SLC5A3 is important for cervical cancer cell growth.

Novel molecular targets for cervical cancer must be identified. This study examined the role of SLC5A3, a myo-inositol transporter, in the pathogenesis of cervical cancer. Through boinformatics analysis, we showed that the SLC5A3 mRNA levels were upregulated in cervical cancer tissues. The upregulated SLC5A3 mRNA levels were negatively correlated with survival and progression-free interval. Genes co-expressed with SLC5A3 were enriched in multiple signaling cascades involved in cancer progression. In primary/established cervical cancer cells, SLC5A3 shRNA/knockout (KO) exerted growth-inhibitory effects and promoted cell death/apoptosis. Furthermore, SLC5A3 knockdown or KO downregulated myo-inositol levels, induced oxidative injury, and decreased Akt-mTOR activation in cervical cancer cells. In contrast, supplementation of myo-inositol or n-acetyl-L-cysteine or transduction of a constitutively active Akt1 construct mitigated SLC5A3 KO-induced cytotoxicity in cervical cancer cells. Lentiviral SLC5A3 overexpression construct transduction upregulated the cellular myo-inositol level and promoted Akt-mTOR activation, enhancing cervical cancer cell proliferation and migration. The binding of TonEBP to the SLC5A3 promoter was upregulated in cervical cancer. In vivo studies showed that intratumoral injection of SLC5A3 shRNA-expressing virus arrested cervical cancer xenograft growth in mice. SLC5A3 KO also inhibited pCCa-1 cervical cancer xenograft growth. The SLC5A3-depleted xenograft tissues exhibited myo-inositol downregulation, Akt-mTOR inactivation, and oxidative injury. Transduction of sh-TonEBP AAV construct downregulated SLC5A3 expression and inhibited pCCa-1 cervical cancer xenograft growth. Together, overexpressed SLC5A3 promotes growth of cervical cancer cells, representing as a novel therapeutic oncotarget for the devastating disease.

Astaxanthin Ameliorates Worsened Muscle Dysfunction of MDX Mice Fed with a High-Fat Diet through Reducing Lipotoxicity and Regulating Gut Microbiota.

Duchenne muscular dystrophy (DMD), a severe X-linked inherited neuromuscular disease, has a high prevalence of obesity. Obesity exacerbates muscle damage and results in adverse clinical outcomes. Preventing obesity helps DMD patients delay disease progression and improve quality of life. Astaxanthin (AX) is a kind of carotenoid which has antioxidant and anti-adipogenesis effects. In this study, male C57BL/10ScSnDmdmdx/J mice were fed with a normal diet, a high-fat diet (HFD), and an HFD containing AX for 16 weeks, respectively. The results showed that AX significantly increased gastrocnemius fiber cross-section area and grip strength, improved treadmill endurance test and mitochondrial morphology, and reduced muscle triglyceride and malonaldehyde levels compared to the HFD. Lipidomic analysis revealed that AX decreased high levels of triglyceride, diglyceride, ceramides, and wax ester induced by HFD. Gut microbiota analysis indicated that AX supplementation failed to alleviate abnormal microbiota diversity, but increased the relative abundances of Akkermansia, Bifidobacterium, Butyricicoccus, and Staphylococcus. In conclusion, AX was expected to alleviate disease progression associated with obesity in DMD patients by reducing lipotoxicity and increasing the abundance of beneficial bacteria.

A paraventricular thalamus to central amygdala neural circuit modulates acute stress-induced heightened wakefulness.

Heightened wakefulness in response to stressors is essential for survival but can also lead to sleep disorders like insomnia. The paraventricular thalamus (PVT) is both a critical thalamic area for wakefulness and a stress-sensitive brain region. However, whether the PVT and its neural circuitries are involved in controlling wakefulness in stress conditions remains unknown. Here, we find that PVT neurons projecting to the central amygdala (CeA) are activated by different stressors. These neurons are wakefulness-active and increase their activities upon sleep to wakefulness transitions. Optogenetic activation of the PVT-CeA circuit evokes transitions from sleep to wakefulness, whereas selectively silencing the activity of this circuit decreases time spent in wakefulness. Specifically, chemogenetic inhibition of CeA-projecting PVT neurons not only alleviates stress responses but also attenuates the acute stress-induced increase of wakefulness. Thus, our results demonstrate that the PVT-CeA circuit controls physiological wakefulness and modulates acute stress-induced heightened wakefulness.

Effects of Whey Protein or Its Hydrolysate Supplements Combined with an Energy-Restricted Diet on Weight Loss: A Randomized Controlled Trial in Older Women.

An energy-restricted weight-loss approach has limitations when it used in the elderly, especially because of muscle loss. We aimed to assess the effects of whey protein (WP) or WP hydrolysate (WPH) combined with an energy-restricted diet (ERD) on weight reduction and muscle preservation in older women with overweight and obesity. A total of 60 women were randomized to the control (ERD), WP (ERD + 20 g/d WP) or WPH (ERD + 20 g/d WPH) group, using a 1:1:1 allocation ratio. After an 8-week intervention, body composition, gut microbiota, and serum metabolomics changes were compared among the three groups. The reductions in body weight (−1.11 ± 1.11 vs. −2.34 ± 1.35, p < 0.05), BMI (−0.46 ± 0.45 vs. −0.97 ± 0.54, p < 0.05), and body fat (−0.70 ± 0.92 vs. −2.45 ± 1.65, p < 0.01) were higher in the WPH group than in the control group. Body fat (%) was significantly decreased in the two protein groups. Fat-free mass did not significantly change among the three groups. Serum metabolomics showed that the tricarboxylic acid cycle pathway was upregulated in the WPH group. No significant changes in microbiota were observed among the groups. In conclusion, WP or WPH supplementation combined with an energy-restricted diet benefits older women during weight loss. WPH was more effective, possibly due to increased energy metabolism.

Effectiveness of yoga therapy for migraine treatment: A meta-analysis of randomized controlled studies.

INTRODUCTION: Yoga therapy may have some potential in treating migraine, and thus this meta-analysis aims to explore the efficacy of yoga therapy for patients with migraine. METHODS: PubMed, EMbase, Web of science, EBSCO and Cochrane library databases have been systematically searched and we included the randomized controlled trials (RCTs) reporting the efficacy of yoga therapy for migraine patients. The outcomes included. RESULTS: This meta-analysis included six RCTs. The results revealed that compared with control group for migraine, yoga therapy was associated with remarkably decreased pain intensity (SMD = -1.21; 95% CI = -2.17 to -0.25; P = 0.01), headache frequency (SMD = -1.43; 95% CI = -2.23 to -0.64; P = 0.0004), headache duration (SMD = -1.03; 95% CI = -1.85 to -0.21; P = 0.01), HIT-6 score (SMD = -2.28; 95% CI = -3.81 to -0.75; P = 0.003) and MIDAS score (SMD = -0.52; 95% CI = -0.77 to -0.27; P < 0.0001). CONCLUSIONS: Yoga therapy may be effective to treat migraine patients, but it should be recommended with caution because of heterogeneity.

Synthesis of Melatonin Derivatives and the Neuroprotective Effects on Parkinson's Disease Models of Caenorhabditis elegans.

Melatonin (MT) is a hormone with antioxidant activity secreted by the pineal gland in the human brain, which is highly efficient in scavenging free radicals and plays an important role in the neuro-immuno-endocrine system. Emerging evidence showed that MT supplementation was a potential therapeutic strategy for Parkinson's disease (PD), which inhibits pathways associated with oxidative stress in PD. In this study, we reported a C7-selective olefination of melatonin under rhodium catalysis with the aid of PIII-directing groups and synthesized 10 new melatonin-C7-cinnamic acid derivatives (6a-6j). The antioxidant potential of the compounds was evaluated both by ABTS and ORAC methods. Among these newly synthesized melatonin derivatives, 6a showed significantly higher activity than MT at 10-5 M. In the transgenic Caenorhabditis elegans model of PD, 6a significantly reduces alpha-synuclein aggregation and dopaminergic neuronal damage in nematodes while reducing intracellular ROS levels and recovers behavioral dysfunction induced by dopaminergic neurodegeneration. Further study of the mechanism of action of this compound can provide new therapeutic ideas and treatment strategies for PD.

Shaoyao Decoction Inhibits Inflammation and Improves Intestinal Barrier Function in Mice With Dextran Sulfate Sodium-Induced Colitis.

Shaoyao decoction (SYD), a classical traditional Chinese medicine formula, is effective for the treatment of inflammatory bowel disease (IBD). This study was designed to investigate the therapeutic effects of SYD on IBD and possible mechanisms. Dextran sulfate sodium (DSS, 3.5%) was used to induce colitis in C57BL/6 mice. Disease phenotypes were investigated based on disease activity index (DAI), colon length, and microscopic and macroscopic scores. Additionally, the presence of proinflammatory cytokines, immune cell infiltrates, intestinal cell proliferation, apoptosis, epithelial permeability, signal transducer and activator of transcription 3 (STAT3), and nuclear factor-κB (NF-κB) signaling, as well as the intestinal mucosal barrier function, were investigated. The administration of SYD significantly ameliorated the clinical signs, suppressed the levels of proinflammatory cytokines, and reduced immune cell infiltrates into colonic tissues of DSS-induced colitis model mice. SYD also significantly reduced the DSS-induced activation of STAT3 and NF-κB signaling. Furthermore, SYD promoted epithelial integrity by regulating epithelial cell apoptosis and epithelial permeability. Finally, we demonstrated that SYD protected the intestinal barrier function by significantly regulating the mucus layer genes Muc1, Muc2, Muc4, and Tff3, as well as the epithelial barrier genes Z O -1 and Occludin. Our results indicate that SYD has a protective effect on DSS-induced colitis, which is attributable to its anti-inflammatory activity and intestinal barrier function-enhancing effects. These results provide valuable insights into the pharmacological actions of SYD for the treatment of IBD.

Characterization of Two Mitochondrial Genomes and Gene Expression Analysis Reveal Clues for Variations, Evolution, and Large-Sclerotium Formation in Medical Fungus Wolfiporia cocos.

Wolfiporia cocos, a precious mushroom with a long history as an edible food and Asian traditional medicine, remains unclear in the genetic mechanism underlying the formation of large sclerotia. Here, two complete circular mitogenomes (BL16, 135,686 bp and MD-104 SS10, 124,842 bp, respectively) were presented in detail first. The salient features in the mitogenomes of W. cocos include an intron in the tRNA (trnQ-UUG2), and an obvious gene rearrangement identified between the two mitogenomes from the widely geographically separated W. cocos strains. Genome comparison and phylogenetic analyses reveal some variations and evolutional characteristics in W. cocos. Whether the mitochondrion is functional in W. cocos sclerotium development was investigated by analyzing the mitogenome synteny of 10 sclerotium-forming fungi and mitochondrial gene expression patterns in different W. cocos sclerotium-developmental stages. Three common homologous genes identified across ten sclerotium-forming fungi were also found to exhibit significant differential expression levels during W. cocos sclerotium development. Most of the mitogenomic genes are not expressed in the mycelial stage but highly expressed in the sclerotium initial or developmental stage. These results indicate that some of mitochondrial genes may play a role in the development of sclerotium in W. cocos, which needs to be further elucidated in future studies. This study will stimulate new ideas on cytoplasmic inheritance of W. cocos and facilitate the research on the role of mitochondria in large sclerotium formation.

Sleep deprivation aggravated lipopolysaccharide/D-galactosamine-induced acute liver injury by suppressing melatonin production.

OBJECTIVE: Sleep loss is common in patients with liver injury, but the effects of sleep deprivation (SD) on liver injury remain unclear. In the present study, the potential effects of SD on acute liver injury and the underlying mechanisms have been investigated. METHODS: The sleep of male BALB/c mice has been deprived by using a modified multiple platform water bath for 3 days and acute liver injury was induced by intraperitoneal injection of lipopolysaccharide (LPS) and D-galactosamine (D-Gal). The degree of liver injury was detected by aminotransferase determination, histopathology and survival rate analysis. Inflammatory response and melatonin (MT) were measured by enzyme-linked immunosorbent assay (ELISA). In addition, hepatocyte apoptosis was determined by caspase activity measurement and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay. RESULTS: We observed that SD increased plasma aminotransferases, TUNEL-positive hepatocytes, histological abnormalities and mortality rates in mice with LPS/D-Gal treatment. SD also promoted LPS/D-Gal-induced production of TNF-α and upregulated hepatic caspase-8, caspase-9, and caspase-3 activities in LPS/D-Gal-exposed mice. In addition, SD significantly decreased MT contents in plasma of mice with acute liver injury, but supplementation with MT reversed these SD-promoted changes. CONCLUSION: Our data suggested that SD exacerbated LPS/D-Gal-induced liver injury via decreasing melatonin production.

Dihydromyricetin Ameliorates Nonalcoholic Fatty Liver Disease by Improving Mitochondrial Respiratory Capacity and Redox Homeostasis Through Modulation of SIRT3 Signaling.

Aims: Our previous clinical trial indicated that the flavonoid dihydromyricetin (DHM) could improve hepatic steatosis in patients with nonalcoholic fatty liver disease (NAFLD), altough the potential mechanisms of these effects remained elusive. Here, we investigated the hepatoprotective role of DHM on high-fat diet (HFD)-induced NAFLD. Results: DHM supplementation could effectively ameliorate the development of NAFLD by inhibiting hepatic lipid accumulation both in HFD-fed wild-type mice and in palmitic acid-induced hepatocytes. We reveal for the first time that mitochondrial dysfunction characterized by ATP depletion and augmented oxidative stress could be reversed by DHM treatment. Moreover, DHM enhanced the mitochondrial respiratory capacity by increasing the expression and enzymatic activities of mitochondrial complexes and increased mitochondrial reactive oxygen species scavenging by restoring manganese superoxide dismutase (SOD2) activity. Interestingly, the benefits of DHM were abrogated in SIRT3 knockout (SIRT3KO) mice and in hepatocytes transfected with SIRT3 siRNA or treated with an SIRT3-specific inhibitor. We further showed that DHM could increase SIRT3 expression by activating the adenosine monophosphate-activated protein kinase (AMPK)-peroxisome proliferator-activated receptor-γ coactivator-1 alpha (PGC1α)/estrogen-related receptor-α (ERRα) signaling pathway. Innovation: Our work indicates that SIRT3 plays a critical role in the DHM-mediated beneficial effects that include ameliorating mitochondrial dysfunction and oxidative stress in a nutritional NAFLD model both in vivo and in vitro.Conclusion: Our results suggest that DHM prevents NAFLD by improving mitochondrial respiratory capacity and redox homeostasis in hepatocytes through a SIRT3-dependent mechanism. These results could provide a foundation to identify new DHM-based preventive and therapeutic strategies for NAFLD.