SummaryPseudomonas aeruginosa causes serious acute and chronic infections in humans. Major differences exist in disease pathogenesis, clinical treatment and outcomes between acute and chronic infections. P. aeruginosa acute infection characteristically involves the type III secretion systems (T3SS) while chronic infection is often associated with the formation of biofilms, a major cause of difficulties to eradicate chronic infections. The choice between acute and chronic infection or the switch between them by P. aeruginosa is controlled by regulatory pathways that control major virulence factors and genes associated with biofilm formation. In this study, we characterized a hybrid sensor kinase PA1611 that controls the expression of genes associated with acute and chronic infections in P. aeruginosa PAO1. Expression of PA1611 completely repressed T3SS and swarming motility while it promoted biofilm formation. The protein PA1611 regulates two small RNAs (sRNAs), rsmY and rsmZ which in turn control RsmA. Independent of phosphate relay, PA1611 interacts directly with RetS in vivo. The positive effect of RetS on factors associated with acute infection could presumably be restrained by PA1611 when chronic infection conditions are present. This RetS-PA1611 interaction, together with the known RetS-GacS interaction, may control disease progression and the lifestyle choice of P. aeruginosa.
Paraquat is a nitrogen herbicide imposing severe organ toxicity in human leading to acute lung injury and heart failure. The present study was designed to examine the impact of ablation of the innate proinflammatory mediator toll-like receptor 4 (TLR4) in paraquat-induced cardiac contractile dysfunction and the underlying mechanisms involved with a focus on endoplasmic reticulum (ER) stress and apoptosis. Adult male wild-type (WT) and TLR4 knockout (TLR4 ) mice were challenged with paraquat (45 mg/kg, i.p.) for 48 h prior to the assessment of myocardial and cardiomyocyte sarcomere function, ER stress, apoptosis and inflammation. Acute paraquat challenge exerted myocardial functional and geometric alterations including enlarged left ventricular end systolic diameter (LVESD), reduced fractional shortening, decreased sarcomere shortening, maximal velocities of sarcomere shortening and relengthening associated with unchanged LV posterior wall thickness, septal thickness, LV end diastolic diameter (LVEDD), heart rate, sarcomere length, time-to-peak shortening and time-to-90% relengthening. Although TLR4 ablation did not affect mechanical properties in the heart, it significantly attenuated or ablated paraquat-induced cardiac contractile anomalies. Moreover, paraquat imposed overt ER stress, apoptosis and inflammation as evidenced by upregulation of Bip, CHOP, Caspase-3, -9, Bax, Bad, and IL-1β, phosphorylation of PERK, eIF2α and IΚB, as well as activation of the stress molecules ERK and p38, with unchanged Caspase-8, Bcl2, TNF-α, p53, HMGB1, MyD88 and phosphorylation of Akt, GSK3β and JNK, the effects of which were attenuated or negated by TLR4 knockout. Taken together, our results suggested that TLR4 ablation alleviated paraquat-induced myocardial contractile dysfunction possibly through attenuation of ER stress, apoptosis and inflammation. © 2016 Wiley Periodicals, Inc. Environ Toxicol 32: 656-668, 2017.
Background and Aims Liver regeneration after extreme hepatocyte loss occurs through transdifferentiation of biliary epithelial cells (BECs), which includes dedifferentiation of BECs into bipotential progenitor cells (BPPCs) and subsequent redifferentiation into nascent hepatocytes and BECs. Although multiple molecules and signaling pathways have been implicated to play roles in the BEC‐mediated liver regeneration, mechanisms underlying the dedifferentiation‐redifferentiation transition and the early phase of BPPC redifferentiation that is pivotal for both hepatocyte and BEC directions remain largely unknown. Approach and Results The zebrafish extreme liver damage model, genetic mutation, pharmacological inhibition, transgenic lines, whole‐mount and fluorescent in situ hybridizations and antibody staining, single‐cell RNA sequencing, quantitative real‐time PCR, and heat shock–inducible overexpression were used to investigate roles and mechanisms of farnesoid X receptor (FXR; encoded by nuclear receptor subfamily 1, group H, member 4 [nr1h4]) in regulating BPPC redifferentiation. The nr1h4 expression was significantly up‐regulated in response to extreme liver injury. Genetic mutation or pharmacological inhibition of FXR was ineffective to BEC‐to‐BPPC dedifferentiation but blocked the redifferentiation of BPPCs to both hepatocytes and BECs, leading to accumulation of undifferentiated or less‐differentiated BPPCs. Mechanistically, induced overexpression of extracellular signal‐related kinase (ERK) 1 (encoded by mitogen‐activated protein kinase 3) rescued the defective BPPC‐to‐hepatocyte redifferentiation in the nr1h4 mutant, and ERK1 itself was necessary for the BPPC‐to‐hepatocyte redifferentiation. The Notch activities in the regenerating liver of nr1h4 mutant attenuated, and induced Notch activation rescued the defective BPPC‐to‐BEC redifferentiation in the nr1h4 mutant. Conclusions FXR regulates BPPC‐to‐hepatocyte and BPPC‐to‐BEC redifferentiations through ERK1 and Notch, respectively. Given recent applications of FXR agonists in the clinical trials for liver diseases, this study proposes potential underpinning mechanisms by characterizing roles of FXR in the stimulation of dedifferentiation‐redifferentiation transition and BPPC redifferentiation.
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