Vascular dysfunction is a common pathological basis for complications in individuals affected by diabetes. Previous studies have established that endothelial dysfunction is the primary contributor to vascular complications in type 2 diabetes (T2DM). However, the role of vascular smooth muscle cells (VSMCs) in vascular complications associated with T2DM is still not completely understood. The aim of this study is to explore the potential mechanisms associated with Ca2+ handling dysfunction and how this dysfunction contributes to diabetic vascular smooth muscle impairment. The results indicated that endothelium-dependent vasodilation was impaired in diabetic aortae, but endothelium-independent vasodilation was not altered. Various vasoconstrictors such as phenylephrine, U46619 and 5-HT could induce vasoconstriction in a concentration-dependent manner, such that the dose-response curve was parallel shifted to the right in diabetic aortae, compared to the control. Vasoconstrictions mediated by L-type calcium (Cavy. A role for the adhesion G-protein coupled receptor ADGRE2 (EMR2) in mechanosensing was revealed by the finding of a missense substitution (p.C492Y) associated with familial vibratory urticaria (VU). In these patients, friction of the skin induces mast cell hyper-degranulation through p.C492Y-ADGRE2, causing localized hives, flushing and hypotension. We have now characterized the responses and intracellular signals elicited by mechanical activation in human mast cells expressing p.C492Y-ADGRE2 and attached to dermatan sulfate, a ligand for ADGRE2. The presence of p.C492Y-ADGRE2 reduced the threshold to activation and increased the extent of degranulation along with the percentage of mast cells responding. Vibration caused PLC activation, transient increases in cytosolic calcium, and downstream activation of PI3K and ERK1/2 by Gβγ, Gαq/11 and Gαi/o-independent mechanisms. Degranulation induced by vibration was dependent on PLC pathways, including calcium, PKC and PI3K but not ERK1/2 pathways, along with pertussis toxin (PTX)-sensitive signals. In addition, mechanoactivation of mast cells stimulated the synthesis and release of PGD2, a previously unreported mediator in VU, and ERK1/2 activation was required for this response together with calcium, PKC and, to some extent, PI3K. Our studies thus identify critical molecular events initiated by mechanical forces and potential therapeutic targets for patients with VU. Histone post-translational modifications (PTMs) have been shown to be highly associated with inflammation response, suggesting a therapeutic significance of pharmacologically editing histone PTMs. Currently reported anti-inflammation small-molecules mainly target histone PTMs writers or erasers for methylation, phosphorylation, and acetylation. Although histone chaperones also appear to be involved in inflammation signaling cascades, whether small-molecules could target histone chaperones to show anti-inflammation effects has still been rarely discovered. In this study, natural product artone was found to show obvious inhibitory effects on microglia-mediated neuroinflammation by directly targeting ASF1a, which is a histone-remodeling chaperone. Mechanism study revealed that artone modulated histone H3 PTMs profile by down-regulating acetylation and trimethylation modification levels at sites K4, K9, K18 and K27. Artone-dependent regulations on PTMs further caused an effective inhibition on transcription factor NF-κB assembling to promoters of pro-inflammatory cytokine genes including Tnf-α, Il-6 and Rgs3, indicating a distinctive anti-neuroinflammation mechanism. Collectively, we reported artone as the first small-molecule targeting histone-remodeling chaperone ASF1a for anti-neuroinflammation. Moreover, these findings broaden our knowledge of histone chaperone as a druggable target protein for neuroinflammation inhibition, and open a new avenue to novel therapy strategy for inflammation-associated neurological disorders. Bimatoprost, latanoprost, and unoprostone are prostaglandin F2α analogs (PGAs) and are used to lower intraocular pressure. We investigated the free acid effects of these three prostaglandin analogs bimatoprost, latanoprost, and unoprostone on human matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMP) in the trabecular meshwork (TM) cells. this website Immunoblot results show that all three PGAs generally increased MMPs-1,9 and TIMPs-4. Additionally, bimatoprost and latanoprost both increased MMP-3 and TIMP-2, while unoprostone had an indeterminate effect on both. Zymography results show that all three PGAs except unoprostone increased intermediate MMP-1 activity while bimatoprost and latanoprost increased MMP-9 activity. Together, these data suggest that the balance between MMPs and TIMPs correlate to the relative intraocular pressure lowering effectiveness observed in clinical studies of these PGAs. How the absence of gravity affects the physiology of human beings is generating global research interest as space exploration, including missions aboard the International Space Station, continues to push boundaries. Here, we examined changes in retinal microcirculation and visual electrophysiology in mice suspended by their tails to simulate the cephalad movement of blood that occurs under microgravity conditions. Tail suspension was performed with a head-down tilt with a recommended angle of 30°. Mice in the control groups were similarly attached to a tether but could maintain a normal position. Morphologically, the 15-day tail-suspended mice showed retinal microvascular dilation, tortuosity, and a relatively long fluorescence retention; however, the average diameter of the major retinal vessels was not notably changed. In addition, optical coherence tomography showed their optic nerve head had an increased diameter. However, the mice could adapt to the change, with microcirculation and the optic nerve head t to the short-term change of retinal microcirculation, indicating new conditions that could be combined with, or could enhance, simulated microgravity for further studying the impact of short- or long-term outer space conditions on the retina.