300 research outputs found

    Propofol inhibits prokaryotic voltage-gated Na+ channels by promoting activation-coupled inactivation

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    Propofol is widely used in the clinic for the induction and maintenance of general anesthesia. As with most general anesthetics, however, our understanding of its mechanism of action remains incomplete. Local and general anesthetics largely inhibit voltage-gated Na+ channels (Navs) by inducing an apparent stabilization of the inactivated state, associated in some instances with pore block. To determine the biophysical and molecular basis of propofol action in Navs, we investigated NaChBac and NavMs, two prokaryotic Navs with distinct voltage dependencies and gating kinetics, by whole-cell patch clamp electrophysiology in the absence and presence of propofol at clinically relevant concentrations (2-10 μM). In both Navs, propofol induced a hyperpolarizing shift of the pre-pulse inactivation curve without any significant effects on recovery from inactivation at strongly hyperpolarized voltages, demonstrating that propofol does not stabilize the inactivated state. Moreover, there was no evidence of fast or slow pore block by propofol in a non-inactivating NaChBac mutant (T220A). Propofol also induced hyperpolarizing shifts of the conductance-voltage relationships with negligible effects on the time constants of deactivation at hyperpolarized voltages, indicating that propofol does not stabilize the open state. Instead, propofol decreases the time constants of macroscopic activation and inactivation. Adopting a kinetic scheme of Nav gating that assumes preferential closed-state recovery from inactivation, a 1.7-fold acceleration of the rate constant of activation and a 1.4-fold acceleration of the rate constant of inactivation were sufficient to reproduce experimental observations with computer simulations. In addition, molecular dynamics simulations and molecular docking suggest that propofol binding involves interactions with gating machinery in the S4-S5 linker and external pore regions. Our findings show that propofol is primarily a positive gating modulator of prokaryotic Navs, which ultimately inhibits the channels by promoting activation-coupled inactivation. © 2018 Yang et al

    Nanostructured Carbon Nitride for Continuous-Flow Trifluoromethylation of (Hetero)arenes

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    Efficient catalytic methods for the trifluoromethy-lation of (hetero)arenes are of particular importance in organic and pharmaceutical manufacturing. However, many existing protocols rely on toxic reagents and expensive or sterically hindered homogeneous catalysts. One promising alternative to conduct this transformation involves the use of carbon nitride, a non-toxic photocatalyst prepared from inexpensive precursors. Nonetheless, there is still little understanding regarding the interplay between physicochemical features of this photocatalyst and the correspond-ing effects on the reaction rate. In this work, we elucidate the role of carbon nitride nanostructuring on the catalytic performance, understanding the effect of surface area and band gap tuning via metal insertion. Our findings provide new insights into the structure-function relationships of the catalyst, which we exploit to design a continuous-flow process that maximizes catalyst-light interaction, facilitates catalyst reusability, and enables intensified reaction scale-up. This is particularly significant given that photocatalyzed batch protocols often face challenges during industrial exploitation. Finally, we extrapolate the rapid and simplified continuous-flow method to the synthesis of a variety of functionalized heteroaromatics, which have numerous applications in the pharmaceutical and fine chemical industries

    Estrogens in males: what have we learned in the last 10 years?

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    This review focuses on the role of estrogen in men, mainly in male reproduction. The continuing increase in data obtained, and recent discoveries in this area will enable a better understanding of male physiology; these, in turn, will have important clinical implications

    Propofol inhibits the voltage-gated sodium channel NaChBac at multiple sites.

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    Voltage-gated sodium (NaV) channels are important targets of general anesthetics, including the intravenous anesthetic propofol. Electrophysiology studies on the prokaryotic NaV channel NaChBac have demonstrated that propofol promotes channel activation and accelerates activation-coupled inactivation, but the molecular mechanisms of these effects are unclear. Here, guided by computational docking and molecular dynamics simulations, we predict several propofol-binding sites in NaChBac. We then strategically place small fluorinated probes at these putative binding sites and experimentally quantify the interaction strengths with a fluorinated propofol analogue, 4-fluoropropofol. In vitro and in vivo measurements show that 4-fluoropropofol and propofol have similar effects on NaChBac function and nearly identical anesthetizing effects on tadpole mobility. Using quantitative analysis by 19F-NMR saturation transfer difference spectroscopy, we reveal strong intermolecular cross-relaxation rate constants between 4-fluoropropofol and four different regions of NaChBac, including the activation gate and selectivity filter in the pore, the voltage sensing domain, and the S4-S5 linker. Unlike volatile anesthetics, 4-fluoropropofol does not bind to the extracellular interface of the pore domain. Collectively, our results show that propofol inhibits NaChBac at multiple sites, likely with distinct modes of action. This study provides a molecular basis for understanding the net inhibitory action of propofol on NaV channels. © 2018 Wang et al

    Could chronic Vardenafil administration influence the cardiovascular risk in men with type 2 diabetes mellitus?

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    Introduction Appropriate algorithms for the prediction of cardiovascular risk are strongly suggested in clinical practice, although still controversial. In type 2 diabetes mellitus (T2DM), the benefi- cial effect of phosphodiesterase (PDE)-5 inhibitors is demonstrated on endothelial function but not on the estimation of cardiovascular risk. Aim To study whether the chronic Vardenafil administration to men with T2DM influences vari- ables correlated with the predicted long-term cardiovascular risk calculated by different vali- dated algorithms. Methods Per-protocol analysis of a longitudinal, prospective, randomized, placebo-controlled, dou- ble-blind, investigator-started, clinical trial. 54 male patients affected by T2DM were assigned to study (26patients) and control-group (28patients), respectively. The study included a treatment phase (24weeks) (Vardenafil/placebo 10mg twice-daily) and a follow- up phase (24weeks). Three time points were considered: baseline(V0), end of treatment (V1) and end of the study(V2). Parameters evaluated: endothelial health-related parameters and cardiovascular risk, assessed by calculating the Framingham (coronary hart disease [CHD], myocardial infarction [MI], stroke and cardiovascular disease [CVD]), ASSIGN and CUORE equations. Results Predicted cardiovascular risk at ten years resulted different using the three algorithms cho- sen, without differences between study and control groups and among visits. IL-6 was directly related to CHD, CVD and CUORE scores at V1 and with MI and STROKE at V2. Similarly, hs-CRP was directly related to CHD, MI, STROKE and CUORE only at V1 in the study group. Testosterone serum levels were inversely related to CHD and MI at V1 in study group. Discussion The predicted cardiovascular risk is different depending on the algorithm chosen. Despite no predictive risk reduction after six months of treatment, a possible effect of Vardenafil could be hypothesized through its action on inflammation markers reduction and through restoration of normal testosterone levels

    Paraneoplastic pemphigus: insight into the autoimmune pathogenesis, clinical features and therapy

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    Paraneoplastic pemphigus is a rare autoimmune skin disease that is always associated with a neoplasm. Usually, oral, skin, and mucosal lesions are the earliest manifestations shown by paraneoplastic pemphigus patients. The pathogenesis of paraneoplastic pemphigus is not yet completely understood, although some immunological aspects have been recently clarified. Because of its rarity, several diagnostic criteria have been proposed. Besides, several diagnostic procedures have been used for the diagnosis, including indirect immunofluorescence, direct immunofluorescence, and ELISA. We reviewed the most recent literature, searching on PubMed "paraneoplastic pemphigus". We included also papers in French, German, and Spanish. We found 613 papers for "paraneoplastic pemphigus". Among them, 169 were review papers. Because of its varying clinical features, paraneoplastic pemphigus still represents a challenge for clinicians. Furthermore, diagnosis and management of paraneoplastic pemphigus requires close collaboration between physicians, including dermatologist, oncologist, and otorhinolaryngologist.Paraneoplastic pemphigus is a rare autoimmune skin disease that is always associated with a neoplasm. Usually, oral, skin, and mucosal lesions are the earliest manifestations shown by paraneoplastic pemphigus patients. The pathogenesis of paraneoplastic pemphigus is not yet completely understood, although some immunological aspects have been recently clarified. Because of its rarity, several diagnostic criteria have been proposed. Besides, several diagnostic procedures have been used for the diagnosis, including indirect immunofluorescence, direct immunofluorescence, and ELISA. We reviewed the most recent literature, searching on PubMed “paraneoplastic pemphigus”. We included also papers in French, German, and Spanish. We found 613 papers for “paraneoplastic pemphigus”. Among them, 169 were review papers. Because of its varying clinical features, paraneoplastic pemphigus still represents a challenge for clinicians. Furthermore, diagnosis and management of paraneoplastic pemphigus requires close collaboration between physicians, including dermatologist, oncologist, and otorhinolaryngologist

    The 24th organ: the aorta. The main concept of new EACTS/STS Guidelines

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