PMID: 

J Cell Mol Med. 2019 02 ;23(2):750-760. Epub 2018 Nov 24. PMID: 30472806

Abstract Title: 

Therapeutic effects of lentinan on inflammatory bowel disease and colitis-associated cancer.

Abstract: 

In this study, we investigated the therapeutic potential of lentinan in mouse models of inflammatory bowel disease (IBD) and colitis-associated cancer (CAC). Lentinan decreased the disease activity index and macroscopic and microscopic colon tissue damage in dextran sulphate sodium (DSS)-induced or TNBS-induced models of colitis. High-dose lentinan was more effective than salicylazosulfapyridine in the mouse models of colitis. Lentinan decreased the number of tumours, inflammatory cell infiltration, atypical hyperplasia and nuclear atypia in azoxymethane/DSS-induced CAC model. It also decreased the expression of pro-inflammatory cytokines, such as IL-13 and CD30L, in IBD and CAC model mice possibly by inhibiting Toll-like receptor 4 (TLR4)/NF-κB signalling and the expression of colon cancer markers, such as carcinoembryonic antigen, cytokeratin 8, CK18 and p53, in CAC model mice. In addition, lentinan restored the intestinal bacterial microbiotal community structure in IBD model mice. Thus, it shows therapeutic potential in IBD and CACmodel mice possibly by inhibiting TLR4/NF-κB signalling-mediated inflammatory responses and disruption of the intestinal microbiotal structure.

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PMID: 

Food Funct. 2019 Apr 17 ;10(4):2094-2101. PMID: 30916667

Abstract Title: 

Lentinan administration relieves gut barrier dysfunction induced by rotavirus in a weaned piglet model.

Abstract: 

Rotavirus (RV) is a pathogen that induces severe diarrhea in infants and young animals. Shiitake mushroom is a traditional food, which can improve physiological function, including gut health. Lentinan (LNT) is the main functional component of Shiitake mushroom. This study aimed to verify whether LNT administration could improve intestinal barrier function, thereby decreasing RV-induced diarrhea in a porcine model. According to initial weight and origin, a total of 28 weaned piglets were randomly fed 2 diets containing 0 or 84 mg kg-1 LNT for 19 d (n = 14). On day 15, RV was orally infused to half of the pigs in each group. RV-induced diarrhea (P

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PMID: 

Prog Mol Biol Transl Sci. 2019 ;163:297-328. Epub 2019 Apr 4. PMID: 31030752

Abstract Title: 

Mushroom polysaccharide lentinan for treating different types of cancers: A review of 12 years clinical studies in China.

Abstract: 

Lentinula edodes has been used to improve general health for thousands of years in Asia. It is the second largest cultivated and the most popular edible mushroom in the world known as"Xianggu"in China and"Shiitake"in Japan. Lentinan is a polysaccharide extracted from Lentinula edodes.β-Glucan is the major bioactive component in lentinan with immunostimulatory effect. The antitumor property of lentinan was reported in 1960s. Biochemical studies indicate that immunocytes can be activated by lentinan through multiple signaling pathways, such as TLR4/Dectin1-MAPK and Syk-PKC-NFκBpathways. Though it has been approved as an adjuvant therapeutic drug both in China and Japan for treating cancers since 1980s, a systematic review of clinical studies of lentinan has not been conducted elaborately. In this review, over 9474 reported lentinan-associated cancer treatment cases are evaluated and summarized from 135 independent studies in China during the past 12 years (2004-2016) based on CNKI (China National Knowledge Infrastructure), VIP (Chongqing VIP Chinese Scientific Journals Database) and Wanfang database. The 9474 reported lentinan-associated cancer treatment cases include lung cancer (3469 cases), gastric cancer (3039 cases), colorectal cancer (1646 cases), ovarian cancer (183 cases), cervical cancer (130 cases), Non-Hodgkin lymphoma (70 cases), pancreatic cancer (15 cases), cardiac cancer (15 cases), nasopharyngeal cancer (14 cases), duodenal cancer (1 case) and110 cancer cases with no classifying patient information. Overall clinical data show solid effect of lentinan on improving the quality of life and on promoting the efficacy of chemotherapy and radiation therapy during cancer treatment.

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PMID: 

J Cosmet Dermatol. 2020 Feb ;19(2):502-507. Epub 2019 May 28. PMID: 31135098

Abstract Title: 

Lentinan inhibits oxidative stress and inflammatory cytokine production induced by benzo(a)pyrene in human keratinocytes.

Abstract: 

BACKGROUND: Benzo(a)pyrene, a major environmental pollutant, is known to accelerate skin aging through oxidative stress, increase the production of inflammatory mediators, and cause skin cancer. Lentinan, prepared from Lentinus edodes (Shiitake mushroom), has been reported to exhibit anti-coagulant, anti-viral, anti-cancer, anti-tumor, and anti-coagulant effects. However, the effect of lentinan on human keratinocytes treated with benzo(a)pyrene is unknown.AIMS: The aim of this study was to explore whether lentinan inhibits benzo(a)pyrene-induced oxidative stress and inflammatory cytokine production in human keratinocytes.METHODS: We investigated the effect of lentinan on benzo(a)pyrene-induced oxidative stress indicators (malondialdehyde, superoxide dismutase, and glutathione peroxidase) in human immortalized keratinocytes (HaCaT cells). We also assessed the production of inflammatory factors interleukin-8 and chemokine ligand-2 induced by benzo(a)pyrene exposure at both mRNA and protein levels.RESULTS: Lentinan inhibited oxidative stress induced by benzo(a)pyrene, as shown by the concentration-dependent reduction in reactive oxygen species in HaCaT cells. In addition, malondialdehyde levels were reduced to 53% of those of cells treated with benzo(a)pyrene without lentinan. The activities of superoxide dismutase and glutathione peroxidase were approximately 18- and 2.7-fold higher in benzo(a)pyrene-treated cells with lentinan than in those without lentinan. Moreover, lentinan significantly reduced interleukin-8 and chemokine ligand-2 mRNA and protein levels.CONCLUSIONS: These findings suggest that lentinan has two biological activities that are potentially useful for managing inflammatory skin diseases or disorders related to oxidative stress induced by benzo(a)pyrene. Therefore, cosmetics containing L edodes have promising dermatological applications, with potential utility in protecting the skin against environmental pollutants.

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PMID: 

Artif Cells Nanomed Biotechnol. 2019 Dec ;47(1):3938-3946. PMID: 31581847

Abstract Title: 

Lentinan protects cardiomyocytes against hypoxia-induced injury by regulation of microRNA-22/Sirt1.

Abstract: 

Myocardial ischemia is a serious disease which threatens human's life. Lentinan (LEN) possesses multiple biological properties: anticancer, antibacterial, antiviral and antioxidant effects. Our study investigated the effects of LEN on hypoxia-stimulated cardiomyocytes and the underlying mechanism. Primary neonatal rat ventricular cardiomyocytes (PNCM) were isolated from neonate rat pups. PNCM and H9c2 cells were stimulated by hypoxia and treated by LEN. Cell viability and apoptosis were detected by cell counting kit-8 and flow cytometry, respectively. Moreover, apoptotic factors were examined by western blot. Phosphatidylinositol 3'-kinase (PI3K)/protein kinase B (AKT) andβ-catenin pathways related proteins were analyzed by western blot. Furthermore, the expression of microRNA-22 (miR-22) was detected by qRT-PCR. Altered expression of miR-22 and silenced information regulator 1 (Sirt1) was achieved by transfection. The relationship between miR-22 and Sirt1 was verified by luciferase assay. We found that LEN promoted cell viability and decreased apoptosis which led to the contrary results with what hypoxia induced. Moreover, LEN decreased the ratio of Bax to Bcl-2 and the level of cleaved caspase-3, as well as activated PI3K/AKT and β-catenin. LEN decreased the expression of miR-22 which was upregulated by hypoxia. miR-22 overexpression broken the promoting effects led by LEN. Moreover, Sirt1 was verified to be a target of miR-22. Silence of Sirt1 led to the opposite results with LEN. In conclusion, LEN relieved hypoxia-induced cellular injuries evidenced by increasing viability and decreasing apoptosis via down-regulation of miR-22, which was accompanied by activation of PI3K/AKT and β-catenin pathways. Highlights Lentinan alleviates hypoxia-induced injuries of PNCM and H9c2 cells; microRNA-22 expression is decreased by lentinan; Lentinan reduceshypoxia-induced injury by microRNA-22 downregulation; Lentinan regulates PI3K/AKT and Wnt/β-catenin by regulation of microRNA-22/Sirt1.

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PMID: 

J Med Food. 2019 Dec ;22(12):1262-1270. PMID: 31834842

Abstract Title: 

Effects ofWater Extract on Alcoholic and Nonalcoholic Fatty Liver Impairment.

Abstract: 

The aim of this study was to investigate the potential protective effects of the hot water extract of(EJW) on EtOH- or free fatty acid (FFA)-induced fatty liver injury. HepG2/2E1 cells were exposed to EtOH and HepG2 cells were exposed to a mixture of FFAs (oleic acid:palmitic acid, 2:1) to stimulate oxidative stress and to induce lipid accumulation, respectively. Antioxidant activity was significantly increased and lipid accumulation was inhibited in cells pretreated with EJW compared to those in cells exposed to EtOH or FFA only. Also, 5'adenosine monophosphate (AMP)-activated protein kinase (AMPK) and acetyl-coenzyme A carboxylase (ACC) phosphorylations were considerably increased, indicating activation of AMPK. Furthermore, EJW reduced the messenger RNA (mRNA) expression of lipogenesis-associated factors such as ACC, sterol regulatory element binding protein-1c (SREBP-1c), and fatty acid synthase (FAS), and increased mRNA expression related to components of the fatty acid-oxidation pathway, such as AMPK, carnitine palmitoyltransferase 1 (CPT-1), and peroxisome proliferator-activated receptor alpha (PPAR). These results suggest that EJW possessed potential preventive effects against both EtOH- and FFA-induced fatty liver disease by alleviation of oxidative stress and lipid accumulation in hepatocytes.

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PMID: 

J Alzheimers Dis. 2020 Jan 24. Epub 2020 Jan 24. PMID: 31985470

Abstract Title: 

Dietary Lactoferrin Supplementation Prevents Memory Impairment and Reduces Amyloid-β Generation in J20 Mice.

Abstract: 

Lactoferrin (LF) is present in senile plaques and neurofibrillary tangles in the brains of Alzheimer's disease (AD) patients and amyloid-β protein precursor transgenic (AβPP-Tg) mice. LF has anti-inflammatory and antioxidant functions, which exert neuroprotective effects against AD. However, its effects on memory impairment and AD pathogenesis have not been fully examined. In this study, we examined the effects of LF on memory impairment and AD pathogenesis in AβPP-Tg mice (J20 mice). Nine-month-old J20 mice were fed with control, 2% lactoferrin-containing (LF), and 0.5% pepsin-hydrolyzed lactoferrin-containing (LF-hyd) diets for 3 months. We found that both the LF and LF-hyd diets attenuated memory impairment in J20 mice and decreased brain Aβ 40 and Aβ 42 levels through the inhibition of amyloidogenic processing of AβPP, as it decreased β-site amyloid protein precursor cleaving enzyme 1 (BACE1) levels. Furthermore, we found for the first time that LF and LF-hyd treatments increased both ApoE secretion and ATP-binding cassette A1 (ABCA1) protein levels in the brains of J20 mice and in primary astrocyte cultures. Moreover, LF and LF-hyd promoted extracellular degradation of Aβ in primary astrocyte cultures. These findings indicate that the reduction in Aβ levels in the brains of mice fed with both the LF and LF-hyd diets may also be mediated by increased ApoE secretion and ABCA1 protein levels, which in turn leads to the enhanced degradation of Aβ in the brains of J20 mice. Our findings suggest that LF and LF-hyd can be used for the treatment and/or prevention of the development of AD.

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PMID: 

Biol Open. 2017 Oct 15 ;6(10):1416-1422. Epub 2017 Oct 15. PMID: 28838965

Abstract Title: 

Blocking autophagy enhances the pro-apoptotic effect of bufalin on human gastric cancer cells through endoplasmic reticulum stress.

Abstract: 

Bufalin has been used to treat cancer for several years. However, the molecular mechanisms for its anti-tumor function are not fully understood. This work aimed to investigate the effect of bufalin on the proliferation and apoptosis of human gastric cancer (HGC) cells and the roles of endoplasmic reticulum (ER) stress and autophagy in bufalin-induced apoptosis. HGC cell lines, SGC7901 and BGC823, were treated with different concentrations of bufalin or 80 nmol/l bufalin for 1, 2, 3 and 4 days. Cell counting kit-8 (CCK-8) assay and direct cell counting method were used to detect proliferation. Cell cycle arrest and apoptosis was detected using flow cytometry. Protein levels of caspase-3, -8, Bax/Bcl-2, Beclin-1, LC3, inositol-requiring enzyme 1 (IRE1) and C/EBP homologous protein (CHOP) were determined using western blotting. Autophagy was blocked using 3-methyladenine (3MA) or Atg5 siRNA to evaluate the effect of autophagy on bufalin-induced apoptosis. The IRE1 and CHOP were knocked down using specific siRNA to determine the pathway involved in bufalin-induced autophagy. It was found that bufalin significantly suppressed proliferation of SGC7901 and BGC823 cells and induced apoptosis in a time- and dose-dependent manner. The mechanism responsible for bufalin-induced apoptosis was the formation of ER stress via the IRE1-JNK pathway. Moreover, autophagy was activated during ER stress, and blocking autophagy significantly exacerbated bufalin-induced apoptosis.

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PMID: 

Oncotarget. 2017 Sep 8 ;8(38):63311-63323. Epub 2017 Jun 28. PMID: 28968991

Abstract Title: 

Bufalin-loaded bovine serum albumin nanoparticles demonstrated improved anti-tumor activity against hepatocellular carcinoma: preparation, characterization, pharmacokinetics and tissue distribution.

Abstract: 

OBJECTIVE: To prepare and evaluate the liver-targeted drug delivery system of Bufalin with higher liver uptake and stronger antitumor activity against hepatocellular carcinoma.METHODS: Bufalin-loaded bovine serum albumin nanoparticle was prepared by desolvation method, to investigate therelease performance and to evaluate the pharmacokinetic and tissue distribution. The antitumor activity against hepatocellular carcinoma was evaluatedand, respectively.RESULTS: The Bufalin-loaded bovine serum albumin nanoparticle with an average particle size of 125.1 nm exhibited a sustained release behavior. The half-life, blood plasma area under the curve and apparent volume of distribution of Bufalin-loaded bovine serum albumin nanoparticle were significantly higher than that of Bufalin, whereas the clearance rate was lower than Bufalin group. The uptake of liver for Bufalin-loaded bovine serum albumin nanoparticle was 352.045± 35.665 ng/g while for Bufalin was 164.465 ± 48.080 ng/g (0.01) at 5 min. The uptake of tumor for Bufalin-loaded bovine serum albumin nanoparticle was significantly higher than that of Bufalin both at 5 min (50.169± 11.708 ng/g, 93.415±13.828 ng/g,0.01) and 15 min (43.683± 11.499 ng/g, 64.219 ± 17.684 ng/g,0.05). Bufalin-loaded bovine serum albumin nanoparticle and Bufalin have similar antitumor activity. The tumor inhibition effect of Bufalin-loaded bovine serum albumin nanoparticle was stronger than that of Bufalin alone.CONCLUSION: Bufalin-loaded bovine serum albumin nanoparticle is a promising liver-targeted drug delivery system with higher liver uptake and stronger antitumor activity against hepatocellular carcinoma.

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PMID: 

Sci Rep. 2018 03 1 ;8(1):3891. Epub 2018 Mar 1. PMID: 29497076

Abstract Title: 

Bufalin suppresses hepatocarcinogenesis by targetingβ-catenin/TCF signaling via cell cycle-related kinase.

Abstract: 

Hepatocellular carcinoma (HCC) is one of the most aggressive malignant tumors, of which treatment options are limited especially in advanced stage. Bufalin, the major digoxin-like component of the traditional Chinese medicine Chansu, exhibits significant antitumor activities in hepatoma cells, but the potential mechanism is obscure. Cell cycle-related kinase (CCRK) is recently identified to be a crucial oncogenic master regulator to drive hepatocarcinogenesis. Here we investigated the molecular function of bufalin on CCRK-regulated signaling pathway, and expounded the underlying mechanism in HCC suppression. In vitro with PLC5 HCC cells and human immortal LO2 cells, proliferation, malignant transformation and cell cycle progression assays were performed to evaluate the antitumor effect of bufalin. In vivo with xenograft and orthotopic mice models, tumor growths with weight and volume change were assessed with or without bufalin treatment. Western blot, RT-qPCR, immunofluorescence and immunohistochemistry were conducted to examine the expression level of CCRK andβ-catenin/TCF signaling cascade. We revealed that bufalin suppresses PLC5 HCC cell proliferation, transformation and cell cycle progression rather than LO2 cells, which is correlated with CCRK-mediated β-catenin/TCF signaling. It was also confirmed in mice model. Thus, bufalin is a potential anti-HCC therapeutic candidate through the inhibition of CCRK-driven β-catenin/TCF oncogenic signaling pathway.

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