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: To investigate the changes in autophagy of mesenchymal stem cells (MSCs) from patients with ankylosing spondylitis and explore the mechanism for decreased autophagy in ASMSCs. METHODS: MSCs collected from 14 patients with AS (ASMSCs) and from 15 healthy donors (HDMSCs) were cultured in the absence or presence of 25 ng/mL TNF-α for 6 h. Autophagy of the cells was determined by immunofluorescence staining of GFP-LC3B, and the results were confirmed by detecting the protein expressions of autophagy markers LC3 II/LC3 I and P62. The mRNA expressions of the related genes were detected using qRT-PCR, and the protein expressions of the autophagy markers and signaling pathway-related molecules were determined with Western blotting. TG100713 was used to block the PI3K/AKT/mTOR signal pathway, and its effect on autophagy of ASMSCs was evaluated. RESULTS: ASMSCs showed significantly weaker GFP-LC3B puncta staining and lower protein expression levels of LC3 II/LC3 I but higher levels of P62 protein (P < 0.05), indicating a decreased autophagy capacity as compared with HDMSCs. TNF-α-induced ASMSCs showed significantly higher protein expressions of p-PI3K/ PI3K, p-AKT/AKT and p-mTOR/mTOR than HDMSCs (P < 0.05), suggesting hyperactivation of the PI3K/AKT/mTOR signaling pathway in ASMSCs. Blocking PI3K/AKT/mTOR signaling with TG100713 eliminated the difference in TNF-α-induced autophagy between HDMSCs and ASMSCs. CONCLUSION In patients with AS, hyperactivation of the PI3K/AKT/mTOR signaling pathway results in decreased autophagy of the MSCs and potentially contributes to chronic inflammation.
Autophagy ; Humans ; Mesenchymal Stem Cells/metabolism* ; Phosphatidylinositol 3-Kinases/metabolism* ; Proto-Oncogene Proteins c-akt/metabolism* ; Signal Transduction ; Spondylitis, Ankylosing ; TOR Serine-Threonine Kinases/metabolism* ; Tumor Necrosis Factor-alpha/metabolism*

OBJECTIVE: To compare the clinical effect differences between "'s five-needle method" and routine acupoint selection on allergic rhinitis and asthma syndrome. METHODS: A total of 210 patients with allergic rhinitis and asthma syndrome were randomly divided into an observation group (105 cases, 4 cases dropped off) and a control group (105 cases, 4 cases dropped off). The patients in the observation group were treated with "'s five-needling method", and the acupoints of Feishu (BL 13), Dazhui (GV 14), Fengmen (BL 12), Yintang (GV 29), Shangyingxiang (EX-HN 8) and Hegu (LI 4), etc. were selected; the patients in the control group was treated with routine acupuncture, and the acupoints of Feishu (BL 13), Zhongfu (LU 1), Taiyuan (LU 9), Dingchuan (EX-B 1), Danzhong (CV 17), Yintang (GV 29), Fengmen (BL 12) and Zusanli (ST 36), etc. were selected. The treatment in the two groups was given once a day, 6 times a week, for 4 weeks. The score of symptoms and signs was observed before and after treatment as well as 1 month, 2 months and 3 months after treatment. The forced expiratory volume in 1 second (FEV1), peak expiratory flow (PEF) and eosinophils in peripheral blood were measured before and after treatment in the two groups. After treatment, the clinical therapeutic effect was compared between the two groups. RESULTS: The total effective rate was 98.0% (99/101) in the observation group, which was superior to 94.1% (95/101) in the control group (<0.01). Compared before treatment, the total score of symptoms and signs in the two groups was significantly decreased at 1, 2, 3 and 4 weeks of treatment (<0.01); after treatment and at each time point of follow-up, the total score of symptoms and signs in the observation group was lower than that in the control group (<0.01). Compared with 4 weeks of treatment, the total score of symptoms and signs at each time point of follow-up was not statistically different in the observation group (>0.05), and the total score of symptoms and signs in the third month of follow-up in the control group was significantly increased (<0.05). After treatment, FEV1 and PEF in the two groups were increased (<0.01), eosinophil count in peripheral blood was decreased (<0.01), and the improvement in the observation group was greater than that in the control group (<0.01, <0.05). CONCLUSION "'s five-needle method" can improve the clinical symptoms and pulmonary function, reduce the count of eosinophils in peripheral blood in patients with allergic rhinitis and asthma syndrome, and the curative effect is better than routine acupuncture.
Acupuncture Points ; Acupuncture Therapy ; Asthma ; therapy ; Humans ; Needles ; Rhinitis, Allergic ; therapy ; Treatment Outcome

Background:Clinical outcomes of undifferentiated arthritis (UA) are diverse,and only 40 ％ of patients with UA develop rheumatoid arthritis (RA) after 3 years.Discovering predictive markers at disease onset for further intervention is critical.Therefore,our objective was to analyze the clinical outcomes of UA and ascertain the predictors for RA development.Methods:We performed a prospective,multi-center study from January 2013 to October 2016 among Chinese patients diagnosed with UA in 22 tertiary-care hospitals.Clinical and serological parameters were obtained at recruitment.Follow-up was undertaken in all patients every 12 weeks for 2 years.Predictive factors of disease progression were identified using multivariate Cox proportional hazards regression.Results:A total of 234 patients were recruited in this study,and 17 (7.3％) patients failed to follow up during the study.Among the 217 patients who completed the study,83 (38.2％) patients went into remission.UA patients who developed RA had a higher rheumatoid factor (RF)-positivity (42.9％ vs.16.8％,x2=8.228,P=0.008),anti-cyclic citrullinated peptide (CCP) antibodypositivity (66.7％ vs.10.7％,x2 =43.897,P ＜ 0.001),and double-positivity rate of RF and anti-CCP antibody (38.1％ vs.4.1％,x2 =32.131,P ＜ 0.001) than those who did not.Anti-CCP antibody but not RF was an independent predictor for RA development (hazard ratio 18.017,95％ confidence interval:5.803-55.938;P ＜ 0.001).Conclusion:As an independent predictor of RA,anti-CCP antibody should be tested at disease onset in all patients with UA.

The present study was designed to further investigate the C steroidal glycosides in Cynanchum plants. Two new steroidal glycosides based on a 13, 14:14, 15-disecopregnane-type aglycone, komaroside P (1) and komaroside Q (2), together with three known compounds (3-5) were isolated from the whole herbs of Cynanchum komarovii. The aglycones of compounds 1 and 2 were two new disecopregnane. Their structures were elucidated on the basis of 1D, 2D NMR spectroscopic data and acid hydrolysis. All the compounds (1-5) showed potent inhibitory activities against human leukemia cell lines (HL-60) with IC values ranging from 16.6 to 26.3 μmol·L, compared to the positive control 5-fluorouracil (6.4 μmol·L).
Cell Survival ; drug effects ; Cynanchum ; chemistry ; Drugs, Chinese Herbal ; chemistry ; isolation & purification ; pharmacology ; Glycosides ; chemistry ; isolation & purification ; pharmacology ; HL-60 Cells ; Humans ; Magnetic Resonance Spectroscopy ; Molecular Structure ; Steroids ; chemistry ; isolation & purification ; pharmacology

A Kinase Anchor Proteins ; genetics ; metabolism ; Animals ; Cell Cycle Proteins ; genetics ; metabolism ; Humans ; Neoplasms ; genetics ; metabolism

Objective To observe effects of Qinjiao (Gentianae macrophyllae Pall.) in different combinations in wind-damp-heat arthralgia RA model rats and its mechanism.Methods SD rats were randomly divided into eight groups:normal group,disease model group (type Ⅱ collagen),syndrome model group (type Ⅱ collagen + rheumaticfever),positive drug group,Qinjiao group,Qinjiao + Weilingxian (Clematis chinensis Osbeck) group,Qinjiao + Sangjisheng (Taxillus chinensis)group,Qinjiao + Fangji (Stephaniatetrandra) group,each group had ten rats.In the first day of the experiment,the rats in the other groups were given two points on the back,one point at the end of the tail,shaved and intradermally 0.1 mL of collagen Ⅱ (C Ⅱ).In the second day of the experiment,except for the normal group and disease model group,the other groups were reconstructed with the reconstructed artificial climate box for rheumatism and fever model for 11 days.On the 12th day of the experiment,0.1 mL of C Ⅱ emulsion was injected into the left hind paw of the plantar vein to further stimulateand then into the artificial climate box for rheumatoid fever model for 7 days.At the end of the model,the rats in each group were given the corresponding drug by 15 mL · kg-1;the normal group,the disease model group and the syndrome model gronp were given the same amount of saline once a day for 21 days.The first 39 days of the experiment,takingthe ankle joint,the degree of damage of ankle joint was observed by pathological staining with hematoxylin eosin (HE).The expression of nuclear factor kappa B (NF-κB) protein in ankle jointwas determined by immunohistochemical method.The NF-κB expression was semi-quantitative analysis by Western blot.Results The expression of NF-κB protein in the disease model group and the syndrome model group was 170.57 ± 8.93 and 180.02 ± 6.93,respectively.Compared with the expression of NF-κB in the normal group of 105.08 ± 7.97,the difference was statistically significant (all P ＜ 0.05).And the syndrome model group was higher than the disease model group.After administration,compared with others drug groups,the expression of NF-κB protein was 112.37 ± 7.34 in Qinjiao + Fangji group statistically significant (P ＜ 0.05).Compared with the normal model group (0.41 ± 0.16),relative expression of NF-κB protein in the disease model group and the syndrome model group were 0.78 ± 0.12,1.08 ± 0.11,which was significantly higher than that in normal group,and the difference was statistically significant (all P ＜ 0.05).Compared with the syndrome model group,the relative expression of NF-κB protein in Qinjiao + Fangji group was 0.53 ± 0.04,and the difference was statistically significant (P ＜ 0.05).Conclusion Different compatibility of Qinjiao may down expression of NF-κB to protect on RA,among then the combined effect of mild and cold traditional Chinese medicine (TCM) is better than the combined effect of mild and warm TCM,the combined effect of mild and mild TCM.

OBJECTIVETo investigate the effects of human umbilical cord blood-derived mesenchymal stem cells(HUCMSC) on the leukemic cell line HL-60 and acute lymphoblastic leukemia cell line Jurkat as well as the role of CXCL12/CXCR4.

METHODSHL-60 cells and Jurkat cells were co-cultured with human umbilical cord blood mesenchymal stem cell (HUCMSC), and the model was treated with G-CSF, AMD3100 and their combination. The cell viability and cell cycle were measured by Cell Counting Kit-8 (CCK-8), the apoptosis and the cell-cycle analysis were assessed by flow cytometry with the Annexin V/PI double staining. The expression of surface CXCR4 protein and total CXCR4 protein of leukemic cells were detected by flow cytometry and Western blot respectively.

RESULTSHUCMSC could decrease the viability of HL-60 cells and Jurkat cells, as well as the percentage of apoptotic cells, they could also increase the number of G/Gcells, while G-CSF and AMD3100 could reduce the proliferation of HL-60 cells and Jurkat cells in HUCMSC co-culture model, destructed the anti-apoptotic effect of HUCMSC on HL-60 cells and Jurkat cells, and the combination of 2 drugs resulted in a synergistic effect. The G-CSF could reduce the expression of surface CXCR4 protein and total CXCR4 protein in leukemic cells, while AMD3100 could only decrease the expression of surface CXCR4 protein of leukemia cell membrane, having no effect on the expression of CXCR4 protein in cytoplasm.

CONCLUSIONHuman umbilical cord blood mesenchymal stem cells can inhibit the proliferation and apoptosis of acute leukemia cells and increase the number of G/Gphase cells in leukemic cells. The AMD3100 can decrease the expression of surface CXCR4 protein in leukemia cells, G-CSF can decrease expression of total CXCR4 protein as well as membrane CXCR4 protein. Both of them can block the CXCL12/CXCR4 signal axis, weakening the relationship between leukemia cells and microenvironment. And on the basic of HUCMSC influenced leukemia cells' growth and proliferation, the cell viability will be weakened, its apoptosis will be promoted, and the percentage of G/Gphase cells in leukemia cells will be decreased.

OBJECTIVETo investigate the therapeutic efficacy of anticoagulation(AC) and its combination with catheter-directed thrombolysis(CDT) for deep venous thrombosis of lower extremities.

METHODSOne hundred and thirty-nine patients with deep venous thrombosis of early lower extremities treated in our hospital from May 2011 to September 2013 were selected and randomly divided into the AC group(n= 66) and CDT+AC group(n= 73). The thrombolytic effects, adverse reactions, post-thrombotic syndrome (PTS) and quality of life were evaluated.

RESULTSThere were no serious adverse events during treatment and after treatment in the 2 groups. Hematomas in 2 cases and gross hematuria in 3 cases were observed in the CDT+AC group. The gums bleed or gross hematuria in 3 cases were observed in the AC group. Compared with the AC group, the number of grade I thrombolysis in CDT+AC group decreased significantly (60.61% vs 9.59%)(P< 0.05), and the number of grade III thrombolysis increased significantly(7.57% vs 49.31%)(P< 0.05). During follow-up, the incidence of PTS in both groups showed increase year by year, and none of the patients had severe PTS. The incidence PTS in CDT+AC group at 12 months and 18 months were lower than those of AC group(17.81% vs 33.33%, 24.66% vs 43.94%)(P< 0.05). Compared with the AC group, the scores of physiological role and vitality in CDT+AC group at 6 months, 12 months and 18 months were higher (P< 0.05).

CONCLUSIONCatheter-directed thrombolysis combined with AC therapy can promote the mitigation of clinical symptoms in patients with DVT of lower extremities and is beneficial to promoting the life quality of patients.

Objective To explore the effect of intracoronary recombinant human urokinase (Pro-uk) and tirofiban in ST-segment elevation myocardial infarction (STEMI) patients undergoing primary percutanous coronary intervention (PCI) by observing coronary blood flow,myocardial damage and the major adverse cardiovascular events major (MACE).Methods Ninety-eight patients with STEMI who underwent emergency PCI were randomly divided into treatment group(n =48) and control group (n =50).All patients were treated with aspirin 300 mg and ticagrelor 180 mg before coronary angiography (CAG).Treatment group was given Pro-uk 10 mg and tirofiban 10 μg · kg-1 after CAG.Control group was received PCI.The number of correction thrombolysis in myocardial infarction (TIM1) frames (CTFC) and myocardial perfusion grade (TMP) were observed after PCI.The levels of creatine kinase-MB (CK-MB) and troponin Ⅰ (cTn Ⅰ) were measured before and after operation.The major cardiac adverse events were recorded 30 days after PCI.Results The TIMI score of the arteries in treatment group was higher than that in control group.The number of corrected TIMI frame count (CTFC) in treatment group and control group were 21.97 ± 5.21,30.56 ± 4.85,with significant difference (P ＜ 0.05).The percentage of TMP level 2 and more in treatment group and control groups were 75.00％,56.00％,with significant difference (P ＜ 0.05).The levels of CK-MB and cTn Ⅰ in treatment group were (29.24 ± 8.87),(8.34 ± 2.01)ng · mL-1,had significant difference with those in control group,which were (36.93 ± 9.45),(9.36 ± 1.68)ng · mL-1 (P ＜ 0.05).There was 1 case of severe heart failure(2.08％),and there were 8 cases (16.00％) of severe heart failure and 6 cases (12.00％) of malignant arrhythmia in control group,with significant difference in two groups(P ＜ 0.05).Conclusion Intracoronary use of Pro-uk and tirofiban can alleviate myocardial injury,improve myocardial microcirculation perfusion,and decrease the MACE.