Inhibition of Slc39a14/Slc39a8 reduce vascular calcification via alleviating iron overload induced ferroptosis in vascular smooth muscle cells.

BACKGROUND: Vascular calcification (VC) is an independent risk factor for cardiovascular diseases. Recently, ferroptosis has been recognised as a novel therapeutic target for cardiovascular diseases. Although an association between ferroptosis and vascular calcification has been reported, the role and mechanism of iron overload in vascular calcification are still poorly understood. Specifically, further in-depth research is required on whether metalloproteins SLC39a14 and SLC39a8 are involved in ferroptosis induced by iron overload. METHODS: R language was employed for the differential analysis of the dataset, revealing the correlation between ferroptosis and calcification. The experimental approaches encompassed both in vitro and in vivo studies, incorporating the use of iron chelators and models of iron overload. Additionally, gain- and loss-of-function experiments were conducted to investigate iron's effects on vascular calcification comprehensively. Electron microscopy, immunofluorescence, western blotting, and real-time polymerase chain reaction were used to elucidate how Slc39a14 and Slc39a8 mediate iron overload and promote calcification. RESULTS: Ferroptosis was observed in conjunction with vascular calcification (VC); the association was consistently confirmed by in vitro and in vivo studies. Our results showed a positive correlation between iron overload in VSMCs and calcification. Iron chelators are effective in reversing VC and iron overload exacerbates this process. The expression levels of the metal transport proteins Slc39a14 and Slc39a8 were significantly upregulated during calcification; the inhibition of their expression alleviated VC. Conversely, Slc39a14 overexpression exacerbates calcification and promotes intracellular iron accumulation in VSMCs. CONCLUSIONS: Our research demonstrates that iron overload occurs during VC, and that inhibition of Slc39a14 and Slc39a8 significantly relieves VC by intercepting iron overload-induced ferroptosis in VSMCs, providing new insights into the VC treatment.

Effect of platelet-rich plasma combined with negative pressure wound therapy in treating patients with chronic wounds: A meta-analysis.

A meta-analysis was conducted to comprehensively explore the effects of platelet-rich plasma (PRP) combined with negative pressure wound therapy (NPWT) in treating patients with chronic wounds. Computer searches were conducted, from database infection to November 2023, in EMBASE, Google Scholar, Cochrane Library, PubMed, Wanfang and China National Knowledge Infrastructure databases for randomized controlled trials (RCTs) on the use of PRP combined with NPWT technology for treating chronic wounds. Two researchers independently screened the literature, extracted data and conducted quality assessments according to the inclusion and exclusion criteria. Stata 17.0 software was employed for data analysis. Overall, 18 RCTs involving 1294 patients with chronic wounds were included. The analysis revealed that, compared with NPWT alone, the use of PRP combined with NPWT technology significantly improved the healing rate (odds ratios [OR] = 1.92, 95% confidence intervals [CIs]: 1.43-2.58, p < 0.001) and total effective rate (OR = 1.31, 95% CI: 1.23-1.39, p < 0.001), and also significantly shortened the healing time of the wound (standardized mean difference = -2.01, 95% CI: -2.58 to -1.45, p < 0.001). This study indicates that the treatment of chronic wounds with PRP combined with NPWT technology can significantly enhance clinical repair effectiveness and accelerate wound healing, with a high healing rate, and is worth further promotion and practice.

[Antibody druggability screening process and evaluation strategy].

Since the approval of OKT3 as the first therapeutic monoclonal antibody in 1986, there has been rapid development in antibody technology and antibody drugs. Monoclonal antibodies, antibody fragments, bi (multi) specific antibodies, fusion proteins, nanobodies, and antibody-drug conjugates (ADCs) have been introduced and play a significant role in the treatment of oncology, hematology, immunology, respiratory, metabolic and other related diseases. The process of antibody drug discovery involves multiple rounds of biological function and druggability assessments to identify the best candidate sequences that are safe, effective, stable, and scalable. This lays the foundation for the efficiency and success of drug development and clinical studies. In the phase of antibody drug discovery, "druggability screening and evaluation" has received increasing attention. It involves drug discovery and design, screening and optimization of lead molecules as well as the validation of candidate molecules, with the aim of detecting potential physicochemical risk factors and evaluating controllability to ensure the quality stability of the subsequent drug development process. This paper classifies and defines the process of druggability screening and evaluation in the antibody discovery phase, covering monoclonal antibodies, bispecific antibodies, nanobodies, ADCs and other related technologies and drug forms. It also summarizes the quality attributes and high-throughput detection technology that should be emphasized in the druggability screening and evaluation. The systematic elaboration of the druggability development process and strategy provides a reference for the druggability screening and evaluation of emerging innovative drugs, significantly improving the efficiency and success rate of antibody drug development.

The effect of low molecular weight heparin combined with air pressure in the prevention of lower extremity venous thrombosis after cesarean section: A single-center retrospective study.

In this study, we investigated the effect of low-molecular-weight heparin combined with pneumatic pressure in preventing lower extremity deep vein thrombosis after cesarean section, as well as on the visual analog scale (VAS) score. 120 women who underwent cesarean sections at full term in our hospital from January 2019 to January 2022 were included and divided into a control group (55 cases) and an observation group (65 cases) based on the different treatment methods: the control group was treated with low-molecular-weight heparin and the observation group was treated with pneumatic compression therapy based on the control group. The 2 groups were analyzed for thrombosis, clinical efficacy of the treatment methods, and VAS scores. The incidence of deep vein thrombosis in the observation group were significantly lower than in the control group (4.62% vs 21.82%, P < .05). There were no statistically significant differences in activated partial thromboplastin time, prothrombin time, and thrombin time between the 2 groups (P > .05) before treatment; however, after treatment, activated partial thromboplastin time, prothrombin time, and thrombin time in the observation group were significantly higher than those in the control group (P < .05). The clinical efficacy was significantly higher in the observation group compared with the control group (95.38% vs 78.18%, respectively). The VAS scores in the observation group were significantly lower than those in the control group (P < .05). Hence, low-molecular-weight heparin combined with pneumatic pressure therapy significantly reduces the incidence of lower limb deep vein thrombosis after cesarean section. It also improves the coagulation index and reduces post-operative pain. Therefore, it should be considered for use in clinical practice.

IL-9 aggravates the development of atherosclerosis in ApoE-/- mice.

AIMS: Recently, interleukin (IL)-9 was found to be involved in the pathogenesis of many inflammatory diseases. Here, we tested whether IL-9 was related to atherosclerosis and investigated the underlying mechanisms. METHODS AND RESULTS: IL-9R was expressed in mouse aortic endothelial cells (MAECs) and aortic tissues, and IL-9 levels were elevated in plasma and aortic arches in Apolipoprotein E-deficient (ApoE-/-) mice. ApoE-/- mice fed a western diet for 10 weeks were administered recombinant mouse IL-9 (rIL-9) or anti-IL-9 neutralizing monoclonal antibody (mAb). Mice treated with rIL-9 developed markedly larger plaques in both the aorta and aortic root. Immunohistochemical studies demonstrated increases in both vascular endothelial adhesion molecule-1 (VCAM-1) expression and the infiltration of inflammatory cells, including T cells and macrophages, in plaques. However, treatment with the anti-IL-9 mAb caused the opposite effect. The administration of rIL-9 did not affect the splenic T cell or peripheral monocyte subsets. Meanwhile, IL-9 induced VCAM-1 expression in MAECs mainly via a STAT3-dependent pathway, consequently increasing monocyte-endothelial adhesion. Moreover, treatment with anti-VCAM-1 mAb partially abrogated the IL-9-induced increase in plaque area. In addition, CD4(+)IL-9(+) T cells and IL-9 were increased in patients with acute coronary syndrome, and the levels of IL-9 in culture supernatants and soluble VCAM-1 (sVCAM-1) in plasma were significantly positively correlated in the enrolled patients. CONCLUSION: Our results demonstrated that IL-9 exerted pro-atherosclerotic effects in ApoE-/- mice at least partially by inducing VCAM-1 expression, which mediated inflammatory cell infiltration into atherosclerotic lesions.

Discovery of a Negative Allosteric Modulator of GABAB Receptors.

Initialized from the scaffold of CGP7930, an allosteric agonist of GABAB receptors, a series of noncompetitive antagonists were discovered. Among these compounds, compounds 3, 6, and 14 decreased agonist GABA-induced maximal effect of IP3 production in HEK293 cells overexpressing GABAB receptors and Gqi9 proteins without changing the EC50. Compounds 3, 6, and 14 not only inhibited agonist baclofen-induced ERK1/2 phosphorylation but also blocked CGP7930-induced ERK1/2 phosphorylation in HEK293 cells overexpressing GABAB receptors. The results suggested that compounds 3, 6, and 14 are negative allosteric modulators of GABAB receptors. The representative compound 14 decreased GABA-induced IP3 production with IC50 of 37.9 µM and had no effect on other GPCR Class C members such as mGluR1, mGluR2, and mGluR5. Finally, we showed that compound 14 did not bind to the orthosteric binding sites of GABAB receptors, demonstrating that compound 14 negatively modulated GABAB receptors activity as a negative allosteric modulator.