Kamaljeet Kaur

Adiponectin deficiency: Role in chronic inflammation induced colon cancer

Adiponectin (APN), an adipokine, exerts an anti-inflammatory and anti-cancerous activity with its role in glucose and lipid metabolism and its absence related to several obesity related malignancies including colorectal cancer. The aim of this study is to determine the effect of APN deficiency on the chronic inflammation-induced colon cancer. This was achieved by inducing inflammation and colon cancer in both APN knockout (KO) and C57B1/6 wild type (WT) mice. They were divided into four treatment groups (n=6): 1) control (no treatment); 2) treatment with three cycles of dextran sodium sulfate (DSS); 3) weekly doses of 1,2-dimethylhydrazine (DMH) (20mg/kg of mouse body weight) for twelve weeks; 4) a single dose of DMH followed by 3 cycles of DSS (DMH+DSS). Mice were observed for diarrhea, stool hemoccult, and weight loss and were sacrificed on day 153. Tumor area and number were counted. Colonic tissues were collected for Western blot and immunohistochemistry analyses. APNKO mice were more protected than WT mice from DSS induced colitis during first DSS cycle, but lost this protection during the second and the third DSS cycles. APNKO mice had significantly severe symptoms and showed greater number and larger area of tumors with higher immune cell infiltration and inflammation than WT mice. This result was further confirmed by proteomic study including pSTAT3, pAMPK and Cox-2 by western blot and Immunohistochemistry. Conclusively, APN deficiency contributes to inflammation-induced colon cancer. Hence, APN may play an important role in colorectal cancer prevention by modulating genes involved in chronic inflammation and tumorigenesis.

Dietary Agents and Phytochemicals in the Prevention and Treatment of Experimental Ulcerative Colitis

Inflammatory bowel diseases (IBDs), consisting mainly of ulcerative colitis (UC) and Crohn′s disease (CD), are important immune-mediated diseases of the gastrointestinal tract. The etiology of the disease includes environmental and genetic factors. Its management presents a constant challenge for gastroenterologists and conventional surgeon. 5-Amninosalicylates, antibiotics, steroids, and immune modulators have been used to reduce the symptoms and for maintenance of remission. Unfortunately, long-term usage of these agents has been found to lead to severe toxicities, which are deterrent to the users. Pre-clinical studies carried out in the recent past have shown that certain dietary agents, spices, oils, and dietary phytochemicals that are consumed regularly possess beneficial effects in preventing/ameliorating UC. For the first time, this review addresses the use of these dietary agents and spices in the treatment and prevention of IBD and also emphasizes on the mechanisms responsible for their effects.

The role of adipose tissue-associated macrophages and T lymphocytes in the pathogenesis of inflammatory bowel disease

Inflammatory bowel diseases (IBDs) are chronic inflammatory disorders of the gastrointestinal tract that affect more than 3 million people worldwide, but the pathological etiology is still unknown. The overall purpose of our investigations was to elucidate the possibility of pathological causes of IBD, and therefore, we determined the difference of inflammatory cytokine profiles in adipose tissue macrophages (ATMs) and T lymphocytes (ATTs) obtained near active lesions of IBD; investigated whether the alteration in ATM activation induces genes involved in collagen formation; and evaluated the effects of fatty acid oxidation inhibitors on factors involved in inflammation and collagen production by ATMs in IBD. Adipose tissues (ATs) were collected near active lesions and also at the margin of resected segments of the bowel from IBD patients with ulcerative colitis (UC) and CD (n=14/group). Normal appearing ATs from control subjects (n=14) who had colon resection for adenocarcinoma were collected as far away from the cancer lesion as possible to rule out possible changes. Compared with inactive disease lesions, ATMs and ATTs from active lesions released more IL-6, IL-4 and IL-13. Treatments of cytokine IL-4 and/or IL-13 to ATMs reduced iNOS expression but increased Arg-I expression which were exacerbated when treated with T cell- and adipocyte-conditioned medium. However, fatty acid oxidation inhibitors prevented the effects of cytokines IL-4 and/or IL-13 on iNOS and Arg-I expressions. This study was the first to show the effect of IL-4 and IL-13 on collagen formation, through iNOS and Arg-I expressions, that was exacerbated in a condition that mimics in vivo condition of active lesions. Moreover, our study was the first to provide potential benefits of fatty acid oxidation inhibitors to ATMs on preventing collagen formation; thus, providing therapeutic implications for individuals with intestinal fibrosis and stricture lesions, although future study should be guaranteed to elucidate the underlying mechanisms.

Short-term moderate sleep restriction decreases insulin sensitivity in young healthy adults

CONTEXT AND PURPOSE The literature suggests that severe sleep loss of more than a few hours a night decreases glucose tolerance and insulin sensitivity. The aim of this study was to determine whether moderate sleep restriction had similar effects. METHODS Fifteen healthy non-obese (BMI=24.5±3.4 kg/m2) young adults (20.6±1.3 years) completed two 2-hour oral glucose tolerance tests (OGTT): one was after 3 days of time-in-bed restriction by 1-3 hours each night, and the other was after 3 days of ad libitum sleep. Glucose and insulin concentrations during OGTT, and fasting glucagon and cortisol concentrations were determined. The homeostasis model of insulin resistance (HOMA-IR), Matsuda index, and the quantitative insulin sensitivity check index (QUICKI) were calculated. RESULTS The total time-in-bed during the sleep restriction and the ad libitum phase was 5.98±0.76 and 7.98±0.54 hours/day, and total sleep time was 5.16±0.49 and 6.65±0.64 hours/day, respectively. Glucose concentrations before and 30, 60, 90, and 120 minutes following consumption of glucose and area under the curve were not different for the two OGTT (p > 0.10 for all). Insulin concentration at fasting and area under the curve during the OGTT were significantly higher (p = 0.034 and 0.038, respectively) following restricted sleep than following ad libitum sleep. Fasting glucagon concentration was also higher (p = 0.003). The HOMA-IR, Matsuda index, and QUICKI all suggested decreased insulin sensitivity following restricted sleep. CONCLUSION Short-term moderate sleep restriction reduced insulin sensitivity compared to ad libitum sleep in this group of healthy young adults.

Dietary selenium protects adiponectin knockout mice against chronic inflammation induced colon cancer

ABSTRACT Selenium (Se) is an essential dietary micronutrient that has been examined for protection against different types of cancers including colon cancer. Despite an established inverse association between Se and chronic inflammation induced colon cancer (CICC), the mechanistic understanding of Ses protective effects requires additional in-vivo studies using preclinical animal models of CICC. Adiponectin (APN) is an adipocytokine that is protective against CICC as well. However, its role in the anti-mutagenic effects of the Se-diet remains unknown. To address this knowledge gap, here we examine the ability of dietary Se in reducing CICC in APN knockout mice (KO) and its wild-type C57BL/6. CICC was induced with the colon cancer agent 1,2 dimethyl hydrazine (DMH) along with dextran sodium sulfate (DSS). Se-enhanced diet increased selenoproteins, Gpx-1 and Gpx-2, in the colon tissues, thereby reducing oxidative stress. Se-mediated reduction of CICC was evident from the histopathological studies in both mouse models. In both mice, reduction in inflammation and tumorigenesis associated well with reduced p65 phosphorylation and elevated 53 phosphorylation. Finally, we show that in both models Se-administration promotes goblet cell differentiation with a concomitant increase in the levels of associated proteins, Muc-2 and Math-1. Our findings suggest that Ses protection against CICC involves both colonic epithelial protection and anti-tumor effects that are independent of APN.

Polyphenols in the Prevention of Ulcerative Colitis: Past, Present and Future

Ulcerative colitis (UC) is an idiopathic disease of the intestine. The etiology ranges from immune dysfunction, bacterial infiltration, and genetics to environment. Several medications have been employed to treat UC, but most have several side effects. To counter this problem, alternate therapy has been employed, which includes the use of plant-derived phytochemicals that have been investigated. Reports indicate them to be effective in reducing the severity of symptoms associated with UC with concomitant reductions in several markers of inflammation. This chapter deals with polyphenols in the prevention of UC due to their widely accepted benefits and ease of availability. Polyphenols have several applications, ranging from industrial to household and recently in medicine. They have been implicated in the treatment of several diseases and disorders like hypertension, allergies, cancer, diabetes, inflammatory bowel disease, hypercholesterolemia, and several other metabolic and genetic disorders. Several polyphenols, including curcumin and their role in the different pathways leading to the inflammation and pathology of UC, are discussed in this chapter. Curcumin is an active compound found in the turmeric plant and has been found to reduce inflammation, ulcerations and prevent the formation of the pre-cancerous lesions. Clinical trials have shown that curcumin could prevent clinical relapse in patients with inflammatory bowel disease (IBD) with an additional benefit of free radical scavenging leading to reduced oxidative stress. Tea, native to China and Southeast Asia, has several active components like catechins, flavonols, gallic acids and theanine, which were found to be protective against colitis by downregulation of pro-inflammatory cytokines and COX-2. Grape seed polyphenols were also found to be effective in reducing the macroscopic and microscopic lesions of colitis, histological score and reducing translocation of NF-κB in the colon mucosa. Cocoa, another common beverage and the content of chocolate, was found to be protective when co-administered with dextran sodium sulfate (DSS) and decreased colon crypt damage and leucocyte infiltration. Resveratrol is another common polyphenol produced by plants under stress led by pathogenic attack like bacteria and fungi. It is widely accepted for its anti-inflammatory and anti-cancerous effects and has also been found to reduce the pathology of UC. It mediates its protective effects by decreasing neutrophil’s percentage and downregulation of inflammatory markers with reduced myeloperoxidase (MPO) and lipid peroxidation in colon. It is mainly found in the skin of red grapes. Therefore, although the amount in red wine is insignificant, it is available commercially for use as a supplement. Quercetin, silymarin, kaempferol, ellagic acid, and rutoside are some of the other polyphenols discussed in this chapter. They were found to be effective in reducing the pathology and symptoms associated with UC. There are very few studies that indicate the adverse effects of these polyphenols, including the oral administration of 1% green tea polyphenols which increased kidney weight and decreased mRNA expression of HSPs and several antioxidant enzymes. There could be a few exceptions regarding the safety of the use of polyphenols as therapeutic agents in the treatment of UC, and hence more intensive research is needed to declare polyphenols, or any other phytochemicals obtained, as safe for medicinal use. Also, their dosage and the adverse effects of different polyphenols in different disease models need to be established with human studies before the declaration of their use in a particular disease.

Antibiotic-mediated bacteriome depletion in Apc Min/+ mice is associated with reduction in mucus-producing goblet cells and increased colorectal cancer progression

Recent epidemiological evidence suggests that exposure to antibiotics in early‐to‐middle adulthood is associated with an increased risk of colorectal adenoma. However, mechanistic studies in established preclinical cancer to examine these claims are extremely limited. Therefore, we investigated the effect of long‐term exposure of an antibiotic cocktail composed of Vancomycin, Neomycin, and Streptomycin, on tumor development and progression in the ApcMin/+ mouse, an established genetic model for familial adenomatous polyposis. Clinical pathologies related to tumor development as well as intestinal and colon tissue histopathology were studied at ages 8, 12, and 16 weeks of age, which correspond to the approximate ages of development of neoplasia, gut inflammation with polyposis, and cancer progression, respectively, in this animal model. We show that the antibiotics significantly increase the severity of clinical symptoms, including effects on intestinal histology and goblet cell numbers. In addition, they promote small intestinal polyposis. Finally, metagenomic analysis of fecal samples demonstrated that antibiotic exposure is associated with a significant but nonuniform depletion of the animals natural gut flora. Overall, these findings support the premise that long‐term antibiotic exposure mediates the selected depletion of gut microbial communities and the concomitant thinning of the protective mucus layer, resulting in an increase in tumor development.

Medicinal Benefits of Ginger in Various Gastrointestinal Ailments: Use in Geriatric Conditions

Ginger, the rhizome of Zingiber officinale Roscoe (family Zingiberaceae), is not only a food condiment but also a medicinal agent with numerous medicinal properties. Ginger has been shown to reduce the severity of several diseases, especially of the gastrointestinal system, and studies have clearly indicated that the various extracts of ginger and its principal phytochemicals – gingerols, zingerone, shogaols, and paradols – have a protective role in gastric ailments and irritations such ulcers, vomiting, nausea, dyspepsia, stomach ache, spasm, and gastrointestinal cancer. This chapter summarizes the traditional and scientific observations of the gastrointestinal protective effect of ginger. It also addresses the lacunae in these published studies, and emphasizes the need for further investigations so ginger can be used in clinics in the future.

Effects of Adiponectin on DSS-induced Acute Ulcerative Colitis in Mice: P-182 YI

disease development in the T cell transfer model of colitis. RESULTS: We found that, in vitro, Gfi1-deficient effector T cells express elevated levels of IL-10 mRNA and protein relative to Gfi1-sufficient cells and ectopic expression of Gfi1 results in significantly diminished expression of IL-10. We also demonstrated that Gf1 binds the Il10 promoter in effector CD4 T cells that were differentiated in vitro or isolated from mice with ongoing colitis. Notably, in the T cell transfer model of colitis, deficiency of Gfi1 in CD4 T cells resulted in delayed or diminished disease development, which could be at least partially restored by co-deletion of Il10. CONCLUSION(S): Collectively, our data identify Gfi1 as a central node in the negative regulation of Il10 expression in CD4 T cells and suggest the possibility of utilizing Gf1-dependent pathways for therapeutic manipulation of IL-10 expression.