key genes and their associated proteins that were initially identified with Affymetrix gene expression analysis.

Werner syndrome (WS) is a premature aging disorder caused by mutations in a DNA helicase/exonuclease. Mice lacking the helicase domain of this protein exhibit metabolic abnormalities that are reversed by vitamin C. In this study, we used a targeted metabolomic approach to identify serum metabolites significantly altered in young mutant mice treated with or without vitamin C. We also measured several serum inflammatory and cardiometabolic factors. We show that young mutant mice exhibit an increase in serum hydroxyproline and plasminogen activator inhibitor-1 (PAI-1), markers of cardiovascular diseases and inflammation, before they exhibit morphological anomalies in different tissues. We also observed an increase in three very long chain lysophosphatidylcholines underlying peroxisome perturbation. Vitamin C reversed the concentrations of these metabolites and PAI-1 to wild type values. Transcriptomic analyses on the liver of mutant mice revealed a decrease in the expression of genes involved in fatty acid degradation compared to wild type animals. Vitamin C treatment increased the expression of genes involved in glutathione metabolism and the synthesis of unsaturated fatty acids in these mice. These results show that changes at the transcriptomic level concord with the alterations of several serum metabolites in these mice. Finally, we found that a mislocalization of the Wrn mutant protein in the liver endoplasmic reticulum fraction increased oxidative stress in that cellular compartment. Vitamin C reversed this oxidative stress. To conclude, this study provides novel potential predictive cardiometabolic biomarkers in WS that will allow the assessment of the impact of vitamin C on patients with WS.

Curcuma longa has long been used in China and India as anti-inflammatory agent to treat a wide variety of conditions and also as a spice for varied curry preparations. The chemoprofile of the Curcuma species exhibits the presence of varied phytochemicals with curcumin being present in all three species but AA only being shown in C. longa. This study explored the effect of a curcumin/AA combination on human cancer cell lines. The curcumin/AA combination was assessed by isobologram analysis using the Loewe additivity drug interaction model. The drug combination showed additive cytotoxicity toward CCRF-CEM and CEM/ADR5000 leukemia cell lines and HCT116p53(+/+) and HCT116p53(-/-) colon cancer cell line, while the glioblastoma cell lines U87MG and U87MG.ΔEGFR showed additive to supra-additive cytotoxicity. Gene expression profiles predicting sensitivity and resistance of tumor cells to induction by curcumin and AA were determined by microarray-based mRNA expressions, COMPARE, and hierarchical cluster analyses. Numerous genes involved in transcription (TFAM, TCERG1, RGS13, C11orf31), apoptosis-regulation (CRADD, CDK7, CDK19, CD81, TOM1) signal transduction (NR1D2, HMGN1, ABCA1, DE4ND4B, TRIM27) DNA repair (TOPBP1, RPA2), mRNA metabolism (RBBP4, HNRNPR, SRSF4, NR2F2, PDK1, TGM2), and transporter genes (ABCA1) correlated with cellular responsiveness to curcumin and ascorbic acid. In conclusion, this study shows the effect of the curcumin/AA combination and identifies several candidate genes that may regulate the response of varied cancer cells to curcumin and AA.

One of the most common integrative medicine (IM) modalities is yoga and related practices. Previous work has shown that yoga may improve wellness in healthy people and have benefits for patients. However, the mechanisms of how yoga may positively affect the mind-body system are largely unknown. Here we have assessed possible rapid changes in global gene expression profiles in the peripheral blood mononuclear cells (PBMCs) in healthy people that practiced either a comprehensive yoga program or a control regimen. The experimental sessions included gentle yoga postures, breathing exercises, and meditation (Sudarshan Kriya and Related Practices--SK&P) compared with a control regimen of a nature walk and listening to relaxing music. We show that the SK&P program has a rapid and significantly greater effect on gene expression in PBMCs compared with the control regimen. These data suggest that yoga and related practices result in rapid gene expression alterations which may be the basis for their longer term cell biological and higher level health effects.

One of the most common integrative medicine (IM) modalities is yoga and related practices. Previous work has shown that yoga may improve wellness in healthy people and have benefits for patients. However, the mechanisms of how yoga may positively affect the mind-body system are largely unknown. Here we have assessed possible rapid changes in global gene expression profiles in the peripheral blood mononuclear cells (PBMCs) in healthy people that practiced either a comprehensive yoga program or a control regimen. The experimental sessions included gentle yoga postures, breathing exercises, and meditation (Sudarshan Kriya and Related Practices--SK&P) compared with a control regimen of a nature walk and listening to relaxing music. We show that the SK&P program has a rapid and significantly greater effect on gene expression in PBMCs compared with the control regimen. These data suggest that yoga and related practices result in rapid gene expression alterations which may be the basis for their longer term cell biological and higher level health effects.

OBJECTIVE:The purpose of this study was to investigate whether low-level light therapy (LLLT) was capable of modulating expression of ultraviolet (UV) light-responsive genes in vivo.

MATERIALS AND METHODS:The effects of 670 nm light-emitting diode (LED) array irradiation were investigated in a hairless SHK-1 mouse epidermis model. Mice were given a single dose of UVA/UVB light, or three doses of red light (670 nm @ 8 mW/cm(2) x 312 sec, 2.5 J/cm(2) per session) spread over 24 h along with combinations of pre- and post-UV treatment with red light. Levels of 14 UV-responsive mRNAs were quantified 24 h after UV irradiation by real-time quantitative reverse transcription polymerase chain reaction (qRT-PCR).

RESULTS:The transcription of mRNAs encoding for cluster of differentiation molecule 11b (CD11b) (p < 0.05) and interferon (IFN)-γ (p < 0.012) increased after irradiation with red light alone, whereas expression level of cyclooxygenase (COX)-2 (p < 0.02) was downregulated. Genes unresponsive to UV did not change their expression levels after exposure to red light either. Pretreatment with red light significantly modified response of Fos to UV exposure (p < 0.01). A synergy of UV and post-treatment with red light in reducing the transcription levels of CD11b (p < 0.05) and inducible nitric oxide synthase (iNOS) (p < 0.05) was observed.

CONCLUSIONS:This is an initial observation that in mouse red light LLLT more often than not causes opposite gene expression changes or reduces those caused by moderate UVA-UVB irradiation.

Breast cancer metastasis is one of the major reasons for the high morbidity and mortality of breast cancer patients. In spite of surgical interventions, chemotherapy, radiation therapy and targeted therapy, some patients are considering alternative therapies with herbal/natural products. In the present study, we evaluated a well-characterized extract from the medicinal mushroom Ganoderma lucidum (GLE) for its affects on tumor growth and breast-to-lung cancer metastasis. MDA-MB-231 human breast cancer cells were implanted into the mammary fat pads of nude mice. GLE (100 mg/kg/every other day) was administered to the mice by an oral gavage for 4 weeks, and tumor size was measuredusing microcalipers. Lung metastases were evaluated by hematoxylin and eosin (H&E) staining. Gene expression in MDA-MB-231 cells was determined by DNA microarray analysis and confirmed by quantitative PCR. Identified genes were silenced by siRNA, and cell migration was determined in Boyden chambers and by wound-healing assay. Although an oral administration of GLE only slightly suppressed the growth of large tumors, the same treatment significantly inhibited the number of breast-to-lung cancer metastases. GLE also downregulated the expression of genes associated with invasive behavior (HRAS, VIL2, S100A4, MCAM, I2PP2A and FN1) in MDA-MB-231 cells. Gene silencing of HRAS, VIL2, S100A4, I2PP2A and FN1 by siRNA suppressed migration of MDA-MB‑231 cells. Our study suggests that an oral administration of GLE can inhibit breast-to-lung cancer metastases through the downregulation of genes responsible for cell invasiveness. The anti-metastatic benefits of GLE warrant further clinical studies.

SCOPE:The study investigates the effects of pterostilbene (PTE) on exercise endurance and circadian rhythm in sleep-restricted (SR) mice.

METHODS AND RESULTS:The SR model is established by keeping mice awake during the first 8 h of light period for 5 d and PTE (100 mg kgd) is given once a day. PTE improves endurance in SR mice by significantly prolonging the exhaustive swimming time and ameliorating exercise fatigue biochemical parameters, including creatine kinase and lactate dehydrogenase. It is observed that PTE effectively regained mitochondrial function by improving mitochondrial swelling and maintaining oxidative phosphorylation system-related genes expression, and inhibited the decrease of mitochondrial biogenesis-related genes expression. Furthermore, PTE restores rhythms of AMP-activated protein kinase (AMPK) phosphorylation activity, silent information regulator 1 (SIRT1) deacetylation activity, and SIRT1-mediated peroxisome proliferator-activated receptor coactivator 1α (PGC-1α) deacetylation in SR mice. Finally, the results demonstrate that the AMPK/SIRT1/PGC-1α pathway may be correlated with the relationships between mitochondrial function and circadian rhythms, markedly regulating the expression of skeletal muscle clock genes, circadian locomotor output cycles kaput, and brain and muscle arnt-like 1.

CONCLUSIONS:PTE ameliorates SR-induced exercise intolerance associated with circadian misalignment and mitochondrial dysfunction through AMPK/SIRT1/PGC-1α pathway.

Vitamin C is an important antioxidant and cofactor which is involved in the regulation of development, function and maintenance of several cell types in the body. Deficiencies in vitamin C can lead to conditions such as scurvy, which, among other ailments, causes gingivia, bone pain and impaired wound healing. This review examines the functional importance of vitamin C as it relates to the development and maintenance of bone tissues. Analysis of several epidemiological studies and genetic mouse models regarding the effect of vitamin C shows a positive effect on bone health. Overall, vitamin C exerts a positive effect on trabecular bone formation by influencing expression of bone matrix genes in osteoblasts. Recent studies on the molecular pathway for vitamin C actions that include direct effects of vitamin C on transcriptional regulation of target genes by influencing the activity of transcription factors and by epigenetic modification of key genes involved in skeletal development and maintenance are discussed. With an understanding of mechanisms involved in the uptake and metabolism of vitamin C and knowledge of precise molecular pathways for vitamin C actions in bone cells, it is possible that novel therapeutic strategies can be developed or existing therapies can be modified for the treatment of osteoporotic fractures. This article is protected by copyright. All rights reserved.