Antibiotic-mediated bacteriome depletion in ApcMin/+ 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 animal's 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.

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

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 Se's 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 Se's protection against CICC involves both colonic epithelial protection and anti-tumor effects that are independent of APN.

Fluoroquinolone-related neuropsychiatric and mitochondrial toxicity: a collaborative investigation by scientists and members of a social network.

BACKGROUND: The 3 fluoroquinolone (FQ) antibiotics - ciprofoxacin, levofoxacin, and moxifoxacin - are commonly administered to oncology patients. Although these oral antibiotics are approved by the US Food and Drug Administration (FDA) for treatment of urinary tract infections, acute bacterial sinusitis, or bacterial infection in patients with chronic obstructive pulmonary disease, they are commonly prescribed off-label to neutropenic cancer patients for the prevention and treatment of infections associated with febrile neutropenia. New serious FQ-associated safety concerns have been identified through novel collaborations between FQ-treated persons who have developed long-term neuropsychiatric (NP) toxicity, pharmacovigilance experts, and basic scientists. OBJECTIVE: To conduct basic science and clinical investigations of a newly identified adverse drug reaction, termed FQ-associated disability. METHODS: 5 groups of C57BL/6 mice receiving the antibiotic ciprofoxacin in 10-mg increments (10 mg/kg-50 mg/kg) and 1 group of control mice were evaluated. The Southern Network on Adverse Reactions (SONAR) and a social network of FQ-treated persons with long-term NP toxicity (the Floxed Network) conducted a web-based survey. The clinical toxicity manifestations reported by 94 respondents to the web-based survey of persons who had received 1 or more doses of an FQ prescribed for any indication (generally at FDA-approved dosages) and who subsequently experienced possible adverse drug reactions were compared with adverse event information included on the product label for levofoxacin and with FQ-associated adverse events reported to the FDA's MedWatch program. RESULTS: Mice treated with ciprofoxacin had lower grip strengths, reduced balance, and depressive behavior compared with the controls. For the survey, 93 of 94 respondents reported FQ-associated events including anxiety, depression, insomnia, panic attacks, clouded thinking, depersonalization, suicidal thoughts, psychosis, nightmares, and impaired memory beginning within days of FQ initiation or days to months of FQ discontinuation. The FDA Adverse Event Reporting System (FAERS) included 210,705 adverse events and 2,991 fatalities for FQs. Levofoxacin and ciprofoxacin toxicities were neurologic (30% and 26%, respectively), tendon damage (8% and 6%), and psychiatric (10% and 2%). In 2013, an FDA safety review reported that FQs affect mammalian topoisomerase II, especially in mitochondria. In 2013 and 2014, SONAR fled citizen petitions requesting black box revisions identifying neuropsychiatric toxicities and mitochrondrial toxicity as serious levofoxacin-associated adverse drug reactions. In 2015, FDA advisors recommended that FQ product labels be revised to include information about this newly identified disability syndrome termed "FQ-associated disability" (FQAD). LIMITATIONS: Basic science studies evaluated NP toxicity for only 1 FQ, ciprofoxacin. CONCLUSION: Pharmacovigilance investigators, a social network, and basic scientists can collaborate on pharmacovigilance investigations. Revised product labels describing a new serious adverse drug reaction, levofoxacin-associated long-term disability, as recommended by an FDA advisory committee, are advised.

Chemokine and cytokine levels in inflammatory bowel disease patients.

Crohn's disease (CD) and ulcerative colitis (UC), two forms of inflammatory bowel disease (IBD), are chronic, relapsing, and tissue destructive lesions that are accompanied by the uncontrolled activation of effector immune cells in the mucosa. Recent estimates indicate that there are 1.3 million annual cases of IBD in the United States, 50% of which consists of CD and 50% of UC. Chemokines and cytokines play a pivotal role in the regulation of mucosal inflammation by promoting leukocyte migration to sites of inflammation ultimately leading to tissue damage and destruction. In recent years, experimental studies in rodents have led to a better understanding of the role played by these inflammatory mediators in the development and progression of colitis. However, the clinical literature on IBD remains limited. Therefore, the aim of this study was to evaluate systemic concentrations of key chemokines and cytokines in forty-two IBD patients with a range of disease activity compared to levels found in ten healthy donors. We found a significant increase in an array of chemokines including macrophage migration factor (MIF), CCL25, CCL23, CXCL5, CXCL13, CXCL10, CXCL11, MCP1, and CCL21 in IBD patients as compared to normal healthy donors (P<0.05). Further, we also report increases in the inflammatory cytokines IL-16, IFN-γ, IL-1ß and TNF-α in IBD patients when compared to healthy donors (P<0.05). These data clearly indicate an increase in circulating levels of specific chemokines and cytokines that are known to modulate systemic level through immune cells results in affecting local intestinal inflammation and tissue damage in IBD patients. Blockade of these inflammatory mediators should be explored as a mechanism to alleviate or even reverse symptoms of IBD.

Effects of exercise training together with tamoxifen in reducing mammary tumor burden in mice: Possible underlying pathway of miR-21.

Exercise training has an anti-tumor effect and can reduce tumor growth; however, the exact underlying mechanisms of its protective effects are still obscure. MicroRNA (miR)-21 is a predictor in cancer survival, and has a potential use as an indicator of therapeutic outcome in breast malignancies. Forty-eight female BALB/c mice were equally divided into six groups to investigate the effects of interval exercise training with tamoxifen on miR-21 expression and its possible assumed mechanisms in an estrogen receptor-positive breast cancer model. ELISA, immunohistochemistry, western blot, qRT-PCR assays were performed at the end of the study. Tumor size was significantly declined in exercise training and tamoxifen groups compared to tumor group (P<0.05). Expression of miR-21 was significantly down-regulated in trained and tamoxifen treated mice in comparison with tumor group (P<0.05). Exercise training was as effective as tamoxifen treatment in decreasing serum estradiol and ER-α expression (P<0.05). Exercise training and tamoxifen reduced tumor IL-6 levels, NF-kB and STAT3 expressions, and up-regulated TPM1 and PDCD4 expressions (P<0.05). Both exercise and tamoxifen had synergistic effects in reducing miR-21 and Bcl-2, and up-regulating PDCD4 expression. Results showed that interval exercise training may reduce mammary tumor burden in mice through possible underlying pathway of miR-21.

Mucus mediated protection against acute colitis in adiponectin deficient mice.

BACKGROUND: Acute ulcerative colitis is an inflammation-driven condition of the bowel. It hampers the general homeostasis of gut, resulting in decreased mucus production and epithelial cell renewal. Adiponectin (APN), an adipocytokine, is secreted by the adipose tissue and has been debated both as a pro-inflammatory or anti-inflammatory protein depending on the disease condition and microenvironment. The present study delineates the role of APN depletion in mucus modulation in a model of acute colitis. METHODS: APNKO and C57BL/6 (WT) male mice were given 2% DSS ad libidum for 5 days in drinking water, followed by normal drinking water for the next 5 days. Hematoxyline-eosin and Alcian Blue staining was used to observe the general colonic morphology and goblet cell quantification respectively. Protein expression levels were quantified by Western blot for MATH1, Hes1, MUC2 and MUC4. ELISA was used to study the levels of TNF-α, IL-6 and IL-1ß. RESULTS: APNKO mice showed significantly higher goblet to epithelial cell ratios, lower pro-inflammatory cytokines and higher MUC2 levels as compared to the WT mice. The protein expression levels for the mucin MUC2 supported the histopathological findings. An increase in colon tissue-secreted levels of pro-inflammatory with a reduction in anti-inflammatory cytokines in presence of APN support the pro-inflammatory role of APN during acute inflammation. CONCLUSION: Absence of APN is protective against DSS-induced acute colonic inflammation by means of reducing colon tissue-secreted pro-inflammatory cytokines, modulating goblet and epithelial cell expressions, and increasing the levels of secretory mucin MUC2.

Liver inflammation and metabolic signaling in ApcMin/+ mice: the role of cachexia progression.

The ApcMin/+ mouse exhibits an intestinal tumor associated loss of muscle and fat that is accompanied by chronic inflammation, insulin resistance and hyperlipidemia. Since the liver governs systemic energy demands through regulation of glucose and lipid metabolism, it is likely that the liver is a pathological target of cachexia progression in the ApcMin/+ mouse. The purpose of this study was to determine if cancer and the progression of cachexia affected liver endoplasmic reticulum (ER)-stress, inflammation, metabolism, and protein synthesis signaling. The effect of cancer (without cachexia) was examined in wild-type and weight-stable ApcMin/+ mice. Cachexia progression was examined in weight-stable, pre-cachectic, and severely-cachectic ApcMin/+ mice. Livers were analyzed for morphology, glycogen content, ER-stress, inflammation, and metabolic changes. Cancer induced hepatic expression of ER-stress markers BiP (binding immunoglobulin protein), IRE-1α (endoplasmic reticulum to nucleus signaling 1), and inflammatory intermediate STAT-3 (signal transducer and activator of transcription 3). While gluconeogenic enzyme phosphoenolpyruvate carboxykinase (PEPCK) mRNA expression was suppressed by cancer, glycogen content or protein synthesis signaling remained unaffected. Cachexia progression depleted liver glycogen content and increased mRNA expression of glycolytic enzyme PFK (phosphofrucktokinase) and gluconeogenic enzyme PEPCK. Cachexia progression further increased pSTAT-3 but suppressed p-65 and JNK (c-Jun NH2-terminal kinase) activation. Interestingly, progression of cachexia suppressed upstream ER-stress markers BiP and IRE-1α, while inducing its downstream target CHOP (DNA-damage inducible transcript 3). Cachectic mice exhibited a dysregulation of protein synthesis signaling, with an induction of p-mTOR (mechanistic target of rapamycin), despite a suppression of Akt (thymoma viral proto-oncogene 1) and S6 (ribosomal protein S6) phosphorylation. Thus, cancer induced ER-stress markers in the liver, however cachexia progression further deteriorated liver ER-stress, disrupted protein synthesis regulation and caused a differential inflammatory response related to STAT-3 and NF-κB (Nuclear factor-κB) signaling.

The influence of obesity on blood mercury levels for U.S. non-pregnant adults and children: NHANES 2007-2010.

BACKGROUND: In animal studies obesity is associated with higher blood and tissue mercury concentrations; however human studies are lacking. Although the mechanism underlying this association is uncertain, obesity may alter the metabolism and distribution of methylmercury. OBJECTIVES: We determined whether obesity influenced blood mercury levels, the majority of which was methylmercury, for U.S. non-pregnant adults (≥20 years) and children (2-19 years) after controlling for methylmercury intake through fish and shellfish consumption, and other confounders. METHODS: We completed secondary data analysis of the National Health and Nutrition Examination Survey (NHANES) (2007-2010) for participants who consumed fish/shellfish within 24h of blood collection for mercury analysis. Weighted least squares regression models related blood mercury levels (the dependent variable) to methylmercury exposure (µg) from fish consumed in the previous 24h, body mass index (BMI) (for adults), BMI z-scores (for children), and other confounders. RESULTS: In adjusted models, blood mercury levels were inversely correlated with BMI for adults [ß, 95% confidence interval (CI)=-0.54 (-0.90, -0.18)]. For children, blood mercury levels were inversely correlated with BMI z-scores but the trend was not significant [ß (95% CI)=-0.016 (-0.066, 0.035)]. When obese adults or children were compared with those who were overweight/normal weight, blood mercury averaged 22% lower for obese adults (95% CI: -33%, -8.2%), while blood mercury did not differ significantly for obese children [ß (95% CI)=-1.7% (-31%, +39%)]. CONCLUSIONS: After adjusting for the main, if not exclusive, exogenous source of methylmercury exposure (through fish/shellfish intake) and other confounders, our results support potential changes in the metabolism, distribution or excretion of methylmercury with increasing BMI (for adults).

Randomization to plant-based dietary approaches leads to larger short-term improvements in Dietary Inflammatory Index scores and macronutrient intake compared with diets that contain meat.

Studies have examined nutrient differences among people following different plant-based diets. However, all of these studies have been observational. The aim of the present study was to examine differences in nutrient intake and Dietary Inflammatory Index (DII) scores among overweight and obese (body mass index 25.0-49.9 kg/m(2)) adults randomized to receive dietary instruction on a vegan (n = 12), vegetarian (n = 13), pescovegetarian (n = 13), semivegetarian (n = 13), or omnivorous (n = 12) diet during a 6-month randomized controlled trial. Nutrient intake, nutrient adequacy, and DII score were assessed via two 24-hour dietary recalls (Automated Self-Administered 24-Hour Dietary Recall) at baseline and at 2 and 6 months. Differences in nutrient intake and the DII were examined using general linear models with follow-up tests at each time point. We hypothesized that individuals randomized to the vegan diet would have lower DII scores and greater improvements in fiber, carbohydrate, fat, saturated fat, and cholesterol at both 2 and 6 months as compared with the other 4 diets. Participants randomized to the vegan diet had significantly greater changes in most macronutrients at both time points, including fat and saturated fat, as well as cholesterol and, at 2 months, fiber, as compared with most of the other diet groups (Ps < .05). Vegan, vegetarian, and pescovegetarian participants all saw significant improvements in the DII score as compared with semivegetarian participants at 2 months (Ps < .05) with no differences at 6 months. Given the greater impact on macronutrients and the DII during the short term, finding ways to provide support for adoption and maintenance of plant-based dietary approaches, such as vegan and vegetarian diets, should be given consideration.

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.

Negative Effects of Time in Bed Extension: A Pilot Study.

Epidemiologic studies have consistently shown an association of long sleep (≥8 hr) with mortality and multiple morbidities. However, there has been little experimental investigation of the effects of sleep extension. The aim of this study was to examine the effects of time in bed (TIB) extension, on depression, anxiety, sleepiness, and systemic inflammation. Following baseline, 14 healthy sleepers (31.79±10.94 years) were randomized to one of two one-week treatments: (1) a TIB extension treatment involving a fixed sleep schedule in which TIB was increased by 3 hours/night compared with the participants' median baseline TIB; (2) a control treatment involving a fixed schedule in which TIB was the same as the participants' median baseline TIB. Actigraphic recording of sleep was assessed throughout both weeks. Self-reported depression, state anxiety, sleepiness, and sleep quality, as well as blood pressure, and inflammation were assessed at baseline and following the treatment week. Compared with baseline, TIB increased by 127.12±3.92 min and total sleep time increased by 119.88±18.52 min during TIB extension, but decreased slightly in the control treatment. Depression was elevated more following TIB extension (effect size (ES)=-0.86) vs. control (ES=-0.50). Interleukin-6 levels increased by 2-fold following TIB extension (ES=-0.65), but did not change following the control treatment. Sleepiness increased after TIB extension, but decreased after the control treatment. The results revealed negative effects of TIB extension on mood and inflammation. Larger-scale studies involving more prolonged, but less profound sleep extension, are warranted.

Quantitative acoustic contrast tomography reveals unique multiscale physical fluctuations during aflatoxin synthesis in Aspergillus parasiticus.

Fungal pathogens need regulated mechanical and morphological fine-tuning for pushing through substrates to meet their metabolic and functional needs. Currently very little is understood on how coordinated colony level morphomechanical modifications regulate their behavior. This is due to an absence of a method that can simultaneously map, quantify, and correlate global fluctuations in physical properties of the expanding fungal colonies. Here, we show that three-dimensional ultrasonic reflections upon decoding can render acoustic contrast tomographs that contain information on material property and morphology in the same time scale of one important phytopathogen, Aspergillus parasiticus, at multiple length scales. By quantitative analysis of the changes in acoustic signatures collected as the A. parasiticus colony expands with time, we further demonstrate that the pathogen displays unique acoustic signatures during synthesis and release of its hepatocarcinogenic secondary metabolite, aflatoxin, suggesting an involvement of a multiscale morphomechanical reorganization of the colony in this process. Our studies illustrate for the first time, the feasibility of generating in any invading cell population, four-dimensional maps of global physical properties, with minimal physical perturbation of the specimens. Our developed method that we term quantitative acoustic contrast tomography (Q-ACT), provides a novel diagnostic framework for the identification of in-cell molecular factors and discovery of small molecules that may modulate pathogen invasion in a host.

Cachectic skeletal muscle response to a novel bout of low-frequency stimulation.

While exercise benefits have been well documented in patients with chronic diseases, the mechanistic understanding of cachectic muscle's response to contraction is essentially unknown. We previously demonstrated that treadmill exercise training attenuates the initiation of cancer cachexia and the development of metabolic syndrome symptoms (Puppa MJ, White JP, Velazquez KT, Baltgalvis KA, Sato S, Baynes JW, Carson JA. J Cachexia Sarcopenia Muscle 3: 117-137, 2012). However, cachectic muscle's metabolic signaling response to a novel, acute bout of low-frequency contraction has not been determined. The purpose of this study was to determine whether severe cancer cachexia disrupts the acute contraction-induced response to low-frequency muscle contraction [low-frequency stimulation (LoFS)]. Metabolic gene expression and signaling was examined 3 h after a novel 30-min bout of contraction (10 Hz) in cachectic Apc(Min/+) (Min) and C57BL/6 (BL-6) mice. Pyrrolidine dithiocarbamate, a STAT/NF-κB inhibitor and free radical scavenger, was administered systemically to a subset of mice to determine whether this altered the muscle contraction response. Although glucose transporter-4 mRNA was decreased by cachexia, LoFS increased muscle glucose transporter-4 mRNA in both BL-6 and Min mice. LoFS also induced muscle peroxisome proliferator-activated receptor-γ and peroxisome proliferator-activated receptor-α coactivator-1 mRNA. However, in Min mice, LoFS was not able to induce muscle proliferator-activated receptor-α coactivator-1 targets nuclear respiratory factor-1 and mitochondrial transcription factor A mRNA. LoFS induced phosphorylated-S6 in BL-6 mice, but this induction was blocked by cachexia. Administration of pyrrolidine dithiocarbamate for 24 h rescued LoFS-induced phosphorylated-S6 in cachectic muscle. LoFS increased muscle phosphorylated-AMP-activated protein kinase and p38 in BL-6 and Min mice. These data demonstrate that cachexia alters the muscle metabolic response to acute LoFS, and combination therapies in concert with muscle contraction may be beneficial for improving muscle mass and function during cachexia.

Resveratrol improves muscle function but not oxidative capacity in young mdx mice.

Patients with Duchenne muscular dystrophy (DMD) have reduced muscle function due to chronic muscle damage, inflammation, oxidative stress, and reduced oxidative capacity. Resveratrol reduces inflammation and oxidative stress, and increases oxidative capacity in other disease models. The purpose of this study was to determine the effects of resveratrol on muscle function, muscle pathology, and oxidative capacity in young mdx mice. For this, 4- to 5-week-old male mdx mice were randomized into control or resveratrol-treated groups and given resveratrol (100 mg/kg body mass) or an equal volume of water by gavage every other day for 8 weeks. Muscle function was assessed pre- and post-treatment. Central nucleation, total immune cell infiltrate, oxidative stress, and oxidative capacity were measured post-treatment. Resveratrol mediated substantial improvements in rotarod performance and in-situ peak tension by 53% and 17%, respectively, and slight improvements in central nucleation and oxidative stress. Resveratrol did not affect total immune cell infiltrate at 12 weeks of age, and had no effect on oxidative capacity. Resveratrol improves muscle function in mdx mice despite small changes in muscle pathology. The likely mechanism is a resveratrol-mediated reduction in immune cell infiltrate at the early stages of this disease, as previously reported by our laboratory.

The Indian Spice Turmeric Delays and Mitigates Radiation-Induced Oral Mucositis in Patients Undergoing Treatment for Head and Neck Cancer: An Investigational Study.

PURPOSE: Radiation-induced oral mucositis is an acute morbidity seen in patients undergoing treatment for head and neck cancers. In this study, we evaluated the efficacy of turmeric in preventing radiation-induced mucositis. METHODS: This was a single-blinded, randomized, controlled clinical trial and was conducted with head and neck cancer patients requiring 70 Gy of radiation or chemoradiotherapy (daily radiotherapy plus carboplatin once a week). Eligible patients (n = 80) were randomly assigned to receive either turmeric gargle (n = 40) or povidone-iodine ([n = 40] active comparator condition) during chemo/radiotherapy during the period of treatment. Oral mucositis was assessed using the RTOG (Radiation Therapy Oncology Group) grading system before the start, during, and at the end of the treatment by an investigator unaware of the treatment. The primary endpoint of this study was the incidence of mucositis every week during the 7-week period. The secondary endpoint was the effect of turmeric gargle on the incidence of treatment breaks, loss of scheduled treatment days, and decrease in body weight at the end of the treatment. RESULTS: This study clearly suggests that when compared with the cohorts using povidone-iodine gargle, the group using turmeric as a mouthwash had delayed and reduced the levels of radiation-induced oral mucositis and was statistically significant at all time points (P< 0.001 toP< 0.0001). Additionally, the cohorts using turmeric had decreased intolerable mucositis (P< 0.001) and lesser incidence of treatment breaks in the first half of the treatment schedule before 4 weeks (P< 0.01) and reduced change in body weight (P< 0.001). CONCLUSIONS: Gargling with turmeric by head and neck cancer patients undergoing radiation therapy provided significant benefit by delaying and reducing the severity of mucositis. Turmeric is readily available, relatively inexpensive, and highly accepted making it useful in cancer treatment.

The emerging role of leptin antagonist as potential therapeutic option for inflammatory bowel disease.

Inflammatory bowel disease (IBD) is a chronic relapsing immune-mediated inflammatory disorder that affects millions of people around the world. Leptin is a satiety hormone produced primarily by adipose tissue and acts both centrally and peripherally. Leptin has been shown to play a major role in regulating metabolism, which increases during IBD progression. Leptin mediates several physiological functions including elevated blood pressure, tumorogenesis, cardiovascular pathologies and enhanced immune response in many autoimmune diseases. Recent development of a leptin mutant antagonist that blocks leptin activity raises great hope and opens up new possibilities for therapy in many autoimmune diseases including IBD. To this end, preliminary data from an ongoing study in our laboratory on pegylated leptin antagonist mutant L39A/D40A/F41A (PEG-MLA) treatment shows an inhibition of chronic colitis in IL-10-/- mice. PEG-MLA effectively attenuates the overall clinical scores, reverses colitis-associated pathogenesis including a decrease in body weight, and decreases systemic leptin level. PEG-MLA induces both central and peripheral leptin deficiency by mediating the cellular immune response. In summary, after blocking leptin activity, the correlative outcome between leptin-mediated cellular immune response, systemic leptin levels, and amount of adipose tissue together may provide new strategies for therapeutic intervention in autoimmune diseases, especially for intestinal inflammation.

Validation of a novel protocol for calculating estimated energy requirements and average daily physical activity ratio for the US population: 2005-2006.

OBJECTIVE: To validate the PAR protocol, a novel method for calculating population-level estimated energy requirements (EERs) and average physical activity ratio (APAR), in a nationally representative sample of US adults. METHODS: Estimates of EER and APAR values were calculated via a factorial equation from a nationally representative sample of 2597 adults aged 20 and 74 years (US National Health and Nutrition Examination Survey; data collected between January 1, 2005, and December 31, 2006). Validation of the PAR protocol-derived EER (EER(PAR)) values was performed via comparison with values from the Institute of Medicine EER equations (EER(IOM)). RESULTS: The correlation between EER(PAR) and EER(IOM) was high (0.98; P<.001). The difference between EER(PAR) and EER(IOM) values ranged from 40 kcal/d (1.2% higher than EER(IOM)) in obese (body mass index [BMI] ≥30) men to 148 kcal/d (5.7% higher) in obese women. The 2005-2006 EERs for the US population were 2940 kcal/d for men and 2275 kcal/d for women and ranged from 3230 kcal/d in obese (BMI ≥30) men to 2026 kcal/d in normal weight (BMI <25) women. There were significant inverse relationships between APAR and both obesity and age. For men and women, the APAR values were 1.53 and 1.52, respectively. Obese men and women had lower APAR values than normal weight individuals (P».023 and P».015, respectively) [corrected], and younger individuals had higher APAR values than older individuals (P<.001). CONCLUSION: The PAR protocol is an accurate method for deriving nationally representative estimates of EER and APAR values. These descriptive data provide novel quantitative baseline values for future investigations into associations of physical activity and health.

Protective role of resting heart rate on all-cause and cardiovascular disease mortality.

OBJECTIVE: To study the protective role of lower resting heart rate (RHR) in cardiovascular disease (CVD) and all-cause mortality. PATIENTS AND METHODS: Patients (n=53,322) who received a baseline medical examination between January 1, 1974, and December 31, 2002, were recruited from the Cooper Clinic, Dallas, Texas. They completed a medical questionnaire and underwent clinical evaluation. Patients with CVD or cancer or who had less than 1 year of mortality follow-up were excluded from the study. Relative risks and 95% CIs for all-cause and CVD mortality across RHR categories were estimated using Cox proportional hazards models. RESULTS: Highest cardiorespiratory fitness with lower mortality was found in individuals with an RHR of less than 60 beats/min. Similarly, patients with a higher RHR (≥80 beats/min) were at greater risk for CVD and all-cause mortality compared with an RHR of less than 60 beats/min. This analysis was followed by stratification of the data by hypertension, where hypertensive individuals with high RHRs (≥80 beats/min) were found to be at greater risk for CVD and all-cause mortality compared with those with hypertension and lower RHRs (<60 beats/min). In addition, unfit individuals with high RHRs had the greatest risk of CVD and all-cause mortality. The unfit with low RHR group had a similar risk for CVD and all-cause mortality as the fit with high RHR group. CONCLUSION: Lower cardiorespiratory fitness levels and higher RHRs are linked to greater CVD and all-cause mortality.

Leptin antagonist ameliorates chronic colitis in IL-10⁻/⁻ mice.

BACKGROUND: Although the etiology of two major forms of inflammatory bowel disease (IBD), Crohn's disease (CD) and ulcerative colitis (UC) are unknown and evidence suggests that chronic intestinal inflammation is caused by an excessive immune response to mucosal antigens. Previous studies support the role for TGF-ß1 through 3 in the initiation and maintenance of tolerance via the induction of regulatory T cells (Tregs) to control intestinal inflammation. Leptin, a satiety hormone produced primarily by adipose tissue, has been shown to increase during colitis progression and is believed to contribute to disease genesis and/or progression. AIM: We investigated the ability of a pegylated leptin antagonist (PG-MLA) to ameliorate the development of chronic experimental colitis. RESULTS: Compared to vehicle control animals, PG-MLA treatment of mice resulted in an (1) attenuated clinical score; (2) reversed colitis-associated pathogenesis including a decrease in body weight; (3) reduced systemic and mucosal inflammatory cytokine expression; (4) increased insulin levels and (5) enhanced systemic and mucosal Tregs and CD39⁺ Tregs in mice with chronic colitis. The percentage of systemic and mucosal TGF-ß1, -ß2 and -ß3 expressing CD4⁺ T cells were augmented after PG-MLA treatment. The activation of STAT1 and STAT3 and the expression of Smad7 were also reduced after PG-MLA treatment in the colitic mice. These findings clearly suggest that PG-MLA treatment reduces intestinal Smad7 expression, restores TGF-ß1-3 signaling and reduces STAT1/STAT3 activation that may increase the number of Tregs to ameliorate chronic colitis. CONCLUSION: This study clearly links inflammation with the metabolic hormone leptin suggesting that nutritional status influences immune tolerance through the induction of functional Tregs. Inhibiting leptin activity through PG-MLA might provide a new and novel therapeutic strategy for the treatment of IBD.

A review of the gastroprotective effects of ginger (Zingiber officinale Roscoe).

The rhizomes of Zingiber officinale Roscoe (Zingiberaceae), commonly known as ginger is an important kitchen spice and also possess a myriad health benefits. The rhizomes have been used since antiquity in the various traditional systems of medicine to treat arthritis, rheumatism, sprains, muscular aches, pains, sore throats, cramps, hypertension, dementia, fever, infectious diseases, catarrh, nervous diseases, gingivitis, toothache, asthma, stroke and diabetes. Ginger is also used as home remedy and is of immense value in treating various gastric ailments like constipation, dyspepsia, belching, bloating, gastritis, epigastric discomfort, gastric ulcerations, indigestion, nausea and vomiting and scientific studies have validated the ethnomedicinal uses. Ginger is also shown to be effective in preventing gastric ulcers induced by nonsteroidal anti-inflammatory drugs [NSAIDs like indomethacin, aspirin], reserpine, ethanol, stress (hypothermic and swimming), acetic acid and Helicobacter pylori-induced gastric ulcerations in laboratory animals. Various preclinical and clinical studies have also shown ginger to possess anti-emetic effects against different emetogenic stimuli. However, conflicting reports especially in the prevention of chemotherapy-induced nausea and vomiting and motion sickness prevent us from drawing any firm conclusion on its effectiveness as a broad spectrum anti-emetic. Ginger has been shown to possess free radical scavenging, antioxidant; inhibition of lipid peroxidation and that these properties might have contributed to the observed gastroprotective effects. This review summarizes the various gastroprotective effects of ginger and also emphasizes on aspects that warranty future research to establish its activity and utility as a gastroprotective agent in humans.