Over-consumption of high-fat diets (HFDs) is associated with several pathologies. Although the intestine is the organ that comes into direct contact with all diet components, the impact of HFD has mostly been studied in organs that are linked to obesity and obesity related disorders. We used Drosophila as a simple model to disentangle the effects of a HFD on the intestinal structure and physiology from the plethora of other effects caused by this nutritional intervention. Here, we show that a HFD, composed of triglycerides with saturated fatty acids, triggers activation of intestinal stem cells in the Drosophila midgut. This stem cell activation was transient and dependent on the presence of an intestinal microbiota, as it was completely absent in germ free animals. Moreover, major components of the signal transduction pathway have been elucidated. Here, JNK (basket) in enterocytes was necessary to trigger synthesis of the cytokine upd3 in these cells. This ligand in turn activated the JAK/STAT pathway in intestinal stem cells. Chronic subjection to a HFD markedly altered both the microbiota composition and the bacterial load. Although HFD-induced stem cell activity was transient, long-lasting changes to the cellular composition, including a substantial increase in the number of enteroendocrine cells, were observed. Taken together, a HFD enhances stem cell activity in the Drosophila gut and this effect is completely reliant on the indigenous microbiota and also dependent on JNK signaling within intestinal enterocytes. High-fat diets have been associated with a plethora of morbidities. The major research focus has been on its effects on obesity related disorders, mostly omitting the intestine, although it is the organ that makes the first contact with all diet components. Here, we aimed to understand the effects of HFD on the intestine itself. Using Drosophila as a model, we showed that a HFD and more specifically, trigylcerides with saturated fatty acids, induced a transient activation of intestinal stem cells. This response completely depended on the presence of an intestinal microbiota, as in germ free flies this reaction was completely abolished. Mechanistically, we found that HFD induces JNK signaling in enterocytes, which triggers production of the cytokine upd3. This ligand of the JAK/STAT pathway, in turn activates STAT signaling in intestinal stem cells, leading to their activation. All these components of the JNK- and JAK/STAT-pathways are necessary for a HFD to lead to increased stem cell production. Moreover, HFD changed both, composition and abundance of the microbiota. As fecal transfer experiments failed to recapitulate the HFD phenotype, we assume that the increased bacterial load is the major cause for the HFD triggered stem cell activation in the intestine.

Objective(s): This study aimed to evaluate the anti-arthritic activity of Ricinus communis leaves’ and Withania somnifera roots’ hydroalcoholic extracts in Complete Freund’s adjuvant-induced arthritis in Wistar rats. Materials and Methods: HPLC and FT-IR analysis detected pharmacologically important phytocompounds in both plant extracts. Oral treatments including methotrexate (MTX; 3 mg/kg twice a week) and extracts at 250 and 500 mg/kg/day were initiated after arthritis induction. Changes in paw swelling, arthritic score, body weight, organ indices (thymus and spleen), hematological and biochemical parameters, and pro-/anti-inflammatory cytokine expression using qRT-PCR were assessed. Oxidative stress markers in hepatic tissue were determined. Histopathological and radiological examinations were also performed. Results: RCE (R. communis extract) and WSE (W. somnifera extract) demonstrated a reduction in paw swelling, arthritic score, and restoration of body weight and organ indices. Hematological parameters, serum inflammatory markers such as CRP and RF, and liver function markers of arthritic rats were significantly (p <0.01) ameliorated with RCE and WSE treatment. Both plants persuasively down-regulated IL-1β, IL-6, IL-17a, TNF-α, and RANKL and up-regulated IL-4, INF-γ, and OPG relative expression as well as alleviating hepatic oxidative stress parameters. Histopathological and radiological findings revealed a marked reduction in tissue inflammation and bone erosion in extracts treated groups. Conclusion: The study findings suggest that R. communis leaves and W. somnifera roots have markedly subsided inflammation and improved health through modulating pro-/anti-inflammatory cytokine expression and reducing oxidative stress.

The gut microbiome is comprised of various types of bacteria, fungi, protozoa, and viruses naturally occurring in humans and animals as normal microflora. Gut microorganisms are typically host specific, and their number and type vary according to different host species and environment. Gut microbes contribute directly and/or indirectly to various physiological processes including immune modulation, regulation of various neurotransmitter, and hormones, as well as production of many antioxidants and metabolites. They also play a role as antibiotic, anti-inflammatory, anti-diabetic, and anti-carcinogenic agents. Moreover, the ability of gut microbes to attenuate various systemic diseases like coronary heart disease, irritable bowel syndrome, metabolic diseases like diabetes mellitus, and infectious diseases like diarrhea has recently been reported. Current research findings have enough evidence to suggest that gut microbiome is a new organ system mainly due to the microorganisms’ specific biochemical interaction with their hosts and their systemic integration into the host biology. Investigations into the potential ability of gut microbiome to influence metabolism inside their host via biochemical interaction with antibiotics and other drugs has recently been initiated. This chapter specifically focuses on the importance of gut microorganisms as a new organ system.

Herein, we evaluated the in vivo effects of meloxicam and curcumin co-encapsulated PLGA nanoparticles in experimental acute models of pyrexia, nociception, and inflammation. Seven groups (n = 6) were designed for each investigation and pretreated intraperitoneally (i.p.): the control group, meloxicam (4 mg/kg b.w.), curcumin (15 mg/kg b.w.), and equivalent content containing PLGA capped nanoparticles of meloxicam (Mlx-NP) and curcumin (Cur-NP) alone and in combination (Mlx-Cur-NP; at two doses). The results showed that PLGA encapsulation significantly (p ≤ 0.05) improved the in vivo activities of each compound. Furthermore, co-encapsulation of meloxicam and curcumin potentiated the anti-pyretic effect on yeast-induced pyretic rats, anti-nociceptive effect on nociception induced in rats by formalin and heat, and anti-edematogenic activity in xylene-induced ear edema in rats in a dose-dependent manner. In carrageenan-induced paw inflammation in rats, meloxicam and curcumin co-loading (Mlx-Cur-NP) resulted in significant (p ≤ 0.05) inhibition of paw inflammation, reduction in TNF-α and PGE2 levels, downregulation of expressions of pro-inflammatory cytokines (TNF-α, IL-1β, and IL-6), as well as a decrease in histopathological changes and TNF-α immunoexpression in paw tissues. Moreover, Mlx-Cur-NP demonstrated noteworthy potentiation in pharmacological effects compared to free compounds and mono-compound-loaded nanoparticles. Thus, the association of meloxicam with curcumin in a biodegradable nanocarrier system could provide a promising anti-pyretic, anti-nociceptive, and anti-inflammatory therapeutic approach for acute conditions.

This study aimed to evaluate the anti-arthritic activity of curcumin and meloxicam co-loaded PLGA nanoparticles in adjuvant-induced arthritic rats. PLGA nanoparticles encapsulating curcumin (nCur) and meloxicam (nMlx) alone and in combination (nCur/Mlx) were used to characterize zeta size and potential, polydispersity index, encapsulation efficiency (%), compound–polymer interactions (FT-IR analysis), and surface morphology (SEM imaging). In vivo, Complete Freund’s adjuvant-induced arthritic rats were intraperitoneally (i.p.) administered with curcumin, meloxicam, curcumin plus meloxicam, nCur, nMlx, and nCur/Mlx for 28 consecutive days. Results showed that nCur, nMlx, and nCur/Mlx significantly (p ≤ 0.05) reduced paw swelling and arthritic score, restored body weight and the immune organ index (thymus and spleen), as well as attenuated serum inflammatory markers (RF, CRP, and PGE2) and oxidative stress parameters (MDA, SOD, and CAT) in adjuvant-induced arthritic rats compared to free compounds. In addition, mono- and dual-compound-loaded nanoparticles significantly (p ≤ 0.05) down-regulated pro-inflammatory cytokines (TNF-α, IL-1β, and IL-6), up-regulated anti-inflammatory cytokines (IL-4, IL-10, and IFN-γ), and modulated OPG and RANKL expressions in paw tissue. The aforementioned results were further confirmed through radiological and histopathological examinations. Furthermore, the anti-arthritic effect of nCur/Mlx was notably (p ≤ 0.05) enhanced compared to nCur or nMlx alone. In conclusion, the co-nanoencapsulation of curcumin could potentiate the anti-arthritic activity of meloxicam and could provide a novel therapeutic approach for the formulation of nanocarrier pharmaceutical products for the management of arthritis.