Crocin Ameliorates Diabetic Nephropathy through Regulating Metabolism, CYP4A11/PPARγ, and TGF-ß/Smad Pathways in Mice.

INTRODUCTION: Crocin is one of the main components of Crocus sativus L. and can alleviate oxidative stress and inflammation in diabetic nephropathy (DN). However, the specific mechanism by which crocin treats DN still needs to be further elucidated. METHOD: In the present study, a mouse model of DN was first established to investigate the therapeutic effect of crocin on DN mice. Subsequently, non-targeted metabolomics techniques were used to analyze the mechanisms of action of crocin in the treatment of DN. The effects of crocin on CYP4A11/PPARγ and TGF-ß/Smad pathway were also investigated. RESULT: Results showed that crocin exhibited significant therapeutic and anti-inflammatory, and anti-oxidative effects on DN mice. In addition, the non-targeted metabolomics results indicated that crocin treatment affected several metabolites in kidney. These metabolites were mainly associated with biotin metabolism, riboflavin metabolism, and arachidonic acid metabolism. Furthermore, crocin treatment upregulated the decreased levels of CYP4A11 and phosphorylated PPARγ, and reduced the increased levels of TGF-ß1 and phosphorylated Smad2/3 in the kidneys of DN mice. CONCLUSION: In conclusion, our study validated the considerable therapeutic, anti-inflammatory, and antioxidative impacts of crocin on DN mice. The mechanism of crocin treatment may be related to the regulation of biotin riboflavin and arachidonic acid metabolism, the activation of CYP4A11/PPARγ pathway, and the inhibition of TGF-ß/Smad pathway in the kidney.

Association between low blood selenium concentrations and poor hand grip strength in United States adults participating in NHANES (2011-2014).

The trace element selenium, which is found in selenoproteins, plays an antioxidant role in preventing muscle tissue injury. A positive association between selenium concentrations and hand grip strength has been reported in older adults; however, the evidence of this association is scarce in general adults. In this study, we aimed to evaluate the association between blood selenium concentrations and low hand grip strength using the data from the National Health and Nutrition Examination Survey 2011-2012 and 2013-2014 in the United States (US). Logistic regression was used to calculate the odds ratio (OR) of low hand grip strength, with blood selenium level adjusted for potential confounders. Among 8158 adults (women: 51.59%) with a mean age of 47 (range: 18-80) years, women and non-Hispanic Blacks tended to have low blood selenium concentrations. Notably, participants with high blood selenium concentrations (range, 178.1-192.5 µg/L) were more likely to have a low risk of low hand grip strength after adjusting for the potential covariates (OR: 0.60, 95% confidence interval (CI): 0.38-0.95) than those with low blood selenium concentrations. After excluding participants with chronic diseases, high blood selenium concentrations were found to be associated with a low risk of low hand grip strength (OR: 0.30, 95% CI: 0.14-0.65). A J-shaped relationship was found between selenium concentrations and low hand grip strength (P for nonlinear trend <0.0001). Subgroup analyses revealed a significantly consistent relationship among women, non-Hispanic Whites and others, and individuals with overweight or obesity (P < 0.05). Our study suggests that blood selenium concentrations are inversely associated with hand grip strength in general US adults. However, further prospective studies are required to confirm the causality between selenium concentrations and hand grip strength.

Sodium alginate and galactooligosaccharides ameliorate metabolic disorders and alter the composition of the gut microbiota in mice with high-fat diet-induced obesity.

We aimed to investigate the effects of sodium alginate (SA) and galactooligosaccharides (GOS) on the metabolism and gut microbiota of high-fat diet (HFD)-fed obese mice. GOS and SA delayed high-fat diet-induced obesity, reduced the epididymal fat and liver indices, and improved the circulating lipid profile. Low- and high-dose GOS reduced weight gain by 48.8 % and 35.3 %, and low- and high-dose SA reduced it by 37.7 % and 34.4 %, respectively. GOS and SA reduced blood glucose concentration, probably by increasing the expression of glucose transporter 4. GOS and SA increased the expression of tight junction proteins (ZO-1 and occludin), reduced the D-lactic acid (D-LA) and lipopolysaccharide concentrations, and reduced the expression of toll-like receptors, consistent with improved intestinal barrier function. GOS and SA also increased the abundance of Bacteroidota, Bifidobacterium, and Lactobacillus; and reduced that of Patescibacteria in the gut. The abundance of Parabacteroides positively correlated with the circulating low-density lipoprotein-cholesterol (LDL-C) concentration; that of Lactobacillus negatively correlated with LDL-C, D-LA, and tumor necrosis factor-α concentration; and that of Bifidobacterium positively correlated with high-density lipoprotein-cholesterol concentration, according to Spearman correlation analysis. In conclusion, SA and GOS ameliorate obesity and the associated metabolic disorders in mice, and also modulate their gut microbial composition.

Fucoidan Protects Against High-Fat Diet-Induced Obesity and Modulates Gut Microbiota in Institute of Cancer Research Mice.

Fucoidan possesses various biological activities, such as anticoagulant, immunomodulatory, anti-inflammatory, potential antioxidant, and others. In this study, we investigated the effect of fucoidan on high-fat diet-induced obesity, inflammation, and gut microbiota in Institute of Cancer Research mice. Mice were gavaged with 50 mg/(kg·d) (Fuc0.5 group) or 250 mg/(kg·d) (Fuc2.5 group) of fucoidan for 5 weeks. Fucoidan alleviated obesity and tissue damage by decreasing body weight and body mass index, decreasing body weight gain, improved organ index, liver steatosis, and improved the structure of the small intestine. In addition, fucoidan decreased total cholesterol, triglyceride, and low-density lipoprotein cholesterol, and increased high-density lipoprotein cholesterol. Moreover, fucoidan reduced serum lipopolysaccharide concentrations, tumor necrosis factor-α, and total bile acid. Furthermore, fucoidan improved the structure of gut microbiota and significantly increased the abundance (Shannon diversity index, evenness, and Faecalibacterium prausnitzii) determined by denaturing gradient gel electrophoresis and quantitative PCR. In conclusion, our study provides a scientific basis for fucoidan as a functional food for modulating the gut microbiota and protecting against obesity.

Ginsenoside Rb1 can ameliorate the key inflammatory cytokines TNF-α and IL-6 in a cancer cachexia mouse model.

BACKGROUND: Cancer cachexia is a severe condition that leads to the death of advanced cancer patients, and approximately 50~80% of cancer patients have cancer cachexia. Ginseng extract has been reported to have substantial anticancer and immune-enhancing effects; however, no study has reported the use of ginseng alone to treat cancer cachexia. Our study's purpose was to investigate the therapeutic effects of ginseng-related monomers or mixtures on a cancer cachexia mouse model. METHODS: We selected BALB/c mice and injected the mice subcutaneously with C26 colon cancer cells to construct a cancer cachexia experimental animal model. The water extract of ginseng (WEG), two types of ginseng extracts (ginsenosides at doses of 5 mg/kg (GE5) and 50 mg/kg (GE50)) and ginsenoside Rb1 (Rb1) were used to treat cancer cachexia mice. Enzyme-linked immunosorbent assays (ELISAs) were used to analyze the inhibitory effects on two key inflammatory cytokines, tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6). RESULTS: Our experimental results show that GE5, GE50 and Rb1 significantly reduced the levels of TNF-α (P < 0.01) and IL-6 (P < 0.01), which are closely related to cancer cachexia; however, WEG, GE5, GE50 and Rb1 did not significantly improve the gastrocnemius muscle weight or the epididymal fat weight of mice with cancer cachexia. CONCLUSIONS: These results indicate that GE5, GE50 and Rb1 may be useful for reducing symptoms due to inflammation by reducing the TNF-α and IL-6 cytokine levels in cancer cachexia mice, thereby ameliorating the symptoms of cancer cachexia. Our results may be beneficial for future studies on the use of Chinese herbal medicines to treat cancer cachexia.

Uncovering the Pharmacological Mechanism of Stemazole in the Treatment of Neurodegenerative Diseases Based on a Network Pharmacology Approach.

Stemazole exerts potent pharmacological effects against neurodegenerative diseases and protective effects in stem cells. However, on the basis of the current understanding, the molecular mechanisms underlying the effects of stemazole in the treatment of Alzheimer's disease and Parkinson's disease have not been fully elucidated. In this study, a network pharmacology-based strategy integrating target prediction, network construction, gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses, and molecular docking was adopted to predict the targets of stemazole relevant to the treatment of neurodegenerative diseases and to further explore the involved pharmacological mechanisms. The majority of the predicted targets were highly involved in the mitogen-activated protein kinase (MAPK) signaling pathway. RAC-alpha serine/threonine-protein kinase (AKT1), caspase-3 (CASP3), caspase-8 (CASP8), mitogen-activated protein kinase 8 (MAPK8), and mitogen-activated protein kinase 14 (MAPK14) are the core targets regulated by stemazole and play a central role in its anti-apoptosis effects. This work provides a scientific basis for further elucidating the mechanism underlying the effects of stemazole in the treatment of neurodegenerative diseases.

Fucoidan and galactooligosaccharides ameliorate high-fat diet-induced dyslipidemia in rats by modulating the gut microbiota and bile acid metabolism.

OBJECTIVES: Dyslipidemia is an important risk factor for cardiovascular diseases. Fucoidan (FUC) is a polysaccharide extracted from brown marine algae with various biological activities. Galactooligosaccharides (GOS) are important prebiotics that exert benefits on the intestinal microbiota. The aim of this study was to investigate the effects of FUC and GOS on dyslipidemia in rats by modulating the gut microbiota and bile acid metabolism. METHODS: Twenty-four male inbred Sprague-Dawley (SD) rats aged 8 wk were fed a normal or high-fat diet (HFD) for 8 wk. During the feeding period, rats were gavaged with normal saline solution, FUC solution (100 mg/kg),or GOS solution (800 mg/kg), or a combination of both once daily. Serum biochemical parameters were determined, and the gut microbiota were analyzed via 16S rRNA gene sequencing. Bile salt hydrolase (BSH) activity in the small intestinal contents was also analyzed. The effects of FUC and GOS on Lactobacillus casei DM8121 were analyzed in vitro. RESULTS: In rats, GOS and FUC supplementation significantly improved serum total cholesterol, low-density lipoprotein cholesterol, lipopolysaccharide, serum total bile acid, hepatic tissue steatosis, aortic arch injury, gut microbiota, serum high-density lipoprotein cholesterol, cholesterol 7-alpha hydroxylase expression in the liver, and BSH activity in the small intestinal contents. In an in vitro experiment, GOS and FUC supplementation significantly increased L. casei DM8121's BSH activity. CONCLUSIONS: In rats, FUC and GOS supplementation improved serum dyslipidemia, gut microbiota, BSH activity, and bile acid metabolism-related pathways. In vitro, GOS and FUC supplementation increased L. casei DM8121's BSH activity.

Myricetin suppresses breast cancer metastasis through down-regulating the activity of matrix metalloproteinase (MMP)-2/9.

Tumour metastasis is the major cause of breast cancer mortality. Myricetin, a natural polyphenol, is found in teas, wines, and berries. The pharmacodynamic action and molecular mechanism of myricetin on breast cancer metastasis remain unknown. Here, we investigated the effect of myricetin on MDA-Mb-231Br cell viability, migration, invasion, and 4T1 mouse lung metastasis mouse models. MMP-2/9 protein expression and ST6GALNAC5 expression were analysed using western blot assays and quantitative real-time polymerase chain reaction, respectively. Cell migration and invasion were detected by wound-healing and Boyden transwell assays. The antimetastatic effect in vivo was evaluated by lung metastasis model. Myricetin significantly decreased the activities of MMP-2/9 and mRNA levels of ST6GALNAC5. In addition, the migration, invasion, and adhesion were effectively inhibited in a concentration-dependent manner. On the other hand, mice treated with myricetin exhibited smaller tumour nodules compared with the vehicle mice, with only 17.78 ± 15.41% after treatment with 50 mg/kg myricetin. In conclusion, myricetin could significantly block invasion of MDA-Mb-231Br cells through suppressing the protein expression of MMP-2/9 and the expression of ST6GALNAC5, as well as lung metastasis in a mouse model, which suggests that myricetin should be developed as a potential therapeutic candidate for breast cancer.

Effects of insertion depth on spatial speech perception in noise for simulations of cochlear implants and single-sided deafness.

OBJECTIVE: This study evaluated the effects of insertion depth on spatial speech perception in noise for simulations of cochlear implants (CI) and single-sided deafness (SSD). DESIGN: Mandarin speech recognition thresholds were adaptively measured in five listening conditions and four spatial configurations. The original signal was delivered to the left ear. The right ear received either no input, one of three CI simulations in which the insertion depth was varied, or the original signal. Speech and noise were presented at either front, left, or right. STUDY SAMPLE: Ten Mandarin-speaking NH listeners with pure-tone thresholds less than 20 dB HL. RESULTS: Relative to no input in the right ear, the CI simulations provided significant improvements in head shadow benefit for all insertion depths, as well as better spatial release of masking (SRM) for the deepest simulated insertion. There were no significant improvements in summation or squelch for any of the CI simulations. CONCLUSIONS: The benefits of cochlear implantation were largely limited to head shadow, with some benefit for SRM. The greatest benefits were observed for the deepest simulated CI insertion, suggesting that reducing mismatch between acoustic and electric hearing may increase the benefit of cochlear implantation.

Traditional Herbal Medicine-Derived Sulforaphene LFS-01 Reverses Colitis in Mice by Selectively Altering the Gut Microbiota and Promoting Intestinal Gamma-Delta T Cells.

Sulforaphene (LFS-01) is a natural compound derived from traditional herbal medicine. Here, we show that oral administration of LFS-01 is able to dramatically alter the skewed gut microbiota and reverse colitis in model mice associated with an increase of intestinal γδT cells. Through 16S rDNA sequencing, we showed that LFS-01 can selectively suppress enteric pathogens such as Escherichia-Shigella and Helicobacter whereas the protective strains including Lactobacillus and Lachnospiraceae were significantly expanded after LFS-01 treatment. Interestingly, we demonstrated that LFS-01 administration can significantly promote the IL-17+γδT cells in model mice in response to the expanded Lactobacillus. We verified that the intracellular components of Lactobacillus can stimulate the growth of IL-17+γδT cells upon preincubation. The increased IL-17A after LFS-01 treatment in turn recovers the disrupted occludin subcellular location and protects the epithelial barrier in the colon of model mice. Remarkably, LFS-01 does not show apparent toxicity to animals and we demonstrated that LFS-01 also exerts strong protective effects in TNBS-induced colitis rats. Therefore, LFS-01 holds great promise for the treatment of inflammatory bowel disease (IBD) and warrants translation for use in clinical trials. Our work provided a new avenue for the treatment of IBD based on the strategy of harnessing intestinal symbiosis.

TmcN is involved in ATP regulation of tautomycetin biosynthesis in Streptomyces griseochromogenes.

The regulatory mechanism of tautomycetin (TMC) biosynthesis remains largely unknown, although it has been of great interest to the pharmaceutical industry. Our previous study showed that intracellular adenosine triphosphate (inATP) level is negatively correlated with secondary metabolite biosynthesis in various Streptomyces spp. In this study, by exogenous treatment of ATP, we also found a negative correlation between TMC biosynthesis and inATP level in Streptomyces griseochromogenes (S. griseochromogenes). However, the underlying mechanism remains unclear. TmcN, a pathway-specific transcriptional regulator of TMC biosynthetic genes, was previously revealed as a large ATP-binding LuxR (LAL) family protein. The predicted amino acid sequence of TmcN shows highly conserved Walker A and B binding motifs, which suggest an ATPase function of TmcN. We therefore hypothesized that the ATPase domain of TmcN may play a role in sensing endogenous pool of ATP, and is thus involved in the ATP regulation of TMC biosynthesis. To test the hypothesis, we first explored the key residue that affects the ATPase activity of TmcN by amino acid sequence alignment and structural simulation. After that, we disrupted tmcN gene in S. griseochromogenes, and the tmcN or site-direct-mutated tmcN were re-introduced to get the complementary and ATPase domain disrupted strains. The transcription level of tmcN, TMC yield, and inATP, as well as the effect of ATP on TMC production of different mutants were evaluated. Deletion of tmcN or site-direct mutation of ATPase domain of TmcN in S. griseochromogenes significantly reduced the TMC production, and it was not affected by exogenous ATP treatment. In addition, a relatively high level of inATP was detected in tmcN deletion and site-direct mutation strains. Our results here suggested that TmcN, especially its ATPase domain, is involved in consuming of endogenous ATP pool and thus plays pivotal role in connecting the primary and secondary metabolite in S. griseochromogenes.

LC-MS/MS determination of 1-O-acetylbritannilactone in rat plasma and its application to a preclinical pharmacokinetic study.

A novel, rapid and sensitive LC-MS/MS method for the determination of 1-O-Acetylbritannilactone (ABL), a sesquiterpene lactone abundant in Inula britannica, was developed and validated using heteroclitin D as internal standard. Separation was achieved on a reversed phase Hypersil Gold C18 column (50 × 4.6 mm, i.d., 3.0 µm) using isocratic elution with methanol-5 mM ammonium acetate buffer aqueous solution (80:20, v/v) at a flow rate of 0.4 mL/min. Calibration curve was linear (r > 0.99) in a concentration range of 1.60-800 ng/mL with the lower limit of quantification of 1.60 ng/mL. Intra- and inter-day accuracy and precision were validated by relative error (RE) and relative standard deviation (RSD) values, respectively, which were both less than ±15%. The validated method has been successfully applied to a pharmacokinetic study of ABL in rats. The elimination half-lives were 0.412 ± 0.068, 0.415 ± 0.092 and 0.453 ± 0.071 h after a single intravenous administration of 0.14, 0.42, and 1.26 mg/kg ABL, respectively. The area under the plasma concentration-time curve from time zero to the last quantifiable time point and from time zero to infinity and the plasma concentrations at 2 min were linearly related to the doses tested.

[Treating chronic persistent bronchial asthma children with abnormal myocardial enzyme spectrum by Yupingfeng powder: an efficacy observation].

OBJECTIVE: To observe the clinical efficacy of treating chronic persistent bronchial asthma (CPBA) children with abnormal myocardial enzyme spectrum (AMES) by Yupingfeng Powder (YP) combined routine therapy. METHODS: From January 2010 to December 2012, 156 CPBA children patients with AMES were randomly assigned to the treatment group (80 cases) and the control group (76 cases). All patients received routine treatment (inhaled corticosteroids and/or leukotriene regulator). Besides, those in the treatment group took YP. The treatment duration was 3 months. The scores of children asthma control test (C-ACT), pulmonary function (FEV,% and PEF%), myocardial enzyme spectrum were observed before and after treatment, and 3 months before and after treatment. The myocardial enzyme spectrum of 40 healthy children at the baby clinics during the same period were recruited as the control. RESULTS: Compared with the control group, creatine kinase isoenzyme (CK-MB), creatine kinase(CK), and lactate dehydrogenase (LDH) increased in the two treatment groups (P <0.01), but there was no statistical difference in AST (P >0.05). Compared with before treatment in the same group, CK-MB, CK, LDH, and AST decreased in the treatment group after treatment and 3 months after treatment (P <0.01). CK-MB, CK, LDH, and AST decreased in the control group 3 months after treatment (P <0.01, P <0.05).Compared with after treatment, CK decreased in the control group 3 months after treatment (P <0.01). C-ACT score, FEV(1),%, and PEF% all increased in the two groups after treatment and 3 months after treatment (P <0.01, P <0.05). Compared with after treatment in the same group, CK decreased in the control group 3 months after treatment (P <0. 01). Compared with the control group in the same period, post-treatment CK-MB and CK decreased (P <0. 01, P <0. 05), while post-treatment C-ACT score, FEV, %, and PEF% increased (P <0.05) in the treatment group (P <0.05). CONCLUSION: YP could strengthen specific and non-specific immunity of the organism, and improve clinical symptoms and the level of myocardial enzyme spectrum.