Inhibition of TTX-S Na currents by a novel blocker QLS-278 for antinociception.

Genetic loss-of-function mutations of the Na1.7 channel, abundantly expressed in peripheral nociceptive neurons, cause congenital insensitivity to pain in humans, indicating that selective inhibition of the channel may lead to potential therapy for pain disorders. In this study, we investigated a novel compound, 5-chloro-N-(cyclopropylsulfonyl)-2-fluoro-4-(2-(8-(furan-2-ylmethyl)-8-azaspiro [4.

Fusarolides A-C, Three Pyran-Macrolide Hybrids from a Marine Derived Fungal G102 as 1 Inhibitor and Phytopathogenic Fungicides.

Three undescribed 20-membered macrolides, fusarolides A-C (-), with relatively rare pyran-macrolide structures and complex chiral centers, were isolated from a marine derived fungal G102. Their chemical structures and stereoconfigurations were well elaborated. Compound promoted cholesterol efflux from Huh-7 cells in a concentration-dependent manner by inhibiting 1 (ASGR1), which was identified as a new therapeutic target in hypercholesterolemia in liver.

UCF-101 ameliorates traumatic brain injury by promoting microglia M2 polarization via AMPK/NF-κB pathways in LPS-induced BV2 cells.

Traumatic brain injury (TBI) is a common neurosurgical emergency. As a macrophage in brain, microglia involves in secondary TBI injury. UCF-101, an Omi/HtrA2 inhibitor, protects against neurological disorders.

Identification of a new retigabine derivative with improved photostability for selective activation of neuronal Kv7 channels and antiseizure activity.

Objective: Pharmacological activation of neuronal Kv7 channels by the antiepileptic drug retigabine (RTG; ezogabine) has been proven effective in treating partial epilepsy. However, RTG was withdrawn from the market due to the toxicity caused by its phenazinium dimer metabolites, leading to peripheral skin discoloration and retinal abnormalities. To address the undesirable metabolic properties of RTG and prevent the formation of phenazinium dimers, we made chemical modifications to RTG, resulting in a new RTG derivative, 1025c, N,N'-{4-[(4-fluorobenzyl) (prop-2-yn-1-yl)amino]-1,2-phenylene}bis(3,3-dimethylbutanamide).

A novel dual serotonin transporter and M-channel inhibitor D01 for antidepression and cognitive improvement.

Cognitive dysfunction is a core symptom common in psychiatric disorders including depression that is primarily managed by antidepressants lacking efficacy in improving cognition. In this study, we report a novel dual serotonin transporter and voltage-gated potassium Kv7/KCNQ/M-channel inhibitor D01 (a 2-methyl-3-aryloxy-3-heteroarylpropylamines derivative) that exhibits both anti-depression effects and improvements in cognition. D01 inhibits serotonin transporters ( = 30.

Allosteric Activation of α7 Nicotinic Acetylcholine Receptors by Novel 2-Arylamino-thiazole-5-carboxylic Acid Amide Derivatives for the Improvement of Cognitive Deficits in Mice.

Enhancing α7 nAChR function serves as a therapeutic strategy for cognitive disorders. Here, we report the synthesis and evaluation of 2-arylamino-thiazole-5-carboxylic acid amide derivatives - that as positive allosteric modulators (PAMs) activate human α7 nAChR current expressed in ooctyes. Among the 4-amino derivatives, a representative atypical type I PAM exhibits potent activation of α7 current with an EC of 1.

Three Rounds of Stability-Guided Optimization and Systematical Evaluation of Oncolytic Peptide LTX-315.

Oncolytic peptides represent promising novel candidates for anticancer treatments. In our efforts to develop oncolytic peptides possessing both high protease stability and durable anticancer efficiency, three rounds of optimization were conducted on the first-in-class oncolytic peptide LTX-315. The robust synthetic method, in vitro and in vivo anticancer activity, and anticancer mechanism were investigated.

Inhibition of Cardiac Kv4.3/KChIP2 Channels by Sulfonylurea Drug Gliquidone.

The Kv4.3 channel features fast N-type inactivation and also undergoes a slow C-type inactivation. The gain-of-function mutations of Kv4.

Selective inhibition of overactive warmth-sensitive Ca-permeable TRPV3 channels by antispasmodic agent flopropione for alleviation of skin inflammation.

The temperature-sensitive Ca-permeable TRPV3 ion channel is robustly expressed in the skin keratinocytes, and its gain-of-function mutations are involved in the pathology of skin lesions. Here, we report the identification of an antispasmodic agent flopropione that alleviates skin inflammation by selective inhibition of TRPV3. In whole-cell patch clamp recordings, flopropione selectively inhibits macroscopic TRPV3 currents in a concentration-dependent manner with an IC value of 17.

Inhibition of cutaneous heat-sensitive Ca -permeable transient receptor potential vanilloid 3 channels alleviates UVB-induced skin lesions in mice.

Ultraviolet B (UVB) radiation causes skin injury by trigging excessive calcium influx and signaling cascades in the skin keratinocytes. The heat-sensitive Ca -permeable transient receptor potential vanilloid 3 (TRPV3) channels robustly expressed in the keratinocytes play an important role in skin barrier formation and wound healing. Here, we report that inhibition of cutaneous TRPV3 alleviates UVB radiation-induced skin lesions.

Design, synthesis and anticancer evaluation of novel oncolytic peptide-chlorambucil conjugates.

Nitrogen mustards (NMs) are an important class of chemotherapeutic drugs and have been widely employed for the treatment of various cancers. However, due to the high reactivity of nitrogen mustard, most NMs react with proteins and phospholipids within the cell membrane. Therefore, only a very small fraction of NMs can reach the reach nucleus, alkylating and cross-linking DNA.

A prospective observational study on utility of serum mesencephalic astrocyte-derived neurotrophic factor as a promising prognostic biomarker of severe traumatic brain injury in humans.

Background: Mesencephalic astrocyte-derived neurotrophic factor (MANF) is released under endoplasmic reticulum stress, thereby exerting neuroprotective effects. We determined whether serum MANF may be a prognostic biomarker of human severe traumatic brain injury (sTBI).

Methods: Serum MANF concentrations of 137 sTBI patients and 137 controls were quantified in this prospective cohort study.

Design, synthesis, and biological evaluation of acyl sulfonamide derivatives with spiro cycles as Na1.7 inhibitors for antinociception.

Chronic pain, as an unmet medical need, severely impacts the quality of life. The voltage-gated sodium channel Na1.7 preferentially expressed in sensory neurons of dorsal root ganglia (DRG) serves a promising target for pain therapy.

A Novel Role of Uricosuric Agent Benzbromarone in BK Channel Activation and Reduction of Airway Smooth Muscle Contraction.

The uricosuric drug benzbromarone, widely used for treatment of gout, hyperpolarizes the membrane potential of airway smooth muscle cells, but how it works remains unknown. Here we show a novel role of benzbromarone in activation of large conductance calcium-activated K channels. Benzbromarone results in dose-dependent activation of macroscopic big potassium (BK) currents about 1.

Attenuation of Epileptogenesis and Cognitive Deficits by a Selective and Potent Kv7 Channel Opener in Rodent Models of Seizures.

Targeting neuronal Kv7 channels by pharmacological activation has been proven to be an attractive therapeutic strategy for epilepsy. Here, we show that activation of Kv7 channels by an opener SCR2682 dose-dependently reduces seizure activity and severity in rodent models of epilepsy induced by a GABAa receptor antagonist pentylenetetrazole (PTZ), maximal electroshock, and a glutamate receptor agonist kainic acid (KA). Electroencephalographic recordings of rat cerebral cortex confirm that SCR2682 also decreases epileptiform discharges in KA-induced seizures.

An antigen processing and presentation signature for prognostic evaluation and immunotherapy selection in advanced gastric cancer.

Objective: The aim of the study was to propose a signature based on genes associated with antigen processing and presentation (APscore) to predict prognosis and response to immune checkpoint inhibitors (ICIs) in advanced gastric cancer (aGC).

Background: How antigen presentation-related genes affected the immunotherapy response and whether they could predict the clinical outcomes of the immune checkpoint inhibitor (ICI) in aGC remain largely unknown.

Methods: In this study, an aGC cohort (Kim cohort, RNAseq, N=45) treated by ICIs, and 467 aGC patients from seven cohorts were conducted to investigate the value of the APscore predicting the prognosis and response to ICIs.

Discovery of Potent and Selective Transient Receptor Potential Vanilloid 1 (TRPV1) Agonists with Analgesic Effects Based on the Functional Conversion Induced by Altering the Orientation of the Indazole Core.

Transient receptor potential vanilloid 1 (TRPV1) is a promising target for developing antinociceptive agents. Here, we report the synthesis of -indazole-4-aryl piperazine carboxamide analogues as TRPV1 modulators. The structure-activity relationship (SAR) reveals that substituting indazole at the 5-/6-position leads to TRPV1 agonism, whereas the 4- and 7-positions of indazole obtain mild antagonism and loss of activity, respectively.

Utilization of boron carbide nanosheet in the recognition cathinone drug concentration in the human body.

This study adopted density functional theory (DFT) and analyzed the interaction of the conventional cathinone (CA) drug with perfect and defected monolayer nanosheets of boron carbide (BC3). BC3 was found to have poor interactions with CA. Hence, the perfect nanosheets had poor CA sensitivity.

Intestinal perforation with abdominal abscess caused by extramedullary plasmacytoma of small intestine: A case report and literature review.

Background: Extramedullary plasmacytoma (EMP) of the gastrointestinal tract is an extremely rare disease. Clinical manifestations of EMPs are varied and depend on the location and progression of the tumor.

Case Summary: Here, we firstly report a case of intestinal perforation with abdominal abscess caused by EMP of the small intestine in a 55-year-old female patient.

The hybrid oncolytic peptide NTP-385 potently inhibits adherent cancer cells by targeting the nucleus.

The use of oncolytic peptides with activity against a wide range of cancer entities as a new and promising cancer therapeutic strategy has drawn increasing attention. The oncolytic peptide LTX-315 derived from bovine lactoferricin (LfcinB) was found to be highly effective against suspension cancer cells, but not adherent cancer cells. In this study, we tactically fused LTX-315 with rhodamine B through a hybridization strategy to design and synthesize a series of nucleus-targeting hybrid peptides and evaluated their activity against adherent cancer cells.

YAP plays a protective role in T-2 toxin-induced inhibition of chondrocyte proliferation and matrix degradation.

Previous research has shown that T-2 toxin can damage cartilage, resulting in a disease phenotype similar to osteoarthritis. The precise molecular mechanism by which T-2 toxin causes chondrocyte injury, however, is unknown. The purpose of this study was to look into the role of YAP in T-2 toxin-induced rat chondrocyte injury.

Serum Sulfonylurea Receptor-1 Levels After Acute Supratentorial Intracerebral Hemorrhage: Implication for Prognosis.

Objective: Sulfonylurea receptor-1 (SUR1) is implicated in acute brain injury. This study was designed to determine relationship between serum SUR1 levels and severity, early neurologic deterioration (END) plus clinical outcome after intracerebral hemorrhage (ICH).

Methods: Serum SUR1 levels of 131 ICH patients and 131 healthy controls were quantified in this prospective, observational study.

Inhibition of intracellular proton-sensitive Ca-permeable TRPV3 channels protects against ischemic brain injury.

Ischemic brain stroke is pathologically characterized by tissue acidosis, sustained calcium entry and progressive cell death. Previous studies focusing on antagonizing -methyl-d-aspartate (NMDA) receptors have failed to translate any clinical benefits, suggesting a non-NMDA mechanism involved in the sustained injury after stroke. Here, we report that inhibition of intracellular proton-sensitive Ca-permeable transient receptor potential vanilloid 3 (TRPV3) channel protects against cerebral ischemia/reperfusion (I/R) injury.