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.

Background and objective Radiation therapy is one of the most common treatments for non-small cell lung cancer(NSCLC).However,the insensitivity of some tumor cells to radiation is one of the major reasons for the poor efficacy of radiotherapy and the poor prognosis of patients,and exploring the underlying mechanisms behind radioresistance is the key to solving this clinical challenge.This study aimed to identify the molecules associated with radioresistance in lung ad-enocarcinoma(LUAD),identified thyroid hormone receptor interactor 13(TRIP13)as the main target initially,and explored whether TRIP 13 is related to radioresistance in LUAD and the specific mechanism,with the aim of providing theoretical basis and potential targets for the combination therapy of LUAD patients receiving radiotherapy in the clinic.Methods Three data-sets,GSE18842,GSE19188 and GSE33532,were selected from the Gene Expression Omnibus(GEO)database and screened for differentially expressed genes(|log FC|＞1.5,P＜0.05)in each of the three datasets using the R 4.1.3 software,and then Venn diagram was used to find out the differentially expressed genes common to the three datasets.The screened differential genes were then subjected to protein-protein interaction(PPI)analysis and module analysis with the help of STRING online tool and Cytoscape software,and survival prognosis analysis was performed for each gene with the help of Kaplan-Meier Plotter database,and the TRIP13 gene was identified as the main molecule for subsequent studies.Subsequently,the human LUAD cell line H292 was irradiated with multiple X-rays using a sub-lethal dose irradiation method to construct a radioresistant cell line,H292DR.The radioresistance of H292DR cells was verified using cell counting kit-8(CCK-8)assay and clone formation assay.The expression levels of TRIP 13 in H292 and H292DR cells were measured by Western blot.Small interfering RNA(siRNA)was used to silence the expression of TRIP 13 in H292DR cells and Western blot assay was performed.The clone formation ability and migration ability of H292DR cells were observed after TRIP13 silencing,followed by the detection of changes in the expression levels of proteins closely related to homologous recombination,such as ataxia telangiectasia mutated(ATM)protein.Results Screening of multiple GEO datasets,validation of external datasets and survival analysis revealed that TRIP 13 was highly expressed in LUAD and was associated with poor prognosis in LUAD patients who had received radiation therapy.And the results of gene set enrichment analysis(GSEA)of TRIP13 suggested that TRIP13 might be closely associated with LUAD radioresistance by promoting homologous recombination repair after radiation therapy.Experimentally,TRIP13 expression was found to be upregulated in H292DR,and silencing of TRIP13 was able to increase the sensitivity of H292DR cells to radiation.Conclusion TRIP13 is associated with poor prognosis in LUAD patients treated with radiation,possibly by promoting a homologous recombination repair pathway to mediate resistance of LUAD cells to radiation.

Objective To analyze the effects of massage therapy on the inflammatory state and lung function of pediatric refractory Mycoplasma pneumonia (RMPP). Methods A total of 320 children with RMPP treated in Hebei Seventh People′s Hospital from September 2022 to August 2023 were selected in the study. According to different treatment methods, they were divided into two groups, with 160 cases in each group. The western medicine group was given conventional anti-inflammatory and other symptomatic treatment, while the massage group was given dialectical massage treatment based on the western medicine group. The clinical efficacy, duration of disappearance of clinical symptoms, pulmonary function indexes, serum inflammatory factors, immune function indexes and total incidence of adverse reactions were compared between the two groups. Results The total effective rate of massage group was higher than that of control group (P < 0.05). The disappearance time of fever, cough, sputum and lung moist rales in observation group was shorter than that in control group (P < 0.05). After treatment, the peak expiratory flow (PEF), maximum mid-expiratory flow (MMEF) and forced vital capacity (FVC) in the massage group were higher than those in the control group (P < 0.05). The levels of serum C-reactive protein (CRP), tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) in the massage group were lower than those in the control group after treatment (P < 0.05). After treatment, CD3⁺, CD4⁺, CD4⁺/CD8⁺ in the massage group were higher than those in the control group (P < 0.05), and CD8⁺ was lower than that in the control group (P < 0.05). There was nosignificant difference in the total incidence of adverse reactions between the massage group and the western medicine group (P>0.05). Conclusion Massage based on syndrome differentiation combined with western medicine can effectively relieve fever, cough and other symptoms of RMPP children, reduce inflammatory response, improve lung function and immune function, and has less adverse reactions.

BACKGROUND: Low-density computed tomography (LDCT) improved early lung cancer diagnosis but introduces an excess of false-positive pulmonary nodules data. Hence, accurate diagnosis of early-stage lung cancer remains challenging. The purpose of the study was to assess the feasibility of using circulating tumour cells (CTCs) to differentiate malignant from benign pulmonary nodules. METHODS: 122 patients with suspected malignant pulmonary nodules detected on chest CT in preparation for surgery were prospectively recruited. Peripheral blood samples were collected before surgery, and CTCs were identified upon isolation by size of epithelial tumour cells and morphological analysis. Laser capture microdissection, MALBAC amplification, and whole-exome sequencing were performed on 8 samples. The diagnostic efficacy of CTCs counting, and the genomic variation profile of benign and malignant CTCs samples were analysed. RESULTS: Using 2.5 cells/5 mL as the cut-off value, the area under the receiver operating characteristic curve was of 0.651 (95% confidence interval: 0.538-0.764), with a sensitivity and specificity of 0.526 and 0.800, respectively, and positive and negative predictive values of 91.1% and 30.3%, respectively. Distinct sequence variations differences in DNA damage repair-related and driver genes were observed in benign and malignant samples. TP53 mutations were identified in CTCs of four malignant cases; in particular, g.7578115T>C, g.7578645C>T, and g.7579472G>C were exclusively detected in all four malignant samples. CONCLUSIONS CTCs play an ancillary role in the diagnosis of pulmonary nodules. TP53 mutations in CTCs might be used to identify benign and malignant pulmonary nodules.
Humans ; Lung Neoplasms ; Exome Sequencing ; Multiple Pulmonary Nodules ; Carcinoma ; DNA Repair

Urea transporters (UT) play a vital role in the mechanism of urine concentration and are recognized as novel targets for the development of salt-sparing diuretics. Thus, UT inhibitors are promising for development as novel diuretics. In the present study, a novel UT inhibitor with a diarylamide scaffold was discovered by high-throughput screening. Optimization of the inhibitor led to the identification of a promising preclinical candidate,

Objective:To explore effective schemes for improving cognitive function in patients with subjective cognitive decline (SCD) by EEG neurofeedback (NF) technique.Methods:Ten SCD patients recruited in Department of Neurology, Xuanwu Hospital, Capital Medical University from April 2019 to August 2019, were chosen in our study; all patients were subjected to neuro-regulation of mismatched negativity (MMN) for 5 times in 2 weeks by EEG NF technique. By using the midlines of frontal zone (Fz), central zone (Cz) and peak zone (Pz) as training electrodes, auditory tones (1000 Hz as standard stimulus, individual hearing discrimination threshold as deviation stimulus) were used to induce MMN characteristics of event-related potential (ERP) via Oddball paradigm. SCD patients received visual disc stimulation feedback with dynamic neural signal activity. ERP waveforms and standard MMN characteristics (amplitude and latency) before and after training were used to evaluate the changes in neural activity of these patients; nine N-Back working memory tasks (three types×three gradients) and hearing discrimination ability tests were used in these patients to evaluate the improvement of cognitive competence.Results:ERP analysis showed that the MMN waveforms in SCD patients after training were obviously different as compared with those before training; their standard stimulus and deviant stimulus in the point-by-point paired t-test analysis were significant different ( P<0.05). The MMN amplitudes at the Fz, Cz and Pz electrodes in these patients after training were significantly higher than those before training ( P<0.05). The accuracy of auditory tone 3-Back task in SCD patients was statistically significant before and after training ( P<0.05). Conclusion:NF based on MMN can significantly improve the MMN amplitude and accuracy of auditory working memory task in patients with SCD, which might provide a potentially effective cognitive intervention method for patients with early AD and the elderly with normal memory decline.

Objective To explore the effects of detail nursing in septic shock patients. Methods From January 2017 to June 2018, we selected 70 septic shock patients at West China Hospital of Sichuan University by convenience sampling. All patients were divided into control group (n=35) and observation group (n=35) with the method of random number table. Control group carried out routine nursing. On the basis of that in control group, observation group implemented detail nursing for two weeks. We compared the clinical effects, hemodynamics, health condition and the score of Glasgow coma scale (GCS) of patients between two groups before and after intervention. Results The effective rate of treatment of septic shock patients in observation group was 88.57％ higher than that (65.71％) in control group with a statistical difference (P < 0.05). The hospitalization time, time using ventilator, time of consciousness recovery, disappearance time of symptoms and signs of observation group were shorter than those of control group; the serum C-reactive protein of observation group was lower than that of control group; the differences were all statistical (P<0.01). After intervention, the cardiac index, mean arterial pressure, venous oxygen saturation of patients in observation group were higher than those in control group; the heart rate of patients in observation group was lower than that in control group; the differences were all statistical (P < 0.05). After intervention, the score of health condition of patients in observation group was lower than that in control group; the score of GCS of patients was higher than that in control group;the differences were all statistical (P < 0.05). Conclusions Detail nursing for septic shock patients can improve the quality of life of patients and has a little influence on hemodynamics which is worthy of clinical generalization and application.

BACKGROUND: It was believed that immunoglobulin G (IgG) was synthesized only by B cells. However, in recent years, researchers have found that a variety of cancer cells can also synthesize IgG (cancer-IgG) which promote the development of tumors. This study analyzed the expression and clinical significance of cancer-IgG in non-small cell lung cancer (NSCLC), and initially explored its mechanism. METHODS: The expression of IgG1 heavy chain gamma 1 (IGHG1) and cancer-IgG were detected by bioinformatics and immunohistochemistry in NSCLC; The gene set enrichment analysis (GSEA) method was used to explore the signaling pathways involved in IGHG1 regulation. RESULTS: The expression level of cancer-IgG in NSCLC was significantly higher than that in normal tissues. The high expression group had a poor prognosis and was associated with clinical stage (P=0.042), T stage (P=0.044) and metastasis (P=0.007). GSEA analysis showed that IGHG1 was associated with cell adhesion, cytokine interaction and chemokine signaling pathway. CONCLUSIONS High expression of cancer-IgG in NSCLC is a poor prognosis factor, which may be related to the promotion of tumor invasion and metastasis.
Adult ; Aged ; Biomarkers, Tumor ; metabolism ; Carcinoma, Non-Small-Cell Lung ; genetics ; metabolism ; pathology ; Carrier Proteins ; genetics ; metabolism ; Computational Biology ; Female ; Humans ; Immunoglobulin G ; genetics ; metabolism ; Immunohistochemistry ; Lung Neoplasms ; genetics ; metabolism ; pathology ; Male ; Middle Aged ; Neoplasm Staging ; Young Adult

Objective To investigate the influence of enteral nutrition on body weight,nutritional status,treatment toxicities,and short-term outcomes in esophageal carcinoma patients treated with concurrent chemoradiotherapy(CCRT). Methods Eligible esophageal carcinoma patients were randomly assigned(2:1) to receive either CCRT combined with enteral nutrition (study group) or CCRT alone (control group). The primary endpoint was changes in the body weight during and after radiotherapy. The secondary endpoints were nutrition-related hematological parameters,the toxicities of chemoradiotherapy,the completion rate of treatment,and short-term outcomes. The differences was using χ2 or t-test. Results Between September 2014 and June 2017,203 patients were included in the study,consisting of 139 patients in the study group and 64 patients in the control group. Compared with the control group,the study group had significantly less body weight loss during and after radiotherapy (P<0.05) and significantly less decreases in serum albumin and hemoglobin (P<0.05),but there was no significant difference in the reduction in total lymphocyte count between the two groups (P>0.05).The study group had significantly lower incidence rates of grade ≥3 myelosuppression and infection and a significantly higher completion rate of chemoradiotherapy compared with the control group (P<0.05).The incidence of radiation pneumonitis and esophagitis showed no significant difference between the two groups (P>0.05).The study group had an insignificantly higher objective response rate than the control group (P>0.05). Conclusions For esophageal carcinoma patients treated with CCRT,enteral nutrition can reduce body weight loss during and after radiotherapy,improve nutritional status and treatment tolerance,and reduce toxicities.

Objective To establish the methods for controlling quality of Yiqi Congming Pills, and to improve the quality standard for the pills. Methods Yiqi Congming Pills were sampled from the products of 3 mainpharmaceutical companies in China market, 2 batched from each company. Radix Puerariae, Radix Astragali, Fructus Viticis, Cortex Phellodendri Chinensis, Radix Codonopsis in Yiqi Congming Pills were observed under microscope for microscopic identification. Radix Astragali, Rhizoma Cimicifugae, Radix Paeoniae Alba, and Cortex Phellodendri Chinensis were identified by thin-layer chromatography (TLC) for qualitative differentiation. The contents of puerarin and paeoniflorin in Yiqi Congming Pills were determined by high performance liquid chromatography(HPLC). Results The microscopic characteristics of Radix Puerariae, Radix Astragali, Fructus Viticis, Cortex Phellodendri Chinensis, Radix Codonopsis in the pills were obvious and were easy for discrimination. The spots in thin-layer chromatography (TLC) chromatograms of Radix Astragali, Rhizoma Cimicifugae, Radix Paeoniae Alba, and Cortex Phellodendri Chinensis were clear without interference of negative reference. Puerarin had a good linearity in the range of 0.00112~3.50676μg, and the average recovery rate was 98.2%(sR=1.4%, N=9 ). Paeoniflorin had a good linearity in the range of 0.00333 ~ 3.328 μg, and the average recovery rate was 98.4%(sR = 1.8%, N = 9). Great differences existed in the contents of puerarin and paeoniflorin of Yiqi Congming Pills from the three pharmaceutical companies. Conclusion The established qualitative and quantitative methods are of accuracy, credibility and repeatability, and are effective for controling the quality of Yiqi Congming Pills.