Effect of chondroitin sulfate modified polyethyleneimine on mediating oligodeoxynucleotide YW002 in the treatment of periodontitis.

PURPOSE: In a previous study, we found that oligodeoxynucleotide (ODN) YW002 could induce the activity of alkaline phosphatase of early osteogenesis in human periodontal membrane stem cells, and downregulate the synthesis of nitric oxide in RAW 264.7 cells in the late inflammatory stage, laying the experimental foundation for the subsequent application of ODN YW002 in periodontitis. However, free ODN does not easily adhere to cells and is easily hydrolyzed by nuclease, so the immune effect of ODN is greatly reduced. Therefore, the nano-drug delivery system provides a method for efficient delivery and uptake of ODN. METHODS: We synthesized a polyethyleneimine (PEI) modified chondroitin sulfate (CS) derivative (PEI-CS) via Michael addition to deliver ODN YW002. We aimed to evaluate whether PEI-CS could effectively deliver YW002 to RAW 264.7 cells and if it can regulate inflammation in vitro. PEI-CS/YW002 nanocomplexes were locally injected into a mouse periodontitis model, and the therapeutic effects were evaluated by microcomputed tomography (micro-CT) and hematoxylin-eosin (H&E) staining. RESULTS: The results indicated that PEI-CS had good biocompatibility and could form a stable nanocomplex with YW002 at a mass ratio of 4 : 1. Moreover, PEI-CS could deliver YW002 into RAW 246.7 cells and markedly decreased the expression levels of interleukin (IL)-1ß, IL-6 and tumor necrosis factor (TNF)-α. Histological evaluation and micro-CT scanning showed that PEI-CS/YW002 nanocomplexes effectively inhibited periodontitis and reduced alveolar bone resorption in mice. CONCLUSION: Our study has underscored the potential of PEI-CS/YW002 nanocomplexes as promising agents for the prevention and treatment of periodontitis due to their potent anti-inflammatory effects.

Improved protective properties of Mg alloy AZ31 using bis-[triethoxysilylpropyl] tetrasulfide silane films modified with nano TiO2 by electrochemically assisted deposition.

Magnesium (Mg) and its alloys were favored by biomedical practitioners thanks to availability of bioactivity and degradability. However, the mismatch between the degradation properties of Mg alloys and the rate of osteogenesis often led to implant failure and bacterial infections within the desired period. The goal of this study was to improve the corrosion resistance of Mg alloys, providing theoretical guidance for solving the problems of implantable Mg-based materials. In this experiment, we prepared a dense and uniform BTESPT/TiO2 film layer on the surface of Mg substrate by electrochemically assisted deposition. The BTESPT/TiO2 film layer provided a physical barrier to avoid direct contact between AZ31 and the corrosive medium. When the addition amount was 2 g/L TiO2, the coating had the best corrosion resistance behavior, its corrosion current density could be up to 9.973×10-8 A/cm2. The BTESPT/TiO2 revealed good cell viability as well as osteogenic differentiation potential on MC3T3-E1 cells.

Hypochlorite-mediated degradation and detoxification of sulfathiazole in aqueous solution and soil slurry.

Although various activated sodium hypochlorite (NaClO) systems were proven to be promising strategies for recalcitrant organics treatment, the direct interaction between NaClO and pollutants without explicit activation is quite limited. In this work, a revolutionary approach to degrade sulfathiazole (STZ) in aqueous and soil slurry by single NaClO without any activator was proposed. The results demonstrated that 100% and 94.11% of STZ could be degraded by 0.025 mM and 5 mM NaClO in water and soil slurry, respectively. The elimination of STZ was shown to involve superoxide anion (O2•-), chlorine oxygen radical (ClO•), and hydroxyl radical (•OH), according to quenching experiments and the analysis of electron paramagnetic resonance. The addition of Cl-, HCO3-, SO42-, and humic acid (HA) marginally impeded the decomposition of STZ, while NO3-, Fe3+, and Mn2+ facilitated the process. The NaClO process exhibited significant removal effectiveness at a neutral initial pH. Moreover, the NaClO facilitated application in various soil samples and water matrices, and the procedure was also successful in effectively eliminating a range of sulfonamides. The suggested NaClO degradation mechanism of STZ was based on the observed intermediates, and the majority of the products exhibited lower ecotoxicity than STZ. Besides, the experiment results by using X-ray diffraction (XRD) and a fourier transform infrared spectrometer (FTIR) indicated the negligible effects on the composition and structure of soil by the treatment of NaClO. Simultaneously, the experimental results also illustrated that the bioavailability of heavy metals and the physiochemical characteristics of the soil before and after the remediation did not change to a significant extent. Following the remediation of NaClO, the phytotoxicity tests showed reduced toxicity to wheat and cucumber seeds. As a result, treating soil and water contaminated with STZ by using NaClO was a reasonably practical and eco-friendly method.

Exposure to different surface-modified polystyrene nanoparticles caused anxiety, depression, and social deficit in mice via damaging mitochondria in neurons.

Nanoplastics (NPs) are unavoidable hazardous materials that result from the human production and use of plastics. While there is evidence that NPs can bioaccumulate in the brain, no enough research regarding the pathways by which NPs reach the brain was conducted, and it is also urgently needed to evaluate the health threat to the nervous system. Here, we observed accumulation of polystyrene nanoplastics (PS-NPs) with different surface modifications (PS, PS-COOH, and PS-NH2) in mouse brains. Further studies showed that PS-NPs disrupted the tight junctions between endothelial cells and transport into endothelial cells via the endocytosis and macropinocytosis pathways. Additionally, NPs exposure induced a series of alternations in behavioral tests, including anxiety- and depression-like changes and impaired social interaction performance. Further results identified that NPs could be internalized into neurons and localized in the mitochondria, bringing about mitochondrial dysfunction and a concurrent decline of ATP production, which might be associated with abnormal animal behaviors. The findings provide novel insights into the neurotoxicity of NPs and provide a basis for the formulation of policy on plastic production and usage by relevant government agencies.

Phosphate in Cardiovascular Disease: From New Insights Into Molecular Mechanisms to Clinical Implications.

Hyperphosphatemia is a common feature in patients with impaired kidney function and is associated with increased risk of cardiovascular disease. This phenomenon extends to the general population, whereby elevations of serum phosphate within the normal range increase risk; however, the mechanism by which this occurs is multifaceted, and many aspects are poorly understood. Less than 1% of total body phosphate is found in the circulation and extracellular space, and its regulation involves multiple organ cross talk and hormones to coordinate absorption from the small intestine and excretion by the kidneys. For phosphate to be regulated, it must be sensed. While mostly enigmatic, various phosphate sensors have been elucidated in recent years. Phosphate in the circulation can be buffered, either through regulated exchange between extracellular and cellular spaces or through chelation by circulating proteins (ie, fetuin-A) to form calciprotein particles, which in themselves serve a function for bulk mineral transport and signaling. Either through direct signaling or through mediators like hormones, calciprotein particles, or calcifying extracellular vesicles, phosphate can induce various cardiovascular disease pathologies: most notably, ectopic cardiovascular calcification but also left ventricular hypertrophy, as well as bone and kidney diseases, which then propagate phosphate dysregulation further. Therapies targeting phosphate have mostly focused on intestinal binding, of which appreciation and understanding of paracellular transport has greatly advanced the field. However, pharmacotherapies that target cardiovascular consequences of phosphate directly, such as vascular calcification, are still an area of great unmet medical need.

Mediation of association between semen microcystin exposure and semen quality by sex hormones in Chinese men.

Numerous studies have shown microcystins (MCs) inducing male reproductive toxicity, but the underlying mechanisms in humans are unclear. Therefore, this study aimed to evaluate the mediating role of serum sex hormones in the association between MC exposure and semen quality. In this study, we measured the levels of semen MCs and serum sex hormones in Chinese men [sample 1 (n = 649); sample 2 (n = 924)]. The results showed that there was a non-significant dose-dependent relationship between semen MCs and semen volume reduction (p for trend = 0.079) in sample 1, and semen MCs were significantly negatively associated with total motility, progressive motility, curvilinear velocity, mean angular displacement and acrosome integrity (p < 0.05) in sample 2. We also found that semen MCs were significantly positively associated with serum follicle stimulating hormone (FSH) (ß = 0.151; 95% CI: 0.065, 0.236), but negatively associated with serum inhibin B (INHB) (ß = -0.605; 95% CI: -0.944, -0.265), and these linear associations were confirmed in restricted cubic spline (RCS) models (all pnon-linearity > 0.1). Furthermore, mediation analysis revealed that serum INHB mediated 19.86% of the adverse effect of MC exposure on acrosome integrity. In conclusion, this study reveals the mediating roles of serum sex hormones in the relationship between MC exposure and decreased semen quality in men.

Toxicity assessment of organophosphate flame retardant triphenyl phosphate (TPHP) on intestines in mice.

Triphenyl phosphate (TPHP), one widely used organophosphate flame retardant, has attracted accumulating attention due to its high detection rate in human biological samples. Up to date, the effects of TPHP exposure on intestinal health remain unexplored. In this study, BALB/c mice were used as a model and exposed to TPHP at dose of 2, 10, or 50 mg/kg body weight for 28 days. We observed Crohn's disease-like features in ileum and ulcerative colitis disease-like features in colon, such as shorter colon length, ileum/colon structure impairment, intestinal epithelial cell apoptosis, enrichment of proinflammatory cytokines and immune cells, and disruption of tight junction. Furthermore, we found that TPHP induced production of reactive oxygen species and apoptosis in intestinal epithelial Caco-2 cells, accompanied by disruption of tight junction between cells. To understand the molecular mechanism underlying TPHP-induced changes in intestines, we build the adverse outcome pathway (AOP) framework based on Comparative Toxicogenomics and GeneCards database. The AOP framework revealed that PI3K/AKT and FoxO signaling pathway might be associated with cellular apoptosis, an increase in ROS production, and increased inflammation response in mouse ileum and colon tissues challenged with TPHP. These results identified that TPHP induced IBD-like features and provided new perspectives for toxicity evaluation of TPHP.

RhoA Promotes Synovial Proliferation and Bone Erosion in Rheumatoid Arthritis through Wnt/PCP Pathway.

Ras homolog gene family member A (RhoA) plays a major role in the Wnt/planar cell polarity (PCP) pathway, which is significantly activated in patients with rheumatoid arthritis (RA). The function of RhoA in RA synovitis and bone erosion is still elusive. Here, we not only explored the impact of RhoA on the proliferation and invasion of RA fibroblast-like synoviocytes (FLSs) but also elucidated its effect on mouse osteoclast and a mouse model of collagen-induced arthritis (CIA). Results showed that RhoA was overexpressed in RA and CIA synovial tissues. Lentivirus-mediated silencing of RhoA increased apoptosis, attenuated invasion, and dramatically upregulated osteoprotegerin/receptor activator of nuclear factor-κB ligand (OPG/RANKL) ratio in RA-FLSs. Additionally, the silencing of RhoA inhibited mouse osteoclast differentiation in vitro and alleviated synovial hyperplasia and bone erosion in the CIA mouse model. These effects in RA-FLSs and osteoclasts were all regulated by RhoA/Rho-associated protein kinase 2 (ROCK2) and might interact with Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathways.

Co-exposure to polystyrene microplastics and microcystin-LR aggravated male reproductive toxicity in mice.

Microplastics (MPs) are plastic pollutants with a diameter of less than 5 mm and microcystins (MCs) are natural toxins produced by cyanobacteria. In recent years, the pollution of MPs and MCs attracted widespread attention. However, our understanding about the toxic effects of co-exposure of MPs and MCs on male reproduction is limited. Mice were continuously exposed to 0.04mg/(kg*bw) microcystin-leucine-arginine (MC-LR) or 45 mg/(kg*bw) polystyrene microplastics (PS-MPs) or a mixed solution of 0.04mg/(kg*bw) MC-LR and 45 mg/(kg*bw) PS-MPs by gavage for 28 days in this study. The results showed that PS-MPs could absorb MC-LR in ddH2O and MC-LR content in testis was increased in the group with combined exposure when compared to the group only exposed to MC-LR. Exposure to PS-MPs or MC-LR individually could destroy testis structure, increase the level of tissue apoptosis and decrease the quality of sperm, while the co-exposure enhanced the toxic effects. Furthermore, PS-MPs could carry MC-LR into testis Leydig cells, reduce testosterone levels and mRNA expression levels of key molecules involved in testosterone synthesis (StAR, P450scc, P450c17,3ß-HSD and 17ß-HSD). Among them, the combined effect of PS-MPs-MC-LR was the most severe. In summary, this study provides new insights into the toxicity of MPs and MCs in mammals.

MiR-9-1 controls osteoblastic regulation of lymphopoiesis.

The highly conserved MicroRNA-9 (miR-9) family consists of three members. We discovered that miR-9-1 deletion reduced mature miR-9 expression, causing 43% of the mice to display smaller size and postweaning lethality. MiR-9-1-deficient mice with growth defects experienced severe lymphopenia, but other blood cells were unaffected. The lymphopenia wasn't due to defects in hematopoietic progenitors, as mutant bone marrow (BM) cells underwent normal lymphopoiesis after transplantation into wild-type recipients. Additionally, miR-9-1-deficient mice exhibited impaired osteoblastic bone formation, as mutant mesenchymal stem cells (MSCs) failed to differentiate into osteoblastic cells (OBs). RNA sequencing revealed reduced expression of master transcription factors for osteoblastic differentiation, Runt-related transcription factor 2 (Runx2) and Osterix (Osx), and genes related to collagen formation, extracellular matrix organization, and cell adhesion, in miR-9-1-deficient MSCs. Follistatin (Fst), an antagonist of bone morphogenetic proteins (BMPs), was found to be a direct target of miR-9-1. Its deficiency led to the up-regulation of Fst, inhibiting BMP signaling in MSCs, and reducing IL-7 and IGF-1. Thus, miR-9-1 controls osteoblastic regulation of lymphopoiesis by targeting the Fst/BMP/Smad signaling axis.

Sertoli cell-derived extracellular vesicles traverse the blood-testis barrier and deliver miR-24-3p inhibitor into germ cells improving sperm mobility.

Asthenozoospermia, characterized by poor sperm motility, is a common cause of male infertility. Improving energy metabolism and alleviating oxidative stress through drug regimens are potential therapeutic strategies. In this study, we observed upregulated miR-24-3p levels in asthenozoospermia spermatozoa, contributing to energy metabolism disorder and oxidative stress by reducing GSK3ß expression. Thus, reducing miR-24-3p levels using drugs is expected to improve sperm motility. The blood-testis barrier (BTB) protects the testis from xenobiotics and drugs. In this study, we found that Sertoli cell-derived small extracellular vesicles (SC-sEV) can traverse the BTB and enter germ cells. We successfully loaded miR-24-3p inhibitor into SC-sEV, creating the nano-drug SC-sEV@miR-24-3p inhibitor, which effectively delivers miR-24-3p inhibitor into germ cells. In a gossypol-induced mouse asthenozoospermia model, administration of SC-sEV@miR-24-3p inhibitor significantly improved sperm motility, in vitro fertilization success, and blastocyst formation rates. As anticipated, it also improved the litter size of asthenozoospermia mice. These results suggest that SC-sEV@miR-24-3p inhibitor holds promise as a potential clinical treatment for asthenospermia.

Association of Dietary Potassium Intake With Abdominal Aortic Calcification and Pulse Pressure in US Adults.

OBJECTIVES: Arterial calcification contributes to cardiovascular mortality. Based on a recent animal study, we hypothesized that higher dietary potassium intake was associated with less abdominal aortic calcification (AAC) and lower arterial stiffness among adults in the United States. METHODS: Cross-sectional analyses were performed on participants over 40 years old from the National Health and Nutrition Examination Survey 2013-2014. Dietary potassium intake was categorized into quartiles (Q1: <1911, Q2: 1911-2461, Q3: 2462-3119, and Q4: >3119 mg/d). Primary outcome AAC was quantified using the Kauppila scoring system. AAC scores were categorized into no AAC (AAC = 0, reference group), mild/moderate (AAC >0 to ≤ 6), and severe AAC (AAC >6). Pulse pressure was used as a surrogate for arterial stiffness and examined as a secondary outcome. RESULTS: Among 2,418 participants, there was not a linear association between dietary potassium intake and AAC. Higher dietary potassium intake was associated with less severe AAC when comparing dietary potassium intake in Q2 with Q1 (odds ratio 0.55; 95% confidence interval: 0.34 to 0.92; P = .03). Higher dietary potassium intake was significantly associated with lower pulse pressure (P = .007): per 1000 mg/d higher dietary potassium intake, pulse pressure was 1.47 mmHg lower in the fully adjusted model. Compared to participants with dietary potassium intake in Q1, pulse pressure was 2.84 mmHg lower in Q4 (P = .04). CONCLUSIONS: We did not find a linear association between dietary potassium intake and AAC. Dietary potassium intake was negatively associated with pulse pressure.

Cationic proteins from eosinophils bind bone morphogenetic protein receptors promoting vascular calcification and atherogenesis.

AIMS: Blood eosinophil count and eosinophil cationic protein (ECP) concentration are risk factors of cardiovascular diseases. This study tested whether and how eosinophils and ECP contribute to vascular calcification and atherogenesis. METHODS AND RESULTS: Immunostaining revealed eosinophil accumulation in human and mouse atherosclerotic lesions. Eosinophil deficiency in ΔdblGATA mice slowed atherogenesis with increased lesion smooth muscle cell (SMC) content and reduced calcification. This protection in ΔdblGATA mice was muted when mice received donor eosinophils from wild-type (WT), Il4-/-, and Il13-/- mice or mouse eosinophil-associated-ribonuclease-1 (mEar1), a murine homologue of ECP. Eosinophils or mEar1 but not interleukin (IL) 4 or IL13 increased the calcification of SMC from WT mice but not those from Runt-related transcription factor-2 (Runx2) knockout mice. Immunoblot analyses showed that eosinophils and mEar1 activated Smad-1/5/8 but did not affect Smad-2/3 activation or expression of bone morphogenetic protein receptors (BMPR-1A/1B/2) or transforming growth factor (TGF)-ß receptors (TGFBR1/2) in SMC from WT and Runx2 knockout mice. Immunoprecipitation showed that mEar1 formed immune complexes with BMPR-1A/1B but not TGFBR1/2. Immunofluorescence double-staining, ligand binding, and Scatchard plot analysis demonstrated that mEar1 bound to BMPR-1A and BMPR-1B with similar affinity. Likewise, human ECP and eosinophil-derived neurotoxin (EDN) also bound to BMPR-1A/1B on human vascular SMC and promoted SMC osteogenic differentiation. In a cohort of 5864 men from the Danish Cardiovascular Screening trial and its subpopulation of 394 participants, blood eosinophil counts and ECP levels correlated with the calcification scores of different arterial segments from coronary arteries to iliac arteries. CONCLUSION: Eosinophils release cationic proteins that can promote SMC calcification and atherogenesis using the BMPR-1A/1B-Smad-1/5/8-Runx2 signalling pathway.

Differently surface-labeled polystyrene nanoplastics at an environmentally relevant concentration induced Crohn's ileitis-like features via triggering intestinal epithelial cell necroptosis.

Nanoplastics (NPs), regarded as the emerging contaminants, can enter and be mostly accumulated in the digest tract, which pose the potential threat to intestinal health. In this study, mice were orally exposed to polystyrene (PS), PS-COOH and PS-NH2 NPs with the size of ∼100 nm at a human equivalent dose for 28 consecutive days. All three kinds of PS-NPs triggered Crohn's ileitis-like features, such as ileum structure impairment, increased proinflammatory cytokines and intestinal epithelial cell (IEC) necroptosis, and PS-COOH/PS-NH2 NPs exhibited higher adverse effects on ileum tissues. Furthermore, we found PS-NPs induced necroptosis rather than apoptosis via activating RIPK3/MLKL pathway in IECs. Mechanistically, we found that PS-NPs accumulated in the mitochondria and subsequently caused mitochondrial stress, which initiated PINK1/Parkin-mediated mitophagy. However, mitophagic flux was blocked due to lysosomal deacidification caused by PS-NPs, and thus led to IEC necroptosis. We further found that mitophagic flux recovery by rapamycin can alleviate NP-induced IEC necroptosis. Our findings revealed the underlying mechanisms concerning NP-triggered Crohn's ileitis-like features and might provide new insights for the further safety assessment of NPs.

Impaired intracellular calcium homeostasis enhances protein O-GlcNAcylation and promotes vascular calcification and stiffness in diabetes.

Vascular calcification is accelerated in patients with diabetes mellitus and increases risk of cardiovascular events and mortality. Vascular smooth muscle cells (VSMC) play a key role in regulating vascular tone and contribute significantly to the development of diabetic vasculopathy. In this study, the function of stromal interaction molecule 1 (STIM1), an important regulator for intracellular calcium homeostasis, in diabetic vascular calcification was investigated, and the underlying molecular mechanisms were uncovered. A SMC-specific STIM1 deletion mouse model (STIM1Δ/Δ) was generated by breeding the STIM1 floxed mice (STIM1f/f) with SM22α-Cre transgenic mice. Using aortic arteries from the STIM1Δ/Δ mice and their STIM1f/f littermates, we found that SMC-specific STIM1 deletion induced calcification of aortic arteries cultured in osteogenic media ex vivo. Furthermore, STIM1 deficiency promoted osteogenic differentiation and calcification of VSMC from the STIM1Δ/Δ mice. In the low-dose streptozotocin (STZ)-induced mouse model of diabetes, SMC-specific STIM1 deletion markedly enhanced STZ-induced vascular calcification and stiffness in the STIM1Δ/Δ mice. The diabetic mice with SMC-specific STIM1 ablation also exhibited increased aortic expression of the key osteogenic transcription factor, Runx2, and protein O-GlcNAcylation, an important post-translational modulation that we have reported to promote vascular calcification and stiffness in diabetes. Consistently, elevation of O-GlcNAcylation was demonstrated in aortic arteries and VSMC from the STIM1Δ/Δ mice. Inhibition of O-GlcNAcylation with a pharmacological inhibitor abolished STIM1 deficiency-induced VSMC calcification, supporting a critical role of O-GlcNAcylation in mediating STIM1 deficiency-induced VSMC calcification. Mechanistically, we identified that STIM1 deficiency resulted in impaired calcium homeostasis, which activated calcium signaling and increased endoplasmic reticulum (ER) stress in VSMC, while inhibition of ER stress attenuated STIM1-induced elevation of protein O-GlcNAcylation. In conclusion, the study has demonstrated a causative role of SMC-expressed STIM1 in regulating vascular calcification and stiffness in diabetes. We have further identified a novel mechanisms underlying STIM1 deficiency-induced impairment of calcium homeostasis and ER stress in upregulation of protein O-GlcNAcylation in VSMC, which promotes VSMC osteogenic differentiation and calcification in diabetes.

COP9 Signalosome Promotes Neointimal Hyperplasia via Deneddylation and CSN5-Mediated Nuclear Export.

BACKGROUND: Neointimal hyperplasia (NH) is a common pathological response to vascular injury and mediated primarily by vascular smooth muscle cell (VSMC) migration and proliferation. The COP9 signalosome (CSN) is formed by 8 canonical subunits (CSN1 through CSN8) with its deneddylation activity residing in CSN5. Each or some of CSN subunits may have deneddylation-independent function. Despite strong evidence linking the CSN to cell cycle regulation in cancer cells, the role of the CSN in vascular biology remains obscure. METHODS: Neointimal CSN5 expression in the lung tissue of pulmonary hypertension (PAH) patients was assessed with immunohistochemistry. Adult mice with smooth muscle cell-restricted CSN5 knockout (CSN5-SMKO) or CSN8 hypomorphism (CSN8-hypo) and cultured mouse VSMCs were studied to determine the role and governing mechanisms of the CSN in NH. NH was induced by ligation of the left common carotid artery (LCCA) and PDGF-BB stimulation was used to mimic the vascular injury in cell cultures. RESULTS: Remarkably higher CSN5 levels were detected in the neointimal VSMCs of the pulmonary arteries of human PAH. LCCA ligation induced NH and significantly increased the mRNA and protein levels of CSN subunits in the LCCA wall of adult wild type mice. CSN5-SMKO impaired Cullin deneddylation and the nuclear export of p27 in vessel walls and markedly inhibited VSMC proliferation in mice. On the contrary, CSN8-hypo significantly exacerbated NH and VSMC proliferation in vivo and in cellulo . Cytoplasmic CSN5 mini-complexes and the nuclear export of p27 were significantly increased in CSN8-hypo mouse vessels and cultured CSN8-hypo VSMCs. Nuclear export inhibition with leptomycin attenuated the PDGF-BB-induced increases in VSMC proliferation in both CSN8-hypo and control VSMCs. Further, genetically disabling CSN5 nuclear export but not disabling CSN5 deneddylase activity suppressed the hyperproliferation and restored p27 nuclear localization in CSN8 hypomorphic VSMCs. Interestingly, CSN deneddylase inhibition by CSN5i-3 did not alter the hyperproliferation of cultured CSN8-hypo VSMCs but suppressed wild type VSMC proliferation in cellulo and in vivo and blocked neointimal formation in wild type mice. CONCLUSION: The CSN promotes VSMC proliferation and NH in injured vessels through deneddylation activity and CSN5-mediated nuclear export.

Molecular Mechanisms of Vascular Health: Insights From Vascular Aging and Calcification.

Cardiovascular disease is the most common cause of death worldwide, especially beyond the age of 65 years, with the vast majority of morbidity and mortality due to myocardial infarction and stroke. Vascular pathology stems from a combination of genetic risk, environmental factors, and the biologic changes associated with aging. The pathogenesis underlying the development of vascular aging, and vascular calcification with aging, in particular, is still not fully understood. Accumulating data suggests that genetic risk, likely compounded by epigenetic modifications, environmental factors, including diabetes and chronic kidney disease, and the plasticity of vascular smooth muscle cells to acquire an osteogenic phenotype are major determinants of age-associated vascular calcification. Understanding the molecular mechanisms underlying genetic and modifiable risk factors in regulating age-associated vascular pathology may inspire strategies to promote healthy vascular aging. This article summarizes current knowledge of concepts and mechanisms of age-associated vascular disease, with an emphasis on vascular calcification.

Promoting Lymphangiogenesis and Lymphatic Growth and Remodeling to Treat Cardiovascular and Metabolic Diseases.

Lymphatic vessels are low-pressure, blind-ended tubular structures that play a crucial role in the maintenance of tissue fluid homeostasis, immune cell trafficking, and dietary lipid uptake and transport. Emerging research has indicated that the promotion of lymphatic vascular growth, remodeling, and function can reduce inflammation and diminish disease severity in several pathophysiologic conditions. In particular, recent groundbreaking studies have shown that lymphangiogenesis, which describes the formation of new lymphatic vessels from the existing lymphatic vasculature, can be beneficial for the alleviation and resolution of metabolic and cardiovascular diseases. Therefore, promoting lymphangiogenesis represents a promising therapeutic approach. This brief review summarizes the most recent findings related to the modulation of lymphatic function to treat metabolic and cardiovascular diseases such as obesity, myocardial infarction, atherosclerosis, and hypertension. We also discuss experimental and therapeutic approaches to enforce lymphatic growth and remodeling as well as efforts to define the molecular and cellular mechanisms underlying these processes.