Nucleotide-binding domain and leucine-rich repeat (LRR)-containing family protein 3 (NLRP3) regulated the maturation of inflammation-related cytokines by forming NLRP3 inflammasome, which plays pivotal roles in sepsis pathogenesis. In this study, we evaluated the genetic association of NLRP3 polymorphisms with sepsis (640 patients and 769 controls) and characterized the impact of NLRP3 polymorphisms on NLRP3 expression and inflammatory responses. No significant differences were observed in genotype/allelic frequencies of NLRP3 29940G>C between sepsis cases and controls. The G allele was significantly overrepresented in patients with septic shock than those in sepsis subgroup, and the GC/GG genetypes were related to the 28-day mortality of sepsis. Lipopolysaccharide challenge to peripheral blood mononuclear cells showed a significant suppression of NLRP3 mRNA expression and release of IL-1β and TNF-α in CC compared with the GC/GG genotype category. Functional experiments with luciferase reporter vectors containing the NLRP3 3′-UTR with the 29940 G-to-C variation in HUVECs and THP-1 cells showed a potential suppressive effect of miR-146a on NLRP3 transcription in the presence of the C allele. Taken together, these results demonstrated that the 29940 G-to-C mutation within the NLRP3 3′-UTR was a gain-of-function alteration that caused the suppression of NLRP3 expression and downstream inflammatory cytokine production via binding with miR-146a, which ultimately protected patients against susceptibility to sepsis progression and poor clinical outcome.
Background
Nafamostat mesilate (NM), a broad-spectrum and potent serine protease inhibitor, can be used as an anticoagulant during extracorporeal circulation, as well as a promising drug effective against coronavirus disease 2019 (COVID-19). We conducted a systematic meta-analysis to evaluate the safety and efficacy of NM administration in critically ill patients who underwent blood purification therapy (BPT).
Methods
The Cochrane Library, Web of Science and PubMed were comprehensively searched from inception to August 20, 2021, for potential studies.
Results
Four randomized controlled trials (RCTs) and seven observational studies with 2723 patients met the inclusion criteria. The meta-analysis demonstrated that conventional therapy (CT) significantly increased hospital mortality compared with NM administration (RR = 1.25,
p
= 0.0007). In subgroup analyses, the in-hospital mortality of the NM group was significantly lower than that of the anticoagulant-free (NA) group (RR = 1.31,
p
= 0.002). The CT interventions markedly elevated the risk ratio of bleeding complications by 45% (RR = 1.45,
p
= 0.010) compared with NM interventions. In another subgroup analysis, NM used exhibited a significantly lower risk of bleeding complications than those of the low-molecular-weight heparin (LMWH) used (RR = 4.58,
p
= 0.020). The filter lifespan was decreased significantly (MD = −10.59,
p
< 0.0001) in the NA groups compared with the NM groups. Due to the poor quality of the included RCTs, these results should be interpreted with caution.
Conclusion
Given the better survival outcomes, lower risk of bleeding, NM anticoagulation seems to be a safe and efficient approach for BPT patients and could yield a favorable filter lifespan. More multi-center RCTs with large samples are required for further validation of this study.
Background
Sepsis has a complex pathogenesis in which the uncontrolled systemic inflammatory response triggered by infection leads to vascular barrier disruption, microcirculation dysfunction and multiple organ dysfunction syndrome. Numerous recent studies reveal that a disintegrin and metalloproteinase 10 (ADAM10) acts as a “molecular scissor” playing a pivotal role in the inflammatory response during sepsis by regulating proteolysis by cleaving various membrane protein substrates, including proinflammatory cytokines, cadherins and Notch, which are involved in intercellular communication. ADAM10 can also act as the cellular receptor for Staphylococcus aureus α-toxin, leading to lethal sepsis. However, its substrate-specific modulation and precise targets in sepsis have not yet to be elucidated.
Methods
We performed a computer-based online search using PubMed and Google Scholar for published articles concerning ADAM10 and sepsis.
Conclusions
In this review, we focus on the functions of ADAM10 in sepsis-related complex endothelium-immune cell interactions and microcirculation dysfunction through the diversity of its substrates and its enzymatic activity. In addition, we highlight the posttranslational mechanisms of ADAM10 at specific subcellular sites, or in multimolecular complexes, which will provide the insight to intervene in the pathophysiological process of sepsis caused by ADAM10 dysregulation.
Review question / Objective: How do PDT and lasers affect the clinical results of nonsurgical treatment in patients with periimplant diseases? Does PDT and lasers, when used as an adjunctive treatment, provide superior clinical and patientpreferred outcomes compared with nonsurgical mechanical debridement in patients with peri-implant diseases? What was the rankings on the effect of PDTs and different lasers as an non-surgical INPLASY 1
Review question / Objective: 1. For BPT patients, is NM more effective in extending fi l t e r l i f e s p a n t h a n c o n v e n t i o n a l anticoagulant therapy? 2. For BPT patients, does administration of NM result in a lower risk of bleeding complications than a d m i n i s t r a t i o n o f c o n v e n t i o n a l anticoagulant therapy? 3. For BPT patients, INPLASY
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