Comparative effectiveness of GLP-1 receptor agonists on glycaemic control, body weight, and lipid profile for type 2 diabetes: systematic review and network meta-analysis.

OBJECTIVE: To evaluate the comparative efficacy and safety of glucagon-like peptide-1 receptor agonists (GLP-1RAs) on glycaemic control, body weight, and lipid profile in adults with type 2 diabetes. DESIGN: Systematic review and network meta-analysis. DATA SOURCES: PubMed, Web of Science, Cochrane Central Register of Controlled Trials (CENTRAL), and Embase from database inception to 19 August 2023. ELIGIBILITY CRITERIA FOR SELECTING STUDIES: Eligible randomised controlled trials enrolled adults with type 2 diabetes who received GLP-1RA treatments and compared effects with placebo or any GLP-1RA drug, with a follow-up duration of at least 12 weeks. Trials with a crossover design, non-inferiority studies comparing GLP-1RA and other drug classes without a placebo group, using withdrawn drugs, and non-English studies were deemed ineligible. RESULTS: 76 eligible trials involving 15 GLP-1RA drugs and 39 246 participants were included in this network meta-analysis; all subsequent estimates refer to the comparison with placebo. All 15 GLP-1RAs effectively lowered haemoglobin A1c and fasting plasma glucose concentrations. Tirzepatide induced the largest reduction of haemoglobin A1c concentrations (mean difference -2.10% (95% confidence interval -2.47% to -1.74%), surface under the cumulative ranking curve 94.2%; high confidence of evidence), and fasting plasma glucose concentrations (-3.12 mmol/L (-3.59 to -2.66), 97.2%; high confidence), and proved the most effective GLP-1RA drug for glycaemic control. Furthermore, GLP-1RAs were shown to have strong benefits to weight management for patients with type 2 diabetes. CagriSema (semaglutide with cagrilintide) resulted in the highest weight loss (mean difference -14.03 kg (95% confidence interval -17.05 to -11.00); high confidence of evidence), followed by tirzepatide (-8.47 kg (-9.68 to -7.26); high confidence). Semaglutide was effective in lowering the concentration of low density lipoprotein (-0.16 mmol/L (-0.30 to -0.02)) and total cholesterol (-0.48 mmol/L (-0.84 to -0.11)). Moreover, this study also raises awareness of gastrointestinal adverse events induced by GLP-1RAs, and concerns about safety are especially warranted for high dose administration. CONCLUSIONS: GLP-1RAs are efficacious in treating adults with type 2 diabetes. Compared with the placebo, tirzepatide was the most effective GLP-1RA drug for glycaemic control by reducing haemoglobin A1c and fasting plasma glucose concentrations. GLP-1RAs also significantly improved weight management for type 2 diabetes, with CagriSema performing the best for weight loss. The results prompt safety concerns for GLP-1RAs, especially with high dose administration, regarding gastrointestinal adverse events. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42022342845.

Emerging insights into inflammatory bowel disease from the intestinal microbiota perspective: a bibliometric analysis.

Background: Inflammatory bowel disease (IBD) has caused severe health concerns worldwide. Studies on gut microbiota have provided new targets for preventing and treating IBD. Therefore, it is essential to have a comprehensive understanding of the current status and evolution of gut microbiota and IBD studies. Methods: A bibliometric analysis was performed on documents during 2003-2022 retrieved from the Scopus database, including bibliographical profiles, citation patterns, and collaboration details. Software programs of VOSviewer, CiteSpace, and the Bibliometrix R package visually displayed the mass data presented in the scientific landscapes and networks. Results: 10479 publications were retrieved, showing a steadily growing tendency in interest. Xavier Ramnik J. group led the total number of publications (73 papers) and 19787 citations, whose productive work aroused widespread concern. Among the 1977 academic journals, the most prolific ones were Inflammatory Bowel Diseases, Frontiers in Immunology, and Nutrients. Research outputs from the United States (US, 9196 publications), China (5587), and Italy (2305) were highly ranked. Conclusion: Our bibliometric study revealed that the role of gut microbiota has become a hot topic of IBD research worldwide. These findings are expected to improve understanding of research characteristics and to guide future directions in this field.

Probiotics fortify intestinal barrier function: a systematic review and meta-analysis of randomized trials.

Background: Probiotics play a vital role in treating immune and inflammatory diseases by improving intestinal barrier function; however, a comprehensive evaluation is missing. The present study aimed to explore the impact of probiotics on the intestinal barrier and related immune function, inflammation, and microbiota composition. A systematic review and meta-analyses were conducted. Methods: Four major databases (PubMed, Science Citation Index Expanded, CENTRAL, and Embase) were thoroughly searched. Weighted mean differences were calculated for continuous outcomes with corresponding 95% confidence intervals (CIs), heterogeneity among studies was evaluated utilizing I2 statistic (Chi-Square test), and data were pooled using random effects meta-analyses. Results: Meta-analysis of data from a total of 26 RCTs (n = 1891) indicated that probiotics significantly improved gut barrier function measured by levels of TER (MD, 5.27, 95% CI, 3.82 to 6.72, P < 0.00001), serum zonulin (SMD, -1.58, 95% CI, -2.49 to -0.66, P = 0.0007), endotoxin (SMD, -3.20, 95% CI, -5.41 to -0.98, P = 0.005), and LPS (SMD, -0.47, 95% CI, -0.85 to -0.09, P = 0.02). Furthermore, probiotic groups demonstrated better efficacy over control groups in reducing inflammatory factors, including CRP, TNF-α, and IL-6. Probiotics can also modulate the gut microbiota structure by boosting the enrichment of Bifidobacterium and Lactobacillus. Conclusion: The present work revealed that probiotics could improve intestinal barrier function, and alleviate inflammation and microbial dysbiosis. Further high-quality RCTs are warranted to achieve a more definitive conclusion. Clinical trial registration: https://www.crd.york.ac.uk/PROSPERO/display_record.php?RecordID=281822, identifier CRD42021281822.

Ginseng-Containing Sijunzi Decoction Ameliorates Ulcerative Colitis by Orchestrating Gut Homeostasis in Microbial Modulation and Intestinal Barrier Integrity.

Ulcerative colitis (UC) has become a global epidemic, and the lack of an effective cure highlights the necessity and urgency to explore novel therapies. Sijunzi Decoction (SJZD), a classical Chinese herbal formula, has been comprehensively applied and clinically proven effective in treating UC; however, the pharmacological mechanism behind its therapeutic benefits is largely obscure. Here, we find that SJZD can restore microbiota homeostasis and intestinal barrier integrity in DSS-induced colitis. SJZD significantly alleviated the colonic tissue damage and improved the goblet cell count, MUC2 secretion, and tight junction protein expressions, which indicated enhanced intestinal barrier integrity. SJZD remarkedly suppressed the abundance of phylum Proteobacteria and genus Escherichia-Shigella, which are typical features of microbial dysbiosis. Escherichia-Shigella was negatively correlated with body weight and colon length, and positively correlated with disease activity index and IL-1[Formula: see text]. Furthermore, through gut microbiota depletion, we confirmed that SJZD exerted anti-inflammatory activities in a gut microbiota-dependent manner, and fecal microbiota transplantation (FMT) validated the mediating role of gut microbiota in the SJZD treatment of UC. Through gut microbiota, SJZD modulates the biosynthesis of bile acids (BAs), especially tauroursodeoxycholic acid (TUDCA), which has been identified as the signature BA during SJZD treatment. Cumulatively, our findings disclose that SJZD attenuates UC via orchestrating gut homeostasis in microbial modulation and intestinal barrier integrity, thus offering a promising alternative approach to the clinical management of UC.

Gut microbiota induces DNA methylation via SCFAs predisposing obesity-prone individuals to diabetes.

Obesity-prone (OP) individuals have a significant predisposition to obesity and diabetes. Previously, we have found that OP individuals, despite being normal in weight and BMI, have already exhibited diabetes-related DNA methylation signatures. However, the underlying mechanisms remain obscure. Here we determined the effects of gut microbiota on DNA methylation and investigated the underlying mechanism from microbial-derived short-chain fatty acids (SCFAs). Diabetes-related DNA methylation loci were screened and validated in a new OP cohort. Moreover, the OP group was revealed to have distinct gut microbiota compositions, and fecal microbiota transplantation (FMT) demonstrated the role of gut microbiota in inducing diabetes-related DNA methylations and glucolipid disorders. UPLC-ESI-MS/MS analysis indicated a significantly lower level of total fecal SCFAs in the OP group. The gut microbiota from OP subjects yielded markedly decreased total SCFAs, while notably enriched propionate. Additionally, propionate was also identified by variable importance in projection (VIP) score as the most symbolic SCFAs of the OP group. Further cellular experiments verified that propionate could induce hypermethylation at locus cg26345888 and subsequently inhibit the expression of the target gene DAB1, which was crucially associated with clinical vitamin D deficiency and thus may affect the development and progression of diabetes. In conclusion, our study revealed that gut microbiota-derived propionate induces specific DNA methylation, thus predisposing OP individuals to diabetes. The findings partially illuminate the mechanisms of diabetes susceptibility in OP populations, implying gut microbiota and SCFAs may serve as promising targets both for clinical treatment and medication development of diabetes.

Chemical profiling of root bark extract from Oplopanax elatus and its in vitro biotransformation by human intestinal microbiota.

Oplopanax elatus (Nakai) Nakai, in the Araliaceae family, has been used in traditional Chinese medicine (TCM) to treat diseases as an adaptogen for thousands of years. This study established an ultra-performance liquid chromatography coupled with quadrupole time-of-flight tandem mass spectrometry (UPLC-Q-TOF/MS) method to identify chemical components and biotransformation metabolites of root bark extract from O. elatus. A total of 18 compounds were characterized in O. elatus extract, and 62 metabolites by human intestinal microbiota were detected. Two polyynes, falcarindiol and oplopandiol were recognized as the main components of O. elatus, whose metabolites are further illustrated. Several metabolic pathways were proposed to generate the detected metabolites, including methylation, hydrogenation, demethylation, dehydroxylation, and hydroxylation. These findings indicated that intestinal microbiota might play an essential role in mediating the bioactivity of O. elatus.

Epigenetic Studies of Chinese Herbal Medicine: Pleiotropic Role of DNA Methylation.

Accumulating knowledge has been achieved on DNA methylation participating in numerous cellular processes and multiple human diseases; however, few studies have addressed the pleiotropic role of DNA methylation in Chinese herbal medicine (CHM). CHM has been used worldwide for the prevention and treatment of multiple diseases. Newly developed epigenetic techniques have brought great opportunities for the development of CHM. In this review, we summarize the DNA methylation studies and portray the pleiotropic role of DNA methylation in CHM. DNA methylation serves as a mediator participating in plant responses to environmental factors, and thus affecting CHM medicinal plants growth and bioactive compound biosynthesis which are vital for therapeutic effects. Furthermore, DNA methylation helps to uncover the pharmaceutical mechanisms of CHM formulae, herbs, and herbal-derived compounds. It also provides scientific validation for constitution theory and other essential issues of CHM. This newly developed field of DNA methylation is up-and-coming to address many complicated scientific questions of CHM; it thus not only promotes disease treatment but also facilitates health maintenance.

Dissecting the Interplay Mechanism between Epigenetics and Gut Microbiota: Health Maintenance and Disease Prevention.

The gut microbiota exists throughout the full life cycle of the human body, and it has been proven to have extensive impacts on health and disease. Accumulating evidence demonstrates that the interplay between gut microbiota and host epigenetics plays a multifaceted role in health maintenance and disease prevention. Intestinal microflora, along with their metabolites, could regulate multiple epigenetic pathways; e.g., DNA methylation, miRNA, or histone modification. Moreover, epigenetic factors can serve as mediators to coordinate gut microbiota within the host. Aiming to dissect this interplay mechanism, the present review summarizes the research profile of gut microbiota and epigenetics in detail, and further interprets the biofunctions of this interplay, especially the regulation of intestinal inflammation, the improvement of metabolic disturbances, and the inhibition of colitis events. This review provides new insights into the interplay of epigenetics and gut microbiota, and attempts to reveal the mysteries of health maintenance and disease prevention from this new perspective.

Human intestinal microbiota derived metabolism signature from a North American native botanical Oplopanax horridus with UPLC/Q-TOF-MS analysis.

Oplopanax horridus, widely distributed in North America, is an herbal medicine traditionally used by Pacific indigenous peoples for various medical conditions. After oral ingestion, constituents in O. horridus extract (OhE) could be converted to their metabolites by the enteric microbiome before absorption. In this study, in order to mimic gut environment, the OhE was biotransformed using the enteric microbiome of healthy human subjects. For accurate and reliable data collection with optimized approaches in sample preparation and analytical conditions, ultra-performance liquid chromatography and quadrupole time-of-flight mass spectrometry were used to characterize parent constituents and their metabolites. In the extract, 20 parent compounds were identified including polyynes, sesquiterpenes, monoterpeondids, phenylpropanoids and phenolic acids. After the biotransformation, a total of 78 metabolites were identified, of which 37 belonged to polyynes metabolites. The common biotransformation pathways are hydroxylation, acetylization, methylation and demethylation. Based on the pathway distributions, the metabolism signature of OhE has been explored. The metabolism pathways of OhE compounds are dependent on their structural classifications and hydrophilic/hydrophobic properties. In summary, with comprehensive analysis, we systematically investigated human microbiome-derived OhE metabolites. The enteric microbial metabolism signature provides novel information for future effective use of O. horridus.

Ginseng berry polysaccharides on inflammation-associated colon cancer: inhibiting T-cell differentiation, promoting apoptosis, and enhancing the effects of 5-fluorouracil.

BACKGROUND: Ginseng is a commonly used herbal medicine in treating various medical conditions. Chronic gut inflammation is a recognized factor for the development of colorectal cancer (CRC). In this project, Asian ginseng berry polysaccharide preparations were used to assess their effects on CRC and related immune regulation mechanisms. METHODS: Ginseng berry polysaccharide extract (GBPE) and purified ginseng berry polysaccharide portion (GBPP) were used to evaluate their activities on human HCT-116 and HT-29 CRC cell proliferation. Interleukin-8 secretion analysis was performed on HT-29 cells. Naive CD4 cell isolation and T-helper cell differentiation were performed and determined using flow cytometry for Th1 and Treg in addition to cell cycle and apoptotic investigation. RESULTS: GBPE and GBPP significantly inhibited interleukin-8 secretion and cancer cell proliferation, inhibited CD4+IFN-γ+ cell (Th1) differentiation, and decreased CD4+FoxP3+ cell (Treg) differentiation. Compared to the GBPE, GBPP showed more potent antiinflammatory activities on the malignant cells. This is consistent with the observation that GBPP can also inhibit Th1-cell differentiation better, suggesting that it has an important role in antiinflammation, whereas Treg cells hinder the body's immune response against malignancies. Supported by cell cycle and apoptosis data, GBPE and GBPP, at various degrees, remarkably enhanced the anticancer activities of 5-fluorouracil. CONCLUSION: Data from this project suggested that Asian ginseng berry potentially has clinical utility in managing enteric inflammation and suppressing CRC through immunomodulation mechanisms.

Deglycosylation of wogonoside enhances its anticancer potential.

INTRODUCTION: Scutellaria baicalensis is commonly used in Asia as an herbal medicine to treat a variety of ailments, including cancer. Wogonoside, one major constituent of S. baicalensis, can be primarily converted to wogonin through deglycosylation via enteric microbiome metabolism. MATERIALS AND METHODS: The antiproliferative effects of the glycoside (wogonoside) and its deglycosylated compound (wogonin) on a panel of human cancer cell lines from the most common solid tumors were evaluated using the MTS colorimetric assay. Cell cycle and apoptosis were determined using flow cytometry. Enzymatic activities of caspases were measured, and the interactions of wogonin and caspases were explored by a docking analysis. RESULTS: Wogonoside did not have obvious antiproliferative effects on the cancer cells. In contrast, wogonin showed significant antiproliferative activities on all the tested cancer cells. Wogonin arrested the cells in the G1 phase and significantly induced cell apoptosis. The compound also activated the expression of caspases 3 and 9. The docking results suggest that the compound forms hydrogen bonds with Phe250 and Ser251, and π-π interactions with Phe256 in caspase 3, and with Asp228 in caspase 9. CONCLUSIONS: After wogonoside deglycosylation, wogonin significantly enhanced its anticancer potential as a potent anticancer compound derived from S. baicalensis.

American ginseng microbial metabolites attenuate DSS-induced colitis and abdominal pain.

Inflammatory bowel disease (IBD) is a significant public health problem in the United States. Abdominal pain is a major complaint among individuals with IBD. Successful IBD management not only controls enteric inflammation, but also reduces abdominal discomfort. Recently, increased attention has been focused on alternative strategies for IBD management. HPLC/Q-TOF-MS analysis was employed to evaluate the intestinal microbiome's biotransformation of parent American ginseng compounds into their metabolites. Using a DSS mouse model, the effects of American ginseng microbial metabolites on chemically induced colitis was investigated with disease activity index and histological assessment. Expressions of inflammatory cytokines were determined using real-time PCR and ELISA. Abdominal pain was evaluated using the von Frey filament test. After the gut microbiome's biotransformation, the major metabolites were found to be the compound K and ginsenoside Rg3. Compared with the DSS animal group, American ginseng treatment significantly attenuated experimental colitis, as supported by the histological assessment. The enteric microbiome-derived metabolites of ginseng significantly attenuated the abdominal pain. American ginseng treatment significantly reduced gut inflammation, consistent with pro-inflammatory cytokine level changes. The gut microbial metabolite compound K showed significant anti-inflammatory effects even at low concentrations, compared to its parent ginsenoside Rb1. American ginseng intestinal microbial metabolites significantly reduced chemically-induced colitis and abdominal pain, as mediated by the inhibition of pro-inflammatory cytokine expression. Intestinal microbial metabolism plays a critical role in American ginseng mediated colitis management.

Bibliometric analysis of research on the role of intestinal microbiota in obesity.

BACKGROUND: Obesity is a key public health problem. The advancement of gut microbiota research sheds new light on this field. This article aims to present the research trends in global intestinal microbiota studies within the domain of obesity research. METHODS: Bibliographic information of the publications on intestinal microbiota and obesity was retrieved from the Scopus database, and then analyzed by using bibliometric approaches. RESULTS: A total of 3,446 references were retrieved; the data indicated a steady growth and an exponential increase in publication numbers. The references were written in 23 different languages (93.8% in English). A number of 3,056 English journal papers were included in the further analyses. Among the 940 journals, the most prolific ones were PLOS ONE, Scientific Reports, and British Journal of Nutrition. North America and Europe were the highest publication output areas. The US (995 publications) ranked first in the number of publications, followed by the China (243 publications) and France (242 publications). The publication numbers were significantly correlated with gross domestic product (GDP), human development index (HDI), and population number (PN). International collaboration analysis also shows that most of the collaborations are among developed countries. DISCUSSION: This comprehensive bibliometric study indicates that gut microbiota is a significant topic in the obesity research. The structured information may be helpful in understanding research trends, and locating research hot spots and gaps in this domain.

Effects of compound K, an enteric microbiome metabolite of ginseng, in the treatment of inflammation associated colon cancer.

Ginsenoside Rb1, a major component of different ginseng species, can be bioconverted into compound K by gut microbiota, and the latter possess much stronger cancer chemopreventive potential. However, while the initiation and progression of colorectal cancer is closely associated with gut inflammation, to date, the effects of compound K on inflammation-linked cancer chemoprevention have not been reported. In the present study, liquid chromatography quadrupole time-of-flight mass spectrometry analysis was applied to evaluate the biotransformation of Rb1 in American ginseng by human enteric microflora. The in vitro inhibitory effects of Rb1 and compound K were compared using the HCT-116 and HT-19 human colorectal cancer cell lines by a MTS assay. Cell cycle and cell apoptosis were assayed using flow cytometry. Using ELISA, the anti-inflammatory effects of Rb1 and compound K were compared for their inhibition of interleukin-8 secretion in HT-29 cells, induced by lipopolysaccharide. The results revealed that compound K is the major intestinal microbiome metabolite of Rb1. When compared with Rb1, compound K had significantly stronger anti-proliferative effects in HCT-116 and HT-29 cell lines (P<0.01). Compound K significantly arrested HCT-116 and HT-29 cells in the G1 phase, and induced cell apoptosis (P<0.01). By contrast, Rb1 did not markedly influence the cell cycle or apoptosis. Furthermore, compound K exerted significant anti-inflammatory effects even at low concentrations (P<0.05), while Rb1 did not have any distinct effects. The data obtained from the present study demonstrated that compound K, an intestinal microbiome metabolite of Rb1, may have a potential clinical value in the prevention of inflammatory-associated colorectal cancer.

Antigout Effects of Plantago asiatica: Xanthine Oxidase Inhibitory Activities Assessed by Electrochemical Biosensing Method.

The XOD inhibitory effects of Plantaginis Semen, that is, the seeds of P. asiatisca, and its representative four single compounds, acteoside, 1H-indolo-3-carbaldehyde, isoacteoside, and myristic acid, were evaluated by electron transfer signal blocking activities (ETSBA), which is based on the electron transfer signal of XOD enzymatic reaction. The blocking activities were detected using an electrochemical biosensing method. Compared with control, significant effects were observed after the addition of P. asiatica extract, acteoside, and 1H-indolo-3-carbaldehyde (all p < 0.05). The IC50 values of the extract and acteoside are 89.14 and 7.55 µg·mL-1, respectively. The IC20 values of the extract, acteoside, and 1H-indolo-3-carbaldehyde are 24.28, 3.88, and 16.16 µg·mL-1, respectively. Due to the relatively lower inhibitory potential of 1H-indolo-3-carbaldehyde, its IC50 was not obtained. In addition, isoacteoside and myristic acid did not show any XOD inhibitory effects. Our data demonstrated that the XOD inhibitory effects of the extract, acteoside, and 1H-indolo-3-carbaldehyde can be accurately evaluated by the ETSBA method. The results from this study indicated that Plantaginis Semen significantly inhibited XOD activities to reduce hyperuricemia and treat gout. The study also proves that measuring the electron transfer signal blocking activities is a simple, sensitive, and accurate method to evaluate the XOD inhibitory effects.

Genome-Wide DNA Methylation Profiles of Phlegm-Dampness Constitution.

BACKGROUND/AIMS: Metabolic diseases are leading health concerns in today's global society. In traditional Chinese medicine (TCM), one body type studied is the phlegm-dampness constitution (PC), which predisposes individuals to complex metabolic disorders. Genomic studies have revealed the potential metabolic disorders and the molecular features of PC. The role of epigenetics in the regulation of PC, however, is unknown. METHODS: We analyzed a genome-wide DNA methylation in 12 volunteers using Illumina Infinium Human Methylation450 BeadChip on peripheral blood mononuclear cells (PBMCs). Eight volunteers had PC and 4 had balanced constitutions. RESULTS: Methylation data indicated a genome-scale hyper-methylation pattern in PC. We located 288 differentially methylated probes (DMPs). A total of 256 genes were mapped, and some of these were metabolic-related. SQSTM1, DLGAP2 and DAB1 indicated diabetes mellitus; HOXC4 and SMPD3, obesity; and GRWD1 and ATP10A, insulin resistance. According to Ingenuity Pathway Analysis (IPA), differentially methylated genes were abundant in multiple metabolic pathways. CONCLUSION: Our results suggest the potential risk for metabolic disorders in individuals with PC. We also explain the clinical characteristics of PC with DNA methylation features.

Red American ginseng enhances the effect of fluorouracil on human colon cancer cells via both paraptosis and apoptosis pathways.

INTRODUCTION: As a commonly used chemotherapeutic agent, fluorouracil (5-FU) has serious dose-limiting side effects. In this study, we evaluated the synergy between red American ginseng (RAG) and 5-FU on human colorectal cancer cells, and explored the potential mechanisms. METHODS: Ginsenoside contents of white American ginseng (WAG) and RAG were determined by HPLC. Cell proliferation was evaluated by MTS assay. Combination Index (CI) analysis was executed using CompuSyn software. Paraptotic events were observed after crystal violet staining. Cell cycle distribution, cyclin A expression and apoptotic induction were analyzed using flow cytometry. RESULTS: We observed the heat treatment remarkably increased levels of ginsenoside Rg3, 20R-Rg3, Rk1 and Rg5. When the combinations of 5-FU and RAG were applied, cell proliferation inhibition rates were notably increased, indicating that RAG significantly enhanced 5-FU's effect. Additionally, CI analysis suggested that there was a synergistic action of 5-FU and RAG when combined. The cell cycle data indicated 5-FU induced S phase arrest, and the combination of 5-FU and RAG increased G1 phase. Further, the RAG's ability to enhance the anti-cancer effects of 5-FU was linked to both paraptosis and apoptosis inductions. CONCLUSION: RAG may have clinical utility to decrease the dosage of 5-FU in colorectal cancer therapeutics.

Multiple Effects of Ginseng Berry Polysaccharides: Plasma Cholesterol Level Reduction and Enteric Neoplasm Prevention.

The root of Asian ginseng (Panax ginseng C.A. Meyer) has been used for centuries in Oriental medicine to improve general well-being and to relieve various medical conditions. It is commonly understood that ginsenosides are responsible for the pharmacological activities of ginseng. Compared to the root of ginseng, studies on the berry are considerably limited. In this study, we evaluated the effects of polysaccharides from Asian ginseng berries on plasma lipid levels, chemically-induced enteric inflammation and neoplasm, and cancer chemoprevention in different experimental models. We tested two polysaccharide preparations: regular ginseng berry polysaccharide extract (GBPE) and ginseng berry polysaccharide portion (GBPP, removed MV [Formula: see text]). We first observed that both oral GBPE and oral GBPP significantly reduced plasma cholesterol and triglycerides levels in a dose-related manner in ob/ob mice, without obvious body weight changes. Then, in AOM/DSS-induced acute colitis mice, GBPE and GBPP significantly ameliorated the increased gut disease activity index and inhibited the reduction of the colon length. Further, the berry polysaccharides significantly suppressed chemically-induced pro-inflammatory cytokine levels. This is consistent with the observation that GBPE and GBPP attenuated tumorigenesis in mice by significantly and dose-dependently reducing tumor load. Finally, in vitro HCT-116 and HT-29 human colon cancer cells were used. While these berry preparations had better antiproliferation effects on the HCT-116 than the HT-29 cells, the GBPE had significantly stronger inhibitory effects than GBPP. The observed in vitro GBPE's effect could contribute to the actions of its small-molecule non-polysaccharide compounds due to their direct antiproliferative activities. Results obtained from the present study suggest that ginseng berry polysaccharides may have a therapeutic role in the management of high lipid levels, enteric inflammation, and colon malignancies.

Dynamic Changes in Neutral and Acidic Ginsenosides with Different Cultivation Ages and Harvest Seasons: Identification of Chemical Characteristics for Panax ginseng Quality Control.

In this study, dynamic changes in ginsenoside content and ratios in the Panax ginseng root were investigated with different cultivation ages and different collection months, using high-performance liquid chromatography (HPLC). Our data indicate that changes in ginsenoside Ro and malonyl ginsenosides content were dependent on the ginseng cultivation age (p < 0.05); especially, the Ro content varied from 0.16 to 4.91 mg/g, with a difference about 30-fold. Further, we found that the samples of 5 and 6-year-old P. ginseng had high Ro/Re ratio, whereas two and three-year-old P. ginseng possessed low Ro/Re ratio. Thus, the Ro/Re ratio can be used as a characteristic marker for differentiating the age of the root. The relative content of ginsenosides Rg1 and Re were affected by the ginseng's harvest season. The Re content was higher than the Rg1 content in May and June, but lower than the Rg1 content from August to October. Thus, the Rg1/Re ratio can be used as a characteristic marker for differentiating the ginseng's harvest seasons. These results indicate that the chemical characteristics of P. ginseng at different cultivation ages and harvest seasons are clearly different, which may cause differences in pharmacological activities and therapeutic effects. In addition, we developed HPLC coupled with hierarchical cluster analysis and principal component analysis methods to identify the cultivation age and harvest season of P. ginseng using characteristic ginsenosides. Our results showed that this method can be used to discriminate the cultivation age and harvest season of P. ginseng.

Desensitizing Mitochondrial Permeability Transition by ERK-Cyclophilin D Axis Contributes to the Neuroprotective Effect of Gallic Acid against Cerebral Ischemia/Reperfusion Injury.

Ischemic stroke is a devastating disease with complex pathophysiology. Much evidence confirms that opening of the mitochondrial permeability transition pore (MPTP) is related with mitochondrial dysfunction to apoptosis in ischemic stroke, thus elucidating its signaling mechanism and screening novel MPTP inhibitor is therefore of paramount importance. Our earlier studies identified that gallic acid (GA), a naturally occurring plant phenol, endows with effect on inhibition of mitochondrial dysfunction, which has significant neuroprotective effect in cerebral ischemia/reperfusion injury. However, its molecular mechanisms regulating mitochondrial dysfunction remain elusive. Here, we uncover a role of GA in protecting mitochondria via MPTP inhibition. In addition to inhibit CypD binding to adenine nucleotide translocator, GA potentiates extracellular signal-regulated kinases (ERK) phosphorylation, leading to a decrease in cyclophilin D (CypD) expression, resulting in a desensitization to induction of MPTP, thus inhibiting caspase activation and ultimately giving rise to cellular survival. Our study firstly identifies ERK-CypD axis is one of the cornerstones of the cell death pathways following ischemic stroke, and confirms GA is a novel inhibitor of MPTP, which inhibits apoptosis depending on regulating the ERK-CypD axis.