Epidemiological studies have found that diabetes and cognitive dysfunction are closely related. Quercetin has been certified with the effect on improving diabetes mellitus (DM) and cognitive ...impairment. However, the effect and related mechanism of quercetin on diabetic encephalopathy (DE) are still ambiguous. In this study, we used the db/db mice (diabetic model) to discover whether quercetin could improve DE through the Sirtuin1/NLRP3 (NOD‐, LRR‐ and pyrin domain‐containing 3) pathway. Behavioural results (Morris water maze and new object recognition tests) showed that quercetin (70 mg/kg) improved the learning and memory. Furthermore, quercetin alleviated insulin resistance and the level of fasting blood glucose. Besides, Western blot analysis also showed that quercetin increased the protein expressions of nerve‐ and synapse‐related protein, including postsynapticdensity 93 (PSD93), postsynapticdensity 95 (PSD95), brain‐derived neurotrophic factor (BDNF) and nerve growth factor (NGF) in the brain of db/db mice. Quercetin also increased the protein expression of SIRT1 and decreased the expression of NLRP3 inflammation‐related proteins, including NLRP3, the adaptor protein ASC and cleaved Caspase‐1, the pro‐inflammatory cytokines IL‐1β and IL‐18. In conclusion, the present results indicate that the SIRT1/NLRP3 pathway may be a crucial mechanism for the neuroprotective effect of quercetin against DE.
•Network pharmacology indicated AGEs/RAGE pathway for HLJDD against diabetic nephropathy.•HLJDD possessed beneficial effects on diabetic nephropathy in db/db mice.•HLJDD ameliorated diabetic ...nephropathy via regulation of AGEs/RAGE/Akt/Nrf2 pathway and metabolic profiling.
Diabetic nephropathy (DN) is a severe diabetic complication that is the principal cause of end-stage kidney disease worldwide. Huang-Lian-Jie-Du Decoction (HLJDD) is widely used to treat diabetes clinically. However, the nephroprotective effects and potential mechanism of action of HLJDD against DN have not yet been fully elucidated.
This study aimed to investigate the potential roles of HLJDD in DN and elucidate its mechanisms in db/db mice.
An integrated strategy of network pharmacology, pharmacodynamics, molecular biology, and metabolomics was used to reveal the mechanisms of HLJDD in the treatment of DN. First, network pharmacology was utilized to predict the possible pathways for DN using the absorbed ingredients of HLJDD in rat plasma in silico. Then, combined with histopathological examination, biochemical evaluation immunohistochemistry/immunofluorescence assay, western blot analysis, and UPLC-Q-Orbitrap HRMS/MS-based metabolomics approach were applied to evaluate the efficacy of HLJDD against DN and its underlying mechanisms in vivo.
In silico, network pharmacology indicated that the AGEs/RAGE pathway was the most prominent pathway for HLJDD against DN. In vivo, HLJDD exerted protective effects against DN by ameliorating glycolipid metabolic disorders and kidney injury. Furthermore, we verified that HLJDD protected against DN by regulating the AGEs/RAGE/Akt/Nrf2 pathway for the first time. In addition, 22 potential biomarkers were identified in urine, including phenylalanine metabolism, tryptophan metabolism, glucose metabolism, and sphingolipid metabolism.
These findings suggest that HLJDD ameliorates DN by regulating the AGEs/RAGE/Akt/Nrf2 pathway and metabolic profiling.
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The aim of this study was to perform molecular characterization for and determine the antimicrobial susceptibility profiles of Clostridium difficile collected from hospitals during a 4-year period ...(2009-2013) in China.
Strains of toxigenic C. difficile were isolated from patients with diarrhoea, and this was followed by typing using multilocus sequence typing (MLST) and testing for susceptibility to 10 antimicrobials by using the E-test. The mechanisms of resistance to moxifloxacin, erythromycin, clindamycin and tetracycline were investigated by PCR.
A total of 405 non-duplicate toxigenic C. difficile isolates were identified, while 31 sequence types (STs) were identified. A predominant type, ST-54, accounted for 20.2 % of the STs, followed by ST-35 (16.3 %) and ST-37 (13.6 %). We found that 6.2 % of the isolates were binary toxin genes-positive, and 83.7 % of these belonged to ST-5. All of the isolates demonstrated 100 % susceptibility to first-line Clostridium difficile infection (CDI) therapies (i.e. metronidazole and vancomycin), while the resistance rates varied for the other antibiotics tested. Two hundred and ninety three (72.3 %) isolates were susceptible to moxifloxacin. All 112 moxifloxacin-resistant isolates had mutations resulting in an amino acid substitution in gryA and/or gyrB. The ermB gene was detected in 86.7 % (241/278) of the erythromycin- and clindamycin-resistant isolates, while the tetM gene was present in 97.1 % (85/87) of the tetracycline-resistant isolates.
MLST typing revealed a wide variety of STs causing CDI, while ST-54 was the most common ST. All of the isolates were susceptible to metronidazole and vancomycin, while the resistance rates varied for the other antibiotics tested. There were no changes in the trends for the STs and antibiotic susceptibility profiles over 4 years.
Lactobacillus salivarius LI01, isolated from healthy humans, has demonstrated probiotic properties in the prevention and treatment of liver failure. Tolerance to bile stress is crucial to allow ...lactobacilli to survive in the gastrointestinal tract and exert their benefits. In this work, we used a Digital Gene Expression transcriptomic and iTRAQ LC-MS/MS proteomic approach to examine the characteristics of LI01 in response to bile stress. Using culture medium with or without 0.15% ox bile, 591 differentially transcribed genes and 347 differentially expressed proteins were detected in LI01. Overall, we found the bile resistance of LI01 to be based on a highly remodeled cell envelope and a reinforced bile efflux system rather than on the activity of bile salt hydrolases. Additionally, some differentially expressed genes related to regulatory systems, the general stress response and central metabolism processes, also play roles in stress sensing, bile-induced damage prevention and energy efficiency. Moreover, bile salts appear to enhance proteolysis and amino acid uptake (especially aromatic amino acids) by LI01, which may support the liver protection properties of this strain. Altogether, this study establishes a model of global response mechanism to bile stress in L. salivarius LI01.
L. salivarius strain LI01 exhibits not only antibacterial and antifungal properties but also exerts a good health-promoting effect in acute liver failure. As a potential probiotic strain, the bile-tolerance trait of strain LI01 is important, though this has not yet been explored. In this study, an analysis based on DGE and iTRAQ was performed to investigate the gene expression in strain LI01 under bile stress at the mRNA and protein levels, respectively. To our knowledge, this work also represents the first combined transcriptomic and proteomic analysis of the bile stress response mechanism in L. salivarius.
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•An integrated transcriptomic and proteomic investigation of bile response mechanism was first performed conducted in L. salivarius by using strain LI01.•L. salivarius LI01 is a non-BSH-producing strain. Its bile resistance was is mainly based on a highly remodeled cell envelopes and reinforced bile efflux systems.•Bile-induced alterations in regulatory systems, cell surface, general stress response and central metabolism processes were observed and also to contributed to the bile resistance of LI01.•Bile-induced potential alterations of LI 01 such as the uptake of aromatic amino acids may be helpful forin liver protection.
Clostridium difficile infection (CDI) is caused by toxin-producing strains. It accounts for 20-30 % of antibiotic-associated diarrhoea and particularly accounts for 90 % of pseudomembranous colitis. ...The epidemiological study of C. difficile is thus important. In this study, we report the molecular epidemiology and ward distribution of C. difficile in a tertiary hospital of China. A total of 161 toxigenic strains were isolated from 1845 patients originating from different wards and the strains were characterized based on toxin profile and multilocus sequence typing. Variable isolation rates were observed in different wards and the occurrence was higher in intensive care unit and geriatric wards. Toxin gene profiling revealed that, out of the 161 isolates, 134 (83.2)% were positive for both toxin A (tcdA) and toxin B (tcdB) (A+B+) followed by toxin A-negative and B-positive (A-B+) (16.8 %) isolates. However, only three of the toxigenic strains (1.9 %) were positive for both the cdtA and cdtB genes. Based on the molecular epidemiology study, a total of 30 different sequence types (STs), including one new ST (ST-220), were distinguishable. ST-54 was the most prevalent (23.0 %), followed by ST-35 (19.3 %) and ST-37 (10.0 %). None of the isolates belonged to ST-1 (ribotype 027) or ST-11 (ribotype 078). Taken together, the toxin profile and the molecular epidemiological data showed that all the ST-37 clades were of toxin type A-B+, which accounted for 59.3 % of all type A-B+ isolates. Meanwhile the clade 1 genotype, ST-54, was widely distributed among the geriatric, infection and haematology wards. There was no outbreak of C. difficile infection during our study; however the possibility of prolonged outbreaks cannot be completely ignored.
Baicalin, a plant-derived flavonoid, has been reported to exert neuroprotective effects on ischemia-like or excitotoxic injury. To confirm this function and explore the possible mechanism, we ...investigated the protective effect of baicalin on an in-vitro model of ischemia (oxygen-glucose deprivation-treated endothelial cell). In the present study, we found that baicalin (100 μM) inhibited cell death, reduced cell membrane damage, and maintained the integrity of the nucleus. Flow cytometric analysis and Hoechst 33258/propidium iodide double staining results showed that the necroptosis ratio decreased with baicalin treatment. Western blot analysis showed that baicalin regulated the expression of RIP-1 and RIP-3 in bEnd.3 cells and the use of detection kits showed that baicalin inhibited the production of reactive oxygen species and malondialdehyde, and increased the activity of superoxide dismutase in oxygen-glucose deprivation-treated bEnd.3 cells. These results indicated that baicalin effectively alleviated the oxidative stress, decreased the proportion of cells undergoing necrosis, and reduced cell damage.
Kai Xin San (KXS, containing ginseng, hoelen, polygala, and acorus), a traditional Chinese herbal compound, has been found to regulate cognitive dysfunction; however, its mechanism of action is still ...unclear. In this study, 72 specific-pathogen-free male Kunming mice aged 8 weeks were randomly divided into a vehicle control group, scopolamine group, low-dose KXS group, moderate-dose KXS group, high-dose KXS group, and positive control group. Except for the vehicle control group and scopolamine groups (which received physiological saline), the doses of KXS (0.7, 1.4 and 2.8 g/kg per day) and donepezil (3 mg/kg per day) were gastrointestinally administered once daily for 2 weeks. On day 8 after intragastric treatment, the behavioral tests were carried out. Scopolamine group and intervention groups received scopolamine 3 mg/kg per day through intraperitoneal injection. The effects of KXS on spatial learning and memory, pathological changes of brain tissue, expression of apoptosis factors, oxidative stress injury factors, synapse-associated protein, and cholinergic neurotransmitter were measured. The results confirmed the following. (1) KXS shortened the escape latency and increased residence time in the target quadrant and the number of platform crossings in the Morris water maze. (2) KXS increased the percentage of alternations between the labyrinth arms in the mice of KXS groups in the Y-maze. (3) Nissl and terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling staining revealed that KXS promoted the production of Nissl bodies and inhibited the formation of apoptotic bodies. (4) Western blot assay showed that KXS up-regulated the expression of anti-apoptotic protein Bcl-2 and inhibited the expression of pro-apoptotic protein Bax. KXS up-regulated the expression of postsynaptic density 95, synaptophysin, and brain-derived neurotrophic factor in the cerebral cortex and hippocampus. (5) KXS increased the level and activity of choline acetyltransferase, acetylcholine, superoxide dismutase, and glutathione peroxidase, and reduced the level and activity of acetyl cholinesterase, reactive oxygen species, and malondialdehyde through acting on the cholinergic system and reducing oxidative stress damage. These results indicate that KXS plays a neuroprotective role and improves cognitive function through reducing apoptosis and oxidative stress, and regulating synapse-associated protein and cholinergic neurotransmitters.
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