Ampicillin exacerbates acetaminophen-induced acute liver injury by inducing intestinal microbiota imbalance and butyrate reduction.

BACKGROUND AND AIMS: Antibiotics (ATBx) and acetaminophen (APAP) are widely used worldwide. APAP is the most common cause of acute liver injury (ALI) and might be used in combination with ATBx in clinics. However, the impact of ATBx on APAP-induced ALI has rarely been studied. METHODS: First, we compared the effects of seven ATBx on APAP-induced ALI. Then, we analysed faecal, serum and liver samples to investigate the impact of the gut microbiota on this process. Finally, we assessed the role of short-chain fatty acids in this process. RESULTS: In this work, we found that the ALI was significantly aggravated in the mice treated with ampicillin (Amp) instead of other ATBx. Amp exposure reduced the diversity and altered the composition of gut microbiota. The altered gut microbiota aggravated APAP-induced ALF, which was proven by faecal microbiota transplantation from ATBx-treated mice. Metagenomic analysis showed a significantly decreased Lactobacillus abundance in Amp-treated mice. Gavage with Lactobacillus, especially Lactobacillus rhamnosus, significantly reversed the severer ALF induced by APAP and Amp. Moreover, Lactobacillus supplementation increased butyrate-producing clostridia and lowered butyrate levels in Amp-treated mice. In accordance, butyrate supplementation could also alleviate Amp-aggravated ALI. In addition, inhibition of nuclear factor erythroid 2-related factor 2 counteracted the protective effect of butyrate on aggravated ALI induced by Amp and APAP. CONCLUSION: Together, this study revealed a potential health impact of Amp that may exacerbate liver damage when co-exposed to excess APAP.

Host ALDH2 deficiency aggravates nonalcoholic steatohepatitis through gut-liver axis.

Nonalcoholic steatohepatitis (NASH) is the major cause of liver dysfunction. Animal and population studies have shown that mitochondrial aldehyde dehydrogenase (ALDH2) is implicated in fatty liver disease. However, the role of ALDH2 in NASH and the underlying mechanisms remains unclear. To address this issue, ALDH2 knockout (ALDH2-/-) mice and wild-type littermate mice were fed a methionine-and choline-deficient (MCD) diet to induce a NASH model. Fecal, serum, and liver samples were collected and analyzed to investigate the impact of the gut microbiota and bile acids on this process. We found that MCD-fed ALDH2-/- mice exhibited increased serum pro-inflammation cytokines, hepatic inflammation and fat accumulation than their wild-type littermates. MCD-fed ALDH2-/- mice exhibited worsened MCD-induced intestinal inflammation and barrier damage, and gut microbiota disorder. Furthermore, mice receiving microbiota from MCD-fed ALDH2-/- mice had increased severity of NASH compared to those receiving microbiota from MCD-fed wild-type mice. Notably, the intestinal Lactobacillus was significantly reduced in MCD-fed ALDH2-/- mice, and gavage with Lactobacillus cocktail significantly improved MCD-induced NASH. Finally, we found that ALDH2-/- mice had reduced levels of bile salt hydrolase and specific bile acids, especially lithocholic acid (LCA), accompanied by downregulated expression of the intestinal FXR-FGF15 pathway. Supplementation of LCA in ALDH2-/- mice upregulated intestinal FXR-FGF15 pathway and alleviated NASH. In summary, ALDH2 plays a critical role in the development of NASH through modulation of gut microbiota and bile acid. The findings suggest that supplementing with Lactobacillus or LCA could be a promising therapeutic approach for treating NASH exacerbated by ALDH2 deficiency.

An Energy-Restricted Diet Including Yogurt, Fruit, and Vegetables Alleviates High-Fat Diet-Induced Metabolic Syndrome in Mice by Modulating the Gut Microbiota.

BACKGROUND: The importance of the composition of an energy-restricted diet in the treatment of metabolic syndrome (MetS) is unknown. OBJECTIVES: In this study we aimed to investigate the benefits of a novel dietary treatment (50% calorie restriction diet composed of yogurt, fruit, and vegetables [CR-YD]) in mice with MetS. METHODS: Forty 7-wk-old male C57BL/6 J mice were randomly assigned to 4 groups (n = 10/group) that were fed for 14 wk ad libitum with a normal diet (ND; 10%:70%:20% energy from fat: carbohydrate: protein) or for 12 wk with a high-fat diet (HFD; 60:20:20) or the HFD followed by 2 wk of feeding with a 50% calorie-restricted HFD (CR-HFD) or YD (CR-YD, 21.2%:65.4%:13.4% energy). Body weight, fat deposition, hepatic steatosis, serum concentrations of inflammatory biomarkers, and glucose homeostasis were assessed. Fecal microbiota transplantation (FMT) was used to validate the roles of gut microbiota in MetS. RESULTS: The HFD group had 50% greater body weight and 475% greater fat deposition than the ND group (P < 0.05). Compared with the HFD group, the CR-HFD and CR-YD groups had 22% and 31% lower body weight and 49% and 75% less fat deposition, respectively (P < 0.05). Compared with the CR-HFD group, the CR-YD group had 11% lower body weight, 96% less fat deposition, 500% less hepatic steatosis, 75% lower glucose, and 450% more hepatic Akkermansia bacteria (P < 0.05). The CR-YD group also had 50% lower histopathology scores and 1.35-fold higher levels of Claudin4 than the CR-HFD group (P < 0.05). The HFD + CR-YD fecal group had 10.6% lower body weight, 119% lower steatosis, and 17.9% lower glucose (P < 0.05) than the HFD + CR-HFD fecal group. CONCLUSIONS: Compared with CR alone, the CR-YD diet has a better therapeutic effect in mice with HFD-induced MetS.

Calorie restriction conferred improvement effect on long-term rehabilitation of ischemic stroke via gut microbiota.

Calorie restriction can modulate the gut microbiota and protect against many diseases including ischemic stroke. However, the role of calorie-restriction-induced microbiota alteration remained unknown in ischemic stroke rehabilitation. Here we conducted 30% reduction of caloric intake on mice for four weeks, to evaluate its role on ischemic stroke rehabilitation. Significantly, this calorie restriction led to better long-term rehabilitation in comparison of normal control. Notably, the transplantation of gut microbiome from calorie-restriction-treated mice to post-stroke mice was eligible to obtain better long-term rehabilitation of stroke mice. Bifidobacterium identified by 16 S ribosomal RNA sequencing were enriched in those of calorie-restriction mice. Then we administrated Bifidobacterium to stroke mice and found Bifidobacterium treatment could successfully improve the long-term rehabilitation of cerebral ischemia mice. Furthermore, the metabolomics analysis revealed a panel of upshifting metabolites, suggesting that calorie restriction greatly altered the gut microbiota composition and its metabolism. Hence, we discovered the novel effect of CR on long-term rehabilitation of ischemic stroke and the underlying role of gut microbiota, which might provide novel thoughts for the clinical post-stroke rehabilitation.

Alcohol and HBV synergistically promote hepatic steatosis.

BACKGROUND AND AIMS: Hepatitis virus and alcohol are the main factors leading to liver damage. Synergy between hepatitis B virus (HBV) and alcohol in promoting liver cell damage and disease progression has been reported. However, the interaction of HBV and ethanol in hepatic steatosis development has not been fully elucidated. METHODS: Eight-week-old male C57BL/6 mice were treated with or without HBV, ethanol, or the combination of HBV and ethanol (HBV+EtOH), followed by a three-week high-fat diet (HFD) regimen. Liver histology, serum biomarkers, and liver triglyceride levels were analysed. Furthermore, a meta-analysis of the effects of alcohol and HBV on hepatic steatosis in populations was performed. RESULTS: Hepatic steatosis was significantly more severe in the HBV+EtOH group than in the other groups. The serum alanine aminotransferase, aspartate aminotransferase and liver triglyceride levels in the HBV+EtOH group were also significantly higher than those in the other groups. The HBeAg and HBsAg levels in the HBV+EtOH group were significantly higher than those in the pair-fed HBV-infected mice. In addition, the meta-analysis showed that alcohol consumption increased the risk of hepatic steatosis by 43% in HBV-infected patients (pooled risk ratio (RR)=1.43, P<0.01). CONCLUSIONS: Alcohol and HBV synergistically promote high-fat diet-induced hepatic steatosis in mice. In addition, alcohol consumption increases the risk of hepatic steatosis in HBV-infected patients.

The ALDH2 gene rs671 polymorphism is not associated with essential hypertension.

Essential hypertension (EH) is a worldwide problem. Acetaldehyde dehydrogenase 2 (ALDH2) gene has been suggested to be correlated with EH. However, the results are inconsistent. This study aimed to investigate the associations of ALDH2 rs671 polymorphism with EH in a Chinese Han population in Shanghai. Genotype of ALDH2 rs671 was analyzed in 1923 EH patients and 1115 control subjects. We found no association between ALDH2 rs671 and EH risk or EH-related quantitative blood chemistry values. Furthermore, a meta-analysis was performed and the summary results from 11220 patients and 8339 control subjects were consistent with our findings. These results indicated that rs671 of ALDH2 may not associate with the risk of EH.

Annonaceous acetogenins mimic AA005 targets mitochondrial trifunctional enzyme alpha subunit to treat obesity in male mice.

Obesity and related diseases pose a major health risk, yet current anti-obesity drugs inadequately addressing clinical needs. Here we show AA005, an annonaceous acetogenin mimic, resists obesity induced by high-fat diets and leptin mutations at non-toxic doses, with the alpha subunit of the mitochondrial trifunctional protein (HADHA) as a target identified through proteomics and in vitro validation. Pharmacokinetic analysis shows AA005 enriches in adipose tissue, prompting the creation of adipose-specific Hadha-deficient mice. These mice significantly mitigate diet-induced obesity, echoing AA005's anti-obesity effects. AA005 treatment and Hadha deletion in adipose tissues increase body temperature and energy expenditure in high-fat diet-fed mice. The beneficial impact of AA005 on obesity mitigation is ineffective without uncoupling protein 1 (UCP1), essential for thermogenesis regulation. Our investigation shows the interaction between AA005 and HADHA in mitochondria, activating the UCP1-mediated thermogenic pathway. This substantiates AA005 as a promising compound for obesity treatment, targeting HADHA specifically.

Fecal microbiome transplant from patients with lactation mastitis promotes mastitis in conventional lactating mice.

Introduction: Lactation mastitis seriously severely affects the health of lactating females and their infants, yet the underlying causes of clinical lactation mastitis remain unclear. Methods: In this study, we used microbiota-humanized mice as a model to investigate the role of gut microbiota in lactation mastitis. We compared the fecal microbiota of lactation mastitis patients and healthy individuals and conducted fecal microbiota transplantation (FMT) experiments in an antibiotic-pretreated mouse model to test whether gut microbes contribute to human lactation mastitis. Results: Our results showed that gut microbiota diversity was reduced and dysbiosis was present in lactating mastitis patients. FMT from lactation mastitis patients (M-FMT), but not from healthy individuals (H-FMT), to antibiotic-treated mice resulted in lactation mastitis. The inflammation in mice caused by gut microbiota from lactating mastitis patients appears to be pervasive, as hepatocytes from mice that received feces from lactating mastitis patients showed marked swelling. In addition, serum pro-inflammatory factors, including IL-4, IL-17, MPO, IL-6, IL-1ß, and TNF-α, were significantly increased in the M-FMT group. The Firmicutes/Bacteroidetes ratio (F/B), a biomarker of gut dysbiosis, was significantly increased in the M-FMT group. At the phylum level, Actinobacteria were significantly increased, and Verrucomicrobia were significantly decreased in the M-FMT group. At the genus level, Ruminococcus and Faecalibacterium were significantly reduced, while Parabacteroides were significantly increased in the feces of both patients with lactation mastitis and M-FMT mice. Moreover, our study revealed an "amplification effect" on microbiota differences and mastitis disease following human-to-mouse FMT. Conclusion: Collectively, our findings demonstrate that the gut microbiota in lactating mastitis patients is dysbiotic and contributes to the pathogenesis of mastitis.

The antitumour effects of caloric restriction are mediated by the gut microbiome.

Calorie restriction (CR) and intermittent fasting (IF) without malnutrition reduce the risk of cancer development. Separately, CR and IF can also lead to gut microbiota remodelling. However, whether the gut microbiota has a role in the antitumour effect related to CR or IF is still unknown. Here we show that CR, but not IF, protects against subcutaneous MC38 tumour formation through a mechanism that is dependent on the gut microbiota in female mice. After CR, we identify enrichment of Bifidobacterium through 16S rRNA sequencing of the gut microbiome. Moreover, Bifidobacterium bifidum administration is sufficient to rescue the antitumour effect of CR in microbiota-depleted mice. Mechanistically, B. bifidum mediates the CR-induced antitumour effect through acetate production and this effect is also dependent on the accumulation of interferon-γ+CD8+ T cells in the tumour microenvironment. Our results demonstrate that CR can modulate the gut taxonomic composition, which should be of oncological significance in tumour growth kinetics and cancer immunosurveillance.

Lacticaseibacillus paracasei sh2020 induced antitumor immunity and synergized with anti-programmed cell death 1 to reduce tumor burden in mice.

The gut microbiota was emerging as critical regulatory elements in shaping the outcome of cancer immunotherapy. However, the underlying mechanisms by which the gut commensal species enhance antitumor immunity remain largely unexplored. Here, we show that the gut microbiota from healthy individuals conferred considerable sensitivity to anti-PD-1 in the colorectal cancer (CRC) tumor-bearing mice, whereas gut microbiota from CRC patients failed to do so. By 16S rRNA gene sequencing, we identified Lactobacillus that was significantly increased in the mice with good response to anti-PD-1, and significantly correlated with anti-tumor immunity. After a series of screening, we isolated a novel Lacticaseibacillus strain, named L. paracasei sh2020. L. paracasei sh2020 showed the most notable anti-tumor immunity in the mice with gut dysbiosis. Mechanistically, the antitumor immune response elicited by L. paracasei sh2020 was dependent on CD8+ T cell. In vitro and in vivo studies revealed that L. paracasei sh2020 stimulation triggered the upregulated expression of CXCL10 in the tumors and subsequently enhanced CD8+ T cell recruitment. Meanwhile, the modulation of gut microbiota caused by L. paracasei sh2020 enhanced its antitumor effect and gut barrier function. Overall, our study offered novel insights into the mechanism by which gut microbiota shaped the outcome of cancer immunotherapy and, more importantly, the novel strain L. paracasei sh2020 might serve as an easy and effective way to promote anti-PD-1 effect in clinical practice.

Probiotic yogurt blunts the increase of blood pressure in spontaneously hypertensive rats via remodeling of the gut microbiota.

Dietary intake of probiotic yogurt, which has beneficial effects on intestinal microecology, is associated with a lower incidence of hypertension. Recent studies have shown that the gut microbiota plays a vital role in the development of hypertension. However, the impact of the gut microbiota in the antihypertensive effect of probiotic yogurt remains unclear. Here, we evaluated the impact of the gut microbiota in the antihypertensive effect of probiotic yogurt in spontaneously hypertensive rats (SHR). SHR were treated with probiotic yogurt (0.2 mL per 100 g body weight) (SHR-Y group) for seven weeks and compared with whole milk-treated (0.2 mL per 100 g body weight) SHR (SHR group) and with normotensive Wistar-Kyoto rats (WKY group). The blood pressure and heart function of the rats in the WKY, SHR, and SHR-Y groups were measured. Fecal microbiota was assessed by 16S ribosomal RNA (16S rRNA) gene sequencing. To investigate whether probiotic yogurt prevents hypertension in spontaneously hypertensive rats through the gut microbiota, we co-housed SHR rats (SHRCOH) with SHR-Y rats (SHRCOH-Y), thus allowing the transfer of microbiota via coprophagy. Compared with whole milk, supplementation of probiotic yogurt significantly reduced the blood pressure, heart rate (HR), and cardiac function. We found that the probiotic yogurt modified the gut microbiota populations and increased the alpha diversity. Gut microbiota remodeling by co-housing partly rescued the increase of blood pressure and impaired the cardiac function of SHR rats. Moreover, probiotic yogurt modulated the gut microbiota in mice by increasing the abundance of short-chain fatty acid (SCFA)-producing bacteria and SCFA levels (acetic acid, propionic acid, butyric acid, and valeic acid) in the feces. Together, the presented data revealed that probiotic yogurt exhibited antihypertensive effects in SHR rats via remodeling of the gut microbiota.

Pectin supplement significantly enhanced the anti-PD-1 efficacy in tumor-bearing mice humanized with gut microbiota from patients with colorectal cancer.

Background: Anti-PD-1-based immunotherapy has emerged as a promising therapy for several cancers. However, it only benefits a small subset of colorectal cancer (CRC) patients. Mounting data supports the pivotal role of gut microbiota in shaping immune system. Pectin, a widely consumed soluble fiber, has been reported to ameliorate the imbalance of gut microbiota. Therefore, we aimed to explore the effect and the underlying mechanisms of pectin in improving anti-PD-1 mAb efficacy. Methods: The C57BL/6 mice were treated with a broad-spectrum antibiotic (ATB) cocktail to depleted endogenous gut microbiota and subsequently humanized with feces from healthy controls or newly diagnosed CRC patients. The antitumor efficacies of anti-PD-1 mAb combined with or without pectin were assessed using these mice. Flow cytometry and immunohistochemistry (IHC) were conducted to investigate the tumor immune microenvironment after treatment. The gut microbiota profiles and short-chain fatty acids (SCFAs) levels were determined by 16S ribosomal RNA (16S rRNA) gene sequencing and gas chromatography-mass spectrometry (GC-MS), respectively. The effect of gut microbiota on anti-PD-1 mAb efficacy after pectin supplement was further tested by fecal microbiota transplantation (FMT). Results: The anti-PD-1 mAb efficacy was largely impaired in the mice humanized with feces from newly diagnosed CRC patients compared to those from healthy controls. However, pectin significantly enhanced the anti-PD-1 mAb efficacy in the tumor-bearing mice humanized with CRC patient gut microbiota. Flow cytometry and IHC analysis revealed increased T cell infiltration and activation in the tumor microenvironment of mice treated with anti-PD-1 mAb plus pectin. In vivo depletion of CD8+ T cells diminished the anti-tumor effect of anti-PD-1 mAb combined with pectin. 16S rRNA gene sequencing showed that pectin significantly increased gut microbial diversity and beneficially regulated microbial composition. In addition, we identified unique bacterial modules that were significantly enriched in the anti-PD-1 mAb + pectin group, which composed of butyrate-producing bacteria indicative of good response to immunotherapy. Meanwhile, GC-MS showed that pectin altered the level of SCFA butyrate. Furthermore, butyrate, a main product of dietary fiber in gut microbial fermentation, was found to be sufficient to promote T cells infiltration and thus enhance the efficacy of anti-PD-1 mAb. In addition, FMT demonstrated the effects of pectin were dependent on gut microbiota. Importantly, the beneficial effects of pectin were confirmed in the mice humanized with gut microbiota from patient with resistance to anti-PD-1 mAb. Conclusion: Pectin facilitated the anti-PD-1 mAb efficacy in CRC via regulating the T cell infiltration in the tumor microenvironment, which was potentially mediated by the metabolite butyrate.

Low EGR1 expression predicts poor prognosis in clear cell renal cell carcinoma.

Clear cell renal cell carcinoma (ccRCC) is resistant to conventional therapy due to the deletion of the von Hippel-Lindau (VHL) gene, and novel treatment options are urgently needed. Here, using tissue microarray analysis of 445 cancer tissues and 326 adjacent normal renal tissues obtained from patients with ccRCC, we present the early growth response-1 (EGR1) protein levels are significantly decreased in ccRCC cancer tissues. Consistently, the EGR1 mRNA expression also decreased in cancer tissues based on the transcriptomic data for 599 tumor and normal samples from The Cancer Genome Atlas. Moreover, Patients with ccRCC presenting low EGR1 expression are more prone to exhibit metastasis and a poor prognosis than those with high EGR1 expression. By multivariate Cox regression analysis, EGR1 is determined to serve as an independent prognostic factor for patients with ccRCC. Further cellular biochemical function analyses show that EGR1 may inhibit proliferation, invasion and metastasis of ccRCC. These findings will deepen our understanding of EGR1 function and shed light on precise treatment for ccRCC patients.

Gut and Cutaneous Microbiome Featuring Abundance of Lactobacillus reuteri Protected Against Psoriasis-Like Inflammation in Mice.

BACKGROUND: Psoriasis is a chronic autoinflammatory skin disease, and its aetiology remains incompletely understood. Recently, gut microbial dysbiosis is found to be tightly associated with psoriasis. OBJECTIVE: We sought to reveal the causal role of gut microbiota dysbiosis in psoriasis pathogenesis and investigate the protective effect of healthy commensal bacteria against imiquimod -induced psoriasis-like skin response. METHODS: By using fecal microbial transplantation (FMT), 16S rRNA gene-based taxonomic profiling and Lactobacillus supplement, we have assessed the effect of FMT from healthy individuals on psoriasis-like skin inflammation and associated immune disorders in imiquimod-induced psoriasis mice. RESULTS: Here, by using psoriasis mice humanized with the stools from healthy donors and psoriasis patients, the imiquimod-induced psoriasis in mice with psoriasis patient stool was found to be significantly aggravated as compared to the mice with healthy donor stools. Further analysis showed fecal microbiota of healthy individuals protected against Treg/Th17 imbalance in psoriasis. Moreover, we found the gut and skin microbiome in mice receipted with gut microbiota of healthy individuals (HD) differed from those of mice receipted with gut microbiota of psoriasis patients (PSD). 16S rRNA sequencing revealed that Lactobacillus reuteri was greatly enriched in fecal and cutaneous microbiome of HD mice as compared to PSD mice. Intriguingly, supplement with Lactobacillus reuteri was sufficient to increase the expression of anti-inflammatory gene IL-10, reduce Th17 cells counts and confer resistance to imiquimod-induced inflammation on the mice with gut microbiota dysbiosis. CONCLUSION: Our results suggested that the gut microbiota dysbiosis is the potential causal factor for psoriasis and the gut microbiota may serve as promising therapy target for psoriasis patients.

An approach using Caenorhabditis elegans screening novel targets to suppress tumour cell proliferation.

OBJECTIVES: Tumour cell proliferation requires high metabolism to meet the bioenergetics and biosynthetic needs. Dauer in Caenorhabditis elegans is characterized by lower metabolism, and we established an approach with C elegans to find potential tumour therapy targets. MATERIALS AND METHODS: RNAi screening was used to find dauer-related genes, and these genes were further analysed in glp-1(-) mutants for tumour-suppressing testing. The identified tumour-related genes were verified in clinical tumour tissues. RESULTS: The lifespan of glp-1(-) mutants was found to be extended by classical dauer formation signalling. Then, 61 of 287 kinase-coding genes in Caenorhabditis elegans were identified as dauer-related genes, of which 27 were found to be homologous to human oncogenes. Furthermore, 12 dauer-related genes were randomly selected for tumour-suppressing test, and six genes significantly extended the lifespan of glp-1(-) mutants. Of these six genes, F47D12.9, W02B12.12 and gcy-21 were newly linked to dauer formation. These three new dauer-related genes significantly suppressed tumour cell proliferation and thus extended the lifespan of glp-1(-) mutants in a longevity- or dauer-independent manner. The mRNA expression profiles indicated that these dauer-related genes trigged similar low metabolism pattern in glp-1(-) mutants. Notably, the expression of homolog gene DCAF4L2/F47D12.9, TSSK6/W02B12.12 and NPR1/gcy-21 was found to be higher in glioma compared with adjacent normal tissue. In addition, the high expression of TSSK6/W02B12.12 and NPR1/gcy-21 correlated with a worse survival in glioma patients. CONCLUSIONS: Dauer gene screening in combination with tumour-suppressing test in glp-1(-) mutants provided a useful approach to find potential targets for tumour therapy via suppressing tumour cell proliferation and rewiring tumour cell metabolism.

The up-regulation of NDRG1 by HIF counteracts the cancer-promoting effect of HIF in VHL-deficient clear cell renal cell carcinoma.

BACKGROUND: Hypoxia-inducible factors (HIFs) are thought to play important roles in the carcinogenesis and progression of VHL-deficient clear cell renal cell carcinoma (ccRCC). METHODS: The roles of HIF-1/2α in VHL-deficient clear cell renal cell carcinoma were evaluated by bioinformatics analysis, immunohistochemistry staining and Kaplan-Meier survival analysis. The downstream genes that counteract the cancer-promoting effect of HIF were analysed by unbiased proteomics and verified by in vitro and in vivo assays. RESULTS: There was no correlation between the high protein level of HIF-1/2α and the poor prognosis of ccRCC patients in our large set of clinical data. Furthermore, NDRG1 was found to be up-regulated by both HIF-1α and -2α at the cellular level and in ccRCC tissues. Intriguingly, the high NDRG1 expression was correlated with lower Furman grade, TNM stage and longer survival for ccRCC patients compared with the low NDRG1 expression. In addition, NDRG1 suppressed the expression of series oncogenes as well as the proliferation, metastasis and invasion of VHL-deficient ccRCC cells in vitro and vivo. CONCLUSIONS: Our study demonstrated that HIF downstream gene of NDRG1 may counteract the cancer-promoting effect of HIF. These results provided evidence that NDRG1 may be a potential prognostic biomarker as well as a therapeutic target in ccRCC.

Diet Consisting of Balanced Yogurt, Fruit, and Vegetables Modifies the Gut Microbiota and Protects Mice against Nonalcoholic Fatty Liver Disease.

BACKGROUND: Calorie restriction (CR) is a therapeutically effective method for nonalcoholic fatty liver disease. However, the compliance of the CR method is relatively poor. New CR methods are needed. METHODS AND RESULTS: Each week, mice are given a 5-day high-fat diet (HFD) ad libitum plus 2 days of an intermittent calorie restriction (ICR) diet (50% calorie restriction) consisting of yogurt, fruit, and vegetables, for 16 weeks. The effect of the ICR diet model on the fatty liver of mice is examined. Compared with continuous HFD-fed mice, the mice feeding HFD+ICR have lower body weight and hepatic steatosis, reduced serum lipid and transaminase levels, increased fatty acid oxidation gene of Cpt1a, and decreased hepatic lipid synthesis gene of Pparγ and Srebf-1c, as well as improved insulin resistance and lower level of inflammation. Moreover, ICR reverses the dysbacteriosis in HFD group, including the lower Shannon diversity indexes and lower abundance of Lactobacillus. CONCLUSION: An ICR diet consisting of yogurt, fruit, and vegetables attenuates the development of HFD-induced hepatic steatosis in mice. Furthermore, HFD+ICR diet is associated with a different fecal microbiota that tends to be more similar to normal diet controls.

Circulating thyroid stimulating hormone receptor messenger RNA and differentiated thyroid cancer: A diagnostic meta-analysis.

Thyroid stimulating hormone receptor messenger RNA (TSHR-mRNA) is over-expressed in thyroid cancer patients, which indicates that TSHR-mRNA is a potential biomarker of thyroid cancer. However, system evaluation for TSHR-mRNA as a diagnostic biomarker of thyroid cancer is deficient. The performance of TSHR-mRNA for thyroid cancer diagnosis was evaluated in this study. Three common international databases as well as a Chinese database were applied for literature researching. Quality assessment of the included literatures was conducted by the QUADAS-2 tool. Totally, 1027 patients from nine studies eligible for the meta-analysis were included in this study. Global sensitivity and specificity for the positivity of TSHR-mRNA in the thyroid cancer diagnosis is 72% and 82%. The value of AUC for this test performance was 0.84. Our meta-analysis suggests that TSHR-mRNA might be a potential biomarker to complete present diagnostic methods for early and precision diagnosis of thyroid cancer. Notably, this findings need validation thorough large-scale clinical studies.