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Inflammatory bowel diseases (IBD), including Crohn's disease and ulcerative colitis, are classified as chronic inflammatory disorders and typically require anti-inflammatory drug therapies, such as glucocorticoid regimens, non-steroidal anti-inflammatory drugs, and biologics, aimed at reducing inflammation in the bowel wall. However, each of these therapies is accompanied by a list of possible serious side effects. Because of this, there remains an urgent need to identify new pharmacologic options to reduce or prevent the pro-inflammatory events of IBD while minimizing adverse side effects, and to make available more cost-effective treatment modalities. We have previously identified several herbal extracts that demonstrate potent bio-inhibitory activity of the innate immune response. In particular, Laurus nobilis (LN), or more commonly called bay laurel, demonstrated significant anti-inflammatory function by inhibiting nuclear factor-κB activation. Based upon our original in vitro findings, we have now examined the effects of this herbal extract on a murine dextran sodium sulfate (DSS) model of IBD. Hematoxylin and eosin-stained paraffin sections prepared from DSS treated animals show clear epithelial damage, including ulcerations, extensive neutrophil infiltration into the mucosal layer, and granuloma formation. Tissue from DSS treated animals that also received LN extract showed improved tissue morphology more closely resembling that from control animals. In addition, DSS treated mice with co-administration of LN extract showed a significant reduction in CD4+ antibody staining within the mucosal layer in colonic sections indicating reduced lymphocyte infiltration. Based on these findings, we believe that administration of LN extracts may be effective in reducing the intestinal epithelial damage seen in human IBD and warrants further investigation through clinical trials. Lay Summary: Inflammatory bowel diseases (IBD), such as Crohn's disease (CD) and ulcerative colitis (UC), manifest as chronic inflammation and ulceration of tissues lining the digestive tract. CD involves inflammation of the deeper layers of the digestive tract, including both the small and large intestines, and less commonly, the upper digestive tract. UC involves inflammation along the lining of the colon and rectum. Steroid or biologic treatments for IBD are common, however, are limited due to significant side effects and/or prohibitive cost. In the present study, we provide evidence for use of the natural product, Laurus nobilis (bay leaf), as a safe and effective anti-inflammatory therapy for IBD.

Abstract A large number of genome-wide association studies, transferability studies, and candidate gene studies performed in diverse populations around the world have identified gene variants that are associated with common human obesity. The mounting evidence suggests that these obesity gene variants interact with multiple environmental factors and increase susceptibility to this complex metabolic disease. The objective of this review article is to provide concise and updated information on energy balance, heritability of body weight, origins of gene variants, and gene-nutrient interactions in relation to human obesity. It is proposed that knowledge of these related topics will provide valuable insight for future preventative lifestyle intervention using targeted nutritional and medicinal therapies.

Obesity often leads to increased systemic inflammation which is now thought to play a causative role in the development of atherosclerotic disease and insulin resistance. This inflammatory response originates within large adipose tissue depots and is initiated by classically activated macrophages that infiltrate the tissue from the circulation. The large number of macrophages residing in obese adipose tissue leads to significant increases in interleukin-6 (IL-6) and tumor necrosis factor-α (TNFα) secretion; achieving levels sufficient to elevate circulating plasma concentrations. These cytokines activate potent signals to initiate lipolysis, to release free fatty acids from triacylglycerol stores and contribute to hyperlipidemia in obese individuals. Obese adipose tissue responds to normal β-adrenergic and glucagon stimuli to recover from negative energy balance by inducing lipolysis. However, it is not clear what quantitative influence additional lipolytic stimulation by IL-6 and TNFα has on normal β-adrenergic activity. Although, β-adrenergic and cytokine signaling activate separate pathways for lipolytic activation, it is undefined whether the effects of multiple signaling events on lipolysis are additive or coincident. To clarify this issue, we measured lipolytic activity in 3T3-L1-derived adipocytes stimulated by a β-adrenergic agonist (isoproterenol), IL-6 or TNFα individually and in combinations as co- and tri-stimulation. Treatment of adipocytes with isoproterenol and either IL-6 or TNFα as co-stimulants increased lipolytic activation by approximately the sum of the individual ligands, suggesting contributions from two independent pathways. Co-stimulation with IL-6 and TNFα provided slightly more than an additive response indicating signaling contributions from independent and common pathways. Tri-stimulation resulted in the largest level of lipolytic activation with a value approximate to adding isoproterenol stimulation to a combined treatment of IL-6 and TNFα. The additive nature of cytokine signaling to β-adrenergic activity suggests its therapeutic inhibition will prevent excessive lipolysis, yet minimally interfere with maintaining normal responses to varying energy demands.

Examines the stationary point of abstraction reaction at the fully optimized reaction space (FORS) level. Single-point calculations by unrestricted Moller-Plesset fourth order perturbation theory; Values of the activation energies.

Nonsteroidal anti-inflammatory drugs (NSAIDs) are a primary choice of therapy for diseases with a chronic inflammatory component. Unfortunately, long-term NSAID therapy is often accompanied by severe side effects, including cardiovascular and gastrointestinal complications. Because of this, there is critical need for identification of new and safer treatments for chronic inflammation to circumvent these side effects. Inflammatory diseases have been successfully remedied with natural herbs by many cultures. To better understand the potential of natural herbs in treating chronic inflammation and to identify their mechanism of action, we have evaluated the anti-inflammatory activities of 20 medicinal herbs commonly used in the Hispanic culture. We have established a standardized method for preparing aqueous extracts (teas) from the selected medicinal herbs and screened for inhibition of tumor necrosis factor-α-induced activation of nuclear factor κB (NF-κB), which is the central signaling pathway of the inflammatory response. A number of herbal teas were identified that exhibited significant anti-inflammatory activity. In particular, tea from the herb commonly called laurel was found to be an especially potent inhibitor of NF-κB-dependent cyclooxygenase-2 gene expression and prostaglandin E2production in cultured murine macrophages. These findings indicate that laurel tea extract contains potent anti-inflammatory compounds that function by inhibiting the major signal transduction pathway responsible for inducing an inflammatory event. Based on these results, laurel may represent a new, safe therapeutic agent for managing chronic inflammation. [ABSTRACT FROM AUTHOR]

Increased adiposity results in a heightened infiltration of immune cells into fat depots, which in turn generates a pro-inflammatory phenotype in obese individuals. To better understand the causal factors that establish this pro-inflammatory profile, we examined events leading to crosstalk between adipocytes and immune cells. Using isolated spleen-derived immune cells, stimulated with LPS, together with cultured adipocytes, we differentiated the effects of paracrine factors and cell-cell contact on TNFα, IL-6 and MCP-1 secretion levels and secretion profiles. When splenocytes and adipocytes were co-cultured without direct contact, permitting only paracrine communication, secretion of IL-6 and MCP-1 were increased by 3- and 2.5-fold, respectively, over what was secreted by individual cultures, whereas TNFα secretion was reduced by 55%. When cells were co-cultured with direct cell-cell contact, IL-6 and MCP-1 secretion were increased by an additional 36% and 38%, respectively, over that measured from just paracrine stimulation alone, indicating that cell contact provides a synergistic signal that amplifies elevated cytokine secretion stimulated by paracrine signals. Using splenocytes from TNFα(-/-) mice showed that the absence of TNFα has little effect on paracrine stimulation of cytokine secretion, but attenuates cell contact-mediated enhancement of IL-6 and MCP-1 secretion. Furthermore, TNFα supports cell contact-mediated signaling in part, but not exclusively, through Nuclear Factor-κB activation. These findings indicate that engagement of cell contact between immune cells and adipocytes, in conjunction with locally secreted paracrine factors, activates a unique signaling pathway that mediates crosstalk between these cell types leading to marked effects on cytokine secretion and profile.

Amyloid-like plaques are characteristic lesions defining the neuropathology of Alzheimer's disease (AD). The size and density of these plaques are closely associated with cognitive decline. To combat this disease, the few therapies that are available rely on drugs that increase neurotransmission; however, this approach has had limited success as it has simply slowed an imminent decline and failed to target the root cause of AD. Amyloid-like deposits result from aggregation of the Aβ peptide, and thus, reducing amyloid burden by preventing Aβ aggregation represents an attractive approach to improve the therapeutic arsenal for AD. Recent studies have shown that the natural product curcumin is capable of crossing the blood-brain barrier in the CNS in sufficient quantities so as to reduce amyloid plaque burden. Based upon this bioactivity, we hypothesized that curcumin presents molecular features that make it an excellent lead compound for the development of more effective inhibitors of Aβ aggregation. To explore this hypothesis, we screened a library of curcumin analogs and identified structural features that contribute to the anti-oligomerization activity of curcumin and its analogs. First, at least one enone group in the spacer between aryl rings is necessary for measureable anti-Aβ aggregation activity. Second, an unsaturated carbon spacer between aryl rings is essential for inhibitory activity, as none of the saturated carbon spacers showed any margin of improvement over that of native curcumin. Third, methoxyl and hydroxyl substitutions in the meta- and para-positions on the aryl rings appear necessary for some measure of improved inhibitory activity. The best lead inhibitors have either their meta- and para-substituted methoxyl and hydroxyl groups reversed from that of curcumin or methoxyl or hydroxyl groups placed in both positions. The simple substitution of the para-hydroxy group on curcumin with a methoxy substitution improved inhibitor function by 6-7-fold over that measured for curcumin.