Novel insights into the TRPV3mediated itch in atopic dermatitisTo the Editor:Chronic pruritus (itch) is a widespread and debilitating condition associated with dermatologic, systemic, neuropathic, or psychogenic disorders. The pathophysiologic mechanisms underpinning the transduction and potentiation of this refractory pruritus remain unclear. Current therapeutics are largely ineffective. 1 Thus, we have aimed to address this gap in knowledge by specifically focusing on clinically relevant intercellular communication in human skin cells, murine models of acute and chronic itch, and samples from human atopic dermatitis (AD) and psoriasis.In conditions of chronic dermatologic itch such as AD and psoriasis, certain members of the transient receptor potential (TRP) ion channel superfamily play an important role in the propagation of itch signaling. TRP vanilloid channel 3 (TRPV3) is a calcium-permeable cation channel that is abundantly expressed in epidermal keratinocytes. TRPV3 detects warm temperatures (>338C), is gated by a wide range of chemical stimuli, and plays an essential role in skin homeostasis and repair. Heatinduced activation of TRPV3 stimulates the release of a potent itch inducer, thymic stromal lymphopoietin (TSLP), from cultured murine keratinocytes. 2 In mice, intradermal injection of carvacrol, a TRPV3 agonist, elicits scratching behaviors. Gain-of-function mutations in TRPV3 have been confirmed in Olmsted syndrome, a rare pruritic genodermatosis in humans 3 and associated with AD-like inflammation in rodents. TRPV3 is upregulated in the skin of patients with AD. 2 Despite this, much remains unknown about the clinical relevance of TRPV3-linked pathways in human dermatitis and pruritus.Herein, real-time PCR was used to quantify TRPV3 expression in the skin of AD-like protease-activated receptor 2 (PAR2)overexpressing mouse (Grhl3PAR2 /1 mice). The level of TRPV3 transcripts was significantly increased in lesional skin of Grhl3PAR2 /1 mice versus in age-matched wild-type controls (Fig 1, A). Moreover, relative TRPV3 levels were significantly higher in lesional skin of Grhl3PAR2 /1 mice than in nonlesional Grhl3PAR2/ 1 mice (Fig 1, A), suggesting that TRPV3 expression is associated with the severity of dermatitis.Human skin samples were then examined to evaluate the clinical relevance of these murine findings. Specimens were collected from patients with AD (both lesional AD [LAD] and nonlesional AD [NLAD]), from patients with psoriasis (both lesional psoriasis [LPS] and nonlesional psoriasis [NLPS]), and from healthy controls (HC). All were analyzed by RNA sequencing, with data indicating the mean change in transcript level relative to HC. In LAD samples, TRPV3 was the only member of the TRPV family to be upregulated, with transcripts showing greater than a 2-fold increase over the HC levels (Fig 1, B). Similar to our murine model, this upregulation was absent in NLAD skin (Fig 1, C). Levels of TRPV3 transcripts were also increased in LPS skin samples versus in HC skin samples, but not in NLPS sample...

The orexin system is involved in arginine vasopressin (AVP) regulation, and its overactivation has been implicated in hypertension. However, its role in salt-sensitive hypertension (SSHTN) is unknown. Here, we tested the hypothesis that hyperactivity of the orexin system in the paraventricular nucleus (PVN) contributes to SSHTN via enhancing AVP signaling. Eight-week-old male Dahl salt-sensitive (Dahl S) and age- and sex-matched Sprague-Dawley (SD) rats were placed on a high-salt (HS; 8% NaCl) or normal-salt (NS; 0.4% NaCl) diet for 4 wk. HS intake did not alter mean arterial pressure (MAP), PVN mRNA levels of orexin receptor 1 (OX1R), or OX2R but slightly increased PVN AVP mRNA expression in SD rats. HS diet induced significant increases in MAP and PVN mRNA levels of OX1R, OX2R, and AVP in Dahl S rats. Intracerebroventricular infusion of orexin A (0.2 nmol) dramatically increased AVP mRNA levels and immunoreactivity in the PVN of SD rats. Incubation of cultured hypothalamus neurons from newborn SD rats with orexin A increased AVP mRNA expression, which was attenuated by OX1R blockade. In addition, increased cerebrospinal fluid Na concentration through intracerebroventricular infusion of NaCl solution (4 µmol) increased PVN OX1R and AVP mRNA levels and immunoreactivity in SD rats. Furthermore, bilateral PVN microinjection of the OX1R antagonist SB-408124 resulted in a greater reduction in MAP in HS intake (-16 ± 5 mmHg) compared with NS-fed (-4 ± 4 mmHg) anesthetized Dahl S rats. These results suggest that elevated PVN OX1R activation may contribute to SSHTN by enhancing AVP signaling. To our best knowledge, this study is the first to investigate the involvement of the orexin system in salt-sensitive hypertension. Our results suggest that the orexin system may contribute to the Dahl model of salt-sensitive hypertension by enhancing vasopressin signaling in the hypothalamic paraventricular nucleus.

Accumulating evidence indicates that inflammation is implicated in hypertension. However, the role of brain proinflammatory cytokines (PICs) in salt sensitive hypertension remains to be determined. Thus, the objective of this study was to test the hypothesis that high salt (HS) diet increases PICs expression in the paraventricular nucleus (PVN) and leads to PVN neuronal activation. Eight-week-old male Dahl salt sensitive (Dahl S) rats, and age and sex matched normal Sprague Dawley (SD) rats were divided into two groups and fed with either a HS (4% NaCl) or normal salt (NS, 0.4% NaCl) diet for 5 consecutive weeks. HS diet induced hypertension and significantly increased cerebrospinal fluid (CSF) sodium concentration ([Na+]) in Dahl S rats, but not in normal SD rats. In addition, HS diet intake triggered increases in mRNA levels and immunoreactivities of PVN PICs including TNF-α, IL-6, and IL-1β, as well as Fra1, a chronic marker of neuronal activation, in Dahl S rats, but not in SD rats. Next, we investigated whether this increase in the expression of PVN PICs and Fra1 was induced by increased CSF [Na+]. Adult male SD rats were intracerebroventricular (ICV) infused with 8 μl of either hypertonic salt (4 μmol NaCl), mannitol (8 μmol, as osmolarity control), or isotonic salt (0.9% NaCl as vehicle control). Three hours following the ICV infusion, rats were euthanized and their PVN PICs expression was measured. The results showed that central administration of hypertonic saline in SD rats significantly increased the expression of PICs including TNF-α, IL-6, and IL-1β, as well as neuronal activation marker Fra1, compared to isotonic NaCl controls and osmolarity controls. Finally, we tested whether the increase in PICs expression occurred in neurons. Incubation of hypothalamic neurons with 10 mM NaCl in a culture medium for 6 h elicited significant increases in TNF-α, IL-6, and Fra1 mRNA levels. These observations, coupled with the important role of PICs in modulating neuronal activity and stimulating vasopressin release, suggest that HS intake induces an inflammatory state in the PVN, which, may in turn, augments sympathetic nerve activity and vasopressin secretion, contributing to the development of salt sensitive hypertension.

Aim: Accumulating evidence suggests that orexin signalling is involved in the regulation of blood pressure and cardiovascular function. However, the underlying mechanisms are not clear. Here, we test the hypothesis that upregulated orexin A signalling in the paraventricular nucleus (PVN) increases sympathetic nerve activity (SNA) through stimulating expression of proinflammatory cytokines (PICs). Methods: In vivo sympathetic nerve recordings were performed to test the impact of PVN orexin signalling on sympathetic outflow in Sprague Dawley (SD) rats. Real-time PCR was carried out to assess effects of central administration of orexin A on PVN PICs expression in SD rats. To test whether orexin A-induced increases in PICs were exclusively mediated by orexin receptor 1 (OX1R), OX1R-expressing PC12 (PC12-OX1R) cells were incubated with different dose of orexin A, and then, PICs mRNA and immunoreactivity were measured. Results: Orexin A microinjection (25 pmol) into the PVN significantly increased splanchnic SNA (93.5%) and renal SNA (83.3%) in SD rats, and these increases were attenuated by OX1R antagonist SB408124. Intracerebroventricular injection of orexin A (0.2 nmol) into SD rats increased mRNA levels of PICs including IL-1-β (2.7-fold), IL-6 (1.7-fold) and TNF-α (1.5-fold), as well as Fra1 (1.6-fold) in the PVN. Orexin A treatment in PC12-OX1R cells resulted in a dose- and time-dependent increase in the expression of PICs and Fra1, a subunit of AP1 transcriptional factor. The increase in the PICs was blocked by AP1 blocker curcumin. Conclusion: Paraventricular nucleus orexin system activation is involved in SNA regulation maybe through triggering AP1-PICs pathway.

Nausea and vomiting of pregnancy (NVP) is a common condition that affects up to 70% of pregnant women. Hyperemesis gravidarum (HG) is considered the serious form of NVP, which is reported in 0.3–10.8% of pregnant women. NVP has a relatively benign course, but HG can be linked with some poor maternal, fetal, and offspring outcomes. The exact causes of NVP and HG are unknown, but various factors have been hypothesized to be associated with pathogenesis. With the advance of precision medicine and molecular biology, some genetic factors such as growth/differentiation factor 15 (GDF15) have become therapeutic targets. In our review, we summarize the historical hypotheses of the pathogenesis of NVP and HG including hormonal factors, Helicobacter pylori, gastrointestinal dysmotility, placenta-related factors, psychosocial factors, and new factors identified by genetics. We also highlight some approaches to the management of NVP and HG, including pharmacological treatment, complementary treatment, and some supporting treatments. Looking to the future, progress in understanding NVP and HG may reduce the adverse outcomes and improve the maternal quality of life during pregnancy.

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We report a novel methodology for fabricating large-area, multilayer, thin-film, high aspect ratio, 3D microfluidic structures with through-layer vias and open channels that can be bonded between hard substrates.

ICG forms aggregates in positively charged mesoporous silica, which show an enhanced type I photoreaction pathway.