Background: Quercetin-3-rutinoside is an inhibitor of protein disulfide isomerase, a potential target for antithrombotic therapy. Results: Quercetin-3-rutinoside induces a compact conformation in PDI and binds to PDI with an IC 50 of about 10 M. Conclusion: Quercetin-3-rutinoside interacts with the bЈx domain of protein disulfide isomerase with a 1:1 stoichiometry. Significance: The bЈx domain reverses the antithrombotic properties of quercetin-3-rutinoside in a thrombosis model in a live mouse.
• ERp5, like its family members PDI and ERp57, accumulates at sites of vessel wall injury.• Both platelets and endothelium secrete ERp5 on activation and contribute ERp5 necessary for thrombus formation in vivo.Protein disulfide isomerase (PDI) and endoplasmic reticulum protein 57 (ERp57) are emerging as important regulators of thrombus formation. Another thiol isomerase, endoplasmic reticulum protein 5 (ERp5), is involved in platelet activation. We show here the involvement of ERp5 in thrombus formation using the mouse laser-injury model of thrombosis and a specific antibody raised against recombinant ERp5. Anti-ERp5 antibody inhibited ERp5-dependent platelet and endothelial cell disulfide reductase activity in vitro. ERp5 release at the thrombus site was detected after infusion of Alexa Fluor 488-labeled anti-ERp5 antibody at 0.05 mg/g body weight, a dose that does not inhibit thrombus formation. Anti-ERp5 at 3 mg/g body weight inhibited laser-induced thrombus formation in vivo by causing a 70% decrease in the deposition of platelets and a 62% decrease in fibrin accumulation compared to infusion of control antibody (P < .01). ERp5 binds to b3 integrin with an equilibrium dissociation constant (K D ) of 21 mM, measured by surface plasmon resonance. The cysteine residues in the ERp5 active sites are not required for binding to b3 integrin. These results provide evidence for a novel role of ERp5 in thrombus formation, a function that may be mediated through its association with aIIbb3.
Diarrhoea and water-borne diseases are leading causes of mortality in developing countries. To understand the socio-cultural factors impacting on water safety, we documented knowledge, attitudes and practices of water handling and usage, sanitation and defecation in rural Tamilnadu, India, using questionnaires and focus group discussions, in a village divided into an upper caste Main village and a lower caste Harijan colony. Our survey showed that all households stored drinking water in wide-mouthed containers. The quantity of water supplied was less in the Harijan colony, than in the Main village (P<0.001). Residents did not associate unsafe water with diarrhoea, attributing it to 'heat', spicy food, ingesting hair, mud or mosquitoes. Among 97 households interviewed, 30 (30.9%) had toilets but only 25 (83.3%) used them. Seventy-two (74.2%) of respondents defecated in fields, and there was no stigma associated with this traditional practice. Hand washing with soap after defecation and before meals was common only in children under 15 years (86.4%). After adjusting for other factors, perception of quantity of water received (P<0.001), stated causation of diarrhoea (P=0.02) and low socio-economic status (P<0.001) were significantly different between the Main village and the Harijan colony. Traditional practices may pose a significant challenge to programmes aimed at toilet usage and better sanitation.
Key Points Hermansky-Pudlak syndrome exhibits impaired granule exocytosis and PDI secretion that contribute to its associated bleeding disorder. Endothelial cells deficient in HPS6 show defective secretion of granules, including Weibel-Palade bodies.
Summary OBJECTIVE To investigate the effects of nutritional supplementation on the outcome and nutritional status of south Indian patients with tuberculosis (TB) with and without human immunodeficiency virus (HIV) coinfection on anti-tuberculous therapy. METHOD Randomized controlled trial on the effect of a locally prepared cereal–lentil mixture providing 930 kcal and a multivitamin micronutrient supplement during anti-tuberculous therapy in 81 newly diagnosed TB alone and 22 TB–HIV-coinfected patients, among whom 51 received and 52 did not receive the supplement. The primary outcome evaluated at completion of TB therapy was outcome of TB treatment, as classified by the national programme. Secondary outcomes were body composition, compliance and condition on follow-up 1 year after cessation of TB therapy and supplementation. RESULTS There was no significant difference in TB outcomes at the end of treatment, but HIV–TB coinfected individuals had four times greater odds of poor outcome than those with TB alone. Among patients with TB, 1/35 (2.9%) supplemented and 5/42(12%) of those not supplemented had poor outcomes, while among TB–HIV-coinfected individuals, 4/13 (31%) supplemented and 3/7 (42.8%) non-supplemented patients had poor outcomes at the end of treatment, and the differences were more marked after 1 year of follow-up. Although there was some trend of benefit for both TB alone and TB–HIV coinfection, the results were not statistically significant at the end of TB treatment, possibly because of limited sample size. CONCLUSION Nutritional supplements in patients are a potentially feasible, low-cost intervention, which could impact patients with TB and TB–HIV. The public health importance of these diseases in resource-limited settings suggests the need for large, multi-centre randomized control trials on nutritional supplementation.
Essentials Nitric oxide synthesis controls protein disulfide isomerase (PDI) function. Nitric oxide (NO) modulation of PDI controls endothelial thrombogenicity. S-nitrosylated PDI inhibits platelet function and thrombosis. Nitric oxide maintains vascular quiescence in part through inhibition of PDI. SUMMARY: Background Protein disulfide isomerase (PDI) plays an essential role in thrombus formation, and PDI inhibition is being evaluated clinically as a novel anticoagulant strategy. However, little is known about the regulation of PDI in the vasculature. Thiols within the catalytic motif of PDI are essential for its role in thrombosis. These same thiols bind nitric oxide (NO), which is a potent regulator of vessel function. To determine whether regulation of PDI represents a mechanism by which NO controls vascular quiescence, we evaluated the effect of NO on PDI function in endothelial cells and platelets, and thrombus formation in vivo. Aim To assess the effect of S-nitrosylation on the regulation of PDI and other thiol isomerases in the vasculature. Methods and results The role of endogenous NO in PDI activity was evaluated by incubating endothelium with an NO scavenger, which resulted in exposure of free thiols, increased thiol isomerase activity, and enhanced thrombin generation on the cell membrane. Conversely, exposure of endothelium to NO carriers or elevation of endogenous NO levels by induction of NO synthesis resulted in S-nitrosylation of PDI and decreased surface thiol reductase activity. S-nitrosylation of platelet PDI inhibited its reductase activity, and S-nitrosylated PDI interfered with platelet aggregation, α-granule release, and thrombin generation on platelets. S-nitrosylated PDI also blocked laser-induced thrombus formation when infused into mice. S-nitrosylated ERp5 and ERp57 were found to have similar inhibitory activity. Conclusions These studies identify NO as a critical regulator of vascular PDI, and show that regulation of PDI function is an important mechanism by which NO maintains vascular quiescence.
Background Vascular remodeling associated with hemophilic arthropathy (HA) may contribute to bleed propagation, but the mechanisms remain poorly understood. Objectives To explore molecular mechanisms of HA and the effects of hemostasis correction on synovial vascular remodeling after joint injury in hypocoagulable mice. Methods Factor VIII (FVIII)‐deficient mice +/− FVIII treatment and hypocoagulable wild‐type mice (HypoBALB/c) were subjected to subpatellar puncture. HypoBALB/c mice were treated with warfarin and anti‐FVIII before injury, after which warfarin was continued for 2 weeks or reversed +/− continuous anti‐FVIII until harvest. Synovial vascularity was analyzed at baseline and 2 to 4 weeks post injury by histology, musculoskeletal ultrasound with power Doppler (microvascular flow), and Evans blue extravasation (vascular permeability). Synovial gene expression and systemic markers of vascular collagen turnover were studied in FVIII‐deficient mice by RNA sequencing and enzyme‐linked immunosorbent assay. Results Vascular changes occurred in FVIII‐deficient and HypoBALB/c mice after injury with minimal effect of hemostasis correction. Increased vascular permeability was only significant in FVIII‐deficient mice, who exhibited more pronounced vascular remodeling than HypoBALB/c mice despite similar bleed volumes. FVIII‐deficient mice exhibited a strong transcriptional response in synovium that was only partially affected by FVIII treatment and involved genes relating to angiogenesis and extracellular matrix remodeling, with vascular collagen turnover markers detected systemically. Conclusions Intact hemostasis at the time of hemarthrosis and during healing are both critical to prevent vascular remodeling, which appears worse with severe and prolonged FVIII deficiency. Unbiased RNA sequencing revealed potential targets for intervention and biomarker development to improve management of HA.
Molecularly targeted anti-cancer therapies have revolutionized cancer treatment by improving both quality of life and survival in cancer patients. However, many of these drugs are associated with cardiovascular toxicities that are sometimes dose-limiting. Moreover, the long-term cardiovascular consequences of these drugs, some of which are used chronically, are not yet known. Although the scope and mechanisms of the cardiac toxicities are better defined, the mechanisms for vascular toxicities are only beginning to be elucidated. This review summarizes what is known about the vascular adverse events associated with three classes of novel anti-cancer therapies: vascular endothelial growth factor (VEGF) inhibitors, breakpoint cluster-Abelson (BCR-ABL) kinase inhibitors used to treat chronic myelogenous leukaemia (CML) and immunomodulatory agents (IMiDs) used in myeloma therapeutics. Three of the best described vascular toxicities are reviewed including hypertension, increased risk of acute cardiovascular ischaemic events and arteriovenous thrombosis. The available data regarding the mechanism by which each therapy causes vascular complication are summarized. When data are limited, potential mechanisms are inferred from the known effects of inhibiting each target on vascular cell function and disease. Enhanced understanding of the molecular mechanisms of vascular side effects of targeted cancer therapy is necessary to effectively manage cancer patients and to design safer targeted cancer therapies for the future.
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