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.

AIM:To explore the correlation between trimethylamine-N-oxide(TMAO)and type 2 diabetic kidney disease(DKD),and to provide new ideas for the early clinical diagnosis of DKD.METHODS:A total 246 patients with type 2 diabetes mellitus(T2DM)ad-mitted to the Department of Endocrinology of the First Hospital of Lanzhou University from January 1,2020 to May 31,2020 were divided into diabetic kidney disease group(DKD group)and simple diabetes mellitus group(NDKD group).According to urinary albumin/creatinine ratio(UACR),the patients were divided into A1,A2 and A3 subgroups.According to the estimated glomerular filtration rate(eGFR),the patients were divided into G1,G2,G3 and G4-5 sub-groups.According to the Kidney Disease:Improving Global Outcomes(KDIGO)guidelines,the risk of progression of DKD was assessed(low,medium,high or very high risk).General clinical data and laboratory indicators were collected.TMAO level was measured by euzymelinked immunosorbent assay.SPSS 25.0 software was used for statistical analysis.RESULTS:In T2DM patients,TMAO level was positively correlated with UACR(r=0.515,P<0.01)and negatively correlated with eGFR(r=-0.409,P<0.01).TMAO is an indepen-dent risk factor for the onset and progression of DKD.In diagnostic model,the AUROC was 0.745 with op-timal cut-off value was 5.37μmol/L.CONCLUSION:TMAO is closely related to the occurrence and de-velopment of DKD,and it has certain clinical predictive value for DKD.Therefore,TMAO may become a po-tential target for the early diagnosis and treatment of DKD.

OBJECTIVE: To investigate the therapeutic effects of total saponins from Panax notognseng (PNS) combined with cyclophosphamide (CTX) in mice bearing hepatocellular carcinoma H₂₂ cell xenograft. METHODS: We examined the effects of treatment with different concentrations of PNS on H₂₂ cell proliferation for 24 to 72 h in vitro using CCK8 colorimetric assay. Annexin V/PI double fluorescence staining was used to detect the effect of PNS on apoptosis of H₂₂ cells. Mouse models bearing H₂₂ cell xenograft were established and treated with CTX (25 mg/kg), PNS (120, 240 or 480 mg/kg), alone or in combinations. After treatments for consecutive 10 days, the mice were euthanized for examinations of carbon clearance ability of the monocytes and macrophages, splenic lymphocyte proliferation, tumor necrosis factor (TNF-α), interleukin-2 (IL-2), serum hemolysin antibody level, blood indicators, and the tumor inhibition rate. RESULTS: Treatment with PNS concentration-dependently inhibited the proliferation and significantly promoted apoptosis of cultured H₂₂ cells (P < 0.01). In the tumor-bearing mouse models, PNS alone and its combination with CTX both resulted in obvious enhancement of phagocytosis of the monocyte-macrophages, stimulated the proliferation of splenic lymphocytes, promoted the release of TNF-α and IL-2 and the production of serum hemolysin antibody, and increased the number of white blood cells, red blood cells and lymphocytes in the peripheral blood. Treatment with 480 mg/kg PNS combined with CTX resulted in a tumor inhibition rate of 83.28% (P < 0.01) and a life prolonging rate of 131.25% in the mouse models (P < 0.05). CONCLUSION PNS alone or in combination with CTX can improve the immunity and tumor inhibition rate and prolong the survival time of H₂₂ tumor-bearing mice.
Animals ; Carcinoma, Hepatocellular/pathology* ; Cyclophosphamide/therapeutic use* ; Hemolysin Proteins ; Heterografts ; Humans ; Interleukin-2 ; Liver Neoplasms/pathology* ; Mice ; Panax notoginseng ; Saponins/therapeutic use* ; Tumor Necrosis Factor-alpha

UNC-51-like kinase 1 (ULK1), as a serine/threonine kinase, is an autophagic initiator in mammals and a homologous protein of autophagy related protein (Atg) 1 in yeast and of UNC-51 in Caenorhabditis elegans. ULK1 is well-known for autophagy activation, which is evolutionarily conserved in protein transport and indispensable to maintain cell homeostasis. As the direct target of energy and nutrition-sensing kinase, ULK1 may contribute to the distribution and utilization of cellular resources in response to metabolism and is closely associated with multiple pathophysiological processes. Moreover, ULK1 has been widely reported to play a crucial role in human diseases, including cancer, neurodegenerative diseases, cardiovascular disease, and infections, and subsequently targeted small-molecule inhibitors or activators are also demonstrated. Interestingly, the non-autophagy function of ULK1 has been emerging, indicating that non-autophagy-relevant ULK1 signaling network is also linked with diseases under some specific contexts. Therefore, in this review, we summarized the structure and functions of ULK1 as an autophagic initiator, with a focus on some new approaches, and further elucidated the key roles of ULK1 in autophagy and non-autophagy. Additionally, we also discussed the relationships between ULK1 and human diseases, as well as illustrated a rapid progress for better understanding of the discovery of more candidate small-molecule drugs targeting ULK1, which will provide a clue on novel ULK1-targeted therapeutics in the future.

OBJECTIVE: To explore the molecular mechanism by which microRNA let-7g-3p regulates biological behaviors of bladder cancer cells. METHODS: The expression levels of let-7g-3p in bladder cancer and adjacent tissues, normal bladder epithelial cells (HUC cells) and bladder cancer cells (T24, 5637 and EJ cells) were detected using qRT- PCR. T24 cells were transfected with let-7g-3p mimic or inhibitor, and the changes in cell proliferation, migration, invasion, and apoptosis were examined. Transcriptome sequencing was carried out in cells overexpressing let-7g-3p, and the results of bioinformatics analysis, double luciferase reporter gene assay, qRT-PCR and Western blotting confirmed that HMGB2 gene was the target gene of let-7g-3p. The expression of HMGB2 was examined in HUC, T24, 5637 and EJ cells, and in cells with HMGB2 knockdown, the effect of let-7g-3p knockdown on the biological behaviors were observed. RESULTS: qRT-qPCR confirmed that let-7g-3p expression was significantly lower in bladder cancer tissues and cells (P < 0.01). Overexpression of let-7g-3p inhibited cell proliferation, migration and invasion, and promoted cell apoptosis, while let-7g-3p knock-down produced the opposite effects. Bioinformatics and transcriptome sequencing results showed that HMGB2 was the key molecule that mediate the effect of let-7g-3p on bladder cancer cells. Luciferase reporter gene assay, qRT-PCR and Western blotting all confirmed that HMGB2 was negatively regulated by let-7g-3p (P < 0.01). Knocking down HMGB2 could partially reverse the effect of let-7g-3p knockdown on the biological behaviors of the bladder cancer cells. CONCLUSION The microRNA let-7g-3p can inhibit the biological behavior of bladder cancer cells by negatively regulating HMGB2 gene.
Apoptosis ; Cell Line, Tumor ; Cell Movement/physiology* ; Cell Proliferation ; Epithelial Cells/metabolism* ; Gene Expression Regulation, Neoplastic ; HMGB2 Protein/metabolism* ; Humans ; MicroRNAs/metabolism* ; Urinary Bladder ; Urinary Bladder Neoplasms/genetics*

BACKGROUND: Microwave treatment is a common physical therapy method that can increase the temperature and blood circulation of deep tissues, and is used for improving fracture repair. However, microwave treatment cannot be used if there is surgically implanted metal plate or screw. OBJECTIVE: To observe the dame of microwave treatment to the tissues surrounding the titanium alloy implants. METHODS: Forty-four New Zealand white rabbits were randomized into experimental and control groups. The model of the fracture at the middle of the femur was established in all rabbits, and the rabbits in the experimental group were implanted with titanium alloy internal fixation systems. A 30-day microwave treatment (2 450 MHz, 20 W or 40 W, 20 minutes daily) was applied to the fracture site in all rabbits at 3 days after operation. RESULTS AND CONCLUSION: After 20 W of wave microwave treatment, the temperature of tissues around the implants showed no significant increase or severe heat injury. While, 40 W of wave microwave treatment significantly increased the temperature of tissues around the implants and the tissue was damaged severely. Our results indicate that, the low-dosage microwave treatment may be a promising method in the rehabilitation therapy of fractures with titanium alloy internal fixation.

OBJECTIVE To evaluate the validity and safety of Dachaihu Granule in treating chronic cholecystitis due to Stagnant Heat in Liver and Gallbladder.METHODS A stratified-block randomized,double-blind,double-dummy,parallel,placebo-controlled trial was designed,with 600 cases with chronic cholecystitis from 8 centers being selected and the ratio of treatment group,placebo group and cholagogic tablet group being 360:120:120.Patients in different groups were separately given Dachaihu Granule and cholagogic tablet simulator,Dachaihu Granule simulator and cholagogic tablet simulator,Dachaihu Granule simulator and cholagogic tablet.Then the validity and safety were assessed after 7 days' treatment.RESULTS ①In terms of the comprehensive curative effect of TCM syndromes,it was noticed that there existed no difference between the treatment group and positive medicine group in the integral reduction and disappearance of upper quadrant pain and tenderness,quadrant pain relief evaluated by patients,total symptom scores,integral reduction and disappearance of bitter taste,thirst,constipation and yellow urine,disappearance of vomit,change of gallbladder wall thickness and ultrasonic Murphy's character before and after the treatment,while both the treatment group and positive medicine group were superior to the placebo group(P<0.05~0.01).②The treatment group and positive medicine group has no difference from the placebo group in integral reduction and disappearance o ffever and nausea integral reduction of vomit,change of gallbladder size and inside diameter of common bile duct.③Good safety was noticed.CONCLUSION Chronic cholecystitis due to stagnant heat in liver and gallbladder treated by Dachaihu Granule is safe and effective.

Objective To assess the changes in iodine status and dietary iodine intake among Shanghai residents since common salt was iodized 20 years ago.Methods As-CE Catalysis spectrophotometry was used to determinate the urine iodine level in school-age children,pregnant women,wet nurse and adults of Shanghai between 1995 and 2015.B ultrasonic was used to determinate the thyroid volume of school-age children.And then the goiter rate was calculated.Direct titration or arbitration methods were applied to detect the household salt iodine level quantitatively.The survey was conducted by using 3 days 24-hour dietary questionnaire and condiment weighing methods to analyze the level of iodine intake and sources for the cases of all iodized salt consumption and all consumption of non-iodized salt.Results The median urine iodine concentration (UIC) of school age children was 72.3 μg/L in 1995,rose to 214-231 μg/L from 1997-1999,and then became stable between 100 μg/L and 200 μg/L since 2002.The goiter rate was below 5% among children aged 8-10 from 1995-2015 in Shanghai.The median urine iodine of pregnant women was between 126.5 μg/L and 139.8 μg/L.The median UIC of other populations were all between 100 μg/L and 200 μg/L: with adults,lactating women,infants and young children and women of childbearing age,the median urinary iodine was 138.4,123.1-131.1,150.1 and 125.6 μg/L.The qualified iodized salt at household consumption rate was 90% from 2001 to 2009,the percentage declined year by year from 2010.In the cases of all taking iodine salt,the median iodine intake volume for male aged 7-10,11-13,14-18 and over 18 was 200.3,235.5,252.7 and 215.4 μg/L;women aged 7-10,11-13,14-18 and over 18 was 193.0,213.8,208.3 and 186.1 μg/L.The contribution rate of iodine salt in the diet were 51.6%-54.1% and 49.1%-53% in men and women.Kelp,seaweed and fish and shrimp on the contribution of iodine are 7.6%-16.6% and 4.5%-7.4%.Conclusion In the past about 20 years,iodine nutritional status of residents in Shanghai has stabilized totally in a appropriate and safe level.However,the iodine nutrition of pregnant women was insufficient.As iodized salt is the major source of dietary iodine in coastal areas,it is still necessary to continue the policy of universal salt iodized in Shanghai to ensure residents'' needs for iodine and control the risk of iodine deficiency.

Fluoroquinolone can cause pathologic lesions in tendon tissue (tendinopathy).In some cases,fluoroquinolone usage can lead to partly rupture or complete rupture of the tendon and substantial subsequent permanent disability.This article reviews fluoroquinolone tendinopathy symptoms,diagnosis,risk factors and toxic mechanisms.

To explore the new method of discriminating Cistanche deserticola, Cynomorium songaricum and Orobanche pycnostachya by using PCR amplification of specific alleles. 30 samples of the different C. deserticola, 21 samples of C. songaricum and O. pycnostachya were collected. The total DNA of the samples were extracted, the ITS sequences from C. deserticola, C. songaricum and O. pycnostachya were amplified by PCR and sequenced unidirectionally. These sequences were aligned by using ClustulW. Specific primer was designed according to the ITS sequences of specific alleles, and PCR reaction system was optimized. Additionally, compare with the identification of specific PCR method and DNA sequence analysis method. The result showed that the 331 bp identification band for C. deserticola and the adulterants not amplified bands by a single PCR reaction, which showed good identification ability to the three species. PCR amplification of specific alleles can be used to identify C. deserticola, C. songaricum and O. pycnostachya successfully.
Alleles ; Cistanche ; classification ; genetics ; DNA Primers ; genetics ; DNA, Intergenic ; genetics ; DNA, Plant ; genetics ; Drug Contamination ; prevention & control ; Phylogeny ; Polymerase Chain Reaction ; methods