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-1β 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.

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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.

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 to P < 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.

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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.

Objective To study the protective role of lower resting heart rate (RHR) on cardiovascular disease (CVD) and all-cause mortality. Patients and Methods Participants (n=51,936) 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. Participants with CVD or cancer, those who did not achieve at least 85% of their age-predicted maximal heart rate or who had <1 year of mortality follow-up were excluded from the study. SAS was used for statistical analysis. Relative risks and 95% confidence intervals of all-cause and CVD mortality across RHR categories were estimated using Cox proportional hazard models. Results Highest cardiorespiratory fitness (CRF) with lower mortality was found in individuals with a RHR <60 bpm. Similarly, participants with a higher RHR, >80 bpm, were at greater risk for both CVD and all-cause mortality when compared with RHR <60 bpm. This analysis was followed by the stratification of the data by hypertension, where hypertensive individuals with high RHRs (≥80 bpm) were found at greater risk for CVD and all-cause mortality when compared to those with hypertension and lower RHRs (<60 bpm). Additionally unfit individuals with high RHR had the greatest risk for CVD and all-cause mortality. Interestingly, the unfit with low RHR group had a similar risk for both CVD and all-cause mortality as the fit with high RHR group. Conclusion Lower levels of CRF and higher RHR are linked with greater CVD and all-cause mortality1.

ATP-gated ion channel P2X receptors are expressed on the surface of most immune cells and can trigger multiple cellular responses, such as membrane permeabilization, cytokine production, and cell proliferation or apoptosis. Despite broad distribution and pleiotropic activities, signaling pathways downstream of these ionotropic receptors are still poorly understood. Here, we describe intracellular signaling events in Jurkat cells treated with millimolar concentrations of extracellular ATP. Within minutes, ATP treatment resulted in the phosphorylation and activation of p56 lck kinase, extracellular signalregulated kinase (ERK), and c-Jun N-terminal kinase but not p38 kinase. These effects were wholly dependent upon the presence of extracellular Ca 2؉ ions in the culture medium. Nevertheless, calmodulin antagonist calmidazolium and CaM kinase inhibitor KN-93 both had no effect on the activation of p56 lck and ERK, whereas a pretreatment of Jurkat cells with MAP kinase kinase inhibitor P098059 was able to abrogate phosphorylation of ERK. Extracellular ATP and other nucleotides act through specific cell surface receptors and can regulate a variety of cellular responses in many cell types and tissues (1-7). Among them are such different phenomena as platelet aggregation, smooth muscle contractility, excitatory transmitter function, mitogenic stimulation, or induction of cell death (reviewed in Refs. 1 and 8). The biological effects of extracellular nucleotides are mediated via stimulation of two primary classes of purinergic receptors, P1 and P2. The P1 receptors are responsive to adenosine, whereas the P2 receptors respond to a variety of nucleotides, including ATP (7, 9). The P2 receptors are subdivided in two mechanistically distinct subclasses, the metabotropic G protein-coupled P2Y receptors (P2Y1, P2Y2, P2Y4, P2Y6, and P2Y11-13) and the ionotropic ligand-gated channel P2X receptors (P2X1-7) (9 -12). Activation of the P2Y receptors generally induces downstream signaling through the G protein-coupled activation of phospholipase C, followed by Ca 2ϩ mobilization from intracellular stores (13,14). The P2Y11 also activates adenylyl cyclase, whereas the P2Y12 inhibits it (15). The seven subunits of the ionotrophic ATP-gated P2X receptor family comprise a different subclass, ranging from 379 to 595 amino acids in length and regulating the intracellular level of Ca 2ϩ by ligand-stimulated increase in cell membrane permeability for extracellular Ca 2ϩ ions (7,16,17). The P2X7 receptor is a 595-amino acid polypeptide and has a structure similar to that of other P2X receptors with two membrane-spanning domains, a large extracellular loop, and intracellular N-and C-terminal domains (18,19). In contrast to other P2X receptors, the P2X7 C-terminal intracellular chain is about 200 amino acids longer (20,21). The P2X7 has a pharmacological profile similar to the receptor previously designated as P2Z, with prominent expression in many immune cells (lymphocytes, monocytes/macrophages, dendritic, mesangial, and microglial cells) (...