Advancements and applications of loop-mediated isothermal amplification technology: a comprehensive overview.

Loop-mediated isothermal amplification (LAMP) is a novel method for nucleic acid detection known for its isothermal properties, high efficiency, sensitivity, and specificity. LAMP employs 4 to 6 primers targeting 6 to 8 regions of the desired sequence, allowing for amplification at temperatures between 60 and 65°C and the production of up to 109 copies within a single hour. The product can be monitored by various methods such as turbidimetry, fluorometry, and colorimetry. However, it faces limitations such as the risk of non-specific amplification, challenges in primer design, unsuitability for short gene sequences, and difficulty in multiplexing. Recent advancements in polymerase and primer design have enhanced the speed and convenience of the LAMP reaction. Additionally, integrating LAMP with technologies like rolling circle amplification (RCA), recombinase polymerase amplification (RPA), and CRISPR-Cas systems has enhanced its efficiency. The combination of LAMP with various biosensors has enabled real-time analysis, broadening its application in point-of-care testing (POCT). Microfluidic technology has further facilitated the automation and miniaturization of LAMP assays, allowing for the simultaneous detection of multiple targets and preventing contamination. This review highlights advancements in LAMP, focusing on primer design, polymerase engineering, and its integration with other technologies. Continuous improvements and integration of LAMP with complementary technologies have significantly enhanced its diagnostic capabilities, making it a robust tool for rapid, sensitive, and specific nucleic acid detection with promising implications for healthcare, agriculture, and environmental monitoring.

Intercalating Architecture for the Design of Charge Density Wave in Metallic MA2Z4 Materials.

We present a novel approach to induce charge density waves (CDWs) in metallic MA2Z4 materials, resembling the behavior observed in transition metal dichalcogenides (TMDCs). This method leverages the intercalating architecture to maintain the same crystal field and Fermi surface topologies. Our investigation reveals that CDW instability in these materials arises from electron-phonon coupling (EPC) between the d band and longitudinal acoustic (LA) phonons, mirroring TMDC's behavior. By combining α-MA2Z4 with 1H-MX2 materials in a predictive CDW phase diagram using critical EPC constants, we demonstrate the feasibility of extending CDW across material families with comparable crystal fields and reveal the crucial role in CDW instability of the competition between ionic charge transfer and electron correlation. We further uncover a strain-induced Mott transition in ß2-NbGe2N4 monolayer featuring star-of-David patterns. This work highlights the potential of intercalating architecture to engineer CDW materials, expanding our understanding of CDW instability and correlation physics.

Small molecule π-π stacking promotes efficient photoelectrocatalytic splitting of aqueous hydrogen production from polyaniline.

The efficiency of photoelectrocatalysis is fundamentally dependent on the sufficient absorption of light and efficient utilisation of photogenerated carriers, but is largely limited by the reactivity from the inefficient charge transfer and surface sites of the catalyst. In this study, π-π stacking of polar small molecules on aromatic ring-rich polyaniline (PANI) was carried out to improve its photoelectrocatalytic splitting of water for hydrogen production. Detailed photoelectrochemical experiments and density-functional theory (DFT) calculations show that small molecules of p-aminobenzoic acid (PABA) and PANI have the best π-π stacking (compared to p-toluenesulfonic acid (PTA)), which promotes the separation of carriers on the PANI surface. In addition, the polar effect of the small molecules also improves the reactivity of the PANI surface and also reduces the potential barrier for H2 evolution. The current density of PANI-PABA reached -0.12 mA/cm2 (1.23 V vs. RHE) 2.53 times higher than that of pure PANI in linear voltammetric scanning tests under light. This strategy of introducing polar small molecules into organocatalysts via π-π stacking will provide new ideas for the preparation of efficient organic photoelectrocatalysis.

The spectrum of novel ABCB11 gene variations in children with progressive familial intrahepatic cholestasis type 2 in Pakistani cohorts.

Progressive familial intrahepatic cholestasis (PFIC) is a rare childhood manifested disease associated with impaired bile secretion with severe pruritus yellow stool, and sometimes hepatosplenomegaly. PFIC is caused by mutations in ATP8B1, ABCB11, ABCB4, TJP2, NR1H4, SLC51A, USP53, KIF12, ZFYVE19, and MYO5B genes depending on its type. ABCB11 mutations lead to PFIC2 that encodes the bile salt export pump (BSEP). Different mutations of ABCB11 have been reported in different population groups but no data available in Pakistani population being a consanguineous one. We sequenced coding exons of the ABCB11 gene along with its flanking regions in 66 unrelated Pakistani children along with parents with PFIC2 phenotype. We identified 20 variations of ABCB11: 12 in homozygous form, one compound heterozygous, and seven heterozygous. These variants include 11 missenses, two frameshifts, two nonsense mutations, and five splicing variants. Seven variants are novel candidate variants and are not detected in any of the 120 chromosomes from normal ethnically matched individuals. Insilico analysis revealed that four homozygous missense variations have high pathogenic scores. Minigene analysis of splicing variants showed exon skipping and the addition of exon. This data is a useful addition to the disease variants genomic database and would be used in the future to build a diagnostic algorithm.

Preparation of multi-modified/carbonized/gelatinized starch and its de-risking effect on Cd(II) and hymexazol in wastewater.

In this study, starch (S) was gelatinized and carbonized to prepare carbonized/gelatinized S (CGS) as the research material. Then, peat extract (Pe) and surfactants with different ratios were single- and multi-modified on CGS, respectively, to prepare Pe-modified CGS (Pe-CGS) and multi-modified CGS, respectively. The microscopic morphology of multi-modified CGS was studied using various testing methods. The de-risking effect on Cd(II) and hymexazol in wastewater was investigated, and the effects of temperature, pH, and ionic strength were compared. The spheroidal structure of S was destroyed after carbonization, and Pe and surfactants were modified on the surface and changed the surface properties of CGS. The adsorption processes of Cd(II) and hymexazol were suitable to be described by the Langmuir and Freundlich models, respectively. The maximum adsorption capacities (qm) of Cd(II) and adsorption capacity parameter (k) of hymexazol on different modified CGSs presented the peak value at BS/Pe-CGS. With the increase in the modification ratio of Pe, BS, and SDS, qm and k increased, which showed a high value at 100 % modification. Increases in temperature and pH were beneficial to Cd(II) adsorption but were not conducive to hymexazol adsorption. The adsorption amount decreased for Cd(II) and increased first and then reduced for hymexazol with the rise in ionic strength. The adsorption process exhibited spontaneity, endothermic behavior for Cd(II), exothermic behavior for hymexazol, and an entropy-increasing reaction. The adsorption amount of Cd(II) and hymexazol by multi-modified CGS maintained approximately 81 % of the original sample after three rounds of regeneration.

Disruption of the peripheral biological clock may play a role in sleep deprivation-induced dysregulation of lipid metabolism in both the daytime and nighttime phases.

STUDY OBJECTIVES: This study aimed to examine the effect of sleep deprivation (SD) on lipid metabolism or lipid metabolism regulation in the liver and white adipose tissue (WAT) during the light and dark phases and explored the possible mechanisms underlying the diurnal effect of SD on lipid metabolism associated with clock genes. METHODS: Male C57BL/6J mice aged 2 months were deprived of sleep daily for 20 h for ten consecutive days with weakly forced locomotion. The body weights and food consumption levels of the SD and control mice were recorded, and the mice were then sacrificed at ZT (zeitgeber time) 2 and ZT 14. The peripheral clock genes, enzymes involved in fat synthesis and catabolism in the WAT, and melatonin signalling pathway-mediated lipid metabolism in the liver were assessed. Untargeted metabolomics and tandem mass tag (TMT) proteomics were used to identify differential lipid metabolism pathways in the liver. RESULTS: Bodyweight gain and daily food consumption were dramatically elevated after SD. Profound disruptions in the diurnal regulation of the hepatic peripheral clock and enzymes involved in fat synthesis and catabolism in the WAT were observed, with a strong emphasis on hepatic lipid metabolic pathways, while melatonin signalling pathway-mediated lipid metabolism exhibited moderate changes. CONCLUSIONS: In mice, ten consecutive days of SD increased body weight gain and daily food consumption. In addition, SD profoundly disrupted lipid metabolism in the WAT and liver during the light and dark periods. These diurnal changes may be related to disorders of the peripheral biological clock.

Antibacterial effect of the metal nanocomposite on Escherichia coli.

Ag nanocomposites (NAs) have been found to induce irreversible harm to pathogenic bacteria, however, NAs tend to aggregate easily when used alone. These nanocomposites also show increased toxicity and their underlying antibacterial mechanism is still unknown. In short, practical applications of NA materials face the following obstacles: elucidating the mechanism of antibacterial action, reducing cytotoxicity to body cells, and enhancing antibacterial activity. This study synthesized a core-shell structured ZnFe2O4 @Cu-ZIF-8 @Ag (FUA) nanocomposite with high antibacterial activity and low cytotoxicity. The nanocomposites achieved a 99.99 % antibacterial rate against Escherichia coli (E. coli) and tetracycline-resistant E. coli (T - E. coli), in under 20 min at 100 µg/mL. The nanocomposites were able to inactivate E. coli due to the gradual release of Cu2+, Zn2+, and Ag+ ions, which synergistically form •OH from FUA in an aerobic environment. The presence of •OH has significant effects on the antibacterial activity. The released metal ions combine with •OH to cause damage to the bacterial cell wall, resulting in the leakage of electrolytes and ions. Moreover, in comparison to NA, the toxicity of FUA is considerably reduced. This study is expected to inspire the development of other silver-based nanocomposite materials for the inactivation of drug-resistant bacteria.

Urban heatwave, green spaces, and mental health: A review based on environmental health risk assessment framework.

Utilizing the framework of environmental health risk assessment and healing, the article reviews the effectiveness and potential of green space systems in mitigating the impact of high temperatures, promoting mental health, and improving the risk characteristics of high-temperature heat waves. We utilized CiteSpace software to conduct a time-zone analysis of the relationship between heatwaves, green spaces, and health using clustered data from 2001 to 2023. This study evaluates the role of green space systems in mitigating high temperatures and enhancing mental health within the environmental health risk assessment framework. Using CiteSpace software, we analyzed literature from 2001 to 2023, focusing on the interactions among heatwaves, green spaces, and health. Our results indicate that most existing research concentrates on hazard identification, with insufficient exploration of the dose-response relationships between green spaces and temperature reduction. Quantitative studies on green space design and spatial optimization are scarce, and guidance on effective configurations remains limited. Additionally, the health impacts of heatwaves vary by region, with a noticeable imbalance in research focus; Asia and Africa, in particular, are underrepresented in studies addressing heatwave effects. We conclude that effective mitigation strategies require: (1) a comprehensive environmental health risk assessment framework that integrates advanced methods like big data analysis and geospatial simulations to improve green space planning and design; (2) further theoretical exploration into the mechanisms by which green spaces regulate temperature and mental health, including detailed analysis of spatiotemporal patterns and the functional optimization of green space structures; and (3) the development of robust parameterized design guidance based on specific therapeutic dosages (green space stimulus) to optimize configurations and enhance the effectiveness of green spaces in mitigating adverse mental health impacts from deteriorating thermal environments. Future research should prioritize underrepresented regions, focusing on exposure levels, dose-response relationships, and high-temperature warning systems while fostering multidisciplinary collaboration to develop effective urban planning and climate adaptation strategies.

Microcystis aeruginosa aggravated arsenic accumulation in silver carp during silver carp controlling algal bloom in arsenic-contaminated water.

Silver carp mediated biological control techniques are often advocated for controlling cyanobacteria blooms in eutrophic water, which are often enriched with arsenic (As). However, the transfer and fate of As during the biological control of cyanobacteria blooms by silver carp in As-rich eutrophic water remain unclear. Based on the simulated ecosystem experiment, the accumulation of As in silver carp and the transfer and fate of As in the water-algae-silver carp system during Microcystis aeruginosa blooms controlled by silver carp were investigated. Microcystis aeruginosa showed high tolerance to As(V). The accumulation of As in different tissues of silver carp was different, as follows: intestine > liver > gill > skin > muscle. After silver carp ingested As-rich Microcystis aeruginosa, As accumulation in the intestine, liver, gill, and skin of silver carp was enhanced under the action of digestion and skin contact. Compared with the system without algal, As accumulation in the intestine, liver, gill, and skin of silver carp increased by 1.1, 3.3, 3.3, and 9.6 times, respectively, after incubation for 30 days in the system with Microcystis aeruginosa, while the accumulation of As in the muscle was only slightly increased by 0.56 mg/kg. This work revealed the transfer and fate of As during algal control by silver carp, elucidated the accumulation mechanism of As in water-algae-silver carp system, enriched our understanding of As bioaccumulation and transformation in As-rich eutrophication water, and provided a scientific basis for assessing and predicting As migration and enrichment in water-algae-silver carp system.

Unfolding the downloads of datasets: A multifaceted exploration of influencing factors.

Scientific data are essential to advancing scientific knowledge and are increasingly valued as scholarly output. Understanding what drives dataset downloads is crucial for their effective dissemination and reuse. Our study, analysing 55,473 datasets from 69 data repositories, identifies key factors driving dataset downloads, focusing on interpretability, reliability, and accessibility. We find that while lengthy descriptive texts can deter users due to complexity and time requirements, readability boosts a dataset's appeal. Reliability, evidenced by factors like institutional reputation and citation counts of related papers, also significantly increases a dataset's attractiveness and usage. Additionally, our research shows that open access to datasets increases their downloads and amplifies the importance of interpretability and reliability. This indicates that easy access enhances the overall attractiveness and usage of datasets in the scholarly community. By emphasizing interpretability, reliability, and accessibility, this study offers a comprehensive framework for future research and guides data management practices toward ensuring clarity, credibility, and open access to maximize the impact of scientific datasets.

The significant mechanism and treatments of cell death in heatstroke.

With global warming, extreme environmental heat is becoming a social issue of concern, which can cause adverse health results including heatstroke (HS). Severe heat stress is characterized by cell death of direct heat damage, excessive inflammatory responses, and coagulation disorders that can lead to multiple organ dysfunction (MODS) and even death. However, the significant pathophysiological mechanism and treatment of HS are still not fully clear. Various modes of cell death, including apoptosis, pyroptosis, ferroptosis, necroptosis and PANoptosis are involved in MODS induced by heatstroke. In this review, we summarized molecular mechanism, key transcriptional regulation as for HSF1, NRF2, NF-κB and PARP-1, and potential therapies of cell death resulting in CNS, liver, intestine, reproductive system and kidney injury induced by heat stress. Understanding the mechanism of cell death provides new targets to protect multi-organ function in HS.

A Comparative Study of a Nomogram and Machine Learning Models in Predicting Early Hematoma Expansion in Hypertensive Intracerebral Hemorrhage.

RATIONALE AND OBJECTIVES: Early identification for hematoma expansion can help improve patient outcomes. Presently, there are many methods to predict hematoma expansion. This study compared a variety of models to find a model suitable for clinical promotion. MATERIALS AND METHODS: Non-contrast head CT images and clinical data were collected from 203 patients diagnosed with hypertensive intracerebral hemorrhage. Radiomics features were extracted from all CT images, and the dataset was randomly divided into training and validation sets (7:3 ratio) after applying the synthetic minority oversampling method. The radiomics score (Radscore) was calculated using least absolute shrinkage and selection operator (LASSO) regression, combined with selected clinical predictors, to develop a nomogram and four machine learning (ML) models: logistic regression, random forest, support vector machine, and extreme gradient boosting (XGBoost). Discrimination, calibration and clinical usefulness of the nomogram and ML models were assessed. RESULTS: The nomogram and ML models were integrated with Radscore and clinical predictors. The nomogram demonstrated favorable discriminatory ability in the training set with an AUC of 0.80, which was confirmed in the validation set (AUC=0.76). Among the ML models, the XGBoost model achieved the highest AUC (training set=0.89 and validation set=0.85), surpassing that of the nomogram. The XGBoost model exhibited good clinical usefulness. CONCLUSION: Both the nomogram and ML models constructed by non-contrast head CT image-based Radscore integrated with clinical predictors can predict early hematoma expansion of hypertensive intracerebral hemorrhage, and the XGBoost model had the highest prediction performance and best clinical usefulness.

Dynamic Mechanical Properties and Modified Material Constitutive Model for Hot Forged Ti2AlNb over Wide Ranges of Temperature and Strain Rate.

In this paper, the stress-strain curves of Ti2AlNb are established based on uniaxial impact tests over wide ranges of temperature and strain rate. The Ti2AlNb exhibited the work hardening effect but did not show an obvious yield stage during a quasi-static compression test. In the SHPB test, an obvious temperature softening effect was found, the strain rate strengthening effect was detected when the strain rate was 4000-8000 s-1, and the strain rate softening effect was detected in the range of 8000-12,000 s-1. A function describing the effect of strain rate on the strain rate strengthening parameters under various temperatures was proposed to modify the basic J-C constitutive model. The relative errors between the experimental measured value and predicted values in various experimental conditions with a modified J-C model were less than 5.0%. The results verified that the modified J-C model could accurately describe the dynamic mechanical properties of Ti2AlNb at high temperatures and strain rates. The research could help to illustrate the cutting mechanism and finite element simulation of Ti2AlNb alloy.

Chemerin attracts neutrophil reverse migration by interacting with C-C motif chemokine receptor-like 2.

Neutrophil reverse migration (rM) is a recently identified phenomenon in which neutrophils migrate away from the inflammatory site back into the vasculature following initial infiltration, which involved in the resolution of loci inflammatory response or dissemination of inflammation. Present study was aimed to explore the mechanisms in neutrophil rM. By scRNA-seq on the white blood cells in acute lung injury model, we found rM-ed neutrophils exhibited increased gene expression of C-C motif chemokine receptor-like 2 (Ccrl2), an atypical chemokine receptor. Furthermore, an air pouch model was established to directly track rM-ed neutrophils in vivo. Air pouches were generated by 3 ml filtered sterile air injected subcutaneously for 3 days, and then LPS (2 mg/kg) was injected into the pouches to mimic the inflammatory state. For the rM-ed neutrophil tracking system, cell tracker CMFDA were injected into the air pouch to stain the inflammatory loci cells, and after 6 h, stained cells in blood were regarded as the rM-ed neutrophil. Based on this tracking system, we confirmed that rM-ed neutrophils showed increased CCRL2. We also found that the concentrations of the CCRL2 ligand chemerin in plasma was increased in the late stage. Neutralizing chemerin decreased the rM-ed neutrophil ratio in the blood. These results suggest that circulating chemerin attracts neutrophils to leave inflammatory sites by interacting with CCRL2, which might involve in the dissemination of inflammation.

Heatstroke Comorbid with SARS-CoV-2 Infection: A Case Report and Literature Review.

Background: Hyperthermia and multiple organ dysfunction syndrome (MODS) are the main characteristics of heatstroke and COVID-19. Differentiating between these illnesses is crucial during a summer COVID-19 pandemic, but cases of heatstroke comorbid with COVID-19 are rarely reported. Case description: We report the first case of heatstroke comorbid with Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection in a 52-year-old male. After receiving intravenous antibiotics, organ protection measures, and treatment for coagulation disorders, his fever and coma resolved. However, he developed dyspnea and cerebral hemorrhage after several days. This patient experienced a multi-pathogen pulmonary infection and an intractable coagulopathy that ultimately resulted in MODS and death. Conclusion: The combination of heatstroke and SARS-CoV-2 infection exacerbated inflammation, immune abnormalities, and coagulation disorders. The interaction between inflammation and coagulation disturbances contributed to the underlying mechanism in this case, highlighting the importance of early anti-infection, treatment for coagulopathy, immune regulation, and organ protection as crucial interventions.

From 2e- to 4e- pathway in the alkaline oxygen reduction reaction on Au(100): Kinetic circumvention of the volcano curve.

We report the free energy barriers for the elementary reactions in the 2e- and 4e- oxygen reduction reaction (ORR) steps on Au(100) in an alkaline solution. Due to the weak adsorption energy of O2 on Au(100), the barrier for the association channel is very low, and the 2e- pathway is clearly favored, while the barrier for the O-O dissociation channel is significantly higher at 0.5 eV. Above 0.7 V reversible hydrogen electrode (RHE), the association channel becomes thermodynamically unfavorable, which opens up the O-O dissociation channel, leading to the 4e- pathway. The low adsorption energy of oxygenated species on Au is now an advantage, and residue ORR current can be observed up to the 1.0-1.2 V region (RHE). In contrast, the O-O dissociation barrier on Au(111) is significantly higher, at close to 0.9 eV, due to coupling with surface reorganization, which explains the lower ORR activity on Au(111) than that on Au(100). In combination with the previously suggested outer sphere electron transfer to O2 for its initial adsorption, these results provide a consistent explanation for the features in the experimentally measured polarization curve for the alkaline ORR on Au(100) and demonstrate an ORR mechanism distinct from that on Pt(111). It also highlights the importance to consider the spin state of O2 in ORR and to understand the activation barriers, in addition to the adsorption energies, to account for the features observed in electrochemical measurements.

Molecular basis for receptor recognition and broad host tropism for merbecovirus MjHKU4r-CoV-1.

A novel pangolin-origin MERS-like coronavirus (CoV), MjHKU4r-CoV-1, was recently identified. It is closely related to bat HKU4-CoV, and is infectious in human organs and transgenic mice. MjHKU4r-CoV-1 uses the dipeptidyl peptidase 4 (DPP4 or CD26) receptor for virus entry and has a broad host tropism. However, the molecular mechanism of its receptor binding and determinants of host range are not yet clear. Herein, we determine the structure of the MjHKU4r-CoV-1 spike (S) protein receptor-binding domain (RBD) complexed with human CD26 (hCD26) to reveal the basis for its receptor binding. Measuring binding capacity toward multiple animal receptors for MjHKU4r-CoV-1, mutagenesis analyses, and homology modeling highlight that residue sites 291, 292, 294, 295, 336, and 344 of CD26 are the crucial host range determinants for MjHKU4r-CoV-1. These results broaden our understanding of this potentially high-risk virus and will help us prepare for possible outbreaks in the future.

Piezoelectric Materials and Pyroelectric Materials:High Efficient Catalysts for Photoelectrochemical Water Splitting.

Directly transforming solar energy into chemical compounds via photocatalytic water splitting can continually producing hydrogen, regarded as one of the ultimate sustainable energy sources. The key point of achieving high photoelectrochemical (PEC) water splitting performance depends on the successful design and synthesis of high-efficient photocatalysts. However, the slow separation and fast recombination of photo generated charge carriers greatly limit the utilization of solar energy, resulting in low PEC water splitting efficiency. Recently, piezoelectric/pyroelectric effect assisted PEC water splitting brings new sight on improving charger separate and transfer behaviors. In this review, the recent advancements and state-of-the-art progress in piezoelectric/pyroelectric effect assisted PEC water splitting are summarized and discussed. Different types of photocatalysts are classified according to their chemical constitutions and the corresponding advantages of each type are also discussed. Furthermore, the progress of coupling piezoelectric effect and pyroelectric effect in one PEC water splitting system is also introduced. Finally, the prospects, critical challenges and promising strategies for the application of piezoelectric/pyroelectric materials in PEC water splitting are highlighted.

Exportin XPO6 upregulation activates the TLR2/MyD88/NF-κB signaling by facilitating TLR2 mRNA nuclear export in COPD pulmonary monocytes.

Chronic obstructive pulmonary disease (COPD) poses a significant health threat characterized by lung inflammation primarily triggered by pulmonary monocytes. Despite the centrality of inflammation in COPD, the regulatory mechanisms governing this response remain elusive, presenting a challenge for anti-inflammatory interventions. In this study, we assessed the expression of exportins in COPD mouse models, revealing a notable upregulation of XPO6 in the mouse lung (P = 0.0011). Intriguingly, we observed a consistent upregulation of XPO6 in pulmonary monocytes from both human and mouse COPD subjects (P < 0.0001). Furthermore, in human lung tissue, XPO6 expression exhibited a positive correlation with TLR2 expression (P = 0). In vitro investigations demonstrated that XPO6 enhances TLR2 expression, activating the MyD88/NF-κB inflammatory signaling pathway. This activation, in turn, promotes the secretion of pro-inflammatory cytokines such as TNFα, IL-6, and IL-1ß in monocytes. Mechanistically, XPO6 facilitates the nuclear export of TLR2 mRNA, ensuring its stability and subsequent protein expression in monocytes. In conclusion, our findings unveil that the upregulation of XPO6 in COPD pulmonary monocytes activates the MyD88/NF-κB inflammatory signaling pathway by facilitating the nuclear export of TLR2 mRNA, thereby identifying XPO6 as a promising therapeutic target for anti-inflammatory interventions in COPD.

The suppression of HSPA8 attenuates NLRP3 ubiquitination through SKP2 to promote pyroptosis in sepsis-induced lung injury.

BACKGROUND: Acute lung injury (ALI) is strongly associated with hospitalization and mortality in patients with sepsis. Recent evidence suggests that pyroptosis mediated by NLRP3(NOD-, LRR- and pyrin domain-containing 3) inflammasome activation plays a key role in sepsis. However, the mechanism of NLRP3 inflammasome activation in sepsis-induced lung injury remains unclear. RESULTS: in this study, we demonstrated that NLRP3 inflammasome was activated by the down-regulation of heat shock protein family A member 8 (HSPA8) in Lipopolysaccharide (LPS) and adenosine triphosphate (ATP)-treated mouse alveolar epithelial cells (AECs). Geranylgeranylacetone (GGA)-induced HSPA8 overexpression in cecum ligation and puncture (CLP) mice could significantly reduce systemic inflammatory response and mortality, effectively protect lung function, whilst HSPA8 inhibitor VER155008 aggravated this effect. The inhibition of HSPA8 was involved in sepsis induced acute lung injury by promoting pyroptosis of AECs. The down-regulation of HSPA8 activated NLRP3 inflammasome to mediate pyroptosis by promoting the degradation of E3 ubiquitin ligase S-phase kinase-associated protein 2 (SKP2). In addition, when stimulated by LPS and ATP, down-regulated SKP2 promoted pyroptosis of AECs by further attenuating ubiquitination of NLRP3. Adeno-associated virus 9-SKP2(AAV9-SKP2) could promote NLRP3 ubiquitination and degradation, alleviate lung injury and inhibit systemic inflammatory response in vivo. CONCLUSION: in summary, our study shows there is strong statistical evidence that the suppression of HSPA8 mediates alveolar epithelial pyroptosis by promoting the degradation of E3 ubiquitin ligase SKP2 and subsequently attenuating the ubiquitination of NLRP3 to activate the NLRP3 inflammasome, which provides a new perspective and therapeutic target for the treatment of sepsis-induced lung injury.