Targeting the alternative bile acid synthetic pathway for metabolic diseases

The gut microbiota is profoundly involved in glucose and lipid metabolism, in part by regulating bile acid (BA) metabolism and affecting multiple BA-receptor signaling pathways. BAs are synthesized in the liver by multi-step reactions catalyzed via two distinct routes, the classical pathway (producing the 12α-hydroxylated primary BA, cholic acid), and the alternative pathway (producing the non-12α-hydroxylated primary BA, chenodeoxycholic acid). BA synthesis and excretion is a major pathway of cholesterol and lipid catabolism, and thus, is implicated in a variety of metabolic diseases including obesity, insulin resistance, and nonalcoholic fatty liver disease. Additionally, both oxysterols and BAs function as signaling molecules that activate multiple nuclear and membrane receptor-mediated signaling pathways in various tissues, regulating glucose, lipid homeostasis, inflammation, and energy expenditure. Modulating BA synthesis and composition to regulate BA signaling is an interesting and novel direction for developing therapies for metabolic disease. In this review, we summarize the most recent findings on the role of BA synthetic pathways, with a focus on the role of the alternative pathway, which has been under-investigated, in treating hyperglycemia and fatty liver disease. We also discuss future perspectives to develop promising pharmacological strategies targeting the alternative BA synthetic pathway for the treatment of metabolic diseases.

Gut microbiota alterations are distinct for primary colorectal cancer and hepatocellular carcinoma

Colorectal cancer (CRC) and hepatocellular carcinoma (HCC) are the second and third most common causes of death by cancer, respectively. The etiologies of the two cancers are either infectious insult or due to chronic use of alcohol, smoking, diet, obesity and diabetes. Pathological changes in the composition of the gut microbiota that lead to intestinal inflammation are a common factor for both HCC and CRC. However, the gut microbiota of the cancer patient evolves with disease pathogenesis in unique ways that are affected by etiologies and environmental factors. In this review, we examine the changes that occur in the composition of the gut microbiota across the stages of the HCC and CRC. Based on the idea that the gut microbiota are an additional "lifeline" and contribute to the tumor microenvironment, we can observe from previously published literature how the microbiota can cause a shift in the balance from normal → inflammation → diminished inflammation from early to later disease stages. This pattern leads to the hypothesis that tumor survival depends on a less pro-inflammatory tumor microenvironment. The differences observed in the gut microbiota composition between different disease etiologies as well as between HCC and CRC suggest that the tumor microenvironment is unique for each case.

The mediating effects of self-control and rumination between neuroticism and insomnia in college students / 中华行为医学与脑科学杂志

Objective:To explore the mediating effects of self-control and rumination between neuroticism and insomnia in college students.Methods:A cross-sectional survey was conducted among 767 college students from a university in Sichuan province with Chinese big five personality inventory-15, insomnia severity index, ruminative responses scale, and self-control scale.Results:The prevalence of insomnia was 36.6% among college students.The scores of neuroticism (9.63±3.41), rumination (22.27±5.44) and ISI (6.61±4.28) were positively correlated with each other ( r=0.281-0.389, P<0.01), while each of them was negatively correlated ( r=-0.453--0.194, all P<0.01) with self-control (60.71±9.41). Analysis of mediating effects revealed that neuroticism not only directly affected insomnia, but also indirectly affected insomnia through the mediating effects of rumination and self-control respectively. Conclusion:Self-control and rumination have mediating effects between neuroticism and insomnia in college students.

Intranasal Administration of Oxytocin Attenuates Stress Responses Following Chronic Complicated Stress in Rats

BACKGROUND/AIMS: Gastrointestinal (GI) symptoms may develop when we fail to adapt to various stressors of our daily life. Central oxytocin (OXT) can counteract the biological actions of corticotropin-releasing factor (CRF), and in turn attenuates stress responses. Administration (intracerebroventricular) of OXT significantly antagonized the inhibitory effects of chronic complicated stress (CCS) on GI dysmotility in rats. However, intracerebroventricular administration is an invasive pathway. Intranasal administration can rapidly deliver peptides to the brain avoiding stress response. The effects of intranasal OXT on hypothalamus-pituitary-adrenal axis and GI motility in CCS conditions have not been investigated. METHODS: A CCS rat model was set up, OXT 5, 10, or 20 μg were intranasal administered, 30 minutes prior to stress loading. Central CRF and OXT expression levels were analyzed, serum corticosterone and OXT concentrations were measured, and gastric and colonic motor functions were evaluated by gastric emptying, fecal pellet output, and motility recording system. RESULTS: Rats in CCS condition showed significantly increased CRF expression and corticosterone concentration, which resulted in delayed gastric emptying and increased fecal pellet output, attenuated gastric motility and enhanced colonic motility were also recorded. OXT 10 μg or 20 μg significantly reduced CRF mRNA expression and the corticosterone concentration, OXT 20 μg also helped to restore GI motor dysfunction induced by CCS. CONCLUSION: Intranasal administration of OXT has an anxiolytic effect and attenuates the hypothalamus-pituitary-adrenal axis in response to CCS, and gave effects which helped to restore GI dysmotility, and might be a new approach for the treatment of stress-induced GI motility disorders.

Calorie restriction and its impact on gut microbial composition and global metabolism / 医学前沿

Calorie restriction (CR) is a dietary regimen that reduces calorie intake without incurring malnutrition or a reduction in essential nutrients. It has long been recognized as a natural strategy for promoting health, extending longevity, and prevents the development of metabolic and age-related diseases. In the present review, we focus on the general effect of CR on gut microbiota composition and global metabolism. We also propose mechanisms for its beneficial effect. Results showed that probiotic and butyrate-producing microbes increased their relative abundance, whereas proinflammatory strains exhibited suppressed relative abundance following CR. Analyses of the gut microbial and host metabolisms revealed that most host microbial co-metabolites were changed due to CR. Examples of dramatic CR-induced changes in host metabolism included a decrease in the rate of lipid biosynthesis and an increase in the rates of fatty acid catabolism, β-oxidation, glycogenolysis, and gluconeogenesis. The observed phenotypes and the further verification of the direct link between gut microbiota and metabolome may benefit patients that are at risk for developing metabolic disease. Thus, improved gut microbiota composition and metabolome are potential biomarkers for determining the effectiveness of dietary interventions for age-related and metabolic diseases.

Research progress of the bidirectional interaction between gut microbiota and brain / 上海交通大学学报（医学版）

The gut-brain axis (GBA) is a nerve-endocrine mediated bidirectional communication system between the gut and brain, which links the cognition and emotion in brain to peripheral intestinal function. In recent years, many researches have showed that colonized intestinal microbiota plays an important role in the communication between gut and brain. On one hand, microbiota can influence the development and function of brain via GBA. On the other hand, brain can also change the composition of gut microbiota. These findings gradually become a novel medical research highlight, i.e. the microbiota-gut-brain axis. This paper reviews the interaction between gut microbiota and brain via GBA in order to provide supports for studying functions of gastrointestinal tract and brain, as well as the treatment of related diseases.

The Application of Metabolomics in Pharmacokinetics to Multicomponent Herbal Medicine / 世界科学技术-中医药现代化

The traditional approaches of pharmacokinetics (PK) focused on the dynamic changing process of single or several effective components of drugs in vivo,which was noted as limitations for the complexity studies on PK of multicomponent herbal medicine featuring multi-component,multi-target and multi-effect.It was turned into a bottleneck in the modernization process of traditional Chinese medicine,which could have made misunderstanding of pharmacological and toxicological knowledge of Chinese herbal medicine and its combination drugs.Owing to the advanced high-throughput platforms and various big data mining technology,metabolomics was capable for simultaneously detecting and depicting the variations of hundreds or even thousands of small molecules offering new opportunities for the PK studies on some complicated components.This review summarized recent PK studies over multicomponent drugs and chiefly introduced two remarkable applications to metabolomics in pharmacokinetics research,Chinmedomics and Poly-PK,integrating the theories of both metabolomics and traditional PK.The challenges and strengths of the two new strategies were also expounded.

NK4 growth inhibition of human Raji lymphoma xenografts by competitive interrupting HGF/Met signal pathway / 中华病理学杂志

<p><b>OBJECTIVE</b>To observe the inhibition of NK4 protein in the proliferation of human Raji lymphoma xenografts in nude mice, and to explore its molecular mechanism.</p><p><b>METHODS</b>Models of human Raji lymphoma xenograft transfected with HGF gene were established by subcutaneous inoculation in nude mice. After establishment of the models, the mice received continuous NK4 protein via tail vein for 4 weeks, and the weight and tumor growth were monitored every week. After 8 weeks, the expression of HGF mRNA and c-Met mRNA of tumor tissues was measured by real-time fluorescent quantitation PCR. The apoptotic index (AI) and microvessel density (MVD) were evaluated by terminal deoxynucleotidyl transferase-mediated nick end labeling (TUNEL) and immunohistochemistry, respectively.</p><p><b>RESULTS</b>The models of human Raji lymphoma xenograft were successfully established. Although the animal weights of all groups declined, especially in the groups with NK4 protein injection, there was no statistical significance (P > 0.05). The tumor volume in HGF gene transfected group was larger than those of the control groups (P < 0.01), and there was no statistical significance among the control groups (P > 0.05). However, the tumor volume of the NK4 protein injection group decreased significantly (P < 0.01). Expression of HGF mRNA and c-Met mRNA in HGF gene transfected group increased significantly after injection of NK4 protein (P < 0.01). AI in HGF gene transfected group (33.5% ± 12.3%) was significantly lower than that of control groups (89.1% ± 22.3% vs. 81.9% ± 27.0%, P < 0.05), but became significantly higher (119.1% ± 18.9%) after NK4 protein injection (P < 0.01). MVD in HGF gene transfected group (28.5 ± 2.0) was higher than that of control groups (12.2 ± 1.4, 13.8 ± 1.3, P < 0.01), although declined (15.5 ± 2.5) after NK4 protein injection (P < 0.01).</p><p><b>CONCLUSIONS</b>NK4 protein suppresses significantly the growth of human Raji lymphoma xenografts transfected with HGF gene. The pathogenesis may be involved in promoting tumor cell apoptosis and restraining tumor angiogenesis through competitive interrupting HGF/Met signal pathway.</p>

Expression, purification and preliminary activity study of recombinant hepatocyte growth factor protein in E.coli / 中华微生物学和免疫学杂志

Objective To prepare hepatocyte growth factor(HGF) recombinant protein and confirm its activity preliminarily according to building HGF gene prokaryotic expression vector and transforming into E.coli.Methods Clone HGF inserted into the vector pET-26b(+) to construct prokaryotic expression vector pET-26b(+)-HGF and transform into E.coli Rosseta(DE3).The transformed bacteria induced by IPTG was purified through Ni-NTA resin affinity chromatography frozen-drying after renaturation.Results HGF gene recombinant prokaryotic expression vector pET-26b(+)-HGF was constructed successfully.E.coli Rosseta(DE3) which was transformed into pET-26b(+)-HGF expresses the target protein as the form of inclusion bodies,accounting for 38％ of the total bacterial proteins,and confirmed by Western blot.HGF protein which was purified by Ni-NTA resin affinity chromatography,has a purity of about 95％,and can promote proliferation,migration,and inhibition of apoptosis for human non-small cell lung cancer cell line A549 cells after interaction.Conclusion HGF gene recombinant prokaryotic expression vector pET-26b (+)-HGF was constructed and expressed in transformed E.coli Rosseta(DE3) successfully.They resumed their recombinant HGF protein structure after purification and renaturation,and had biological activity confirmed by in vitro studies.