As the number of patients with compromised immune function increases and fungal resistance develops, so does the risk of contracting deadly fungi in humans. Both fungi and humans are eukaryotes, so identifying unique targets for antifungal drug development is difficult. In addition, the existing antifungal drugs are limited by toxicity, drug interaction and drug resistance in practical application, which leads to the increasing incidence and fatal rate of fungal infections. Therefore, it is urgent to develop new antifungal drugs. The semi-synthetic technology using microbial fermentation products from natural sources as lead compounds has become the most used method in structural modification of antifungal drugs due to its advantages of few reaction steps and easy operation. This paper will introduce the current status of natural antifungal drugs in clinical use, as well as the latest progress in the research and development of new semi-synthetic antifungal drugs, and summarize their mechanism of action, structural modifications, advantages and disadvantages, so as to provide reference for the subsequent development of new antifungal drugs.

OBJECTIVE: The study aim was to investigate the effects of exposure to multiple environmental organic pollutants on cardiopulmonary health with a focus on the potential mediating role of oxidative stress. METHODS: A repeated-measures randomized crossover study involving healthy college students in Beijing was conducted. Biological samples, including morning urine and venous blood, were collected to measure concentrations of 29 typical organic pollutants, including hydroxy polycyclic aromatic hydrocarbons (OH-PAHs), bisphenol A and its substitutes, phthalates and their metabolites, parabens, and five biomarkers of oxidative stress. Health assessments included blood pressure measurements and lung function indicators. RESULTS: Urinary concentrations of 2-hydroxyphenanthrene (2-OH-PHE) ( β = 4.35% [95% confidence interval ( CI): 0.85%, 7.97%]), 3-hydroxyphenanthrene ( β = 3.44% [95% CI: 0.19%, 6.79%]), and 4-hydroxyphenanthrene (4-OH-PHE) ( β = 5.78% [95% CI: 1.27%, 10.5%]) were significantly and positively associated with systolic blood pressure. Exposures to 1-hydroxypyrene (1-OH-PYR) ( β = 3.05% [95% CI: -4.66%, -1.41%]), 2-OH-PHE ( β = 2.68% [95% CI: -4%, -1.34%]), and 4-OH-PHE ( β = 3% [95% CI: -4.68%, -1.29%]) were negatively associated with the ratio of forced expiratory volume in the first second to forced vital capacity. These findings highlight the adverse effects of exposure to multiple pollutants on cardiopulmonary health. Biomarkers of oxidative stress, including 8-hydroxy-2'-deoxyguanosine and extracellular superoxide dismutase, mediated the effects of multiple OH-PAHs on blood pressure and lung function. CONCLUSION Exposure to multiple organic pollutants can adversely affect cardiopulmonary health. Oxidative stress is a key mediator of the effects of OH-PAHs on blood pressure and lung function.
Humans ; Oxidative Stress/drug effects* ; Male ; Cross-Over Studies ; Female ; Young Adult ; Environmental Pollutants/toxicity* ; Environmental Exposure/adverse effects* ; Biomarkers/blood* ; Adult ; Blood Pressure/drug effects* ; Polycyclic Aromatic Hydrocarbons/urine* ; Beijing

Objective To construct a regulatory network of competing endogenous RNA(ceRNA)with prognostic value for bladder urothelial carcinoma(BLCA),and analyze the relationship between key messenger RNA(mRNA)and immune function.Methods The UCSC Xena database was used to download mRNA expression data from 404 BLCA patients and 28 normal individuals and key mRNAs were screened by differential analysis.ENCORI database was utilized to search microRNAs(miRNAs)that bind to key mRNAs and all long non-coding RNAs(LncRNAs)that bind to miRNAs.The expression data of miRNA and LncRNA were downloaded from TCGA database,co-expression analysis was performed to identify key mRNA with all miRNAs and miRNA with all LncRNAs,and thus key miRNAs and LncRNAs were screened out.Survival analysis was conducted based on the differences in expression levels of these key mRNAs,miRNAs,and LncRNAs between tumor patients and normal individuals,and finally a ceRNA regulatory network was constructed.The correlation between key mRNAs and immune cells,immune checkpoints(CD274,PDCD1 and CTLA4),and immune cell marker genes(IG)was analyzed using the TIMER 2.0 database.Results A total of 22 key mRNAs were screened,with the most significant difference being proline 3-hydroxylase 4(P3H4).The expression of P3H4 in patients with BLCA was high,and survival time was shorter in patients with high expression.A sum of 33 miRNAs and 14 LncRNAs were screened using the key mRNAs as the central link.Through co-expression analysis and survival analysis,hsa-miR-151a-3p and MIR100 HG were identified as the key miRNA and key LncRNA with prognostic value.The differences in the above analysis results were statistically significant(all P＜0.05).Based on these findings,a ceRNA regulatory network consisting of 1 mRNA,1 miRNA,and 1 LncRNA was constructed.Immunoassay firstly revealed a significant positive correlation between double positive T cells and P3H4 expression in the tumor microenvironment of BLCA.Moreover,there were 3 types of immune cells(tumor-associated neutrophils,and tumor-associated macrophages,dendritic cells),3 immune checkpoints(CD274,PDCD1,CTLA4),and 15 IGs with significant correlation with P3H4.These differences were statistically significant(all P＜0.01).Conclusion This study could help to reveal the progression mechanism of BLCA.The constructed ceRNA network and immune analysis can offer new insights into potential biological targets and immunotherapy directions for the diagnosis,treatment,and prediction of BLCA patients.

Objective To explore the treatment of infection after spinal internal fixation.Methods The clinical data of 6 patients with infection after spinal internal fixation in our hospital were analyzed retrospectively.The bacterial culture and drug susceptibility testing were performed to identify the pathogenic bacteria and sensitive antibiotics.Moxifloxacin and/or vancomycin were used empirically for anti-infective therapies first,and then sensitive antibiotics were used according to the results of bacterial culture and drug susceptibility testing.At the same time,imaging examination was performed to determine the infection site and internal fixation,and surgical treatment was decided based on the patients'condition.After operation,the body temperature,inflammatory indexes and drainage of patients were monitored continuously,and the drainage fluid was taken for bacterial culture regularly to evaluate the therapeutic effect.Results The results of bacterial culture in 5 patients were positive and the pathogenic bacteria was staphylococcus aureus,with the susceptibility to vancomycin by susceptibility testing.Among them,1 patient was treated with vancomycin for about 8 weeks because of his advanced age,more basic diseases and high risk of operation;the other 4 patients were received surgery combined with anti-infective treatment with vancomycin for 2 to 4 weeks.One case with negative bacterial culture received surgery combined with anti-infective treatment with imipenem and moxifloxacin.The wound of all patients healed in grade A,the body temperature and inflammatory indexes returned to normal,the low back pain disappeared,and the nerve root symptoms of lower extremities were significantly improved.Conclusion Once the patients with infection after spinal internal fixation are diagnosed,the pathogenic bacterial should be identified as early as possible and sensitive antibiotics should be used.Meanwhile,the internal fixation is removed or re-implanted depending on whether it is infected.

The bacterial ATP-competitive GyrB/ParE subunits of type II topoisomerase are important anti-bacterial targets to treat super drug-resistant bacterial infections. Herein we discovered novel pyrrolamide-type GyrB/ParE inhibitors based on the structural modifications of the candidate AZD5099 that was withdrawn from the clinical trials due to safety liabilities such as mitochondrial toxicity. The hydroxyisopropyl pyridazine compound 28 had a significant inhibitory effect on Gyrase (GyrB, IC₅₀ = 49 nmol/L) and a modest inhibitory effect on Topo IV (ParE, IC₅₀ = 1.513 μmol/L) of Staphylococcus aureus. It also had significant antibacterial activities on susceptible and resistant Gram-positive bacteria with a minimum inhibitory concentration (MIC) of less than 0.03 μg/mL, which showed a time-dependent bactericidal effect and low frequencies of spontaneous resistance against S. aureus. Compound 28 had better protective effects than the positive control drugs such as DS-2969 ( 5) and AZD5099 ( 6) in mouse models of sepsis induced by methicillin-resistant Staphylococcus aureus (MRSA) infection. It also showed better bactericidal activities than clinically used vancomycin in the mouse thigh MRSA infection models. Moreover, compound 28 has much lower mitochondrial toxicity than AZD5099 ( 6) as well as excellent therapeutic indexes and pharmacokinetic properties. At present, compound 28 has been evaluated as a pre-clinical drug candidate for the treatment of drug-resistant Gram-positive bacterial infection. On the other hand, compound 28 also has good inhibitory activities against stubborn Gram-negative bacteria such as Escherichia coli (MIC = 1 μg/mL), which is comparable with the most potent pyrrolamide-type GyrB/ParE inhibitors reported recently. In addition, the structure-activity relationships of the compounds were also studied.

This paper aims to investigate the effects and mechanisms of adipose-derived stem cells-exosomes(ADSCs-exos) toge-ther with aucubin in protecting human-derived nucleus pulposus cells(NPCs) from inflammatory injury, senescence, and apoptosis. The tert-butyl hydroperoxide(TBHP)-induced NPCs were assigned into normal, model, aucubin, ADSCs-exos, and aucubin+ADSCs-exos groups. The cell viability was examined by cell counting kit-8(CCK-8), cell proliferation by EdU staining, cell senescence by senescence-associated-β-galactosidase(SA-β-Gal), and cell cycle and apoptosis by flow cytometry. Enzyme-linked immunosorbent assay was employed to examine the expression of interleukin-1β(IL-1β), IL-10, and tumor necrosis factor-α(TNF-α). Real-time fluorescence quantitative PCR and Western blot were employed to determine the mRNA and protein levels of aggregated proteoglycan(aggrecan), type Ⅱ collagen alpha 1(COL2A1), Toll-like receptor 4(TLR4), and nuclear factor-kappa B(NF-κB). The results showed that compared with the model group, the aucubin or ADSCs-exos group showed enhanced viability and proliferation of NPCs, decreased proportion of G_0/G_1 phase cells, increased proportion of S phase cells, reduced apoptosis and proportion of cells in senescence, lowered IL-1β and TNF-α levels, elevated IL-10 level, down-regulated mRNA and protein levels of TLR4 and NF-κB, and up-regulated mRNA and protein levels of aggrecan and COL2A1. Compared with the aucubin or ADSCs-exos group, the aucubin+ADSCs-exos combination further increased the viability and proliferation of NPCs, decreased the proportion of G_0/G_1 phase cells, increased the proportion of S phase cells, reduced the apoptosis and proportion of cells in senescence, lowered the IL-1β and TNF-α levels, elevated the IL-10 level, down-regulated the mRNA and protein levels of TLR4 and NF-κB, and up-regulated the mRNA and protein levels of aggrecan and COL2A1. In summary, both aucubin and ADSCs-exos could exert protective effects by inhibiting inflammatory responses, reducing apoptosis and senescence of NPCs, improving cell viability and proliferation as well as extracellular matrix synthesis, which may be associated with the inhibition of TLR4/NF-κB signaling pathway activation. The combination of both plays a synergistic role in the protective effects.
Humans ; NF-kappa B/metabolism* ; Interleukin-10 ; Nucleus Pulposus/metabolism* ; Tumor Necrosis Factor-alpha/metabolism* ; Aggrecans/metabolism* ; Toll-Like Receptor 4/metabolism* ; RNA, Messenger/metabolism*

Objective:To screen key genes of renal clear cell carcinoma based on bioinformatics methods, identify possible microRNA (miRNA)-mRNA action axis, and explore the expression of related genes in clear cell renal cell carcinoma tissues and cells.Methods:Gene expression profiles of GSE40435 and GSE71302 datasets were obtained from the Gene Expression Omnibus (GEO) database. TCGA-KIRC datasets were obtained from The Cancer Genome Atlas (TCGA) database. R software was used to identify the differentially expressed mRNA and miRNA, and the functional enrichment analysis was performed. STRING database and Cytoscape software were used to perform the protein interaction analysis. The prognosis-related differentially expressed miRNA was evaluated by the Oncomir database. The potential targeted genes regulated by miRNA were determined by using TargetScan and miRDB targeted gene prediction tools. The tissue samples and clinicopathological features of 34 patients with clear cell renal cell carcinoma in the First Hospital of Shanxi Medical University from June to December 2021 were collected, and normal renal cell line 293T and clear cell renal cell carcinoma cell line 786O were selected. The real-time fluorescence quantitative polymerase chain reaction (qRT-PCR), was used to detect the relative expression of genes; Western blotting and immunohistochemical staining were used to detect the expression levels of the targeted proteins. The dual luciferase reporter gene assay was carried out to verify the targeting relationship between genes.Results:A total of 1 351 differentially expressed mRNA and 50 differentially expressed miRNA were screened and identified. The result of functional enrichment analysis suggested that the fatty acid metabolism pathway and xenobiotic metabolism pathway were suppressed in clear cell renal cell carcinoma, while the apoptosis and immune response pathways were activated. Protein interaction analysis suggested that the signal transduction and protein ubiquitination pathways might play a key role in clear cell renal cell carcinoma. The screening results showed that miRNA-224-5p (miR-224-5p) was most closely associated with clear cell renal cell carcinoma progression and was highly expressed in tumor tissues, and its prognosis-related target gene was NEDD4L. The relative expression of NEDD4L mRNA in clear cell renal cell carcinoma tissues and paraneoplastic tissues were 0.138±0.103 and 1.000±0.026 ( t = 46.23, P < 0.05), and the relative expression of miR-224-5p was 1.000±0.043 and 0.129±0.108 ( t = 45.28, P < 0.05). The differences of NEDD4L mRNA and miR-224-5p expressions in different grades and stages of clear cell renal cell carcinoma tissues were statistically significant (all P < 0.05). The expression of NEDD4L protein was decreased in clear cell renal cell carcinoma. The relative expression of NEDD4L gene in 293T and 786O cells were 1.000±0.125 and 0.210±0.044 ( t = 17.52, P < 0.05); the relative expressions of miR-224-5p gene were 0.209±0.049 and 1.000±0.234 ( t = 10.61, P < 0.05). The relative expressions of NEDD4L mRNA in miRNA mimic group and negative control group were 0.236±0.062 and 1.000±0.024, and the difference was statistically significant ( t = 43.56, P < 0.05). NEDD4L protein expression was reduced in the miRNA mimic group. Dual luciferase reporter gene assay suggested that NEDD4L was a direct target gene of miR-224-5p. Conclusions:In clear cell renal cell carcinoma, miR-224-5p targets and regulates NEDD4L expression, and this mechanism may be related to carcinogenesis and progression of clear cell renal cell carcinoma.

OBJECTIVE: To explore clinical efficacy of Ilizarov hemilateral bone longitudinal transport technique in treating hemilateral bone defects associated with chronic osteomyelitis of lower extremity long bones. METHODS: Clinical data of 13 patients with hemilateral bone defects caused by chronic osteomyelitis of lower extremity long bones and treated by Ilizarov hemilateral bone longitudinal transport technique were retrospective analyzed, including 10 males and 3 female, aged from 14 to 55 years old;4 patients occurred femoral and 9 patients occurred tibial;10 patients were diagnosed as traumatic osteomyelitis and 3 patients as hematogenous osteomyelitis. The anatomical classification of Cierny-Mader in 13 patients was type Ⅲ. Bone and wound healing, postopertaive complication, and bony and functional results were observed by Paley evaluation standard. RESULTS: After removing external fixator, all patients were followed up from 6 to 70 months. Transporting time ranged from 54 to 158 d. And the time in external fixation ranged from 6.8 to 19.5 months. External fixation index (EFI) ranged from 1.23 to 1.6 months/cm. According to Paley's evaluation criteria, bony results were excellent in 13 patients;functional results showed excellent in 12 patients and good in 1 patient. Two patients occurred poor union on the docking sites and healed with autogenous iliac bone graft. The callus at the extended area was poorly mineralized and improved significantly when treated with low-intensity pulsed ultrasound in one patient. All patients had good wound healing without recurrence of osteomyelitis and refracture. There was no vascular and nerve injury and axial deviation in all patients and they were satisfied with the appearance and function of lower limbs. The range of motion of knee and ankle joint before operation was 120 ° to 150 ° and 35 °to 80 ° respectively, and at the latest follow-up was 110 ° to 140 ° and 30 ° to 75 ° . CONCLUSION Ilizarov hemilateral bone longitudinal transport technique is effective in treating infective hemilateral bone defects of lower extremity long bones, which could not only simplify architecture of external fixation, but also reduce the number of fixation pins, shorten the time in external fixator and decrease the incidence of pin tract infection. However, this technique is highly demanding, and the growth of callus in extended region and healing of bone apposition should be noticed.
Male ; Humans ; Female ; Adolescent ; Young Adult ; Adult ; Middle Aged ; Retrospective Studies ; Lower Extremity/surgery* ; Tibia/surgery* ; Femur ; Ankle Joint

Objective: To explore the percentage of in-use electronic sphygmomanometers independently validated clinically in China. Methods: We conducted a cross-sectional survey and Beijing, Shenzhen, Shijiazhuang, Datong, and Shihezi were selected according to the geographical location and economic level. In each site, one tertiary hospital, two community health centers, and 20 families with electronic sphygmomanometers in use were chosen. The information of electronic sphygmomanometers including brand, model, manufacturer and production date were obtained by the trained staff. Ten electronic sphygmomanometers from each hospital, five electronic sphygmomanometers from each community health center, and one electronic sphygmomanometer from each family were surveyed, and the user's subjective judgment results and judgment basis on the accuracy of the electronic sphygmomanometer measurement were collected. We searched six registration websites (Medaval, Stride BP, dabl Educational Trust, British and Irish Hypertension Society, American Medical Association and Hypertension Canada) and two research databases (PubMed and CNKI) for the clinical validation status of each electronic sphygmomanometer. Results: A total of 200 electronic sphygmomanometers were investigated in this study, of which only 29.0% (58/200) passed independent clinical validation. When stratified by users, the percentage of being clinical validated was 46.0% (23/50) for electronic sphygmomanometers in hospitals, 42.0% (21/50) for those in community health centers and 14.0% (14/100) for those in home use, respectively, and the proportions between the three groups were significantly difference (P<0.001). Doctors in tertiary hospitals and community health service centers judged the accuracy of electronic sphygmomanometers mainly on the basis of "regular correction" (41.0% (41/100)) and "comparison with other electronic sphygmomanometers" (20.0% (20/100)), while among home users, 41.0% (41/100) were not clear about the accuracy of electronic sphygmomanometers, and 40.0% (40/100) made the judgment by "comparison with the devices in hospitals". Conclusion: The clinical validation of in-use electronic sphygmomanometers in China is low. Most of users, including healthcare professionals, are not aware of clinical validation of electronic sphygmomanometers.
Humans ; Blood Pressure Determination ; Cross-Sectional Studies ; Sphygmomanometers ; Hypertension/diagnosis* ; China ; Electronics ; Blood Pressure

Objective: To compare the effects and safety of dydrogesterone (DG) and medroxyprogesterone acetate (MPA) on the treatment in patients with endometrial hyperplasia without atypia (EH). Methods: This was a single-center, open-label, prospective non-inferior randomized controlled phase Ⅲ trial. From February 2019 to November 2021, patients with EH admitted to the Obstetrics and Gynecology Hospital of Fudan University were recruited. Enrolled patients were stratified according to the pathological types of simple hyperplasia (SH) or complex hyperplasia (CH), and were randomised to receive MPA or DG. Untill May 14, 2022, the median follow-up time after complete response (CR) was 9.3 months (1.1-17.2 months). The primary endpoint was the 6-month CR rate (6m-CR rate). The secondary endpoints included the 3-month CR rate (3m-CR rate), adverse events rate, recurrence rate, and pregnancy rate in one year after CR. Results: (1) A total of 292 patients with EH were enrolled in the study with the median age of 39 years (31-45 years). A total of 135 SH patients were randomly assigned to MPA group (n=67) and DG group (n=68), and 157 CH patients were randomly assigned to MPA group (n=79) and DG group (n=78). (2) Among 292 patients, 205 patients enrolled into the primary endpoint analysis, including 92 SH patients and 113 CH patients, with 100 patients in MPA group and 105 in DG group, respectively. The 6m-CR rate of MPA group and DG group were 90.0% (90/100) and 88.6% (93/105) respectively, and there were no statistical significance (χ²=0.11, P=0.741), with the rate difference (RD) was -1.4% (95%CI:-9.9%-7.0%). Stratified by the pathology types, the 6m-CR rate of SH patients was 93.5% (86/92), and MPA group and DG group were respectively 91.1% (41/45) and 95.7% (45/47); and the 6m-CR rate of CH patients was 85.8% (97/113), and MPA group and DG group were 89.1% (49/55) and 82.8% (48/58) respectively. The 6m-CR rates of the two treatments had no statistical significance either (all P>0.05). A total of 194 EH patients enrolled into the secondary endpoint analysis, including 88 SH patients and 106 CH patients, and 96 patients in MPA group and 98 in DG group, respectively. The 3m-CR rate of SH patients were 87.5% (77/88), while the 3m-CR rates of MPA group and DG group were 90.7% (39/43) and 84.4% (38/45), respectively; the 3m-CR rate of CH patients was 66.0% (70/106), and MPA group and DG group had the same 3m-CR rate of 66.0% (35/53). No statistical significance was found between the two treatments both in SH and CH patients (all P>0.05). (3) The incidence of adverse events between MPA group and DG group had no statistical significance (P>0.05). (4) A total of 93 SH patients achieved CR, and the cumulative recurrence rate in one year after CR were 5.9% and 0 in MPA group and DG group, respectively. While 112 CH patients achieved CR, and the cumulative recurrence rate in one year after CR were 8.8% and 6.5% in MPA group and DG group, respectively. There were no statistical significance between two treatment groups (all P>0.05). Among the 93 SH patients, 10 patients had family planning but no pregnancy happened during the follow-up period. Among the 112 CH patients, 21 were actively preparing for pregnancy, and the pregnancy rate and live-birth rate in one year after CR in MPA group were 7/9 and 2/7, while in DG group were respectively 4/12 and 2/4, and there were no statistical significance in pregnancy rate and live-birth rate between the two treatment groups (all P>0.05). Conclusions: Compared with MPA, DG is of good efficacy and safety in treating EH. DG is a favorable alternative treatment for EH patients.
Female ; Humans ; Adult ; Medroxyprogesterone Acetate/adverse effects* ; Endometrial Hyperplasia/pathology* ; Dydrogesterone/adverse effects* ; Hyperplasia ; Prospective Studies