Protective Effects and Therapeutics of Ginsenosides for Improving Endothelial Dysfunction: From Therapeutic Potentials, Pharmaceutical Developments to Clinical Trials.

The endothelium covers the internal lumen of the entire circulatory system and plays an important modulatory role in vascular homeostasis. Endothelium dysfunction, characterized by a vasoconstrictive, pro-inflammatory, and pro-coagulant state, usually manifests as a significant pathological process of vascular diseases, including hypertension, atherosclerosis (AS), stroke, diabetes mellitus, coronary artery disease, and cancer. Therefore, there is an urgent necessity to seek promising therapeutic drugs or remedies to ameliorate endothelial dysfunction-induced vascular ailments and complications. Recently, much attention has been attached to ginsenosides, the most significant active components of ginseng, which have always been referred to as "all-healing" and widely used for its extensively medicinal value. Surprisingly, ginsenosides have diverse biological activity which might be related to inflammation, apoptosis, oxidative stress, and angiogenesis. In this review, a brief introduction about endothelial dysfunction and ginsenosides was demonstrated, and the emphasis was put on summarizing multi-faceted pharmacological effects and underlying molecular mechanisms of ginsenosides on the endothelium, including vasorelaxation, anti-oxidation, anti-inflammation, and angio-modulation. Beyond that, nanotechnology to improve efficacy and the existing clinical trials of ginsenosides were concluded. Hopefully, our work will give suggestions for promoting clinical application of traditional Chinese medicine, e.g., hypertension, AS, diabetes, ischemic stroke, and cancer. This review provides a comprehensive base of knowledge for ginsenosides to prevention and treatment of vascular injury- related diseases with clinical significance.

Platelet membrane-cloaked selenium/ginsenoside Rb1 nanosystem as biomimetic reactor for atherosclerosis therapy.

Cardiovascular disease remains the dominant contributor to human mortality, and the main etiology of which is atherosclerosis (AS). Enhancing the targeted ability of nanosystem and improving plaque stability are critical challenges for the current management of AS. Herein, we leverage the marked role of platelets in AS to construct a biomimetic nanodrug delivery system (PM@Se/Rb1 NPs), which prepared by cloaking platelet membrane (PM) around Selenium (Se) and ginsenoside Rb1 nanoparticles (Se/Rb1 NPs) core. The core endows the delivery system antioxidant, lipid metabolism and anti-inflammatory effects for AS effective treatment. Moreover, PM-coated nanoparticles reserve platelets' inherent biological elements to deliver drugs to plaques. We further explored the potential effect of PM@Se/Rb1 NPs' combination with the clinical anticoagulant drug warfarin (War) to treat AS and elucidated the possible drug interaction mechanism. As a result, the PM@Se/Rb1 NPs are not only capable of improving inflammatory behaviors such as inhibitory adhesion ability and anti-angiogenesis therapeutic effect in vitro, but also administer efficiently localizing to atherosclerotic plaque explaining by aortic samples from established ApoE-/- mice. Therefore, this study provided a theoretical basis of biomimetic nanodrug in the treatment of AS as well as an effective reference for the combined application of nanodrug and clinical drugs.

Artemisinin suppresses hepatocellular carcinoma cell growth, migration and invasion by targeting cellular bioenergetics and Hippo-YAP signaling.

The primary liver cancer (PLC) is one of the leading causes of cancer-related death worldwide. The predominant form of PLC is hepatocellular carcinoma (HCC), which accounts for about 85% of all PLC. Artemisinin (ART) was clinically used as anti-malarial agents. Recently, it was demonstrated to inhibit cell growth and migration in multiple cancer types. However, the molecular mechanism underlying these anti-cancer activity remains largely unknown. Herein, it is discovered that ART dramatically suppresses HCC cell growth in vitro through arresting cell cycle progression, and represses cell migration and invasion via regulating N-cadherin-Snail-E-cadherin axis. In addition, the disruption of cellular bioenergetics contributed to ART-caused cell growth, migration and invasion inhibition. Moreover, ART (100 mg/kg, intraperitoneally) substantially inhibits HCC xenograft growth in vivo. Importantly, Hippo-YAP signal transduction is remarkably inactivated in HCC cells upon ART administration. Collectively, these data reveal a novel mechanism of ART in regulating HCC cell growth, migration, and invasion, which indicates that ART could be considered as a potential drug for the treatment of HCC.

Carrier-free nanodrug: A novel strategy of cancer diagnosis and synergistic therapy.

Nanoformulations with advantages in drug delivery, safety and pharmacodynamics have been booming as a promising strategy for cancer therapy. However, the traditional nanocarrier still suffers from the low drug loading capacity, potential systematic toxicity, unclear metabolism, and other uncertainties. To overcome these issues, carrier-free nanodrugs with desirable bioactivity were developed rapidly and drawn considerable attention. Meanwhile, the multifunctional self-delivery nanoarcheticture fabricated by a simple and "green" method, has significant advantages in synergistic cancer therapy and inhibition of multidrug resistant (MDR). Till now, carrier-free nanoparticles for tumor theranostics, phototherapy, chemotherapy, diagnose and synergistic therapy, have made outstanding progress. In this review, we make an integrated and exhaustive overview of lately reports on carrier-free nanodrug delivery systems formed by several active agents. We summarize the self-assembly and modified strategies, with emphasis on application superiority of carrier-free nanocrystal, and give new insight into the establishment of ideal nanosystems for cancer treatment.

Probiotic Clostridium butyricum Improves the Growth Performance, Immune Function, and Gut Microbiota of Weaning Rex Rabbits.

Probiotics could promote animal growth and enhance immune function. This study investigated the effects of Clostridium butyricum (CB) on the growth performance, intestinal immune, and gut microbiota of weaning rex rabbits. A total of 60 healthy female rabbits (5-month-old) were divided equally into four groups and mated on the same day: control group (CTRL, fed with basal feed), low-dose group (LDG, fed with basal feed + 1.0 × 103 CFU/g CB), middle-dose group (MDG, fed with basal feed + 1.0 × 104 CFU/g CB), and high-dose group (HDG, fed with basal feed + 1.0 × 105 CFU/g CB). Then, 30 weaning rex rabbits (35-day-old) were collected from each group for this experiment, and they were offered the same feeds as their mother. The results demonstrated that high-dose CB treatment significantly increased average daily weight gain of weaning rex rabbits. Further studies suggested that CB enhanced small intestinal digestive enzyme activity and improved mucosal morphology and antioxidant status. Supplemented with CB, small intestinal barrier function was maintained with the upregulation of mRNA levels of ZO-1, claudin, and occludin as well as the increase of sIgA production. Moreover, the relative expressions of MyD88, TLR2, and TLR4 were elevated in HDG; simultaneously, pro-inflammatory cytokines including IL-6, INF-γ, and TNF-α were decreased after CB administration. In addition, CB showed beneficial effects in improving weaning rex rabbit intestinal microflora via increasing the abundance of beneficial bacteria. Therefore, our results indicated CB can promote rex rabbit growth, which is likely to the enhancement of immune function and the improvement of intestinal microbiota.

The effectiveness of long-needle acupuncture at acupoints BL30 and BL35 for CP/CPPS: a randomized controlled pilot study.

BACKGROUND: The chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) is one of the commonest chronic inflammatory diseases in adult men, for which acupuncture has been used to relieve related symptoms. The present study aimed to evaluate the therapeutic effect of the long-needle acupuncture on CP/CPPS. METHODS: A randomized traditional acupuncture-controlled single blind study was conducted on 77 patients who were randomized into long-needle acupuncture (LA) and traditional acupuncture (TA) groups. The patients received six sessions of acupuncture for 2 weeks and a follow-up was scheduled at week 24. The primary outcome was measured by the total National Institutes of Health-Chronic Prostatitis Symptom Index (NIH-CPSI) score at week 2. Four domains of the NIH-CPSI (urination, pain or discomfort, effects of symptoms, and quality of life) and the clinical efficacy score served as the secondary outcome. RESULTS: The total NIH-CPSI score at week 2 and week 24 was significantly improved in the LA group compared with the TA group. LA significantly improved urination, pain or discomfort, the effects of symptoms, and the quality of life at week 2 and week 24 and patients undergoing LA treatment had a higher clinical efficacy score. CONCLUSION: Needling at the BL30 and BL35 using LA benefits patients with CP/CPPS. TRIAL REGISTRATION: The study was registered at the Chinese Clinical Trial Register ( ChiCTR-ICR-15006138 ).

Bidirectional immunomodulating activity of fermented polysaccharides from Yupingfeng.

Accumulating evidence has proven the immunomodulating activity of Yupingfeng. This study compared the immunomodulatory activity in vitro of the unfermented Yupingfeng dreg polysaccharides (UYDP) with that of the fermented Yupingfeng dreg polysaccharides (FYDP) obtained using Rhizopus oligosporus SH. Results consistently elucidated the duality of the immunomodulatory roles of UYDP and FYDP in regulating proliferation, and cytokines expressions in murine lymphocytes and macrophages. Compared with UYDP, FYDP effectively enhanced the proliferation of lymphocytes and promoted mRNA expression of inducible nitric oxide synthase (iNOS), IL-6, TNF-α, INF-γ, nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), and TLR-4 in lymphocytes and macrophages. Moreover, compared with UYDP, FYDP effectively normalized cell proliferation and downregulated mRNA expression levels of pro-inflammatory cytokines, NF-κB, TLR-4, and iNOs in lipopolysaccharide-induced chronic inflammation cells. The results revealed that the bidirectional immunomodulatory effects in vitro of UYDP and FYDP, and the bi-directional immunomodulatory activity of FYDP is superior over that of UYDP. Moreover, more studies in vivo that needs to be studied further.

Illumina Miseq platform analysis caecum bacterial communities of rex rabbits fed with different antibiotics.

Antibiotics have been widely used for the prevention and the treatment of diseases to humans and animals, and they have fed additives for agricultural animals to promote growth. However, there is a growing concern over the practice due to its side effects on intestinal microbial communities which plays a vital role in animals' health. To investigate the effect of antibiotics on the bacterial population of the caecum in rex rabbits, 80 rex rabbits were randomly divided into four groups: control group (B, basal diet), chlortetracycline group (C, 50 mg/kg), colistin sulfate group (S, 20 mg/kg) and zinc bacitracin group (Z, 40 mg/kg). Caecum microbial communities of rex rabbits from the four groups were analyzed through Illumina Miseq platform after being fed 28 days. The results showed that most obtained sequences belongs to Firmicutes followed by Bacteroidetes, and the ratio of Bacteroidetes/Firmicutes in C group (42.31 %) was higher than that in Z group (21.84 %). Zinc bacitracin supplementation caused a significant decreased of the Proteobacteria phylum and Lactobacillus spp. (P < 0.05), while the Lactobacillus spp. significantly increased in S group (P < 0.05). In addition, Ruminococcus spp., especially Ruminococcus albus were the predominant bacterial species found in both S and Z groups. The proportion of Coprococcus spp. significantly increased in Z group (P < 0.05). These findings suggested that the antibiotics used may cause significant changes in the caecum microbiota of rex rabbits, and we also found C group had a similarity caecum bacteria structure with B group which was probably due to the high levels of chlortetracycline resistance.

Fermented Yupingfeng polysaccharides enhance immunity by improving the foregut microflora and intestinal barrier in weaning rex rabbits.

Yupingfeng (YPF) is a kind of Astragali radix-based ancient Chinese herbal supplemented with Atractylodis Macrocephalae Rhizoma and Radix Saposhnikoviae. Increasing evidence has proven the beneficial immunomodulating activity of YPF. However, the action mechanism(s) of it is not known. Here, we explored the immunomodulatory activity of unfermented Yupingfeng polysaccharides (UYP) and fermented Yupingfeng polysaccharides (FYP) obtained using Rhizopus oligosporus SH in weaning Rex rabbits. The results showed that both UYP and FYP exhibited notable growth-promoting and immune-enhancing activities, improvement of the intestinal flora homeostasis, and maintenance of intestinal barrier integrity and functionality. Notably, compared with UYP, FYP effectively enhanced average daily gain, organ indices, interleukin-2 (IL-2), IL-4, IL-10, tumor necrosis factor-alpha (TNF-α), TLR2, and TLR4 mRNA levels in spleen, IL-1, IL-2, IL-4, IL-6, IL-10, IL-12, TNF-α, and IFN-γ protein concentrations in serum, and TLR2 and TLR4 mRNA expressions in the gastrointestinal tract (GIT). Moreover, FYP exhibited greater beneficial effects in improving the intestinal flora, including augment flora diversity and the abundance of cellulolytic bacteria, reduction the abundance of Streptococcus spp. and Enterococcus spp. in the GIT, particularly the foregut and maintaining the intestinal barrier integrity and functionality by upregulating zonula occludens 1, claudin, polymeric immunoglobulin receptor, trefoil factor, and epidermal growth factor mRNA levels in the jejunum and ileum. Our results indicated the immunoenhancement effect of FYP is superior over that of UYP, which is probably related with the amelioration of the intestinal microflora and intestinal barrier in the foregut.