Abstract Osteoporosis is a widespread condition that induces an inflammatory microenvironment, limiting the effectiveness of conventional therapies and presenting significant challenges for bone defect repair. To address these issues, a high‐strength gelatin hydrogel scaffold loaded with roxadustat is developed, specifically designed to remodel the inflammatory microenvironment and enhance osteoporotic bone regeneration. By incorporating minimal methacrylated hyaluronic acid (HAMA) into an o ‐nitrobenzyl functionalized gelatin (GelNB) matrix, a gelatin hydrogel with a fracture strength of 10 MPa is achieved, providing exceptional structural stability and enabling precise scaffold fabrication through digital light processing (DLP) 3D printing. Validated through cell experiments and animal studies, the hydrogel scaffold supports cell adhesion and migration, offers excellent tissue compatibility, and is fully degradable, meeting the requirements of a therapeutic scaffold. Including roxadustat further enhances the scaffold's functionality by regulating the inflammatory microenvironment via hypoxia‐inducible factor‐1α (HIF‐1α) signaling, significantly improving bone defect repair in osteoporotic models. This drug‐loaded scaffold effectively addresses inflammation‐induced limitations and enhances the regenerative capacity of the affected area, paving the way for improved therapeutic outcomes in osteoporotic bone repair.
Background: Atherosclerosis is the chronic inflammation of the vascular wall initiated by endothelial cell dysfunction. SIRT3 is a mitochondrial protein deacetylase with a better defined role in regulating mitochondrial metabolism. There are also some indirect evidence suggesting its function in protecting endothelial cell function. However, there lacks information on the effect of SIRT3 in the endothelium in vivo during atherogenesis and also the underlying mechanisms. Methods: Endothelial cell (EC) selective knockout of Sirt3 was achieved by crossing the Sirt3 floxP/floxP mice (kindly provided by Prof Johan Auwerx) with Cdh5 Cre/+ mice (from Jackson Laboratory) to generate Sirt3f/f (or Sirt3 EC-WT ) as wild type, and Sirt3f/f; Cdh5Cre/+ (or Sirt3 EC-KO ) as endothelium-selective SIRT3 knockout mice. Mice were injected with adeno-associated virus to overexpress PCSK9 for decreasing hepatic LDLR and fed with high cholesterol diet to induce hypercholesterolemic atherosclerosis mouse model. Vascular reactivity was measured in aorta by wire myograph (DMT). Human umbilical vein endothelial cells (HUVECs) were used for in vitro experiments. Results: Endothelium-selective knockout of Sirt3 enhanced plaque formation, with increased levels of infiltrating macrophages, endothelial adhesion molecules in the plaque area, and expression of inflammatory cytokines. Sirt3 EC-KO mice also had reduced plasma level of L-arginine. Further analysis in HUVECs showed that silencing of SIRT3 caused hyperacetylation of mitochondrial proteins, including ASS1 (Argininosuccinate Synthase 1), responsible for recycling L-arginine. L-arginine supplementation reduced plaque size, vascular inflammation in Sirt3 EC-KO mice. L-arginine also attenuated endothelial activation in HUVECs, and improved endothelium-dependent vasodilation in the aorta from Sirt3 EC-KO mice. Conclusion: Our data demonstrated the important role of SIRT3 in protecting endothelial function and identified ASS1-dependent metabolism of arginine regulated by SIRT3 as an underlying mechanism (supported by GRF14109519).
Aims: The role of endothelium-derived contracting factors (EDCFs) in regulating renovascular function is yet to be elucidated in renovascular hypertension (RH). The current study investigated whether oxidative stress-dependent cyclooxygenase (COX)-2-derived prostaglandin F2α (PGF2α) impairs endothelial function in renal arteries of renovascular hypertensive rats (RHR). Results: Renal hypertension was induced in rats by renal artery stenosis of both kidneys using the 2-kidney 2-clip model. Acute treatment with reactive oxygen species (ROS) scavengers, COX-2 inhibitors, and thromboxane-prostanoid receptor antagonists, but not COX-1 inhibitors, improved endothelium-dependent relaxations and eliminated endothelium-dependent contractions in RHR renal arteries. Five weeks of treatment with celecoxib or tempol reduced blood pressure, increased renal blood flow, and restored endothelial function in RHRs. Increased ROS production in RHR arteries was inhibited by ROS scavengers, but unaffected by COX-2 inhibitors; whereas increased PGF2α release was reduced by both ROS scavengers and COX-2 inhibitors. ROS also induced COX-2-dependent contraction in RHR renal arteries, which was accompanied by the release of COX-2-derived PGF2α. Further, chronic tempol treatment reduced COX-2 and BMP4 upregulation, p38MAPK phosphorylation, and the nitrotyrosine level in RHR renal arteries. Conclusion: These findings demonstrate the functional importance of oxidative stress, which serves as an initiator of increased COX-2 activity, and that COX-2-derived PGF2α plays an important role in mediating endothelial dysfunction in RH. Innovation: The current study, thus, suggests that drugs targeting oxidative stress-dependent COX-2-derived PGF2α may be useful in the prevention and management of RH. Antioxid. Redox Signal. 16, 363–373.
Background: Brugada syndrome (BrS) is a cardiac ion channelopathy that predisposes affected individuals to sudden cardiac death (SCD). Type 1 BrS is thought to take a more malignant clinical course than non-type 1 BrS. We hypothesized that the degrees of abnormal repolarization and conduction are greater in type 1 subjects and these differences can be detected by electrocardiography (ECG). Methods: Electrocardiographic data from spontaneous type 1 and non-type 1 BrS patients were analyzed. ECG parameters were measured from leads V1 to V3. Values were expressed as median [lower quartile-upper quartile] and compared using Kruskal-Wallis ANOVA. Results: Compared to non-type 1 BrS patients (n = 29), patients with spontaneous type 1 patterns (n = 22) showed similar (P > 0.05) heart rate (73 [64-77] vs. 68 [62-80] bpm), QRS duration (136 [124-161] vs. 127 [117-144] ms), uncorrected QT (418 [393-443] vs. 402 [386-424] ms) and corrected QT intervals (457 [414-474] vs. 430 [417-457] ms), JTpeak intervals (174 [144-183] vs. 174 [150-188] ms), Tpeak- Tend intervals (101 [93-120] vs. 99 [90-105] ms), Tpeak- Tend/QT ratios (0.25 [0.23-0.27] vs. 0.24 [0.22-0.27]), Tpeak- Tend/QRS (0.77 [0.62-0.87] vs. 0.77 [0.69-0.86]), Tpeak- Tend/(QRS × QT) (0.00074 [0.00034-0.00096] vs. 0.00073 [0.00048-0.00012] ms-1), index of Cardiac Electrophysiological Balance (iCEB, QT/QRS, marker of wavelength: 3.14 [2.56-3.35] vs. 3.21 [2.85-3.46]) and corrected iCEB (QTc/QRS: 3.25 [2.91-3.73] vs. 3.49 [2.99-3.78]). Higher QRS dispersion was seen in type 1 subjects (QRSd: 34 [24-66] vs. 24 [12-34] ms) but QT dispersion (QTd: 48 [39-71] vs. 43 [22-94] ms), QTc dispersion (QTcd: 52 [41-79] vs. 46 [23-104] ms), JTpeak dispersion (44 [23-62] vs. 45 [30-62] ms), Tpeak- Tend dispersion (28 [15-34] vs. 29 [22-53] ms) or Tpeak- Tend/QT dispersion (0.06 [0.03-0.08] vs. 0.08 [0.04-0.12]) did not differ between the two groups. Type 1 subjects showed higher (QRSd × Tpeak- Tend)/QRS (25 [19-44] vs. 19 [9-30] ms) but similar iCEB dispersion (0.83 [0.49-1.14] vs. 0.61 [0.34-0.92]) and iCEBc dispersion (0.93 [0.51-1.15] vs. 0.65 [0.39-0.96]). Conclusion: Higher levels of dispersion in conduction and repolarization are found in type 1 than non-type 1 BrS patients, potentially explaining the higher incidence of ventricular arrhythmias in the former group.
Abstract Aims To compare the effects of metformin and sulphonylurea on new-onset dementia, anxiety disorder and depression, and all-cause mortality in patients with type 2 diabetes mellitus. Methods This is a retrospective population-based cohort study of type 2 diabetes mellitus patients exposed to either metformin or sulphonylureas attending the Hospital Authority of Hong Kong between 1 st and 31 st December 2009. The follow-up was until 31 st December 2019. The primary outcome was a new diagnosis of dementia, and anxiety disorder/depression. Propensity score matching (1:1 ratio) between metformin and sulphonylurea users based on demographics, CAIDE score, CHA-DS-VASc score, Charlson comorbidity index, past comorbidities, medications, and total cholesterol was performed. Cox regression was used to identify significant risk predictors. Cause-specific and subdistribution hazard models were also used. Results A total of 89,711 patients (46% men, mean age: 67 years old [SD: 12]) followed-up for 1,579 days (SD: 650). Metformin users were at a lower risk of dementia (before: 0.78 [0.72, 0.84], P-value < 0.0001; after: 0.88 [0.80, 0.97], P-value = 0.0074), anxiety disorder and depression (before: 0.77 [0.69, 0.86], P-value < 0.0001; after: 0.71 [0.61, 0.82], P-value < 0.0001), and all-cause mortality (before: 0.69 [0.68, 0.71], P-value < 0.0001; after: 0.83 [0.80, 0.85], P-value < 0.0001). These associations remained significant in the competing risk models. Conclusion Metformin use is associated with lower risks of dementia, new-onset anxiety disorder and depression, and all-cause mortality, compared to sulphonylurea use. The protective effects of metformin and possible use in drug repurposing for indications beyond diabetes warrant further investigation. Highlights Patients with type 2 diabetes have an increased risk of cognitive, anxiety or depressive problems Metformin use was associated with lower risks of new diagnosis of dementia, anxiety disorder and depression Patients who developed dementia had lower levels of albumin, alanine transaminase and HbA1c compared to those who developed anxiety disorder and depression Appropriate glycemic control and maintenance of normal liver function are important in slowing cognitive decline in type 2 diabetes mellitus
This article was migrated. The article was marked as recommended. Recent expansions in the development and availability of three-dimensional printing (3Dp) have led to the uptake of this valuable and effective technology within the modern context of medical education. It is proposed that 3Dp is entirely appropriate for the creation of anatomical models for purposes of teaching and training due to the ability of this technology to produce accurate 3D physical representations based on a processed data set acquired from sources including magnetic resonance imaging (MRI) and computed tomography (CT). When investigating the currently available educational research with respect to 3Dp, it is important that the best evidence supporting the practical and theoretical benefits of this technology in teaching and training can be identified, while any obstacles to the effective implementation of 3Dp can also be determined. Here, literature describing recent primary research with respect to the capability and utility of 3Dp in anatomy and surgery have been explored in a narrative review. The impact on resources of implementing this technology within medical education have also been investigated. In order to emphasise wider applications in medicine, the role of 3Dp in medical practice and research have also been examined. To identify recent literature appropriate for this review published up to March 2017, suitable search terms were determined and applied using PubMed and results were judged against an established checklist. The research identified was then allocated with respect to the agreed topic areas of anatomy education, surgical training, medical usage and medical research. A student partnership approach was utilised for this review and the focus of the work was driven by undergraduate students in collaboration with anatomy and medical educators. Preliminary findings from this narrative review support the implementation of 3Dp in anatomy education and surgical training as a supplement to traditional learning approaches.
BACKGROUND AND PURPOSE HMG‐CoA reductase inhibitors, statins, with lipid‐reducing properties combat against atherosclerosis and diabetes. The favourable modulation of endothelial function may play a significant role in this effect. The present study aimed to investigate the cellular mechanisms responsible for the therapeutic benefits of rosuvastatin in ameliorating diabetes‐associated endothelial dysfunction. EXPERIMENTAL APPROACH Twelve‐week‐old db/db diabetic mice were treated with rosuvastatin at 20 mg·kg −1 ·day −1 p.o.for 6 weeks. Isometric force was measured in isolated aortae and renal arteries. Protein expressions including angiotensin II type 1 receptor (AT 1 R), NOX4, p22 phox , p67 phox , Rac‐1, nitrotyrosine, phospho‐ERK1/2 and phospho‐p38 were determined by Western blotting, while reactive oxygen species (ROS) accumulation in the vascular wall was evaluated by dihydroethidium fluorescence and lucigenin assay. KEY RESULTS Rosuvastatin treatment of db/db mice reversed the impaired ACh‐induced endothelium‐dependent dilatations in both renal arteries and aortae and prevented the exaggerated contractions to angiotensin II and phenylephrine in db/db mouse renal arteries and aortae. Rosuvastatin reduced the elevated expressions of AT 1 R, p22 phox and p67 phox , NOX4, Rac1, nitrotyrosine and phosphorylation of ERK1/2 and p38 MAPK and inhibited ROS production in aortae from db/db mice. CONCLUSIONS AND IMPLICATIONS The vasoprotective effects of rosuvastatin are attributed to an increase in NO bioavailability, which is probably achieved by its inhibition of ROS production from the AT 1 R‐NAD(P)H oxidase cascade.
For directed differentiation of embryonic stem cells (ESCs) to endothelial cells (ECs), we need more information regarding the genes that are activated or suppressed, and their temporal order of activation, during EC specification. Accordingly, we sought to use heterokaryons (the stable fusion product of two different cell types) to identify critical determinants of EC differentiation. The premise is that cytoplasmic factors in the EC that maintain its phenotype will act on the ESC nucleus in the heterokaryon to reprogram it toward EC lineage. Using murine specific probes, or RNAseq, we will identify key genes that are modulated during early EC determination. Accordingly, we employed murine ESC labelled by transduction with retroviruses encoding GFP, and human ECs labelled with CellTracker Red, and induced heterokaryon formation using sendai virus-enveloped protein. Multi-nucleated heterokaryons were generated, which contained punctate murine nuclei and diffusely staining human nuclei. The dual-stained heterokaryons were sorted from the unfused cells and homokaryons by FACS. The extent and timing of differentiation of the murine ESCs within the heterokaryons were examined by probing for EC specific genes (KDR, CD144, vWF and CD31) and ES pluripotency markers (Nanog, Sox2 and Oct4) using murine specific primers. Intriguingly, heterokaryons appear to recapitulate ontogeny, in that early mesodermal genes (eg. KDR) are upregulated in murine ESC at 6h, whereas more EC-specific genes are not upregulated until later (eg. vWF at 24h). Data from RNAseq studies further confirmed the major transcriptional factors and regulators and identified some novel factors for endothelial differentiation. These novel genes will be confirmed using gain- and loss- of function studies of ESCs undergoing differentiation. These studies shall provide new knowledge regarding the hierarchy of genes regulating differentiation to the EC lineage and thus provide insight into vascular development, and ultimately new therapeutic avenues for vascular regeneration.
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