Antidepressant effect of carvedilol on streptozotocin-induced diabetic peripheral neuropathy mice by altering gut microbiota.

Rationale: Although diabetic peripheral neuropathic pain (DPNP) and depression have been recognized for many years, their co-morbidity relationship and effective treatment choices remain uncertain.

Objectives: To evaluate the antidepressant effect of carvedilol on streptozotocin-induced DPNP mice, and the relationship with gut microbiota.

Methods: The hyperalgesia and depressive behaviors of mice with comorbidity of DPNP and depression were confirmed by pain threshold of the mechanical sensitivity test (MST), immobility time of the tail suspension test (TST) and the forced swimming test (FST).

Discovery of a novel anti-osteoporotic agent from marine fungus-derived structurally diverse sirenins.

Thirteen new sirenin derivatives named eupenicisirenins C-O (1-13), along with a biosynthetically related known one (14), were isolated from the mangrove sediment-derived fungus Penicillium sp. SCSIO 41410. The structures, which possessed a rare cyclopropane moiety, were confirmed by extensive analyses of the spectroscopic data, quantum chemical calculations, and X-ray diffraction.

The volume regulated anion channel VRAC regulates NLRP3 inflammasome by modulating itaconate efflux and mitochondria function.

The NLRP3 inflammasome is a supramolecular complex that is linked to sterile and pathogen-dependent inflammation, and its excessive activation underlies many diseases. Ion flux disturbance and cell volume regulation are both reported to mediate NLRP3 inflammasome activation, but the underlying orchestrating signaling remains not fully elucidated. The volume-regulated anion channel (VRAC), formed by LRRC8 proteins, is an important constituent that controls cell volume by permeating chloride and organic osmolytes in response to cell swelling.

A novel TWIK2 channel inhibitor binds at the bottom of the selectivity filter and protects against LPS-induced experimental endotoxemia in vivo.

TWIK2 channel plays a critical role in NLRP3 inflammasome activation and mice deficient in TWIK2 channel are protected from sepsis and inflammatory lung injury. However, inhibitors of TWIK2 channel are currently in an early stage of development, and the molecular determinants underlying the chemical modulation of TWIK2 channel remain unexplored. In this study, we identified NPBA and the synthesized derivative NPBA-4 potently and selectively inhibited TWIK2 channel by using whole-cell patch clamp techniques.

TRPV4 channel is involved in HSV-2 infection in human vaginal epithelial cells through triggering Ca oscillation.

Herpes simplex virus (HSV) infection induces a rapid and transient increase in intracellular calcium concentration ([Ca]), which plays a critical role in facilitating viral entry. T-type calcium channel blockers and EGTA, a chelate of extracellular Ca, suppress HSV-2 infection. But the cellular mechanisms mediating HSV infection-activated Ca signaling have not been completely defined.

Novel DCPIB analogs as dual inhibitors of VRAC/TREK1 channels reduced cGAS-STING mediated interferon responses.

The enzyme cyclic GMP-AMP synthase (cGAS) senses cytosolic DNA and catalyzes the formation of 2'3'-cyclic-GMP-AMP (cGAMP), which in turn triggers interferon (IFN) production. Inappropriate activation of cGAS and production of cGAMP have been linked to a diversity of autoimmune diseases. The volume-regulated anion channels (VRACs) have been recently demonstrated to permeate cGAMP, thus making the channel essential for the activation of the cGAS-cGAMP-STING axis.

Pharmacological inhibition of K1.3 channel impairs TLR3/4 activation and type I IFN response and confers protection against Listeria monocytogenes infection.

Emerging data have demonstrated the critical roles of potassium efflux in the innate immune system. However, the role of potassium efflux in TLR3/4 activation and type I interferon (IFN) responses are not well elucidated. In the present study, we found potassium efflux is essential for TLR3/4 signaling, which mediates the expression of IFN and its inducible gene Cxcl10 and proinflammatory cytokine gene TNF-α.

Total Ginsenoside Extract from Panax ginseng Enhances Neural Stem Cell Proliferation and Neuronal Differentiation by Inactivating GSK-3β.

Objective: To study the effects of total ginsenosides (TG) extract from Panax ginseng on neural stem cell (NSC) proliferation and differentiation and their underlying mechanisms.

Methods: The migration of NSCs after treatment with various concentrations of TG extract (50, 100, or 200 µ g/mL) were monitored. The proliferation of NSCs was examined by a combination of cell counting kit-8 and neurosphere assays.

Discovery of novel verinurad analogs as dual inhibitors of URAT1 and GLUT9 with improved Druggability for the treatment of hyperuricemia.

Verinurad (RDEA3170) is a selective URAT1 inhibitor under investigation for the treatment of gout and hyperuricemia. In an effort to further improve the pharmacodynamics/pharmacokinetics of verinurad and to increase the structural diversity, we designed novel verinurad analogs by introducing a linker (e.g.

ML365 inhibits TWIK2 channel to block ATP-induced NLRP3 inflammasome.

Dysregulation of NLRP3 inflammasome results in uncontrolled inflammation, which participates in various chronic diseases. TWIK2 potassium channel mediates potassium efflux that has been reported to be an essential upstream mechanism for ATP-induced NLRP3 inflammasome activation. Thus, TWIK2 potassium channel could be a potential drug target for NLRP3-related inflammatory diseases.

Apigenin ameliorates hyperuricemic nephropathy by inhibiting URAT1 and GLUT9 and relieving renal fibrosis via the Wnt/β-catenin pathway.

Background: Hyperuricemia (HUA) is characterized by abnormal serum uric acid (UA) levels and demonstrated to be involved in renal injury leading to hyperuricemic nephropathy (HN). Apigenin (API), a flavonoid naturally present in tea, berries, fruits, and vegetables, exhibits various biological functions, such as antioxidant and anti-inflammatory activity.

Purpose: To investigate the effect of API treatment in HN and to reveal its underlying mechanisms.

CDER167, a dual inhibitor of URAT1 and GLUT9, is a novel and potent uricosuric candidate for the treatment of hyperuricemia.

Urate transporter 1 (URAT1) and glucose transporter 9 (GLUT9) are important targets for the development of uric acid-lowering drugs. We previously showed that the flexible linkers of URAT1 inhibitors could enhance their potency. In this study we designed and synthesized CDER167, a novel RDEA3710 analogue, by introducing a linker (methylene) between the naphthalene and pyridine rings to increase flexibility, and characterized its pharmacological and pharmacokinetics properties in vitro and in vivo.

Distinct Molecular Mechanisms Underlying Potassium Efflux for NLRP3 Inflammasome Activation.

The NLRP3 inflammasome is a core component of innate immunity, and dysregulation of NLRP3 inflammasome involves developing autoimmune, metabolic, and neurodegenerative diseases. Potassium efflux has been reported to be essential for NLRP3 inflammasome activation by structurally diverse pathogen-associated molecular patterns (PAMPs) or danger-associated molecular patterns (DAMPs). Thus, the molecular mechanisms underlying potassium efflux to activate NLRP3 inflammasome are under extensive investigation.

Structural Insights into the Atomistic Mechanisms of Uric Acid Recognition and Translocation of Human Urate Anion Transporter 1.

: Human urate transporter 1 (hURAT1) is the most pivotal therapeutic target for treating hyperuricemia. However, the molecular interactions between uric acid and URAT1 are still unknown due to lack of structural details. : In the present study, several methods (homology modeling, sequence alignment, docking, and mutagenesis) were used to explain the atomistic mechanisms of uric acid transport of hURAT1.

T-type calcium channels blockers inhibit HSV-2 infection at the late stage of genome replication.

Herpes simplex virus type 2 (HSV-2) is a highly contagious sexually transmitted virus. The increasing emergence of drug-resistant viral strains has highlighted the crucial need for the development of new anti-HSV-2 drugs with different mechanisms. Ion channels that govern a wide range of cellular functions represent attractive targets for viral manipulation.

Baicalein alleviates hyperuricemia by promoting uric acid excretion and inhibiting xanthine oxidase.

Background: Insufficient renal urate excretion and/or overproduction of uric acid (UA) are the dominant causes of hyperuricemia. Baicalein (BAL) is widely distributed in dietary plants and has extensive biological activities, including antioxidative, anti-inflammatory and antihypertensive activities.

Purpose: To investigate the anti-hyperuricemic effects of BAL and the underlying mechanisms in vitro and in vivo.

Inhibition of hyperpolarization-activated cyclic nucleotide-gated channels with natural flavonoid quercetin.

Quercetin is a natural flavonoid which has been reported to be analgesic in different animal models of pain. However, the mechanism underlying the pain-relieving effects is still unclear. Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels play critical roles in controlling pacemaker activity in cardiac and nervous systems, making the channel a new target for therapeutic exploration.

Characterizations of the Urate Transporter, GLUT9, and Its Potent Inhibitors by Patch-Clamp Technique.

Glucose transporter 9 (GLUT9), which transports urate in an electrogenic and voltage-dependent manner, plays an important role in the maintenance of normal blood uric acid/urate levels. In the present study, we established a cell model based on the single-electrode patch-clamp technique for characterization of GLUT9 and explored the inhibitory effects of benzobromarone (BM) and probenecid (PB) on urate-induced currents in mouse GLUT9a (mGLUT9a)-expressing HEK-293T cells. The results showed that uric acid, rather than glucose perfusion, led to a rapid and large outward current by mGLUT9a in dose-, voltage-, and pH-dependent manners.

Resveratrol promotes HSV-2 replication by increasing histone acetylation and activating NF-κB.

Resveratrol is a natural compound found in many plant species that has broad therapeutic benefits. Here, we investigated the effects of resveratrol on the replication of HSV-2. We found that resveratrol accelerated replication of HSV-2 and increased release of progeny virion.

Protective effects of S-carvedilol on doxorubicin-induced damages to human umbilical vein endothelial cells and rats.

Doxorubicin (DOX) is a highly active anticancer drug with severe cytotoxicity, which is strongly associated with oxidative stress. Carvedilol (CAR), used as its racemate with S-CAR and R-CAR (1:1), has been previously reported to ameliorate the DOX-induced cytotoxicity. However, the main contributor from CAR of its protective effects has not been clear.

DCPIB, an Inhibitor of Volume-Regulated Anion Channels, Distinctly Modulates K2P Channels.

K2P potassium channels stabilize the resting membrane potential in nearly all cells and have been implicated in several neuronal, cardiovascular, and immune diseases. DCPIB, a known specific and potent inhibitor of volume-regulated anion channels (VRAC), has been reported to activate TREK1 and TREK2 in astrocytes and in vitro recently. In the present study, we demonstrated DCPIB also voltage dependently activated TRAAK besides TREK1/TREK2, showing DCPIB activated all TREK subfamily members.

Identification and characterization of a series of novel HCN channel inhibitors.

Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels play a critical role in controlling pacemaker activity in both heart and nervous system. Developing HCN channel inhibitors has been proposed to be an important strategy for the treatment of pain, heart failure, arrhythmias, and epilepsy. One HCN channel inhibitor, ivabradine, has been clinically approved for the treatment of angina pectoris and heart failure.

Inhibition of hyperpolarization-activated cyclic nucleotide-gated channels by β-blocker carvedilol.

Background And Purpose: Carvedilol is a clinically effective β-blocker broadly used for treating congestive heart failure (CHF), and several clinical trials have demonstrated that it shows a favourable effect compared with other β-blockers in patients with CHF. The mechanism underlying this beneficial effect of carvedilol compared to other β-blockers is not clearly understood. In addition to β-blockers, inhibitors of hyperpolarization-activated cyclic nucleotide (HCN)-gated channels, which play a critical role in spontaneous rhythmic activity in the heart, have also been proposed to be suitable drugs for reducing heart rate and, therefore, beneficial for treating CHF.