Cost-Utility Analysis of Vericiguat in Heart Failure with Reduced Ejection Fraction After Worsening Heart Failure Events in China.

OBJECTIVE: Vericiguat is a new medication to demonstrate clinical efficacy in heart failure with reduced ejection fraction (HFrEF) after worsening heart failure (WHF) events, but its cost-utility was unknown. We aimed to assess the cost-utility of combining the application of vericiguat with standard treatment in HFrEF patients who had WHF events. METHODS: A multistate Markov model was implemented to mimic the economic results of HFrEF patients who had WHF events in China after receiving vericiguat or placebo. An analysis of cost-utility was conducted; most parameters were set according to the published studies and related databases. All the utilities and costs were decreased at a rate of 5% annually. The incremental cost-effectiveness ratios (ICERs) were the primary outcome measure. We also conducted sensitivity analyses. RESULTS: Over a 20 year lifetime horizon, additional use of vericiguat led to an elevated cost from US$9725.03 to US$20,660.76 at the current vericiguat costs. This was related to increased quality-adjusted life years (QALYs) from 2.50 to 2.66, along with an ICER of US$65,057.24 per QALY, which was over the willingness-to-pay (WTP) threshold of US$36,096.30 per QALY. If the vericiguat costs were discounted at 80%, it contributed to an ICER of US$12,226.77 per QALY. Additional use of vericiguat for patients with plasma N-terminal pro-B-type natriuretic peptide (NT-proBNP) of ≤ 5314 pg per ml produced an ICER of US$23,688.46 per QALY. The outcomes of the one-way sensitivity analysis showed the risk of death from cardiovascular disease in both groups was variable with the highest sensitivity. The probabilistic sensitivity analysis showed that 41.6% of the mimicked population receiving vericiguat combined with standard therapy was cost-effective at the WTP threshold of US$36,096.30 per QALY. CONCLUSIONS: From the perspective of Chinese public healthcare system, the combined use of vericiguat and standard treatment in patients with HFrEF following WHF events did not generate advantages in cost-utility in China but was a cost-effective therapeutic strategy for those who with plasma NT-proBNP of ≤ 5314 pg per ml.

The causal relationship between serum metabolites and the risk of psoriasis: a Mendelian randomization and meta-analysis study.

Objective: To explore the influence of serum metabolites on the risk of psoriasis. Methods: In the initial stage, we applied Mendelian randomization to evaluate the association between 1,400 serum metabolites and the risk of psoriasis. Causal effects were primarily assessed through the Inverse-Variance Weighted method and Wald Ratio's odds ratios, and 95% confidence intervals. False Discovery Rate was used for multiple comparison corrections. Sensitivity analyses were conducted using Cochran's Q Test, MR-PRESSO. MR-Steiger Test was employed to check for reverse causality. In the validation stage, we sought other sources of psoriasis GWAS data to verify the initial results and used meta-analysis to combine the effect sizes to obtain robust causal relationships. In addition, we also conducted metabolic pathway enrichment analysis on known metabolites that have a causal relationship with the risk of psoriasis in both stages. Results: In the initial stage, we identified 112 metabolites causally associated with psoriasis, including 32 metabolite ratios and 80 metabolites (69 known and 11 unknown). In the validation stage, 24 metabolites (16 known, 1 unknown, and 7 metabolite ratios) were confirmed to have a causal relationship with psoriasis onset. Meta-analysis results showed that the overall effect of combined metabolites was consistent with the main analysis in direction and robust in the causal relationship with psoriasis onset. Of the 16 known metabolites, most were attributed to lipid metabolism, with 5 as risk factors and 8 as protective factors for psoriasis. Peptidic metabolite Gamma-glutamylvaline levels had a negative causal relationship with psoriasis, while exogenous metabolite Catechol sulfate levels and amino acid 3-methylglutaconate levels had a positive causal relationship with the disease onset. The metabolites associated with psoriasis risk in the two stages are mainly enriched in the following metabolic pathways: Glutathione metabolism, Alpha Linolenic Acid and Linoleic Acid Metabolism, Biosynthesis of unsaturated fatty acids, Arachidonic acid metabolism, Glycerophospholipid metabolism. Conclusion: Circulating metabolites may have a potential causal relationship with psoriasis risk, and targeting specific metabolites may benefit psoriasis diagnosis, disease assessment, and treatment.

Network pharmacology and gut microbiota insights: unraveling Shenling Baizhu powder's role in psoriasis treatment.

Background: Psoriasis, a chronic skin condition characterized by systemic inflammation and altered gut microbiota, has been a target of Traditional Chinese Medicine (TCM) for centuries. Shenling Baizhu Powder (SLBZP), a TCM formulation, holds promise for treating inflammatory diseases, but its specific role in psoriasis and impact on gut microbiota is not fully understood. Objective: This study aims to elucidate the mechanism of SLBZP in treating psoriasis, integrating component analysis, network pharmacology, and experimental validation in mice models. Methods: We commenced with a detailed component analysis of SLBZP using liquid chromatograph and mass spectrometer (LC-MS). Network pharmacology analysis was used to predict the potential action targets and pathways of SLBZP in psoriasis. An in vivo experiment was conducted with psoriasis mice models, treated with SLBZP. Therapeutic effects were assessed via symptomatology, histopathology, and immunohistochemical analysis. Gut microbiota composition was analyzed using 16S rRNA gene sequencing. Results: A total of 42 main components and quality markers were identified, primarily from licorice and ginseng, including flavonoids, saponins and other markers. PPI topology analysis showed that TNF, IL-6, IL-1ß, TP53 and JUN were the core DEPs. 168 signaling pathways including lipid and atherosclerosis, AGE-RAGE signaling pathway, IL-17 signaling pathway and Th17 cell differentiation were enriched by KEGG. SLBZP demonstrated significant therapeutic effects on psoriasis in mice, with alterations in skin pathology and biomarkers. Additionally, notable changes in gut microbiota composition were observed post-treatment, indicating a possible gut-skin axis involvement. Conclusion: This research has pinpointed lipid metabolism as a key pathway in the treatment of psoriasis with SLBZP. It explores how SLBZP's modulation of gut microbiota and lipid metabolism can alleviate psoriasis, suggesting that balancing gut microbiota may reduce inflammation mediators and offer therapeutic benefits. This underscores lipid metabolism modulation as a potential new strategy in psoriasis treatment.

A bibliometrics study on the status quo and hot topics of pathogenesis of psoriasis based on Web of Science.

BACKGROUND: Psoriasis is an immune-mediated chronic inflammatory skin disease. Great progress has been made in the pathogenesis of psoriasis in recent years, but there is no bibliometric study on the pathogenesis of psoriasis. The purpose of this study was to use bibliometrics method to analyze the research overview and hot spots of pathogenesis of psoriasis in recent 10 years, so as to further understand the development trend and frontier of this field. METHODS: The core literatures on the pathogenesis of psoriasis were searched in the Web of Science database, and analyzed by VOSviewer, CiteSpace, and Bibliometrix in terms of the annual publication volume, country, institution, author, journal, keywords, and so on. RESULTS: A total of 3570 literatures were included. China and the United States were the main research countries in this field, and Rockefeller University was the main research institution. Krueger JG, the author, had the highest number of publications and the greatest influence, and Boehncke (2015) was the most cited local literature. J INVEST DERMATOL takes the top spot in terms of the number of Dermatol articles and citation frequency. The main research hotspots in the pathogenesis of psoriasis are as follows: (1) The interaction between innate and adaptive immunity and the related inflammatory loop dominated by Th17 cells and IL-23/IL-17 axis are still the key mechanisms of psoriasis; (2) molecular genetic studies represented by Long Non-Coding RNA (LncRNA); (3) integrated research of multi-omics techniques represented by gut microbiota; and (4) Exploring the comorbidity mechanism of psoriasis represented by Metabolic Syndrome (MetS). CONCLUSION: This study is a summary of the current research status and hot trend of the pathogenesis of psoriasis, which will provide some reference for the scholars studying the pathogenesis of psoriasis.

Phytochemicals: Targeting autophagy to treat psoriasis.

BACKGROUND: Psoriasis is an immune-mediated chronic inflammatory skin disease characterized by well-defined erythema and white scales, which affects approximately 2% of the worldwide population and causes long-term distress to patients. Therefore, development of safe and effective therapeutic drugs is imminent. Autophagy, an evolutionarily conserved catabolic process, degrades intracellular constituents to maintain cellular energy homeostasis. Numerous studies have revealed that autophagy is closely related to immune function, such as removal of intracellular bacteria, inflammatory cytokine secretion, antigen presentation, and lymphocyte development. Phytochemicals derived from natural plants are often used to treat psoriasis due to their unique therapeutic properties and favorable safety. So far, a mass of phytochemicals have been proven to be able to activate autophagy and thus alleviate psoriasis. This review aimed to provide directions for finding phytochemicals that target autophagy to treat psoriasis. METHODS: The relevant literatures were collected from classical TCM books and a variety of databases (PubMed, Google Scholar, ScienceDirect, Springer Link, Web of Science and China National Knowledge Infrastructure) till December 2022. Search terms were "Phytochemical", "Psoriasis" and "Autophagy". The retrieved data followed PRISMA criteria (preferred reporting items for systematic review). RESULTS: Phytochemicals treat psoriasis mainly through regulating immune cell function, inhibiting excessive inflammatory response, and reducing oxidative stress. While the role and mechanism of autophagy in the pathogenesis of psoriasis have been confirmed in human trials, most of the evidence for phytochemicals that target autophagy to treat psoriasis comes from animal studies. The research focusing on the role of phytochemical-mediated autophagy in the prevention and treatment of psoriasis is limited, and the definite relationship between phytochemical-regulated autophagy and treatment of psoriasis still deserves further experimental confirmation. CONCLUSIONS: Phytochemicals with autophagic activities will provide new insights into the therapeutic intervention for psoriasis.

Analysis of the potential pyroptosis mechanism in psoriasis and experimental validation of NLRP3 in vitro and in vivo.

Pyroptosis provides new perspectives on the mechanisms underlying psoriasis and the development of new treatment strategies. Here, we aimed to identify pyroptosis-related genes (PRGs) involved in the pathogenesis and progression of psoriasis. Based on the inclusion/exclusion criteria, three gene datasets were downloaded from the Gene Expression Omnibus (GEO) database. Differential gene expression, weighted gene co-expression network analysis (WGCNA), and functional enrichment analyses were performed to identify candidate PRGs for psoriasis. Least absolute shrinkage and selection operator (LASSO) regression was used to identify hub genes, and receiver operating characteristic (ROC) curves were used to determine the clinical value of the hub genes. Imiquimod-inducedpsoriasis-like mice and lipopolysaccharide (LPS)-induced RAW 264.7 cells were employed to verify the pro-inflammatory factors that may drive changes in pyroptosis. In total, 159 skin samples were analysed, and a total of 21 common targets were obtained by crossing PRGs with all the differentially expressed genes (DEGs) in different disease states. 11 genes were identified via LASSO screening. Similarly, the last six PRGs biomarkers and the green module genes were screened. All hub genes with an area under the ROC curve > 0.5 were intersected, and NLRP3 was identified. NLRP3 expression was elevated in imiquimod-induced psoriatic lesions in mice and LPS-stimulated RAW 264.7 cells. The mice exhibited reduced psoriasis area and severity index scores, hyperproliferation, and inflammation after treatment with MCC950 (a specific inhibitor of NLRP3). MCC950 decreased IL-1ß, IL-6, and TNF-α mRNA expression, and NLRP3 and p-p65 protein levels in LPS-stimulated RAW 264.7 cells. Our study indicates that NLRP3 may be a promising therapeutic target for the treatment of psoriasis.

Rational Modulation of BODIPY Photosensitizers to Design Metal-Organic Framework-Based NIR Nanocomposites for High-Efficiency Photodynamic Therapy in a Hypoxic Environment.

Photodynamic therapy (PDT) is a promising noninvasive treatment that has drawn great attention. However, the hypoxic environment in tumors seriously limits the therapeutic effect of oxygen-dependent chemicals and PDT. Herein, a versatile nanocomposite DF-BODIPY@ZIF-8 with oxygen-generating ability was developed based on zeolitic imidazolate framework-8 (ZIF-8) by loading the near-infrared photosensitizer DF-BODIPY to overcome hypoxia-induced drug resistance in cancer therapy. ZIF-8 can catalyze the decomposition of hydrogen peroxide in tumors and increase the dissolved oxygen concentration, resulting in a significant improvement in PDT efficacy. Additionally, we found that enhancing the electronegativity of substituents can effectively reduce the energy level difference (ΔEst) between the minimum singlet state (S1) and the lowest triplet state (T1), leading to the enhancement of the singlet oxygen quantum yield. In vitro experiments suggested that DF-BODIPY@ZIF-8 indeed had a higher singlet oxygen quantum yield and better tumor cell phototoxicity than free DF-BODIPY. In vivo experiments also demonstrated that DF-BODIPY@ZIF-8 could effectively eliminate 4T1 tumors under light irradiation. Thus, we conclude that increasing the electronegativity of substituents and introducing a ZIF-8 material can effectively improve the singlet oxygen quantum yield and overcome the hypoxia limitations for high-efficiency PDT.

A chemical biology toolbox to overcome the hypoxic tumor microenvironment for photodynamic therapy: a review.

Cancer is a disease that seriously threatens human health. Over the past few decades, researchers have continued to find ways to cure cancer. Currently, the most commonly used clinical techniques are surgery, chemotherapy, radiotherapy and so on. Among them, photodynamic therapy (PDT) has received extensive attention due to its better therapeutic effect and lower side effects. However, the inherent microenvironmental hypoxia of tumor tissue leads to unsatisfactory therapeutic effects. Therefore, researchers have conducted in-depth research on the hypoxia problem in PDT therapy. This review classified photodynamic therapy according to the response mechanism and summarized the strategies developed to overcome tumor hypoxia in recent years. Among them, research strategies can be divided into five types: type I PDT photosensitizers, introducing exogenous oxygen, O2 carriers using nanomaterials, generating endogenous oxygen by catalytic reactions, and combination with prodrugs that inhibit the consumption of endogenous oxygen. Finally, we also list some studies using combination therapy, such as microbes, photothermal therapy, etc. It can be guaranteed that the review can provide theoretical guidance for the development of anti-hypoxic PDT tools.

Dexmedetomidine alleviates myocardial ischemia/reperfusion-induced injury and Ca2+ overload via the microRNA-346-3p/CaMKIId axis.

Myocardial ischemia/reperfusion (MI/R) may impair cardiac functions. Dexmedetomidine (DEX) is protective in various clinical cases. Therefore, this study investigated the role and mechanism of DEX in MI/R. The myocardial infarct size, apoptosis, and levels of myocardial enzymes, SOD, ROS, Ca2+, and inflammatory factors in DEX-treated MI/R rats were measured. Differentially expressed microRNAs (miRs) in DEX-treated MI/R rats were detected. miR-346-3p was intervened to assess the effects of DEX on MI/R rats. The targeted binding relationship between miR-346-3p and CaMKIId was predicted and verified. DEX effect on hypoxia/reoxygenation (H/R)-induced cell model was evaluated. The role of CaMKIId in DEX protection was assessed after CaMKIId overexpression in H/R cells. NF-κB pathway and NLRP3 inflammasome-related protein levels were detected. DEX alleviated the myocardial injury and Ca2+ overload in MI/R rats, as evidenced by reduced infarct size, apoptosis and levels of myocardial enzymes, ROS, Ca2+, and inflammatory factors. DEX promoted miR-346-3p expression in MI/R rats, and miR-346-3p knockdown reversed DEX protection on MI/R rats. miR-346-3p targeted CaMKIId. DEX improved H/R-induced cell injury and Ca2+ overload and inhibited NF-κB/NLRP3 inflammasome-related protein levels, which were all reversed by CaMKIId overexpression. DEX alleviated injury and Ca2+ overload in MI/R via regulating the miR-346-3p/CaMKIId axis and inhibiting the NF-κB/NLRP3 inflammasome pathway.

Enhancer of zeste homolog 2 participates in the process of atherosclerosis by modulating microRNA-139-5p methylation and signal transducer and activator of transcription 1 expression.

Atherosclerosis (AS) is the main cause of coronary heart disease, in which enhancer of zeste homolog 2 (EZH2) has been implied to participate in this process. Thus, this work proposed to explore the effect of EZH2 on AS from microRNA-139-5p (miR-139-5p)/signal transducer and activator of transcription 1 (STAT1) axis. EZH2, miR-139-5p, and STAT1 expression in arterial tissues of AS patients were detected. Human arterial smooth muscle cells (HASMCs) induced with oxidized low-density lipoprotein (ox-LDL) and the mice fed with high fat diet were treated with silenced EZH2 or upregulated miR-139-5p to explore their roles in proliferation and apoptosis of HASMCs, together with inflammation response and oxidative stress of mice. Chromatin immunoprecipitation experiment was applied to verify the regulatory effect of EZH2 on miR-139-5p through methylation of H3K27me3. The targeting relationship between miR-139-5p and STAT1 was verified by online website and luciferase activity assay. Reduced miR-139-5p and overexpressed EHZ2 and STAT1 were found in AS. Silenced EZH2 or elevated miR-139-5p decreased the production of cholesterol and inhibited inflammation reaction in serum of mice with AS. Silenced EZH2 or elevated miR-139-5p facilitated proliferation and restrained apoptosis of ox-LDL-treated HASMCs, and restrained oxidative stress and cell apoptosis in arterial tissues of AS mice. EZH2 regulated miR-139-5p through H3K27me3, and miR-139-5p targeted STAT1. miR-139-5p silencing antagonized the effects of EZH2 down-regulation on AS. This study manifests that down-regulated EZH2 or elevated miR-139-5p inhibits ox-LDL-induced HASMCs apoptosis, plaque formation, and inflammatory response in AS mice, which may be related to down-regulated STAT1.

Optimal Revascularization Strategy on Medina 0,1,0 Left Main Bifurcation Lesions in Type 2 Diabetes.

Aim. Diabetes mellitus (DM) is a major risk factor for cardiovascular disease. The implications of a diagnosis of DM are as severe as the diagnosis of coronary artery disease. For many patients with complex coronary artery disease, optimal revascularization strategy selection and optimal medical therapy are equally important. In this study, we compared the hemodynamic results of different stenting techniques for Medina 0,1,0 left main bifurcation lesions. Methods. We use idealized left main bifurcation models and computational fluid dynamics analysis to evaluate hemodynamic parameters which are known to affect the risk of restenosis and thrombosis at stented bifurcation. The surface integrals of time-averaged wall shear stress (TAWSS) and oscillatory shear index (OSI) at bifurcation site were quantified. Results. Crossover stenting without final kissing balloon angioplasty provided the most favorable hemodynamic results (integrated values of TAWSS = 2.96 × 10-4 N, OSI = 4.75 × 10-6 m2) with bifurcation area subjected to OSI values >0.25, >0.35, and >0.45 calculated as 0.39 mm2, 0.06 mm2, and 0 mm2, respectively. Conclusion. Crossover stenting only offers hemodynamic advantages over other stenting techniques for Medina 0,1,0 left main bifurcation lesions and large bifurcation angle is associated with unfavorable flow profiles.

Randomized Comparison of the Crush Versus the Culotte Stenting for Coronary Artery Bifurcation Lesions.

BACKGROUND: The crush and the culotte stenting were both reported to be effective for complex bifurcation lesion treatment. However, their comparative performance remains elusive. METHODS: A total of 300 patients with coronary bifurcation lesions were randomly assigned to crush (n = 150) and culotte (n = 150) treatment. The primary endpoint was the occurrence of major adverse cardiac events (MACEs) at 12 months including cardiac death, myocardial infarction, stent thrombosis, and target vessel revascularization. Index lesion restenosis at 12 months was a secondary endpoint. The surface integrals of time-averaged wall shear stress at bifurcation sites were also be quantified. RESULTS: There were no significant differences in MACE rates between the two groups at 12-month follow-up: Crush 6.7%, culotte 5.3% (P = 0.48). The rates of index lesion restenosis were 12.7% versus 6.0% (P = 0.047) in the crush and the culotte groups, respectively. At 12-month follow-up, the surface integrals of time-averaged wall shear stress at bifurcation sites in the crush group were significantly lower than the culotte group ([5.01 ± 0.95] × 10-4 Newton and [6.08 ± 1.16] × 10-4 Newton, respectively; P = 0.003). CONCLUSIONS: Both the crush and the culotte bifurcation stenting techniques showed satisfying clinical and angiographic results at 12-month follow-up. Bifurcation lesions treated with the culotte technique tended to have lower restenosis rates and more favorable flow patterns.

[Effects and mechanism of fibroblast growth factor 21 on rat vascular smooth muscle cells calcification].

OBJECTIVE: To observe the effect and mechanism of fibroblast growth factor 21 (FGF21) on rat vascular smooth muscle cells (VSMCs) calcification in vitro. METHODS: VSMCs was treated with calcification medium containing calcium chloride and ß-glycerophosphate to induce rat VSMCs calcification in vitro. VSMCs were divided into 5 groups: the control group (cultured in normal medium), the calcification group (incubated in calcified medium), the FGF21 group (cultured in calcified medium and FGF21), the PD166866 group (cultured in calcified medium and FGF21 and PD166866, inhibitor of fibroblast growth factor receptor-1 (FGFR1)), the GW9662 group (cultured in calcified medium and FGF21 and GW9662, inhibitor of peroxisome proliferators activated receptor-γ (PPAR-γ)). The calcification of VSMCs was detected by calcium content, alkaline phosphatase activity and alizarin red staining. The protein and mRNA expression of FGFR1, ß-Klotho, osteocalcin and smooth muscle 22α (SM22α) were determined by western blot analysis and realtime-PCR, respectively. RESULTS: (1) The mRNA (P < 0.01) and protein expressions of ß-Klotho and FGFR1 were significantly downregulated in calcification group compared with control group (P < 0.05 or 0.01). (2) The protein levels and mRNA expression of calcium content, alkaline phosphatase activity and osteocalcin were significantly downregulated, while the protein levels and mRNA of SM22α were significantly increased in FGF21 group compared with calcification group (all P < 0.05). Moreover, alizarin red staining verified positive red nodules on calcified VSMCs was significantly reduced in FGF21 group than in calcification group. (3) Calcium content, alkaline phosphatase activity and alizarin red staining were similar between PD166866 group and calcification group (all P > 0.05). (4) Calcium content, alkaline phosphatase activity and alizarin red staining were similar between GW9662 group and calcification group (all P > 0.05). CONCLUSION: The inhibition of VSMCs calcification by FGF21 is mediated by further downregulating FGFR1 and ß-Klotho while activating PPAR-γ pathways.

Three-dimensional virtual surgery models for percutaneous coronary intervention (PCI) optimization strategies.

Percutaneous coronary intervention (PCI), especially coronary stent implantation, has been shown to be an effective treatment for coronary artery disease. However, in-stent restenosis is one of the longstanding unsolvable problems following PCI. Although stents implanted inside narrowed vessels recover normal flux of blood flows, they instantaneously change the wall shear stress (WSS) distribution on the vessel surface. Improper stent implantation positions bring high possibilities of restenosis as it enlarges the low WSS regions and subsequently stimulates more epithelial cell outgrowth on vessel walls. To optimize the stent position for lowering the risk of restenosis, we successfully established a digital three-dimensional (3-D) model based on a real clinical coronary artery and analysed the optimal stenting strategies by computational simulation. Via microfabrication and 3-D printing technology, the digital model was also converted into in vitro microfluidic models with 3-D micro channels. Simultaneously, physicians placed real stents inside them; i.e., they performed "virtual surgeries". The hydrodynamic experimental results showed that the microfluidic models highly inosculated the simulations. Therefore, our study not only demonstrated that the half-cross stenting strategy could maximally reduce restenosis risks but also indicated that 3-D printing combined with clinical image reconstruction is a promising method for future angiocardiopathy research.