Hypertension is a global public health issue and the leading cause of premature death in humans. Despite more than a century of research, hypertension remains difficult to cure due to its complex mechanisms involving multiple interactive factors and our limited understanding of it. Hypertension is a condition that is named after its clinical features. Vascular function is a factor that affects blood pressure directly, and it is a main strategy for clinically controlling BP to regulate constriction/relaxation function of blood vessels. Vascular elasticity, caliber, and reactivity are all characteristic indicators reflecting vascular function. Blood vessels are composed of three distinct layers, out of which the endothelial cells in intima and the smooth muscle cells in media are the main performers of vascular function. The alterations in signaling pathways in these cells are the key molecular mechanisms underlying vascular dysfunction and hypertension development. In this manuscript, we will comprehensively review the signaling pathways involved in vascular function regulation and hypertension progression, including calcium pathway, NO-NOsGC-cGMP pathway, various vascular remodeling pathways and some important upstream pathways such as renin-angiotensin-aldosterone system, oxidative stress-related signaling pathway, immunity/inflammation pathway, etc. Meanwhile, we will also summarize the treatment methods of hypertension that targets vascular function regulation and discuss the possibility of these signaling pathways being applied to clinical work.

Aims: This study aimed to identify potential therapeutic targets in the progression from non-alcoholic fatty liver disease (NAFLD) to hepatocellular carcinoma (HCC), with a focus on genes that could influence disease development and progression. Background: Hepatocellular carcinoma, significantly driven by non-alcoholic fatty liver disease, represents a major global health challenge due to late-stage diagnosis and limited treatment options. This study utilized bioinformatics to analyze data from GEO and TCGA, aiming to uncover molecular biomarkers that bridge NAFLD to HCC. Through identifying critical genes and pathways, our research seeks to advance early detection and develop targeted therapies, potentially improving prognosis and personalizing treatment for NAFLD-HCC patients. Objective: Identify key genes that differ between NAFLD and HCC; Analyze these genes to understand their roles in disease progression; Validate the functions of these genes in NAFLD to HCC transition. Methods: Initially, we identified a set of genes differentially expressed in both NAFLD and HCC using second-generation sequencing data from the GEO and TCGA databases. We then employed a Cox proportional hazards model and a Lasso regression model, applying machine learning techniques to the large sample data from TCGA. This approach was used to screen for key disease-related genes, and an external dataset was utilized for model validation. Additionally, pseudo-temporal sequencing analysis of single-cell sequencing data was performed to further examine the variations in these genes in NAFLD and HCC. Results: The machine learning analysis identified IGSF3, CENPW, CDT1, and CDC6 as key genes. Furthermore, constructing a machine learning model for CDT1 revealed it to be the most critical gene, with model validation yielding an ROC value greater than 0.80. The single-cell sequencing data analysis confirmed significant variations in the four predicted key genes between the NAFLD and HCC groups. Conclusion: Our study underscores the pivotal role of CDT1 in the progression from NAFLD to HCC. This finding opens new avenues for early diagnosis and targeted therapy of HCC, highlighting CDT1 as a potential therapeutic target.

Background/Aims: Interleukin-1β (IL-1β) is one of the critical inflammatory factors during atherogenesis. CCAAT/enhancer binding proteins β (C/EBPβ), a regulator of IL-1β production, recently been evidenced as a key player in the development of atherosclerosis. However, the mechanisms of how C/EBPβ regulates the production of IL-1β are unclear. In this study, we aimed to explore the role of C/EBPβ in regulating IL-1β production in macrophages after oxidized low-density lipoprotein (ox-LDL) exposure and the underlying mechanisms. Methods: RAW264.7 macrophages were treated with 0, 25, 50 or 100 μg/ml ox-LDL for 12, 24 or 48 h. Small interfering RNAs were used to silence related proteins. The gene and protein expression levels were determined by quantitative real-time polymerase chain reaction or western blot (WB). IL-1β secretion was assessed by enzyme-linked immunosorbent assay. The cytoplasmic and nuclear proteins were evaluated by nuclear fractionation followed by WB. Localization of p65 was observed by immunofluorescence. The binding activity of p65 to IL-1β was tested by dual-luciferase reporter assay. Results: Ox-LDL increased IL-1β production, accompanied with increasing C/EBPβ and p65 expression in a dose- and time-dependent manner. Moreover, C/EBPβ deficiency in macrophages blocked ox-LDL-induced increases in IL-1β expression, maturation as well as p65 activation. However, p65 deficiency inhibited the increase in IL-1β production, but not C/EBPβ expression. Dual-luciferase reporter results showed that overexpression of C/EBPβ significantly enhanced binding activity of p65 to IL-1β promoter. In addition, C/EBP 1β deficiency in macrophages abolished the ox-LDL-induced gene transcription increases of IL-1β, IL-6, p65 and caspase-1. Conclusions: Our results demonstrate that C/EBPβ acts upstream of NF-κB p65 subunit in ox-LDL-induced IL-1β production in macrophages and may regulate IL-1β maturation by promoting caspase-1. C/EBPβ may be a promising candidate for the prevention and treatment of atherosclerosis.

Objective: The aim of this study was to compare the periprosthetic BMD changes around Tri‐Lock “Bone Preserving Stem” with the other two common and longer stems (Corail and Summit) after THA.Methods: It was a retrospective cohort study followed patients underwent the total hip arthroplasty from January 2013 to December 2015. They were selected and followed from January 2013 to Janaury 2020. Patients without osteoporosis underwent hip replacements with three aimed stems were included. Among the 138 patients included, 49 patients received the Tri‐Lock stem, 44 patients received the Corail stem, and 45 patients received the Summit stem. The periprosthetic BMD changes evaluated by the Dual energy X‐ray absorptiometry (iDXA) measurement according to the seven Gruen zones was the primary outcome. The Radiographic changes including spot welds, pedestal sign and grade of stress shielding was evaluated by the consecutive hip images. Einzel‐Bild‐Roentgen‐Analyze‐femoral component analysis (EBRA‐FCA) was used to measure the stem migration at 5 years postoperatively. Patient‐reported outcomes (PROMs) and adverse events were assessed and compared in three groups. Finally, the subgroups for the periprosthetic BMD changes, radiological and clinical outcomes were made based on the age, gender and length of follow‐up.Results: A total of 138 patients were retrospectively followed for an average of 4.66 years. Excepting the different stems used in three groups, the age, gender and other characteristics of patients included were similar between groups. There was no significant difference between the three groups in periprosthetic BMD changes over postoperative 5 years. The Summit stem shown more BMD loss in Gruen zone 1 compared with the Tri‐Lock and Corail stems without significant difference (7.49%, −1.89% and −2.62%, respectively, P = 0.42). And the most prominent BMD loss was found in Gruen zone 7 for all three stems (−12.60%, −11.84%, and −9.56%, respectively, P = 0.91). The spot weld was significantly more common around the Corail stem, while there was no difference in the stem migration between three groups. Patient reported outcomes (PROMs) were significantly improved compared with the preoperative values. Regarding the rate of postoperative complications, two patients underwent the dislocation and 25 patients sometimes felt mild to moderate thigh pain. Subgroup analysis showed that female patients older than 50 years lost more BMD and had lower clinical scores, while the stem stability was not good enough in male patients.Conclusions: The Tri‐Lock Bone Preserving Stem did not show significant difference in periprosthetic BMD changes compared with the other two conventional longer stems at 5 years after THA.

Arterial stiffness is a critical factor in cardiovascular and cerebrovascular events, yet clinical practice lacks specific therapeutic targets and biomarkers for its assessment. Hyperlipidemia closely correlates with arterial stiffness, and we observed elevated CCAAT/enhancer-binding protein β (C/EBPβ) expression in atherosclerotic mouse arterial walls. As the arterial medial layer predominantly consists of vascular smooth muscle cells (VSMCs), C/EBPβ‘s role in VSMCs under hyperlipidemia remains unclear. Our findings demonstrate that cholesterol-induced phenotypic transition of contractile VSMCs to macrophage-like cells coincides with C/EBPβ upregulation and activation. The activation of C/EBPβ is closely related to cellular assembly and organization, regulating the cytoskeleton via Disheveled-associated activator of morphogenesis 1 (Daam1). Conditional knockout of C/EBPβ in VSMCs of ApoE^−/− mice alleviated hyperlipidemia-induced vascular remodeling and reduced the elevation of aortic pulse wave velocity. Additionally, C/EBPβ-regulated cytokine platelet-derived growth factor-CC (PDGF-CC) is correlated with brachial-ankle pulse wave velocity in humans. These results indicate that the activation of C/EBPβ promotes the transition of VSMCs from a contractile phenotype to a macrophage-like phenotype by regulating morphological changes, and C/EBPβ activation contributes to hyperlipidemia-induced arterial stiffness. PDGF-CC exhibited a significant association with arterial stiffness and may serve as a promising indicator of arterial stiffness in humans. Our study reveals molecular mechanisms behind hyperlipidemia-induced arterial stiffness and provides potential therapeutic targets and biomarkers.