Knockdown of PHLDA1 alleviates sepsis-induced acute lung injury by downregulating NLRP3 inflammasome activation

Abstract

Objective: To investigate the regulatory mechanism of pleckstrin homology-like domain, family A, member 1 (PHLDA1) in sepsis-induced acute lung injury (ALI). Method: Mice model of sepsis were established by cecal ligation and puncture (CLP). The expression of PHLDA1 was reduced by injecting short hairpin RNA (shRNA)–PHLDA1 into the tail vein. The levels of PHLDA1, pro-inflammatory cytokines, such as interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), IL-1β, IL-18, super-oxide dismutase (SOD), malondialdehyde (MDA), and glutathione (GSH), molecular mechanism related to pyroptosis, such as caspase 1, adaptor apoptosis-associated speck-like protein containing a CARD (ASC), and gasdermin D (GSDMD)-N, and nucleotide oligomerization domain (NOD)-like receptor family pyrin domain-containing 3 (NLRP3) were tested by Western blot analysis, quantitative real-time polymerase chain reaction, and enzyme-linked-immunosorbent serologic assay. Pathological changes in lung tissues were examined by hematoxylin and eosin staining. Wet–dry weight ratio of lung tissues was observed. Results: The expression of PHLDA1 was up-regulated in lung tissues from CLP-induced septic mice. Knockdown of PHLDA1 could reduce lung injury and wet–dry weight ratio in mice with sepsis-induced ALI. Moreover, silencing of PHLDA1 decreased the expressions of IL-1β, TNF-α, IL-18, IL-6, and MDA but increased SOD and GSH expressions in CLP-induced septic mice. The expressions of NLRP3, GSDMD-N, ASC, and caspase 1 were decreased by PHLDA1 silencing. Conclusion: Knockdown of PHLDA1 inhibited lung inflammation and pyroptosis in mice with sepsis-induced ALI by down-regulating NLRP3.

Sepsis‑induced cardiac dysfunction and pathogenetic mechanisms (Review)

“…N-GSDMD indirectly promotes NLRP3 inflammasome assembly via K + efflux, which aggravates pyroptosis ( 124 , 125 ). Studies have found that doxorubicin upregulates NADPH oxidase 1 and NADPH oxidase 4 expression, thereby activating dynamin-related protein-1and promoting mitochondrial fission, leading to excessive accumulation of ROS in mitochondria and activation of the NLRP3 inflammasome and caspase-1dependent apoptosis ( 126 , 127 ) Certain studies have found that GSDMD knockout significantly decreases NLRP3 and caspase-1 expression, increases survival and improves cardiac dysfunction in mice ( 128 , 129 ). Moreover, LPS directly affects nuclear localization of sting and interferon regulatory factor-3-activated sting then activates NLRP3, leading to cardiac dysfunction as well as pyroptosis ( 130 ).…”

Therapeutic potential of mangiferin in cancer: Unveiling regulatory pathways, mechanisms of action, and bioavailability enhancements – An updated review

“…Various studies show that MGF possesses some antioxidant actions, a role in treating obesity, the therapeutic potential for osteoarthritis (Aboyewa et al., 2021 ) protection of the gastrointestinal tract, an antidiabetic role, and in vitro repressing properties on type‐II 5α‐reductase, modulatory response in the immune system, that is, maybe suppressive or stimulative, hepatoprotective, and cardioprotective effects in various diseases in rodents (Khoobchandani et al., 2021 ; Liu et al., 2021 ; Mubashir et al., 2022 ; Xiao et al., 2021 ). It also shows photoprotective, analgesic, neuroprotective, anti‐Alzheimer (Grauzdytė et al., 2019 ), and anti‐allergic potential (Meng et al., 2023 ; Thitikornpong et al., 2019 ). The solubility of water for MGF is barely 0.111 mg/mL, which is much lower, limits its practical use, and consequently, no foodstuffs are in the marketplace.…”