Elucidating VSMC phenotypic transition mechanisms to bridge insights into cardiovascular disease implications.

Cardiovascular diseases (CVD) are the leading cause of death worldwide, despite advances in understanding cardiovascular health. Significant barriers still exist in effectively preventing and managing these diseases. Vascular smooth muscle cells (VSMCs) are crucial for maintaining vascular integrity and can switch between contractile and synthetic functions in response to stimuli such as hypoxia and inflammation. These transformations play a pivotal role in the progression of cardiovascular diseases, facilitating vascular modifications and disease advancement. This article synthesizes the current understanding of the mechanisms and signaling pathways regulating VSMC phenotypic transitions, highlighting their potential as therapeutic targets in cardiovascular disease interventions.

Exogenous abscisic acid (ABA) improves the filling process of maize grains at different ear positions by promoting starch accumulation and regulating hormone levels under high planting density.

BACKGROUND: Higher planting densities typically cause a decline in grain weight, limiting the potential for high maize yield. Additionally, variations in grain filling occur at different positions within the maize ear. Abscisic acid (ABA) is important for grain filling and regulates grain weight. However, the effects of exogenous ABA on the filling process of maize grains at different ear positions under high planting density are poorly understood. In this study, two summer maize hybrids (DengHai605 (DH605) and ZhengDan958 (ZD958)) commonly grown in China were used to examine the effects of ABA application during the flowering stage on grain filling properties, starch accumulation, starch biosynthesis associated enzyme activities, and hormone levels of maize grain (including inferior grain (IG) and superior grain (SG)) under high planting density. RESULTS: Our results showed that exogenous ABA significantly increased maize yield, primarily owing to a higher grain weight resulting from an accelerated grain filling rate relative to the control. There was no significant difference in yield between DH605 and ZD958 in the control and ABA treatments. Moreover, applying ABA promoted starch accumulation by raising the activities of sucrose synthase, ADP-glucose pyrophosphorylase, granule-bound starch synthases, soluble starch synthase, and starch branching enzyme in grains. It also increased the levels of zeatin riboside, indole-3-acetic acid, and ABA and decreased the level of gibberellin in grains, resulting in more efficient grain filling. Notably, IG exhibited a less efficient filling process compared to SG, probably due to lower starch biosynthesis associated enzyme activities and an imbalance in hormone contents. Nevertheless, IG displayed greater sensitivity to exogenous ABA than SG, suggesting that appropriate cultural measures to improve IG filling may be a viable strategy to further increase maize yield. CONCLUSIONS: According to our results, spraying exogenous ABA could effectively improve grain filling properties, accelerate starch accumulation by increasing relevant enzyme activities, and regulate hormone levels in grains, resulting in higher grain weight and yield of maize under high planting density. Our findings offer more evidence for using exogenous hormones to improve maize yield under high planting density.

Roles of cGAS-STING Pathway in Radiotherapy Combined with Immunotherapy for Hepatocellular Carcinoma.

Although great strides have been made in the management and treatment of hepatocellular carcinoma (HCC), its prognosis is still poor yielding a high mortality. Immunotherapy is recommended for treating advanced HCC, but its efficiency is hampered because of hepatic immunosuppression. Stimulator of interferon genes (STING) pathway, serving as a critical cytoplasmic DNA-sensing process, is reported to initiate the antitumor immune response, and link the innate immunity to the adaptive immune system. Radiotherapy has been well acknowledged to induce destruction and release of tumor-derived DNA into the cytoplasm, which then activates the cGAS-STING pathway. On this basis, radiotherapy can be used as a sensitizer for immunotherapy, and its combination with immunotherapy may bring in changes to the suboptimal efficacy of immune checkpoint inhibitor monotherapy. In this review, we summarized the roles of cGAS-STING pathway in regulation of radiotherapy combined with immunotherapy for treating HCC.

Effects of 6-Benzyladenine (6-BA) on the Filling Process of Maize Grains Placed at Different Ear Positions under High Planting Density.

Increasing grain weight under dense planting conditions can further improve maize yield. 6-BA is known to be involved in regulating grain development and influencing grain weight. Maize grain development is closely linked to starch accumulation and hormone levels. In this work, the effects of applying 6-BA at the flowering stage under high density on the grain filling characteristics, starch content, starch synthesis critical enzyme activity, and endogenous hormones levels of maize grains (including inferior grains (IGs) and superior grains (SGs)) of two high-yielding summer maize varieties widely cultivated in China were investigated. The findings indicated that applying 6-BA significantly improved maize yield compared to the control, mainly as a result of increased grain weight due to a faster grain filling rate. Additionally, the activities of enzymes associated with starch synthesis, including sucrose synthase (SuSy), ADP-glucose pyrophosphorylase (AGPase), granule-bound starch synthase (GBSS), soluble starch synthase (SSS), and starch branching enzyme (SBE), were all increased following 6-BA application, thus facilitating starch accumulation in the grains. Applying 6-BA also increased the zeatin riboside (ZR), indole-3-acetic acid (IAA), and abscisic acid (ABA) levels, and reduced the gibberellin (GA3) level in the grains, which further improved grain filling. It is worth noting that IG had a poorer filling process than SG, possibly due to the low activities of critical enzymes for starch synthesis and imbalanced endogenous hormones levels. However, IG responded more strongly to exogenous 6-BA than SG. It appears that applying 6-BA is beneficial in improving filling characteristics, promoting starch accumulation by enhancing the activities of critical enzymes for starch synthesis, and altering endogenous hormones levels in the grains, thus improving grain filling and increasing the final grain weight and yield of maize grown under crowded conditions. These results provide theoretical and technical support for the further utilization of exogenous hormones in high-density maize production.

San Jie Tong Mai Fang Protects Against Atherosclerosis Progression by Regulating Macroautophagy through the PI3K/AKT/mTOR Signaling Pathway.

ABSTRACT: Many studies have confirmed that macrophage autophagy injury negatively impacts the pathogenesis of atherosclerosis (AS). Meanwhile, the phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) signaling pathway affects AS progression by regulating macrophage autophagy. We previously reported that the herbal formula San Jie Tong Mai Fang (SJTMF) elicits lipid regulatory and anti-inflammatory properties. Hence, the current study used an ApoE -/- high-fat diet-fed mouse model to determine whether SJTMF elicits protective effects against AS progression by means of the regulation of macrophage autophagy through the PI3K/AKT/mTOR signaling pathway. Our results show that SJTMF reduced the number of atherosclerotic plaques, foam cell formation, and intimal thickness in mouse aorta. In addition, SJTMF improved blood lipid metabolism and inflammatory levels in mice. We also observed that SJTMF caused macrophages to be polarized toward the M2 phenotype through the inhibition of the PI3K/AKT/mTOR signaling pathway. In addition, the abundances of LC3-II/I and beclin1 proteins-key autophagy molecules-were increased, whereas that of p62 was decreased, resulting in the promotion of macrophage autophagy. Taken together, these findings indicate that SJTMF may regulate the polarization of macrophages by inhibiting the PI3K/AKT/mTOR signaling pathway, thereby reducing atherosclerotic plaque damage in ApoE -/- mice, thereby promoting macrophage autophagy and eliciting a significant antiarteriosclerosis effect. Hence, SJTMF may represent a promising new candidate drug for the treatment of AS.

Midkine inhibition enhances anti-PD-1 immunotherapy in sorafenib-treated hepatocellular carcinoma via preventing immunosuppressive MDSCs infiltration.

Sorafenib, a multiple-target tyrosine kinase inhibitor, is the standard of care for patients with advanced hepatocellular carcinoma (HCC), but provides limited benefits. Emerging evidences suggest that prolonged sorafenib treatment induces an immunosuppressive HCC microenvironment, but the underling mechanism is undetermined. In the present study, the potential function of midkine, a heparin-binding growth factor/cytokine, was evaluated in sorafenib-treated HCC tumors. Infiltrating immune cells of orthotopic HCC tumors were measured by flow cytometry. Differentially expressed genes in sorafenib-treated HCC tumors were evaluated by transcriptome RNA sequencing. The potential function of midkine were evaluated by western blot, T cell suppression assay, immunohistochemistry (IHC) staining and tumor xenograft model. We found that sorafenib treatment increased intratumoral hypoxia and altered HCC microenvironment towards an immune-resistant state in orthotopic HCC tumors. Sorafenib treatment promoted midkine expression and secretion by HCC cells. Moreover, forced midkine expression stimulated immunosuppressive myeloid-derived suppressor cells (MDSCs) accumulation in HCC microenvironment, while knockdown of midkine exhibited opposite effects. Furthermore, midkine overexpression promoted CD11b+CD33+HLA-DR- MDSCs expansion from human PBMCs, while midkine depletion suppressed this effect. PD-1 blockade showed no obvious inhibition on tumor growth of sorafenib-treated HCC tumors, but the inhibitory effect was greatly enhanced by midkine knockdown. Besides, midkine overexpression promoted multiple pathways activation and IL-10 production by MDSCs. Our data elucidated a novel role of midkine in the immunosuppressive microenvironment of sorafenib-treated HCC tumors. Mikdine might be a potential target for the combination of anti-PD-1 immunotherapy in HCC patients.

Evaluation of the effectiveness and safety of acupuncture in the treatment of premature ventricular contractions: A protocol for systematic review and meta-analysis.

BACKGROUND: Premature ventricular contractions are the most common type of arrhythmia. The clinical symptoms are mainly palpitations. In severe cases, syncope, angina pectoris and heart failure may occur, which seriously affect people's lives and ability to work. Antiarrhythmic drugs have many side effects and should not be taken for long periods. Acupuncture has a significant effect on the treatment of premature ventricular contractions. Therefore, to evaluate the effectiveness and safety of acupuncture in the treatment of premature ventricular contractions, we conducted this study, with the goal of providing a scientific methodology for this alternative treatment. METHODS: We searched PubMed, Embase, Web of Science, Cochrane Library, China National Knowledge Infrastructure, Wanfang Database, China Science Journal Database, and China Biomedical Literature Database. We selected all randomized clinical trials related to the use of acupuncture in the treatment of premature ventricular contractions published on or before October 10, 2021, and we will conduct literature screening and data extraction based on specific inclusion and exclusion criteria. We will use the bias risk assessment tool from the Cochrane Systematic Review Manual to evaluate the quality of the research selected for inclusion in our study. RevMan5.3 software will be used to perform statistical analysis on the data. RESULTS: The results of this study will provide evidence for the effectiveness and safety of acupuncture in the treatment of premature ventricular contractions. CONCLUSION: The purpose of this study is to explore the efficacy of acupuncture in the treatment of patients with premature ventricular contractions and to provide an effective reference for clinicians and patients on its use. INPLASY REGISTRATION NUMBER: INPLASY2021100040.