Phaseolus vulgaris L. Extract: Alpha-amylase inhibition against metabolic syndrome in mice

To examine the effects of the alpha-amylase inhibitor isoform 1 called phaseolamin, a standardized extract from white kidney beans (Phaseolus vulgaris L) was tested against the hallmarks of metabolic syndrome. The efficacy of a per os repeated treatment with P. vulgaris extract (500 mg/kg) was compared with metformin (100 mg/kg) and atorvastatin (10 mg/kg) in a model of metabolic syndrome evoked by prolonged high fat diet (HFD; week 1 to week 19) in C57BL/6 mice. Bean extract and compounds administration started after metabolic syndrome establishment (week 11). P. vulgaris extract reduced the body weight overtime, as well as effectively lowered glycaemia, triglycerides, and cholesterol. On week 19, bean extract normalized the HFD-evoked tolerance to glucose and insulin. According to the phytochemical characterization, it inhibited the alpha-amylase activity. Animals treated with the extract were rescued from motor impairments and nociceptive threshold alterations induced by HFD. Specific organs analysis revealed that P. vulgaris extract decreased hepatic steatosis and lipid peroxidation in liver. It protected the heart from HFD oxidative alterations increasing the expression of the detoxifying enzymes catalase and glutathione reductase, and normalizing NADH dehydrogenase level. The histological analysis of aorta showed a protection about the development of fatty streaks in the muscular layers. In conclusion, a prolonged treatment with the standardized extract of P. vulgaris significantly reduced several pathological features related to a metabolic syndrome-like condition; a multifactorial approach that candidates this vegetal product as a possible therapeutic option against metabolic syndrome

Characterization of New TRPM8 Modulators in Pain Perception

Background: Transient Receptor Potential Melastatin-8 (TRPM8) is a non-selective cation channel activated by cold temperature and by cooling agents. Several studies have proved that this channel is involved in pain perception. Although some studies indicate that TRPM8 inhibition is necessary to reduce acute and chronic pain, it is also reported that TRPM8 activation produces analgesia. These conflicting results could be explained by extracellular Ca2+-dependent desensitization that is induced by an excessive activation. Likely, this effect is due to phosphatidylinositol 4,5-bisphosphate (PIP2) depletion that leads to modification of TRPM8 channel activity, shifting voltage dependence towards more positive potentials. This phenomenon needs further evaluation and confirmation that would allow us to understand better the role of this channel and to develop new therapeutic strategies for controlling pain. Experimental approach: To understand the role of TRPM8 in pain perception, we tested two specific TRPM8-modulating compounds, an antagonist (IGM-18) and an agonist (IGM-5), in either acute or chronic animal pain models using male Sprague-Dawley rats or CD1 mice, after systemic or topical routes of administration. Results: IGM-18 and IGM-5 were fully characterized in vivo. The wet-dog shake test and the body temperature measurements highlighted the antagonist activity of IGM-18 on TRPM8 channels. Moreover, IGM-18 exerted an analgesic effect on formalin-induced orofacial pain and chronic constriction injury-induced neuropathic pain, demonstrating the involvement of TRPM8 channels in these two pain models. Finally, the results were consistent with TRPM8 downregulation by agonist IGM-5, due to its excessive activation. Conclusions: TRPM8 channels are strongly involved in pain modulation, and their selective antagonist is able to reduce both acute and chronic pain

Oral sodium butyrate supplementation ameliorates paclitaxel-induced behavioral and intestinal dysfunction

Paclitaxel (PTX) is one of the most broadly used chemotherapeutic agents for the treatment of several tumor types including ovarian, breast, and non-small cell lung cancer. However, its use is limited by debilitating side effects, involving both gastrointestinal and behavioral dysfunctions. Due to growing evidence showing a link between impaired gut function and chemotherapy-associated behavioral changes, the aim of this study was to identify a novel therapeutic approach to manage PTX-induced gut and brain comorbidities. Mice were pre-treated with sodium butyrate (BuNa) for 30 days before receiving PTX. After 14 days, mice underwent to behavioral analysis and biochemical investigations of gut barrier integrity and microbiota composition. Paired evaluations of gut functions revealed that the treatment with BuNa restored PTX-induced altered gut barrier integrity, microbiota composition and food intake suggesting a gut-to-brain communication. The treatment with BuNa also ameliorated depressive- and anxiety-like behaviors induced by PTX in mice, and these effects were associated with neuroprotective and anti-inflammatory outcomes. These results propose that diet supplementation with this safe postbiotic might be considered when managing PTX-induced central side effects during cancer therapy

Insights into Thymus Development and Viral Thymic Infections

T-cell development in the thymus is a complex and highly regulated process, involving a wide variety of cells and molecules which orchestrate thymocyte maturation into either CD4+ or CD8+ single-positive (SP) T cells. Here, we briefly review the process regulating T-cell differentiation, which includes the latest advances in this field. In particular, we highlight how, starting from a pool of hematopoietic stem cells in the bone marrow, the sequential action of transcriptional factors and cytokines dictates the proliferation, restriction of lineage potential, T-cell antigen receptors (TCR) gene rearrangements, and selection events on the T-cell progenitors, ultimately leading to the generation of mature T cells. Moreover, this review discusses paradigmatic examples of viral infections affecting the thymus that, by inducing functional changes within this lymphoid gland, consequently influence the behavior of peripheral mature T-lymphocytes

Intestinal inflammation increases convulsant activity and reduces antiepileptic drug efficacy in a mouse model of epilepsy

We studied the effects of intestinal inflammation on pentylenetetrazole (PTZ)-induced seizures in mice and the effects thereon of some antiepileptic and anti-inflammatory treatments to establish if a link may exist. The agents tested were: alpha-lactoalbumin (ALAC), a whey protein rich in tryptophan, effective in some animal models of epilepsy and on colon/intestine inflammation, valproic acid (VPA), an effective antiepileptic drug in this seizure model, mesalazine (MSZ) an effective aminosalicylate anti-inflammatory treatment against ulcerative colitis and sodium butyrate (NaB), a short chain fatty acid (SCFA) normally produced in the intestine by gut microbiota, important in maintaining gut health and reducing gut inflammation and oxidative stress. Intestinal inflammation was induced by dextran sulfate sodium (DSS) administration for 6 days. Drug treatment was started on day 3 and lasted 11 days, when seizure susceptibility to PTZ was measured along with intestinal inflammatory markers (i.e. NF-\u3baB, I\u3ba-B\u3b1, COX-2, iNOS), histological damage, disease activity index (DAI) and SCFA concentration in stools. DSS-induced colitis increased seizure susceptibility and while all treatments were able to reduce intestinal inflammation, only ALAC and NaB exhibited significant antiepileptic properties in mice with induced colitis, while they were ineffective as antiepileptics at the same doses in control mice without colitis. Interestingly, in DSS-treated mice, VPA lost part of its antiepileptic efficacy in comparison to preventing seizures in non-DSS-treated mice while MSZ remained ineffective in both groups. Our study demonstrates that reducing intestinal inflammation through ALAC or NaB administration has specific anticonvulsant effects in PTZ-treated mice. Furthermore, it appears that intestinal inflammation may reduce the antiepileptic effects of VPA, although we confirm that it decreases seizure threshold in this group. Therefore, we suggest that intestinal inflammation may represent a valid antiepileptic target which should also be considered as a participating factor to seizure incidence in susceptible patients and also could be relevant in reducing standard antiepileptic drug efficacy

Intestinal inflammation increases convulsant activity and reduces antiepileptic drug efficacy in a mouse model of epilepsy

We studied the effects of intestinal inflammation on pentylenetetrazole (PTZ)-induced seizures in mice and the effects thereon of some antiepileptic and anti-inflammatory treatments to establish if a link may exist. The agents tested were: alpha-lactoalbumin (ALAC), a whey protein rich in tryptophan, effective in some animal models of epilepsy and on colon/intestine inflammation, valproic acid (VPA), an effective antiepileptic drug in this seizure model, mesalazine (MSZ) an effective aminosalicylate anti-inflammatory treatment against ulcerative colitis and sodium butyrate (NaB), a short chain fatty acid (SCFA) normally produced in the intestine by gut microbiota, important in maintaining gut health and reducing gut inflammation and oxidative stress. Intestinal inflammation was induced by dextran sulfate sodium (DSS) administration for 6 days. Drug treatment was started on day 3 and lasted 11 days, when seizure susceptibility to PTZ was measured along with intestinal inflammatory markers (i.e. NF-κB, Iκ-Bα, COX-2, iNOS), histological damage, disease activity index (DAI) and SCFA concentration in stools. DSS-induced colitis increased seizure susceptibility and while all treatments were able to reduce intestinal inflammation, only ALAC and NaB exhibited significant antiepileptic properties in mice with induced colitis, while they were ineffective as antiepileptics at the same doses in control mice without colitis. Interestingly, in DSS-treated mice, VPA lost part of its antiepileptic efficacy in comparison to preventing seizures in non-DSS-treated mice while MSZ remained ineffective in both groups. Our study demonstrates that reducing intestinal inflammation through ALAC or NaB administration has specific anticonvulsant effects in PTZ-treated mice. Furthermore, it appears that intestinal inflammation may reduce the antiepileptic effects of VPA, although we confirm that it decreases seizure threshold in this group. Therefore, we suggest that intestinal inflammation may represent a valid antiepileptic target which should also be considered as a participating factor to seizure incidence in susceptible patients and also could be relevant in reducing standard antiepileptic drug efficacy

Modulation of pain sensitivity by chronic consumption of highly palatable food followed by abstinence: emerging role of fatty acid amide hydrolase

There is a strong relationship between palatable diet and pain sensitivity, and the cannabinoid and opioid systems might play an important role in this correlation. The palatable diet used in many animal models of obesity is the cafeteria (CAF) diet, based on human food with high sugar, salt, and fat content. In this study, we investigated whether long-term exposure to a CAF diet could modify pain sensitivity and explored the role of the cannabinergic system in this modification. Male Sprague–Dawley rats were divided into two groups: one fed with standard chow only (CO) and the other with extended access (EA) to a CAF diet. Hot plate and tail flick tests were used to evaluate pain sensitivity. At the end of a 40-day CAF exposure, EA rats showed a significant increase in the pain threshold compared to CO rats, finding probably due to up-regulation of CB1 and mu-opioid receptors. Instead, during abstinence from palatable foods, EA animals showed a significant increase in pain sensibility, which was ameliorated by repeated treatment with a fatty acid amide hydrolase inhibitor, PF-3845 (10 mg/kg, intraperitoneally), every other day for 28 days. Ex vivo analysis of the brains of these rats clearly showed that this effect was mediated by mu-opioid receptors, which were up-regulated following repeated treatment of PF-3845. Our data add to the knowledge about changes in pain perception in obese subjects, revealing a key role of CB1 and mu-opioid receptors and their possible pharmacological crosstalk and reinforcing the need to consider this modulation in planning effective pain management for obese patients

Dynamic acetylation profile during mammalian neurulation

Neural tube defects (NTDs) result from failure of neural tube closure during embryogenesis. These severe birth defects of the central nervous system include anencephaly and spina bifida, and affect 0.5-2 per 1,000 pregnancies worldwide in humans. It has been demonstrated that acetylation plays a pivotal role during neural tube closure, as animal models for defective histone acetyltransferase proteins display NTDs. Acetylation represents an important component of the complex network of posttranslational regulatory interactions, suggesting a possible fundamental role during primary neurulation events. This study aimed to assess protein acetylation contribution to early patterning of the central nervous system both in human and murine specimens