Novel mechanisms driving renal tubulointerstitial fibrosis / 中国临床药理学与治疗学

Renal fibrosis, especially tubulointerstitial fibrosis, is the most common pathway of all chronic kidney diseases progressing to end-stage renal diseases. Several adaptive reactions occur in renal tubular epithelial cells after chronic injury, such as changes in glycolipid metabolism, unfolded protein response, autophagy and senescence, epithelial-to-mesenchymal transition and G2/M cell cycle arrest. Maladaptive repair mechanisms can induce tubulointerstitial fibrosis. This article will discuss the molecular mechanism of these adaptive responses of renal tubular epithelial cells driving renal tubulointerstitial fibrosis, and provide a basis for exploring new drug targets for renal tubulointerstitial fibrosis.

Establishment and genotype identification of hepatic stellate cell-specific Grk2 gene knockout mouse model / 中国药理学通报

Aim To establish a stable hepatic stellate cell ( HSC ) -specific G protein-coupled receptor kinase 2 ( GRK2 ) knockout mice and provide the important animal model for further studying the biological function of GRK2 in HSC. Methods The loxP-labeled Grk2 gene mouse (Grk2

Clinicopathological study of epithelioid and spindle cell rhabdomysarcoma with EWSR1/FUS-TFCP2 fusion / 中华病理学杂志

Objective: To investigate the clinicopathological and genetic features of epithelioid and spindle cell rhabdomysarcoma with EWSR1-TFCP2 or FUS-TFCP2 fusion. Methods: The clinical, morphological and immunohistochemical features of 14 cases of epithelioid and spindle cell rhabdomysarcoma with EWSR1-TFCP2 or FUS-TFCP2 fusion diagnosed from January 2019 to December 2022 in the Department of Pathology, Foshan Traditional Chinese Medicine Hospital, Foshan, China were retrospectively analyzed. The cases were all subject to FISH or next generation sequencing for analysis of molecular genetic features. The literature was reviewed. Results: There were 5 males and 9 females, with the age at presentation ranging from 6 to 36 years (mean, 22 years). Tumors occurred in the head and neck (9 cases), pelvic region (2 cases), bladder (one case), right humerus (one case), and the abdominal wall, humerus and pubic at the same time (one case). Presenting symptoms varied by location but often included pain or discomfort. Most of the patients showed aggressive radiographic features with soft tissue extension. The tumors had a median size of 6.6 cm (range, 2-23 cm). The tumors were poorly defined and irregularly shaped. Microscopic examination showed diffuse proliferation of spindle or epithelioid cells. While morphologically high-grade tumors displayed obvious cytological atypia, a high mitotic count and tumor necrosis, low-grade tumors grew in sheets and fascicles composed of spindle, epithelioid cells with moderate or abundant amounts of eosinophilic cytoplasm, without pronounced cytological atypia. The tumor cells expressed Desmin, MyoD1, and Myogenin, as well as ALK, EMA, and CKpan. EWSR1/FUS-TFCP2 gene fusion was detected in 14 cases with next generation sequencing and confirmed by FISH. Six cases had EWSR1-TFCP2 fusions and 8 cases showed FUS-TFCP2 fusions. Follow-up information was available in 13 patients, ranged from 5 to 37 months. At the end of follow-up period, 7 patients died of the disease. Six patients were alive:two cases had local recurrences and metastases, two cases of recurrences, one case of metastasis and one case without recurrences and metastasis. Conclusions: Epithelioid and spindle cell rhabdomysarcomas with EWSR1-TFCP2 or FUS-TFCP2 fusion show a very aggressive clinical course, and more commonly occur in the head and neck. Their genetic hallmark is the presence of EWSR1/FUS-TFCP2 fusions. Familiarity with its clinicopathological characteristics is helpful in avoiding misdiagnoses.

Mechanism on Banxia Xiexintang Inducing Ferroptosis in Gastric Cancer Cells Based on Nrf2/GPX4 Signaling Pathway / 中国实验方剂学杂志

ObjectiveTo observe the effect of Banxia Xiexintang （BXT） on the proliferation of human gastric cancer HGC-27， MKN-45， and AGS cells and its mechanism. MethodCell counting kit-8 （CCK-8） was used to detect the effects of different concentrations of BXT-containing serum （5%， 10%， and 20%） on the proliferation of HGC-27， MKN-45， and AGS cells. A mitochondrial membrane potential probe （TMRE） was used to detect the expression of mitochondrial membrane potential in cells. A kit was used to detect iron ion （Fe2+） content， lipid peroxide （LPO）， and superoxide dismutase （SOD） activity. Western blot was used to detect the protein expression levels of glycogen synthase3β （GSK3β）， phosphorylated GSK3β （p-GSK3β）， nuclear factor E2 related factor 2 （Nrf2）， and glutathione peroxidase 4 （GPX4）. The real-time fluorescence quantitative polymerase chain reaction （Real-time PCR） was used to detect the mRNA expression of member 11 of the cystine/glutamic acid reverse transporter solute vector family 7 （SLC7A11）， member 2 of the heavy chain solute vector family 3 （SLC3A2）， transferrin receptor 3 （TFRC）， and tumor protein （TP）53. ResultCCK-8 results showed that BXT and capecitabine could significantly reduce the survival rate of three kinds of gastric cancer cells after treatment with drug-containing serum for 24 h （P<0.01）. After 48 h of intervention with drug-containing serum， the survival rate of three kinds of gastric cancer cells was significantly decreased in both the capecitabine group and the BXT group compared with the blank group. The BXT group was dose-dependent， with 20% BXT having the most significant effect （P<0.01）. In terms of biochemical indicators of ferroptosis， compared with the blank group， BXT and capecitabine significantly decreased the expression of mitochondrial membrane potential （P<0.01） and SOD activity （P<0.01） and significantly increased the contents of LPO and Fe2+ （P<0.01）， so as to improve the sensitivity of gastric cancer cells to ferroptosis. In terms of the Nrf2/GPX4 pathway， compared with the blank group， the BXT group could reduce the protein expressions of p-GSK3β， Nrf2， and GPX4 （P<0.01） in gastric cancer cells and increase mRNA expressions of SLC7A11 and SLC3A2 （P<0.05）. It could also increase the protein expression of GSK3β （P<0.01） and mRNA expression of TP53 and TFRC （P<0.05， P<0.01） in gastric cancer cells. Inhibition of the Nrf2/GPX4 pathway induces ferroptosis in gastric cancer cells. Compared with the capecitabine group， the 20% BXT group showed a more obvious effect. ConclusionBanxia Xiexintang can induce ferroptosis in gastric cancer cells HGC-27， MKN-45， and AGS by inhibiting the Nrf2/GPX4 pathway.

Echocardiographic diagnosis of sinus of Valsalva aneurysm / 中山大学学报(医学科学版)

ObjectiveTo summarize the echocardiographic features of sinus of Valsalva aneurysm （SVA）， analyze the causes of missed diagnosis， thus explore the diagnostic skills and improve the diagnostic accuracy for SVA. MethodsThe echocardiographic features and clinical data of 52 SVA patients who underwent surgery in the First Affiliated Hospital of Sun Yat-sen University from January 2014 to March 2022 were retrospectively reviewed. The patients were divided into 5 types according to modified Sakakibara classification system. ResultsThere were 32 male and 20 female patients with their age of 18~66 （36.1±11.6） years. Of the 52 aneurysms， 44 originated from the right coronary sinus （RCS）， 8 from noncoronary sinus （NCS） and none from left coronary sinus （LCS）. Among the 35 SVAs protruding into the right ventricle， including type I， type Ⅱ and type Ⅲv， 32 （91.4%） were associated with ventricular septal defect （VSD）. There were 2 （17.6%） associated with VSD among the 17 SVAs protruding into the right atrium or other sites of the heart， including type Ⅲa， type Ⅳ and type Ⅴ. SVA was frequently associated with aortic valve disease， 27 cases （51.9%） of which needed surgical valve replacement or valvoplasty. SVA was missed in 4 patients and VSD in 8， with the misdiagnosis rates of 7.7% and 23.5%， respectively. The most commonly missed VSD diagnosis was subarterial VSD with type I SVA. Of the 19 SVAs associated with infective endocarditis （IE）， 2 were missed， with the misdiagnosis rate of 10.5%. ConclusionThe ultrasound images of SVA are diverse and complex. SVA protruding into the right atrium is rarely associated with VSD， while SVA protruding into the right ventricle is frequently associated with VSD. SVA is also prone to be associated with aortic valve disease and IE， which makes the diagnosis more challenging. Therefore， during ultrasound examination， we must vigilantly and flexibly make use of the multiple scan slices so as to decrease the rate of missed diagnosis and improve the diagnostic accuracy for SVA.

Correlation between collateral circulation and cerebral hemodynamics in moyamoya disease and moyamoya syndrome based on 4-dimensional CT angiography-CT perfusion / 中华放射学杂志

Objective:To explore the significance of four-dimensional CT angiography(4D CTA) and CT perfusion (CTP) imaging in evaluating collateral circulation grades in patients with moyamoya disease and moyamoya syndrome and their relationship with cerebral hemodynamics.Methods:The clinical and imaging data of 32 patients with moyamoya disease and moyamoya syndrome in Beijing Hospital from January 2017 to January 2022 were retrospectively analyzed. All patients underwent 4D CTA-CTP imaging. Collateral circulation was scored on CTA images by using Alberta stroke program early CT score system, and on digital subtraction angiography (DSA) images by using American society of interventional and therapeutic neuroradiology/Society of interventional radiology score system, respectively. The patients were divided into Ⅰ-Ⅲ circulation compensation grades based on collateral circulation score. Regions of interest were delineated at basal ganglia on perfusion maps and the perfusion parameters were obtained including cerebral blood volume (CBV), cerebral blood flow (CBF), mean transit time (MTT), mean transit time (TTP) and delay time (DLY). The Kruskal-Wallis test was used to compare the perfusion parameters in different collateral circulation grades, and pairwise comparison was performed with Bonferroni correction. Kappa and Spearman tests were used to analyze the consistency and correlation of 4D CTA and DSA in the classification of collateral circulation.Results:4D CTA and DSA had a moderate consistency (Kappa=0.693, P<0.001) and a strong correlation ( r=0.805, P<0.001) in evaluating collateral grades. There were statistically significant differences in CBF, MTT and TTP among collateral compensation grade Ⅰ, grade Ⅱ and grade Ⅲ ( H values were 7.91, 11.69, 8.93; P values were 0.019, 0.003 and 0.012, respectively). Further pairwise comparison showed that the CBF of collateral compensation grade Ⅰ was lower than that of grade Ⅲ ( P=0.015), MTT of grade Ⅱ was higher than that of grade Ⅲ ( P=0.005), and TTP of grade Ⅰ was higher than that of grade Ⅲ ( P=0.015). There was no statistical significance of other indicators in pairwise comparison. There were no significant differences in CBV and DLY among collateral compensation grade Ⅰ, grade Ⅱ and grade Ⅲ ( P>0.05). Conclusions:4D CTA-CTP is equivalent to DSA in evaluating collateral circulation in patients with moyamoya disease and moyamoya syndrome. It can also evaluate the cerebral hemodynamics comprehensively, which has high clinical significance for disease monitoring.

Advances and challenges in using nirmatrelvir and its derivatives against SARS-CoV-2 infection / 药物分析学报

On December 22,2021,the United States Food and Drug Administration approved the first main protease inhibitor,i.e.,oral antiviral nirmatrelvir(PF-07321332)/ritonavir(Paxlovid),for the treatment of early severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)infection.Nirmatrelvir inhibits SARS-CoV-2 infection,but high doses or long-term treatment may cause embryonic developmental toxicity and changes in host gene expression.The chiral structure of nirmatrelvir plays a key role in its antiviral activity.Ritonavir boosts the efficacy of nirmatrelvir by inactivating cytochrome P450 3A4 expression and occupying the plasma protein binding sites.Multidrug resistance protein 1 inhibitors may increase the efficacy of nirmatrelvir.However,Paxlovid has many contraindications.Some patients treated with Paxlovid experience a second round of coronavirus disease 2019(COVID-19)symptoms soon after re-covery.Interestingly,the antiviral activity of nirmatrelvir metabolites,such as compounds 12-18,is similar to or higher than that of nirmatrelvir.Herein,we review the advances and challenges in using nirmatrelvir and its derivatives with the aim of providing knowledge for drug developers and physicians in the fight against COVID-19.

Research progress on the mechanism of nursing manpower factors on patients' safe / 中国实用护理杂志

This article reviewed the present situation of the research on the relationship between the number of nursing staff, education level, skill combination and patient safety at home and abroad, as well as the indirect mechanism of nursing manpower factors on patient safety through intermediary factors such as working environment, attendance, nursing lack and so on. In view of the problems existing in domestic research, some suggestions were put forward, such as carrying out longitudinal and intervention research on patient safety, optimizing the allocation of nursing human resources and patient safety indicators, exploring the mechanism of multiple nursing factors and patient safety and conducting empirical analysis. To provide reference for hospital managers to improve nursing quality and ensure patient safety.

Grouping characteristics and predictive indexes of psychological symptoms in patients with non-small cell lung cancer during programmed cell death protein 1 monoclonal antibody combined with chemotherapy / 中国实用护理杂志

Objective:To investigate the grouping characteristics of psychological state symptom clusters in patients with non-small cell lung cancer during programmed death 1 (PD-1) monoclonal antibody combined with chemotherapy, and to analyze the predictors of different symptom cluster characteristics.Methods:This study was a cross-sectional study. In the form of a questionnaire, 171 patients with non-small cell lung cancer who received PD-1 monoclonal antibody combined with chemotherapy in Gansu Wuwei Tumor Hospital from March 2019 to March 2021 were selected as the research object by convenient sampling method. The general data questionnaire, Pittsburgh Sleep Quality Index, Cancer-Related Fatigue Survey Scale, Hospital Anxiety and Depression Scale, Physical Activity Measurement Scale for Cancer Patients, Distress Thermometer, and Quality of Life Measurement Scale for Lung Cancer Patients were used for investigation. The latent class model was fitted based on the evaluation results of physical fatigue, anxiety, depression, sleep quality and psychological distress in patients with non-small cell lung cancer during treatment. Latent class model analysis was performed on the scale results to establish a category group model. Logistic regression analysis was used to compare the demographic characteristics, disease stage, classification, and personality characteristics of patients in each group, and to explore the predictive indicators between different categories.Results:According to the symptoms of fatigue, anxiety, depression, sleep disorder and psychological distress in patients with non-small cell lung cancer during PD-1 monoclonal antibody therapy combined with chemotherapy, they were divided into two different categories. The group with high psychological symptoms accounted for 44.44% (76/171) and the group with low psychological symptoms accounted for 55.56% (95/171). The scores of physiological status, social/family status, emotional status, functional status, additional attention and physical activity in the quality of life scale of lung cancer patients with low psychological symptoms were 11.28 ± 5.62, 17.57 ± 4.31, 11.14 ± 3.27, 14.83 ± 5.24, 14.76 ± 4.03 and 88.61 ± 17.38, respectively. The scores were higher than those in the high psychological symptom group 17.82 ± 4.43, 10.76 ± 3.63, 18.62 ± 6.06, 9.34 ± 3.13, 26.26 ± 3.23, 58.04 ± 15.41, the differences were statistically significant ( t values were 10.36-15.84, all P<0.05); logistic regression analysis showed that personality traits [extroverted ( OR=0.08, 95 % CI 0.03-0.23, P<0.05), intermediate ( OR=0.16, 95 % CI 0.08-0.33, P<0.05)] and physical activity in cancer patients ( OR=0.91, 95 % CI 0.88-0.93, P<0.05) were predictors for distinguishing high psychological symptom group. Conclusions:There are obvious classification characteristics of psychological symptom clusters in patients with non-small cell lung cancer during PD-1 monoclonal antibody combined with chemotherapy. Different psychological interventions and nursing care are given according to different psychological symptom characteristics during treatment to improve the quality of life of patients.

Network pharmacology and experimental validation of Maxing Shigan decoction in the treatment of influenza virus-induced ferroptosis / 中国天然药物

Influenza is an acute viral respiratory infection that has caused high morbidity and mortality worldwide. Influenza A virus (IAV) has been found to activate multiple programmed cell death pathways, including ferroptosis. Ferroptosis is a novel form of programmed cell death in which the accumulation of intracellular iron promotes lipid peroxidation, leading to cell death. However, little is known about how influenza viruses induce ferroptosis in the host cells. In this study, based on network pharmacology, we predicted the mechanism of action of Maxing Shigan decoction (MXSGD) in IAV-induced ferroptosis, and found that this process was related to biological processes, cellular components, molecular function and multiple signaling pathways, where the hypoxia inducible factor-1(HIF-1) signaling pathway plays a significant role. Subsequently, we constructed the mouse lung epithelial (MLE-12) cell model by IAV-infected in vitro cell experiments, and revealed that IAV infection induced cellular ferroptosis that was characterized by mitochondrial damage, increased reactive oxygen species (ROS) release, increased total iron and iron ion contents, decreased expression of ferroptosis marker gene recombinant glutathione peroxidase 4 (GPX4), increased expression of acyl-CoA synthetase long chain family member 4 (ACSL4), and enhanced activation of hypoxia inducible factor-1α (HIF-1α), induced nitric oxide synthase (iNOS) and vascular endothelial growth factor (VEGF) in the HIF-1 signaling pathway. Treatment with MXSGD effectively reduced intracellular viral load, while reducing ROS, total iron and ferrous ion contents, repairing mitochondrial results and inhibiting the expression of cellular ferroptosis and the HIF-1 signaling pathway. Finally, based on animal experiments, it was found that MXSGD effectively alleviated pulmonary congestion, edema and inflammation in IAV-infected mice, and inhibited the expression of ferroptosis-related protein and the HIF-1 signaling pathway in lung tissues.

Establishment and Evaluation of Intestinal Injury Model of Mouse Acute Graft Versus Host Disease Based on An Organoid Technology / 中国实验血液学杂志

OBJECTIVE@#To establish an intestinal organoid model that mimic acute graft versus host disease (aGVHD) caused intestinal injuries by using aGVHD murine model serum and organoid culture system, and explore the changes of aGVHD intestine in vitro by advantage of organoid technology.@*METHODS@#20-22 g female C57BL/6 mice and 20-22 g female BALB/c mice were used as donors and recipients for bone marrow transplantation, respectively. Within 4-6 h after receiving a lethal dose (8.0 Gy) of γ ray total body irradiation, a total of 0.25 ml of murine derived bone marrow cells (1×107/mice, n=20) and spleen nucleated cells (5×106/mice, n=20) was infused to establish a mouse model of aGVHD (n=20). The aGVHD mice were anesthetized at the 7th day after transplantation, and the veinal blood was harvested by removing the eyeballs, and the serum was collected by centrifugation. The small intestinal crypts of healthy C57BL/6 mice were harvested and cultivated in 3D culture system that maintaining the growth and proliferation of intestinal stem cells in vitro. In our experiment, 5%, 10%, 20% proportions of aGVHD serum were respectively added into the organoid culture system for 3 days. The formation of small intestinal organoids were observed under an inverted microscope and the morphological characteristics of intestinal organoids in each groups were analyzed. For further evaluation, the aGVHD intestinal organoids were harvested and their pathological changes were observed. Combined with HE staining, intestinal organ morphology evaluation was performed. Combined with Alcian Blue staining, the secretion function of aGVHD intestinal organoids was observed. The distribution and changes of Lgr5+ and Clu+ intestinal stem cells in intestinal organoids were analyzed under the conditions of 5%, 10% and 20% serum concentrations by immunohistochemical stainings.@*RESULTS@#The results of HE staining showed that the integrity of intestinal organoids in the 5% concentration serum group was better than that in the 10% and 20% groups. The 5% concentration serum group showed the highest number of organoids, the highest germination rate and the lowest pathological score among experimental groups, while the 20% group exhibited severe morphological destruction and almost no germination was observed, and the pathological score was the highest among all groups(t=3.668, 4.334,5.309,P<0.05). The results of Alican blue staining showed that the secretion function of intestinal organoids in serum culture of aGVHD in the 20% group was weaker than that of the 5% group and 10% of the organoids, and there was almost no goblet cells, and mucus was stainned in the 20% aGVHD serum group. The immunohistochemical results showed that the number of Lgr5+ cells of intestinal organoids in the 5% group was more than that of the intestinal organoids in the 10% aGVHD serum group and 20% aGVHD serum group. Almost no Clu+ cells were observed in the 5% group. The Lgr5+ cells in the 20% group were seriously injuried and can not be observed. The proportion of Clu+ cells in the 20% group significantly increased.@*CONCLUSION@#The concentration of aGVHD serum in the culture system can affect the number and secretion function of intestinal organoids as well as the number of intestinal stem cells in organoids. The higher the serum concentration, the greater the risk of organoid injury, which reveal the characteristics of the formation and functional change of aGVHD intestinal organoids, and provide a novel tool for the study of intestinal injury in aGVHD.

Benchmark Dose Assessment for Coke Oven Emissions-Induced Mitochondrial DNA Copy Number Damage Effects / 生物医学与环境科学（英文）

OBJECTIVE@#The study aimed to estimate the benchmark dose (BMD) of coke oven emissions (COEs) exposure based on mitochondrial damage with the mitochondrial DNA copy number (mtDNAcn) as a biomarker.@*METHODS@#A total of 782 subjects were recruited, including 238 controls and 544 exposed workers. The mtDNAcn of peripheral leukocytes was detected through the real-time fluorescence-based quantitative polymerase chain reaction. Three BMD approaches were used to calculate the BMD of COEs exposure based on the mitochondrial damage and its 95% confidence lower limit (BMDL).@*RESULTS@#The mtDNAcn of the exposure group was lower than that of the control group (0.60 ± 0.29 vs. 1.03 ± 0.31; P < 0.001). A dose-response relationship was shown between the mtDNAcn damage and COEs. Using the Benchmark Dose Software, the occupational exposure limits (OELs) for COEs exposure in males was 0.00190 mg/m 3. The OELs for COEs exposure using the BBMD were 0.00170 mg/m 3 for the total population, 0.00158 mg/m 3 for males, and 0.00174 mg/m 3 for females. In possible risk obtained from animal studies (PROAST), the OELs of the total population, males, and females were 0.00184, 0.00178, and 0.00192 mg/m 3, respectively.@*CONCLUSION@#Based on our conservative estimate, the BMDL of mitochondrial damage caused by COEs is 0.002 mg/m 3. This value will provide a benchmark for determining possible OELs.

Governor vessel moxibustion combined with western medication for mild to moderate depression with kidney-yang deficiency: a randomized controlled trial / 中国针灸

OBJECTIVE@#To compare the therapeutic efficacy of governor vessel moxibustion combined with fluoxetine hydrochloride capsule, simple fluoxetine hydrochloride capsule and placebo moxibustion combined with fluoxetine hydrochloride capsule for mild to moderate depression with kidney-yang deficiency.@*METHODS@#A total of 126 patients with mild to moderate depression with kidney-yang deficiency were randomized into a governor vessel moxibustion group (42 cases, 2 cases dropped off), a western medication group (42 cases, 1 case dropped off) and a placebo moxibustion group (42 cases, 1 case dropped off). The western medication group was given fluoxetine hydrochloride capsule orally, 20 mg a time, once a day. On the basis of the treatment in the western medication group, governor vessel moxibustion was applied from Dazhui (GV 14) to Yaoshu (GV 2) in the governor vessel moxibustion group, once a week; placebo moxibustion was applied in the placebo moxibustion group, once a week. Treatment of 8 weeks was required in the 3 groups. Before and after treatment, the scores of Hamilton depression scale-17 (HAMD-17), Asberg's rating scale for side effects (SERS) and TCM clinical symptom were compared, and the clinical efficacy was evaluated.@*RESULTS@#After treatment, the scores of HAMD-17, SERS and TCM clinical symptom were decreased compared before treatment in the 3 groups (P<0.05), the decrease ranges of above scores in the governor vessel moxibustion group were larger than those in the western medication group and the placebo moxibustion group (P<0.05). The total effective rate was 92.5% (37/40) in the governor vessel moxibustion group, which was higher than 75.6% (31/41) in the western medication group and 80.5% (33/41) in the placebo moxibustion group (P<0.05).@*CONCLUSION@#Governor vessel moxibustion combined with fluoxetine hydrochloride capsule can improve the degree of depression and relieve the clinical symptoms in mild to moderate depression patients with kidney-yang deficiency, the efficacy is superior to simple fluoxetine hydrochloride capsule, and can reduce the fluoxetine hydrochloride capsule-induced adverse effect to a certain extent.

The Role and Regulatory Mechanism of ZSCAN4 in Early Embryonic and Pluripotent Stem Cells / 中国生物化学与分子生物学报

Zinc finger and SCAN domain containing 4 (ZSCAN4) is specifically expressed as a DNA-binding protein in 2-cell stage embryos and embryonic stem cells. ZSCAN4 regulates early embryonic development by promoting DNA damage repair and correcting chromosomal abnormalities during zygotic genome activation (ZGA) to maintain genomic and chromosomal integrity in preimplantation embryos. During the transition of mouse embryonic stem cells (mESCs) to 2-cell-like cells, ZSCAN4 interacts with ATP-dependent chromatin remodelers to regulate the activity of murine endogenous retroviral L enhancers, and activate the expression of peripheral 2-cell-phase genes to promote the transition of embryonic stem cells to 2-cell-like cells. ZSCAN4 can also promote telomere reorganization and telomere extension by reducing DNA methylation levels to mediate heterochromatin silencing, maintain genome stability and the infinite self-renewal capacity and pluripotency of pluripotent stem cells, and promote mESCs transition to embryonic 2-cell-like cells. In addition, ZSCAN4 can also reactivate early embryonic genes in reprogramming, and significantly increase the generation efficiency of induced pluripotent stem cells (iPSCs). ZSCAN4 reduces DNA damage during iPSCs formation, and preserves genome stability by lengthening telomeres, thereby promoting the generation of high-quality iPSCs without genetic defects. This article focuses on the research advances of the biological functions of ZSCAN4 in regulating early embryonic development, mediating telomere elongation in pluripotent stem cells, and its role in somatic cell reprogramming, which may provide a reference for optimizing the technology to increase the early embryonic development and maintenance of pluripotent stem cells and iPSC generation.

Regulation mechanism of post-translational modification of farnesoid X receptor / 中国临床药理学与治疗学

Farnesoid X receptor (FXR) is a nuclear receptor activated by bile acid that is involved in regulating gene expression related to bile acid, fat, glucose, and amino acid metabolism. The activity of FXR is regulated by a variety of post-translational modifications. Common post-translational modifications of FXR include O-GlcNAcylation, phosphorylation, acetylation, sumoylation, methylation, etc. These post-translational modifications may affect FXR binding of DNA and ligand, heterodimerization, and subcellular localization, and may specifically regulate downstream gene transcription and expression. Different post-translational modifications can lead to changes in FXR stability and biological function, which are closely related to the occurrence of diseases. This paper aims to review the post-translational modification of FXR in the past five years and the mechanisms involved in disease regulation, to explore the effects of post-translational modification on the physiological function of FXR and to provide a theoretical basis for mechanism research targeting FXR.

Research progress of lactate dehydrogenase A in digestive system tumors and related drugs / 中国临床药理学与治疗学

Malignant tumors of digestive system are highly prevalent malignant tumors that seriously threaten human health around the world. At present, the curative efficacy and prognosis of traditional treatment methods cannot reach the expectation, so it is urgent to find new targets for cancer treatment and realize targeted therapy for tumors. Abnormal energy metabolism in tumor cells is regarded as a hallmark of cancer, and malignant tumor cells absorb glucose through aerobic glycolysis pathway, and obtain a small amount of energy and produce lactate under the catalysis of a series of enzymes. Lactate dehydrogenase A (Lactate dehydrogenase A, LDHA), as a key enzyme in the aerobic glycolysis pathway of tumor cells, plays an important role in the metabolic changes of tumor cells. Studies have demonstrated that LDHA has high expression characteristics in a variety of tumor cells,and its high expression in clinic is often related to the poor prognosis and high metastasis rate of tumors, which is expected to be a new target for cancer therapy. This article reviews the role of LDHA in the development of digestive system tumors and the research progress of related drugs.

The pharmacological effects of isatin on Parkinson's disease / 中国药理学通报

Parkinson's disease (PD) is a kind of senile neurodegenerative disease. Dopaminergic drugs and anticholinergic drugs are the two major therapeutic drugs for PD. In the past several decades, great progress has been achieved on dopamines (DAs) and their synergists including monoamine oxidase B (MAO-B) inhibitors, catechol oxygen methyl transferase inhibitors, ergot and nonergot DA receptor agonists, DA precursor drugs, cannabis and isatin. Isatin is the inhibitor of endogenous specific anti-aging enzyme MAO-B, which has a variety of pharmacological activities. Moreover, the pharmacological mechanism of isatin may be associated with the regulatory functions of various protein activities.

Research progress on Astragalus active ingredient in treatment of hepatic fibrosis based on cell signaling pathway / 中国药理学通报

Hepatic fibrosis is present in most chronic liver disease processes, and there are no ideal anti-fibrotic drugs available. Astragalus has a long history of medicinal use, and its anti-fibrotic effects have been confirmed by modern studies. In this study we have searched the literature to identify the signaling pathways and mechanisms of action of Astragalus and its active ingredients on hepatic fibrosis in recent years, so as to provide the basis and ideas for the development of anti-fibrotic drugs and mechanisms of Astragalus. It is showed that the active ingredients of Astragalus act through regulating p38MAPK, TGF-pl/Smads,NF-

In vitro bacteriostatic and serum pharmacological tests of Qiguiyin decoction combined with levofloxacin against pseudomonas aeruginosa / 中国药理学通报

Aim To investigate the antibacterial activity and anti-resistant mutation ability of Qiguiyin decoction (a traditional Chinese herbal formula) combined with levofloxacin against pseudomonas aeruginosa byantibacterial experiment in vitro and serum pharmacology. Methods The minimal inhibitory concentrations (MICs) of levofloxacin and Qiguiyin decoction were detected respectively by the broth dilution technique.The MIC of the combination of two drugs was determined by the micro chessboard dilution method. The effects of combined drugs on enhancing the antibacterial activity of different strains were evaluated respectively by calculating the fractional inhibitory concentration index (FICI). The drug-containing serum of levofloxa-cin group, Qiguiyin decoction group, Qiguiyin decoction combined with levofloxacin group and control group was prepared. The antibacterial rate, MIC and MBC of 10% ~ 90% serum against the two strains were determined. Results Combined with Qiguiyin decoction, MIC of levofloxacin against pseudomonas aeruginosa (standard/resistant) decreased significantly, 0. 5 < FICI

Auranofin reverses acquired resistance to osimertinib in non-small cell lung cancer / 中国药理学通报

Aim To investigate the role of auranofin in reversing acquired resistance to osimertinib in non-small cell lung cancer. Methods Osimertinib-sensi-tive NSCLC cell lines HI975 and PC9 were used to establish osimertinib-resistant NSCLC cell lines HI975/OR and PC9/OR. An FDA approved library of 1470 FDA drugs was used to high-throughput screen the reversal agents of acquired resistant of osimertinib by CCK-8. Compusyn was used to calculate the combination index of osimertinib and auranofin to determine the optimal dose of drug combination. CCK-8, EdU, flow cytometry and Transwell experiments were used to detect osimertinib, auranofin and the combination drug effect on proliferation, apoptosis, migration and invasion of osimertinib acquired NSCLC cell lines. RNA-sequencing was applied to screen differentially expressed mRNAs in osimertinib treatment alone and osimertinib combined with auranofin treatment group. qRT-PCR and western blot were employed to validate the selected gene expression and protein expression. Results Compared with osimertinib sensitive cell lines H1975 and PC9, H1975/OR and PC9/OR showed significantly higher cell viability and lower apoptosis rate after osimertinib treatment. The resistance index was 70. 31 and 136. 99, respectively. In FDA approved 1470 drug library, only auranofin could enhance the sensitivity of osimertinib in H1975/OR and PC9/OR. When 1 μmol • L