Transcription factor PbNAC71 regulates xylem and vessel development to control plant height.

Dwarfism is an important agronomic trait in fruit breeding programs. However, the germplasm resources required to generate dwarf pear (Pyrus spp.) varieties are limited. Moreover, the mechanisms underlying dwarfism remain unclear. In this study, "Yunnan" quince (Cydonia oblonga Mill.) had a dwarfing effect on "Zaosu" pear. Additionally, the dwarfism-related NAC transcription factor gene PbNAC71 was isolated from pear trees comprising "Zaosu" (scion) grafted onto "Yunnan" quince (rootstock). Transgenic Nicotiana benthamiana and pear OHF-333 (Pyrus communis) plants overexpressing PbNAC71 exhibited dwarfism, with a substantially smaller xylem and vessel area relative to the wild-type controls. Yeast one-hybrid, dual-luciferase, chromatin immunoprecipitation-qPCR, and electrophoretic mobility shift assays indicated that PbNAC71 downregulates PbWalls are thin 1 expression by binding to NAC-binding elements in its promoter. Yeast two-hybrid assays showed that PbNAC71 interacts with the E3 ubiquitin ligase PbRING finger protein 217 (PbRNF217). Furthermore, PbRNF217 promotes the ubiquitin-mediated degradation of PbNAC71 by the 26S proteasome, thereby regulating plant height as well as xylem and vessel development. Our findings reveal a mechanism underlying pear dwarfism and expand our understanding of the molecular basis of dwarfism in woody plants.

Primary drug resistance among HIV-1 patients in Hubei Province in 2020-2022 / 公共卫生与预防医学

Objective To investigate the prevalence of primary drug resistance among HIV-1 patients in Hubei Province from 2020 to 2022, and to provide corresponding basis and data support for HIV antiviral therapy (ART) in Hubei Province. Methods During 2020-2022, plasma samples of HIV-1 infected patients before ART were collected., Patients’ demographic data and baseline laboratory test data were also collected. HIV-1 pol region was amplified by in-house method for sub-type typing and drug-resistant mutation site analysis. Results The pol gene sequence was successfully amplified in 242 of 285 cases, with a success rate of 84.9%. CRF07_BC was the predominant HIV-1 sub-type, accounting for 47.11% (114/242), followed by CRF01_AE, accounting for 25.21% (61/242), sub-type B, accounting for 14.16% (35/242), and CRF55_01B, accounting for 4.13% (10/242). The primary resistance rate was 6.20% (15/242). The mutation site of nucleoside reverse transcriptase inhibitors (NRTIs) was mainly M184V, and the mutation sites of non-nucleoside reverse transcriptase inhibitors (NNRTIs) were mainly E138A/G/EG and V179E. These different mutation sites led to different degrees of drug resistance to 12 drugs. The incidence of drug resistance mutation of CRF55_01B sub-type was significantly higher than that of other sub-types. Conclusion The primary drug resistance rate of HIV-1 infected patients is at a slightly high level in Hubei Province, and close monitoring of primary drug resistance and mutation sites should be strengthened before ART, especially for CRF55_01B sub-type.

Intestinal bacteria-a powerful weapon for fungal infections treatment.

The morbidity and mortality of invasive fungal infections are rising gradually. In recent years, fungi have quietly evolved stronger defense capabilities and increased resistance to antibiotics, posing huge challenges to maintaining physical health. Therefore, developing new drugs and strategies to combat these invasive fungi is crucial. There are a large number of microorganisms in the intestinal tract of mammals, collectively referred to as intestinal microbiota. At the same time, these native microorganisms co-evolve with their hosts in symbiotic relationship. Recent researches have shown that some probiotics and intestinal symbiotic bacteria can inhibit the invasion and colonization of fungi. In this paper, we review the mechanism of some intestinal bacteria affecting the growth and invasion of fungi by targeting the virulence factors, quorum sensing system, secreting active metabolites or regulating the host anti-fungal immune response, so as to provide new strategies for resisting invasive fungal infection.

Inhibitory effects of a maleimide compound on the virulence factors of Candida albicans.

Candidiasis caused by Candida albicans infection has long been a serious human health problem. The pathogenicity of C. albicans is mainly due to its virulence factors, which are novel targets of antifungal drugs for low risk of resistance development. In this study, we identified a maleimide compound [1-(4-methoxyphenyl)-1hydro-pyrrole-2,5-dione, MPD] that exerts effective anti-virulence activity. It could inhibit the process of adhesion, filamentation, and biofilm formation in C. albicans. In addition, it exhibited low cytotoxicity, hemolytic activity, and drug resistance development. Moreover, in Galleria mellonella-C. albicans (in vivo) infection model, the survival time of infected larvae was significantly prolonged under the treatment of MPD. Further, mechanism research revealed that MPD increased farnesol secretion by upregulating the expression of Dpp3. The increased farnesol inhibited the activity of Cdc35, which then decreased the intracellular cAMP content resulting in the inhibition of virulence factors via the Ras1-cAMP-Efg1 pathway. In all, this study evaluated the inhibitory effect of MPD on various virulence factors of C. albicans and identified the underlying mechanisms. This suggests a potential application of MPD to overcome fungal infections in clinics.

'Yunnan' quince rootstock promoted flower bud formation of 'Abbé Fetel' pear by altering hormone levels and PbAGL9 expression.

Flower busd formation is an important plant growth process. It has been reported that dwarfing rootstocks can significantly affect the flower bud formation of scions. In this study, we found the dwarfing rootstock 'Yunnan' quince could significantly increase the flowering rate of 'Abbé Fetel' pear scions. The RNA-sequencing data revealed significant changes in the expression of genes related to hormone pathways. Furthermore, hormone analyses indicated that 'Yunnan' quince significantly decreased the GA3 content and increased the cytokinin/auxin ratio in 'Abbé Fetel' pear apical buds. The hormone contents were consistent with the RNA-sequencing data. Moreover, we found the flower development-related genes PbAGL9 and PbCAL-A1 were significantly upregulated and PbTFL1 was significantly downregulated in 'Abbé Fetel'/'Yunnan' quince apical buds. To further clarify the relationship between hormones and flowering-related genes, a hormone response assay was carried out. We found the expression levels of PbCAl-A1, PbTFL1 and PbAGL9 were regulated by hormones including GA3, CPPU and NAA. Y1H and dual-luciferase assays indicated that PbAGL9 significantly decreased the promoter activity of PbTFL1. In summary, 'Yunnan' quince upregulated PbCAL-A1 and PbAGL9, and downregulated PbTFL1 expression by decreasing the GA3 content and increasing the cytokinin/auxin ratio in 'Abbé Fetel' pear apical buds. Additionally, 'Yunnan' quince down-regulate PbTFL1 by upregulating the expression of PbAGL9, and eventually promoted floral induction in 'Abbé Fetel' pear.

Rapid identification of methicillin-resistant Staphylococcus aureus by MALDI-TOF MS: A meta-analysis.

Invasive infections caused by methicillin-resistant Staphylococcus aureus (MRSA) are associated with high mortality and morbidity. The sooner the pathogen is determined, the better it is beneficial to patient. However, routine laboratory inspections are time-consuming and laborious. A thorough research was conducted in PubMed and Web of Science (until June 2021) to identify studies evaluating the accuracy of MRSA identification by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS). STATA 15.0 software was used to analyze the pooled results of sensitivity, specificity, and 95% confidence intervals (CI). The summary receiver operating characteristic curves (SROC) and area under the curve (AUC) were utilized to show the overall performance of MALDI-TOF MS. Fifteen studies involving 2471 isolates were included in this study after the final selection in this meta-analysis. Using the random effects model forest plot to summarize the overall statistics, the sensitivity of MALDI-TOF MS for identifying MRSA was 92% (95% CI: 81%-97%), and the specificity was 97% (95% CI: 89%-99%). In the SROC curve, the AUC reached 0.99 (95% CI: 97%-99%). Deeks' test showed no significant publication bias in this meta-analysis. Compared with clinical reference methods, MALDI-TOF MS identification of MRSA shows a higher degree of sensitivity and specificity.

The value of exhaled nitric oxide in assessing the risk of acute exacerbation and guiding the use of ICS in patients with COPD / 中国医师杂志

Objective:To explore the predictive value of exhaled nitric oxide (FeNO) for the risk of acute exacerbation in stable chronic obstructive pulmonary disease (COPD) patients over the next year and evaluate whether it can guide the use of inhaled corticosteroids (ICS).Methods:This study was a multicenter, retrospective and observational cohort study. The subjects of this study were stable COPD patients who were hospitalized in 12 hospitals in Hunan Province and Guangxi from January 2017 to December 2021. The patient′s basic Demography information, previous acute exacerbation history, pulmonary function, FeNO, chronic obstructive pulmonary disease assessment test questionnaire (CAT) score, modified British Medical Research Council dyspnea questionnaire (mMRC) score, chronic obstructive pulmonary disease control questionnaire (CCQ) score, and detailed treatment plan were collected. Based on FeNO 25 ppb, patients were divided into a high FeNO group and a normal FeNO group. All patients were followed up for 1 year and information on acute exacerbation was recorded.Results:A total of 825 patients were included, aged (63.5±9.1)years, with a median of 25 ppb of FeNO. A number of 825 patients were followed up for 1 year, of which 262(31.8%) experienced acute exacerbation. Multivariate logistic regression found that FeNO, CAT score, smoking cessation, and past history of acute exacerbation were independent factors predicting acute exacerbation in COPD patients in the next year (all P<0.05). High FeNO was a protective factor for acute exacerbation in COPD patients in the next year, with an OR value of 0.10 ( P<0.001). Further analysis found that the proportion of patients in the high FeNO group using ICS was significantly higher than that in the normal FeNO group [58.8%(247/420) vs 48.6%(197/405), P=0.003]. In the high FeNO group, using ICS can reduce the incidence of acute exacerbation of COPD in the next year [8.9%(22/247) vs 15.6%(27/173), P<0.05], while in the normal FeNO group, there was no statistically significant difference in the frequency of acute exacerbation between patients using ICS and those not using ICS ( P>0.05). Conclusions:FeNO is an independent factor predicting the acute exacerbation of COPD in the next year, and patients with high FeNO levels may consider using ICS in combination.

Related factors of acute exacerbation of chronic obstructive pulmonary disease and the value of inhaled glucocorticoid guided by eosinophil in peripheral blood / 中国医师杂志

Objective:To explore the risk factors of acute exacerbation (AE) of chronic obstructive pulmonary disease (COPD) and whether Eosinophil (EOS) in peripheral blood can guide the treatment of inhaled corticosteroids (ICS).Methods:This study was a single center, Prospective cohort study. The subjects of this study were from stable COPD patients who were treated in the Department of Respiratory Medicine of the Xiangya Second Hospital of Central South University from January 2020 to December 2021. Patient general information, past year AE status, exposure risk factors, modified version of the British Medical Research Council Respiratory Difficulty Questionnaire (mMRC) score, Chronic Obstructive Pulmonary Disease Assessment Questionnaire (CAT) score, ICS usage, lung function, blood routine, etc. were collected. We followed up the patient for one year. During the follow-up period, the clinical characteristics of patients with and without AE were compared to analyze the correlation between blood EOS and ICS use.Results:The median blood EOS of 617 stable COPD patients was 0.13×10 9/L, 289 patients (46.8%) with chronic obstructive pulmonary disease had a history of AE, and 207 patients (33.5%) experienced AE during 1-year follow-up. The results of univariate analysis showed that the future occurrence of AE in COPD was correlated with body mass index (BMI), AE history, Global Initiative for Chronic Obstructive Lung Disease (GOLD) grading, GOLD grouping, mMRC score, and CAT score (all P<0.05). The results of logistic multiple factor regression analysis showed that patients with BMI<24 kg/m 2, AE in the past year, severe AE in the past year, smoking history and other exposure factors, GOLD level 2 or above, GOLD C and D groups, and mMRC score≥ 2 had a higher risk of future AE (all P<0.05). There was no statistically significant difference in the incidence of AE between patients with COPD with different levels of EOS and those without ICS during a 1-year follow-up period (all P>0.05). Conclusions:The past 1-year AE history, BMI, exposure risk factors, degree of airflow restriction, and respiratory symptoms of patients with chronic obstructive pulmonary disease can predict future AE risk. There is no significant difference in future AE risk among patients with different levels of EOS, and EOS cannot guide ICS treatment to reduce AE risk.

Symptom scores of patients with chronic obstructive pulmonary disease and their response to different inhalation drug treatments / 中国医师杂志

Objective:To analyze the response of patients with chronic obstructive pulmonary disease (COPD) with multiple and few symptoms to different inhalation drugs, including acute exacerbation and symptom changes.Methods:This study was a multi center, retrospective Cohort study. The subjects of this study were patients with chronic obstructive pulmonary disease in stable stage in 12 hospitals in Hunan and Guangxi from December 2016 to February 2022. Demographics data, lung function, Chronic Obstructive Pulmonary Disease Assessment test questionnaire (CAT) score, modified British Medical Research Council dyspnea questionnaire (mMRC) score and inhalation drug scheme of patients were collected. According to the CAT and mMRC scores, patients were divided into a multi symptom group (CAT≥10 points or mMRC≥2 points) or a few symptom group (CAT<10 points and mMRC<1 point); Subsequently, they were divided into four subgroups based on the inhalation drug regimen: long-acting anticholinergic drugs (LAMA) group, long-acting β2-receptor agonists (LABA)+ inhaled corticosteroids (ICS) group, LABA+ LAMA group, and LABA+ LAMA+ ICS group. All patients were followed up for 1 year, with minimum clinical improvement (MCID) defined as a decrease of ≥2 points in the patient′s CAT score at 6 months, and clinical symptom deterioration (CSD) defined as an increase of ≥2 points in the patient′s CAT score at 6 months.Results:A total of 929 patients with chronic obstructive pulmonary disease were included, including 719(77.4%) with multiple symptoms and 210(22.6%) with few symptoms. There was no statistically significant difference in MCID, CSD, acute exacerbation, hospitalization frequency, and mortality rate among subgroups of asymptomatic COPD patients treated with different inhalation drug regimens (all P>0.05). Among patients with multiple symptoms of chronic obstructive pulmonary disease, compared to those who use LAMA or LABA+ ICS, those who used LABA+ LAMA or LABA+ LAMA+ ICS were more likely to obtain MCID and had a more significant improvement in CAT scores, and the risk of acute exacerbation is lower (all P<0.05). Conclusions:Lesser symptomatic COPD patients should receive single drug LAMA as the initial inhalation treatment drug, while multi symptomatic COPD patients should receive LABA+ LAMA as the initial inhalation treatment drug.

Precision medicine in chronic obstructive pulmonary disease / 中国医师杂志

Chronic obstructive pulmonary disease (COPD) is a complex and heterogeneous chronic Respiratory disease. In the past 20 years, precision medicine has gradually integrated into the management of COPD. At present, individualized treatment is mainly based on its symptoms, acute exacerbation risk and eosinophil count. In the future, with the development of risk factors and their pathophysiology, quantitative imaging technology, biomarkers and gene analysis, precision medicine will have further development in the management of COPD treatment.

Progress and future perspective of epidemiological research of air pollution and climate change in the context of achieving carbon peaking and carbon neutrality goals / 中华流行病学杂志

Climate change is the great health challenge for human beings in the 21st century. Air pollution is also an important public health problem worldwide. China announced the climate commitment to achieve carbon peaking by 2030 and carbon neutrality by 2060. Achieving these goals would not only have far-reaching effects on air pollution control and climate change, but also improve the population health in China. Air pollution and climate change epidemiology are important aspects of environmental epidemiology. In this paper, we discuss the current status and future development of epidemiological research of air pollution and climate change in the context of achieving carbon peaking and carbon neutrality goals to provide ideas and suggestions for environmental and health studies in the future.

Study on molecular mechanism of Jichuanjian improving Yang deficiency constipation based on Ca / 中国药理学通报

Aim To investigate the effect of JiChuanjian(JCJ)on the Yang deficiency constipation based on Ca

Quality Difference Analysis of Raw and Steamed Products of Citri Reticulatae Pericarpium Based on Electronic Eye Technique and Chemical Fingerprint / 中国实验方剂学杂志

ObjectiveTo explore the quality differences between steamed products and raw products of Citri Reticulatae Pericarpium（CRP）. MethodThe color of steamed products and raw products of CRP was determined from the perspective of appearance by electronic eye technique， and the quality differences between them was objectively characterized by the luminous value（L*）， yellow-blue value（b*）， red-green value（a*） and total chromatic value（E*ab）. Based on this， ultra-high performance liquid chromatography（UPLC） was used to establish a fingerprint evaluation method with the mobile phase of acetonitrile（A）-0.1% formic acid aqueous solution（B） for gradient elution（0-5 min， 5%A； 5-30 min， 5%-20%A； 30-60 min， 20%-52%A）， detection wavelength at 270 nm， flow rate of 0.3 mL·min-1 and column temperature of 30 ℃. The quality differences between steamed products and raw products of CRP were compared from the perspective of chemical composition， and correlation analysis was used to reveal the correlation between the difference in appearance color and the difference in internal chemical composition. ResultAfter being steamed， L*， b* and E*ab of CRP showed an overall decreasing trend， indicating that the color of the steamed products darkened and deepened from yellow to blue but still tended to be yellow， while a* showed an overall increasing trend， indicating that the color of the steamed products tended to red. A total of 24 peaks were identified in the fingerprint profiles of raw products and steamed products of CRP， and 13 of the main peaks were identified. The precision， stability and repeatability studies showed that compared with the reference peak （peak 14， hesperidin）， the relative standard deviations（RSDs） of the relative peak area and relative retention time of the remaining peaks were<3.0%.The results of chemometric statistical analysis showed that there were some differences between raw products and steamed products of CRP， and 7 main differential components were identified， among which 5-hydroxymaltol（peak 1） and 5-hydroxymethylfurfural（peak 2） were the characteristic components of steamed products. The correlation analysis results showed that， in addition to the above two characteristic components， four components of peak 4， peak 10 （vicenin-2）， peak 23 （tangeretin） and peak 24 （5-demethylnobiletin） also correlated significantly with the color change （E*ab） of the samples （P<0.05， P<0.01）. ConclusionBefore and after steaming， not only the chemical composition changes， but also the color. Comparing the characteristic peaks of chemical composition difference and color difference before and after steaming of CRP， it is found that 5-hydroxymaltol， 5-hydroxymethylfurfural and peak 4 are common characteristic difference components， which can provide a reference for establishing the characteristic quality control method of steamed products， and quickly evaluating the quality difference between raw products and steamed products of CRP.

Bavachin induces apoptosis in colorectal cancer cells through Gadd45a via the MAPK signaling pathway / 中国天然药物

Bavachin is a dihydroflavonoid compound isolated from Psoralea corylifolia, and exhibits anti-bacterial, anti-inflammatory, anti-tumor and lipid-lowering activities. Recent attention has gradually drawn on bavachin-induced apoptosis in many human cancer cell lines. However, the anti-cancer effects and related mechanisms in colorectal cancer remain unknown. Here, we investigated the effects of bavachin on colorectal cancer in vivo and in vitro. The results showed that bavachin inhibited the proliferation of human colorectal cancer cells and induce apoptosis. These changes were mediated by activating the MAPK signaling pathway, which significantly up-regulated the expression of Gadd45a. Furthermore, Gadd45a silencing obviously attenuated bavachin-mediated cell apoptosis. Inhibition of the MAPK signaling pathway by JNK/ERK/p38 inhibitors also weakened the up-regulation of Gadd45a by bavachin. The anticancer effect of bavachin was also validated using a mouse xenograft model of human colorectal cancer. In conclusion, these findings suggest that bavachin induces the apoptosis of colorectal cancer cells through activating the MAPK signaling pathway.

Effect of fluoxetine combined with Shugan Jieyu capsule in the treatment of patients with depression and its impact on heart rate variability / 四川精神卫生

BackgroundDepression is a kind of disease with relatively high suicide risk， which seriously affects the quality of life of patients and their families， and brings a great burden to society. Antidepressants in western medicine are effective， but the improvement of depressive symptoms is relatively limited by single use， and the combination of two antidepressants may increase the risk of adverse reactions in patients. The rational use of Chinese patent medicine and western medicine may play a complementary role， and the safety of Chinese patent medicine is high. ObjectiveTo explore the early clinical efficacy of fluoxetine combined with Shugan Jieyu capsule in the treatment of depression， and to compare the differences in efficacy， safety and influence on heart rate variability between fluoxetine combined with Shugan Jieyu capsule and fluoxetine alone， so as to provide references for clinical medication of depression patients. MethodsFrom December 2015 to June 2016， 64 patients who met the diagnostic criteria of depression in the Diagnostic and Statistical Manual of Mental Disorders， fifth edition （DSM-5） who were hospitalized in the Second Affiliated Hospital of Xinxiang Medical University were selected as the research objects， and were randomly divided into the combined medication group and the fluoxetine group with 32 patients in each group. Patients in both groups were treated with fluoxetine， while patients in the combined medication group were treated with Shugan Jieyu capsule on this basis. Patients in both groups were assessed with Hamilton Depression Scale-24 item （HAMD-24）， Hamilton Anxiety Scale （HAMA） and Heart Rate Variability （HRV） before treatment， and were assessed with HAMD-24 and Treatment Emergent Symptom Scale （TESS） at the end of the 2nd， 4th and 6th week of treatment， and HRV was analyzed again at the end of the 6th week of treatment. ResultsThe study ultimately included 60 patients with depression， with 30 cases in the combination therapy group and 30 cases in the fluoxetine group. At the end of the 2nd， 4th and 6th week of treatment， the HAMD-24 score of the combined drug group was lower than that of the fluoxetine group （t=-2.677， -3.960， -4.432， P<0.05 or 0.01）. Compared with before treatment， the 24-hour mean standard deviation of normal RR intervals （SDNN）， normal low frequency （nLF） and normal high frequency （nHF） in the combined treatment group were higher at the end of the 6th week （t=-73.970， -31.878， -38.721， P<0.01）， but significant lower in LF/HF （t=3.525， P<0.01）. At the end of the 6th week of treatment， the total effective rate of the combined treatment group was higher than that of fluoxetine group， and the difference was statistically significant （86.67% vs. 70.00%， χ2=18.764， P<0.01）. At the 2nd， 4th and 6th week of treatment， there was no significant difference in the number of adverse reactions between the two groups （P>0.05）. ConclusionCompared with fluoxetine alone， Shugan Jieyu capsule combined with fluoxetine may be better in clinical efficacy and improvement of heart rate variability in patients with depression， without increasing adverse reactions.

PbXND1 Results in a Xylem-Deficient Dwarf Phenotype through Interaction with PbTCP4 in Pear (Pyrus bretschneideri Rehd.).

Dwarfing is an important agronomic characteristic in fruit breeding. However, due to the lack of dwarf cultivars and dwarf stocks, the dwarfing mechanism is poorly understood in pears. In this research, we discovered that the dwarf hybrid seedlings of pear (Pyrus bretschneideri Rehd.), 'Red Zaosu,' exhibited a xylem-deficient dwarf phenotype. The expression level of PbXND1, a suppressor of xylem development, was markedly enhanced in dwarf hybrid seedlings and its overexpression in pear results in a xylem-deficient dwarf phenotype. To further dissect the mechanism of PbXND1, PbTCP4 was isolated as a PbXND1 interaction protein through the pear yeast library. Root transformation experiments showed that PbTCP4 promotes root xylem development. Dual-luciferase assays showed that PbXND1 interactions with PbTCP4 suppressed the function of PbTCP4. PbXND1 expression resulted in a small amount of PbTCP4 sequestration in the cytoplasm and thereby prevented it from activating the gene expression, as assessed by bimolecular fluorescence complementation and co-location analyses. Additionally, PbXND1 affected the DNA-binding ability of PbTCP4, as determined by utilizing an electrophoretic mobility shift assay. These results suggest that PbXND1 regulates the function of PbTCP4 principally by affecting the DNA-binding ability of PbTCP4, whereas the cytoplasmic sequestration of PbTCP4 is only a minor factor. Taken together, this study provides new theoretical support for the extreme dwarfism associated with the absence of xylem caused by PbXND1, and it has significant reference value for the breeding of dwarf varieties and dwarf rootstocks of the pear.

Inhibitory effects of GT0918 on acute lung injury and the molecular mechanisms of anti-inflammatory response

Coronavirus disease 2019 (COVID-19) has caused the public health crisis in the whole world. Anti-androgens block severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) entry and protect against severe clinical COVID-19 outcomes. GT0918, a novel androgen receptor antagonist, accelerated viral clearance and increased recovery rate in outpatients by blocking SARS-CoV-2 infection though down-regulating ACE2 and TMPRSS2 expression. Further clinical study showed that GT0918 reduced mortality rate and shortened hospital stay in hospitalized COVID-19 patients. GT0918 also exhibits protective efficacy in severe COVID-19 patient in critical care. However, the mechanism of GT0918 treatment for severe COVID-19 disease is unknown. Here, we found GT0918 decreased the expression and secretion of proinflammatory cytokines through NF-{kappa}B signaling pathway. The acute lung injury induced by LPS or Poly(I:C) was also attenuated in GT0918-treated mice, compared with vehicle control group. Moreover, GT0918 elevated the NRF2 protein level but not mRNA transcription activity. GT0918 induced proinflammatory cytokines downregulation was partially dependent on NRF2. In conclusion, our data demonstrate that GT0918 reduced cytokine release and suppressed inflammatory responses through inhibiting NF-{kappa}B signaling and activating NRF2. GT0918 is not only effective for treatment of mild to moderate COVID-19 patients, but also a potential therapeutic drug for severe COVID-19 patients by reducing the risk of cytokine storm and acute respiratory distress syndrome.

Effects of Notch1 signaling on regulatory T cells and coronary artery lesions in childhood Kawasaki disease / 中华风湿病学杂志

Objective:To explore the effect of Notch1 signaling on regulatory T cells and its roles in vascular damage in patients with Kawasaki disease (KD).Methods:A total of 42 children with KD were enrolled in the present study from March 2019 to June 2020, as 32 age-matched healthy children were recruited as control. The proportions of CD4 +CD25 hiFoxp 3+ regulatory T cells (Treg) and expressions of transcription factor forkhead box protein 3 (Foxp3), cytotoxic T lymphocyte associated antigen-4 (CTLA4), glucocorticoid-induced tumor necrosis factor receptor (GITR), and Notch1 protein were evaluated by flow cytometry. Chromatin immunoprecipitation was conducted to detect acetylation level of histone H4 (H4Ac) associated with the promoter of Foxp3 gene and its binding abilities of Notch1 intracellular domain 1 (NICD1), recombination signal binding protein for immunoglobulin kappa J region (RBP-J) and p300 in CD4 + T cells. Transcription levels of Foxp3, presenilin 1 (PSEN1), mastermind like transcriptional coactivator 1 (MAML1), and RBP-J in CD4 + T cells were determined by real-time polymerase chain reaction (PCR). Concentrations of interleukin (IL)-10 and transforming growth factor-β (TGF-β) in plasma and culture supernatant stimulated with Jagged1 were measured by enzyme linked immunosorbent assay. Independent-sample t-test, Pearson correlation analysis was used as the statistical method in this study. Results:① The frequencies of Treg in acute KD patients decreased significantly [(4.3±1.5)% vs (7.9±2.9)%; t=6.41, P<0.001], as protein levels of Foxp3, CTLA4 and GITR and concentrations of IL-10 and TGF-β in plasma reduced remarkably in acute KD patients ( t=6.87, P<0.001; t=4.26, P<0.001; t=7.88, P<0.001; t=8.42, P<0.001; t=13.01, P<0.001). All parameters afore-mentioned in patients combined with coronary artery lesions (CAL) were lower than those of patients without coronary artery lesions (NCAL) ( t=5.83, P<0.001; t=3.83, P<0.001; t=3.28, P=0.002; t=5.05, P<0.001; t=5.96, P<0.001; t=5.17, P<0.001), and increased after therapy ( t=7.13, P<0.001; t=6.10, P<0.001; t=4.31, P<0.001; t=6.55, P<0.001; t=7.40, P<0.001; t=7.84, P<0.001). ② H4Ac associated with promoter of Foxp3 gene and the binding abilities of NICD1 and p300 in acute KD patients were lower than those of the controls ( t=10.25, P<0.001; t=6.93, P<0.001; t=6.75, P<0.001), and increased remarkably after therapy ( t=7.72, P<0.001; t=4.16, P<0.001; t=5.76, P<0.001). Meanwhile, the three items in CAL group were found to be less than those of NCAL group ( t=6.08, P<0.001; t=2.66, P=0.011; t=6.02, P<0.001). Pearson correlation analysis showed a positive correlation between H4Ac associated with Foxp3 promoter and its mRNA level in acute KD patients ( r=0.47, P<0.001). No statistical significant difference about the binding ability of RBP-J with Foxp3 promoter were found among the groups ( t=0.57, P>0.05; t=0.61, P>0.05; t=1.20, P>0.05). ③ Protein level of Notch1 and the expressions of PSEN1, MAML1 and RBP-J mRNA in CD4 + T cells from acute KD patients were down-regulated remarkably ( t=5.28, P<0.001; t=6.31, P<0.001; t=11.78, P<0.001; t=8.06, P<0.001), and restored after therapy ( t=4.77, P<0.001; t=6.43, P<0.001; t=11.95, P<0.001; t=7.79, P<0.001). In parallel, the four indexes aforementioned of CAL group were lower than those of NCAL group ( t=3.16, P=0.003; t=4.13, P<0.001; t=5.42, P<0.001; t=4.05, P<0.001). Upon rhJagged1 stimulation for 48 hours, H4Ac level of Foxp3 promoter and its binding abilities with NICD1 and p300 in CD4 + T cells in KD patients and control group was significantly higher than those of untreated group [(KD: t=15.36, P<0.001; t=7.25, P<0.001; t=14.29, P<0.001), (Ctrl: t=7.87, P<0.001; t=5.71, P<0.001; t=8.74, P<0.001)], as the binding ability of RBP-J with Foxp3 promoter increased slightly without statistically significant difference (KD: t=1.11, P>0.05; Ctrl: t=1.37, P>0.05). Simultaneously, H4Ac level of Foxp3 promoter and its binding abilities with NICD1 and p300 in KD group were still lower than those of the control group after stimulation ( t=3.86, P<0.001; t=3.42, P=0.001; t=2.85, P=0.006). ④ After incubation of PBMC from heathy children with KD serum, the proportion of Treg cells, protein level of Foxp3 and expressions of Notch1 and RBP-J in CD4 + T cells in the group treated with IVIG increased significantly compared with the untreated group ( t=7.10, P<0.001; t=10.16, P<0.001; t=8.06, P<0.001; t=9.77, P<0.001), as well as H4Ac level of Foxp3 promoter and its binding abilities with NICD1 in the group treat with IVIG were also higher than the latter ( t=7.24, P<0.001; t=8.24, P<0.001). Conclusion:Insufficiency and impaired function of Treg caused by aberrant Notch1 signaling may be the important factor contributing to immune dysfunction and vascular damage in KD.

Progress in arsenic carcinogenic signaling transduction pathway / 中华地方病学杂志

Arsenic, as a metal element, has metallic and non-metallic properties and is widely distributed in nature. In the list of carcinogens of the International Agency for Research on Cancer, arsenic is clearly listed as the first class of carcinogens. Chronic arsenic poisoning caused by arsenic contamination of drinking water is a major health problem facing human beings worldwide. This kind of pollution occurs naturally due to geological structure, and the most serious one can lead to cancer, among which skin cancer is the most specific. In addition, epidemiological studies have shown that long-term arsenic exposure can also lead to bladder cancer, lung cancer, and liver cancer, etc. However, there have been a number of different views on the potential mechanisms of arsenic carcinogenesis. Carcinogenesis through signal transduction pathway is one of the important molecular mechanisms, including Wnt, mitogen-activated protein kinase (MAPK), phosphatidylinositol 3 kinase-protein kinase B-mammalian target of rapamycin (PI3K/AKT/mTOR), nuclear factor kappa-B (NF-κB) and transforming growth factor-β (TGF-β). When there is a problem in the upstream and downstream or one of its links in the signal transduction pathway, the proliferation and differentiation of human cells are out of control, which can lead to cancer.

Analysis of urinary arsenic methylation metabolites in population exposed to arsenic through drinking water before and after water improvement / 中华地方病学杂志

Objective:To study the effect of water improvement on urinary arsenic methylation metabolism in population exposed to arsenic through drinking water.Methods:A cluster sampling method was used to select drinking water type arsenism areas in Bayannur City, Inner Mongolia Autonomous Region. Permanent residents lived in the arsenism areas for more than 10 years were selected as the survey subjects. Urine samples ( n = 874, 111, 145) were collected in 2004 (before water improvement), 2014 (4 years after water improvement) and 2017 (7 years after water improvement), respectively, and some subjects were followed up in 2014 and 2017. High performance liquid chromatography-inductively coupled plasma mass spectrometry (HPLC-ICP-MS) was used to detect different forms of arsenic metabolites in urine [inorganic arsenic (iAs), monomethylarsonic acid (MMA), dimethylarsenic acid (DMA)], and total arsenic (tAs), the iAs percentage (iAs%), MMA percentage (MMA%), DMA percentage (DMA%), monomethylation rate (PMI), dimethylation rate (SMI), and the ratio of MMA to DMA (MMA/DMA) were calculated. The content and distribution of urinary arsenic metabolites in people exposed to arsenic before and after water improvement were compared and analyzed. Results:Compared with 2004, the levels of iAs, MMA, DMA, tAs and iAs% in urine of arsenic exposed population in 2014 were lower ( Z =-14.12,-12.79,-14.27,-14.21,-6.90, P < 0.001), the levels of MMA%, DMA% and PMI were higher ( Z =-3.22,-2.91,-6.90, P < 0.05); in the same drinking water arsenic exposed population, compared with 2004, the levels of iAs, MMA, DMA, tAs and iAs% in urine ( n = 48) were lower ( Z =-5.57,-5.53,-5.54,-5.55,-2.86, P < 0.05) in 2014, and PMI level was higher ( Z =-2.86, P = 0.004). Compared with 2014, the levels of iAs% and MMA/DMA in urine of arsenic exposed population in 2017 were lower ( Z =-4.97,-2.25, P < 0.05), the levels of MMA, DMA, tAs, DMA%, PMI and SMI were higher ( Z =-4.01,-5.39,-4.77,-4.61,-4.97,-2.25, P < 0.05); in the same drinking water arsenic exposed population, compared with 2014, the level of iAs% in urine ( n = 28) was lower ( Z =-2.87, P = 0.004) in 2017, the levels of DMA% and PMI were higher ( Z =-2.32,-2.87, P < 0.05). Conclusion:Water improvement could significantly reduce the levels of urinary arsenic metabolites iAs, MMA, DMA and tAs and increase the level of DMA% in arsenic exposed population.