Modulation of 5-fluorouracil activation of toll-like/MyD88/NF-κB/MAPK pathway by Saccharomyces boulardii CNCM I-745 probiotic.

BACKGROUND AND AIM: Chemotherapy drugs that act via Toll-like receptors (TLRs) can exacerbate mucosal injury through the production of cytokines. Intestinal mucositis can activate TLR2 and TLR4, resulting in the activation of NF-κB. Intestinal mucositis characterized by intense inflammation is the main side effect associated with 5-fluorouracil (5-FU) treatment. Saccharomyces boulardii CNCM I-745 (S.b) is a probiotic yeast used in the treatment of gastrointestinal disorders. The main objective of the study was to evaluate the effect of S.b treatment on the Toll-like/MyD88/NF-κB/MAPK pathway activated during intestinal mucositis and in Caco-2 cells treated with 5-FU. METHODS: The mice were divided into three groups: saline (control), saline + 5-FU, and 5-FU + S.b (1.6 × 1010 colony forming units/kg). After 3 days of S.b administration by gavage, the mice were euthanized and the jejunum and ileum were removed. In vitro, Caco2 cells were treated with 5-FU (1 mM) alone or in the presence of lipopolysaccharide (1 ng/ml). When indicated, cells were exposed to S.b. The jejunum/ileum samples and Caco2 cells were examined for the expression or concentration of the inflammatory components. RESULTS: Treatment with S.b modulated the expressions of TLR2, TLR4, MyD88, NF-κB, ERK1/2, phospho-p38, phospho-JNK, TNF-α, IL-1ß, and CXCL-1 in the jejunum/ileum and Caco2 cells following treatment with 5-FU. CONCLUSION: Toll-like/MyD88/NF-κB/MAPK pathway are activated during intestinal mucositis and their modulation by S.b suggests a novel and valuable therapeutic strategy for intestinal inflammation.

Antinociceptive effects of hydroalcoholic extract from Euterpe oleracea Mart. (Açaí) in a rodent model of acute and neuropathic pain.

BACKGROUND: Plants rich in flavonoids, such as açaí (Euterpe oleraceae Mart.), can induce antinociception in experimental animals. Here, we tested an extract obtained from the stones of açaí fruits (açaí stone extract, ASE), a native plant from the Amazon region of Brazil, in models of acute/inflammatory and chronic pain. METHODS: Antinociceptive effects of ASE were evaluated in the hot plate, formalin, acetic acid writhing, carrageenan, and neuropathic pain models, as well as in thermal hyperalgesia and mechanical allodynia models induced by spinal nerve ligation. Antinociceptive activities were modulated by the administration of cholinergic, adrenergic, opioid, and L-arginine-NO antagonists. RESULTS: Oral administration of ASE (30, 100, or 300 mg.kg(-1)) dose-dependently reduced nociceptive responses to acute/inflammatory pain in mice, including thermal hyperalgesia, acetic acid-induced writhing, and carrageenan-induced thermal hyperalgesia. Moreover, ASE reduced the neurogenic and inflammatory phases after intraplantar injection of formalin in mice. The antinociceptive effect of ASE (100 mg · kg(-1)) in a hot plate protocol, was inhibited by pre-treatment with naloxone (1 mg · kg(-1)), atropine (2 mg · kg(-1)), yohimbine (5 mg · kg(-1)), or L-NAME (30 mg · kg(-1)). Furthermore, ASE prevented chronic pain in a rat spinal nerve ligation model, including thermal hyperalgesia and mechanical allodynia. CONCLUSION: ASE showed significant antinociceptive effect via a multifactorial mechanism of action, indicating that the extract may be useful in the development of new analgesic drugs.

Docking, synthesis and anti-diabetic activity of novel sulfonylhydrazone derivatives designed as PPAR-gamma agonists.

Diabetes is a metabolic disorder characterized by hyperglycemia. When not properly controlled, complications include neuropathy, coronary artery disease, and renal failure. Several drugs are approved for diabetes treatment; however their use is associated with side effects and lack of efficacy in attenuating the development of long-term complications. This work describes the virtual screening and synthesis of a novel series of sulfonylhydrazone derivatives designed as peroxisome proliferator-activated receptor gamma (PPARγ) agonists and investigation of the analogs for hypoglycemic activity in a murine model of diabetes. Docking studies identified LASSBio-331 (5) as having theoretical affinity for PPARγ similar to the prototype (S)-rosiglitazone. Several structural modifications were proposed for the structure of LASSBio-331, resulting in the synthesis of five novel compounds, which showed experimental affinity for PPARγ. Among these new compounds, LASSBio-1471 (15) had the best theoretical binding energy for PPARγ and was selected for testing in STZ-induced diabetes. Four weeks after single intravenous injection of STZ (60 mg/kg), Wistar rats were treated with vehicle (DMSO) or LASSBio-1471 (20 mg/kg, i.p.) for 7 days. The blood glucose levels of rats treated with LASSBio-1471 were reduced from 548.4 ± 26.0 mg/dL before treatment to 259.6 ± 73.1 mg/dL (P < 0.05). Paw withdrawal threshold was significantly reduced in diabetic rats and was restored from 21.9 ± 1.7 g to 36.7 ± 1.2 g after 7 days of treatment with LASSBio-1471 (P < 0.05). Thus, the novel sulfonylhydrazone derivative is a PPARγ ligand that is effective for treatment of diabetic neuropathy in STZ-injected rats.