Sigma-1 receptor (σ ₁R) has become a focus point of drug discovery for central nervous system (CNS) diseases. A series of novel 1-phenylethan-1-one O-(2-aminoethyl) oxime derivatives were synthesized. In vitro biological evaluation led to the identification of 1a, 14a, 15d and 16d as the most high-affinity (K _i < 4 nmol/L) and selective σ ₁R agonists. Among these, 15d, the most metabolically stable derivative exhibited high selectivity for σ ₁R in relation to σ ₂R and 52 other human targets. In addition to low CYP450 inhibition and induction, 15d also exhibited high brain permeability and excellent oral bioavailability. Importantly, 15d demonstrated effective antipsychotic potency, particularly for alleviating negative symptoms and improving cognitive impairment in experimental animal models, both of which are major challenges for schizophrenia treatment. Moreover, 15d produced no significant extrapyramidal symptoms, exhibiting superior pharmacological profiles in relation to current antipsychotic drugs. Mechanistically, 15d inhibited GSK3β and enhanced prefrontal BDNF expression and excitatory synaptic transmission in pyramidal neurons. Collectively, these in vivo proof-of-concept findings provide substantial experimental evidence to demonstrate that modulating σ ₁R represents a potential new therapeutic approach for schizophrenia. The novel chemical entity along with its favorable drug-like and pharmacological profile of 15d renders it a promising candidate for treating schizophrenia.

Objective To investigate the effects of leonurine on tumor growth and immune function of colon cancer tumor bearing mice.Methods C57BL/6 mice were established a colon cancer bearing mouse model.After modeling,the mice were randomly divided into control group(0.9％NaCl),experimental-L group(180 ng·g-1 leonurine),experimental-H group(360 ng·g-1 Leonurine),experimental-H+NC group(360 ng·g-1 leonurine+no-load plasmid),and experimental-H+sicGAS group(360 ng·g-1 leonurine+cGAS siRNA plasmid).Tumor volume and weight were measured after group treatment.Immunohistochemical staining was used to detect the relative positive expression of cyclic GMP-AMP synthase(cGAS),stimulator of interferon gene(STING)and the average positive number of CD4+T and CD8+T cells in tumor tissues.The killing rate of mouse CD4+T and CD8+T cells to tumor cells was detected by cell counting kit 8.Results The tumor volume of control group,experimental-H group,experimental-H+NC group and experimental-H+cGAS knockout group were(1 088.32±70.82),(468.20±24.28),(480.01±23.78)and(998.99±32.84)mm3,respectively;the relative positive expressions of cGAS were 1.00±0.00,5.18±0.73,5.30±0.80 and 1.12±0.46,respectively;the relative positive expressions of STING were 1.00±0.00,5.64±0.81,5.48±0.75 and 1.14±0.50,respectively;the mean CD4+T positive cells were 40.25±5.82,118.64±15.30,113.25±16.65 and 48.74±7.10,respectively;the average number of CD8+T positive cells were 49.76±6.12,143.68±16.80,135.75±17.42 and 57.01±8.24,respectively.The above indexes in experimental-H group and experimental-H+no-load group were statistically significant compared with control group(all P＜0.05);there were statistically significant differences in the above indexes between the experimental-H+sicGAS group and the experimental-H group(all P＜0.05).Conclusion Leonurine can enhance the proliferation ability of lymphocytes in colon cancer tumor bearing mice by activating cGAS-STING signal,and inhibit tumor growth in mice.

Objective:To investigate the clinical features and risk factors of multiple organ dysfunction syndrome (MODS) caused by wasp sting.Methods:A retrospective cohort study was conducted to collect the general data of wasp sting patients who had a clear history of wasp sting disease and clinical manifestations from June 2016 to December 2020 and were first diagnosed as wasp sting in hospital. Patients with hematological diseases, malignant tumors, severe liver and kidney dysfunction, cardiac insufficiency, and patients who had received hormone therapy before admission were excluded. Patients who were unable to obtain effective laboratory results due to hemolysis or other reasons within 48 h of admission were also excluded. The white blood cell count (WBC), neutrophil count (NEU), lymphocyte count (LYM), hemoglobin count (HB), myoglobin (Mb/MYO), activated partial thromboplastin time (APTT), albumin (ALB), K, Na, and Cl of the blood samples collected within 48 h after admission were recorded. Patients were divided into the MODS group and non-MODS group according to whether MODS occurred during hospitalization. Uni- and multivariate analysis were used to analyze the factors affecting the occurrence of MODS in wasp sting patients during hospitalization, and the receiver operating characteristic (ROC) curve was plotted to evaluate the predictive effect of myoglobin level on the occurrence of MODS in wasp sting patients during hospitalization.Results:Mb, WBC, NEU, APTT and serum potassium in the MODS group [3890.00 (1416.90-4057.00) ng/mL, (21.99 ± 8.18) × 10 9/L, (19.61 ± 7.33)× 10 9/L, (93.75 ± 45.77) s, and (4.99 ± 0.95) mmol/L] were significantly higher than those in the non-MODS group [73.50 (34.30-264.20) ng/mL, (13.40 ± 4.14)× 10 9/L, (11.18±4.73)× 10 9/L, (37.00 ± 17.16) s, and (4.05 ± 0.56) mmol/L] (all P < 0.05); blood chlorine and ALB [(101.50 (98.25-105.00) mmol/L and (35.36 ± 6.44) g/L)] were significantly lower than those in the non-MODS group [(105.00 (103.00-107.00) mmol/L and (40.71 ± 5.48) g/L)] (all P < 0.05). Multivariate logistic regression analysis showed that NEU ( OR = 0.729, 95% CI: 0.542~0.981), Mb ( OR = 0.999, 95% CI: 0.998~1.000), and APTT ( OR = 0.951, 95% CI: 0.921~0.982) were independent risk factors for MODS in wasp sting patients. ROC curve analysis showed that NEU, Mb and APTT could be used to evaluate the occurrence of MODS in wasp sting patients. Among them, Mb had the highest predictive value (AUC = 0.950, 95 % CI: 0.891~0.982). The optimal cutoff value of Mb for predicting the occurrence of MODS in wasp sting patients was 515.30 ng/mL, and the corresponding sensitivity and specificity were 90.62% and 87.23%, respectively. Conclusion:Mb is an independent risk factor for MODS in wasp sting patients, which can be used as a good predictor of MODS in wasp sting patients.

ObjectiveTo explore the guidance value of “treatment of disease in accordance with three conditions” theory in the prevention and treatment of corona virus disease 2019（COVID-19） based on the differences of syndromes and traditional Chinese medicine（TCM） treatments in COVID-19 patients from Xingtai Hospital of Chinese Medicine of Hebei province and Ruili Hospital of Chinese Medicine and Dai Medicine of Yunnan province and discuss its significance in the prevention and treatment of the unexpected acute infectious diseases. MethodDemographics data and clinical characteristics of COVID-19 patients from the two hospitals were collected retrospectively and analyzed by SPSS 18.0. The information on formulas was obtained from the hospital information system （HIS） of the two hospitals and analyzed by the big data intelligent processing and knowledge service system of Guangdong Hospital of Chinese Medicine for frequency statistics and association rules analysis. Heat map-hierarchical clustering analysis was used to explore the correlation between clinical characteristics and formulas. ResultA total of 175 patients with COVID-19 were included in this study. The 70 patients in Xingtai，dominated by young and middle-aged males，had clinical symptoms of fever， abnormal sweating，and fatigue. The main pathogenesis is stagnant cold-dampness in the exterior and impaired yin by depressed heat， with manifest cold， dampness， and deficiency syndromes. The therapeutic methods highlight relieving exterior syndrome and resolving dampness， accompanied by draining depressed heat. The core Chinese medicines used are Poria，Armeniacae Semen Amarum，Gypsum Fibrosum，Citri Reticulatae Pericarpium，and Pogostemonis Herba. By contrast，the 105 patients in Ruili， dominated by young females， had atypical clinical symptoms， and most of them were asymptomatic patients or mild cases. The main pathogenesis is dampness obstructing the lung and the stomach， with obvious dampness and heat syndromes. The therapeutic methods are mainly invigorating the spleen， resolving dampness， and dispersing Qi with light drugs. The core Chinese medicines used are Poria，Atractylodis Macrocephalae Rhizoma，Glycyrrhizae Radix et Rhizoma，Coicis Semen，Platycodonis Radix，Lonicerae Japonicae Flos， and Pogostemonis Herba. ConclusionThe differences in clinical characteristics， TCM syndromes， and medication of COVID-19 patients from the two places may result from different regions，population characteristics， and the time point of the COVID-19 outbreak. The “treatment of disease in accordance with three conditions” theory can help to understand the internal correlation and guide the treatments.

The elements of ethical review related to clinical research of acupuncture and moxibustion is discussed to provide ideas for various institutions to carry out relevant ethical review. It is believed that the ethical review of clinical research of acupuncture and moxibustion needs to focus on the specificity of acupuncture and moxibustion. Starting from the basic theory of traditional Chinese medicine, the theory of meridians and acupoints and the theory of syndrome differentiation along meridians, the key contents of ethical review such as intervention methods, grouping design and placebo control should be considered, so as to standardize the clinical research of acupuncture and moxibustion and protect the health and rights and interests of participants.
Acupuncture Points ; Acupuncture Therapy ; Biomedical Research ; Ethical Review ; Humans ; Meridians ; Moxibustion

Six new tirucallane-type triterpenoids (1-6), along with ten known triterpenoids, were isolated from methylene chloride extract of the resin of Boswellia carterii Birdw. By the application of the comprehensive spectroscopic data, the structures of the compounds were clarified. The experimental electronic circular dichroism spectra were compared with those calculated, which allowed to assign the absolute configurations. Compounds 5 and 6 possesed a 2, 3-seco tirucallane-type triterpenoid skeleton, which were first reported. Their inhibitory activity against NO formation in LPS-activated BV-2 cells were evaluated. Compound 9 showed appreciable inhibitory effect, with an IC

OBJECTIVE: To compare the clinical effect of the combined treatment of acupuncture, moxibustion, Chinese herbal medicine and western medication and simple western medication on polycystic ovary syndrome (PCOS) of kidney deficiency and blood stagnation pattern and explore the effect on endometrial receptivity and the expression of serum homeobox gene A10 (HOXA10). METHODS: A total of 60 patients with PCOS of kidney deficiency and blood stagnation pattern were randomized into a combined treatment group and a western medication group, 30 cases in each one. In the western medication group, on the fifth day of menstruation, clomiphene citrate tablets were taken orally, 50 mg each time, once daily, consecutively for 5 days. On the day when the follicle diameter was ≥ 18 mm, chorionic gonadotrophin for muscular injection, a dose of 10 000 U was given. Before sleep, the aspirin enteric-coated tablets were taken orally, 50 mg (except during menstruation). In the combined treatment group, on the base of the treatment as the western medication group, acupuncture and moxibustion were adopted and the Chinese herbal for tonifying the kidney and activating blood circulation was taken orally. The acupoints were Guanyuan (CV 4), Qihai (CV 6), Zusanli (ST 36), Sanyinjiao (SP 6), Zigong (EX-CA 1), etc. Acupuncture was remained for 30 min each time, once every two days and discontinued during menstruation. Chinese herbal was given from the 3rd day of menstruation till the onset of the next menstruation, one dose each day. After consecutive treatment for 3 menstrual cycles in the two groups, the real-time polymerase chain reaction (RT-PCR) method was adopted to determine the expression of serum HOXA10 before and after treatment in the patients of the two groups. The endometrial thickness at ovulatory phase, uterine arterial flow 7 days after ovulation [including uterine arterial pulsatility index (PI), resistance index (RI), peak systolic velocity (PSV)/end diastolic velocity (EDV), meaning S/D], pregnancy rate and the score of Chinese medicine symptoms before and after treatment were compared in the patients between the two groups. RESULTS: ① After treatment, the expression of serum HOXA10 was higher than that before treatment in the patients of the two groups ( CONCLUSION The combined treatment with acupuncture, moxibustion and medication effectively improves endometrial receptivity and uterine arterial flow in the patients with PCOS of kidney deficiency and blood stagnation pattern and increases pregnancy rate. The therapeutic effect is better than the simple western medication and its mechanism is probably related to the regulation of serum HOXA10 expression.
Acupuncture Points ; Acupuncture Therapy ; Female ; Genes, Homeobox ; Homeobox A10 Proteins ; Humans ; Kidney ; Moxibustion ; Polycystic Ovary Syndrome/genetics* ; Pregnancy

AIM:To investigate the effect of interference in Yes-associated protein(YAP)expression on blad-der cancer cell apoptosis and its mechanisms.METHODS:Bladder cancer cell line T-24 was used as the target and divid-ed into control group(no treatment),small interfering RNA negative control(siRNA-NC)group,and YAP siRNA group. The expression levels of YAP at mRNA and protein levels in the transfected cells of each group were detected by real -time PCR and Western blot,respectively.The cell viability was measured by MTT assay.The apoptosis was analyzed by flow cytometry.The protein expression levels of β-catenin and c-Myc were determined by Western blot.The cells in YAP siRNA group were treated with Wnt/β-catenin signaling pathway inhibitor FH 535, and then the cell viability and apoptosis were analyzed by MTT assay and flow cytometry,respectively.RESULTS:The expression of YAP at mRNA and protein levels in YAP siRNA group was significantly lower than that in control group(P<0.05).The cell viability and the expression levels of c-Myc and β-catenin in YAP siRNA group were significantly lower than those in control group(P<0.05),while the apoptotic rate was significantly higher than that in control group(P<0.05).The cell viability in YAP siRNA+FH535 group was decreased significantly,while the apoptotic rate was increased as compared with YAP siRNA group(P<0.05). CONCLUSION:Interfering with the expression of YAP inhibits the viability of bladder cancer cells by inhibiting the Wnt /β-catenin signaling pathway,thus promoting apoptosis of bladder cancer cells.

Objective To establish a rat model of craniocerebral blast injury caused by the shock wave of cabin explosion.Methods Fifty male adult Sprague-Dawley rats were randomly divided into 5 groups (10 each):3g,5g,8g TNT with vest groups,5g TNT without vest group and control group.Uncased explosives of different equivalent were suspended in the cabin center.After anesthesia,with exception of control group,the rats were placed in prone position about 31 cm below the explosive,facing the explosive with or without vest.After the explosion,the survived rats were observed,serological and pathological examinations were performed at 3h,1d and 3d after the explosion.Results In terms of tissue damage and mortality,compared with the control group,no obvious injury formed in rats of the 3g TNT with vest group,and all of them survived;Rats in 5g TNT with vest group showed mild lung injury,brain tissue edema,enlarged blood vessel,patchy hemorrhage on the brain surface,and with a mortality of 30％;Rats in 8g TNT with vest group showed serious organ damage with a mortality of 80％;Rats in 5g TNT without vest group suffered from severe lung injury,almost all died right after the explosion.Therefore,rats in 5g TNT with vest group were more in line with the experimental needs.Further serum and pathologic examinations showed that the brain water content increased,the serum neuron specific enolase (NSE) and S-100β protein also increased markedly,and necrotic or apoptotic changes happened in the cortex and hippocampus neurons.Conclusion A stable animal model of craniocerebral blast injury may be established with rats in the case of chest and abdomen protected and then exposed to 5g TNT explosion in cabin.

Objective To investigate the injury characteristics of Beagle dogs after warship multi cabin explosion.Methods Forty-eight adult male Beagle dogs were placed in the simulated blast-cabin and adjacent cabin (24 each),and ammunitions respectively containing 0.75kg TNT and 3.50kg TNT were then detonated in the blast-cabin.The survival situation,fluctuation of vital signs,morphological changes of organs and the incidence of various types of injury of the dogs were observed immediately after the explosion to 24h after injury,and the neurological functions score was performed.Results Twenty dogs died immediately after the explosion,and another 9 dogs died 24h after the explosion.The total mortality was 60.42％(29/48),and the mortalities in blastcabin and adjacent cabin were 79.17％(19/24) and 41.67％(10/24),respectively.The dog's skull was penetrated by bomb fragments,and congestion and bleeding were observed in brain tissue,lung,heart,stomach,bowels,liver and kidneys.Extremities fracture,soft tissue contusions,perforation and rupture were also checked out after explosion.The fatality rate of bomb fragment injury,blast injury and combined bomb fragment-blast injury was 27.59％(8/29),17.24％(5/29) and 55.17％(16/29),respectively.Conclusions The combined bomb fragment-blast injury show high incidence and make high fatality rate and serious injury.Combatants should effectually shield themselves with occluded objects as far as possible to avoid damage and reduce fatality.The key of early treatment is to treat the multiple injuries promptly.Intravenous fluid therapy should be practiced after hemodynamic monitoring.