Gouqi-derived nanovesicles (GqDNVs) inhibited dexamethasone-induced muscle atrophy associating with AMPK/SIRT1/PGC1α signaling pathway.

With the increasing trend of global aging, sarcopenia has become a significant public health issue. Goji berry, also known as "Gou qi zi" in China, is a traditional Chinese herb that can enhance the structure and function of muscles and bones. Otherwise, previous excellent publications illustrated that plant-derived exosome-like nanoparticles can exert good bioactive functions in different aging or disease models. Thus, we issued the hypothesis that Gouqi-derived nanovesicles (GqDNVs) may also have the ability to improve skeletal muscle health, though the effect and its mechanism need to be explored. Hence, we have extracted GqDNVs from fresh berries of Lycium barbarum L. (goji) and found that the contents of GqDNVs are rich in saccharides and lipids. Based on the pathway annotations and predictions in non-targeted metabolome analysis, GqDNVs are tightly associated with the pathways in metabolism. In muscle atrophy model mice, intramuscular injection of GqDNVs improves the cross-sectional area of the quadriceps muscle, grip strength and the AMPK/SIRT1/PGC1α pathway expression. After separately inhibiting AMPK or PGC1α in C2C12 cells with dexamethasone administration, we have found that the activated AMPK plays the chief role in improving cell proliferation induced by GqDNVs. Furthermore, the energy-targeted metabolome analysis in the quadriceps muscle demonstrates that the GqDNVs up-regulate the metabolism of amino sugar and nucleotide sugar, autophagy and oxidative phosphorylation process, which indicates the activation of muscle regeneration. Besides, the Spearman rank analysis shows close associations between the quality and function of skeletal muscle, metabolites and expression levels of AMPK and SIRT1. In this study, we provide a new founding that GqDNVs can improve the quality and function of skeletal muscle accompanying the activated AMPK/SIRT1/PGC1α signaling pathway. Therefore, GqDNVs have the effect of anti-aging skeletal muscle as a potential adjuvant or complementary method or idea in future therapy and research.

High-fat diet induces sarcopenic obesity in natural aging rats through the gut-trimethylamine N-oxide-muscle axis.

INTRODUCTION: The lack of suitable animal models for sarcopenic obesity (SO) limits in-depth research into the disease. Emerging studies have demonstrated that gut dysbiosis is involved in the development of SO. As the importance of microbial metabolites is starting to unveil, it is necessary to comprehend the specific metabolites associated with gut microbiota and SO. OBJECTIVES: We aimed to investigate whether high-fat diet (HFD) causes SO in natural aging animal models and specific microbial metabolites that are involved in linking HFD and SO. METHODS: Young rats received HFD or control diet for 80 weeks, and obesity-related metabolic disorders and sarcopenia were measured. 16S rRNA sequencing and non-targeted and targeted metabolomics methods were used to detect fecal gut microbiota and serum metabolites. Gut barrier function was evaluated by intestinal barrier integrity and intestinal permeability. Trimethylamine N-oxide (TMAO) treatment was further conducted for verification. RESULTS: HFD resulted in body weight gain, dyslipidemia, impaired glucose tolerance, insulin resistance, and systemic inflammation in natural aging rats. HFD also caused decreases in muscle mass, strength, function, and fiber cross-sectional area and increase in muscle fatty infiltration in natural aging rats. 16S rRNA sequencing and nontargeted and targeted metabolomics analysis indicated that HFD contributed to gut dysbiosis, mainly characterized by increases in deleterious bacteria and TMAO. HFD destroyed intestinal barrier integrity and increased intestinal permeability, as evaluated by reducing levels of colonic mucin-2, tight junction proteins, goblet cells and elevating serum level of fluorescein isothiocyanate-dextran 4. Correlation analysis showed a positive association between TMAO and SO. In addition, TMAO treatment aggravated the development of SO in HFD-fed aged rats through regulating the ROS-AKT/mTOR signaling pathway. CONCLUSION: HFD leads to SO in natural aging rats, partially through the gut-microbiota-TMAO-muscle axis.

Associations of Various Physical Activities with Mortality and Life Expectancy are Mediated by Telomere Length.

OBJECTIVES: Physical activity (PA) and telomeres both contribute to healthy aging and longevity. To investigate the optimal dosage of various PA for longevity and the role of telomere length in PA and mortality. DESIGN: Prospective cohort study. SETTING AND PARTICIPANTS: A total of 333,865 adults (mean age of 56 years) from the UK Biobank were analyzed. METHODS: Walking, moderate PA (MPA), and vigorous PA (VPA) were self-reported via questionnaire, and leukocyte telomere length (LTL) was measured. Cox proportional hazards regression was used to predict all-cause mortality risk. A flexible parametric Royston-Parmar survival model was used to estimate life expectancy. RESULTS: During a median follow-up of 13.8 years, 19,789 deaths were recorded. Compared with the no-walking group, 90 to 720 minutes/week of walking was similarly associated with 27% to 31% of lower mortality and about 6 years of additional life expectancy. We observed nearly major benefits for mortality and life expectancy among those meeting the PA guidelines [151-300 minutes/wk for MPA: hazard ratio (HR) 0.80, 95% CI 0.75-0.85, 3.40-3.42 additional life years; 76-150 minutes/wk for VPA: HR 0.78, 95% CI 0.75-0.82, 2.61 years (2.33-2.89)] vs the no-PA group. Similar benefits were also observed at 76-150 and 301-375 minutes/wk of MPA (18%-19% lower mortality, 3.20-3.42 gained years) or 151-300 minutes/wk of VPA (20%-26% lower mortality, 2.41-2.61 gained years). The associations between MPA, VPA, and mortality risk were slightly mediated by LTL (≈1% mediation proportion, both P < .001). CONCLUSIONS AND IMPLICATIONS: Our study suggests a more flexible range of PA than the current PA guidelines, which could gain similar benefits and is easier to achieve: 90 to 720 minutes/wk of walking, 75 to 375 minutes/wk of MPA, and 75 to 300 minutes/wk of VPA. Telomeres might be a potential mechanism by which PA promotes longevity.

Effects of Timing and Types of Protein Supplementation on Improving Muscle Mass, Strength, and Physical Performance in Adults Undergoing Resistance Training: A Network Meta-Analysis.

Precise protein supplementation strategies for muscle improvement are still lacking. The timing or type of protein supplementation has been debated as a window of opportunity to improve muscle mass, strength, and physical performance. We conducted a network meta-analysis of randomized controlled trials with protein supplements and resistance training. PubMed, Web of Science, Cochrane Library, and SPORTDiscus databases were searched until May 1, 2023. We included 116 eligible trials with 4,711 participants that reported on 11 timing and 14 types of protein supplementation. Compared with placebo, protein supplementation after exercise (mean difference [MD]: 0.54 kg [95% confidence intervals 0.10, 0.99] for fat-free mass, MD: 0.34 kg [95% confidence intervals 0.10, 0.58] for skeletal muscle mass) and at night (MD: 2.85 kg [0.49, 5.22] for handgrip strength, MD: 12.12 kg [3.26, 20.99] for leg press strength) was most effective in improving muscle mass and strength, respectively (moderate certainty). Milk proteins (milk, whey protein, yogurt, casein, and bovine colostrum), red meat, and mixed protein were effective for gains in both muscle mass and strength (moderate certainty). No timing or type of protein showed a significant enhancement in physical performance (timed up-to-go test, 6-min walk test, and gait speed). Pre/postexercise and Night are key recommended times of protein intake to increase muscle mass and strength, respectively. Milk proteins are the preferred types of protein supplements for improving muscle mass and strength. Future randomized controlled trials that directly compare the effects of protein timing or types are needed. This trial was registered at International Prospective Register of Systematic Reviews as CRD42022358766.

Deoxynivalenol Exposure Induced Colon Damage in Mice Independent of the Gut Microbiota.

SCOPE: To investigate whether deoxynivalenol (DON) can induce intestinal damage through gut microbiota in mice. METHODS AND RESULTS: Mice are orally administered DON (1 mg kg-1 bw day-1 ) for 4 weeks, and then recipient mice receive fecal microbiota transplantation (FMT) from DON-exposed mice after antibiotic treatment. Furthermore, the mice are orally treated with DON (1 mg kg-1 bw day-1 ) for 4 weeks after antibiotic treatment. Histological damage, disruption of tight junction protein expression, and increased oxidative stress and apoptosis in the colon as well as higher serum lipopolysaccharides are observed after DON exposure. Moreover, DON exposure changes the composition and diversity of the gut microbiota as well as the contents of fecal metabolites (mainly bile acids). Differential metabolic pathways may be related to mitochondrial metabolism, apoptosis, and inflammation following DON exposure. However, only a decrease in mRNA levels of occludin and claudin-3 is observed in the colon of recipient mice after FMT. After depleting the gut microbiota in mice, DON exposure can also cause histological damage, disorders of tight junction protein expression, and increased oxidative stress and apoptosis in the colon. CONCLUSIONS: DON exposure can induce colon damage in mice independent of the gut microbiota.

Human milk extracellular vesicles enhance muscle growth and physical performance of immature mice associating with Akt/mTOR/p70s6k signaling pathway.

Extracellular vesicles (EVs) play an important role in human and bovine milk composition. According to excellent published studies, it also exerts various functions in the gut, bone, or immune system. However, the effects of milk-derived EVs on skeletal muscle growth and performance have yet to be fully explored. Firstly, the current study examined the amino acids profile in human milk EVs (HME) and bovine milk EVs (BME) using targeted metabolomics. Secondly, HME and BME were injected in the quadriceps of mice for four weeks (1 time/3 days). Then, related muscle performance, muscle growth markers/pathways, and amino acids profile were detected or measured by grip strength analysis, rotarod performance testing, Jenner-Giemsa/H&E staining, Western blotting, and targeted metabolomics, respectively. Finally, HME and BME were co-cultured with C2C12 cells to detect the above-related indexes and further testify relative phenomena. Our findings mainly demonstrated that HME and BME significantly increase the diameter of C2C12 myotubes. HME treatment demonstrates higher exercise performance and muscle fiber densities than BME treatment. Besides, after KEGG and correlation analyses with biological function after HME and BME treatment, results showed L-Ornithine acts as a "notable marker" after HME treatment to affect mouse skeletal muscle growth or functions. Otherwise, L-Ornithine also significantly positively correlates with the activation of the AKT/mTOR pathway and myogenic regulatory factors (MRFs) and can also be observed in muscle and C2C12 cells after HME treatment. Overall, our study not only provides a novel result for the amino acid composition of HME and BME, but the current study also indicates the advantage of human milk on skeletal muscle growth and performance.

Faecal microbiota transplantation from young rats attenuates age-related sarcopenia revealed by multiomics analysis.

BACKGROUND: Gut microbiota plays a key role in the development of sarcopenia via the 'gut-muscle' axis, and probiotics-based therapy might be a strategy for sarcopenia. Fecal microbiota transplantation from young donors (yFMT) has attracted much attention because of its probiotic function. However, whether or not yFMT is effective for sarcopenia in old recipients is largely unknown. Thus, we aimed to investigate the effect and mechanism of yFMT on age-related sarcopenia. METHODS: The fecal microbiota of either young (12 weeks) or old (88 weeks) donor rats was transplanted into aged recipient rats for 8 weeks. Then, muscle mass, muscle strength, muscle function, muscle atrophy, and muscle regeneration capacity were measured. Analysis of fecal 16 s rRNA, serum non-targeted metabolomic, gut barrier integrity, and muscle transcriptome was conducted to elucidate the interaction between gut microbiota and skeletal muscles. RESULTS: As evaluated by magnetic resonance imaging examination, grip strength test (P < 0.01), rotarod test (P < 0.05), and exhaustive running test (P < 0.05), we found that yFMT mitigated muscle mass loss, muscle strength weakness, and muscle function impairment in aged rats. yFMT also countered age-related atrophy and poor regeneration capacity in fast- and slow-switch muscles, which were manifested by the decrease in slow-switch myofibres (both P < 0.01) and muscle interstitial fibrosis (both P < 0.05) and the increase in the cross-section area of myofibres (both P < 0.001), fast-switch myofibres (both P < 0.01), and muscle satellite cells (both P < 0.001). In addition, yFMT ameliorated age-related dysbiosis of gut microbiota and metabolites by promoting the production of beneficial bacteria and metabolites-Akkermansia, Lactococcus, Lactobacillus, γ-glutamyltyrosine, 3R-hydroxy-butanoic acid, and methoxyacetic acid and inhibiting the production of deleterious bacteria and metabolites-Family_XIII_AD3011_group, Collinsella, indoxyl sulfate, indole-3-carboxilic acid-O-sulphate, and trimethylamine N-oxide. Also, yFMT prevented age-related destruction of gut barrier integrity by increasing the density of goblet cells (P < 0.0001) and the expression levels of mucin-2 (P < 0.0001) and tight junctional proteins (all P < 0.05). Meanwhile, yFMT attenuated age-related impairment of mitochondrial biogenesis and function in fast- and slow-switch muscles. Correlation analysis revealed that yFMT-induced alterations of gut microbiota and metabolites might be closely related to mitochondria-related genes and sarcopenia-related phenotypes. CONCLUSIONS: yFMT could reshape the dysbiosis of gut microbiota and metabolites, maintain gut barrier integrity, and improve muscle mitochondrial dysfunction, eventually alleviating sarcopenia in aged rats. yFMT might be a new therapeutic strategy for age-related sarcopenia.

Association of muscle wasting with mortality risk among adults: A systematic review and meta-analysis of prospective studies.

The relationship between muscle wasting and mortality risk in the general population remains unclear. Our study was conducted to examine and quantify the associations between muscle wasting and all-cause and cause-specific mortality risks. PubMed, Web of Science and Cochrane Library were searched until 22 March 2023 for main data sources and references of retrieved relevant articles. Prospective studies investigating the associations of muscle wasting with risks of all-cause and cause-specific mortality in the general population were eligible. A random-effect model was used to calculate the pooled relative risk (RR) and 95% confidence intervals (CIs) for the lowest versus normal categories of muscle mass. Subgroup analyses and meta-regression were performed to investigate the potential sources of heterogeneities among studies. Dose-response analyses were conducted to evaluate the relationship between muscle mass and mortality risk. Forty-nine prospective studies were included in the meta-analysis. A total of 61 055 deaths were ascertained among 878 349 participants during the 2.5- to 32-year follow-up. Muscle wasting was associated with higher mortality risks of all causes (RR = 1.36, 95% CI, 1.28 to 1.44, I2  = 94.9%, 49 studies), cardiovascular disease (CVD) (RR = 1.29, 95% CI, 1.05 to 1.58, I2  = 88.1%, 8 studies), cancer (RR = 1.14, 95% CI, 1.02 to 1.27, I2  = 38.7%, 3 studies) and respiratory disease (RR = 1.36, 95% CI, 1.11 to 1.67, I2  = 62.8%, 3 studies). Subgroup analyses revealed that muscle wasting, regardless of muscle strength, was significantly associated with a higher all-cause mortality risk. Meta-regression showed that risks of muscle wasting-related all-cause mortality (P = 0.06) and CVD mortality (P = 0.09) were lower in studies with longer follow-ups. An approximately inverse linear dose-response relationship was observed between mid-arm muscle circumference and all-cause mortality risk (P < 0.01 for non-linearity). Muscle wasting was associated with higher mortality risks of all causes, CVD, cancer and respiratory disease in the general population. Early detection and treatment for muscle wasting might be crucial for reducing mortality risk and promoting healthy longevity.

Bone Marrow Mesenchymal Stem-Cell-Derived Exosomes Ameliorate Deoxynivalenol-Induced Mice Liver Damage.

Deoxynivalenol (DON) is a kind of Fusarium toxin that can cause a variety of toxic effects. DON is mainly metabolized and detoxified by the liver. When the concentration of DON exceeds the metabolic capacity of the liver, it will trigger acute or chronic damage to the liver tissue. Previous studies demonstrated that bone marrow mesenchymal stem-cell-secreted exosomes (BMSC-exos) reduce liver injury. Therefore, we issue a hypothesis that in vitro-cultured rat BMSC-secreted exos could ameliorate liver damage after 2 mg/kg bw/day of DON exposure. In total, 144 lipids were identified in BMEC-exos, including high polyunsaturated fatty acid (PUFA) levels. BMSC-exos treatment alleviated liver pathological changes and decreased levels of alanine aminotransferase, aspartate aminotransferase, inflammatory factors interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), and lipid peroxidation. Otherwise, low or high BMSC-exos treatment obviously changes DON-induced hepatic oxylipin patterns. According to the results from our correlation network analysis, Pearson correlation coefficient analysis, and hierarchical clustering analysis, the top 10% oxidized lipids can be classified into two categories: one that was positively correlated with copper-zinc superoxide dismutase (Cu/Zn SOD) and another that was positively correlated with liver injury indicators. Altogether, BMSC-exos administration maintained normal liver function and reduced oxidative damage in liver tissue. Moreover, it could also significantly change the oxylipin profiles under DON conditions.

The circadian rhythm gene Bmal1 ameliorates acute deoxynivalenol-induced liver damage.

Deoxynivalenol (DON) is widely emerging in various grain crops, milk, and wine products, which can trigger different toxic effects on humans and animals by inhalation or ingestion. It also imposes a considerable financial loss on the agriculture and food industry each year. Previous studies have reported acute and chronic toxicity of DON in liver, and liver is not only the main detoxification organ for DON but also the circadian clock oscillator directly or indirectly regulates critical physiologically hepatic functions under different physiological and pathological conditions. However, researches on the association of circadian rhythm in DON-induced liver damage are limited. In the present study, mice were divided into four groups (CON, DON, Bmal1OE, and Bmal1OE + DON) and AAV8 was used to activate (Bmal1) expression in liver. Then mice were gavaged with 5 mg/kg bw/day DON or saline at different time points (ZT24 = 0, 4, 8, 12, 16, and 20 h) in 1 day and were sacrificed 30 min after oral gavage. The inflammatory cytokines, signal transducers, and activators of transcription Janus kinase/signal transducers and activator of transcription 3 (JAKs/STAT3) pathway and bile acids levels were detected by enzyme-linked immunosorbent assay (ELISA), western blotting, and target metabolomics, respectively. The DON group showed significantly elevated interleukin-1ß (IL-1ß), interleukin 6 (IL-6), and tumor necrosis factor-α (TNF-α) levels (P < 0.05 for both) and impaired liver function with rhythm disturbances compared to the CON and Bmal1OE groups. At the molecular level, expressions of some circadian clock proteins were significantly downregulated (P < 0.05 for both) and JAKs/STAT3 pathway was activated during DON exposure, accompanied by indicated circadian rhythm disturbance and inflammatory damage. Importantly, Bmal1 overexpression attenuated DON-induced liver damage, while related hepatic bile acids such as cholic acid (CA) showed a decreasing trend in the DON group compared with the CON group. Our study demonstrates a novel finding that Bmal1 plays a critical role in attenuating liver damage by inhibiting inflammatory levels and maintaining bile acids levels under the DON condition. Therefore, Bmal1 may also be a potential molecular target for reducing the hepatotoxic effects of DON in future studies.

Current studies and potential future research directions on biological effects and related mechanisms of allicin.

Allicin, a thiosulfonate extract from freshly minced garlic, has been reported to have various biological effects on different organs and systems of animals and human. It can reduce oxidative stress, inhibit inflammatory response, resist pathogen infection and regulate intestinal flora. In addition, dozens of studies also demonstrated allicin could reduce blood glucose level, protect cardiovascular system and nervous system, and fight against cancers. Allicin was widely used in disease prevention and health care. However, more investigations on human cohort study are needed to verify the biological or clinical effects of allicin in the future. In this review, we summarized the biological effects of allicin from previous outstanding and valuable studies and provided useful information for future studies on the health effects of allicin.

Non-coding RNAs-associated ceRNA networks involved in the amelioration of skeletal muscle aging after whey protein supplementation.

Whey protein has been reported to be an impactful dietary supplement to ameliorate skeletal muscle aging for a long time. However, whether whey protein could contribute to muscle aging amelioration by post-transcriptional modulation remains unclear. In this study, 19-month-old mice orally received whey protein supplementation (1.0 g/kg/bw/d, whey protein group) or deionized water (the control group) for 3 months. Differentially expressed ncRNAs and mRNAs in quadriceps were identified by RNA-seq. Construction of non-coding RNAs (ncRNAs)-associated competing endogenous RNA (ceRNA) networks as well as GO and KEGG enrichment analyses were also carried out subsequently. Meanwhile, ultrasound measurement, H&E staining, myofiber cross-sectional area measurement, western blotting and RT-qPCR were performed in the quadriceps to evaluate muscle status and verify the RNA-seq data. Whey protein supplementation for 3 months increased quadriceps-body weight ratio and improved the histological as well as ultrasonographic characteristics of aging in muscle. Moreover, the protein expression levels of Myog, Myf4, Myf5 and MyoD1 were all significantly elevated in quadriceps. The expression of 90 lncRNAs, 334 mRNAs, six circRNAs and 52 miRNAs were significantly up or down-regulated in quadriceps after whey protein supplementation. Furthermore, ncRNAs-associated networks and GO and KEGG enrichment analyses revealed whey protein may influence muscle aging process through selected ncRNAs-associated ceRNA networks. Therefore, post-transcriptional modulation could be a potential crucial way to ameliorate skeletal muscle aging after whey protein supplementation. The selected ncRNAs-associated ceRNA networks may provide new insight for the underlying mechanism and profound therapeutic target for skeletal muscle aging.

Meta-analysis of the association between mTORC1-related genes polymorphisms and cancer risk.

BACKGROUND: mTOR, mLST8 and RAPTOR are the core components of mTORC1, which has been found to be closely related to tumorigenesis. Currently, multiple single nucleotide polymorphisms (SNPs) in mTOR gene (rs2295080, rs17036508 and rs1034528), mLST8 gene (rs3160 and rs26865) and RPTOR gene (rs1062935, rs3751932, rs3751834, rs12602885) have been extensively studied for their associations with cancer risk. However, the results remained inconclusive and conflicting. Therefore, we here performed a meta-analysis of all available studies to investigate the association between these SNPs and cancer risk. METHODS: Up to April 2021, 25 related publications were retrieved and included in this meta-analysis. The odds ratios (ORs) and 95% confidence intervals (CIs) calculated by fixed or random effects models were applied to assess the strength of association. Trial Sequential Analysis (TSA) was conducted to weaken the random error and enhance the reliability of evidence. RESULTS: After Bonferroni correction, it was revealed that rs3160, rs26865, rs1062935, rs3751932, rs3751834 and rs10602885 were not associated with cancer risk. However, rs17036508 and rs1034528 showed significant association with total cancer risk. A significant association was also found between rs2295080 and total cancer risk, and stratified analysis by cancer type suggested that rs2295080 was specifically associated with acute lymphoblastic leukemia risk, prostate cancer risk, and breast cancer risk. CONCLUSIONS: The present meta-analysis suggested that the rs2295080, rs17036508 and rs1034528 polymorphisms in mTOR gene may be the susceptive factors for cancer development, while the target genetic polymorphisms in mLST8 gene or RPTOR gene may not be associated with cancer risk. However, these findings remain to be confirmed or further reinforced in large and well-designed studies in different ethnic populations.

Pyruvate Might Bridge Gut Microbiota and Muscle Health in Aging Mice After Chronic High Dose of Leucine Supplementation.

Background: The previous studies demonstrated that there might be complex and close relationships among leucine supplementation, gut microbiota, and muscle health, which still needs further investigation. Aims: This study aimed to explore the associations of gut microbiota with muscle health after leucine intake. Methods: In this study, 19-month-old male C57BL/6j mice (n = 12/group) were supplemented with ultrapure water, low dose of leucine (500 mg/kg·d), and high dose of leucine (1,250 mg/kg·d) for 12 weeks by oral gavage. The mice fecal samples in each group before and after supplementation were collected for baseline and endpoint gut microbiota analysis by using 16S rDNA amplicon sequencing. Meanwhile, ultrasound measurement, H&E staining, myofiber cross-sectional area (CSA) measurement, and western blotting were performed in the quadriceps subsequently. The pyruvate levels were detected in feces. Results: Improvement in muscle of histology and ultrasonography were observed after both low and high dose of leucine supplementation. High dose of leucine supplementation could promote skeletal muscle health in aging mice via regulating AMPKα/SIRT1/PGC-1α. The richness and diversities of microbiota as well as enriched metabolic pathways were altered after leucine supplementation. Firmicutes-Bacteroidetes ratio was significantly decreased in high-leucine group. Moreover, pyruvate fermentation to propanoate I were negatively associated with differential species and the pyruvate levels were significantly increased in feces after high dose of leucine supplementation. Conclusions: Chronic high dose of leucine supplementation changed gut microbiota composition and increased pyruvate levels in the feces, which possibly provides a novel direction for promoting muscle health in aging mice.

The Protective Effect of Heme Oxygenase-1 on Liver Injury Caused by DON-Induced Oxidative Stress and Cytotoxicity.

Deoxynivalenol (DON) is a kind of Fusarium toxin that can cause a variety of toxic effects. Oxidative stress and DNA damage play a critical role in the toxicity of DON. However, previous studies focused more on acute toxicity in vivo/vitro models and lacked subchronic toxicity study in vivo. The potentially harmful effect of DON given at doses comparable to the daily human consumption in target organs, especially the liver, which is the main detoxification organ of DON, is also still not fully understood. Otherwise, Heme Oxygenase-1 (HO-1) has also reduced cell damage under the DON condition according to our previous study. Therefore, we used a rodent model that mimicked daily human exposure to DON and further explored its mechanism of toxic effects on liver tissue and Hepa 1-6 cell line. We also used adeno-associated virus (AAV)-modified HO-1 expressing by tail vein injection and constructed lentivirus-Hepa 1-6 cell line for mimicking HO-1 protective ability under the DON condition. The main results showed that both 30 d and 90 d exposures of DON could cause low-grade inflammatory infiltration around hepatic centrilobular veins. The reactive oxygen species (ROS) and 8-hydroxy-2 deoxyguanosine (8-OHdG) increased during DON exposure, indicating oxidation stress and DNA damage. Significantly, AAV-mediated liver-specific overexpression of HO-1 reduced DON-induced liver damage and indirectly protected the abilities of antioxidant enzyme/DNA damage repair system, while AAV-mediated silence of HO-1 produced the opposite effect. In addition, we found that overexpression of HO-1 could enhance autophagy and combined it with an antioxidant enzyme/DNA damage repair system to inhibit DON-induced hepatocyte damage. Altogether, these data suggest that HO-1 reduces the oxidative stress and DNA damage caused by DON sub-chronic exposure through maintaining DNA repair, antioxidant activity, as well as autophagy.

Narrative review on potential role of gut microbiota in certain substance addiction.

As a neuropsychiatric disorder, substance addiction represents a major public health issue with high prevalence and mortality in many countries. Recently, gut microbiota has been certified to play a part in substance addiction through various mechanisms. Hence, we mainly focused on three substance including alcohol, cocaine and methamphetamine in this review, and summarized their relationships with gut microbiota, respectively. Besides, we also concluded the possible treatments for substance addiction from the perspective of applying gut microbiota. This review aims to build a bridge between substance addiction and gut microbiota according to existing evidences, so as to excavate the possible bi-directional function of microbiota-gut-brain axis in substance addiction for developing therapeutic strategies in the future.

The association study between CYP24A1 gene polymorphisms and risk of liver, lung and gastric cancer in a Chinese population.

Recently, four single nucleotide polymorphisms (rs2585428, rs4809960, rs6022999 and rs6068816) in CYP24A1 gene were extensively studied for their associations with cancer risk. However, these studies included only a few types of cancer, which calls for further investigations. In view of this, we here conducted a case-control study to explore the associations between these four CYP24A1 gene polymorphisms and risk of liver, lung and gastric cancer in a Chinese population. A total of 480 liver cancer patients, 550 lung cancer patients, 460 gastric cancer patients and 800 normal controls were recruited in this study. The genotyping of CYP24A1 gene polymorphisms was applied with Sanger sequencing assay. Single-locus analysis demonstrated that rs6022999 was significantly associated with risk of liver and lung cancer, while rs6068816 was significantly associated with the risk of gastric cancer. Haplotype analysis revealed that haplotype GTAT was associated with an increased risk of liver cancer and a decreased risk of lung cancer, and haplotype ATGC was associated with a decreased risk of lung cancer. The further meta-analysis of rs6068816 and lung cancer risk showed that rs6068816 was not associated with lung cancer risk in Chinese population, which confirmed our present finding. Conclusively, rs6022999 may be a genetic biomarker for liver and lung cancer susceptibility in Chinese population, and rs6068816 may be used to predict gastric cancer risk in Chinese population.

Long noncoding RNA Gm20319, acting as competing endogenous RNA, regulated GNE expression by sponging miR-7240-5p to involve in deoxynivalenol-induced liver damage in vitro.

The regulatory effects of competing endogenous RNA (ceRNA) network have been highlighted on the occurrence and development of diseases. However, the effect of ceRNA network in liver with subchronic deoxynivalenol (DON) exposure has remained unclear so far. Here, lncRNA Gm20319-miR-7240-5p-GNE (glucosamine UDP-N-acetyl-2-epimerase/N-acetylmannosamine kinase) network was identified in DON exposed-liver tissues after DON exposure for 90 days. Subchronic DON exposure induced the mild inflammation in liver tissues. In DON-treated liver tissues and Hepa 1-6 cell line, the expression of Gm20319 and GNE were both downregulated while miR-7240-5p expression was upregulated. The gain- and loss-of-function expression in vitro revealed there was a mutual repression between Gm20319 and miR-7240-5p, and they regulated GNE expression in an opposite direction. Dual luciferase reporter assays showed miR-7240-5p inhibited Gm20319 and GNE expression by directly binding. Co-transfection experiment in vitro revealed Gm20319 and miR-7240-5p could indirectly regulate sialic acid level by directly modulating GNE expression, thereby also influencing the expression of SOD1 and IL-1ß. This study revealed Gm20319-miR-7240-5p-GNE network reduced sialic acid level to influence the expression of SOD1 and IL-1ß in liver, which might involve in liver damage induced by DON. Gm20319 might be a potential research molecular target for DON-induced liver damage.

The mechanisms and treatments for sarcopenia: could exosomes be a perspective research strategy in the future?

The age-related loss of muscle mass and muscle function known as sarcopenia is a primary contributor to the problems faced by the old people. Sarcopenia has been a major public health problem with high prevalence in many countries. The related underlying molecular mechanisms of sarcopenia are not completely understood. This review is focused on the potential mechanisms and current research strategies for sarcopenia with the aim of facilitating the recognition and treatment of age-related sarcopenia. Previous studies suggested that protein synthesis and degradation, autophagy, impaired satellite cell activation, mitochondria dysfunction, and other factors associated with muscle weakness and muscle degeneration may be potential molecular pathophysiology of sarcopenia. Importantly, we also prospectively highlight that exosomes (small vesicles) as carriers can regulate muscle regeneration and protein synthesis according to recent researches. Dietary strategies and exercise represent the interventions that can also alleviate the progression of sarcopenia. At last, building on recent studies pointing to exosomes with the roles in increasing muscle regeneration, mediating the beneficial effects of exercise, and serving as messengers of intercellular communication and as carriers for research strategies of many diseases, we propose that exosomes could be a potential research direction or strategies of sarcopenia in the future.

Heme oxygenase-1 regulates autophagy through carbon-oxygen to alleviate deoxynivalenol-induced hepatic damage.

Deoxynivalenol (DON) cannot be totally removed due to its stable chemical characteristics and chronic exposure to low doses of DON causes significant toxic effects in humans and animals. However, the potential hazard of such low-dose exposure in target organs still remains not completely understood, especially in liver, which is mainly responsible for detoxification of DON. In the present study, we demonstrated for the first time that estimated human daily DON exposure (25 µg/kg bw) for 30 and 90 days caused low-grade inflammatory infiltration around hepatic centrilobular veins, elevated systemic IL-1ß, IL-6 and TNF-α and impaired liver function evidenced by increased serum ALT activity. At the molecular level, expressions of autophagy-related proteins as well as Cleaved Caspase-3 and Cleaved Caspase-7 were upregulated during DON exposure, which indicated the activation of autophagy and apoptosis. Importantly, AAV-mediated liver-specific overexpression of HO-1 reversed DON-induced liver damages, upregulated autophagy and attenuated apoptosis in liver, while AAV-mediated HO-1 silence aggravated DON-induced liver damages, inhibited autophagy and increased apoptosis. Furthermore, in vitro experiments demonstrated that lentivirus-mediated HO-1 overexpression in Hepa 1-6 cells prolonged the duration of autophagy and delayed the onset of apoptosis. HO-1 silence in Hepa 1-6 cells inhibited activation of autophagy and accelerated occurrence of apoptosis, and these could be recovered by CO pre-treatment. Therefore, we suppose that HO-1 might be a potential research target to protect human and animal from liver injuries induced by low dose of DON exposure.