Inhibiting MMP13 Attenuates Deep Vein Thrombosis in a Mouse Model by Reducing the Expression of Pdpn.

OBJECTIVE: Matrix metalloproteinase 13 (MMP13) is an extracellular matrix protease that affects the progression of atherosclerotic plaques and arterial thrombi by degrading collagens, modifying protein structures and regulating inflammatory responses, but its role in deep vein thrombosis (DVT) has not been determined. The purpose of this study was to investigate the potential effects of MMP13 and MMP13-related genes on the formation of DVT. METHODS: We altered the expression level of MMP13 in vivo and conducted a transcriptome study to examine the expression and relationship between MMP13 and MMP13-related genes in a mouse model of DVT. After screening genes possibly related to MMP13 in DVT mice, the expression levels of candidate genes in human umbilical vein endothelial cells (HUVECs) and the venous wall were evaluated. The effect of MMP13 on platelet aggregation in HUVECs was investigated in vitro. RESULTS: Among the differentially expressed genes, interleukin 1 beta, podoplanin (Pdpn), and factor VIII von Willebrand factor (F8VWF) were selected for analysis in mice. When MMP13 was inhibited, the expression level of PDPN decreased significantly in vitro. In HUVECs, overexpression of MMP13 led to an increase in the expression level of PDPN and induced platelet aggregation, while transfection of PDPN-siRNA weakened the ability of MMP13 to increase platelet aggregation. CONCLUSIONS: Inhibiting the expression of MMP13 could reduce the burden of DVT in mice. The mechanism involves downregulating the expression of Pdpn through MMP13, which could provide a novel gene target for DVT diagnosis and treatment.

Dnttip2 is essential for 18S rRNA processing and digestive organ development in zebrafish.

Dnttip2 is one of the components of the small subunit (SSU) processome. In yeast, depletion of dnttip2 leads to an inefficient processing of pre-rRNA and a decrease in synthesis of the mature 18S rRNA. However, the biological roles of Dnttip2 in higher organisms are poorly defined. In this study, we demonstrate that dnttip2 is a maternal gene in zebrafish. Depletion of Dnttip2 leads to embryonic lethal with severe digestive organs hypoplasia. The loss of function of Dnttip2 also leads to partial defects in cleavage at the A0-site and E-site during 18S rRNA processing. In conclusion, Dnttip2 is essential for 18S rRNA processing and digestive organ development in zebrafish.

Clinical implications of PD-L1 expression and pathway-related molecular subtypes in advanced Asian colorectal cancer patients.

The expression level of PD-L1 does not accurately predict the prognosis of advanced colorectal cancer (CRC) patients, but it still reflects the tumor microenvironment to some extent. By stratifying PD-L1 status, gene subtypes in PD-L1 positivity-related pathological pathways were analyzed for their relationship to MSI or TMB to provide more individualized treatment options for CRCs. A total of 752 advanced CRCs were included, and their genomic variance was measured by a targeted next generation sequencing panel in this study. MSI and TMB were both measured by NGS, while PD-L1 expression level was measured using the PD-L1 colon 22C3 pharmDx kit. We found RTK/RAS pathway was positively related to high PD-L1 expression, with BRAF V600E and most KRAS mutations (G12 and G13) subtypes showing a significant correlation. Conversely, the Wnt and p53 pathways were negatively related to high PD-L1 expression, with APC C-terminal alterations and other non-inactivation mutations in TP53 making a primary contribution with significant statistical significance. Major subtypes showing a significantly higher proportion of TMB-H or MSI-H were irrespective of PD-L1 status. These findings demonstrate pathological pathways associated with high PD-L1 expression, suggesting that pathway-induced oncogenic constructive PD-L1 upregulation may be the reason for the corresponding patients' primary resistance to immune checkpoint inhibitors (ICIs), rather than a lack of pre-existing immune responses.

Application of Non-Ligation Technique in Thyroidectomy.

Objective: This study aimed to analyze the difference between non-ligation and traditional ligation techniques for papillary thyroid micro-carcinoma (PTMC) patients. Methods: Patients undergoing thyroidectomy in the Department of General Surgery, Ruijin Hospital, affiliated with Shanghai Jiao Tong University, Lu Wan Branch, were retrospectively enrolled. The gender, age, operation method, operation duration, tumor size, size of thyroidectomy specimen, postoperative bleeding, drainage volume on the first postoperative day, preoperative and postoperative levels of parathyroid hormone (PTH), and blood calcium were collected. Results: Compared with the traditional ligation technique, the non-ligation technique significantly shortened the operation time (69.36 ± 1.38 vs. 82.72 ± 2.12, P < .0001) and reached less variation of the serum calcium (2.32 ± 0.01 vs 2.28 ± 0.01, P < .001) and PTH (26.58 ± 0.08 vs 22.01 ± 1.04, P < .05) on the first postoperative day, and the above biochemical indicators returned to normal 3 weeks after surgery. The PTH in the No-ligation technique group was 7.20± 1.99, which was significantly lower than that in the Traditional ligation group (20.78± 3.78) (P < .01). Conclusion: No-ligation technique can significantly reduce the operation time in thyroidectomy but may temporarily affect the levels of parathyroid hormone and blood calcium, and the above changes returned to normal 3 weeks after surgery. These results highlighted that No-ligation technique can benefit patients and will be a favorable treatment method.

Angiogenic and Fibrogenic Dual-effect of Gremlin1 on Proliferative Diabetic Retinopathy.

Ocular angiogenic diseases, such as proliferative diabetic retinopathy (PDR), are often characterized by pathological new vessels and fibrosis formation. Anti-vascular endothelial growth factor (VEGF) therapy, despite of its efficiency to inhibit new vessels, has limitations, including drug resistance and retinal fibrosis. Here, we identified that Gremlin1, a novel angiogenesis and fibrosis inducer, was secreted from Müller glial cells, and its expression increased in the vitreous fluid from patients with PDR. Mechanistically, Gremlin1 triggered angiogenesis by promoting endothelial-mesenchymal transition via the EGFR/RhoA/ROCK pathway. In addition, Gremlin1 activated microglia to present profibrotic and fibrogenic properties. Further, anti-Gremlin1 antibody inhibited ocular angiogenesis and microglia fibrosis in mouse models. Collectively, Gremlin1 could be a potential therapeutic target in the treatment of ocular angiogenic diseases.

Delayed intestinal perforation associated with peritoneal dialysis: A case report of maintaining dialysis after perforation.

Delayed intestinal perforation has various manifestations. For peritonitis with delayed treatment and multi-bacterial peritonitis, we should be alert to the occurrence of this rare complication. Abdominal CT examination and imaging results judgment based on clinical conditions are particularly important for diagnosis. Delayed intestinal perforation of peritoneal dialysis catheter is a rare but serious complication. We reported a 49-year-old patient who had been hospitalized twice within 3 months due to poor drainage of the peritoneal dialysis catheter. During the first hospitalization, peritoneal dialysis-related peritonitis was diagnosed, and a variety of bacterial infections were cultivated. However, at that time, the actual peritoneal dialysis catheter-related intestinal perforation was missed, and he was discharged after anti-infection treatment until a clinical cure was met. After more than 2 months of normal peritoneal dialysis after returning home, the patient again had poor drainage of the peritoneal dialysis catheter, accompanied by the outflow of yellowish-brown sediment. It was found that the peritoneal dialysis catheter had evidence of intestinal perforation. After the removal of the catheter and intestinal repair, he recovered and was discharged from the hospital and received long-term hemodialysis treatment. In the case of delayed intestinal perforation, peritoneal dialysis was maintained normally for more than 2 months, which was an unprecedented situation in previous case reports. In addition, we should be alert to the occurrence of this rare complication, especially when we find the occurrence of polybacterial Peritonitis. Abdominal CT examination and imaging results judgment based on clinical conditions are particularly important for diagnosis.

Mucin-1-Targeted Chimeric Antigen Receptor T Cells Are Effective and Safe in Controlling Solid Tumors in Immunocompetent Host.

The chimeric antigen receptor (CAR) T-cell therapy in solid epithelial tumors has been explored, however, with limited success. As much of the preclinical work has relied on xenograft models in immunocompromised animals, the immune-related efficacies and toxicities may have been missed. In this study, we engineered syngeneic murine CAR T cells targeting the tumor form of human mucin-1 (tMUC1) and tested the MUC1 CAR T cells' efficacy and toxicity in the immunocompetent human MUC1-expressing mouse models. The MUC1 CAR T cells significantly eliminated murine pancreatic and breast cancer cell lines in vitro. In vivo, MUC1 CAR T cells significantly slowed the mammary gland tumor progression in the spontaneous PyVMT×MUC1.Tg (MMT) mice, prevented lung metastasis, and prolonged survival. Most importantly, there was minimal short or long-term toxicity with acceptable levels of transient liver toxicity but no kidney toxicity. In addition, the mice did not show any signs of weight loss or other behavioral changes with the treatment. We also report that a single dose of MUC1 CAR T-cell treatment modestly reduced the pancreatic tumor burden in a syngeneic orthotopic model of pancreatic ductal adenocarcinoma given at late stage of an established tumor. Taken together, these findings suggested the further development of tMUC1-targeted CAR T cells as an effective and relatively safe treatment modality for various tMUC1-expressing solid tumors.

Grain Engineering of Sb2 S3 Thin Films to Enable Efficient Planar Solar Cells with High Open-Circuit Voltage.

Sb2 S3 is a promising environmentally friendly semiconductor for high performance solar cells. But, like many other polycrystalline materials, Sb2 S3 is limited by nonradiative recombination and carrier scattering by grain boundaries (GBs). This work shows how the GB density in Sb2 S3 films can be significantly reduced from 1068 ± 40 to 327 ± 23 nm µm-2 by incorporating an appropriate amount of Ce3+ into the precursor solution for Sb2 S3 deposition. Through extensive characterization of structural, morphological, and optoelectronic properties, complemented with computations, it is revealed that a critical factor is the formation of an ultrathin Ce2 S3 layer at the CdS/Sb2 S3 interface, which can reduce the interfacial energy and increase the adhesion work between Sb2 S3 and the substrate to encourage heterogeneous nucleation of Sb2 S3 , as well as promote lateral grain growth. Through reductions in nonradiative recombination at GBs and/or the CdS/Sb2 S3 heterointerface, as well as improved charge-carrier transport properties at the heterojunction, this work achieves high performance Sb2 S3 solar cells with a power conversion efficiency reaching 7.66%. An impressive open-circuit voltage (VOC ) of 796 mV is achieved, which is the highest reported thus far for Sb2 S3 solar cells. This work provides a strategy to simultaneously regulate the nucleation and growth of Sb2 S3 absorber films for enhanced device performance.

Preparation of betaine injection and its therapeutic effect in pulmonary arterial hypertension.

Pulmonary arterial hypertension (PAH) is a life-threatening disease characterised by elevated pulmonary pressure, right ventricular failure (RVF) and ultimately death. Aggressive treatment of RVF is considered an important therapeutic strategy to treat PAH. Previous studies have indicated that betaine may be may a promising therapeutic approach for PAH-induced RVF. Therefore, in this study, betaine solution for injection was prepared and characterised using various techniques. The therapeutic efficacy of three different methods of administration (intragastric, nebulised inhalation and intravenous injection) were comprehensively evaluated in terms of pharmacokinetics, tissue distribution and pharmacodynamics. The pharmacokinetic results demonstrated that betaine injection administered via nebulised inhalation significantly prolonged betaine's half-life and increased its internal circulation time compared to the intragastric and intravenous routes. Biodistribution experiments verified that the betaine formulation accumulated in the lung tissue when administered via inhalation. The results of the pharmacodynamic analysis further confirmed that right ventricular systolic pressure, mean pulmonary artery pressure and right ventricular hypertrophy index increased in the model group and that inhaled betaine suppressed these pathological changes to a level comparable to those observed in the control group. Taken together, these results indicate that betaine administered by inhalation is a promising strategy for the treatment of PAH-induced RVF.

Volume-Confined Fabrication of Large-Scale Single-Crystalline Molecular Ferroelectric Thin Films and Their Applications in 2D Materials.

With outstanding advantages of chemical synthesis, structural diversity, and mechanical flexibility, molecular ferroelectrics have attracted increasing attention, demonstrating themselves as promising candidates for next-generation wearable electronics and flexible devices in the film form. However, it remains a challenge to grow high-quality thin films of molecular ferroelectrics. To address the above issue, a volume-confined method is utilized to achieve ultrasmooth single-crystal molecular ferroelectric thin films at the sub-centimeter scale, with the thickness controlled in the range of 100-1000 nm. More importantly, the preparation method is applicable to most molecular ferroelectrics and has no dependency on substrates, showing excellent reproducibility and universality. To demonstrate the application potential, two-dimensional (2D) transitional metal dichalcogenide semiconductor/molecular ferroelectric heterostructures are prepared and investigated by optical spectroscopic method, proving the possibility of integrating molecular ferroelectrics with 2D layered materials. These results may unlock the potential for preparing and developing high-performance devices based on molecular ferroelectric thin films.

Carbon tax and low-carbon credit: Which policy is more beneficial to the capital-constrained manufacturer's remanufacturing activities?

Remanufacturing has attracted much attention for its enormous potential in resource recycling and low-carbon emission reduction. To investigate the effects of different government intervention policies on remanufacturing and carbon emissions, two profit maximization models of the capital-constrained manufacturer under carbon tax and low-carbon credit policies are constructed respectively. Then, through theoretical and numerical analyses, some significant findings are drawn: (1) Both carbon tax and low-carbon credit policies can encourage capital-constrained manufacturers to produce more remanufactured products, but which intervention policy is more advantageous also depends on the carbon emission cost of new products or financing cost of the remanufactured products. (2) Although carbon tax policy can effectively control carbon emissions, it is always at the expense of both capital-constrained manufacturers and consumers; while low-carbon credit policy can help capital-constrained manufacturers achieve the goal of win-win economic and environmental benefits when the remanufacturing carbon savings advantages are more apparent. (3) From the perspective of consumer benefits, carbon tax is more advantageous when the consumer willingness to pay for remanufactured products is higher; otherwise, low-carbon credit policy should be implemented. (4) The higher the environmental damage coefficient is, the more it can highlight the advantages of the two intervention policies in social welfare enhancement, especially the carbon tax policy; and when the environmental damage coefficient is given, the stronger the consumers' willingness to pay for remanufactured products is, the more it is conducive to reducing the negative effects caused by the carbon tax or low-carbon credit policy in social welfare enhancement, or increasing the corresponding positive effects. Based on above findings, some managerial insights and policy implications are provided to capital-constrained manufacturers and policy-makers.

Efficacy of rhizobacteria Paenibacillus polymyxa SY42 for the biological control of Atractylodes chinensis root rot.

Atractylodes chinensis is one of the most commonly used bulk herbs in East Asia; however, root rot can seriously affect its quality and yields. In contrast to chemical pesticides, biological control strategies are environmentally compatible and safe. For this study, 68 antagonistic bacterial strains were isolated from the rhizospheres of healthy Atractylodes chinensis. Strain SY42 exhibited the most potent fungicidal activities, with inhibition rates against F. oxysporum, F. solani, and F. redolens of 67.07 %, 63.40 % and 68.45 %, respectively. Through morphological observation and molecular characterization, strain SY42 was identified as Paenibacillus polymyxa. The volatile organic components (VOCs) produced by SY42 effectively inhibited the mycelial growth of pathogenic fungi through diffusion. SY42 significantly inhibited the germination of pathogenic fungal spores. Following co-culturing with SY42, the mycelium of the pathogenic fungus was deformed, folded, and even ruptured. SY42 could produce cellulases and proteases to degrade fungal cell walls. Pot experiments demonstrated the excellent biocontrol efficacy of SY42. This study revealed that P. polymyxa SY42 inhibited pathogenic fungi through multiple mechanisms, which verified its utility as a biocontrol agent for the control of A. chinensis root rot.

The significance of short-term preoperative calcium and activated vitamin D3 supplementation in thyroidectomy: a randomized trial and prospective study.

Objective: The aim was to explore the effects of preoperative calcium and activated vitamin D3 supplementation on post-thyroidectomy hypocalcemia and hypo-parathyroid hormone-emia (hypo-PTHemia). Methods: A total of 209 patients were randomly divided into control group (CG) and experimental group (EG). Oral calcium and activated vitamin D3 supplementation were preoperatively administered to EG, whereas a placebo was administered to CG. Data on serum calcium, phosphorus, and PTH concentrations before operation, on postoperative day 1 (POPD1), at postoperative week 3 (POPW3), and on the length of postoperative hospitalization were collected. Results: The serum calcium, phosphorus, and PTH concentrations, as well as the incidence of postoperative hypocalcemia and hypo-PTHemia, did not significantly differ between EG and CG. Subgroup analysis revealed that the serum calcium concentrations of the experimental bilateral thyroidectomy subgroup (eBTS) on POPD1 and POPW3 were higher than that of the control bilateral thyroidectomy subgroup (cBTS) (P < 0.05); the reduction of serum calcium in eBTS on POPD1 and POPW3 was less than those in cBTS (P < 0.05). However, significant differences were not observed between the unilateral thyroidectomy subgroups (UTS) (P > 0.05). Moreover, the incidence of postoperative hypocalcemia in cBTS on POPD1 was significantly higher than that in eBTS (65.9% vs 41.7%) (P < 0.05). The length of hospitalization in cBTS (3.55 ± 1.89 days) was significantly longer than that (2.79 ± 1.15 days) in eBTS (P < 0.05). Conclusion: Short-term preoperative prophylactic oral calcium and activated vitamin D3 supplementation could effectively reduce the incidence of postoperative hypocalcemia and decrease the length of postoperative hospitalization in patients who have undergone bilateral thyroidectomy.

Systematic Analysis of Tumor Stem Cell-related Gene Characteristics to Predict the PD-L1 Immunotherapy and Prognosis of Gastric Cancer.

AIMS: We aimed to develop a prognostic model with stemness-correlated genes to evaluate prognosis and immunotherapy responsiveness in gastric cancer (GC). BACKGROUND: Tumor stemness is related to intratumoral heterogeneity, immunosuppression, and anti-tumor resistance. We developed a prognostic model with stemness-correlated genes to evaluate prognosis and immunotherapy responsiveness in GC. OBJECTIVE: We aimed to develop a prognostic model with stemness-correlated genes to evaluate prognosis and immunotherapy responsiveness in GC. METHODS: We downloaded single-cell RNA sequencing (scRNA-seq) data of GC patients from the Gene-Expression Omnibus (GEO) database and screened GC stemness- related genes using CytoTRACE. We characterized the association of tumor stemness with immune checkpoint blockade (ICB) and immunity. Thereafter, a 9-stemness signature-based prognostic model was developed using weighted gene co-expression network analysis (WGCNA), univariate Cox regression analysis, and the least absolute shrinkage and selection operator (LASSO) regression analysis. The model predictive value was evaluated with a nomogram. RESULTS: Early GC patients had significantly higher levels of stemness. The stemness score showed a negative relationship to tumor immune dysfunction and exclusion (TIDE) score and immune infiltration, especially T cells and B cells. A stemness-based signature based on 9 genes (ERCC6L, IQCC, NKAPD1, BLMH, SLC25A15, MRPL4, VPS35, SUMO3, and CINP) was constructed with good performance in prognosis prediction, and its robustness was validated in GSE26942 cohort. Additionally, nomogram and risk score exhibited the most powerful ability for prognosis prediction. High-risk patients exhibited a tendency to develop immune escape and low response to PD-L1 immunotherapy. CONCLUSION: We developed a stemness-based gene signature for prognosis prediction with accuracy and reliability. This signature also helps clinical decision-making of immunotherapy for GC patients.

Comprehensive Functional Analysis of the bZIP Family in Bletilla striata Reveals That BsbZIP13 Could Respond to Multiple Abiotic Stresses.

Basic leucine zipper (bZIP) transcription factors (TFs) are one of the largest families involved in plant physiological processes such as biotic and abiotic responses, growth, and development, etc. In this study, 66 members of the bZIP family were identified in Bletilla striata, which were divided into 10 groups based on their phylogenetic relationships with AtbZIPs. A structural analysis of BsbZIPs revealed significant intron-exon differences among BsbZIPs. A total of 63 bZIP genes were distributed across 16 chromosomes in B. striata. The tissue-specific and germination stage expression patterns of BsbZIPs were based on RNA-seq. Stress-responsive expression analysis revealed that partial BsbZIPs were highly expressed under low temperatures, wounding, oxidative stress, and GA treatments. Furthermore, subcellular localization studies indicated that BsbZIP13 was localized in the nucleus. Yeast two-hybrid (Y2H) and bimolecular fluorescence complementation (BiFC) assays suggested that BsbZIP13 could interact with multiple BsSnRK2s. The results of this study provide insightful data regarding bZIP TF as one of the stress response regulators in B. striata, while providing a theoretical basis for transgenic and functional studies of the bZIP gene family in B. striata.

Red cell distribution width-a potential prognostic indicator for colorectal cancer patients after radical resection in China.

Background: Red cell distribution width (RDW) can signal poor prognosis in inflammatory medical conditions. The purpose of the study was to investigate the relationship between preoperative RDW and colorectal cancer (CRC) in a large cohort of patients. Methods: A total of 6,224 CRC patients who underwent radical resection at the Fudan University Shanghai Cancer Center were evaluated retrospectively. The prognostic significance of RDW for overall survival (OS) and disease-free survival (DFS) was analyzed using Cox proportional hazards models and Kaplan-Meier method. Propensity score matching (PSM) was used based on survival confounding factors. Results: The mean age of the study participants was 59.5±12.0 years and the study cohort was 44% female. The overall median and mean RDW values were 13.3% and 14.0%, respectively. Patients were stratified into three groups based on their RDW value (≤13.3%, 13.4-14.0%, and >14.0%). OS and DFS were shown to significantly deteriorate with increasing RDW category. In the PSM population, OS and DFS were significantly lower in the high RDW group compared with matched controls. However, the differences vanished in the comparisons between the middle RDW group and the control group. Conclusions: Our findings demonstrate that preoperative RDW may represent a simple and powerful prognostic factor for CRC patients after radical resection. Integrating RDW into clinical practice may better inform the prognosis and optimize therapeutic approaches for patients with CRC.

Circulating interleukins and risk of colorectal cancer: a Mendelian randomization study.

BACKGROUND: Recent studies have suggested a potential causal association between Interleukins (ILs) and Colorectal Cancer (CRC), and thus, it is important to examine the causal relationship between them using a Mendelian randomization (MR) approach. METHODS: The instrumental variables were extracted for IL-1ra, IL-6, IL-6ra, IL-8, IL-16, IL-18, IL-27 from genome-wide association studies of European ancestry. Summary statistics of CRC were also retrieved. An inverse variance-weighted MR approach was implemented as the primary method to compute overall effects from multiple instruments. Additional MR approaches and sensitivity and heterogeneity pleiotropy analyses were also conducted respectively. RESULTS: Our analysis suggested a causal effect between an increase of IL-8 and a reduced risk of CRC (odds ratio 0.65; 95% confidence interval, 0.43-0.98; p = 0.041) and did not provide evidence for causal effects of IL-1ra, IL-6, IL-6ra, IL-16, IL-18, IL-27. Sensitivity analyses suggested the robustness of MR results and that they were unlikely to be affected by unbalanced pleiotropy or significant heterogeneity. CONCLUSIONS: This study investigated the role of ILs in the development of CRC and we found a causal effect between an increase of IL-8 and a reduced risk of CRC but not found evidence for causal effects of IL-1ra, IL-6, IL-6ra, IL-16, IL-18, IL-27. Sensitivity analyses suggested the robustness of MR results and that they were unlikely to be affected by unbalanced pleiotropy or significant heterogeneity.

Resolving nanostructure and chemistry of solid-electrolyte interphase on lithium anodes by depth-sensitive plasmon-enhanced Raman spectroscopy.

The solid-electrolyte interphase (SEI) plays crucial roles for the reversible operation of lithium metal batteries. However, fundamental understanding of the mechanisms of SEI formation and evolution is still limited. Herein, we develop a depth-sensitive plasmon-enhanced Raman spectroscopy (DS-PERS) method to enable in-situ and nondestructive characterization of the nanostructure and chemistry of SEI, based on synergistic enhancements of localized surface plasmons from nanostructured Cu, shell-isolated Au nanoparticles and Li deposits at different depths. We monitor the sequential formation of SEI in both ether-based and carbonate-based dual-salt electrolytes on a Cu current collector and then on freshly deposited Li, with dramatic chemical reconstruction. The molecular-level insights from the DS-PERS study unravel the profound influences of Li in modifying SEI formation and in turn the roles of SEI in regulating the Li-ion desolvation and the subsequent Li deposition at SEI-coupled interfaces. Last, we develop a cycling protocol that promotes a favorable direct SEI formation route, which significantly enhances the performance of anode-free Li metal batteries.

Application of transcriptomics and proteomics in pulmonary arterial hypertension.

The onset and progression of pulmonary arterial hypertension (PAH), a malignant disease, are associated with environmental and epigenetic factors. Recent advancements in transcriptomics and proteomics technology have provided new insights into PAH and identified novel gene targets involved in the development of the disease. Transcriptomic analysis has led to the discovery of possible novel pathways, such as miR-483 targeting several PAH-related genes and a mechanistic link between the increase in HERV-K mRNA and protein. Proteomic analysis has revealed crucial details, including the loss of SIRT3 activity and the significance of the CLIC4/Arf6 pathway in PAH pathogenesis. Gene profiles and protein interaction networks of PAH have been analyzed, clarifying the roles of differentially expressed genes or proteins in the occurrence and development of PAH. This article discusses these recent advances.

Integrated proteomic and metabolomic profiling of urine of renal anemia patients uncovers the molecular mechanisms of roxadustat.

Roxadustat (FG-4592) is a hypoxia-inducible factor prolyl hydroxylase inhibitor (HIF-PHI) prescribed to patients with low hemoglobin associated with chronic kidney disease. Due to the various HIF-mediated adaptive responses, FG-4592 has attracted significant interest for therapeutic use against various diseases. However, the clinical application of Roxadustat remains limited due to a lack of understanding of its underlying mechanisms. Herein, we performed label-free quantitative liquid chromatography with tandem mass spectrometry (LC-MS-MS) proteomics and un-targeted metabolomics to study the protein and metabolite alterations in the urine of renal anemia patients before and after Roxadustat therapy. The results were validated by parallel reaction monitoring (PRM). A total of 46 proteins (including 15 upregulated and 31 downregulated proteins) and 207 metabolites were significantly altered after Roxadustat treatment in urine samples obtained from renal anemia patients. Then, the altered proteins were further validated by PRM. Finally, proteomics combined with metabolomics analysis revealed that the Ras signalling pathway, cysteine and methionine metabolism, arginine and proline metabolism, and cholesterol metabolism were the main pathways altered by Roxadustat treatment. The multi-omics analysis revealed that Roxadustat could alter the protein expression and reverse the potential metabolic changes to exert hypotensive, lipid metabolic regulation, and renoprotective effects in clinical practice.