Shambhunath Bose

Role of chemokine CCL2 and its receptor CCR2 in neurodegenerative diseases

Chemokines are members of the chemoattractant cytokine family. They play key roles in the trafficking of leukocytes and in the induction of chemotaxis through the activation of G protein-coupled receptor. Considerable interest has been paid to these molecules to elucidate their roles in the unique inflammatory responses elicited in the central nervous system (CNS). Chemokine CCL2 (also known as monocyte chemoattractant protein-1, MCP-1) is one of the vital chemokines that control the migration and infiltration of monocytes/macrophages. CCL2 and its receptor CCR2 have been shown to be induced and involved in various neurodegenerative disorders including Alzheimer’s disease, multiple sclerosis, and ischemic brain injury. The present review will focus on the biological and pathophysiological aspects of CCL2 and CCR2 in the CNS and the possible therapeutic approaches for targeting these two proteins to combat neurodegenerative diseases.

Flos Lonicera Ameliorates Obesity and Associated Endotoxemia in Rats through Modulation of Gut Permeability and Intestinal Microbiota

Background and Aim Increasing evidence has indicated a close association of host-gut flora metabolic interaction with obesity. Flos Lonicera, a traditional herbal medicine, is used widely in eastern Asia for the treatment of various disorders. The aim of this study was to evaluate whether unfermented or fermented formulations of Flos Lonicera could exert a beneficial impact to combat obesity and related metabolic endotoxemia. Methods Obesity and metabolic endotoxemia were induced separately or together in rats through feeding a eight-week high fat diet either alone (HFD control group) or in combination with a single LPS stimulation (intraperitoneal injection, 0.75 mg/kg) (LPS control group). While, the mechanism of action of the Lonicera formulations was explored in vitro using RAW 264.7 and HCT 116 cell lines as models. Results In cell-based studies, treatment with both unfermented Flos Lonicera (UFL) and fermented Flos Lonicera (FFL) formulations resulted in suppression of LPS-induced NO production and gene expression of vital proinflammatory cytokines (TNF-α, COX-2, and IL-6) in RAW 264.7 cells, reduced the gene expression of zonula occludens (ZO)-1 and claudin-1, and normalized trans epithelial electric resistance (TEER) and horseradish peroxidase (HRP) flux in LPS-treated HCT-116 cells. In an animal study, treatment of HFD as well as HFD+LPS groups with UFL or FFL resulted in a notable decrease in body and adipose tissue weights, ameliorated total cholesterol, HDL, triglyceride, aspartate transaminase and endotoxin levels in serum, reduced the urinary lactulose/mannitol ratio, and markedly alleviated lipid accumulation in liver. In addition, exposure of HFD as well as HFD+LPS groups with UFL or FFL resulted in significant alteration of the distribution of intestinal flora, especially affecting the population of Akkermansia spp. and ratio of Bacteroidetes and Firmicutes. Conclusion This evidence collectively demonstrates that Flos Lonicera ameliorates obesity and related metabolic endotoxemia via regulating distribution of gut flora and gut permeability.

A modified formulation of Chinese traditional medicine improves memory impairment and reduces Aβ level in the Tg-APPswe/PS1dE9 mouse model of Alzheimer's disease

ETHNOPHARMACOLOGICAL RELEVANCE SuHeXiang Wan (SHXW), a Chinese traditional medicine has been used orally for the treatment of seizures, infantile convulsion, stroke and so forth. Previously, we reported the effects of modified SHXW essential oil mixture of the fragrance containing herbs on the sedative effect, anticonvulsant property and antioxidative activity after fragrance inhalation. MATERIALS AND METHODS This study was undertaken to evaluate beneficial effects of a modified recipe of SHXW (termed as KSOP1009) consisting of a ethanol extract of 8 herbs including resin of Liquidambar orientalis Miller, seed of Myristica fragrans Houtt., rhizome of Cnidium officinale Makino, lumber of Santalum album L., fructus of Piper longum L., flower buds of Eugenia caryophyllata Merrill et Perry, pollen of Typha orientalis Presl., and root of Salvia miltiorrhiza Bunge in the neurodegenerative diseases such as Alzheimers disease (AD). The transgenic mice of AD, Tg-APPswe/PS1dE9, were fed KSOP1009 or as a positive control, donepezil for 3 months from 4.5 months of age. Behavioral, immunological and ELISA analyses were used to assess memory impairment, Aβ accumulation and plaque deposition in the brain. Other in vitro works were performed to examine whether KSOP1009 inhibits the Aβ(1-42)-induced neurotoxicity in human neuroblastoma cell line, SH-SY5Y cells. RESULTS Intake of KSOP1009 improved the Aβ-induced memory impairment and suppressed Aβ levels and plaque deposition in the brain of Tg-APPswe/PS1dE9 mice as much as that of donepezil treatment. KSOP1009 prevented the down-regulation of phospho-CREB and increased AKT phosphorylation in the AD-like brains. Moreover, KSOP1009 suppresses Aβ-induced apoptosis and ROS production in SH-SY5Y cells. CONCLUSION The present study suggests that KSOP1009 may develop as a therapeutic drug for treatment of AD patients.

Fermented Rhizoma Atractylodis Macrocephalae alleviates high fat diet-induced obesity in association with regulation of intestinal permeability and microbiota in rats

Accumulating evidence suggests the anti-inflammatory and anti-obesity activities of Rhizoma Atractylodis Macrocephalae (RAM). Here, we evaluated the anti-obesity impact of unfermented (URAM) versus fermented RAM (FRAM) using both in vitro and in vivo models. Both URAM and FRAM exhibited marked anti-inflammatory, anti-adipogenic, and anti-obesity activities, and modulation of the gut microbial distribution. However, FRAM, compared to URAM, resulted in more efficient suppression of NO production and normalization of transepithelial electrical resistance in LPS-treated RAW 264.7 and HCT 116 cells, respectively. Compared to URAM, FRAM more effectively reduced the adipose tissue weight; ameliorated the serum triglyceride and aspartate transaminase levels; restored the serum HDL level and intestinal epithelial barrier function in the LPS control group. The relative abundance of Bifidobacterium and Akkermansia as well as Bacteriodetes/Firmicutes ratio in the gut of the LPS control group was significantly enhanced by both URAM and FRAM. However, FRAM, but not URAM, resulted in a significant increase in the distribution of Bacteriodetes and Lactobacillus in the gut of the HFD + LPS group. Our results suggest that FRAM with probiotics can exert a greater anti-obesity effect than URAM, which is probably mediated at least in part via regulation of the intestinal microbiota and gut permeability.

In vitro and in vivo protective effects of fermented preparations of dietary herbs against lipopolysaccharide insult

Lipopolysaccharide (LPS) is known to produce endotoxic shock by triggering systemic inflammatory responses. Here, we evaluated the protective effects of three fermented/re-fermented herbs, Rhizoma Atractylodis Macrocephalae, Massa Medicata Fermentata, and Dolichoris Semen, in an LPS-mediated inflammatory insult, either individually in vitro using RAW264.7 cells or in combination in in vivo using rats. In general, each of the fermented herbs showed appreciable in vitro anti-inflammatory activity, although the degree of this activity varied with the herb used. Moreover, a mixture of fermented herbal extracts in combination with probiotics significantly attenuated the blood endotoxin and CRP levels, as well as the gut permeability, and significantly augmented the intestinal Lactobacillus spp. colonisation in LPS-treated rats. However, these effects were not observed following the administration of the corresponding mixture of unfermented herbal extracts. Thus, our results highlight the beneficial impacts of the use of fermented herb products with probiotics to combat LPS-mediated inflammatory insults.

Contrasting effects of fresh and fermented kimchi consumption on gut microbiota composition and gene expression related to metabolic syndrome in obese Korean women.

Accumulating evidence suggests relationship of compositional changes of gut microbiota with onset of metabolic disorders and obesity. Kimchi, a traditional Korean side dish, is known for its beneficial impact on metabolic parameters and anti-obesity effects. The current study was designed to evaluate the association between gut microbiota and human genome after kimchi intervention in an effort to understand the molecular mechanism(s) underlying the antiobesity impact of kimchi. Twenty-four obese women were randomly assigned to either fresh or fermented kimchi group for eight weeks of kimchi intervention. Pyrosequencing of fecal microbiota and microarray analyses of blood samples revealed that fresh and fermented kimchi interventions exerted differential effects on the obesity-related clinical parameters. Correlations of these effects with changes in blood gene expression and gut microbial population were more evident in the fermented kimchi group than the fresh kimchi group.

Evaluation of In Vitro Anti-Inflammatory Activities and Protective Effect of Fermented Preparations of Rhizoma Atractylodis Macrocephalae on Intestinal Barrier Function against Lipopolysaccharide Insult

Lipopolysaccharide (LPS), a potent inducer of systemic inflammatory responses, is known to cause impairment of intestinal barrier function. Here, we evaluated the in vitro protective effect of an unfermented formulation of Rhizoma Atractylodis Macrocephalae (RAM), a traditional Chinese herbal medicine widely used in the treatment of many digestive and gastrointestinal disorders, and two fermented preparations of RAM, designated as FRAM-1 (prepared in Luria-Bertani broth) and FRAM-2 (prepared in glucose), on intestinal epithelial cells (IECs) against LPS insult. In general, fermented formulations, especially FRAM-2, but not unfermented RAM, exerted an appreciable protective effect on IECs against LPS-induced perturbation of membrane resistance and permeability. Both fermented formulations exhibited appreciable anti-inflammatory activities in terms of their ability to inhibit LPS-induced gene expression and induced production of a number of key inflammatory mediators and cytokines in RAW 264.7 macrophage cells. However, in most cases, FRAM-2 exhibited stronger anti-inflammatory effects than FRAM-1. Our findings also suggest that suppression of nuclear factor-κ β (NF-κ β) activity might be one of the possible mechanisms by which the fermented RAM exerts its anti-inflammatory effects. Collectively, our results highlight the benefits of using fermented products of RAM to protect against LPS-induced inflammatory insult and impairment in intestinal barrier function.

Targeting chaperones, heat shock factor-1, and unfolded protein response: Promising therapeutic approaches for neurodegenerative disorders

Protein misfolding, which is known to cause several serious diseases, is an emerging field that addresses multiple therapeutic areas. Misfolding of a disease-specific protein in the central nervous system ultimately results in the formation of toxic aggregates that may accumulate in the brain, leading to neuronal cell death and dysfunction, and associated clinical manifestations. A large number of neurodegenerative diseases in humans, including Alzheimers, Parkinsons, Huntingtons, and prion diseases, are primarily caused by protein misfolding and aggregation. Notably, the cellular system is equipped with a protein quality control system encompassing chaperones, ubiquitin proteasome system, and autophagy, as a defense mechanism that monitors protein folding and eliminates inappropriately folded proteins. As the intrinsic molecular mechanisms of protein misfolding become more clearly understood, the novel therapeutic approaches in this arena are gaining considerable interest. The present review will describe the chaperones network and different approaches as the therapeutic targets for neurodegenerative diseases. Current and emerging therapeutic approaches to combat neurodegenerative diseases, addressing the roles of molecular, chemical, and pharmacological chaperones, as well as heat shock factor-1 and the unfolded protein response, are also discussed in detail.

Efficacy of Korean Red Ginseng by Single Nucleotide Polymorphism in Obese Women: Randomized, Double-blind, Placebo-controlled Trial

This study examined the effects of Korean red ginseng (KRG) on obese women and aimed to confirm that the effects of KRG on obesity differ dependently on a gene. Fifty obese women were recruited and randomized to receive KRG (n=24) or placebo (n=26) for 8 wk. Measurements of blood pressure, height, weight, waist circumference, waist-hip ratio (WHR), total fat mass, percentage of body fat, resting metabolic rate, basal body temperature, and daily food intake (FI), blood test (serum lipid, liver and renal function), Korean version of obesity-related quality of life scale (KOQOL), and a gene examination were performed. Comparisons of subjects before and after the administration of KRG revealed significant improvements of obesity in terms of weight, body mass index (BMI), WHR, FI, and KOQOL. However, in the comparison between KRG group and placebo group, only KOQOL was significantly different. KRG displayed significant efficacy on BMI and KOQOL in the CT genotype of the G protein beta 3 gene, but not in the CC genotype, on blood sugar test in the Trp64/Arg genotype of the beta 3 adrenergic receptor gene, but not in Trp64/ Trp genotype, on KOQOL in the DD genotype of the angiotensin I converting enzyme gene, but not in the ID and DD genotypes. The effects of KRG on obesity were confirmed to some extent. However, a distinct effect compared to placebo was not confirmed. KRG is more effective for improving the secondary issues of the quality of life derived from obesity rather than having direct effects on the obesity-related anthropometric assessment and blood test indices.

Evaluation of the in vitro and in vivo protective effects of unfermented and fermented Rhizoma coptidis formulations against lipopolysaccharide insult

Lipopolysaccharide (LPS) can produce endotoxic shock by triggering the systemic inflammatory response. Here, we evaluated the in vitro and in vivo protective effects of unfermented and fermented Rhizoma coptidis (RC and FRC, respectively) against LPS-insult. In general, RC suppressed the LPS-induced expression of key inflammatory mediators in RAW264.7 cells, in a dose-dependent manner. Notably, FRC at a 20 μg/ml dose in combination with the probiotic used for fermentation showed more potent in vitro anti-inflammatory activities than that exhibited by the corresponding dose of RC. Moreover, oral treatment with FRC in association with the probiotic, but not oral administration of RC, significantly attenuated blood endotoxin and C-reactive protein (CRP) levels, and gut permeability, and significantly augmented the intestinal population of Bifodobacterium spp. and Lactobacillus spp. in LPS-treated animals. Our results demonstrate the beneficial impact of fermented RC in combination with the associated probiotic in combating LPS-insult both in vitro and in vivo.