Mucosa-associated lymphoid tissue lymphoma translocation protein 1 inhibition alleviates intestinal impairment induced by chronic heat stress in finisher broilers

Article

作者: Pertiwi, Herinda ; Majdeddin, Maryam ; Zhang, Huaiyong ; Michiels, Joris

Heat stress (HS) in poultry has deleterious effects on intestinal development and barrier function, along with inflammatory outbursts. In the present study, chronic HS reduced body weight of broilers and activated mucosa-associated lymphoid tissue lymphoma translocation protein 1 (Malt1) /nuclear factor kappa B (NF-κB) signaling pathways to elicit the inflammatory cytokine response in jejunum. Subsequently, this study investigated the protective effects of the Malt1 inhibitor on the intestine of broilers under HS conditions. The 21-day-old male broilers were allocated to 8 pens housed in HS room (34°C for 7 h/d) until 28 d of age. During this period, 4 birds were selected from each heat-stressed pen and received intraperitoneal injection of 20 mg/kg body weight Mepazine (a Malt1 inhibitor) or the equivalent volume of phosphate buffer saline (PBS) every other day. When compared to PBS broilers, birds received Mepazine injection exhibited increased relative weight and higher villus height in jejunum (both P < 0.05). Mepazine treatment also increased (P < 0.05) the mRNA of zonula occludens-1 (ZO-1), claudin-1, and cadherin 1 of jejunum, which was companied by the reduced caspase-3 transcription under HS condition. Meanwhile, the gene expression levels of toll-like receptor 4 (TLR4), Malt1, NF-κB, interleukin-6 (IL-6), and tumor necrosis factor alpha (TNF-α) in the jejunum were significantly downregulated by Mepazine administration (P < 0.05). Although there were no significant differences in the relative weight of the thymus and bursa, the transcription levels of T helper 1 (Th1)- and Th17-related cytokines were lower in thymus of birds injected with Mepazine. The cytokines of Treg cytokine transforming growth factor beta (TGF-β) and forkhead box protein P3 (Foxp3) in both the thymus and bursa were not influenced. These results suggest that inhibition of Malt1 protease activity can protect intestinal integrity by promoting the production of tight junction proteins and attenuating NF-κB-mediated intestinal inflammation response under HS conditions.

2023-04-01·Journal of Applied Toxicology

The role of phenothiazine derivatives in autophagy regulation: A systematic review

Review

作者: Stojko, Jerzy ; Rzepecka‐Stojko, Anna ; Otręba, Michał

AbstractIn this review, we summarized the current literature on the impact of phenothiazine derivatives on autophagy in vitro. Phenothiazines are antipsychotic drugs used in the treatment of schizophrenia, which is related to altered neurotransmission and dysregulation of neuronal autophagy. Thus, phenothiazine derivatives can impact autophagy. We identified 35 papers, where the use of the phenothiazines in the in vitro autophagy assays on normal and cancer cell lines, Caenorhabditis elegans, and zebrafish were discussed. Chlorpromazine, fluphenazine, mepazine, methotrimeprazine, perphenazine, prochlorperazine, promethazine, thioridazine, trifluoperazine, and novel derivatives can modulate autophagy. Stimulation of autophagy by phenothiazines may be either mammalian target of rapamycin (mTOR)‐dependent or mTOR‐independent. The final effect depends on the used concentration as well as the cell line. A further investigation of the mechanisms of autophagy regulation by phenothiazine derivatives is required to understand the biological actions and to increase the therapeutic potential of this class of drugs.

2022-09-29·Blood

The Gab2–MALT1 axis regulates thromboinflammation and deep vein thrombosis

Article

作者: Kondreddy, Vijay ; Pendurthi, Usha R. ; Keshava, Shiva ; Das, Kaushik ; Rao, L. Vijaya Mohan ; Magisetty, Jhansi

AbstractDeep vein thrombosis (DVT) is the third most common cause of cardiovascular mortality. Several studies suggest that DVT occurs at the intersection of dysregulated inflammation and coagulation upon activation of inflammasome and secretion of interleukin 1β (IL-1β) in restricted venous flow conditions. Our recent studies showed a signaling adapter protein, Gab2 (Grb2-associated binder 2), plays a crucial role in propagating inflammatory signaling triggered by IL-1β and other inflammatory mediators in endothelial cells. The present study shows that Gab2 facilitates the assembly of the CBM (CARMA3 [CARD recruited membrane-associated guanylate kinase protein 3]–BCL-10 [B-cell lymphoma 10]–MALT1 [mucosa-associated lymphoid tissue lymphoma translocation protein 1]) signalosome, which mediates the activation of Rho and NF-κB in endothelial cells. Gene silencing of Gab2 or MALT1, the effector signaling molecule in the CBM signalosome, or pharmacological inhibition of MALT1 with a specific inhibitor, mepazine, significantly reduced IL-1β–induced Rho-dependent exocytosis of P-selectin and von Willebrand factor (VWF) and the subsequent adhesion of neutrophils to endothelial cells. MALT1 inhibition also reduced IL-1β–induced NF-κB–dependent expression of tissue factor and vascular cell adhesion molecule 1. Consistent with the in vitro data, Gab2 deficiency or pharmacological inhibition of MALT1 suppressed the accumulation of monocytes and neutrophils at the injury site and attenuated venous thrombosis induced by the inferior vena cava ligation-induced stenosis or stasis in mice. Overall, our data reveal a previously unrecognized role of the Gab2–MALT1 axis in thromboinflammation. Targeting the Gab2–MALT1 axis with MALT1 inhibitors may become an effective strategy to treat DVT by suppressing thromboinflammation without inducing bleeding complications.

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