/pdf/the-iuphar-bps-guide-to-pharmacology-database-gtopdb-in-2018-h4enr956fi.pdf

The IUPHAR/BPS Guide to PHARMACOLOGY database (GtoPdb) in 2018: new features and updates

Inflammatory response has been recognized as a pivotal pathophysiological process during cerebral ischemic stroke. NLRP3 inflammasome, involved in the regulation of inflammatory cascade, can simultaneously lead to GSDMD-executed pyroptosis in cerebral ischemia. Low-density lipoprotein receptor (LDLR), responsible for cholesterol uptake, was noted to exert potential anti-inflammatory bioactivities. Nevertheless, the role of LDLR in neuroinflammation mobilized by cerebral ischemia/reperfusion (I/R) has not been investigated. Ischemic stroke mice model was accomplished by middle cerebral artery occlusion. Oxygen-glucose deprivation was employed after primary cortical neuron was extracted and cultured. A pharmacological inhibitor of NLRP3 (CY-09) was administered to suppress NLPR3 activation. Histological and biochemical analysis were performed to assess the neuronal death both in vitro and in vivo. In addition, neurological deficits and behavioral deterioration were evaluated in mice. The expression of LDLR was downregulated following cerebral I/R injury. Genetic knockout of Ldlr enhanced caspase-1-dependent cleavage of GSDMD and resulted in severe neuronal pyroptosis. LDLR deficiency contributed to excessive NLRP3-mediated maturation and release of IL-1β and IL-18 under in vitro and in vivo ischemic conditions. These influences ultimately led to aggravated neurological deficits and long-term cognitive dysfunction. Blockade of NLRP3 substantially retarded neuronal pyroptosis in Ldlr−/− mice and cultured Ldlr−/− neuron after experimental stroke. These results demonstrated that LDLR modulates NLRP3-mediated neuronal pyroptosis and neuroinflammation following ischemic stroke. Our findings characterize a novel role for LDLR as a potential therapeutic target in neuroinflammatory responses to acute cerebral ischemic injury.

/pdf/low-density-lipoprotein-receptor-ldlr-regulates-nlrp3-3fbm79b6ja.pdf

Low-density lipoprotein receptor (LDLR) regulates NLRP3-mediated neuronal pyroptosis following cerebral ischemia/reperfusion injury

Targeting the NLRP3 inflammasome as new therapeutic avenue for inflammatory bowel disease.

Acute kidney injury (AKI) is a worldwide problem, and there is no effective drug to eliminate AKI. The death of renal cells is an important pathological basis of intrinsic AKI. At present, targeted therapy for TEC death is a research hotspot in AKI therapy. There are many ways of cell death involved in the occurrence and development of AKI, such as apoptosis, necrosis, ferroptosis, and pyroptosis. This article mainly focuses on the role of pyroptosis in AKI. The assembly and activation of NLRP3 inflammasome is a key event in the occurrence of pyroptosis, which is affected by many factors, such as the activation of the NF-κB signaling pathway, mitochondrial instability and excessive endoplasmic reticulum (ER) stress. The activation of NLRP3 inflammasome can trigger its downstream inflammatory cytokines, which will lead to pyroptosis and eventually induce AKI. In this paper, we reviewed the possible mechanism of pyroptosis in AKI and the potential effective inhibitors of various key targets in this process. It may provide potential therapeutic targets for novel intrinsic AKI therapies based on pyroptosis, so as to develop better therapeutic strategies. 

Pathway network of pyroptosis and its potential inhibitors in acute kidney injury

Abstract Inflammasomes are large protein complexes that play a major role in sensing inflammatory signals and triggering the innate immune response. Each inflammasome complex has three major components: an upstream sensor molecule that is connected to a downstream effector protein such as caspase-1 through the adapter protein ASC. Inflammasome formation typically occurs in response to infectious agents or cellular damage. The active inflammasome then triggers caspase-1 activation, followed by the secretion of pro-inflammatory cytokines and pyroptotic cell death. Aberrant inflammasome activation and activity contribute to the development of diabetes, cancer, and several cardiovascular and neurodegenerative disorders. As a result, recent research has increasingly focused on investigating the mechanisms that regulate inflammasome assembly and activation, as well as the potential of targeting inflammasomes to treat various diseases. Multiple clinical trials are currently underway to evaluate the therapeutic potential of several distinct inflammasome-targeting therapies. Therefore, understanding how different inflammasomes contribute to disease pathology may have significant implications for developing novel therapeutic strategies. In this article, we provide a summary of the biological and pathological roles of inflammasomes in health and disease. We also highlight key evidence that suggests targeting inflammasomes could be a novel strategy for developing new disease-modifying therapies that may be effective in several conditions. 

The role of inflammasomes in human diseases and their potential as therapeutic targets

Background and purpose Despite recent advances in understanding its pathophysiology, treatment of acute kidney injury (AKI) remains a major unmet medical need, and novel therapeutic strategies are needed. Cathelicidin-related antimicrobial peptide (CRAMP) with immunomodulatory properties has an emerging role in various disease contexts. Here, we aimed to investigate the role of CRAMP and its underlying mechanisms in AKI. Experimental approach The human homologue LL-37 and CRAMP were measured in blood samples of AKI patients and in experimental AKI mice respectively. Experimental AKI was induced in wild-type and CRAMP-deficient (Cnlp-/- ) mice by ischaemia/reperfusion (I/R). Therapeutic evaluation of CRAMP was performed with exogenous CRAMP (5 mg·kg-1 , i.p.) treatment. Key results Cathelicidin expression was inversely related to clinical signs in patients and down-regulated in renal I/R-induced injury in mice. Cnlp-/- mice exhibited exacerbated I/R-induced renal dysfunction, aggravated inflammatory responses and apoptosis. Moreover, over-activation of the NLRP3 inflammasome in Cnlp-/- mice was associated with I/R-induced renal injury. Exogenous CRAMP treatment markedly attenuated I/R-induced renal dysfunction, inflammatory response and apoptosis, correlated with modulation of immune cell infiltration and phenotype. Consistent with Cnlp-/- mouse data, CRAMP administration suppressed renal I/R-induced NLRP3 inflammasome activation, and its renal protective effects were mimicked by a specific NLRP3 inhibitor CY-09. The reno-protective and NLRP3 inhibitory effects of CRAMP required the EGF receptor. Conclusion and implications Our results suggest that CRAMP acts as a novel immunomodulatory mediator of AKI and modulation of CRAMP may represent a potential therapeutic strategy.

Cathelicidin‐related antimicrobial peptide protects against ischaemia reperfusion‐induced acute kidney injury in mice

Aim Patients in the hemodialysis stage are prone to psychological pressure of depression and anxiety and have resistance, which affects the clinical treatment effect. Effective psychological intervention plays a very important role in improving patients' psychological pressure and patients' compliance. The aim of this study is to explore the nursing effect of psychological intervention on uremic hemodialysis patients. Methods There were 126 uremic hemodialysis patients admitted to the hospital from August 2020 to December 2021. The patients were randomly divided into the routine nursing care group (n = 63) and psychological intervention group (n = 63). The routine nursing care group received routine nursing care for uremia hemodialysis patients. The psychological intervention group implemented psychological intervention on uremia hemodialysis patients. The methods of psychological intervention mainly include establishing a good nurse-patient relationship, popularizing hemodialysis knowledge, timely psychological counseling for patients, and organizing patient communication meetings. The treatment compliance, Self-rating Anxiety Scale (SAS) and Self-rating Depression Scale (SDS) of the two groups were compared before and after nursing. SF-36 scale was used to evaluate the quality of life of patients. The incidence of complications and nursing satisfaction were compared between the two groups. Results The treatment compliance rate and nursing satisfaction of hemodialysis uremic patients in the psychological intervention group were significantly higher than the routine nursing care group. The SAS and SDS of hemodialysis uremia patients in the psychological intervention group were significantly lower than the routine nursing care group after psychological intervention, and SF-36 scale was significantly higher than the routine nursing group. The main complications of uremic hemodialysis patients are hypotension, hyperkalemia, internal fistula occlusion, and infection. Compared with the routine nursing care group, the incidence of complications in the psychological intervention group was significantly reduced. Conclusion The implementation of psychological nursing intervention for uremic hemodialysis patients have a very significant effect on reducing the incidence of complications and improving anxiety, depression, treatment compliance, and the quality of life and the nursing satisfaction.

/pdf/study-on-nursing-effect-of-psychological-intervention-on-18ndebsq.pdf

Study on Nursing Effect of Psychological Intervention on Uremic Hemodialysis Patients

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Cathelicidin‐related antimicrobial peptide protects against ischaemia reperfusion‐induced acute kidney injury in mice

Study on Nursing Effect of Psychological Intervention on Uremic Hemodialysis Patients