Dendrobium officinale phenolic extract maintains proteostasis by regulating autophagy in a Caenorhabditis elegans model of Alzheimer's disease.

Alzheimer's disease (AD) is a progressive neurodegenerative disease, and accumulating evidence suggested that proteostatic imbalance is a key feature of the disease. Traditional Chinese medicine exhibits a multi-target therapeutic effect, making it highly suitable for addressing protein homeostasis imbalance in AD. Dendrobium officinale is a traditional Chinese herbs commonly used as tonic agent in China. In this study, we investigated protection effects of D. officinale phenolic extract (SH-F) and examined its underlying mechanisms by using transgenic Caenorhabditis elegans models. We found that treatment with SH-F (50 µg/mL) alleviated Aß and tau protein toxicity in worms, and also reduced aggregation of polyglutamine proteins to help maintain proteostasis. RNA sequencing results showed that SH-F treatment significantly affected the proteolytic process and autophagy-lysosomal pathway. Furthermore, we confirmed that SH-F showing maintainance of proteostasis was dependent on bec-1 by qRT-PCR analysis and RNAi methods. Finally, we identified active components of SH-F by LC-MS method, and found the five major compounds including koaburaside, tyramine dihydroferulate, N-p-trans-coumaroyltyramine, naringenin and isolariciresinol are the main bioactive components responsible for the anti-AD activity of SH-F. Our findings provide new insights to develop a treatment strategy for AD by targeting proteostasis, and SH-F could be an alternative drug for the treatment of AD.

Profile of Patients Diagnosed With Acute Venous Thromboembolism in Routine Clinical Practice: The RE-COVERY DVT/PE™ Study.

BACKGROUND: The safety and efficacy of nonvitamin K antagonist oral anticoagulants (NOACs) for the treatment of venous thromboembolism (VTE) have been established in randomized controlled trials, but limited data are available on their use in clinical practice across geographical regions. METHODS: In the international RE-COVERY DVT/PE observational study (enrollment January 2016 to May 2017), we sought to characterize the patient population and describe the prescribed anticoagulant. Patient characteristics and anticoagulants administered after objective diagnosis of VTE were recorded at the baseline visit and again at hospital discharge or at 14 days after the diagnosis, whichever was later. RESULTS: A total of 6095 patients were included, 50.2% were male, and the mean age was 61.5 years. The most common comorbidities were hypertension (35%), diabetes mellitus (11%), cancer (11%), prior VTE(11%), and trauma/surgery (7%). Overall, 77% of patients received oral anticoagulants, with 54% on NOACs and 23% on vitamin K antagonists (VKAs); 20% received parenteral anticoagulation only. NOACs comprised about 60% of anticoagulant treatment in Europe and Asia but substantially less in Latin America (29%) and the Middle East (21%). For NOAC therapies, the distribution (as a percentage of the total cohort) was rivaroxaban 25.6%, dabigatran 15.5%, apixaban 11.3%, and edoxaban 1.7%. Treatment with NOACs was less frequent in patients who had cancer, chronic renal disease, heart failure, or stroke. CONCLUSIONS: These findings enhance our understanding of baseline characteristics and the initial management of patients with VTE in routine practice.

S-Propargyl-Cysteine, a Novel Hydrogen Sulfide Donor, Inhibits Inflammatory Hepcidin and Relieves Anemia of Inflammation by Inhibiting IL-6/STAT3 Pathway.

Anemia of inflammation (AI) is clinically prevalent and greatly threatens public health. Traditional remedies have raised controversy during clinical practice, calling for alternative therapies. We have recently found that hydrogen sulfide (H2S) inhibits inflammatory hepcidin, the critical mediator of AI. However, due to the chemical property of H2S, there remains an urgent need for a stable H2S donor in AI treatment. Here we reported that S-propargyl-cysteine (SPRC), a novel water-soluble H2S donor, suppressed hepatic hepcidin and corrected hypoferremia induced by lipopolysaccharide. The effects of SPRC were reversed by inhibition of cystathionine γ-lyase, one of the major endogenous H2S synthases. Moreover, SPRC reduced serum hepcidin, improved transferrin saturation, and maintained erythrocyte membrane integrity in a chronic mouse AI model. Consistently, splenomegaly was ameliorated and splenic iron accumulation relieved. Mechanism study indicated that serum IL-6 content and hepatic Il-6 mRNA were decreased by SPRC, in parallel with reduced hepatic JAK2/STAT3 activation. On the whole, our data reveal the inhibition of inflammatory hepcidin by SPRC, and suggest SPRC as a potential remedy against AI.

Hydrogen Sulfide Attenuates Inflammatory Hepcidin by Reducing IL-6 Secretion and Promoting SIRT1-Mediated STAT3 Deacetylation.

AIMS: Anemia of inflammation is quite prevalent in hospitalized patients with poor prognosis. Concerns about the effectiveness and safety of iron supplementation have arisen, driving the demand for alternative therapies. Induction of hepatic hepcidin, the master hormone of iron homeostasis, causes anemia under inflammatory conditions. Previous studies indicated that hydrogen sulfide (H2S), the third gasotransmitter and a well-known regulator of inflammation, may inhibit the secretion of inflammatory cytokines. We thus investigated the effect of H2S on inflammatory hepcidin induction. RESULTS: H2S suppressed lipopolysaccharide (LPS)-induced hepcidin production and regulated iron homeostasis in mice by decreasing serum interleukin-6 (IL-6) and Janus kinase 2 (JAK2)/signal transducer and activator of transcription 3 (STAT3) activation; similar results were obtained in Huh7 cells exposed to conditioned medium from LPS-challenged THP-1 macrophages. Intriguingly, we found H2S also attenuated hepcidin levels in Huh7 cells and mouse primary hepatocytes in a sirtuin 1 (SIRT1)-dependent manner. By promoting SIRT1 expression and stabilizing SIRT1-STAT3 interactions, H2S ameliorated IL-6-induced STAT3 acetylation, resulting in reduced hepcidin production. Inhibition and silencing of SIRT1 diminished H2S-mediated suppression of hepcidin, as opposed to SIRT1 activation and overexpression. Consistent results were observed in vivo. Furthermore, knockout of cystathionine γ-lyase (CSE), an endogenous H2S synthase, exaggerated inflammatory hepcidin expression in mice. INNOVATION: For the first time, we elucidated the effects and possible mechanisms of H2S on inflammatory hepcidin and established a novel regulatory link between SIRT1 and hepcidin. CONCLUSION: Our work demonstrates that H2S attenuates inflammation-induced hepatic hepcidin via multipathways and suggests new treatment strategies for anemia of inflammation.

Genetic and environmental factors are associated with serum 25-hydroxyvitamin D concentrations in older African Americans.

BACKGROUND: Low circulating 25-hydroxyvitamin D [25(OH)D] is prevalent in African Americans, but predictors of vitamin D status are understudied compared to Caucasian populations. OBJECTIVE: We investigated whether certain environmental and genetic factors are predictors of circulating 25(OH)D in 989 elderly African Americans participating in the Health, Aging, and Body Composition (Health ABC) Study. METHODS: Regression analysis estimated the cross-sectional association of nongenetic (environmental) factors with 25(OH)D. Single nucleotide polymorphisms (SNPs) associated with 25(OH)D in Caucasian genome-wide association studies (GWASs) were analyzed for association with serum 25(OH)D, including analyses of all imputed SNPs in identified genomic regions. Genome-wide complex trait analysis (GCTA) evaluated the association of all (genome-wide) genotyped SNPs with serum 25(OH)D in the Health ABC Study with replication in the Multi-Ethnic Study of Atherosclerosis (MESA) cohort. RESULTS: Gender, study site, season of blood draw, body mass index, dietary supplement use, dairy and cereal consumption, Healthy Eating Index score, and walking >180 min/wk were associated with 25(OH)D (P < 0.05), jointly explaining 25% of the variation in circulating 25(OH)D. Multivitamin supplement use was the strongest predictor of circulating 25(OH)D, and supplement users had a 6.3-µg/L higher serum 25(OH)D concentration compared with nonusers. Previous GWAS-identified gene regions were not replicated in African Americans, but the nonsynonymous rs7041 SNP in group-specific component (vitamin D binding protein) was close to significance thresholds (P = 0.08), and there was evidence for an interaction between this SNP and use of multivitamin supplements in relation to serum 25(OH)D concentration (P = 0.04). Twenty-three percent (95% CI: 0%, 52%) of the variation in serum 25(OH)D was explained by total genetic variation in a pooled GCTA of 2087 Health ABC Study and MESA African-American participants, but population substructure effects could not be separated from other genetic influences. CONCLUSIONS: Modifiable dietary and lifestyle predictors of serum 25(OH)D were identified in African Americans. GCTA confirms that a proportion of 25(OH)D variability is attributable to genetic variation, but genomic regions associated with the 25(OH)D phenotype identified in prior GWASs of European Americans were not replicated in the Health ABC Study in African Americans.

Arecoline excites the contraction of distal colonic smooth muscle strips in rats via the M3 receptor-extracellular Ca2+ influx - Ca2+ store release pathway.

Areca is a Chinese herbal medicine that is widely used for constipation. However the mechanisms of its action are not clear. We investigated the effects of arecoline, the most active component of areca, on the motility of rat distal colonic smooth muscle strips. In longitudinal muscle of distal colon (LMDC) and circular muscle of distal colon (CMDC), arecoline increased the contraction in a dose-dependent manner. Tetrodotoxin (TTX) did not inhibit the effects of arecoline. The contractile response to arecoline was completely antagonized by atropine. 4-Diphenylacetoxy-N-methylpiperidine methiodide (4-DAMP) strongly depressed the response to arecoline, but gallamine and methoctramine did not. Nifedipine, 2-aminoethoxydiphenyl borate (2-APB), and Ca2+-free Krebs solution with EGTA partly inhibited the effects of arecoline. The sum of Ca2+-free Krebs solution, EGTA, and 2-APB completely inhibited the effects of arecoline. The results show that arecoline stimulates distal colonic contraction in rats via the muscarinic (M3) receptor - extracellular Ca2+ influx - Ca2+ store release pathway. It is likely that the action of areca in relieving constipation is due to its stimulation of muscle contraction.

Monitoring of immune responses to a herbal immuno-modulator in patients with advanced colorectal cancer.

Many herbal medicines are widely used as immuno-modulators in Asian countries. Ganoderma lucidum (Lingzhi) is one of the most commonly used herbs in Asia and preclinical studies have established that the polysaccharide fractions of G. lucidum have potent immuno-modulating effects. However, clinical evidence for this is scanty. The present open-labeled study aimed to evaluate the effects of G. lucidum polysaccharides on selected immune functions in patients with advanced colorectal cancer. Forty-seven patients were enrolled and treated with oral G. lucidum at 5.4 g/day for 12 weeks. Selected immune parameters were monitored using various immunological methods throughout the study. In 41 assessable cancer patients, treatment with G. lucidum tended to increase mitogenic reactivity to phytohemagglutinin, counts of CD3, CD4, CD8 and CD56 lymphocytes, plasma concentrations of interleukin (IL)-2, IL-6 and interferon (IFN)-gamma, and NK activity, whereas plasma concentrations of IL-1 and tumor necrosis factor (TNF)-alpha were decreased. For all of these parameters, no statistical significance was observed when a comparison was conducted between baseline and those values after a 12-week treatment with G. lucidum. The changes of IL-1 were correlated with those for IL-6, IFN-gamma, CD3, CD4, CD8 and NK activity (p<0.05) and IL-2 changes were correlated with those for IL-6, CD8 and NK activity. The results indicate that G. lucidum may have potential immuno-modulating effect in patients with advanced colorectal cancer. Further studies are needed to explore the benefits and safety of G. lucidum in cancer patients.

Effects of water-soluble Ganoderma lucidum polysaccharides on the immune functions of patients with advanced lung cancer.

Preclinical studies have established that the polysaccharide fractions of Ganoderma lucidum have potential antitumor activity. Recent clinical studies have demonstrated that G. lucidum polysaccharides enhance host immune functions [e.g., enhanced natural killer (NK) cell activity] in patients with advanced solid tumors, although an objective response was not observed. This open-label study aimed to evaluate the effects of water-soluble G. lucidum polysaccharides (Ganopoly, Encore International Corp., Auckland, New Zealand) on immune functions in patients with advanced lung cancer. Thirty-six patients were enrolled and treated with 5.4 g/day Ganopoly for 12 weeks. In the 30 cancer patients who completed the trial, treatment with Ganopoly did not significantly alter the mean mitogenic reactivity to phytohemagglutinin, mean counts of CD3, CD4, CD8, and CD56, mean plasma concentrations of interleukin (IL)-2, IL-6, and interferon (IFN)-gamma, or NK activity in the patients, but the results were significantly variable. However, some cancer patients demonstrated markedly modulated immune functions. The changes in IL-1 were correlated with those for IL-6, IFN-gamma, CD3, CD8, and NK activity (P < .05), and IL-2 changes were correlated with those for IL-6, CD8, and NK activity. The results suggest that subgroups of cancer patients might be responsive to Ganopoly in combination with chemotherapy/radiotherapy. Further studies are needed to explore the efficacy and safety of Ganopoly used alone or in combination with chemotherapy/radiotherapy in lung cancer patients.

Antitumor activity and underlying mechanisms of ganopoly, the refined polysaccharides extracted from Ganoderma lucidum, in mice.

Ganopoly is an aqueous polysaccharide fraction extracted from G. lucidum by patented biochemical technique and has been marketed as an over-the-counter product for chronic diseases including cancer and hepatopathy in many Asian countries. This study was undertaken to explore the anti-tumour effect and the underlying mechanisms of Ganopoly in mice and human tumor cell lines. The maximum tolerated dose (MTD) of Ganopoly in mice was estimated to be 100 mg/kg from a pilot study. Treatment of mice with oral Ganopoly for 10 days significantly reduced the tumour weight of sarcoma-180 in a dose-dependent manner, with inhibition rates of 32.3, 48.2 and 84.9% and growth delays of 1.5, 3.5, and 13.1 days at 20, 50, and 100 mg/kg, respectively. Incubation of Ganopoly at 0.05-1.0 mg/ml for 48 hours showed little or negligible cytotoxicity against human tumor CaSki, SiHa, Hep3B, HepG2, HCT116 HT29, and MCF7 cells in vitro. In contrast, 10 mg/ml of Ganopoly caused significant cytotoxicity in all tumour cells tested except MCF7, with marked apoptotic effect observed in CaSki, HepG2, and HCT116 cells, as indicated by nuclear staining and DNA fragmentation. In addition, Ganopoly enhanced concanavalin A-stimulated proliferation of murine splenocytes by 35.3% at 10 mg/ml, and stimulated the production of nitric oxide in thioglycollate-primed murine peritoneal macrophages in a concentration-dependent manner over 0.05-10 mg/ml. Addition of Ganopoly at 1 mg/ ml to murine peritoneal macrophages also potentiated lipopolysaccharide-induced nitric oxide production by 64.2%. Treatment of healthy mice or mice bearing sarsoma-180 with oral Ganopoly over 20-100 mg/kg for 7 day significantly increased the expression of both TNF-alpha and IFN-gamma (at both mRNA and protein levels) in splenocytes in a dose-dependent manner. Moreover, treatment of Ganopoly over 20-100 mg/kg significantly increased cytotoxic T lymphocyte cytotoxicity and NK activity in mice. The overall findings indicated that Ganopoly had antitumor activity with a broad spectrum of immuno-modulating activities and may represent a novel promising immunotherapeutic agent in cancer treatment.

A randomized, double-blind and placebo-controlled study of a Ganoderma lucidum polysaccharide extract in neurasthenia.

Ganoderma lucidum has been widely used to treat various diseases, including cancer, diabetes, and neurasthenia in many Asian countries. This randomized, double-blind, placebo-controlled parallel study aimed to investigate the efficacy and safety of a polysaccharide extract of G. lucidum (Ganopoly) in Chinese patients with neurasthenia. One hundred thirty-two patients with neurasthenia according to the diagnosis criteria of the 10th International Classification of Diseases were included in this study. Written consents were obtained from the patients, and the study was conducted in accordance with Good Clinical Practice guidelines. Patients were randomized to receive Ganopoly or placebo orally at 1,800 mg three times a day for 8 weeks. Efficacy assessments comprised the Clinical Global Impression (CGI) improvement of severity scale and the Visual Analogues Scales for the sense of fatigue and well-being. In 123 assessable patients in two treatment groups at the end of the study, Ganopoly treatment for 8 weeks resulted in significantly lower scores after 8 weeks in the CGI severity score and sense of fatigue, with a respective reduction of 15.5% and 28.3% from baseline, whereas the reductions in the placebo group were 4.9% and 20.1%, respectively. The score at day 56 in the sense of well-being increased from baseline to 38.7% in the Ganopoly group compared with 29.7% in the placebo group. The distribution of the five possible outcomes from very much improved to minimally worse was significantly different (X (2) = 10.55; df = 4; P = .0322) after treatment with Ganopoly or placebo. There was a percentage of 51.6% (32 of 62) in the Ganopoly group rated as more than minimally improved compared with 24.6% (15 of 61) in the placebo group (X (2) = 9.51; df = 1; P = .002). Ganopoly was well tolerated in the study patients. These findings indicated that Ganopoly was significantly superior to placebo with respect to the clinical improvement of symptoms in neurasthenia.

Ganoderma lucidum polysaccharide fractions accelerate healing of acetic acid-induced ulcers in rats.

The polysaccharide (PS) fractions from several medicinal herbs have been reported to have anti-ulcer effects against experimental ulcers in the rat. The water-soluble PS fractions from Ganoderma lucidum (Reishi mushroom) have been shown to inhibit indomethacin-induced gastric mucosal lesions in rats. This study aimed to investigate the effect of the PS fraction from G. lucidum on the healing of gastric ulcers induced by acetic acid in the rat and to elucidate the underlying mechanisms involved. The abdomen of rats was incised, and the stomach was treated with 10 M acetic acid (100 microL) for 1 minute, and then treated with G. lucidum PS (0.1, 0.5, or 1.0 g/kg) intragastrically, once a day for 14 consecutive days. The results indicated that the oral administration of G. lucidum PS at 0.5 and 1.0 g/kg for 2 weeks caused a significant acceleration of ulcer healing by 40.1% and 55.9%, respectively. In the mechanistic studies, additional rats were treated with 10 M acetic acid to induce acute ulcers, and then treated with G. lucidum PS (1.0 g/kg) for 3, 7, 10, or 14 days. Exposure of the rat stomach to acetic acid led to decreased mucus and increased prostaglandin levels. Treatment with G. lucidum PS at 1.0 g/kg significantly (P < .05) suppressed or restored the decreased gastric mucus levels and increased gastric prostaglandin concentrations compared with the control group. These results indicates that G. lucidum PS is an active component with healing efficacy on acetic acid-induced ulcers in the rat, which may represent a useful herbal preparation for the prevention and treatment of peptic ulcers.