Isaridin E Protects against Sepsis by Inhibiting Von Willebrand Factor-Induced Endothelial Hyperpermeability and Platelet-Endothelium Interaction.

Endothelial hyperpermeability is pivotal in sepsis-associated multi-organ dysfunction. Increased von Willebrand factor (vWF) plasma levels, stemming from activated platelets and endothelium injury during sepsis, can bind to integrin αvβ3, exacerbating endothelial permeability. Hence, targeting this pathway presents a potential therapeutic avenue for sepsis.

Increased intracellular Cl concentration mediates neutrophil extracellular traps formation in atherosclerotic cardiovascular diseases.

Neutrophil extracellular traps (NETs) play crucial roles in atherosclerotic cardiovascular diseases such as acute coronary syndrome (ACS). Our preliminary study shows that oxidized low-density lipoprotein (oxLDL)-induced NET formation is accompanied by an elevated intracellular Cl concentration ([Cl]) and reduced cystic fibrosis transmembrane conductance regulator (CFTR) expression in freshly isolated human blood neutrophils. Herein we investigated whether and how [Cl] regulated NET formation in vitro and in vivo.

CFTR Suppresses Neointimal Formation Through Attenuating Proliferation and Migration of Aortic Smooth Muscle Cells.

Cystic fibrosis transmembrane conductance regulator (CFTR) plays important roles in arterial functions and the fate of cells. To further understand its function in vascular remodeling, we examined whether CFTR directly regulates platelet-derived growth factor-BB (PDGF-BB)-stimulated vascular smooth muscle cells (VSMCs) proliferation and migration, as well as the balloon injury-induced neointimal formation. The CFTR adenoviral gene delivery was used to evaluate the effects of CFTR on neointimal formation in a rat model of carotid artery balloon injury.

Platelet CFTR inhibition enhances arterial thrombosis via increasing intracellular Cl concentration and activation of SGK1 signaling pathway.

Platelet hyperactivity is essential for thrombus formation in coronary artery diseases (CAD). Dysfunction of the cystic fibrosis transmembrane conductance regulator (CFTR) in patients with cystic fibrosis elevates intracellular Cl levels ([Cl]) and enhanced platelet hyperactivity. In this study, we explored whether alteration of [Cl] has a pathological role in regulating platelet hyperactivity and arterial thrombosis formation.

Antiplatelet and Antithrombotic Effects of Isaridin E Isolated from the Marine-Derived Fungus via Downregulating the PI3K/Akt Signaling Pathway.

Isaridin E, a cyclodepsipeptide isolated from the marine-derived fungus (syn. ) SYSU-MS7908, has been demonstrated to possess anti-inflammatory and insecticidal activities. Here, we first found that isaridin E concentration-dependently inhibited ADP-induced platelet aggregation, activation, and secretion in vitro, but did not affect collagen- or thrombin-induced platelet aggregation.

Xyloketal B: A marine compound with medicinal potential.

In recent decades, technological advantages have allowed scientists to isolate medicinal compounds from marine organisms that exhibit unique structure and bioactivity. The mangrove fungus Xylaria sp. from the South China Sea is rich in metabolites and produces a potent therapeutic compound, xyloketal B.

SGK1 mediates the hypotonic protective effect against HO-induced apoptosis of rat basilar artery smooth muscle cells by inhibiting the FOXO3a/Bim signaling pathway.

Serum- and glucocorticoid-inducible kinease-1 (SGK1) is a serine/threonine kinase regulated by hypotonic stimuli, which is involved in regulation of cell cycle and apoptosis. Our previous study shows that activation of volume-regulated Cl channels (VRCCs) protects rat basilar artery smooth muscle cells (BASMCs) against hydrogen peroxide (HO)-induced apoptosis. In the present study, we investigated whether SGK1 was involved in the protective effect of VRCCs in BASMCs.

Endophilin A2 regulates calcium-activated chloride channel activity via selective autophagy-mediated TMEM16A degradation.

TMEM16A Ca-activated chloride channel (CaCC) plays an essential role in vascular homeostasis. In this study we investigated the molecular mechanisms underlying downregulation of TMEM16A CaCC activity during hypertension. In cultured basilar artery smooth muscle cells (BASMCs) isolated from 2k2c renohypertesive rats, treatment with angiotensin II (0.

Smooth muscle-specific TMEM16A expression protects against angiotensin II-induced cerebrovascular remodeling via suppressing extracellular matrix deposition.

Cerebrovascular remodeling is the leading factor for stroke and characterized by increased extracellular matrix deposition, migration and proliferation of vascular smooth muscle cells, and inhibition of their apoptosis. TMEM16A is an important component of Ca-activated Cl channels. Previously, we showed that downregulation of TMEM16A in the basilar artery was negatively correlated with cerebrovascular remodeling during hypertension.

Clcn3 deficiency ameliorates high-fat diet-induced obesity and adipose tissue macrophage inflammation in mice.

Obesity induces accumulation of adipose tissue macrophages (ATMs) and ATM-driven inflammatory responses that promote the development of glucose and lipid metabolism disorders. ClC-3 chloride channel/antiporter, encoded by the Clcn3, is critical for some basic cellular functions. Our previous work has shown significant alleviation of type 2 diabetes in Clcn3 knockout (Clcn3) mice.

Role of Cl channels in primary brain tumour.

There is tight interplay between Ca and Cl flux that can influence brain tumour proliferation, migration and invasion. Glioma is the predominant malignant primary brain tumour, accounting for ˜80% of all cases. Voltage-gated Cl channel family (ClC) proteins and Cl intracellular channel (CLIC) proteins are drastically overexpressed in glioma, and are associated with enhanced cell proliferation, migration and invasion.

Gluconate suppresses seizure activity in developing brains by inhibiting CLC-3 chloride channels.

Neonatal seizures are different from adult seizures, and many antiepileptic drugs that are effective in adults often fail to treat neonates. Here, we report that gluconate inhibits neonatal seizure by inhibiting CLC-3 chloride channels. We detect a voltage-dependent outward rectifying Cl current mediated by CLC-3 Cl channels in early developing brains but not adult mouse brains.

Marine Compound Xyloketal B as a Potential Drug Development Target for Neuroprotection.

Xyloketal B is a natural compound isolated from the mangrove fungus, sp. in the South China Sea. In the past decade, studies have shown that xyloketal B exhibits anti-oxidative, anti-inflammatory, and anti-apoptotic abilities and may serve as a treatment for ischemic stroke.

Transmembrane member 16A participates in hydrogen peroxide-induced apoptosis by facilitating mitochondria-dependent pathway in vascular smooth muscle cells.

Background And Purpose: Transmembrane member 16A (TMEM16A), an intrinsic constituent of the Ca -activated Cl channel, is involved in vascular smooth muscle cell (VSMC) proliferation and hypertension-induced cerebrovascular remodelling. However, the functional significance of TMEM16A for apoptosis in basilar artery smooth muscle cells (BASMCs) remains elusive. Here, we investigated whether and how TMEM16A contributes to apoptosis in BASMCs.

Xyloketal B exerts antihypertensive effect in renovascular hypertensive rats via the NO-sGC-cGMP pathway and calcium signaling.

Xyloketal B (Xyl-B) is a novel marine compound isolated from mangrove fungus Xylaria sp. (No 2508). We previously showed that Xyl-B promoted endothelial NO release and protected against atherosclerosis through the Akt/eNOS pathway.

Blockade of the swelling-induced chloride current attenuates the mouse neonatal hypoxic-ischemic brain injury in vivo.

Activation of swelling-induced Cl current (I) during neonatal hypoxia-ischemia (HI) may induce brain damage. Hypoxic-ischemic brain injury causes chronic neurological morbidity in neonates as well as acute mortality. In this study, we investigated the role of I in hypoxic-ischemic brain injury using a selective blocker, 4-(2-butyl-6,7-dichloro-2-cyclopentylindan-1-on-5-yl) oxybutyric acid (DCPIB).

Ca/Calmodulin-Dependent Protein Kinase II γ-Dependent Serine727 Phosphorylation Is Required for TMEM16A Ca-Activated Cl Channel Regulation in Cerebrovascular Cells.

Background: TMEM16A is a critical component of Ca-activated chloride channels (CaCCs) and mediates basilar arterial smooth muscle cell (BASMC) proliferation in hypertensive cerebrovascular remodeling. CaMKII is a negative regulator of CaCC, and four CaMKII isoforms (α, β, γ and δ) are expressed in vasculature; however, it is unknown which and how CaMKII isoforms affect TMEM16A-associated CaCC and BASMC proliferation.

Methods and results: Patch clamp and small interfering RNA (siRNA) knockdown of different CaMKII isoforms revealed that only CaMKIIγ inhibited native Ca-activated chloride currents (I) in BASMCs.

WNK1 is required for proliferation induced by hypotonic challenge in rat vascular smooth muscle cells.

Hypotonic challenge evoked vascular cell proliferation through activation of volume-regulated Cl channel (VRCC), leading to a decrease in the intracellular Cl concentration ([Cl]). We hypothesize that the decrease in [Cl] may activate one or several Cl-sensitive kinases, resulting in a subsequent signaling cascade. In this study we demonstrated that WNK1, a Cl-sensitive kinase, was involved in VRCC-induced proliferative signaling pathway in A10 vascular smooth muscle cells in vitro.

Xyloketal B alleviates cerebral infarction and neurologic deficits in a mouse stroke model by suppressing the ROS/TLR4/NF-κB inflammatory signaling pathway.

Xyloketal B (Xyl-B) is a novel marine compound isolated from mangrove fungus Xylaria sp. We previously demonstrated that pretreatment with Xyl-B exerted neuroprotective effects and attenuated hypoxic-ischemic brain injury in neonatal mice. In the present study we investigated the neuroprotective effects of pre- and post-treatment with Xyl-B in adult mice using a transient middle cerebral artery occlusion (tMCAO) model, and explored the underlying mechanisms.

LNK deficiency aggravates palmitate-induced preadipocyte apoptosis.

LNK (SH2B3) is an intracellular adaptor protein that negatively regulates cellular proliferation or self-renewal of hematopoietic stem cells and some other progenitor cells. LNK is also recognized as a key regulator of insulin resistance and inflammatory responses in several tissues and organs. The function of LNK in adipose tissue is unknown.

TMEM16A Contributes to Endothelial Dysfunction by Facilitating Nox2 NADPH Oxidase-Derived Reactive Oxygen Species Generation in Hypertension.

Ca-activated Cl channels play a crucial role in various physiological processes. However, the role of TMEM16A in vascular endothelial dysfunction during hypertension is unclear. In this study, we investigated the specific involvement of TMEM16A in regulating endothelial function and blood pressure and the underlying mechanism.

Endophilin A2 Influences Volume-Regulated Chloride Current by Mediating ClC-3 Trafficking in Vascular Smooth Muscle Cells.

Background: Previous research has demonstrated that ClC-3 is responsible for volume-regulated Clcurrent (I) in vascular smooth muscle cells (VSMCs). However, it is still not clear whether and how ClC-3 is transported to cell membranes, resulting in alteration ofI.Methods and Results:Volume-regulated chloride current (I) was recorded by whole-cell patch clamp recording, and Western blotting and co-immunoprecipitation were performed to examine protein expression and protein-protein interaction.

Endophilin A2 protects H2O2-induced apoptosis by blockade of Bax translocation in rat basilar artery smooth muscle cells.

Background: Apoptosis plays a central role in maintaining the normal cell number and tissue homeostasis. Endophilins are a family of evolutionarily conserved proteins that have the critical role in endocytosis. Here, we determined whether endophilin A2 (EndoII) contributes to hydrogen peroxide (H2O2)-induced apoptosis in rat basilar artery smooth muscle cells (BASMCs) and the underlying mechanisms.