Inhibitory effects of a TRPM4 inhibitor 9-phenanthrol on electrical activity of INS-1 pancreatic β-cells / 药学学报

The Ca2+-activated monovalent cation selective transient receptor potential melastatin 4 (TRPM4) channel expressed in pancreatic β-cells is implicated in the β-cell function and insulin secretion, but how pharmacological function of TRPM4 channel affects membrane excitability of β-cells remains largely unknown. Here, we report that pharmacological inhibition of TRPM4 by specific inhibitor 9-phenanthrol attenuates electrical activities of pancreatic β-cells. In whole-cell current clamp recordings, 9-phenanthrol results in inhibition of action potential frequency induced by tolbutamide of the INS-1 pancreatic β-cells in a dose-dependent manner with an IC50 value of 14.99 ± 7.93 μmol·L-1. Similarly, 9-phenanthrol also inhibited action potential firing in INS-1 cells stimulated by current injection. Further recordings of β-cells demonstrate the significant inhibitory effects on action potential peak and action potential amplitude by 9-phenanthrol. Taken together, our results show the involvement of TRPM4 channel function in pancreatic β-cells depolarization and action potential, it provides pharmacological experimental methods and theoretical support for the study of TRPM4 channel in pancreatic β-cells.

A single-center retrospective analysis of 77 traumatic arterial injuries of lower extremities / 中华外科杂志

Objective: To analyze the treatment and clinical prognosis of lower extremity arterial injury caused by trauma. Methods: The clinical data of 77 patients with traumatic lower extremity arterial injury admitted to Department of Vascular Surgery,Yichang Central People's Hospital from January 2013 to June 2021 were collected retrospectively. There were 65 males and 12 females, with an average age of 47.4 years (range: 7 to 75 years). Among the 77 patients, 56 cases (72.7%) had open injury and 21 cases (27.3%) had closed injury. Iliac artery was injured in 9 cases (11.7%), common femoral artery in 7 cases (9.1%), superficial femoral artery in 1 case (1.3%), popliteal artery in 11 cases (14.3%) and inferior knee artery in 49 cases (63.6%). The treatment methods and clinical effects were analyzed. Results: One case with pelvic fracture combined the internal iliac artery injury and 1 case with multiple injuries involving the common femoral artery died of circulatory failure before surgery. Seventy-five cases received vascular-related operations, including arterial ligation in 24 cases, arterial reconstruction in 40 cases, stent graft implantation in 1 case, primary amputation in 2 cases, and arterial embolization in 8 cases. The overall mortality rate was 6.5% (5/77), all of which were closed injuries. Except for 2 cases who died before surgery, 3 cases with pelvic fracture combined the internal iliac artery injury died of multiple organ failure after internal iliac artery embolization. There were 8 cases received amputation (10.4%, 8/77), 5 cases with closed injury and 3 cases with open injury. In addition to 2 cases with primary amputation, 6 cases underwent secondary amputation due to ischemia-reperfusion injury after revascularization (4 cases with popliteal artery injury and 2 cases with subpatellar artery injury). The average followed-up time was 17 months (range: 2 months to 8 years). One patient with femoral artery injury underwent autologous great saphenous vein bypass, and lower limb artery CT angiography was re-examined 6 months after the operation, and 30% distal anastomotic stenosis was found. Ankle brachial index<0.8 was found in two patients 1 year after popliteal artery repair, but none of the patients had intermittent claudication symptoms, and no further intervention was performed. Five patients suffered delayed healing due to severe lower limb injury, fracture and skin injury. Among them, 2 cases had poor wound healing at the stump of amputation, which gradually healed 3 to 5 months after several debridements. The other 3 vascular injury combined with tibial fracture patients had delayed tibial healing after surgery, but no symptoms of vascular ischemia occurred. All the other patients recovered well and no other serious complications occurred. Conclusions: The proportion of death and disability in patients with lower limb artery injury caused by trauma is high. Active and orderly surgical repair according to the site and type of injury can reduce the mortality, save the function of the affected limb, and promote the healing of injury.

Identification of novel selective TRPV3 antagonists based on virtual screening, molecular docking and bioassay / 药学学报

Transient receptor potential vanilloid member 3 (TRPV3) is a temperature-sensitive cation channel protein, which contributes to nociception, itch, hair growth, emotional control and the pathophysiology of migraine. However, research progress on TRPV3 fundamental molecular biology is rather slow, compared to other TRP channels due to the lack of its selective antagonists. It's necessary to identify TRPV3 selective antagonists for the study on TRPV3 physiological functions. In this study, several selective TRPV3 antagonists were identified by ligand-based virtual screening of shape-based similarity and electrostatic matching. The most potent one (V-39) blocked 2-APB-activated currents in a stable human TRPV3 expressed HEK293T cell line with IC50=18.0 ±1.1 μmol·L-1 (n=4). Besides, the interaction pattern between TRPV3 and its antagonists were studied through docking the antagonists into a homology model (TRPV3_HM4) generated from the crystal structure of TPRV1. The docking results show that the binding site of TRPV3 locates between linker domain (of N-terminus and TM1) and TRP Box. There are a π-π stacking interaction and hydrogen bonding interactions between compound V-39 and residues His-310, His-314 and Arg-577 of the pocket. Identification of these antagonists provides new probes for understanding the pharmacological function of TRPV3 channel.

Research progress in medicinal treatment of autism spectrum disorders / 药学学报

Autism spectrum disorders (ASD) are a group of behaviorally defined, etiologically heterogeneous neurodevelopmental disorders characterized by impairment in social reciprocity, disturbances in language and various types of repetitive behaviors. The etiology and pathogenic mechanism of ASD are still unclear and there is no effective treatment available yet. ASD treatment includes behavioral and medicinal interventions. Behavioral interventions are the first line of treatment for ASD, alleviating core symptoms. Medicinal treatments, exert limited effect towards the core symptoms, represent an aide to the behavioral intervention and mainly apply to the so-called associated behavioral symptoms, such as irritability, aggression, self-injury, anxiety, insomnia, hyperactivity, low attention and compulsive behavior. A wide range of different agents are currently being tested in the preclinical and clinical studies, which include antipsychotics, antidepressants, anticonvulsants, anxiolytics, anti-infective drugs, glutamate receptor modulators, GABA receptor modulators, mTOR inhibitors and neuropeptides, etc. The purpose of present review is to cover the research advances in drug development and medicinal treatment of autism spectrum disorders.

Natural modulators of transient receptor potential channels / 药学学报

Transient receptor potential (TRP) channels are non-selective and cation-permeable channels in the cell membrane, widely distributed in tissues and organs of human body. As biosensors, TRP channels can regulate the functions of vision, hearing, taste, pain, and touch, etc. So far, more than 100 different kinds of natural modulators targeting TRP channels have been identified from 70 species of plants or animals. In this review article, we attempt to summarize the effect of known natural active compounds on TRP channels with focuses on their sources, structures, action features and mechanisms. Hopefully this review can provide some useful information that can facilitate discovery of more specific natural modulators, and development of innovative therapeutic drugs targeting TRP channels.

Application of ARIMA-NAR combined model in predicting bacillary dysentery / 第二军医大学学报

Objective To explore the application of autoregressive integrated moving average (ARIMA) model, and ARIMA combined nonlinear autoregressive (ARIMA-NAR) model in predicting bacterial dysentery (BE) incidence. Methods Data of BE monthly incidences from Jan. 2004 to Feb. 2015 in Jiangsu Province were used as fitting samples, the 15-month data from Mar. 2015 to May 2016 were used in the prediction phase. ARIMA model and ARIMA-NAR model were established and the effects of two models were compared according to mean absolute error (MAE), mean square error (MSE), and mean absolute percentage error (MAPE), in which lower values suggested higher prediction accuracy. Results In the fitting phase, the MAE, MSE and MAPE of the ARIMA model were 0. 177 5, 0. 081 4 and 0. 184 7, respectively, while those of the ARIMA-NAR model were 0. 094 1, 0. 029 5 and 0. 104 6, respectively. In the prediction phase, the MAE, MSE and MAPE of the ARIMA model were significantly higher than those of the ARIMA-NAR model. Conclusion ARIMA-NAR combined model is superior to ARIMA model in predicting the time series of BE incidence in Jiangsu Province, suggesting that ARIMA-NAR model can be used to predict the incidence of BD.

The structure-activity relationships of novel α7 nicotinic acetylcholine receptor agonists based on indolizine scaffold / 药学学报

Alpha7 nicotinic acetylcholine receptor (α7 nAChR) is a ligand-gated ion channel critical for cognition, learning and memory. Deficiency of neuronal α7 nAChR has been implicated in the cognitive deficits and neuropsychiatric disorders. Chemical activation of α7 nAChR improves neurological functions in animal models. In this study, we designed and synthesized a series of indolizine derivatives with various substitutions at different positions on the scaffold, and investigated their structure-activity relationships (SAR). All compounds were screened and evaluated for their agonist activity using the two-electrode voltage clamp recording system in Xenopus oocytes expressing human α7 nAChR. Compound 16c carrying 6-methylindolizine moiety activates α7 nAChR with EC50 at 1.60±0.19 μmol·L-1 and maximum effect (Emax) of 69.0%±2.8% compared with 3 mmol·L-1 ACh. Compound 17b with 8-cyclopropyl substitution shows an increased Emax of 81.1%±9.3% with EC50 at 2.74±0.74 μmol·L-1. The SAR of the series shows that introducing the small hydrophobic groups at 6- or 8- position can improve both potency and maximum effect.