Four novel β-galactoside prodrugs were designed and synthesized from anthraquinones HAQ-OH and AQ-OH in an attempt to use the prodrugs to selectively release superoxide anion (O2−) in cancer cells and to achieve selected anticancer activity by utilizing the Warburg effect and the elevated level of β-galactosidase in certain cancer cells. Cellular assays showed that the prodrugs Gal-HAQ and Gal-AQ selectively inhibited the proliferation and induced apoptosis of ovarian cancer OVCAR-3 cells overexpressing β-galactosidase. Using O2− fluorescent probe, it was found that in OVCAR-3 cells Gal-HAQ and Gal-AQ could time-dependently release O2−, which was essential for their anticancer activity. Furthermore, it was found that Gal-HAQ and Gal-AQ were effective senolytics toward senescent cells overexpressing β-galactosidase without affecting the viability of corresponding non-senescent cells, further confirming the β-galactosidase-dependent cytotoxicity of the prodrugs. In conclusion, Gal-HAQ and Gal-AQ, which release O2− in response to β-galactosidase, are expected to serve as candidate prodrugs targeting cancer cells.

Objective To study the regulation effects of Bazhen Decoction combined with Baizhu Fuzi Decoction on glucose metabolism and estrogen level in rats with polycystic ovary syndrome.Methods The rat model of polycystic ovary syndrome was established by subcutaneous injection of human chorionic gonadotropin(HCG)combined with insulin.Rats were randomly divided into the polycystic ovary syndrome group,the Baizhu Fuzi Tang group(6.4 g/kg),the Bazhen Tang group(9.2 g/kg),the Bazhen Tang combined with Baizhu Fuzi Tang group(11.55 g/kg)and the diethylstilbestrol group(0.5 mg/kg).A blank control group(unmodulated rats)was set up with 10 rats in each group.The uterine index of rats was determined and calculated.Fasting blood glucose(FBG),2 h postprandish blood glucose(2 h PBG)and fasting insulin(FINS)were determined and insulin sensitivity index(ISI)and insulin resistance index(IR)were calculated.Serum estradiol(E2),testosterone(T),luteinizing hormone(LH),follicle stimulating hormone(FSH),prolactin(PRL),anti-Mullerian tube hormone(AMH)and insulin-like growth factor 1(IGF-1),C-reactive protein(CRP),interleukin(IL)-6,tumor necrosis factor(TNF)-α,total peroxidase activity(T-AOC),superoxide dismutase(SOD)and malondialdehyde(MDA)levels in ovarian tissue were detected by enzyme-linked immunosorbent assay(ELISA).The pathological changes of ovarian tissue were detected by hematoxylin-eosin(HE)staining.Real-time quantitative polymerase chain reaction(qPCR)was used to determine mRNA levels of ARA70,CBP,SCR1 and HOXA10 in endometrium and mRNA expressions of AMPK,GLUT4 and PPARγ in ovarian tissue.Western blot assay was used to determine expression levels of AMPK,GLUT4 and PPARγ in ovarian tissue.Results Compared with the polycystic ovary syndrome group,uterine index,FINS,FBG,2 h PBG,IR levels,serum T,LH,FSH,PRL,AMH,IGF-1 levels,ovarian tissue CRP,IL-6,TNF-α,T-AOC and MDA level,endometrial ARA70,CBP,SCR1 mRNA level of rats decreased significantly in the Baizhu Fuzi decoction group,the Bazhen decoction group and the Bazhen decoction combined with Baizhu Fuzi decoction group(P＜0.05).ISI level,serum E2 level,ovarian tissue SOD level,endometrial HOXA10 mRNA level,ovarian tissue AMPK,GLUT4 and PPARγ mRNA and protein levels were significantly increased(P＜0.05).The above indexes were significantly changed in the Bazhen decoction and Bazhu Fuzi decoction group than those of the Bazhu Fuzi decoction group and the Bazhen decoction group(P＜0.05).Conclusion Bazhen Decoction combined with Baizhu Fuzi Decoction can regulate glucose metabolism,inhibit ovarian tissue oxidation and inflammatory damage,improve endometrium tolerance,regulate estrogen level,and improve the progression of polycystic ovary syndrome in rats.The mechanism may be related to the regulation of AMPK/GLUT4/PPARγ pathway.

Lipotoxicity is a pivotal factor that initiates and exacerbates liver injury and is involved in the development of metabolic-associated fatty liver disease (MAFLD). However, there are few reported lipotoxicity inhibitors. Here, we identified a natural anti-lipotoxicity candidate, HN-001, from the marine fungus Aspergillus sp. C1. HN-001 dose- and time- dependently reversed palmitic acid (PA)-induced hepatocyte death. This protection was associated with IRE-1α-mediated XBP-1 splicing inhibition, which resulted in suppression of XBP-1s nuclear translocation and transcriptional regulation. Knockdown of XBP-1s attenuated lipotoxicity, but no additional ameliorative effect of HN-001 on lipotoxicity was observed in XBP-1s knockdown hepatocytes. Notably, the ER stress and lipotoxicity amelioration was associated with PLA2. Both HN-001 and the PLA2 inhibitor MAFP inhibited PLA2 activity, reduced lysophosphatidylcholine (LPC) level, subsequently ameliorated lipotoxicity. In contrast, overexpression of PLA2 caused exacerbation of lipotoxicity and weakened the anti-lipotoxic effects of HN-001. Additionally, HN-001 treatment suppressed the downstream pro-apoptotic JNK pathway. In vivo, chronic administration of HN-001 (i.p.) in mice alleviated all manifestations of MAFLD, including hepatic steatosis, liver injury, inflammation, and fibrogenesis. These effects were correlated with PLA2/IRE-1α/XBP-1s axis and JNK signaling suppression. These data indicate that HN-001 has therapeutic potential for MAFLD because it suppresses lipotoxicity, and provide a natural structural basis for developing anti-MAFLD candidates.

Objective To investigate the dietary patterns of rural residents in the high-incidence areas of esophageal cancer (EC), and to explore the clustering and influencing factors of risk factors associated with high-incidence characteristics. Methods A special structured questionnaire was applied to conduct a face-to-face survey on the dietary patterns of rural residents in Yanting county of Sichuan Province from July to August 2021. Univariate and multivariate logistic regression models were used to analyze the influencing factors of risk factor clustering for EC. Results There were 838 valid questionnaires in this study. A total of 90.8% of rural residents used clean water such as tap water. In the past one year, the people who ate fruits and vegetables, soybean products, onions and garlic in high frequency accounted for 69.5%, 32.8% and 74.5%, respectively; the people who ate kimchi, pickled vegetables, sauerkraut, barbecue, hot food and mildew food in low frequency accounted for 59.2%, 79.6%, 68.2%, 90.3%, 80.9% and 90.3%, respectively. The clustering of risk factors for EC was found in 73.3% of residents, and the aggregation of two risk factors was the most common mode (28.2%), among which tumor history and preserved food was the main clustering pattern (4.6%). The logistic regression model revealed that the gender, age, marital status and occupation were independent influencing factors for the risk factors clustering of EC (P<0.05). Conclusion A majority of rural residents in high-incidence areas of EC in Yanting county have good eating habits, but the clustering of some risk factors is still at a high level. Gender, age, marital status, and occupation are influencing factors of the risk factors clustering of EC.

[Objective] To investigate the correlation between human leukocyte antigen (HLA) gene polymorphism and hepatitis B virus (HBV) infection. [Methods] Venous blood samples were collected from 501 healthy individuals undergoing physical examinations at Yan’an Hospital in Kunming, Yunnan Province. Enzyme linked immunosorbent assay (ELISA) was used to detect HBV halves. Based on the results of HBV half detection, the patients were divided into three groups: HBV carrier group, previous infection group, and healthy control group. The HLA-A antigen genotype was detected using polymerase chain reaction with sequence specific primers (PCR-SSP) genotyping technology, and the distribution frequency of HLA-A gene polymorphism was compared between HBV carrier group and healthy control group, as well as between previous infection group and healthy control group. SPSS17.0 software was used for data statistical analysis. [Results] In the healthy control group, the HLA-A2 positivity rate was 47.49%, and the allele frequency was 31.29%.The overall frequency of gene distribution in the healthy control group was consistent with the HLA-A allele table commonly and confirmed in China published by the Chinese Bone Marrow Bank. The HLA-A2 positivity rate and allele frequency in the HBV carrier group were 63.04% and 42.23%, respectively; The difference in HLA-A2 positivity rate and allele frequency among carriers was statistically significant (P<0.05). the HLA-A2 positivity rate and allele frequency in the HBV previous infection group were 56.14% and 35.97%, respectively, which did not significantly differ from those in the healthy control group (P>0.05). [Conclusion] HLA-A2 gene may be a susceptibility gene for chronic hepatitis B HBV carriers.

Recently,the substance P(SP)/neurokinin-1 receptor(NK-1R)system has been found to be involved in various human pathophysiological disorders including the symptoms of coronavirus disease 2019(COVID-19).Besides,studies in the oncological field have demonstrated an intricate correlation between the upregulation of NK-1R and the activation of SP/NK-1R system with the progression of multiple carcinoma types and poor clinical prognosis.These findings indicate that the modulation of SP/NK-1R system with NK-1R antagonists can be a potential broad-spectrum antitumor strategy.This review updates the latest potential and applications of NK-1R antagonists in the treatment of human diseases and cancers,as well as the underlying mechanisms.Furthermore,the strategies to improve the bioavailability and efficacy of NK-1R antagonist drugs are summarized,such as solid dispersion systems,nanonization,and nanoencapsulation.As a radiopharmaceutical therapeutic,the NK-1R antagonist aprepitant was originally developed as radioligand receptor to target NK-1R-overexpressing tumors.However,combining NK-1R antagonists with other drugs can produce a synergistic effect,thereby enhancing the therapeutic effect,alleviating the symptoms,and improving patients'quality of life in several diseases and cancers.

‍ ObjectiveTo investigate the protective effect of safranal against sepsis-related liver injury （SRLI） induced by lipopolysaccharide （LPS） in mice and its mechanism. MethodsA total of 32 experimental male C57BL/6 mice were divided into control group， single drug group， model group， and treatment group using the simple random method， with 8 mice in each group. The mice in the single drug group and the treatment group were intraperitoneally injected with safranal （60 mg/kg） for 7 days of pretreatment， and the mice in the model group and the treatment group were intraperitoneally injected with LPS （10 mg/kg） to induce acute liver injury. The activities of serum alanine aminotransferase （ALT） and aspartate aminotransferase （AST） were measured； HE staining was used to observe liver tissue sections； immunohistochemistry was used to analyze the expression of the downstream protein heme oxygenase-1 （HO-1） in the signal pathway； TUNEL was used to analyze the apoptosis of hepatocytes； Western blot was used to measure the expression of total proteins （nuclear factor erythroid 2-related factor 2 ［Nrf-2］ and HO-1） in liver tissue. The human liver cell line L02 was pretreated with safranal （100 μmol/L）， followed by induction of acute hepatocellular injury with LPS （100 ng/mL）， and DCFH-DA fluorescent labeling was used to detect reactive oxygen species （ROS）. ResultsAfter safranal pretreatment， the treatment group had significantly lower levels of ALT and AST than the model group （both P<0.001）， with a relatively intact pseudolobular structure and a smaller necrotic area in the liver. Compared with the model group， the treatment group had significant increases in the expression levels of Nrf2 and HO-1 in liver tissue after safranal+LPS treatment （both P<0.001）， and immunohistochemistry showed that safranal pretreatment increased the number of HO-1-positive cells. In the cell model of LPS-induced acute liver injury， the treatment group had a significant reduction in the production of ROS compared with the model group. ConclusionSafranal can exert a protective effect against SRLI induced by LPS in mice through the Nrf2/HO-1 pathway.

Based on our previous work, the study herein designed and synthesized eight glycoconjugates of natural product harmine (14a-14h)by introducing a cyclohexylmethyloxyl group at its C7 position and coupling a methyl-2-amino-β-D-glucopyranoside to the N9 position through different lengths of alkyl chains.In vitro anti-tumor activity screening and structure-activity relationship studies showed that the antitumor activity of the conjugates increased with the lengthening of the alkyl chain in the linker.Compound 14h exhibited significantly better proliferative inhibitory activity against MDA-MB-231 breast cancer cells than harmine.As compared to harmine, the introduction of the carbohydrate moiety improved the water solubility of compound 14h and enhanced its tumor cell selectivity through the Warburg effect.Mechanism of action studies revealed that compound 14h induced apoptosis and G0/G1 cell cycle arrest in MDA-MB-231 cells, and inhibited tumor cell migration by interfering with epithelial-mesenchymal transition process.This study provides a new approach for the development of antitumor drugs based on harmine.

Objective:To observe the effects of 0.01% atropine eye drops on ocular biometrics in myopic adolescents.Methods:A prospective cohort study was conducted.Two hundred and nineteen myopic adolescents who visited the First Affiliated Hospital of Zhengzhou University from June 2016 to June 2017 and completed the 1-year follow-up on time were enrolled.The 219 adolescents were divided into a 0.01% atropine+ single-vision spectacles (SV) group (119 cases) wearing single-vision spectacles with one drop of atropine eye drop applied to both eyes once nightly, and a simple SV group (100 cases) wearing SV only.Axial length (AL), corneal power and anterior chamber depth were measured with the IOLMaster.Lens power was calculated using the Bennett-Rabbetts formula.Intraocular pressure was measured by non-contact tonometry.Spherical equivalent (SE) was examined by cycloplegic autorefraction.Total astigmatism and corneal astigmatism were calculated by vector decomposition.The right eye data were analyzed to compare the ocular biometrics changes between the two groups, and multiple linear regression analysis was used to evaluate the influencing factors.This study adhered to the Declaration of Helsinki.The study protocol was approved by the Ethics Committee of First Affiliated Hospital of Zhengzhou University (No.2016-35). Written informed consent was obtained from guardians before any medical examination.Results:The SE change and AL elongation 12 months after treatment in 0.01% atropine+ SV group were (-0.47±0.45) D and (0.37±0.22) mm, respectively, which were significantly lower than (-0.70±0.60)D and (0.46±0.35)mm in simple SV group ( t=5.523, 9.651; both at P<0.001). There were significant differences in SE and AL between before and after treatment in both groups (SE: Fgroup=1.556, P=0.015; Ftime=12.538, P=0.002; AL: Fgroup=3.425, P=0.021; Ftime=18.235, P=0.008). The SE and AL at 4, 8 and 12 months after treatment were all increased in comparison with before treatment in both groups, showing statistically significant differences (all at P<0.001). The SE and AL at 8 and 12 months after treatment in 0.01% atropine+ SV group were smaller than in simple SV group, and the differences were statistically significant (all at P<0.001). At 8 and 12 months after treatment, total astigmatism and the anterior chamber depth were increased and the lens power was decreased in comparison with before treatment in both groups, and the differences were statistically significant (all at P<0.05). There was no significant difference in corneal astigmatism, corneal power and intraocular pressure at different time points before and after treatment between the two groups (all at P>0.05). In the multiple linear regression analysis, an equation of Δmyopic SE=-0.012-2.685×ΔAL-1.002×Δcorneal astigmatism-0.656×Δlens power+ 0.477×Δtotal astigmatism+ 0.363×Δanterior chamber depth-0.060×age+ 0.011×sex was used, showing the change of SE was mainly caused by the change of AL ( β=-2.685), then corneal power, lens power, total astigmatism and anterior chamber depth. Conclusions:In adolescents, 0.01% atropine eye drops can effectively retard myopia progression and axial elongation, showing no effect on astigmatism, corneal power, lens power, anterior chamber depth and intraocular pressure.The controlling effect of 0.01% atropine eye drops in the development of myopia is mainly achieved by reducing axial elongation.

ObjectiveTo monitor the microbes in urban drinking water in Jiangxi from 2016 to 2020， to analyze the change in microbial qualification rate， and to provide a scientific basis for government decision-making. MethodsAccording to the Standard Examination Method for Drinking Water （GB/T 5750‒2006） and the Standards for Drinking Water Quality （GB 5749‒2006）， the water samples were collected， tested and evaluated for hygienic safety. The chi-square test was used to compare the qualification rates among different water periods， water source types， water supply modes， water samples， treatment processes， and disinfection methods. ResultsA total of 10 584 water samples were collected and examined from 2016 to 2020，with a qualification rate of 97.72%. The qualified rate of the microbiological index increased gradually over the years. There was no statistically significant difference in the microbiological qualification rate of water samples monitored in different water periods （χ²=0.718，P=0.398）， and the qualification rates were 97.85% and 97.60% in dry and abundant water periods respectively. There was a statistically significant difference in the qualification rates of water samples monitored in different water source types （χ²=79.560，P=0.398）， with groundwater having a higher qualification rate of 98.83% than surface water （97.70%）. The microbiological pass rate of water samples differed among different water supply methods （χ²=201.836，P<0.001）. The microbiological pass rates of municipal centralized water supply， self-built centralized water supply and secondary water supply were 97.51%， 88.94% and 96.56% respectively. The microbiological pass rates of water samples differed among different treatment processes. There were differences in the qualification rates of the water samples between different treatment processes（χ²=855.034，P<0.001）， with 98.22%， 67.19%， 95.60% and 53.13% of the conventionally treated， precipitated filtered， disinfected only and untreated water samples， respectively. The differences in the microbiological qualification rates of the monitored water samples between different disinfection methods were statistically significant （χ²=904.993，P<0.001）. Chlorination disinfection， chlorine dioxide disinfection， other disinfection methods and non-disinfected water samples had the pass rates of 98.35%， 98.19%， 84.38% and 60.16%， respectively. ConclusionThe qualified rate of the microbiological index of drinking water in Jiangxi increases year by year， but there are still some drinking water without appropriate disinfectants and water quality treatment processes. There is still a need to strengthen the purification， disinfection and monitoring of drinking water.