The Role of Transcription Factor EB in the Vascular Wall Biology

Transcription factor EB (TFEB) is a member of the microphthalmia transcription factor family, with adjacent basic helix-loop-helix and leucine zipper domains. Among them, TFEB has been found to be a master regulator of autophagy and lysosome biogenesis. TFEB is implicated in lysosomal storage diseases and neurodegenerative diseases. However, the role of TFEB in vascular biology is poorly understood. In this study, we aim to explore the role of TFEB and underlying mechanisms in vascular diseases. Growing evidence suggests that endothelial cell dysfunction occurs in the initial stage of atherogenesis. Laminar shear stress, which protects against atherosclerosis, increased TFEB abundance in cultured primary human endothelial cells. The locations with a higher laminar shear stress of the rabbit aorta also show higher expression of TFEB. Furthermore, TFEB overexpression in endothelial cells (ECs) suppressed adhesion molecule and inflammatory cytokine expression., whereas TFEB knockdown aggravated adhesion molecule and inflammatory cytokine expression. TFEB knockdown also diminished the effect of laminar shear stress to suppress adhesion molecule and inflammatory cytokine expression in ECs, indicating TFEB to be a mediator of the anti-inflammatory and anti-atherosclerotic effects of laminar shear stress. The anti-inflammatory effect of TFEB was, at least, partially due to reduced oxidative stress because TFEB overexpression in endothelial cells decreased the concentrations of reactive oxygen species and increased the expression of the antioxidant genes HO1 (which encodes heme oxygenase 1) and SOD2 (which encodes superoxide dismutase 2). Chromatin immunoprecipitation (ChIP) assay and luciferase reporter assay indicated that TFEB directly bound to the promoter of HO1 and SOD2. To study the EC TFEB function in vivo, we generated mTie2-TFEB transgenic mice, in which TFEB was overexpressed in ECs. The transgenic mice exhibited reduced leukocyte recruitment to endothelial cells and decreased atherosclerosis development in ApoE-/- background. Abdominal aortic aneurysm (AAA) has a very high mortality rate in the event of rupture. It would be of high significance to identify novel strategies to prevent or treat AAA. We found that TFEB expression is reduced in the human aneurysm lesion. Both gain- and loss-of-function experiments demonstrated that TFEB inhibited the apoptosis of human aortic smooth muscle cells (HASMCs). Mechanistic studies showed that TFEB upregulated B-cell lymphoma 2 (BCL2) and BCL2 inhibitor abolishes the anti-apoptotic effect of TFEB. ChIP and luciferase reporter assays indicated that TFEB directly bound to the promoter of BCL2, suggesting BCL2 is a direct target of TFEB. To determine the role of TFEB in AAA in vivo, we utilized smooth muscle cell (SMC)- specific Tfeb knockout (KO) mice and applied two different mouse AAA models: β-aminopropionitrile/Angiotensin II- and PCSK9/Angiotensin II-induced murine aneurysm models. Consistent results were observed in the two AAA models, in which TFEB deficiency increases SMC apoptosis and promotes AAA formation. Of significance, we demonstrated that TFEB activator, 2-hydroxypropyl-β-cyclodextrin (HPβCD), attenuates aneurysm formation and inhibits HASMC apoptosis in the PCSK9/Angiotensin II model. Using SMC-TFEB KO mice, we further demonstrated that vascular smooth muscle cell (VSMC) TFEB is essential for the inhibitory effects of HPβCD on AAA formation and VSMC apoptosis in vivo. Our study suggests that TFEB regulates important biological functions in the vascular wall including ECs and VSMCs. As a transcription factor, TFEB directly increases the transcription of anti-oxidant and anti-apoptotic genes. TFEB constitutes a molecular target for the treatment or prevention of vascular diseases such as atherosclerosis and aortic aneurysms.PHDMolecular and Integrative PhysiologyUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttps://deepblue.lib.umich.edu/bitstream/2027.42/149879/1/lhaochen_1.pd

Silencing miR-146a-5p protects against injury-induced osteoarthritis in mice

Osteoarthritis (OA), the most prevalent joint disease and the leading cause of disability, remains an incurable disease largely because the etiology and pathogenesis underlying this degenerative process are poorly understood. Low-grade inflammation within joints is a well-established factor that disturbs joint homeostasis and leads to an imbalance between anabolic and catabolic processes in articular cartilage; however, the complexity of the network between inflammatory factors that often involves positive and negative feedback loops makes current anti-cytokine therapy ineffective. MicroRNAs (miRNAs) have emerged as key regulators to control inflammation, and aberrant miRNAs expression has recently been linked to OA pathophysiology. In the present study, we characterized transcriptomic profiles of miRNAs in primary murine articular chondrocytes in response to a proinflammatory cytokine, IL-1β, and identifie

Genetic insight into putative causes of xanthelasma palpebrarum: a Mendelian randomization study

Xanthelasma palpebrarum (XP) is the most common form of cutaneous xanthoma, with a prevalence of 1.1%~4.4% in the population. However, the cause of XP remains largely unknown. In the present study, we used Mendelian randomization to assess the genetic association between plasma lipids, metabolic traits, and circulating protein with XP, leveraging summary statistics from large genome-wide association studies (GWAS). Genetically predicted plasma cholesterol and LDL-C, but not HDL-C or triglyceride, were significantly associated with XP. Metabolic traits, including BMI, fasting glucose, type 2 diabetes, systolic and diastolic blood pressure, were not significantly associated with XP. Furthermore, we found genetically predicted 12 circulating proteins were associated with XP, including FN1, NTM, FCN2, GOLM1, ICAM5, PDE5A, C5, CLEC11A, CXCL1, CCL2, CCL11, CCL13. In conclusion, this study identified plasma cholesterol, LDL-C, and 12 circulating proteins to be putative causal factors for XP, highlighting the role of plasma cholesterol and inflammatory response in XP development

Case Report: A FBN1 frameshift-and-nonsense mutation and aortic dissection in Marfan syndrome

BackgroundMarfan syndrome (MFS) is an autosomal dominant connective tissue disorder primarily affecting the cardiovascular, ocular, and skeletal systems. Cardiovascular complications are the leading cause of mortality in MFS. Mutations in the FBN1 gene, which encodes fibrillin-1, a critical extracellular matrix protein, are the predominant cause of the disorder.Case presentationOn March 11, 2024, we diagnosed a 30-year-old female proband with MFS based on the revised Ghent criteria, presenting with aortic root aneurysm, aortic dissection, multiple skeletal abnormalities, and a family history of MFS. Whole-exome sequencing followed by Sanger sequencing confirmation identified a novel inherited insertion mutation (c.4991dupA) in exon 40 of the FBN1 gene. We performed valve-sparing aortic root replacement (David Procedure) and total aortic arch replacement using a tetrafurcated graft, along with the implantation of a specially designed frozen elephant trunk in the descending aorta (Sun's Procedure). Postoperatively, the patient underwent biweekly clinical follow-ups for three months. No treatment-related adverse events were reported during the monitoring period.ConclusionThe diagnosis of MFS requires an integrated approach, combining clinical manifestations, imaging studies, and genetic analysis. This novel mutation is associated with severe skeletal manifestations and life-threatening cardiovascular abnormalities, underscoring its clinical relevance. Its association with aggressive phenotypes enhances genotype-phenotype correlations. Importantly, these findings highlight the imperative need for early intervention in high-risk individuals by bridging genetic discovery to clinical practice

Estimation of scrub typhus incidence and spatiotemporal multicomponent characteristics from 2016 to 2023 in Zhejiang Province, China

BackgroundChina is one of the main epidemic areas of scrub typhus, and Zhejiang Province, which is located in the coastal area of southeastern China, is considered a key region of scrub typhus. However, there may be significant bias in the number of reported cases of scrub typhus, to the extent that its epidemiological patterns are not clearly understood. The purpose of this study was to estimate the possible incidence of scrub typhus and to identify the main driving components affecting the occurrence of scrub typhus at the county level.MethodsData on patients with scrub typhus diagnosed at medical institutions between January 2016 and December 2023 were collected from the China Disease Control and Prevention Information System (CDCPIS). The kriging interpolation method was used to estimate the possible incidence of scrub typhus. Additionally, a multivariate time series model was applied to identify the main driving components affecting the occurrence of scrub typhus in different regions.ResultsFrom January 2016 to September 2023, 2,678 cases of scrub typhus were reported in Zhejiang Province, including 1 case of reported death, with an overall case fatality rate of 0.04%. The seasonal characteristics of scrub typhus in Zhejiang Province followed an annual single peak model, and the months of peak onset in different cities were different. The estimated area with case occurrence was relatively wider. There were 41 counties in Zhejiang Province with an annual reported case count of less than 1, while from the estimated annual incidence, the number of counties with less than 1 case decreased to 21. The average annual number of cases in most regions fluctuated between 0 and 15. The numbers of cases in the central urban area of Hangzhou city, Jiaxin city and Huzhou city did not exceed 5. The estimated random effect variance parameters σλ2, σϕ2, and σν2 were 0.48, 1.03 and 3.48, respectively. The endemic component values of the top 10 counties were Shuichang, Cangnan, Chun’an, Xinchang, Pingyang, Xianju, Longquan, Dongyang, Yueqing and Qingyuan. The spatiotemporal component values of the top 10 counties were Pujiang, Anji, Pan’an, Dongyang, Jinyun, Ninghai, Yongjia, Xiaoshan, Yinwu and Shengzhou. The autoregressive component values of the top 10 counties were Lin’an, Cangnan, Chun’an, Yiwu, Pujiang, Longquan, Xinchang, Luqiao, Sanmen and Fuyang.ConclusionThe estimated incidence was higher than the current reported number of cases, and the possible impact area of the epidemic was also wider than the areas with reported cases. The main driving factors of the scrub typhus epidemic in Zhejiang included endemic components such as natural factors, but there was significant heterogeneity in the composition of driving factors in different regions. Some regions were driven by spatiotemporal spread across regions, and the time autoregressive effect in individual regions could not be ignored. These results that monitoring of cases, vectors, and pathogens of scrub typhus should be strengthened. Furthermore, each region should take targeted prevention and control measures based on the main driving factors of the local epidemic to improve the accuracy of prevention and control

DNA methylation-mediated Rbpjk suppression protects against fracture nonunion caused by systemic inflammation

Challenging skeletal repairs are frequently seen in patients experiencing systemic inflammation. To tackle the complexity and heterogeneity of the skeletal repair process, we performed single-cell RNA sequencing and revealed that progenitor cells were one of the major lineages responsive to elevated inflammation and this response adversely affected progenitor differentiation by upregulation of Rbpjk in fracture nonunion. We then validated the interplay between inflammation (via constitutive activation of Ikk2, Ikk2ca) and Rbpjk specifically in progenitors by using genetic animal models. Focusing on epigenetic regulation, we identified Rbpjk as a direct target of Dnmt3b. Mechanistically, inflammation decreased Dnmt3b expression in progenitor cells, consequently leading to Rbpjk upregulation via hypomethylation within its promoter region. We also showed that Dnmt3b loss-of-function mice phenotypically recapitulated the fracture repair defects observed in Ikk2ca-transgenic mice, whereas Dnmt3b-transgenic mice alleviated fracture repair defects induced by Ikk2ca. Moreover, Rbpjk ablation restored fracture repair in both Ikk2ca mice and Dnmt3b loss-of-function mice. Altogether, this work elucidates a common mechanism involving a NF-κB/Dnmt3b/Rbpjk axis within the context of inflamed bone regeneration. Building on this mechanistic insight, we applied local treatment with epigenetically modified progenitor cells in a previously established mouse model of inflammation-mediated fracture nonunion and showed a functional restoration of bone regeneration under inflammatory conditions through an increase in progenitor differentiation potential

The loss of plant functional groups increased arthropod diversity in an alpine meadow on the Tibetan Plateau

Plant species loss, driven by global changes and human activities, can have cascading effects on other trophic levels, such as arthropods, and alter the multitrophic structure of ecosystems. While the relationship between plant diversity and arthropod communities has been well-documented, few studies have explored the effects of species composition variation or plant functional groups. In this study, we conducted a long-term plant removal experiment to investigate the impact of plant functional group loss (specifically targeting tall grasses and sedges, as well as tall or short forbs) on arthropod diversity and their functional groups. Our findings revealed that the removal of plant functional groups resulted in increased arthropod richness, abundance and the exponential of Shannon entropy, contrary to the commonly observed positive correlation between plant diversity and consumer diversity. Furthermore, the removal of different plant groups had varying impacts on arthropod trophic levels. The removal of forbs had a more pronounced impact on herbivores compared to graminoids, but this impact did not consistently cascade to higher-trophic arthropods. Notably, the removal of short forbs had a more significant impact on predators, as evidenced by the increased richness, abundance, the exponential of Shannon entropy, inverse Simpson index and inverse Berger-Parker index of carnivores and abundance of omnivores, likely attributable to distinct underlying mechanisms. Our results highlight the importance of plant species identity in shaping arthropod communities in alpine grasslands. This study emphasizes the crucial role of high plant species diversity in controlling arthropods in natural grasslands, particularly in the context of plant diversity loss caused by global changes and human activities

Transvaginal versus transabdominal specimen extraction surgery for right colon cancer: A propensity matching study

BackgroundThe transvaginal route for specimen extraction is considered ideal for colorectal surgery, but its safety is still questioned. There has been little research on transvaginal natural orifice specimen extraction surgery (NOSES) in the right hemicolectomy. As a result, we conducted a study comparing transvaginal NOSES to traditional transabdominal specimen extraction surgery.Patients and methodsData on female patients who underwent radical right hemicolectomy at the First Affiliated Hospital of Nanchang University between January 2015 and December 2020 were collected retrospectively. A total of 847 patients were compliant, with 51 undergoing the transvaginal specimen extraction surgery (NOSES) group and 796 undergoing the transabdominal specimen extraction surgery (TISES) group. A propensity score matching method (1:2) was used to balance the clinicopathological characteristics of the two groups.ResultsFinally, 138 patients were enrolled in our study, with 46 in the NOSES group and 92 in the TISES group. Compared to the TISES group, the NOSES group had less intraoperative blood loss (p = 0.036), shorter time to first flatus (p < 0.001), shorter time to first liquid diet (p < 0.001), lower postoperative white blood cell counts (p = 0.026), lower C-reactive protein levels (p = 0.027), and lower visual analog scale (VAS) scores (p < 0.001). Regarding the quality of life after surgery, the NOSES group had better role function (p < 0.01), emotional function (p < 0.001), and improved symptoms of postoperative pain (p < 0.001) and diarrhea (p = 0.024). The scar satisfaction was significantly higher in the NOSES group than in the TISES group. Overall survival and disease-free survival in two groups were similar.ConclusionThe short-term results of transvaginal NOSES were superior to conventional transabdominal specimen extraction surgery. At the same time, transvaginal NOSES could improve the abdominal wall appearance and quality of life. The long-term survival was similar in the two surgical approaches. Therefore, transvaginal NOSES is worthy of our implementation and promotion

Modifications of Vitis vinifera L. cv. Petit Verdot grape flavonoids as affected by the different rootstocks in eastern China

Rootstocks are widely used in viticulture because of their strong ability to resist biotic and abiotic stress. In two-successive years (2016−2017), the effects of five rootstocks (101-14MGt, 1103P, Beta, 5BB, and SO4) on the berry flavonoid profiles of Petit Verdot were evaluated by HPLC-MS. The results showed that there was limited influence of rootstocks affecting the technological ripening of Petit Verdot. With respect to flavonoid compounds, 1103P and Beta tended to increase the concentrations of anthocyanin in grape skins in the two seasons. 101-14MGt and 1103P enhanced the flavonol concentrations, whereas Beta showed a detrimental effect on the biosynthesis of flavonols except for syringetin. Additionally, despite the season factor dominating the effect on flavan-3-ols, 101-14MGt tended to show a slight increase in flavan-3-ol concentrations in skins and seeds. In conclusion, based on the evaluation of physicochemical indicators and flavonoid compounds of mature berries, the current study provided data for grafting of Petit Verdot on various rootstocks in eastern China