Drug-Induced Mitochondrial Disruption in the Blood-Brain Barrier Cells: Overlooked Player in Drug Safety Evaluation.

The blood-brain barrier (BBB) is based on the unique pattern of the microvasculature of the central nervous system (CNS), which controls the transport of molecules between the CNS and the blood. The blood-brain barrier is mainly composed of endothelial cells, pericytes, and basement membrane, as well as the astrocytes and immune cells as perivascular macrophages and microglial cells. The dysfunction of this barrier can cause serious neuronal disorders due to the transport of hazardous molecules and immune cells to the CNS. Mitochondria plays a major role in cellular homeostasis in terms of health and disease. This review evaluated the published data about the effect of the drugs on the cells of BBB. Only seven articles were found that considered the effect of drugs on the barrier endothelial cells and mitochondria via different assays. Further studies are recommended to evaluate the impact of used medications on BBB cell bioenergetics. Also, the effect of the newly studied pharmaceutical agents on the BBB bioenergetics should be included within their safety profile studies.

Retinoic Acid Improves Vascular Endothelial Dysfunction by Inhibiting PI3K/AKT/YAP-Mediated Ferroptosis in Diabetes Mellitus.

BACKGROUND: Vascular endothelial dysfunction is the initial factor involved in cardiovascular injury in patients with diabetes. Retinoic acid is involved in improving vascular complications in patients with diabetes, but its protective mechanism is still unclear. This study aimed to evaluate the effect and mechanism of All-Trans Retinoic Acid (ATRA) on endothelial dysfunction induced by diabetes. METHODS: In the present study, streptozotocin (STZ)-induced diabetic rats and high glucose (HG)-induced human umbilical vein endothelial cells (HUVECs) were observed, and the effects of ATRA on HG-induced endothelial dysfunction and ferroptosis were evaluated. RESULTS: ATRA treatment improved impaired vasorelaxation in diabetic aortas in an endothelium-dependent manner, and this effect was accompanied by an increase in the NO concentration and eNOS expression. Ferroptosis, characterized by lipid peroxidation and iron overload induced by HG, was improved by ATRA administration, and a ferroptosis inhibitor (ferrostatin-1, Fer-1) improved endothelial function to a similar extent as ATRA. In addition, the inactivation of phosphoinositol-3-kinase (PI3K)/protein kinases B (AKT) and Yes-Associated Protein (YAP) nuclear localization induced by HG were reversed by ATRA administration. Vascular ring relaxation experiments showed that PI3K/AKT activation and YAP inhibition had similar effects on ferroptosis and endothelial function. However, the vasodilative effect of retinoic acid was affected by PI3K/AKT inhibition, and the inhibitory effects of ATRA on ferroptosis and the improvement of endothelial function were dependent on the retinoic acid receptor. CONCLUSION: ATRA could improve vascular endothelial dysfunction by inhibiting PI3K/AKT/YAP-mediated ferroptosis induced by HG, which provides a new idea for the treatment of vascular lesions in diabetes.

Corneal endothelial density and morphology in long-term soft contact lens users in Japan: a retrospective cross-sectional study of 17,732 eyes.

PURPOSE: There is a lack of long-term and large-scale studies on the adverse effects of soft contact lenses (SCLs) on the corneal endothelia of Asian populations. Here, we aimed to examine the effects of long-term SCL use on corneal endothelial density and morphology. MATERIALS AND METHODS: This retrospective study involved consecutive patients at the Miyata Eye Hospital (Miyazaki, Japan), who had used SCLs for more than 1 year. Patients with ophthalmological disorders without refractive errors were excluded. The period of SCL use, SCL type, corneal endothelial cell density (ECD), appearance rate of hexagonal cells (HEX), and coefficient of variation of cells (CV) were analyzed. RESULTS: In total, 17,732 eyes of 8866 patients were included in the analysis (age, 26.0 ± 8.8 years). The mean period of SCL use was 6.3 ± 5.4 years. Multivariate regression analysis revealed that ECD and HEX were significantly negatively correlated with the period of SCL use, age, and sex (p < 0.001 for all). The CV was significantly positively correlated with the period of use (p < 0.001), sex (p = 0.002), and age (p < 0.001). CONCLUSIONS: Corneal ECD, HEX, and CV were significantly associated with the period of SCL use in long-term users. It is essential to regularly check the corneal endothelium in patients with a history of long-term SCL use.

Matrix Stiffness of GelMA Hydrogels Regulates Lymphatic Endothelial Cells toward Enhanced Lymphangiogenesis.

Lymphatic vessel regeneration is crucial for various tissue engineering strategies, particularly in resolving inflammation and restoring tissue homeostasis. In our study, we focused on investigating how hydrogel matrix stiffness influences lymphatic endothelial cells (LECs) in promoting lymphatic vessel regeneration. Gelatin methacrylate (GelMA) was chosen as our biomaterial due to its versatility in tissue engineering and biofabrication. We fabricated GelMA hydrogels at concentrations of 5, 7.5, and 15% (w/v) with corresponding Young's modulus values of 1.55 kPa (soft matrix), 12.02 kPa (medium matrix), and 48.50 kPa (stiff matrix). Among these, the 7.5% GelMA hydrogel exhibited optimal stiffness for promoting lymphangiogenesis. LECs seeded either on the hydrogel surface or within spontaneously formed a more stable lymphatic capillary network compared with other GelMA formulations. Furthermore, we investigated the enhancement of lymphangiogenesis by incorporating VEGF-C into the GelMA hydrogel, leveraging the synergistic effects of mechanical and chemical cues. Our results underscored the critical role of FAK-phosphorylation in this process; treatment with an FAK-specific inhibitor prevented the formation of tube-like structures by LECs and attenuated the expression of lymphatic markers. Overall, our findings highlight how the mechanical and chemical cues provided by GelMA hydrogels can effectively regulate LEC behavior toward enhanced lymphangiogenesis via the integrin/FAK mechanotransduction pathway. This study proposes a promising strategy for developing hydrogel-based scaffolds or bioinks tailored to promote lymphatic vessel regeneration in therapeutic applications.

LncRNA-SNHG16 Protects Against Oxidative Stress-Induced Vascular Endothelial Cell Injury in Cardiovascular Diseases by Regulating the miR-23a-3p-GLS-Glutamine Metabolism Axis.

Cardiovascular diseases are disorders of the heart and vascular system that cause high mortality rates worldwide. Vascular endothelial cell (VEC) injury caused by oxidative stress (OS) is an important event in the development of various cardiovascular diseases, including ischemic heart disease. This study aimed to investigate the critical roles and molecular mechanisms of long non-coding RNA (lncRNA) SNHG16 in regulating vascular endothelial cell injury under oxidative stress. We demonstrated that SNHG16 was significantly downregulated and miRNA-23a-3p was notably induced in human vascular endothelial cells under OS. Overexpressing SNHG16 or silencing miR-23a-3p effectively mitigated the OS-induced VEC injury. Additionally, glutamine metabolism of VECs was suppressed under OS. SNHG16 protected the OS-suppressed glutamine metabolism, while miR-23a-3p functioned oppositely in VECs. Furthermore, SNHG16 downregulated miR-23a-3p by sponging miR-23a-3p, which direct targeted the glutamine metabolism enzyme, GLS. Finally, restoring miR-23a-3p in SNHG16-overexpressing VECs successfully reversed the protective effect of SNHG16 on vascular endothelial cell injury under OS. In summary, our results revealed the roles and molecular mechanisms of the SNHG16-mediated protection against VEC injury under OS by modulating the miR-23a-3p-GLS pathway.

[Pathogenesis of Fuchs endothelial corneal dystrophy, the fibrillar layer and individualized treatment]. / Pathogenese der Fuchs-Endotheldystrophie, die fibrilläre Schicht und individualisierte Therapie.

Fuchs endothelial corneal dystrophy (FECD) is a genetic and age-associated corneal disease characterized by an accelerated loss of corneal endothelial cells and an increased subendothelial deposition of extracellular matrix (ECM). Clinically, advanced disease leads to corneal edema with subsequent reduction in visual acuity. In the majority of patients with advanced FECD, a fibrillar layer (FL) appears on the posterior corneal surface. This FL is mostly localized in the inferotemporal corneal quadrant, marks areas with significantly reduced endothelial cell density and increased corneal thickness in the sense of edema and can be visualized and measured using Scheimpflug backscatter analysis due to increased backscatter. FECD is currently the most common indication for corneal transplantation worldwide, usually in the form of Descemet membrane endothelial keratoplasty (DMEK). New treatment approaches include variations of DMEK surgery such as hemi- or quarter DMEK with individualized and smaller grafts or Descemet membrane stripping only (DSO). In the future, clinical imaging of the FL as a particularly affected endothelial area could be important for FECD progression assessment and planning of surgical interventions. This article provides an overview of the current state of research on the clinical aspects, pathogenesis, fibrillar layer and individualized treatment of FECD.

Clinical research progress of fruquintinib in the treatment of malignant tumors.

Malignant tumors represent an important cause of mortality within the global population. Tumor angiogenesis, recognized as one of the key hallmarks of malignant tumors, is crucial for supplying essential nutrients and oxygen for tumor growth. Vascular endothelial growth factor (VEGF) and its receptor (VEGFR) are key drivers of tumor angiogenesis. Targeted therapeutic interventions not only effectively inhibit tumor growth by specifically blocking tumor angiogenesis but have also made breakthroughs in the treatment of malignant tumors. Fruquintinib, an anti-angiogenic small molecule drug developed independently in China, functions as a potent tyrosine kinase inhibitor with high selectivity. It effectively curtails tumor growth by binding to and inhibiting VEGFR-1, VEGFR-2, and VEGFR-3. Additionally, fruquintinib offers several advantages including minimal off-target toxicity, robust resistance profiles, and commendable efficacy. This agent can be used alone or in combination with other treatments. It has shown high effectiveness and survival benefits across various malignant tumors such as colorectal cancer, gastric cancer, non-small cell lung cancer, breast cancer, and other malignant tumors. Therefore, this article conducts a systematic review encompassing the mechanism of action, pharmacokinetics, clinical efficacy, and safety profile of fruquintinib. Through this review, we aimed to offer a reference for the clinical application and subsequent development of fruquintinib.

Cerebral small vessel injury in mice with damage to ACE2-expressing cerebral vascular endothelial cells and post COVID-19 patients.

INTRODUCTION: The angiotensin-converting enzyme 2 (ACE2), which is expressed in cerebral vascular endothelial cells (CVECs), has been currently identified as a functional receptor for SARS-CoV-2. METHODS: We specifically induced injury to ACE2-expressing CVECs in mice and evaluated the effects of such targeted damage through magnetic resonance imaging (MRI) and cognitive behavioral tests. In parallel, we recruited a single-center cohort of COVID-19 survivors and further assessed their brain microvascular injury based on cognition and emotional scales, cranial MRI scans, and blood proteomic measurements. RESULTS: Here, we show an array of pathological and behavioral alterations characteristic of cerebral small vessel disease (CSVD) in mice that targeted damage to ACE2-expressing CVECs, and COVID-19 survivors. These CSVD-like manifestations persist for at least 7 months post-recovery from COVID-19. DISCUSSION: Our findings suggest that SARS-CoV-2 may induce cerebral small vessel damage with persistent sequelae, underscoring the imperative for heightened clinical vigilance in mitigating or treating SARS-CoV-2-mediated cerebral endothelial injury throughout infection and convalescence. HIGHLIGHTS: Cerebral small vessel disease-associated changes were observed after targeted damage to angiotensin-converting enzyme 2-expressing cerebral vascular endothelial cells. SARS-CoV-2 may induce cerebral small vessel damage with persistent sequelae. Clinical vigilance is needed in preventing SARS-CoV-2-induced cerebral endothelial damage during infection and recovery.

Sinusoidal communication in chronic liver disease.

The liver sinusoid, mainly composed of liver sinusoidal endothelial cells, hepatic macrophages and hepatic stellate cells, shapes the hepatic vasculature and is key maintaining liver homeostasis and function. During chronic liver disease (CLD), the function of sinusoidal cells is impaired, being directly involved in the progression of liver fibrosis, cirrhosis, and main clinical complications including portal hypertension and hepatocellular carcinoma. In addition to their roles in liver diseases pathobiology, sinusoidal cells' paracrine communication or cross-talk is being studied as a mechanism of disease but also as a remarkable target for treatment. The aim of this review is to gather current knowledge of intercellular signalling in the hepatic sinusoid during the progression of liver disease. We summarise studies developed in pre-clinical models of CLD, specially emphasizing those pathways characterized in human-based clinically relevant models. Finally, we describe pharmacological treatments targeting sinusoidal communication as promising options to treat CLD and its clinical complications.

[EndoArt®: results in patients with glaucoma drainage devices]. / EndoArt®: Ergebnisse bei Patienten mit Glaukom-Drainage-Implantaten.

BACKGROUND: EndoArt® (Eye Yon Medical, Ness Ziona, Israel) is a novel artificial corneal inner layer transplant and an innovative treatment alternative for patients at high risk for graft failure after posterior lamellar corneal transplantation (EK). AIM OF THE STUDY: We present the initial results of the EndoArt® implantation in patients with glaucoma drainage devices (GDD). PATIENTS AND SURGICAL PROCEDURE: In this study 12 eyes with GDD were retrospectively evaluated. All had a high risk of transplant rejection in cases of EK (previous other glaucoma surgery in addition to GDD, n = 8, condition following Descemet membrane endothelial keratoplasty, DMEK, n = 9, uveitis, n = 2, or synechiae, n = 2). The EndoArt® was secured with a gas bubble and one to three holding sutures. The preoperative and postoperative best spectacle-corrected visual acuity (BSCVA) and central corneal thickness (CCT) were determined. The need for additional gas injections (rebubbling) was analyzed. RESULTS: Octafluoropropane (C3F8) 12% was used in nine patients and sulfur hexafluoride (SF6) 20% in three patients as anterior chamber tamponade to ensure adhesion of the EndoArt®. At least one rebubbling was necessary in four eyes. The preoperative BSCVA was 1.6 (±â€¯0.5) logMAR and significantly improved to 1.1 (±â€¯0.6) logMAR after 12 weeks (p = 0.028). The preoperative CCT was 719 µm ± 145.7, which significantly decreased to 622.4 µm ± 174.9 after six weeks (p = 0.004) and to 591.7 µm ± 190.8 after 12 weeks (p = 0.096). In one eye, the prosthesis was explanted due to a suspected fibrotic remodelling of the cornea following multiple previous DMEKs. DISCUSSION: EndoArt® led to a significant improvement in BSCVA and reduction in CCT; however, there was a high rebubbling rate in patients with GDD. In high-risk patients, the use of EndoArt® may be advantageous in avoiding graft failure after EK.

Comprehensive combined analysis of physician-initiated phase II and III clinical trials on a cultured human corneal endothelial cell product for treating bullous keratopathy.

To evaluate the efficacy and safety of a cultured human corneal endothelial cell (cHCEC) product in eyes with bullous keratopathy (BK). Combined analysis of multicenter phase II and III clinical trials. This analysis involved 15 BK eyes in the phase II trial and 12 BK eyes in the phase III trial that underwent cHCEC transplant therapy. Safety was assessed in all the cases. Efficacy was assessed in 17 cases with exclusion of the low- and medium-dose groups in the phase II trial. The primary endpoint was a corneal endothelial cell density of 1000 cells/mm2 or more at 24 weeks post-transplant, which was attained in 94.1% of the eyes (16 of 17), with a 95% CI of 71.3-99.9%. Additionally, 82.4% of the eyes (14 of 17) met the secondary endpoint of reduction in corneal thickness to less than 630 µm without corneal epithelial edema within the same time frame, with a 95% CI of 56.6-96.2%. The mean decrease in corneal thickness from baseline to 24 weeks post-transplant was -187.4 µm (95% CI, -240.2 µm to -134.5 µm). Furthermore, all the eyes exhibited improvement in best-corrected visual acuity from baseline to 24 weeks post-transplant (95% CI, 80.5-100.0%). By 24 weeks post-transplant, 88.9% of the patients (24 of 27) had experienced adverse events, which were mostly local, mild, and transient. The cHCEC product of this study reconstitutes the corneal endothelial layer with high cellular density and restores corneal thickness and improves visual acuity.

Evaluation of Foveal Vasculature by Optical Coherence Tomography Angiography after Pan-Retinal Photocoagulation versus Intravitreal Anti-VEGF Injections.

Purpose: This study aimed to compare macular vascular changes one and three months after treatment with either panretinal photocoagulation (PRP) or intravitreal bevacizumab (IVB). Methods: A total of 62 eyes with very severe non-proliferative diabetic retinopathy or early proliferative diabetic retinopathy without center-involved diabetic macular edema, were included in this retrospective study. Thirty-nine eyes were allocated to the PRP group, while 23 eyes were treated with IVB. Optical coherence tomography angiography (OCTA) was performed to measure foveal avascular zone (FAZ) characteristics as well as the densities of superficial and deep capillary plexuses (SCP and DCP). Results: In the IVB group, the FAZ area and perimeter expanded at month one but returned to baseline level after three months. In the PRP group, however, the FAZ area and perimeter were rather steady. Changes in the FAZ area were significantly different between the treatment groups at month one (P = 0.02), but not at month three (P = 0.31). There was no significant difference in the change in FAZ circularity index between the two groups at each time point (P = 0.55 and P = 0.31). Similarly, changes in SCP density were not statistically significant between the two groups at both time points (all Ps > 0.05). A comparison of the two treatment arms based on the mean change in DCP density revealed a significant difference at month one, but not at month three (P = 0.01 and P = 0.49, respectively). Conclusion: Although bevacizumab and PRP have different short-term macular vascular responses, both therapies have the ability to normalize or stabilize vascular measures over time.

Cytomegalovirus results in poor graft function via bone marrow-derived endothelial progenitor cells.

Introduction: Poor graft function (PGF), characterized by myelosuppression, represents a significant challenge following allogeneic hematopoietic stem cell transplantation (allo-HSCT) with human cytomegalovirus (HCMV) being established as a risk factor for PGF. However, the underlying mechanism remains unclear. Bone marrow endothelial progenitor cells (BM-EPCs) play an important role in supporting hematopoiesis and their dysfunction contributes to PGF development. We aim to explore the effects of CMV on BM-EPCs and its underlying mechanism. Methods: We investigated the compromised functionality of EPCs derived from individuals diagnosed with HCMV viremia accompanied by PGF, as well as after infected by HCMV AD 169 strain in vitro, characterized by decreased cell proliferation, tube formation, migration and hematopoietic support, and increased apoptosis and secretion of TGF-ß1. Results: We demonstrated that HCMV-induced TGF-ß1 secretion by BM-EPCs played a dominant role in hematopoiesis suppression in vitro experiment. Moreover, HCMV down-regulates Vitamin D receptor (VDR) and subsequently activates p38 MAPK pathway to promote TGF-ß1 secretion by BM-EPCs. Discussion: HCMV could infect BM-EPCs and lead to their dysfunction. The secretion of TGF-ß1 by BM-EPCs is enhanced by CMV through the activation of p38 MAPK via a VDR-dependent mechanism, ultimately leading to compromised support for hematopoietic progenitors by BM EPCs, which May significantly contribute to the pathogenesis of PGF following allo-HSCT and provide innovative therapeutic strategies targeting PGF.

A biphasic drug-releasing microneedle with ROS scavenging and angiogenesis for the treatment of diabetic ulcers.

Diabetic ulcers are one of the common complications in diabetic patients. Delayed wound healing is associated with persistent pro-inflammatory M1 polarization, reduced angiogenesis and increased reactive oxygen species (ROS) in the microenvironment. Wound healing consists of multiple phases and therefore requires treatment tailored to each phase. In this study, a biphasic drug-releasing microneedle (MN) was fabricated to achieve early ROS scavenging and late accelerated angiogenesis to promote wound healing. Vascular endothelial growth factor (VEGF) was first encapsulated in methacryloylated sulfonated chitosan (SCSMA) microspheres (V@MP), and then V@MP was loaded into hyaluronic acid (HA) microneedles along with cerium dioxide nanoparticles (CONPs). Rapid dissolution of HA rapidly releases the CONPs to clear ROS, whereas the V@MP stays in the wound. SCSMA slow degradation prolongs the release of VEGF, thereby promoting angiogenesis. In vitro and in vivo studies have shown that this biphasic drug-releasing smart microneedle improves cell proliferation and migration, effectively scavenges ROS, promotes angiogenesis and tissue regeneration, and synergistically promotes M2 macrophage polarization. It provides a new delivery mode for nano-enzymes and growth factors that could be multifunctional and synergistic in the treatment of diabetic ulcers. STATEMENT OF SIGNIFICANCE: In our study, we present a microneedle (V@MP/C@MN) that can release drugs biphasically, which showed good repair ability in diabetic ulcer model. Large amounts of CONPs were rapidly released to alleviate oxidative stress during the inflammation of the wound, and V@MP stayed in the wound for a long period of time to release VEGF and promote angiogenesis in the late stage of wound healing. The results indicated that V@MP/C@MN could promote cell proliferation and migration, effectively scavenge ROS, promote angiogenesis and tissue regeneration, and synergistically promote M2 macrophage polarization, which could play a multifunctional and synergistic role in the treatment of diabetic ulcers.

The neo-potential therapeutic strategy in preeclampsia: Downregulated miR-26a-2-3p motivates endothelial cell injury by targeting 15-LOX-1.

Preeclampsia (PE) poses a life-threatening risk for both mothers and babies, and its onset and progression are linked to endothelial injury. The enzyme 15-lipoxygenase-1 (15-LOX-1), critical in arachidonic acid metabolism, is implicated in various diseases, yet its specific role and precise mechanisms in PE remain largely unknown. In this study, we found that 15-LOX-1 and its main metabolite, 15-HETE, were significantly increased in both the placenta and serum of PE patients. This increase was accompanied by elevated levels of endothelial injury markers, including intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1). A positive correlation between 15-LOX-1 and those markers in the placenta. In Alox15-/- mice, Alox15 deficiency reduced endothelial cell injury in PE-like mice induced by L-NAME. In vitro studies showed that hypoxia-induced upregulation of 15-LOX-1 reduced the cell viability, migration, and angiogenesis of human umbilical vein endothelial cells (HUVECs), while increasing apoptosis and inflammatory cell adhesion. Mechanistically, the p38 MAPK pathway was identified as a downstream target of 15-LOX-1. Knocking down 15-LOX-1 or inhibiting p38 MAPK activation improved endothelial cell injury in hypoxia-treated HUVECs. Furthermore, downregulation of miR-26a-2-3p was found to correlate negatively and colocalize with 15-LOX-1 upregulation in the placenta of PE patients. Luciferase reporter assays further confirmed that miR-26a-2-3p directly bind to the 3'UTR of 15-LOX-1, targeting its expression. Moreover, miR-26a-2-3p agomir ameliorated the PE-like phenotype in mice through the 15-LOX-1/p38 MAPK axis, improving endothelial dysfunction. Therefore, our study provides novel insights into the pathogenesis of PE and highlight modulating the miR-26a-2-3p/15-LOX-1/p38 MAPK axis as a potential therapeutic target for PE.

Noncaloric monosaccharides induce excessive sprouting angiogenesis in zebrafish via foxo1a-marcksl1a signal.

Artificially sweetened beverages containing noncaloric monosaccharides were suggested as healthier alternatives to sugar-sweetened beverages. Nevertheless, the potential detrimental effects of these noncaloric monosaccharides on blood vessel function remain inadequately understood. We have established a zebrafish model that exhibits significant excessive angiogenesis induced by high glucose, resembling the hyperangiogenic characteristics observed in proliferative diabetic retinopathy (PDR). Utilizing this model, we observed that glucose and noncaloric monosaccharides could induce excessive formation of blood vessels, especially intersegmental vessels (ISVs). The excessively branched vessels were observed to be formed by ectopic activation of quiescent endothelial cells (ECs) into tip cells. Single-cell transcriptomic sequencing analysis of the ECs in the embryos exposed to high glucose revealed an augmented ratio of capillary ECs, proliferating ECs, and a series of upregulated proangiogenic genes. Further analysis and experiments validated that reduced foxo1a mediated the excessive angiogenesis induced by monosaccharides via upregulating the expression of marcksl1a. This study has provided new evidence showing the negative effects of noncaloric monosaccharides on the vascular system and the underlying mechanisms.

Consuming too much sugar can damage blood vessels and contribute to diseases like diabetes and heart disease. Artificial sweeteners have been suggested as a healthier alternative, and are now included in many products like sodas and baked goods. However, some studies have suggested that people who consume large amounts of artificial sweeteners also have an increased risk of cardiovascular disease. Others suggest individuals may also experience spikes in blood sugar levels similar to those observed in people with diabetes. Yet few studies have examined how artificial sweeteners affect the network of vessels that transport blood and other substances around the body. To investigate this question, Wang, Zhao, Xu, et al. studied zebrafish embryos which had been exposed to sugar and a type of artificial sweetener known as non-caloric monosaccharides. Various imaging tools revealed that high levels of sugar caused the embryos to produce more new blood vessels via a process called angiogenesis. This excessive growth of blood vessels has previously been linked to diabetic complications, including cardiovascular disease. Wang, Zhao, Xu, et al. found that zebrafish embryos exposed to several different non-caloric monosaccharides developed similar blood vessel problems. All the sweeteners tested caused immature cells lining the blood vessels to develop into active tip cells that promote angiogenesis. This led to more new blood vessels forming that branch off already existing veins and arteries. These findings suggest that artificial sweeteners may cause the same kind of damage to blood vessels as sugar. This may explain why people who consume a lot of artificial sweeteners are at risk of developing heart disease and high blood sugar levels. Future studies could help scientists learn more about how genetics or other factors affect the health impact of sugars and artificial sweeteners. This may lead to a greater understanding of the long-term health effects of artificially sweetened foods.

Identifying specific functional roles for senescence across cell types.

Cellular senescence plays critical roles in aging, regeneration, and disease; yet, the ability to discern its contributions across various cell types to these biological processes remains limited. In this study, we generated an in vivo genetic toolbox consisting of three p16Ink4a-related intersectional genetic systems, enabling pulse-chase tracing (Sn-pTracer), Cre-based tracing and ablation (Sn-cTracer), and gene manipulation combined with tracing (Sn-gTracer) of defined p16Ink4a+ cell types. Using liver injury and repair as an example, we found that macrophages and endothelial cells (ECs) represent distinct senescent cell populations with different fates and functions during liver fibrosis and repair. Notably, clearance of p16Ink4a+ macrophages significantly mitigates hepatocellular damage, whereas eliminating p16Ink4a+ ECs aggravates liver injury. Additionally, targeted reprogramming of p16Ink4a+ ECs through Kdr overexpression markedly reduces liver fibrosis. This study illuminates the functional diversity of p16Ink4a+ cells and offers insights for developing cell-type-specific senolytic therapies in the future.

Characterizing Vascular and Hormonal Changes in Women Across the Lifespan: A Cross-Sectional Analysis.

INTRODUCTION: Vascular dysfunction, marked by lower endothelial function and increased aortic stiffness, are non-traditional risk factors that precede the development of CVD. However, the age at which these changes in vascular function occur in women and the degree to which reproductive hormones mediate these changes has not been characterized. METHODS: Women free from major disease were enrolled across the adult lifespan (aged 18-70, n=140). Endothelial function was assessed as flow-mediated dilation (FMD) of the brachial artery during reactive hyperemia using duplex ultrasound and expressed as percent dilation. Aortic stiffness was measured by carotid-femoral pulse wave velocity (cfPWV). Blood samples were obtained to quantify reproductive hormone concentration. Regression models determined age-related breakpoints and mediating factors between age and vascular outcomes. RESULTS: FMD declined with age with a breakpoint and steeper decline occurring at age 47. Thereafter, age was independently associated with lower FMD (B=-0.13, P<0.001). cfPWV was relatively stable until a breakpoint at age 48, and age was independently associated with higher cfPWV thereafter (B=0.10, P<0.001). Path analysis revealed that the association between age and FMD was partially mediated by follicle stimulating hormone (abind=0.051, P=0.01) and progesterone (abind=0.513, P<0.001) but not estradiol (abind=-0.004, P=0.08). No mediation was present for cfPWV. CONCLUSIONS: Age was associated with endothelial dysfunction and aortic stiffness in women beginning at 47 and 48 years, respectively, 3-4 years prior to the average age of menopause. The association between age and endothelial dysfunction was explained in part by elevations in follicle stimulating hormone and progesterone, but not declining estradiol.

Angiogenic properties and intercellular communication of differentiated porcine endothelial cells in vascular therapy.

Endothelial cell dysfunction can lead to various vascular diseases. Blood flow disorder is a common symptom of vascular diseases. Regenerative angiogenesis, which involves transplanting vascular cells or stem cells into the body to shape new vasculature, can be a good therapeutic strategy. However, there are several limitations to using autologous cells from the patients themselves. We sought to investigate the new vascular cells that can play a role in the formation of angiogenesis in vivo using stem cells from alternative animals suitable for cellular therapy. Porcine is an optimal animal model for xenotransplantation owing to its physiological similarity to humans. We used differentiated porcine endothelial cells (pECs) as a therapeutic strategy to restore vessel function. Differentiated pECs formed vessel-like structures in mice, distinguishing them from stem cells. MMPs activity and migration assays indicated that differentiated pECs possessed angiogenic potential. Tube formation and 3D spheroid sprouting assays further confirmed the angiogenic phenotype of the differentiated pECs. Immunofluorescence and immunoprecipitation analyses revealed claudin-mediated tight junctions and connexin 43-mediated gap junctions between human ECs and differentiated pECs. Additionally, the movement of small RNA from human ECs to differentiated pECs was observed under co-culture conditions. Our findings demonstrated the in vivo viability and angiogenetic potential of differentiated pECs and highlighted the potential for intercellular communication between human and porcine ECs. These results suggest that transplanted cells in vascular regeneration completed after cell therapy have the potential to achieve intercellular communication within the body.

Role of endothelial dysfunction in sleep-disordered breathing in egyptian children with sickle cell disease.

BACKGROUND: Endothelial dysfunction is an integral pathophysiologic mechanism in sickle cell disease (SCD), and can lead to many complications. Sleep-disordered breathing (SDB) is a SCD complication with diverse incidence and pathophysiology. This study aimed to determine the prevalence of SDB in children with SCD and to assess its relation to endothelial dysfunction. METHODS: Sixty children with SCD and 60 healthy controls were enrolled. The levels of TNF-α, IL-6, and IL-17A were evaluated in the entire cohort using enzyme-linked immunosorbent assay (ELISA) kits. Polysomnography (PSG) was performed for all SCD patients after completion of the Pediatric Sleep Questionnaire (PSQ). RESULTS: TNF-α, IL-6, and IL-17A levels were significantly greater in children with SCD than in controls (p-values < 0.001, < 0.001, and 0.006, respectively). The PSQ revealed symptoms suggestive of SDB in 50 children with SCD (83.3%), and PSG revealed obstructive sleep apnea (OSA) in 44 children with SCD (73.3%); 22 patients had mild OSA, and 22 had moderate-to-severe OSA according to the apnea-hypopnea index (AHI). TNF-α was significantly greater in SCD children who reported heavy or loud breathing, trouble breathing or struggle to breathe, and difficulty waking up in the morning (p-values = 0.002, 0.002, and 0.031, respectively). The IL-6 levels were significantly greater in SCD children who stopped growing normally (p-value = 0.002). The levels of IL-6 and IL-17A were significantly greater in SCD children with morning headaches (p-values = 0.007 and 0.004, respectively). CONCLUSION: Children with SCD showed a high prevalence of SDB with significantly elevated levels of markers of endothelial function, highlighting the interplay of SDB and endothelial dysfunction in SCD.