Brain kinin B1 receptor is upregulated by the oxidative stress and its activation leads to stereotypic nociceptive behavior in insulin-resistant rats

Kinin B1 receptor (B1R) is virtually absent under physiological condition, yet it is highly expressed in models of diabetes mellitus. This study aims at determining: (1) whether B1R is induced in the brain of insulin-resistant rat through the oxidative stress; (2) the consequence of B1R activation on stereotypic nocifensive behavior; (3) the role of downstream putative mediators in B1R-induced behavioral activity. Sprague-Dawley rats were fed with 10% d-glucose in their drinking water or tap water (controls) for 4 or 12 weeks, combined either with a standard chow diet or a diet enriched with α-lipoic acid (1 g/kg feed) for 4 weeks. The distribution and density of brain B1R binding sites were assessed by autoradiography. Behavioral activity evoked by i.c.v. injection of the B1R agonist Sar-[D-Phe⁸]-des-Arg⁹-BK (10 μg) was measured before and after i.c.v. treatments with selective antagonists (10 μg) for kinin B1 (R-715, SSR240612), tachykinin NK1 (RP-67580) and glutamate NMDA (DL-AP5) receptors or with the inhibitor of NOS (L-NNA). Results showed significant increases of B1R binding sites in various brain areas of glucose-fed rats that could be prevented by the diet containing α-lipoic acid. The B1R agonist elicited head scratching, grooming, sniffing, rearing, digging, licking, face washing, wet dog shake, teeth chattering and biting in glucose-fed rats, which were absent after treatment with α-lipoic acid or antagonists/inhibitors. Data suggest that kinin B1R is upregulated by the oxidative stress in the brain of insulin-resistant rats and its activation causes stereotypic nocifensive behavior through the release of substance P, glutamate and NO.     

Hypocretins: The Timing of Sleep and Waking

The appropriate time and place for sleep and waking are important factors for survival. Sleep and waking, rest and activity, flight and fight, feeding, and reproduction are all organized in relation to the day and night. A biological clock, the suprachiasmatic nucleus (SCN), synchronized by photic influences and other environmental cues, provides an endogenous timing signal that entrains circadian body rhythms and is complemented by a homeostatic sleep pressure factor. Cholinergic, catecholaminergic, serotonergic, and histaminergic nuclei control wakefulness and mutually interact with the SCN as well as sleep- and wake-promoting neurons in the hypothalamus to form a bistable switch that controlls the timing of behavioral state transitions. Hypocretin neurons integrate circadian-photic and nutritional-metabolic influences and act as a conductor in the aminergic orchestra. Their loss causes narcolepsy, a disease conferring the inability to separate sleep and waking. Their role in appetitive behavior, stress, and memory functions is important to our understanding of addiction and compulsion.     

Synthesis of thromboxane B2 in incubates of dog platelet-rich plasma with arachidonic acid and its inhibition by different drugs

Dog platelets in citrated plasma fail to aggregate upon addition of AA, even though, as demonstrated by bioassay procedures and now by the radioimmunoassay, TxA2 is formed as in case of aggregating human platelets. Imidazole inhibited formation of TxB2 and increased the amounts of PGE2 formed, indicating specific inhibition of thromboxane synthetase. Other drugs tested (benzimidazolamine, compound L8027, indomethacin and isoprenaline) inhibited either cyclo-oxygenase alone, or together with thromboxane synthetase.     

RIP3 blockade prevents immune-mediated hepatitis through a myeloid-derived suppressor cell dependent mechanism

Autoimmune hepatitis (AIH) is an immune-mediated chronic inflammatory liver disease, and its pathogenesis is not fully understood. Our previous study discovered that receptor interacting protein kinase 3 (RIP3) is correlated with serum transaminase levels in AIH patients. However, its role and underlying mechanism in AIH are poorly understood. Here, we detected the increased expression and activation of RIP3 in livers of patients and animal models with AIH. The inhibition of RIP3 kinase by GSK872 prevented concanavalin A (ConA)-induced immune-mediated hepatitis (IMH) by reduced hepatic proinflammatory cytokines and immune cells including Th17 cells and macrophages. Further experiments revealed that RIP3 inhibition resulted in an increase in CD11b⁺Gr1⁺ myeloid-derived suppressor cells (MDSCs) with immunoregulatory properties in the liver, spleen, and peripheral blood. Moreover, the depletion of Gr-1⁺ MDSCs abrogated the protective effect and immune suppression function of GSK872 in ConA-induced IMH. Altogether, our data demonstrate that RIP3 blockade prevents ConA-induced IMH through promoting MDSCs infiltration. Inhibition of RIP3 kinase may be a novel therapeutic avenue for AIH treatment.     

Molecular profile of the NF‐κB signalling pathway in human colorectal cancer

The development and progression of colorectal cancer (CRC) have been associated with inflammation processes that involve the overactivation of the NF‐κB signalling pathway. The characterization of the NF‐κB expression profile in CRC is an important topic since the suppression of NF‐κB represents a potential therapeutic approach. In this study, we assessed the expression levels of 84 NF‐κB‐related genes in paired tumoral (T) and peritumoral (PT) tissues from 18 CRC patients and 18 normal colonic mucosae, and the expression levels of three miRNAs targeting the most dysregulated genes revealed by the case–control analysis. Comparing the gene expression profile of T and controls, 60 genes were dysregulated. The comparison of T and PT revealed 17 dysregulated genes in the tumoral tissues, with IL1B, CXCL8, IL1A, and CSF2 being the most upregulated. Notably, through a bioinformatics analysis, the differential gene expression of 11 out of the 17 genes was validated on a larger cohort of 308 CRC patients compared with 41 controls. Moreover, a decrease in the levels of RELA, NOD1, CASP8, BCL2L1, ELK1, and IKBKB was identified in poorly differentiated tumours compared to moderately differentiated tumours. The analysis of the three miRNAs targeting IL1B, CXCL8, IL1A, and CSF2 showed that miR‐182‐5p was upregulated in T compared with PT, whereas miR‐10b‐5p was downregulated in T compared with PT and control tissues. Our results may contribute to the design of new experimental therapeutic strategies based on endogenous molecules, such as miRNAs, to target the genetic key players of the NF‐ κB pathway.