Gut microbial genomes with paired isolates from China illustrate probiotic and cardiometabolic effects.

The gut microbiome displays genetic differences among populations, and characterization of the genomic landscape of the gut microbiome in China remains limited. Here, we present the Chinese Gut Microbial Reference (CGMR) set, comprising 101,060 high-quality metagenomic assembled genomes (MAGs) of 3,707 nonredundant species from 3,234 fecal samples across primarily rural Chinese locations, 1,376 live isolates mainly from lactic acid bacteria, and 987 novel species relative to worldwide databases. We observed region-specific coexisting MAGs and MAGs with probiotic and cardiometabolic functionalities. Preliminary mouse experiments suggest a probiotic effect of two Faecalibacillus intestinalis isolates in alleviating constipation, cardiometabolic influences of three Bacteroides fragilis_A isolates in obesity, and isolates from the genera Parabacteroides and Lactobacillus in host lipid metabolism. Our study expands the current microbial genomes with paired isolates and demonstrates potential host effects, contributing to the mechanistic understanding of host-microbe interactions.

Bifidobacterium animalis subsp. lactis boosts neonatal immunity: unravelling systemic defences against Salmonella.

Bifidobacterium animalis subsp. lactis may be a useful probiotic intervention for regulating neonatal intestinal immune responses and counteracting Salmonella infection. However, recent research has focused on intestinal immunity, leaving uncertainties regarding the central, peripheral, and neural immune responses in neonates. Therefore, this study investigated the role and mechanisms of B. animalis subsp. lactis in the systemic immune responses of neonatal rats following Salmonella infection. Through extremely early pretreatment with B. animalis subsp. lactis (6 hours postnatal), the neonatal rat gut microbiota was effectively reshaped, especially the Bifidobacterium community. In the rats pretreated with B. animalis subsp. lactis, Salmonella was less prevalent in the blood, liver, spleen, and intestines following infection. The intervention promoted T lymphocyte subset balance in the spleen and thymus and fostered neurodevelopment and neuroimmune balance in the brain. Furthermore, metabolic profiling showed a strong correlation between the metabolites in the serum and colon, supporting the view that B. animalis subsp. lactis pretreatment influences the systemic immune response by modifying the composition and metabolism of the gut microbiota. Overall, the results imply that B. animalis subsp. lactis pretreatment, through the coordinated regulation of colonic and serum metabolites, influences the systemic immune responses of neonatal rats against Salmonella infection.

A key genetic factor governing arabinan utilization in the gut microbiome alleviates constipation.

Impaired gastrointestinal motility is associated with gut dysbiosis. Probiotics, such as Bifidobacteria, can improve this bowel disorder; however, efficacy is strain-dependent. We determine that a genetic factor, the abfA cluster governing arabinan utilization, in Bifidobacterium longum impacts treatment efficacy against functional constipation (FC). In mice with FC, B. longum, but not an abfA mutant, improved gastrointestinal transit time, an affect that was dependent upon dietary arabinan. abfA genes were identified in other commensal bacteria, whose effects in ameliorating murine FC were similarly abfA-dependent. In a double-blind, randomized, placebo-controlled clinical trial, supplementation with abfA-cluster-carrying B. longum, but not an abfA-deficient strain, enriched arabinan-utilization residents, increased beneficial metabolites, and improved FC symptoms. Across human cohorts, abfA-cluster abundance can predict FC, and transplantation of abfA cluster-enriched human microbiota to FC-induced germ-free mice improved gut motility. Collectively, these findings demonstrate a role for microbial abfA cluster in ameliorating FC, establishing principles for genomics-directed probiotic therapies.

Native microbiome dominates over host factors in shaping the probiotic genetic evolution in the gut.

Probiotics often acquire potentially adaptive mutations in vivo, gaining new functional traits through gut selection. While both the host and microbiome can contribute to probiotics' genetic evolution, separating the microbiome and the host's contribution to such selective pressures remains challenging. Here, we introduced germ-free (GF) and specific pathogen-free (SPF) mouse models to track how probiotic strains, i.e., Lactiplantibacillus plantarum HNU082 (Lp082) and Bifidobacterium animalis subsp. lactis V9 (BV9), genetically evolved under selection pressures derived from host factors alone and both host and microbial ecological factors. Notably, compared to the genome of a probiotic strain before consumption, the host only elicited <15 probiotic mutations in probiotic genomes that emerged in the luminal environment of GF mice, while a total of 840 mutations in Lp082 mutants and 21,579 mutations in BV9 were found in SPF mice, <0.25% of those derived from both factors that were never captured by other experimental evolution studies, indicating that keen microbial competitions exhibited the predominant evolutionary force in shaping probiotic genetic composition (>99.75%). For a given probiotic, functional genes occurring in potentially adaptive mutations induced by hosts (GF mice) were all shared with those found in mutants of SPF mice. Collectively, the native microbiome consistently drove a more rapid and divergent genetic evolution of probiotic strains in seven days of colonization than host factors did. Our study further laid a theoretical foundation for genetically engineering probiotics for better gut adaptation through in vitro artificial gut ecosystems without the selection pressures derived from host factors.

Lactiplantibacillus plantarum CCFM8661 alleviates D-galactose-induced brain aging in mice by the regulation of the gut microbiota.

Aging is characterized by a decline in biological functions, leading to various health issues. There is significant interest in mitigating age and age-related health issues. Gut microbiota has emerged as a crucial target for combating aging and influencing host health. This study evaluated the anti-aging effects of Lactiplantibacillus plantarum CCFM8661 in mice and the role of the gut microbiota in mediating its effects. Aging was induced in mice using D-galactose, and L. plantarum CCFM8661 was orally administered for 8 weeks to evaluate its effects on age-related decline and the gut microbiota. The results demonstrated that supplementation with L. plantarum CCFM8661 effectively alleviated cognitive impairment and oxidative stress in the aging brain, as well as liver oxidation and bone damage, and impaired intestinal barrier function in aging mice. Furthermore, L. plantarum CCFM8661 modulated the gut microbiota of aging mice, increasing the abundance of beneficial bacteria, such as Ruminococcaceae, and influenced the functionality of the gut microbiota to promote the production of active metabolites. These findings suggest that L. plantarum CCFM8661 has a mitigating effect on organismal aging, especially brain aging.

Combined Ganoderma lucidum polysaccharide and ciprofloxacin therapy alleviates Salmonella enterica infection, protects the intestinal barrier, and regulates gut microbiota.

Clinical antibiotics used worldwide could diminish the intestinal barrier, enhance contact with microbiota and intestinal immune cells, and induce inflammation. We found that ciprofloxacin treatment of Salmonella enterica serovar Typhimurium infection resulted in the destruction of the intestinal barrier, with decreased concentrations of MUC2, ZO-1, and occludin in the jejunum and colon. Ganoderma lucidum ethanol extracts (GLE), as a prebiotic food extract, significantly decreased inflammation-related enzymes, including COX-2, MPO, and iNOS, and pro-inflammatory cytokines (IL-6, IL-1ß, IL-17, and TNF-α), and protected the intestinal barrier by increasing the concentration of MUC2, ZO-1, and occludin. Meanwhile it significantly increased the abundances of Salmonella, Parabacteroides, Acinetobacter, Enterococcus, and Escherichia-Shigella, which increased the risk of pathogenic bacterial infections. Prebiotic G. lucidum polysaccharide (GLP) provided a significant intestinal barrier, improving the concentration of ZO-1, occludin, and MUC2 in the colon and jejunum. The synergistic effects of GLP and ciprofloxacin were hypothesized to reverse the negative effects resulting from ciprofloxacin alone, as the concentrations of ZO-1, occludin, and MUC2 were significantly increased in the jejunum and colon, especially in the colon. Also, the synergistic effect increased the abundances of probiotic bacteria Lachnospiraceae NK4A136, Ruminococcaceae UGG-014, Lactobacillus, and Parabacteroides. In conclusion, combined GLP and ciprofloxacin therapy against Salmonella infection alleviated the side effects resulting from the clinical application of the antibiotic alone, and increased the probiotic bacterial population.

Cholestasis: exploring the triangular relationship of gut microbiota-bile acid-cholestasis and the potential probiotic strategies.

Cholestasis is a condition characterized by the abnormal production or excretion of bile, and it can be induced by a variety of causes, the factors of which are extremely complex. Although great progress has been made in understanding cholestasis pathogenesis, the specific mechanisms remain unclear. Therefore, it is important to understand and distinguish cholestasis from different etiologies, which will also provide indispensable theoretical support for the development of corresponding therapeutic drugs. At present, the treatment of cholestasis mainly involves several bile acids (BAs) and their derivatives, most of which are in the clinical stage of development. Multiple lines of evidence indicate that ecological disorders of the gut microbiota are strongly related to the occurrence of cholestasis, in which BAs also play a pivotal role. Recent studies indicate that probiotics seem to have certain effects on cholestasis, but further confirmation from clinical trials is required. This paper reviews the etiology of and therapeutic strategies for cholestasis; summarizes the similarities and differences in inducement, symptoms, and mechanisms of related diseases; and provides information about the latest pharmacological therapies currently available and those under research for cholestasis. We also reviewed the highly intertwined relationship between gut microbiota-BA-cholestasis, revealing the potential role and possible mechanism of probiotics in the treatment of cholestasis.

Neuroprotective Effects of Bifidobacterium breve CCFM1067 in MPTP-Induced Mouse Models of Parkinson's Disease.

There is mounting evidence that the microbiota-gut-brain axis (MGBA) is critical in the pathogenesis and progression of Parkinson's disease (PD), suggesting that probiotic therapy restoring gut microecology may slow down disease progression. In this study, we examined the disease-alleviating effects of Bifidobacterium breve CCFM1067, orally administered for 5 weeks in a PD mouse model. Our study shows that supplementation with the probiotic B. breve CCFM1067 protected dopaminergic neurons and suppressed glial cell hyperactivation and neuroinflammation in PD mice. In addition, the antioxidant capacity of the central nervous system was enhanced and oxidative stress was alleviated. Moreover, B. breve CCFM1067 protected the blood-brain and intestinal barriers from damage in the MPTP-induced mouse model. The results of fecal microbiota analysis showed that B. breve CCFM1067 intervention could act on the MPTP-induced microecological imbalance in the intestinal microbiota, suppressing the number of pathogenic bacteria (Escherichia-Shigella) while increasing the number of beneficial bacteria (Bifidobacterium and Akkermansia) in PD mice. In addition, the increase in short chain fatty acids (acetic and butyric acids) may explain the anti-inflammatory action of B. breve CCFM1067 in the gut or brain of the MPTP-induced PD mouse model. In conclusion, we demonstrated that the probiotic B. breve CCFM1067, which can prevent or treat PD by modulating the gut-brain axis, can be utilized as a possible new oral supplement for PD therapy.

Species- or genus-dependent immunostimulatory effects of gut-derived potential probiotics.

The immune regulatory effects of probiotics have been widely recognized to be strain-specific. However it is unknown if there is a species- or genus-dependent manner. In this study, we use an in vitro mesenteric lymph node (MLN) model to systematically evaluate the immunostimulatory effects of gut-derived potential probiotics. The results exhibit an obvious species or genus consensus immune response pattern. RNA-seq shows that T cell-dependent B cell activation and antibody responses may be inherent to this model. Of the five tested genera, Akkermansia spp. and Clostridium butyrium directly activate the immune response in vitro, as indicated by the secretion of interleukin-10. Bifidobacterium spp. and Bacteroides spp. activate immune response with the help of stimuli (anti-CD3 and anti-CD28 antibodies). Lactobacillus spp. blunt the immune response with or without stimuli. Further investigations show that the cell surface protein of A. muciniphila AH39, which may serve as a T cell receptor cognate antigen, might evoke an in vitro immune activation. In vivo, oral administration of A. muciniphila AH39 influences the proportion of T regulatory cells (Tregs) in MLNs and the spleen under homeostasis in both specific pathogen-free and germ-free mice. All these findings indicate the distinct effects of different genera or species of potential gut-derived probiotics on intestinal and systemic immunity.

Modulation of the Gut Microbiota Structure with Probiotics and Isoflavone Alleviates Metabolic Disorder in Ovariectomized Mice.

The decrease in ovarian hormone secretion that occurs during menopause results in an increase in body weight and adipose tissue mass. Probiotics and soy isoflavones (SIFs) could affect the gut microbiota and exert anti-obesity effects. The objective of this study was to investigate the effects of probiotics and a diet containing SIF (SIF diet) on ovariectomized mice with menopausal obesity, including the gut microbiome. The results demonstrate that Bifidobacterium longum 15M1 can reverse menopausal obesity, whilst the combination of Lactobacillus plantarum 30M5 and a SIF diet was more effective in alleviating menopausal lipid metabolism disorder than either components alone. Probiotics and SIFs play different anti-obesity roles in menopausal mice. Furthermore, 30M5 alters the metabolites of the gut microbiota that increase the circulating estrogen level, upregulates the expression of estrogen receptor α in abdominal adipose tissue and improves the production of short-chain fatty acids (SCFAs). A SIF diet can significantly alter the structure of the fecal bacterial community and enrich the pathways related to SCFAs production. Moreover, 30M5 and a SIF diet acted synergistically to effectively resolve abnormal serum lipid levels in ovariectomized mice, and these effects appear to be associated with regulation of the diversity and structure of the intestinal microbiota to enhance SCFAs production and promote estrogen circulation.

Resolvin D1 and D2 inhibit tumour growth and inflammation via modulating macrophage polarization.

Plastic polarization of macrophage is involved in tumorigenesis. M1-polarized macrophage mediates rapid inflammation, entity clearance and may also cause inflammation-induced mutagenesis. M2-polarized macrophage inhibits rapid inflammation but can promote tumour aggravation. ω-3 long-chain polyunsaturated fatty acid (PUFA)-derived metabolites show a strong anti-inflammatory effect because they can skew macrophage polarization from M1 to M2. However, their role in tumour promotive M2 macrophage is still unknown. Resolvin D1 and D2 (RvD1 and RvD2) are docosahexaenoic acid (DHA)-derived docosanoids converted by 15-lipoxygenase then 5-lipoxygenase successively. We found that although dietary DHA can inhibit prostate cancer in vivo, neither DHA (10 µmol/L) nor RvD (100 nmol/L) can directly inhibit the proliferation of prostate cancer cells in vitro. Unexpectedly, in a cancer cell-macrophage co-culture system, both DHA and RvD significantly inhibited cancer cell proliferation. RvD1 and RvD2 inhibited tumour-associated macrophage (TAM or M2d) polarization. Meanwhile, RvD1 and RvD2 also exhibited anti-inflammatory effects by inhibiting LPS-interferon (IFN)-γ-induced M1 polarization as well as promoting interleukin-4 (IL-4)-mediated M2a polarization. These differential polarization processes were mediated, at least in part, by protein kinase A. These results suggest that regulation of macrophage polarization using RvDs may be a potential therapeutic approach in the management of prostate cancer.

Effects of Ginsenoside Rg1 Regulating Wnt/ß-Catenin Signaling on Neural Stem Cells to Delay Brain Senescence.

This is a study on the relationship between the protective effect of ginsenoside Rg1 on senescent neural stem cells and Wnt-ß/catenin signaling pathway. Background. Recent studies have shown that overactivation of the Wnt/ß-catenin signaling pathway is closely related to stem cell senescence. Whether Rg1 delays the senescence of NSCs is related to the regulation of this signaling pathway. Methods. The whole brain of Nestin-GFP transgenic newborn rat was extracted, and NSCs were extracted and cultured to P3 generation. The following indicators were detected: (1) NSC culture identification, (2) the effect of LiCl on the proliferation and survival rate of NSCs, (3) the effect of ginsenoside Rg1 on the proliferation and survival of NSCs, (4) the growth of NSCs in each group observed by an optical microscope, (5) the cell cycle of each group detected by flow cytometry, (6) the proliferative ability of each group detected by BrdU, (7) the fluorescence intensity of Nestin and Sox2 of NSCs in each group observed by a fluorescence microscope, (8) the positive rate of senescence staining analyzed by SA-ß-Gal staining, (9) the localization of ß-catenin in NSCs observed by laser confocal microscopy, and (10) the changes of the Wnt/ß-catenin pathway-related proteins in each group detected by Western blotting. Results. LiCl activates the Wnt/ß-catenin pathway and promotes mouse neural stem cell senescence. Ginsenoside Rg1 promotes proliferation of neural stem cells and inhibits Wnt/ß-catenin pathway activation. Conclusions. LiCl can activate the Wnt/ß-catenin signaling pathway of NSCs, and ginsenoside Rg1 can antagonize the senescence of NSCs caused by activation of the Wnt/ß-catenin signaling pathway and delay brain aging.

Effect of Angelica polysaccharide on brain senescence of Nestin-GFP mice induced by D-galactose.

The incidence of neurodegenerative diseases is severely increasing with the aging. It has been proposed that NSCs (neural stem cells) help to control aging, but the mechanisms responsible remain unclear. Angelica polysaccharide is an active ingredient of Angelica sinensis in traditional Chinese medicine, which possesses versatile pharmacological activities including anti-oxidative and anti-aging effects. In this study, D-gal (D-galactose) was used to construct an aging model of Nestin-GFP transgenic mice brain tissues and NSCs. Mouse model was subcutaneously injected with D-gal, as we observed that mice consistently displayed acceleration of aging-like behavior change, energy metabolism decreased, the expression of aging-related genes was up-regulated. Conversely, aging retardation was achieved in Nestin-GFP mice Induced by D-gal that was locally injected with ASP (Angelica polysaccharide). Mechanistically, we isolated and cultured NSCs in vitro. ASP protected NSCs by increasing the cell proliferation; decreasing the number of SA-ß-gal stained neurons; increasing the activity of SOD(superoxide dismutase) and T-AOC(total antioxidant capacity), decreasing the content of MDA(malondialdehyde); decreasing the levels of IL-1b,IL-6,TNF-a and ROS; and down-regulated the expression of cellular senescence associated genes p53, p21 in the aging NSCs. In conclusion, ASP can delay aging speed by protecting NSCs and promote neurogenesis by enhancing the antioxidant and anti-inflammatory capacity, up-regulation of p53/p21 signaling pathway. As to provide theoretical basis for treatment for brain aging related diseases, add new scientific connotation for "qi and blood theory" and "supplement blood and delay aging" of Traditional Chinese Medicine.

Metabolic Shift Induced by ω -3 PUFAs and Rapamycin Lead to Cancer Cell Death.

BACKGROUND/AIMS: Rapamycin (Rp), the main mammalian target of rapamycin complex inhibitor, is a promising therapeutic agent for breast cancer. However, metabolic disorders and drug resistance reduce its efficacy. Epidemiological, clinical, and experimental studies have demonstrated that omega-3 polyunsaturated fatty acids (ω-3 PUFAs) significantly reduce the incidence and mortality of breast cancer and improve metabolic disorders. METHODS: Three breast cancer cell lines and immunocompetent and immunodeficient mice were used to evaluate the therapeutic effects of Rp plus ω-3 PUFA treatment. The production of reactive oxygen species (ROS) and glucose uptake were examined by flow cytometry. Metabolic shift was examined by metabonomics, seahorse experiments, and western blot analysis. RESULTS: We found that ω-3 PUFAs and Rp synergistically induced cell cycle arrest and apoptosis in vitro and in vivo, accompanied by autophagy blockage. In addition, Rp-induced hypertriglyceridemia and hypercholesterolemia were completely abolished by ω-3 PUFA supplementation. Moreover, the combined treatment of ω-3 PUFA and Rp significantly inhibited glycolysis and glutamine metabolism. The anti-tumor effects of this combination treatment were dependent on ROS production, which was increased by ß-oxidation and oxidative phosphorylation. CONCLUSION: Our study revealed that ω-3 PUFA enhanced the anti-tumor activity of Rp while minimizing its side effects in vitro and in vivo. These results provide novel insights into the mechanisms underlying the potential beneficial effects of Rp combined with ω-3 PUFAs on the prevention of breast cancer.

Dietary supplementation of α-linolenic acid induced conversion of n-3 LCPUFAs and reduced prostate cancer growth in a mouse model.

BACKGROUND: α-linolenic acid (ALA) is an n-3 polyunsaturated fatty acid (PUFA) and the substrate for long-chain n-3 PUFAs. The beneficial effects of ALA on chronic diseases are still in dispute, unlike those of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). METHODS: The primary objective of this investigation was to evaluate the efficiency of ALA uptake from a vegetable oil source and its subsequent conversion to n-3 long-chain PUFAs (LCPUFAs) in the tissues of growing mice, and to investigate its protective role in a prostate cancer animal model. We carried out the investigation in prostate-specific Pten-knockout mice with specified low-ALA (L-ALA, 2.5%) and high-ALA (H-ALA, 7.5%) diets. Total fatty acids in blood, liver, epididymal fat pad, prostate were detected and prostate weight were adjusted for body weight (mg/25 g). RESULTS: We found that dietary ALA triggered significant increases in ALA, EPA, docosapentaenoic acid (DPA) and DHA levels and a significant decrease in arachidonic acid levels during the mice's growth stage. A dose-dependent effect was observed for ALA, EPA and DPA, but not DHA. Furthermore, the average prostate weights in the L-ALA and H-ALA groups were lower than those in the control and n-6 groups, and similar to those in the EPA and n-3 groups. CONCLUSIONS: Our data suggest that dietary supplementation with ALA is an efficient means of improving n-3 LCPUFAs in vivo, and it has a biologically effective role to play in prostate cancer, similar to that of fish oils.

Clove extract functions as a natural fatty acid synthesis inhibitor and prevents obesity in a mouse model.

Numerous medicinal plants have been reported to prevent various chronic diseases. In this study, we screened a new FASN inhibitor-alcohol extract of clove (AEC) using a fast microplate method developed in our laboratory. The major components of AEC were: eugenol (42.27%), acetyl eugenol (29.12%), caryophyllene (15.40%), and humulene (3.22%). Fatty acid synthase (FASN) is a key enzyme for de novo lipogenesis, and it has been suggested as a potential therapeutic target in cancer and obesity. We have tested the ability of AEC to inhibit FASN in mammalian cells and tissues. Furthermore, we found that AEC as a FASN inhibitor could inhibit the S-phase DNA replication of HepG2 cells and adipocyte differentiation of OP9 cells. AEC also limited the development of high fat diet (HFD) induced obesity. AEC supplementation significantly reduced body weight and abdominal adipose tissue weight, lowered lipid accumulation in the liver and epididymal adipose tissue compared with the HFD control group. The serum lipid profiles showed that AEC could regulate the content of total triglyceride (TG), low-density lipoprotein cholesterol (LDL-C). Collectively, our data suggest that FASN inhibitor AEC is a potential therapeutic agent for obesity.

Dietary intake of n-3 PUFAs modifies the absorption, distribution and bioavailability of fatty acids in the mouse gastrointestinal tract.

BACKGROUND: Dietary polyunsaturated fatty acids (PUFAs), especially n-3 PUFAs, are important for human health. The intestinal tract, a location that is heavily colonized by microorganisms, is the main organ for absorbing fatty acids. METHODS: The purpose of this study was to analyze the effects of dietary n-3 and n-6 PUFAs on the distribution of different types of fatty acids and their bioavailability along the gut. Mice were fed for a week with experimental diets containing high n-3 or high n-6 fatty acid levels. Blood was collected at different time points, and after 7 days the mice were euthanized and their digestive tract was divided into 17 segments for fatty acids analyses. RESULTS: We found that supplementing n-3 fatty acids significantly changed the ratio of n-6/n-3 PUFAs, increased the bioavailability of n-3 PUFAs, and altered fatty acid distribution. In addition, in the n-3 diet group, the absorption of saturated fatty acids (SFAs) along the gut was found to be inhibited, which was confirmed by feeding the mice with a diet containing deuterium-labeled palmitic acid and stearic acid. CONCLUSION: These results show that a diet rich in n-3 PUFAs can significantly modify the distribution and bioavailability of fatty acids, and particularly, may block the absorption of SFAs in the mouse gastrointestinal (GI) tract.

Molecular grafting onto a stable framework yields novel cyclic peptides for the treatment of multiple sclerosis.

Multiple sclerosis (MS) is an inflammatory disease of the central nervous system (CNS) and is characterized by the destruction of myelin and axons leading to progressive disability. Peptide epitopes from CNS proteins, such as myelin oligodendrocyte glycoprotein (MOG), possess promising immunoregulatory potential for treating MS; however, their instability and poor bioavailability is a major impediment for their use clinically. To overcome this problem, we used molecular grafting to incorporate peptide sequences from the MOG35-55 epitope onto a cyclotide, which is a macrocyclic peptide scaffold that has been shown to be intrinsically stable. Using this approach, we designed novel cyclic peptides that retained the structure and stability of the parent scaffold. One of the grafted peptides, MOG3, displayed potent ability to prevent disease development in a mouse model of MS. These results demonstrate the potential of bioengineered cyclic peptides for the treatment of MS.

[Research of anti-aging mechanism of ginsenoside Rg1 on brain].

Neurodegenerative disease is common and frequently occurs in elderly patients. Previous studies have shown that ginsenoside Rg1 was able to inhibit senescent of brain, but the mechanism on the brain during the treatment remains elucidated. To study the mechanism of ginsenoside Rg1 in the process of anti-aging of brain, forty male SD rats were randomly divided into normal group, Rg1 normal group, brain aging model group and Rg1 brain aging model group, each group with 10 rats (brain aging model group: subcutaneous injection of D-galactose (120 mg kg(-1)), qd for 42 consecutive days; Rg1 brain aging model group: while copying the same test as that of brain aging model group, begin intraperitoneal injection of ginsenosides Rg1 (20 mg x kg(-1)) qd for 27 d from 16 d. Rg1 normal group: subcutaneous injection of the same amount of saline; begin intraperitoneal injection of ginsenosides Rg1 (20 mg x kg(-1)) qd for 27 d from 16 d. Normal: injected with an equal volume of saline within the same time. Perform the related experiment on the second day after finishing copying the model or the completion of the first two days of drug injections). Learning and memory abilities were measured by Morris water maze. The number of senescent cells was detected by SA-beta-Gal staining while the level of IL-1 and IL-6 proinflammatory cytokines in hippocampus were detected by ELISA. The activities of SOD, contents of GSH in hippo- campus were quantified by chromatometry. The change of telomerase activities and telomerase length were performed by TRAP-PCR and southern blotting assay, respectively. It is pointed that, in brain aging model group, the spatial learning and memory capacities were weaken, SA-beta-Gal positive granules increased in section of brain tissue, the activity of antioxidant enzyme SOD and the contents of GSH decreased in hippocampus, the level of IL-1 and IL-6 increased in hippocampus, while the length of telomere and the activity of telomerase decreased in hippocampus. Rats of Rg1 brain aging group had their spatial learning and memory capacities enhanced, SA-beta-Gal positive granules in section of brain tissue decreased, the activity of antioxidant enzyme SOD and the contents of GSH increased in hippocampus, the level of IL-1 and IL-6 in hippocampus decreased, the length contraction of telomere suppressed while the change of telomerase activity increased in hippocampus. Compared with that of normal group, the spatial learning and memory capacities were enhanced in Rg1 normal group, SA-beta-Gal positive granules in section of brain tissue decreased in Rg1 normal group, the level of IL-1 and IL-6 in hippocampus decreased in Rg1 normal group. The results indicated that improvement of antioxidant ability, regulating the level of proinflammatory cytokines and regulation of telomerase system may be the underlying anti-aging mechanism of Ginsenoside Rg1.

Noninvasive renal sympathetic denervation by extracorporeal high-intensity focused ultrasound in a pre-clinical canine model.

OBJECTIVES: This study investigated the feasibility of noninvasive renal sympathetic denervation (RSD) by using the novel approach of extracorporeal high-intensity focused ultrasound (HIFU). BACKGROUND: Catheter-based RSD has achieved promising clinical outcomes. METHODS: Under the guidance of Doppler flow imaging, therapeutic ablations (250 W × 2 s) were performed by using extracorporeal HIFU on the bilateral renal nerves (36.3 ± 2.8 HIFU emissions in each animal) in a mean 27.4-min procedure in 18 healthy canines of the ablation group. Similar procedures without acoustic energy treatment were conducted in 5 canines of the sham group. The animals were killed on day 6 or 28. Blood pressure (BP), plasma noradrenaline (NA) level, and renal function were determined on days 0, 6, and 28. Pathological examinations were performed on all retrieved samples. RESULTS: All of the animals survived the treatment. After ablation, BP and NA significantly decreased compared with the baseline values (BP changed -15.9/-13.6 mmHg, NA changed -55.4% [p < 0.001] 28 days after ablation]) and compared with the sham group on days 6 and 28. Ablation lesions around the renal artery adventitia were observed on day 6. A histological examination revealed the disruption of nerve fibers, necrosis of Schwann cells and neurons, and apparent denervation on day 28. No procedure-related complications were observed. CONCLUSIONS: Effective RSD was successfully achieved by using the extracorporeal HIFU method in canines. Thus, noninvasive HIFU may be further explored as an important and novel strategy for RSD.