Besides 36 (28 single-tablets and 8 fixed-dose combinations) used antiretroviral drugs clinically, there are a number of investigational antiretroviral agents currently in phase 2-3 clinical trial. Tenofoviralafenamidefumarate (TAF) is a novel nucleoside analogue reverse transcriptase inhibitor that is potent and less toxicity than tenofovir (TDF). Doravirine is a non-nucleoside analogue reverse transcriptase inhibitor that demonstrates activity against NNRTI-resistant viral strains. GSK744 is an integrase inhibitor with a long acting preparation. In addition, several drugs with new mechanisms are also noted, for example, BMS-663 068 is a small molecule CD4 attachment inhibitors and cenicriviroc is a novel CCR5/CCR2 antagonist with antiretroviral activity and anti-inflammatory effects. Several drug classes that target known pathways in HIV latency have being developed, and leading the list are histone deacetylase inhibitors. Other agents include protein kinase C activators, positive transcription elongation factor activators, DNA methyl-transferase inhibitors and histone methyl-transferase inhibitors and so on. This review is focused on the above-mentioned drug candidates that may be used in clinical in next couple of years and those compounds that can reverse latent HIV infections.
Adenine ; analogs & derivatives ; therapeutic use ; Anti-HIV Agents ; therapeutic use ; HIV Infections ; drug therapy ; Humans ; Organophosphates ; therapeutic use ; Organophosphonates ; therapeutic use ; Piperazines ; therapeutic use ; Pyridones ; therapeutic use ; Reverse Transcriptase Inhibitors ; therapeutic use ; Tenofovir

Objective:To investigate the relationship between psychological factors and the serum level of estrogen in menopausal women with glossdynia.Methods:87 menopausal women with glossdynia and a randomly selected control group (n=82) were comprehensively investigated with the method of case-control study.The serum level of estradiol(E2) and follicle stimulating hormone(FSH) were measured.All cases with glossdynia and control were evaluated by the Self-Rating Annxiety Scale(SAS) and Self-Rating Depression Scale(SDS). Results: The serum level of E2 was significantly lower in menopausal women with glossdynia than that in control group( P

Hematologic Diseases ; diagnosis ; Hematologic Tests ; Humans

Background The development of retinopathy of prematurity(ROP) is associated with many regulatory cytokines related to neovascularization;however,the retinal expression and regulated mechanism of stromal cell-derived factor-1 (SDF-1) in mouse model of oxygen-induced retinopathy (OIR) remain uncertain.Objective This study was to investigate the expression of SDF-1 in retina of mouse model of OIR.Methods Forty 7-day-old C57BL/6J mice were divided into OIR group and control group.In OIR group,20 mice were exposed to 75% oxygen for 5 days and then to room air for 5 days.In control group,20 mice were raised in room air.The expression of SDF-1 in retina of mice was studied by immunochemistry and quantified by real time reverse transcriptase polymerase chain reaction (RT-PCR).Results The positive immunohistochemical staining for SDF-1 was found mainly locating at the ganglion cell layer in 12-day-old mice of OIR group;the stronger positive immunohistochemical staining for SDF-1 was noted mainly locating at the ganglion cell layer,vascular endothelial cells of inner retina,neovascular endothelial cells in 17-day-old mice of OIR group;the delicate positive immunohistochemical staining for SDF-1 was both found mainly locating at the inner retina and being around the retinal vascular in 12-day-old mice of control group and 17-day-old mice of control group.The expression of SDF-1 mRNA in 17-day-old mice of OIR group was higher than that of 12-day-old mice of OIR group (t=8.072,P＜0.05)and 17-day-old mice of control group(t=10.026,P＜0.05),respectively.The expression of SDF-1 mRNA in 12-day-old mice of OIR group was lower than that of 12-day-old mice of control group (t=4.336,P＜0.05).Conclusion SDF-1 might improve the onset of retinal neovascularization of OIR.

Objective:To explore the role of Semaphorins 3A(Sema 3A) and its receptor Neuropilin-1 (Nrp1) in the development of chronic periodontitis of rats and clinical samples.Methods:20 SD rats were divided into 2 groups.Rats in the experimental group were induced into chronic periodontitis models.Rats in control group were not treated.After 8 weeks,maxilla of all the rats were collected for micro-CT scanning and IHC staining.The distance from cementoenamel junction to alveolar bone crest(CEJ-ABC) and the IOD of Sema3A/Nrp1 positive staining in rats were analyzed.20 clinical samples of chronic periodontitis(n =10) and normal periodontal tissues (n =10) were collected for immunofluorescence and qRT-PCR analysis.Results:The CEJ-ABC distance of chronic periodontitis group was higher than that of the control group(P ＜ 0.05).The IOD of Sema3A/Nrp1 in experimental group was lower than that of the control group (P ＜ 0.05) and with a negative correlation with bone loss (P ＜ 0.05).Immunofluorescence and qRT-PCR analysis showed that the expression level of Sema3a/Nrpl in clinical samples with chronic periodontitis was also lower than that of the healthy subjects(P ＜ 0.05).Conclusion:The reduced Sema3A/Nrp1 plays an important role in the development of bone destruction in chronic periodontitis.

Objective To investigate the effect of selective phosphatase inhibitors Salubrinal on autophagy and apoptosis in the lung tissue of rats with acute paraquat (PQ) poisoning,and to explore its mechanism.Methods 200 Wistar rats were randomly divided into four groups by randomized arrangement table formed by computer,with 50 rats in each group.PQ poisoning model was reproduced by one time gastric lavage with 1 mL of 40 mg/kg PQ solution followed by intraperitoneal injection of 1 mL normal saline (NS) once a day.The rats in control group were lavaged once with 1 mL of NS followed by intraperitoneal injection of 1 mL NS twice a day.The rats in Sal 0.5 and Sal 1.0 groups were intraperitoneal injected with 1 mL Salubrinal 0.5 mg/kg or 1.0 mg/kg on the 1st,3rd,and 5th day after PQ poisoning once a day.The lung tissue was harvested on the 7th day after poisoning,and the changes in histomorphology were observed using hematoxylin and eosin (HE) staining.The positive expression of autophagy-related protein LC3-Ⅱ in lung tissue was observed after immunohistochemistry staining,and LC3-Ⅱ and caspase-3 protein expressions were determined by Western Blot.Results HE staining results showed partial abnormal pulmonary structure in the PQ poisoning group:collapse of pulmonary alveoli,enlargement of the cavity,local infiltration of inflammatory cells,increasing thickness in the alveoli wall and obvious bleeding in the local lung tissue.Compared with the PQ poisoning group,the above changes in Sal 0.5 and Sal 1.0 groups were obviously relieved.It was shown by immunohistochemistry staining that compared with control group,the positive expression of LC3-Ⅱ was obviously decreased in the PQ poisoning group,Sal 0.5,and Sal 1.0 groups (A value:78.34 ± 10.71,76.52 ± 8.21,77.48 ± 9.11 vs.117.58 ± 15.26,all P＜0.05).There was no significant difference in positive expression of LC3-Ⅱ between each of the later three groups (all P＞0.05).Western Blot results showed:compared with the control group,the protein expressions of LC3-Ⅱ and caspase-3 were significantly increased in PQ poisoning group [LC3-Ⅱ (A value):0.22 ±0.05 vs.0.14 ±0.03,caspase-3 (A value):0.115 ± 0.013 vs.0.023 ± 0.006,both P＜0.05].Compared with PQ poisoning group,the protein expressions of LC3-Ⅱ and caspase-3 were obviously decreased in the Sal 0.5 and Sal 1.0 groups [LC3-Ⅱ (A value):0.19 ±0.05,0.18 ±0.04 vs.0.22 ±0.05; caspase-3 (A value):0.078 ±0.012,0.076 ±0.010 vs.0.115 ±0.013,all P＜0.05].Conclusions The endoplasmic reticulum stress-autophagy is activated in the pulmonary cell of acute PQ poisoning rats.Salubrinal can decrease the autophagy and apoptosis in the lung of rats with acute PQ poisoning,which play a role in the treatment.

Objective To investigate the effects of ulinastatin on autophagy and apoptosis of lung cells in rats with acute paraquat poisoning.Methods A total of 150 Wistar rats were randomly (random number) divided into three groups.The rats in control group had stomach lavaged once with 1 mL of normal saline followed by intraperitoneal injection of 1 mL normal saline twice a day.PQ poisoning model was produced by stomach lavaged once with 1 mL of 40 mg/kg PQ solution followed by intraperitoneal injection of 1 mL normal saline once a day.In PQ + ulinastatin (PU) group,UTI in dose of 12 000 U/kg was intraperitoneally injected in rats twice a day.The lung tissue was obtained on the 7th day after modeling,and the histopathological changes were observed under microscope after hematoxylin and eosin (HE) staining.The positive expressions of autophagy-related LC3 protein LC3 and Bcl-2 pretein in lung tissue were observed after immunohistochemistry staining,and the levels of LC3、Bax 、Bcl-2 proteins were determined by Western blot.Results HE staining Results showed:it was observed from the PQ poisoning group that the abnormal cellular structure,enlargement in the pulmonary alveoli,leaking a lot of inflammatory cells,increased thickness of the alveoli wall and bleeding in the local area of lung tissue.Compared with the PQ poisoning group,the above changes in ulinastatin groups were relieved.Western blot Results showed:compared with the control group,the protein expressions of LC3-A/B were significantly increased in PQ poisoning group [LC3-A/B expression (A scale):0.22 ± 0.05 vs.0.14 ± 0.03,F =22.48,P ＜ 0.01].compared with PQ group,the expression of LC3 A/B obviously increased in the group of PU [LC3-A/B expression (A scale):0.36 ± 0.08 vs.0.22 ± 0.05,F =22.78,P ＜ 0.01].compared with Con group,the expression of Bcl-2/Bax obviously decreased in the group of PQ [Bcl-2/Bax expression (A scale),0.11 ±0.04 vs.0.83 ± 0.09,F =154.43,P ＜ 0.01].Compared with PQ poisoning group,the protein expressions of Bcl-2/Bax were obviously increased in PU groups [Bcl-2/Bax expression (A scale):(0.63 ± 018) vs.(0.11 ±0.04),F =154.43,P ＜0.01].Immunohistochemistry result:compared with Con group,the expression of LC3 and Bcl-2 obviously decreased in the group of PQ [LC3expression (A scale):(78.34±10.71) vs.(117.58±15.26),F=31.63,P＜0.01) (Bcl-2 expression (A scale):(62.54±9.74)vs.(130.52 ± 9.86,F =118.44,P ＜ 0.01).Compared with PQ poisoning group,the protein expressions of LC3 and Bcl-2 were obviously increased in PU groups [LC3expression (A scale):(162.58 ± 25.76) vs.(78.34 ± 10.71),F=31.63,P＜0.01]; [Bcl-2 expression (A scale):(145.56±10.26) vs.(62.54±9.74),F=118.44,P ＜ 0.01].Conclusions Theendoplasmic reticulum stress-autophagy is activated in the lung cells of rats with acute PQ poisoning.UTI can adjust endoplasmic reticul um stress,increased the expression of Bcl-2 and enhance the proportion of Bcl-2/Bax to protect the lungs of rats from acute PQ poisoning.

To lay a foundation for the type selection of the ambulance helicopter. The type selection was explored from the aspects of platform selection, rescue environment and service requirements, analyzing the rescue in the helicopter and the tendency of the ambulance helicopter in foreign countries and China. The types of the am-bulance helicopter were determined as the specific and modified ambulances, with the considerations such as operation environment, flight performance, cabin structure, onboard equipment, cabin configuration, fixation device and protection. Specific ambulance helicopter is supposed to be based on small- or mediate-sized platform, while the modi-fied ambulance helicopter is supposed to be based on large or heavy platform.

Objective:To study the expressions of vascular endothelial growth factor(VEGF), and thrombospondin (TSP) in oral submucous fibrosis(OSF), and to determine the relationship between VEGF and TSP, so as to investigate their roles in the pathogenesis of OSF. Methods:30 patients with OSF, including early (10 cases), middle (10 cases), late stage (10 cases) were studied. 5 healthy volunteers were chosen as control group. Buccal mucosa biopsies were taken in all samples. Expressions of VEGF and TSP were detected by immunohistochemistry. Results:The expression of VEGF increased in early stage compared with normal oral mucous, and decreased in middle and late stage. The expression of VEGF in early stage had statistical difference compared with control group, middle stage and late stage respectively(P<0.05).The expression of TSP upregulated in early and middle, and downregulated in late stage. There were no statistical significant differences among groups(P>0.05). The expressions of VEGF and TSP had negative correlation(r=-0.620,P<0.05). Conclusions: The abnormal expressions of VEGF and TSP may be a pathogenesis factor of OSF.

Objective To establish an animal model of PCOS and to detect the DNA methylation states of LHR, INSR and AR genes. Methods 24-days-old female Sprague-Dawley (SD) rats were randomly divided into two groups. The rats in the experimental group were given subcutaneous implanting of levonorgestrel silica gel staff and injected 1.5 IU hCG twice daily for 9 days from the 4th day. The rats in the control group were injected with normal saline at the same time. Ovarian morphologic changes, sex hormone levels, fasting serum insulin and glucose were detected. The LHR, INSR and AR genes' DNA methylation patterns were checked by methylation specific PCR in modeling group and control group. Results The ovarian weight and volume in modeling group were higher than those in control group. The ovaries in modeling group showed multiple follicular cysts, and the number of theca cells and interstitial cells increased. Less developed follicles and corpus lutea were seem. The serum level of progesterone, testosterone, luteinizing hormone, fasting insulin and glucose were significantly higher in experimental group than those in control group, so as the LH/FSH ratio and HOMA index. No methylation of LHR and AR genes were found in both groups. The methylation frequency of INSR gene (76.7%) was significantly higher in modeling group than that in control group (P<0. 001). Conclusion The depression of INSR gene's transcriptional induced by DNA methylation is important in the development of insulin resistance in PCOS.