Background/Aims: Stromal interacting molecule-1 (STIM1) aggregation and redistribution to plasma membrane to interact with Orai1 constitute the core mechanism of

/pdf/calsequestrin-1-regulates-store-operated-ca2-entry-by-4sjbezl7zt.pdf

Calsequestrin-1 Regulates Store-Operated Ca2+ Entry by Inhibiting STIM1 Aggregation.

Background/Aims: The aim of this study was to elucidate the usefulness of platelet indices, mean platelet volume (MPV), platelet distribution width (PDW), and platelet count in diagnosis and monitoring of varicocele. Methods: The current study included 525 patients and 379 healthy subjects from five eligible studies. We performed meta-analysis of MPV, PDW, and platelet count and mean differences in these platelet indices between healthy subjects and varicocele patients. Results: The pooled MPVs were 8.168 fL (95% confidence interval [CI] 7.589 to 8.747) and 8.801 fL (95% CI 8.028 to 9.574) in healthy subjects and varicocele patients, respectively. The pooled mean difference in MPV between healthy subjects and varicocele patients was 0.834 fL in case-control studies (95% CI 0.195 to 1.473, P = 0.011). In both healthy subjects and varicocele patients, low platelet count subgroups showed higher MPV than high platelet count subgroups. The mean difference in MPV was higher in low platelet count subgroup. There was no significant difference in PDW between healthy subjects and varicocele patients. Conclusion: Taken together, our data showed that platelet count was significantly lower in varicocele patients than in healthy subjects. Varicocele patients showed significantly higher MPV and lower platelet count than healthy subjects. MPV levels of patients differed according to platelet counts.

/pdf/mean-platelet-volume-platelet-distribution-width-and-4f1n0hhfa5.pdf

Mean Platelet Volume, Platelet Distribution Width, and Platelet Count in Varicocele: A Systematic Review and Meta-Analysis

Background/Aims: Platelets are essential mediators of hemostasis to avoid excessive blood loss. Cirrhosis and chronic liver diseases are characterized by alterations in hemostasis. Alterations in the secondary hemostasis have been well studied, while defects in primary hemostasis, especially the consequences of cholestatic liver disease on platelet function are not well defined. Methods: After bile duct ligation (BDL) platelet activation and thrombus formation were analyzed in mice. Results: BDL in mice had a moderate effect on platelet counts; however, intrinsic platelet activation was strongly reduced upon activation of the collagen receptor GPVI at early time points. 7 days after bile duct ligation, platelets displayed an almost complete loss of activation with reduced agonist-triggered release of alpha and dense granules and expression of integrin αIIbβ3 on the platelet surface. This activation defects resulted in strongly reduced thrombus formation under flow, reduced platelet adhesion to fibrinogen and bleeding complications in BDL mice as measured by tail bleeding experiments. Mechanistically, elevated nitric oxide and prostacyclin levels induced phosphorylation of Vasodilator-stimulated phosphoprotein (VASP), an established inhibitor of platelet activation. Furthermore increased tissue plasminogen activator in plasma of BDL mice led to enhanced plasmin levels that might be responsible for reduced glycoprotein expression of BDL platelets. Besides, high amounts of bile acids contribute to defective signal transduction as shown in platelets from mice fed with a cholic acid diet. Conclusions: Cholestatic liver disease induces multiple platelet activation defects and impairs thrombus formation responsible for bleeding complications at least in mice.

/pdf/defective-platelet-activation-and-bleeding-complications-56vrpkv4wo.pdf

Defective Platelet Activation and Bleeding Complications upon Cholestasis in Mice.

Enhanced transient receptor potential canonical subtype 3 (TRPC3) expression and TRPC3-mediated calcium influx in monocytes from hypertensive rats and patients are associated with increased blood pressure. Daily salt intake is closely related to hypertension, but the relationship between TRPC3 expression and salt intake has not yet been evaluated in hypertensive patients. Using reverse transcription-polymerase chain reaction, we studied the expression of TRPC3 and TRPC3-related store-operated calcium entry (SOCE) in peripheral blood mononuclear cells (PBMCs) from hypertensive and normotensive control subjects. Measurement of SOCE was performed using the fluorescent dye Fura-2 AM. Participants were divided into a low-salt group (<9 g) and a high-salt group (≥9 g) based on 24-h urinary sodium excretion. Increased TRPC3 mRNA expression levels and SOCE were observed in THP-1 cells after high-NaCl treatment. However, administration of the TRPC3-specific inhibitor Pyr3 significantly decreased the effect. Furthermore, the TRPC3 mRNA expression levels in PBMCs from high-salt intake patients with essential hypertension were significantly higher than those in low-salt intake patients compared with those in normotensive control subjects. We also observed significantly increased TRPC3-mediated SOCE in PBMCs from hypertensive subjects (but not from normotensive control subjects), with calcium concentration correlating with salt intake. More importantly, TRPC3 mRNA levels showed a significant correlation with salt intake and systolic blood pressure in patients with essential hypertension. This study demonstrated, for the first time, that increased TRPC3 mRNA levels are associated with elevated salt intake and systolic blood pressure in hypertensive patients.

High-salt intake increases TRPC3 expression and enhances TRPC3-mediated calcium influx and systolic blood pressure in hypertensive patients.

High salt intake is a known risk factor of cardiovascular diseases. Our recent study demonstrated that long-term high salt intake impairs transient receptor potential channel M5 (TRPM5)-mediated aversion to high salt concentrations, consequently promoting high salt intake and hypertension; however, it remains unknown whether TRPM5 activation ameliorates cardiovascular dysfunction. Herein we found that bitter melon extract (BME) and cucurbitacin E (CuE), a major compound in BME, lowered high salt-induced hypertension. Long-term BME intake significantly enhanced the aversion to high salt concentrations by upregulating TRPM5 expression and function, eventually decreasing excessive salt consumption in mice. Moreover, dietary BME ameliorated high salt-induced cardiovascular dysfunction and angiotensin II-induced hypertension in vivo. The mechanistic evidence demonstrated that dietary BME inhibited high salt-induced RhoA/Rho kinase pathway overactivation, leading to reduced phosphorylation levels of myosin light chain kinase and myosin phosphatase targeting subunit 1. Furthermore, CuE inhibited vasoconstriction by attenuating L-type Ca2+ channel-induced Ca2+ influx in vascular smooth muscle cells. To summarize, our findings indicate that dietary BME has a beneficial role in antagonizing excessive salt consumption and thus appears promising for the prevention of high salt-induced cardiovascular dysfunction.

Activation of the bitter taste sensor TRPM5 prevents high salt-induced cardiovascular dysfunction

Background/Aims: Platelet dysfunction plays an important role in thrombosis in diabetes with peripheral artery disease (PAD). Store-operated calcium entry (SOCE) and stromal interaction molecule 1 (STIM1) regulate platelet activity by modulating calcium influx. We hypothesized that enhanced SOCE in platelets is associated with diabetes with PAD. Methods: We studied the activity of platelets from healthy participants and from type 2 diabetic patients. Platelet calcium influx and protein expression of STIM1 and sarcoendoplasmic reticulum Ca2+-ATPase 3 (SERCA3) were investigated. Results: Compared with platelets from diabetic patients without PAD, platelets from diabetic patients with PAD exhibited significantly increased SOCE . Menthol administration completely inhibited calcium influx in platelets from diabetic patients without PAD, but this effect was blunted in those from diabetic patients with PAD. Furthermore, the increase in SOCE was correlated with the ankle brachial index (ABI) in diabetic patients. High glucose significantly up-regulated STIM1 and SERCA3 protein expression and induced the phosphorylation of phospholipase C (PLC) in platelets from healthy participants. This effect was attenuated in the presence of menthol or U73122, an inhibitor of PLC. Similarly, significant increases in STIM1 and SERCA3 protein expression were found in platelets from diabetic patients compared to those from healthy participants. Conclusion: Platelets from diabetic patients with PAD exhibited enhanced Store-operated calcium influx, which was associated with elevated STIM1/SERCA3 expression via a PLC-dependent pathway and was inhibited by menthol.

Enhanced Store-Operated Calcium Entry in Platelets is Associated with Peripheral Artery Disease in Type 2 Diabetes

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Enhanced Store-Operated Calcium Entry in Platelets is Associated with Peripheral Artery Disease in Type 2 Diabetes