Association between red blood cell distribution width and the all-cause mortality of patients with aortic stenosis: A retrospective study.

BACKGROUND: It is essential to assess the risk stratification of patients with aortic stenosis (AS). OBJECTIVE: To clarify the predictive value of red blood cell distribution width (RDW) in AS patients using a large cohort from the MIMIC-IV database. METHODS: Restricted cubic spline, the Kaplan-Meier method, and logistic and Cox regression analyses were used to explore the association between RDW and all-cause mortality in AS patients. Multivariate adjustments, propensity score matching and weighting, and subgroup analysis were conducted to exclude confounding factors. Receiver operating characteristic (ROC) and decision curve analysis (DCA) curves were drawn to evaluate the predictive performance of RDW. RESULTS: 1,148 patients with AS were included. Their death risks gradually increased with the elevation of RDW. Multivariate-adjusted 90-day (OR: 2.12; HR: 1.90; p = 0.001) and 1-year (OR: 2.07; HR: 1.97; p < 0.001) all-cause mortalities were significantly higher in patients with RDW≥14.7 %, which remained robust after propensity score matching and subgroup analysis. For AS patients with high RDW, those < 75 years old had higher death risks than those ≥ 75 years old. The area under the ROC curve of RDW were 0.741 and 0.75 at 90-day and 1-year follow-ups, respectively, exhibiting comparable performance to acute physiology score III and outperforming other critical illness scores in predicting the prognosis of AS patients. DCA curves also illustrated that RDW had a wide range of net benefits. CONCLUSIONS: High RDW was independently associated with increased 90-day and 1-year all-cause mortalities of AS patients, with strong predictive capability of prognosis.

Association of Cardiovascular Health with the Incidence of Venous Thromboembolism: A Prospective Study of 275,149 Participants from the UK Biobank.

BACKGROUND: The Life's Essential 8 (LE8) score, recently proposed by the American Heart Association, represents a new paradigm for evaluating cardiovascular health (CVH). We aimed to explore the association between CVH, estimated using LE8, and venous thromboembolism (VTE) incidence. METHODS: A total of 275,149 participants were recruited from the UK Biobank and divided into high (LE8 score ≥ 80), moderate (LE8 score < 80 but ≥ 50), and low (LE8 score < 50) CVH groups. Restricted cubic spline analysis, the Kaplan-Meier method, and the Cox proportional hazards model were used to explore the association between CVH and VTE. The genetic predisposition to VTE was assessed with a polygenic risk score. Sensitivity analyses were performed to validate the results. RESULTS: During a median follow-up of 12.56 years, VTE developed in 506 (4.09%), 6,069 (2.78%), and 720 (1.66%) participants with low, moderate, and high CVH levels, respectively. Compared with the low CVH group, participants in the moderate and high CVH groups had a 23% (hazard ratio [HR]: 0.77; 95% confidence interval [CI]: 0.71-0.85) and 41% (HR: 0.59; 95% CI: 0.52-0.66) lower risk of VTE, respectively, after adjusting for demographic characteristics, medical history, socioeconomic status, and genetic predisposition. This association remained robust in multiple sensitivity analyses. Higher CVH levels led to a more pronounced reduction in the risk of VTE in females and could appreciably offset the genetic risk of VTE. CONCLUSION: Higher CVH levels were significantly associated with a lower incidence of VTE, encouraging efforts to increase LE8 scores in individuals.

Integrated bioinformatics analysis and experimental animal models identify a robust biomarker and its correlation with the immune microenvironment in pulmonary arterial hypertension.

Background: Pulmonary arterial hypertension (PAH) represents a substantial global risk to human health. This study aims to identify diagnostic biomarkers for PAH and assess their association with the immune microenvironment through the utilization of sophisticated bioinformatics techniques. Methods: Based on two microarray datasets, differentially expressed genes (DEGs) were detected, and hub genes underwent a sequence of machine learning analyses. After pathways associated with PAH were assessed by gene enrichment analysis, the identified genes were validated using external datasets and confirmed in a monocrotaline (MCT)-induced rat model. In addition, three algorithms were employed to estimate the proportions of various immune cell types, and the link between hub genes and immune cells was substantiated. Results: Using SVM, LASSO, and WGCNA, we identified seven hub genes, including (BPIFA1, HBA2, HBB, LOC441081, PI15, S100A9, and WIF1), of which only BPIFA1 remained stable in the external datasets and was validated in an MCT-induced rat model. Furthermore, the results of the functional enrichment analysis established a link between PAH and both metabolism and the immune system. Correlation assessment showed that BPIFA1 expression in the MCP-counter algorithm was negatively associated with various immune cell types, positively correlated with macrophages in the ssGSEA algorithm, and correlated with M1 and M2 macrophages in the CIBERSORT algorithm. Conclusion: BPIFA1 serves as a modulator of PAH, with the potential to impact the immune microenvironment and disease progression, possibly through its regulatory influence on both M1 and M2 macrophages.

Preparation and brain targeting effects study of recombinant human ferritin nanoparticles.

Human heavy-chain ferritin is a naturally occurring protein with high stability and multifunctionality in biological systems. This study aims to utilize a prokaryotic expression system to produce recombinant human heavy-chain ferritin nanoparticles and investigate their targeting ability in brain tissue. The human heavy-chain ferritin gene was cloned into the prokaryotic expression vector pET28a and transformed into Escherichia coli BL21 (DE3) competent cells to explore optimal expression conditions. The recombinant protein was then purified to evaluate its immunoreactivity and characteristics. Additionally, the distribution of the administered protein in normal mice and its permeability in an in vitro blood-brain barrier (BBB) model were measured. The results demonstrate that the purified protein can self-assemble extracellularly into nano-cage structures of approximately 10 nm and is recognized by corresponding antibodies. The protein effectively penetrates the blood-brain barrier and exhibits slow clearance in mouse brain tissue, showing excellent permeability in the in vitro BBB model. This study highlights the stable expression of recombinant human heavy-chain ferritin using the Escherichia coli prokaryotic expression system, characterized by favorable nano-cage structures and biological activity. Its exceptional brain tissue targeting and slow metabolism lay an experimental foundation for its application in neuropharmaceutical delivery and vaccine development fields.

Transcriptome-Wide N6-Methyladenosine Alternations in Pulmonary Arteries of Monocrotaline-Induced Pulmonary Arterial Hypertension in Rats and Novel Therapeutic Targets.

N6-methyladenosine (m6A) is a post-transcriptional epigenetic change with transcriptional stability and functionality regulated by specific m6A-modifying enzymes. However, the significance of genes modified by m6A and enzymes specific to m6A regulation in the context of pulmonary arterial hypertension (PAH) remains largely unexplored. MeRIP-seq and RNA-seq were applied to explore variances in m6A and RNA expression within the pulmonary artery tissues of control and monocrotaline-induced PAH rats. Functional enrichments were analyzed using the Gene Ontology and Kyoto Encyclopedia of Genes and Genomes. To screen candidate m6A-related genes, the STRING and Metascape databases were used to construct a protein-protein interaction network followed by a real-time PCR validation of their expression. The expression level of an m6A regulator was further investigated using immunohistochemical staining, immunofluorescence, and Western blot techniques. Additionally, proliferation assays were conducted on primary rat pulmonary artery smooth muscle cells (PASMCs). We identified forty-two differentially expressed genes that exhibited either hypermethylated or hypomethylated m6A. These genes are predominantly related to the extracellular matrix structure, MAPK, and PI3K/AKT pathways. A candidate gene, centromere protein F (CENPF), was detected with increased expression in the PAH group. Additionally, we first identified an m6A reader, leucine rich pentatricopeptide repeat containing (LRPPRC), which was downregulated in the PAH rat model. The in vitro downregulation of Lrpprc mediated by siRNA resulted in the enhanced proliferation and elevated expression of Cenpf mRNA in primary rat PASMCs. Our study revealed a modified transcriptome-wide m6A landscape and associated regulatory mechanisms in the pulmonary arteries of PAH rats, potentially offering a novel target for therapeutic strategies in the future.

Exploring the immune interactions between Oncomelania hupensis and Schistosoma japonicum, with a cross-comparison of immunological research progress in other intermediate host snails.

Schistosomiasis, the second largest parasitic disease in the world after malaria, poses a significant threat to human health and causes public health issues. The disease primarily affects populations in economically underdeveloped tropical regions, earning it the title of "neglected tropical disease". Schistosomiasis is difficult to eradicate globally if medication alone is used. One of the essential elements of thorough schistosomiasis prevention and control is the management and disruption of the life cycle of intermediate host snails. The key approach to controlling the transmission of schistosomiasis is to control the intermediate hosts of the schistosome to disrupt its life cycle. We believe that approaching it from the perspective of the intermediate host's immunity could be an environmentally friendly and potentially effective method. Currently, globally significant intermediate host snails for schistosomes include Oncomelania hupensis, Biomphalaria glabrata, and Bulinus truncatus. The immune interaction research between B. glabrata and Schistosoma mansoni has a history of several decades, and the complete genome sequencing of both B. glabrata and B. truncatus has been accomplished. We have summarized the immune-related factors and research progress primarily studied in B. glabrata and B. truncatus and compared them with several humoral immune factors that O. hupensis research focuses on: macrophage migration inhibitory factor (MIF), Toll-like receptors (TLRs), and thioredoxin (Trx). We believe that continued exploration of the immune interactions between O. hupensis and Schistosoma japonicum is valuable. This comparative analysis can provide some direction and clues for further in-depth research. Comparative immunological studies between them not only expand our understanding of the immune defense responses of snails that act as intermediaries for schistosomes but also facilitate the development of more comprehensive and integrated strategies for schistosomiasis prevention and control. Furthermore, it offers an excellent opportunity to study the immune system of gastropods and their co-evolution with pathogenic organisms.

Joining Forces: The Combined Application of Therapeutic Viruses and Nanomaterials in Cancer Therapy.

Cancer, on a global scale, presents a monumental challenge to our healthcare systems, posing a significant threat to human health. Despite the considerable progress we have made in the diagnosis and treatment of cancer, realizing precision cancer therapy, reducing side effects, and enhancing efficacy remain daunting tasks. Fortunately, the emergence of therapeutic viruses and nanomaterials provides new possibilities for tackling these issues. Therapeutic viruses possess the ability to accurately locate and attack tumor cells, while nanomaterials serve as efficient drug carriers, delivering medication precisely to tumor tissues. The synergy of these two elements has led to a novel approach to cancer treatment-the combination of therapeutic viruses and nanomaterials. This advantageous combination has overcome the limitations associated with the side effects of oncolytic viruses and the insufficient tumoricidal capacity of nanomedicines, enabling the oncolytic viruses to more effectively breach the tumor's immune barrier. It focuses on the lesion site and even allows for real-time monitoring of the distribution of therapeutic viruses and drug release, achieving a synergistic effect. This article comprehensively explores the application of therapeutic viruses and nanomaterials in tumor treatment, dissecting their working mechanisms, and integrating the latest scientific advancements to predict future development trends. This approach, which combines viral therapy with the application of nanomaterials, represents an innovative and more effective treatment strategy, offering new perspectives in the field of tumor therapy.

A Novel Nitrogen-Fixing Bacterium Raoultella electrica Isolated from the Midgut of the Leafhopper Recilia dorsalis.

Nitrogen is a crucial element for the growth and development of insects, but herbivorous insects often suffer from nitrogen nutrition deficiencies in their diets. Some symbiotic microorganisms can provide insect hosts with nitrogen nutrition through nitrogen fixation. Extensive research has clearly demonstrated the process of nitrogen fixation by symbiotic microorganisms in termites, while evidence supporting the occurrence and significance of nitrogen fixation in the diets of the Hemiptera is less conclusive. In this study, we isolated a strain of R. electrica from the digestive tract of a leafhopper, R. dorsalis, and found that it had nitrogen-fixing capabilities. Fluorescence in situ hybridization results showed that it was located in the gut of the leafhopper. Genome sequencing revealed that R. electrica possessed all the genes required for nitrogen fixation. We further evaluated the growth rate of R. electrica in nitrogen-containing and nitrogen-free media and measured its nitrogenase activity through an acetylene reduction assay. The findings of these studies could shed light on how gut microbes contribute to our understanding of nitrogen fixation.

Association between prothrombin time-international normalized ratio and prognosis of post-cardiac arrest patients: A retrospective cohort study.

Background: Cardiac arrest (CA) can activate blood coagulation. This study aimed to explore the potential prognostic value of prothrombin time-international normalized ratio (INR) in post-CA patients. Methods: The clinical data of eligible subjects diagnosed with CA was extracted from the MIMIC-IV database as the training cohort. Restricted cubic spline (RCS), Kaplan-Meier (K-M) survival curve, and Cox regression analyses were conducted to elucidate the association between the INR and all-cause mortality of post-CA patients. Subgroup analysis, propensity score matching (PSM), and inverse probability of treatment (IPTW) were also conducted to improve stability and reliability. Data of the validation cohort were collected from the eICU database, and logistic-regression analyses were performed to verify the findings of the training cohort. Results: A total of 1,324 subjects were included in the training cohort. A linear correlation existed between INR and the risk of all-cause death of post-CA patients, as shown in RCS analysis, with a hazard ratio (HR) >1 when INR exceeded 1.2. K-M survival curve preliminarily indicated that subjects with INR ≥ 1.2 presented lower survival rate and shorter survival time, and the high level of INR was independently associated with 30-day, 90-day, 1-year, and in-hospital mortalities, with multivariate-adjusted HR of 1.44 (1.20, 1.73), 1.46 (1.23, 1.74), 1.44 (1.23, 1.69), and 1.37 (1.14, 1.64), respectively. These findings were consistent and robust across the subgroup analysis, PSM and IPTW analyses, and validation cohort. Conclusions: We systematically and comprehensively demonstrated that elevated INR was associated with increased short- and long-term all-cause mortality of post-CA patients. Therefore, elevated INR may be a promising biomarker with prognosis significance.

Corrigendum: Association of systemic immune-inflammation index with short-term mortality of congestive heart failure: A retrospective cohort study.

[This corrects the article DOI: 10.3389/fcvm.2021.753133.].

Association of Systemic Immune-Inflammation Index With Short-Term Mortality of Congestive Heart Failure: A Retrospective Cohort Study.

Purpose: The present study aimed to clarify the potential predictive significance of Systemic immune-inflammation index (SII) in assessing the poor prognosis of critically ill patients with congestive heart failure (CHF). Methods: Detailed clinical data were extracted from the Multiparameter Intelligent Monitoring in Intensive Care III database after gaining access and building the local platform. The 30- and 90-day and hospital all-cause mortalities of the patient was the primary outcome, and the readmission rate and the occurrence of major cardiovascular adverse events (MACEs) were the secondary outcomes. the Cox proportional hazard model and Logistic regression analysis were selected to reveal the relationship between SII level and the research outcome. Further, the propensity score matching (PSM) analysis was performed to improve the reliability of results by reducing the imbalance across groups. Results: There were a total of 4,606 subjects who passed the screening process and entered the subsequent analysis. Multivariate regression analysis showed that after adjusting for possible confounders, including age, heart rate, and albumin, etc., the high level of SII was independently associated with 30- and 90-day and hospital mortalities (tertile 3 vs. tertile 1: HR, 95% CIs: 1.23, 1.04-1.45; 1.21, 1.06-1.39; 1.26, 1.05-1.50) and the incidence of MACEs (tertile 3 vs. tertile 1: OR, 95% CI: 1.39, 1.12-1.73) in critically ill patients with CHF, but no significant correlation was found between SII and the readmission rate. Consistently, patients with high SII level still presented a significantly higher short-term mortality than patients with low SII in the PSM subset. Conclusion: In critically ill patients with CHF, high level of SII could effectively predict high 30- and 90-day and hospital mortalities, as well as the high risk of occurrence of MACEs.

Development and Validation of Nomogram to Predict Long-Term Prognosis of Critically Ill Patients with Acute Myocardial Infarction.

PURPOSE: Acute myocardial infarction (AMI) is a common cardiovascular disease with a poor prognosis. The aim of this study was to construct a nomogram for predicting the long-term survival of critically ill patients with AMI. This nomogram will help in assessing disease severity, guiding treatment, and improving prognosis. PATIENTS AND METHODS: The clinical data of patients with AMI were extracted from the MIMIC-III v1.4 database. Cox proportional hazards models were adopted to identify independent prognostic factors. A nomogram for predicting the long-term survival of these patients was developed on the basis of the results of multifactor analysis. The discriminative ability and accuracy of the multifactor analysis were evaluated according to concordance index (C-index) and calibration curves. RESULTS: A total of 1202 patients were included in the analysis. The patients were randomly divided into a training set (n = 841) and a validation set (n = 361). Multivariate analysis revealed that age, blood urea nitrogen, respiratory rate, hemoglobin, pneumonia, cardiogenic shock, dialysis, and mechanical ventilation, all of which were incorporated into the nomogram, were independent predictive factors of AMI. Moreover, the nomogram exhibited favorable performance in predicting the 4-year survival of patients with AMI. The training set and the validation set had a C-index of 0.789 (95% confidence interval [CI]: 0.765-0.813) and 0.762 (95% CI: 0.725-0.799), respectively. CONCLUSION: The nomogram constructed herein can accurately predict the long-term survival of critically ill patients with AMI.

Structural insight into the molecular mechanism of p53-mediated mitochondrial apoptosis.

The tumor suppressor p53 is mutated in approximately half of all human cancers. p53 can induce apoptosis through mitochondrial membrane permeabilization by interacting with and antagonizing the anti-apoptotic proteins BCL-xL and BCL-2. However, the mechanisms by which p53 induces mitochondrial apoptosis remain elusive. Here, we report a 2.5 Å crystal structure of human p53/BCL-xL complex. In this structure, two p53 molecules interact as a homodimer, and bind one BCL-xL molecule to form a ternary complex with a 2:1 stoichiometry. Mutations at the p53 dimer interface or p53/BCL-xL interface disrupt p53/BCL-xL interaction and p53-mediated apoptosis. Overall, our current findings of the bona fide structure of p53/BCL-xL complex reveal the molecular basis of the interaction between p53 and BCL-xL, and provide insight into p53-mediated mitochondrial apoptosis.

The Biodegradation of Soil Organic Matter in Soil-Dwelling Humivorous Fauna.

Soil organic matter contains more carbon than global vegetation and the atmosphere combined. Gaining access to this source of organic carbon is challenging and requires at least partial removal of polyphenolic and/or soil mineral protections, followed by subsequent enzymatic or chemical cleavage of diverse plant polysaccharides. Soil-feeding animals make significant contributions to the recycling of terrestrial organic matter. Some humivorous earthworms, beetles, and termites, among others, have evolved the ability to mineralize recalcitrant soil organic matter, thereby leading to their tremendous ecological success in the (sub)tropical areas. This ability largely relies on their symbiotic associations with a diverse community of gut microbes. Recent integrative omics studies, including genomics, metagenomics, and proteomics, provide deeper insights into the functions of gut symbionts. In reviewing this literature, we emphasized that understanding how these soil-feeding fauna catabolize soil organic substrates not only reveals the key microbes in the intestinal processes but also uncovers the potential novel enzymes with considerable biotechnological interests.

Odorant Receptors for Detecting Flowering Plant Cues Are Functionally Conserved across Moths and Butterflies.

Odorant receptors (ORs) are essential for plant-insect interactions. However, despite the global impacts of Lepidoptera (moths and butterflies) as major herbivores and pollinators, little functional data are available about Lepidoptera ORs involved in plant-volatile detection. Here, we initially characterized the plant-volatile-sensing function(s) of 44 ORs from the cotton bollworm Helicoverpa armigera, and subsequently conducted a large-scale comparative analysis that establishes how most orthologous ORs have functionally diverged among closely related species whereas some rare ORs are functionally conserved. Specifically, our systematic analysis of H. armigera ORs cataloged the wide functional scope of the H. armigera OR repertoire, and also showed that HarmOR42 and its Spodoptera littoralis ortholog are functionally conserved. Pursuing this, we characterized the HarmOR42-orthologous ORs from 11 species across the Glossata suborder and confirmed the HarmOR42 orthologs form a unique OR lineage that has undergone strong purifying selection in Glossata species and whose members are tuned with strong specificity to phenylacetaldehyde, a floral scent component common to most angiosperms. In vivo studies via HarmOR42 knockout support that HarmOR42-related ORs are essential for host-detection by sensing phenylacetaldehyde. Our work also supports that these ORs coevolved with the tube-like proboscis, and has maintained functional stability throughout the long-term coexistence of Lepidoptera with angiosperms. Thus, beyond providing a rich empirical resource for delineating the precise functions of H. armigera ORs, our results enable a comparative analysis of insect ORs that have apparently facilitated and currently sustain the intimate adaptations and ecological interactions among nectar feeding insects and flowering plants.

Dissection of Anti-tumor Activity of Histone Deacetylase Inhibitor SAHA in Nasopharyngeal Carcinoma Cells via Quantitative Phosphoproteomics.

Suberoylanilide hydroxamic acid (SAHA), a pan HDAC inhibitor, has been approved by the Food and Drug Administration (FDA) to treat cutaneous T cell lymphoma (CTCL). Nevertheless, the mechanisms underlying the therapeutic effects of SAHA on tumors are yet not fully understood. Protein phosphorylation is one of the most important means to regulate key biological processes (BPs), such as cell division, growth, migration, differentiation, and intercellular communication. Thus, investigation on the impacts of SAHA treatment on global cellular phosphorylation covering major signaling pathways deepens our understanding on its anti-tumor mechanisms. Here we comprehensively identified and quantified protein phosphorylation for the first time in nasopharyngeal carcinoma (NPC) cells upon SAHA treatment by combining tandem mass tags (TMTs)-based quantitative proteomics and titanium dioxide (TiO2)-based phosphopeptide enrichment. In total, 7,430 phosphorylation sites on 2,456 phosphoproteins were identified in the NPC cell line 5-8F, of which 1,176 phosphorylation sites on 528 phosphoproteins were significantly elevated upon SAHA treatment. Gene ontology (GO) analysis showed that SAHA influenced several BPs, including mRNA/DNA processing and cell cycle. Furthermore, signaling pathway analysis and immunoblotting demonstrated that SAHA activated tumor suppressors like p53 and Rb1 via phosphorylation and promoted cell apoptosis in NPC cells but inactivated energetic pathways such as AMPK signaling. Overall, our study indicated that SAHA exerted anti-tumor roles in NPC cells, which may serve as novel therapeutic for NPC patients.

Computational repositioning of dimethyl fumarate for treating alcoholic liver disease.

Alcoholic liver disease (ALD) is a chronic alcohol-induced disorder of the liver for which there are few effective therapies for severe forms of ALD and for those who do not achieve alcohol abstinence. In this study, we used a systematic drug-repositioning bioinformatics approach querying a large compendium of gene-expression profiles to identify candidate U.S. Food and Drug Administration (FDA)-approved drugs to treat ALD. One of the top compounds predicted to be therapeutic for ALD by our approach was dimethyl fumarate (DMF), an nuclear factor erythroid 2-related factor 2 (NRF2) inducer. We experimentally validated DMF in liver cells and in vivo. Our work demonstrates that DMF is able to significantly upregulate the NRF2 protein level, increase NRF2 phosphorylation, and promote NRF2 nuclear localization in liver cells. DMF also reduced the reactive oxygen species (ROS) level, lipid peroxidation, and ferroptosis. Furthermore, DMF treatment could prevent ethanol-induced liver injury in ALD mice. Our results provide evidence that DMF might serve as a therapeutic option for ALD in humans, and support the use of computational repositioning to discover therapeutic options for ALD.

Combination of Dichloroacetate and Atorvastatin Regulates Excessive Proliferation and Oxidative Stress in Pulmonary Arterial Hypertension Development via p38 Signaling.

Pulmonary arterial hypertension (PAH) is a lethal disease generally characterized by pulmonary artery remodeling. Mitochondrial metabolic disorders have been implicated as a critical regulator of excessively proliferative- and apoptosis-resistant phenotypes in pulmonary artery smooth muscle cells (PASMCs). Dichloroacetate (DCA) is an emerging drug that targets aerobic glycolysis in tumor cells. Atorvastatin (ATO) is widely used for hyperlipemia in various cardiovascular diseases. Considering that DCA and ATO regulate glucose and lipid metabolism, respectively, we hypothesized that the combination of DCA and ATO could be a potential treatment for PAH. A notable decrease in the right ventricular systolic pressure accompanied by reduced right heart hypertrophy was observed in the DCA/ATO combination treatment group compared with the monocrotaline treatment group. The DCA/ATO combination treatment alleviated vascular remodeling, thereby suppressing excessive PASMC proliferation and macrophage infiltration. In vitro, both DCA and ATO alone reduced PASMC viability by upregulating oxidative stress and lowering mitochondrial membrane potential. Surprisingly, when combined, DCA/ATO was able to decrease the levels of reactive oxygen species and cell apoptosis without compromising PASMC proliferation. Furthermore, suppression of the p38 pathway through the specific inhibitor SB203580 attenuated cell death and oxidative stress at a level consistent with that of DCA/ATO combination treatment. These observations suggested a complementary effect of DCA and ATO on rescuing PASMCs from a PAH phenotype through p38 activation via the regulation of mitochondrial-related cell death and oxidative stress. DCA in combination with ATO may represent a novel therapeutic strategy for PAH treatment.

Acetylation-mediated degradation of HSD17B4 regulates the progression of prostate cancer.

Steroidogenic enzymes are crucial in prostate cancer (PCa) progression. 17ß-Hydroxysteroid dehydrogenase type 4 (HSD17B4), encoded by HSD17B4, lacks catalytic capacity in androgen metabolism. Now the detailed role and molecular mechanism of PCa development are largely unknown. Here we showed that the expression of HSD17B4 was increased in PCa tissues compared to paired paratumor tissues. HSD17B4 knockdown in PCa cells significantly suppressed its proliferation, migration and invasion, while overexpressing HSD17B4 had opposite effects. Mechanistically, we found that the protein level of HSD17B4 was regulated by its acetylation at lysine 669(K669). Dihydroxytestosterone (DHT) treatment increased HSD17B4 acetylation and then promoted its degradation via chaperone-mediated autophagy (CMA). SIRT3 directly interacted with HSD17B4 to inhibit its acetylation and enhance its stability. In addition, we identified CREBBP as a regulator of the K669 acetylation and degradation of HSD17B4, affecting PC cell proliferation, migration and invasion. Notably, in PCa tissues and paired paratumor tissues, the level of HSD17B4 was negatively correlated with its K669 acetylation. Taken together, this study identified a novel role of HSD17B4 in PCa progression and suggested that HSD17B4 and its upstream regulators may be potential therapeutic targets for PCa intervention.

A20 targets PFKL and glycolysis to inhibit the progression of hepatocellular carcinoma.

Abnormal expression of the E3 ubiquitin ligase A20 has been found in some malignant cancers, including hepatocellular carcinoma (HCC). Here, we discovered that A20 is an E3 ubiquitin ligase for phosphofructokinase, liver type (PFKL) in HCC A20 interacts with PFKL and promotes its degradation, therefore inhibiting glycolysis in HCC cell lines. Downregulation of A20 in HCC cells promotes proliferation, migration, and glycolysis, all of which can be inhibited by targeting PFKL with RNA interference. Importantly, A20 is downregulated in advanced HCC tissues and inversely correlated with PFKL expression. Thus, our findings establish A20 as a critical regulator of glycolysis and reveal a novel mechanism for A20 in tumor suppression and PFKL regulation. Given that an increased level of glycolysis is linked with HCC, this study also identifies potential therapeutic targets for HCC treatment.