This paper aimed to explore the antidepressant effect of the essential oil from Schizonepeta tenuifolia Briq.(EOST) on the treatment of depression and its mechanism by using a combination of network pharmacology and the mouse model of lipopolysaccharide(LPS)-induced depression. The chemical components in EOST were identified using gas chromatography-mass spectrometer(GC-MS), and 12 active components were selected as the study objects. The targets related to EOST were obtained by Traditional Chinese Medicines Systems Pharmacology(TCMSP) and SwissTargetPrediction database. The targets related to depression were screened out through GeneCards, Therapeutic Target Database(TTD), and Online Mendelian Inheritance in Man(OMIM) database. The Venny 2.1 was applied to screen out the common targets of EOST and depression. The targets were imported into Cytoscape 3.7.2 to generate "drug-active component-diease-target" network diagram. The protein-protein interaction(PPI) network was constructed using STRING 11.5 database and Cytoscape 3.7.2, and the core targets were screened out. DAVID 6.8 database was used for Gene Ontology(GO) func-tional enrichment analysis and Kyoto Encyclopedia of Genes and Genomes(KEGG) pathway enrichment analysis, and subsequently the enrichment results were visualized through the bioinformatics platform. The mouse model of depression was induced by intraperitoneally injecting with LPS in mice. Before modeling, mice were administrated orally with EOST. The antidepressant effect of EOST was evalua-ted by tail suspension test(TST), forced swimming test(FST), and novelty suppressed feeding test(NSFT) after modeling. The content of interleukin(IL)-1β was determined by enzyme-linked immunosorbent assay(ELISA), and the protein expression levels of IL-1β and pro IL-1β in the hippocampus were determined by Western blot. There were 12 main components and 179 targets in EOAT, of which, 116 targets were related to depression, mainly involved in neuroactive ligand-receptor interaction, calcium signaling pathway, and cyclic adenosine monophosphate(cAMP) signaling pathway. Biological processes such as synaptic signal transduction, G-protein coupled receptor signaling pathway, and chemical synaptic transmission were involved. Molecular functions such as neurotransmitter receptor activity, RNA polymerase Ⅱ transcription factor activity, and heme binding were involved. In mice experiments, the results showed that EOST at 100 mg·kg~(-1) and 50 mg·kg~(-1) significantly shortened the immobility time in TST and FST as well as the feeding latency in NSFT compared with the model group, decreased the levels of serum IL-1β and NO, and reduced the protein expression levels of IL-1β and pro IL-1β in the hippocampus. In conclusion, EOST shows a good antidepressant effect in a multi-component, multi-target, and multi-pathway manner. The mechanism may be attributed to the fact that EOST can down-regulate the protein expression levels of IL-1β and pro IL-1β, decrease the release of inflammatory factors, and reduce neuroinflammation response.
Animals ; Mice ; Oils, Volatile ; Depression ; Lipopolysaccharides ; Network Pharmacology ; Databases, Genetic ; Calcium Signaling ; Disease Models, Animal

The generation of a tau-V337M point mutation mouse model using gene editing technology can provide an animal model with fast disease progression and more severe symptoms, which facilitate the study of pathogenesis and treatment of Alzheimer's disease (AD). In this study, single guide RNAs (sgRNA) and single-stranded oligonucleotides (ssODN) were designed and synthesized in vitro. The mixture of sgRNA, Cas9 protein and ssODN was microinjected into the zygotes of C57BL/6J mice. After DNA cutting and recombination, the site homologous to human 337 valine (GTG) in exon 11 was mutated into methionine (ATG). In order to improve the efficiency of recombination, a Rad51 protein was added. The female mice mated with the nonvasectomy male mice were used as the surrogates. Subsequently, the 2-cell stage gene edited embryos were transferred into the unilateral oviduct, and the F0 tau-V337M mutation mice were obtained. Higher mutation efficiency could be obtained by adding Rad51 protein. The F0 tau-V337M point mutation mice can pass the mutation on to the F1 generation mice. In conclusion, this study successfully established the first tau-V337M mutation mouse by using Cas9, ssODN and Rad51. These results provide a new method for developing AD mice model which can be used in further research on the pathogenesis and treatment of AD.
Animals ; Male ; Female ; Mice ; Humans ; CRISPR-Cas Systems/genetics* ; RNA, Guide, CRISPR-Cas Systems ; Rad51 Recombinase/genetics* ; Mice, Inbred C57BL ; Disease Models, Animal ; Recombination, Genetic

OBJECTIVES: To derive general formulas for calculating commonly used kinship index (KI). METHODS: By introducing the Kronecker symbol, the formulas used to calculate the same KI under different genotype combinations were summarized into a unified expression. RESULTS: The general formulas were successfully derived for KI in various case situations, including the paternity index, full sibling index, half sibling index, avuncular index, grandpaternity index, first-cousin index, and second-cousin index between two individuals without or with the mother being involved; grandpaternity index between grandparents and a grandchild without or with the mother being involved; half sibling index between two children with two mothers being involved; full sibling index among three children; and half sibling index among three children with no, one, or two mothers being involved. CONCLUSIONS The general formulas given in this study simplify the calculation of KIs and facilitate fast and accurate calculation through programming.
Female ; Child ; Humans ; Paternity ; Siblings ; Genotype ; Mothers ; Models, Genetic

OBJECTIVE: To compare the accuracy of five warfarin-dosing algorithms and warfarin stable dose model (2.5 mg/day) for Shandong population. METHODS: One hundred and twenty five patients who achieved stable warfarin dose were enrolled. Clinical and genetic data were used to evaluate the value of each algorithm by calculating the percentage of patients whose predicted warfarin dose was within 20% of the actual stable therapeutic dose and mean absolute error (MAE). RESULTS: The frequency of patients with CYP2C9*1/*1, CYP2C9*1/*3 and CYP2C9*1/*2 genotype was 92.00%, 7.20%, 0.80%, respectively. That of VKORC1-1639 AA, AG and GG genotype was 82.40%, 15.20%, 2.40%, respectively. CYP4F2*1/*1, *1/*3, *3/*3 genotype was 50.40%, 39.20%, 10.40%, respectively. With the same genotypes for other loci, patients who carried at least one VKORC1-16398G mutant allele had increased warfarin stable daily dose compared with VKORC1-1639AA. Compared with CYP4F2*1/*1, those carrying at least one CYP4F2*3 mutant allele had warfarin stable daily dose increased by 5.9%-13.00%. The percentage of ideal prediction calculated from IWPC model (59.20%), Huang model (57.60%) and Ohno model (52.80%) were higher than others. The MAE were 0.35 (95%CI: 0.11-0.49), 0.15 (95%CI: 0.10-0.32), 0.39 (95%CI: 0.12-0.51), respectively. CONCLUSION The polymorphisms of CYP2C9, VKORC1 and CYP4F2 genes can influence the stable dose of warfarin in Shandong population. IWPC algorithm is suitable for guiding the use of warfarin in this population.
Anticoagulants ; administration & dosage ; Aryl Hydrocarbon Hydroxylases ; Cytochrome P-450 CYP2C9 ; genetics ; Cytochrome P450 Family 4 ; genetics ; Dose-Response Relationship, Drug ; Genotype ; Humans ; Models, Theoretical ; Polymorphism, Genetic ; Vitamin K Epoxide Reductases ; genetics ; Warfarin ; administration & dosage

The 2019 novel coronavirus disease (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has occurred in China and around the world. SARS-CoV-2-infected patients with severe pneumonia rapidly develop acute respiratory distress syndrome (ARDS) and die of multiple organ failure. Despite advances in supportive care approaches, ARDS is still associated with high mortality and morbidity. Mesenchymal stem cell (MSC)-based therapy may be an potential alternative strategy for treating ARDS by targeting the various pathophysiological events of ARDS. By releasing a variety of paracrine factors and extracellular vesicles, MSC can exert anti-inflammatory, anti-apoptotic, anti-microbial, and pro-angiogenic effects, promote bacterial and alveolar fluid clearance, disrupt the pulmonary endothelial and epithelial cell damage, eventually avoiding the lung and distal organ injuries to rescue patients with ARDS. An increasing number of experimental animal studies and early clinical studies verify the safety and efficacy of MSC therapy in ARDS. Since low cell engraftment and survival in lung limit MSC therapeutic potentials, several strategies have been developed to enhance their engraftment in the lung and their intrinsic, therapeutic properties. Here, we provide a comprehensive review of the mechanisms and optimization of MSC therapy in ARDS and highlighted the potentials and possible barriers of MSC therapy for COVID-19 patients with ARDS.
Adoptive Transfer ; Alveolar Epithelial Cells ; pathology ; Animals ; Apoptosis ; Betacoronavirus ; Body Fluids ; metabolism ; CD4-Positive T-Lymphocytes ; immunology ; Clinical Trials as Topic ; Coinfection ; prevention & control ; therapy ; Coronavirus Infections ; complications ; immunology ; Disease Models, Animal ; Endothelial Cells ; pathology ; Extracorporeal Membrane Oxygenation ; Genetic Therapy ; methods ; Genetic Vectors ; administration & dosage ; therapeutic use ; Humans ; Immunity, Innate ; Inflammation Mediators ; metabolism ; Lung ; pathology ; physiopathology ; Mesenchymal Stem Cell Transplantation ; methods ; Mesenchymal Stem Cells ; physiology ; Multiple Organ Failure ; etiology ; prevention & control ; Pandemics ; Pneumonia, Viral ; complications ; immunology ; Respiratory Distress Syndrome, Adult ; immunology ; pathology ; therapy ; Translational Medical Research

BACKGROUND: Radial probe endobronchial ultrasound (R-EBUS), is effective for tissue diagnosis of lung lesions. We evaluated the diagnostic performance of R-EBUS both a guide-sheath and fluoroscopy and identified factors associated with accurate diagnosis. The feasibility of molecular and genetic testing, using specimens obtained by R-EBUS, was also investigated. METHODS: The study retrospectively reviewed 211 patients undergoing R-EBUS without a guide-sheath and fluoroscopy, June 2016-May 2017. After excluding 27 patients of which the target lesion was not reached, 184 were finally included. Multivariate logistic regression was used, to identify factors associated with accurate diagnosis. RESULTS: Among 184 patients, R-EBUS-guided biopsy diagnosed malignancy in 109 patients (59%). The remaining 75 patients (41%) with non-malignant results underwent additional work-ups, and 34 were diagnosed with malignancy. Based on final diagnosis, diagnostic accuracy was 80% (136/170), and sensitivity and specificity for malignancy were 76% (109/143) and 100% (27/27), respectively. In multivariate analysis, peripheral location (adjusted odds ratio [aOR], 3.925; 95% confidence interval [CI], 1.203–12.811; p=0.023), and central position of the probe (aOR, 2.435; 95% CI, 1.424–7.013; p=0.035), were associated with accurate diagnosis of malignancy. Molecular and genetic analyses were successful, in all but one case, with inadequate specimens. CONCLUSION: R-EBUS-guided biopsy without equipment, is effective for tissue diagnosis. Peripheral location and central position of the radial probe, were crucial for accurate diagnosis. Performance of molecular and genetic testing, using samples obtained by R-EBUS, was satisfactory.
Biopsy ; Bronchoscopy ; Diagnosis ; Fluoroscopy ; Genetic Testing ; Humans ; Logistic Models ; Lung ; Lung Neoplasms ; Multivariate Analysis ; Odds Ratio ; Retrospective Studies ; Sensitivity and Specificity ; Ultrasonics ; Ultrasonography

PURPOSE: Genome-wide association studies (GWAS) have revealed that common variants on or near EDNRA, HDAC9, SOX17, RP1, CDKN2B-AS1, and RBBP8 genes are associated with intracranial aneurysm (IA) in European or Japanese populations. However, due to population heterogeneity, whether these loci are associated with IA pathogenesis in Chinese individuals is still unknown. The purpose of this study was to investigate associations among GWAS-identified loci and risk of IA in a Chinese population. MATERIALS AND METHODS: A total of 765 individuals (including 230 IA patients and 535 controls) were involved in this study. Twelve single nucleotide polymorphisms (SNPs) of candidate loci were genotyped using the Sequenom MassARRAY platform. Associations were analyzed using univariate or multivariate logistic regression analysis. RESULTS: SNPs in CDKN2B-AS1 (especially rs10757272) showed significant associations with IA in dominant and additive models [odds ratio (OR), 2.99 and 1.43; 95% confidence interval (CI), 1.44–6.24 and 1.10–1.86, respectively]. A SNP near HDAC9 (rs10230207) was associated with IA in the dominant model (OR, 1.42; 95% CI, 1.01–1.99). One SNP near RP1 (rs1072737) showed a protective effect on IA in the dominant model (OR, 0.66; 95% CI, 0.46–0.95), while another SNP in RP1 (rs9298506) showed a risk effect on IA in a recessive model (OR, 3.82; 95% CI, 1.84–7.91). No associations were observed among common variants near EDNRA, SOX17, or RBBP8 and IA. CONCLUSION: These data partially confirmed earlier results and showed that variants in CDKN2B-AS1, RP1, and HDAC9 could be genetic susceptibility factors for IA in a Chinese population.
Asian Continental Ancestry Group ; Genetic Predisposition to Disease ; Genome-Wide Association Study ; Humans ; Intracranial Aneurysm ; Logistic Models ; Polymorphism, Genetic ; Polymorphism, Single Nucleotide ; Population Characteristics

PURPOSE: Mismatch repair (MMR) deficiency plays a critical role in rectal cancer. This study aimed to explore the associations between genetic variations in seven MMR genes and adverse events (AEs) and survival of patients with rectal cancer treated with postoperative chemoradiotherapy (CRT). MATERIALS AND METHODS: Fifty single nucleotide polymorphisms in seven MMR (MLH1, MLH3, MSH2, MSH3, MSH6, PMS1 and PMS2) genes were genotyped by Sequenom MassARRAY method in 365 patients with locally advanced rectal cancer receiving postoperative CRT. The associations between genotypes and AEs were measured by odds ratios and 95% confidence intervals (CIs) by unconditional logistic regression model. The associations between genetic variations and survival were computed by the hazard ratios and 95% CIs by Cox proportional regression model. RESULTS: The most common grade ≥ 2 AEs in those 365 patients, in decreasing order, were diarrhea (44.1%), leukopenia (29.6%), and dermatitis (18.9%). Except 38 cases missing, 61 patients (18.7%) died during the follow-up period. We found MSH3 rs12513549, rs33013 and rs6151627 significantly associated with the risk of grade ≥ 2 diarrhea. PMS1 rs1233255 had an impact on the occurrence of grade ≥2 dermatitis. Meanwhile, PMS1 rs4920657, rs5743030, and rs5743100 were associated with overall survival (OS) time of rectal cancer. CONCLUSION: These results suggest that MSH3 and PMS1 polymorphisms may play important roles in AEs prediction and prognosis of rectal cancer patients receiving postoperative CRT, which can be potential genetic biomarkers for rectal cancer personalized treatment.
Biomarkers ; Chemoradiotherapy ; Dermatitis ; Diarrhea ; DNA Mismatch Repair ; Follow-Up Studies ; Genetic Variation ; Genotype ; Humans ; Leukopenia ; Logistic Models ; Methods ; Odds Ratio ; Polymorphism, Single Nucleotide ; Prognosis ; Rectal Neoplasms

OBJECTIVE: Spermatogenesis is a complex process that is regulated by a number of genes, some of which are involved in folate-dependent 1-carbon metabolism. Methionine synthase (encoded by MTR) is a key enzyme participating in this pathway. This study aimed to investigate the relationship of the MTR 2756A > G polymorphism with idiopathic male fertility in the Iranian population. METHODS: The participants of this study included 100 men with idiopathic infertility and 100 healthy men as the control group. Genotyping of MTR 2756A > G was performed using the polymerase chain reaction and restriction fragment length polymorphism technique. The obtained data were analyzed using SPSS ver. 20.0 with a level of confidence of p< 0.05. RESULTS: The frequencies of the A and G alleles at this locus were 77% and 23% in infertile patients and 84% and 16% in the control group, respectively. The frequencies of the GG, GA, and AA genotypes were 5%, 36%, and 59% in the infertile patients versus 3%, 27%, and 70% in the control group, respectively. No significant difference was observed in any genetic models. CONCLUSION: In general, the findings of this study suggest that the MTR 2756A > G single-nucleotide polymorphism is not a predisposing factor for idiopathic infertility in men.
5-Methyltetrahydrofolate-Homocysteine S-Methyltransferase ; Alleles ; Causality ; Fertility ; Genotype ; Humans ; Infertility ; Infertility, Male ; Male ; Male ; Metabolism ; Methionine ; Models, Genetic ; Polymerase Chain Reaction ; Polymorphism, Restriction Fragment Length ; Spermatogenesis

Parkinson’s disease (PD) is one of the late-onset neurodegenerative movement disorder. Major pathological markers of PD include progressive loss of dopaminergic neurons, Lewy body formation, genetic mutations, and environmental factors. Epigenetic regulation of specific gene expression via impaired histone acetylation is associated with neuronal dysfunction in various neurodegenerative diseases. In this study, we hypothesized that histone deacetylase (HDAC) inhibitor, valproic acid (VPA), can improve motor function by enhancing cell survival in PD genetic model mice with LRRK2 R1441G mutation. To address this question, we administered VPA in LRRK2 R1441G transgenic mice to determine whether VPA affects 1) histone acetylation and HDAC expression, 2) dopaminergic neuron survival, 3) inflammatory responses, 4) motor or non-motor symptoms. As results, VPA administration increased histone acetylation level and the number of tyrosine hydroxylase (TH) positive neurons in substantia nigra of LRRK2 R1441G mice. VPA reduced iba-1 positive activated microglia and the mRNA levels of pro-inflammatory marker genes in LRRK2 R1441G mice. In addition, VPA induced the improvement of PD-like motor and non-motor behavior in LRRK2 R1441G mice. These data suggest that the inhibition of HDAC can be further studied as potential future therapeutics for PD.
Acetylation ; Animals ; Cell Survival ; Dopaminergic Neurons ; Epigenomics ; Gene Expression ; Histone Deacetylases ; Histones ; Lewy Bodies ; Mice ; Mice, Transgenic ; Microglia ; Models, Genetic ; Movement Disorders ; Neurodegenerative Diseases ; Neurons ; Neuroprotection ; RNA, Messenger ; Substantia Nigra ; Tyrosine 3-Monooxygenase ; Valproic Acid