Studies on the Compounds of d4T Combined with Nitric Oxide Donors and Nitric Oxide Synthase Inhibitors and their Anti-HIV and AIDS Activity

Stavudine, a potent anti HIV and AIDS related complex, is one of the Nucleoside Analogue Reverse Transcriptase Inhibitors (NARTIs). It is phosphorylated intracellularly and then inhibits the viral reverse transcriptase by acting as a false substrate. Modifications made on the hydrogen labile at the 5' position on the sugar is an interesting template for the elaboration of new potent anti HIV and AIDS drugs. The expected advantages of the modified stavudine prodrugs can be multiple: synergistic drug activities, enhancement of stavudine intracellular uptake, increase of stavudine brain delivery, and bypass of the first stavudine phosphorylation step into the cells. Nitric oxide synthase inhibitors of stavudine and nitric oxide donors of stavudine may hold significant promise for the treatment of HIV and AIDS.

Regulation of nitric oxide donor JS-K on tumor energy metabolism in H22 tumor-bearing mice

OBJECTIVE To investigate the regulation of {O^2(2,4-dinitrophenyl)1-[(4-ethoxycarbonyl)piperazin-1-yl]diazen-1-ium-1,2-diolate}(JS-K),anitric oxide donor,on tumor energy metabolism in H22 tumor-bearing mice.METHODS The hepatoma animal model in BALB/c mice was established with H22 cell line.The JS-K group and model group were received JS-K(0.75 and 1.5 mg?kg^(-1)) and saline via tail intravenous once every 3 d for 14 d,received 5 injections,respectively.The positive group was received 5-FU 20 mg·kg^(-1) by intraperitoneal injection once a day for 14 d.On the 15 th day mice were sacrificed.The tumor growth inhibition rate were calculated.The activities of hexokinase(HK),phosphofructo kinase(PFK),pyruvate kinase(PK),succinate dehydrogenase(SDH),adenosine triphosphatase(ATPase),and the levels of lactic acid(LD) and adenosine triphosphate(ATP) in tumor tissues were determined by colorimetric method.RESULTS Compared with model group,the tumor mass of JS-K0.75 and 1.5 mg·kg^(-1) group was significantly reduced(P<0.01),and the tumor growth inhibition rate was 23.9% and 50.3%,respectively.The activity of HK,PFK,PK,SDH and ATPase of tumor tissue in model group was(22.6±3.7,14.4±2.6,12.9±3.2 and 10.5±2.6)U·g^(-1) protein and(0.70±0.10)μmol Pi·mg^(-1) protein per hour,respectively;which in JS-K 1.5 mg?kg^(-1) group was dropped by 42.0%,26.6%,22.7%,23.3% and 21.7%(P<0.01,P<0.05).Compared with the model group,the level of ATP and LD in JS-K group was dropped(P<0.01).CONCLUSION JS-K can inhibit the growth of tumor in H22 tumor-bearing mice and its mechanism may be related to regulating the tumor energy metabolism with inhibition of glycolysis and aerobic oxidation.

Use of Nitric Oxide Donor Isosorbide Mononitrate for Cervical Ripening at 41 Weeks’ Gestation

Background: The ideal agent for cervical ripening would induce adequate cervical ripening with minimal adverse effects to the mother and the fetus;the most favorable method for cervical ripening is not fully agreed till now;however, vaginal administration of isosorbide mononitrate (IMN) is considered a low-risk method of labor induction for post term. Our study was designed to assess the effect of IMN on cervical ripening and labor induction among 41 weeks pregnant women. Objectives: To assess the efficacy of the nitric oxide donor isosorbide mononitrate on cervical ripening at 41 weeks gestation. Materials and Methods: This study was conducted on 100 pregnant women recruited from the outpatient clinic fulfilling the inclusion criteria. Cases were divided into 2 groups. In first group 40 mg isosorbide mononitrate (IMN) tablet was applied vaginally in posterior fornix, and in second group placebo was applied vaginally in posterior fornix. Following up the cervical status after 24 hours of administration, the patient were asked about new symptoms especially headache, palpitation, dizziness or abdominal pain and the mode of delivery was assessed. Results: There was a significant improvement in the bishop score in the first group rather than the placebo group. No significant difference between the two groups was as regards the mode of delivery. Conclusion: IMN may be used for cervical preparation only before induction of labor in post term cases.

Recent advances in diverse nanosystems for nitric oxide delivery in cancer therapy

Gas therapy has been proven to be a promising and advantageous treatment option for cancers.Studies have shown that nitric oxide(NO)is one of the smallest structurally significant gas molecules with great potential to suppress cancer.However,there is controversy and concern about its use as it exhibits the opposite physiological effects based on its levels in the tumor.Therefore,the anti-cancer mechanism of NO is the key to cancer treatment,and rationally designed NO delivery systems are crucial to the success of NO biomedical applications.This review summarizes the endogenous production of NO,its physiological mechanisms of action,the application of NO in cancer treatment,and nano-delivery systems for delivering NO donors.Moreover,it briefly reviews challenges in delivering NO from different nanoparticles and the issues associated with its combination treatment strategies.The advantages and challenges of various NO delivery platforms are recapitulated for possible transformation into clinical applications.

Preventive Effects of Nitroglycerine on Glucocorticoid-induced Osteoporosis in Growing Rats

The preventive effects of nitroglycerine （NG） on glucocorticoid-induced osteoporosis in growing rats were studied. Three-month-old female Wistar rats were randomly divided into control group （CON）, dexamethasone group （DXM）, DXM plus a low dose NG group （NG-L）, DXM plus a middle dose NG group （NG-M） and DXM plus a high dose NG group （NG-H）, 8 rats in each group. The rat model of osteoporosis was developed by intramuscular injection of dexamethasone twice a week. NG 0.2, 0.4 and 1.0 mg/kg was administered by oral gavages to the treatment groups every day for 12 weeks. Rats in CON group and DXM group were treated with normal saline of the same amount. After the treatment, the bone mineral density （BMD） and bone metabolism-associated biochemical markers were determined. Compared with CON group, BMD of lumbar spine and femur in DXM group was decreased significantly （P〈0.05 and P〈0.01 respectively）, blood BGP levels and NO levels reduced （both P〈0.01）, and TRAP level increased （P〈0.05）. As compared with DXM group, BMD, serum BGP and NO were increased, and TRAP decreased in NG-L group and NG-M group, but had no significant difference in comparison to CON group. All the markers other than serum NO and TRAP levels had no significant difference between NG-H group and DXM group. It was concluded that low or middle doses of NG could prevent glucocorticoid-induced bone loss in growing rats, but high dose of NG could not. Supplement with NO donor could be considered as a preventive treatment for glucocorticoid-induced osteoporosis in a developing skeleton.

Effect of Modified HIF-1<i>α</i>Linked to Carbonic Anhydrase IX Inhibitor and Glycosylated Cisplatin on Solid Tumors: Short Review

Many cancer cells in solid tumors are hypoxic or pseudohypoxic and create acidic environment for malignancy progression. Under low oxygen conditions (hypoxia), hypoxia-inducible factors (HIFs) play pathological roles in cancer cell survival and spreading. HIF regulates several genes such as genes of glucose transporters that enhance anaerobic glycolysis, angiogenesis, erythropoiesis and carbonic anhydrase IX (CA-IX). CA-IX is a cell-surface glycoprotein that catalyzes the hydration of CO2 to protons and bicarbonate ions (respiratory acidification). This process is involved in adaptation to acidosis and implicated in cancer progression. Therefore, CA-IX inhibitors (such as sulfonamide-based compounds) showed hoping results in reduction malignancy progression. The article aims to reversal the malignant hypoxic environment in solid tumors to create a condition of weakness within the cancer for further focused cisplatin potency. This article suggests the use of modified synthesized HIF as a drug delivery molecule for both carbonic anhydrase IX inhibitor and glycosylated cisplatin that damages the DNA of malignant cell. HIF molecule has high affinity to bind with CA IX-expressing malignant cells, which is followed by cell entrance via endocytosis. Once the HIF-Cisplatin-CA-inhibitor complex enters the cell, the carbonic anhydrase inhibitor will improve the cellular pH that makes the environment unsuitable for HIF 1α function and it may be ubiquitinated. So, the raise in target genes transcription will be arrested. On the other hand, once the synthetized HIF is degraded, the cisplatin molecules will be released inside the malignant cell and start to damage its DNA. This approach may be a good solution for many solid tumors.

Discovery and bioassay of disubstituted β-elemene-NO donor conjugates:synergistic enhancement in the treatment of leukemia

Natural products are essential sources of antitumor drugs.One such molecule,β-elemene,is a potent antitumor compound extracted from Curcuma wenyujin.In the present investigation,a series of novel 13,14-disubstituted nitric oxide(NO)-donorβelemene derivatives were designed,withβ-elemene as the foundational compound,and subsequently synthesized to evaluate their therapeutic potential against leukemia.Notably,the derivative labeled as compound 13d demonstrated a potent anti-proliferative activity against the K562 cell line,with a high NO release.In vivo studies indicated that compound 13d could effectively inhibit tumor growth,exhibiting no discernible toxic manifestations.Specifically,a significant tumor growth inhibition rate of 62.9%was observed in the K562 xenograft tumor mouse model.The accumulated data propound the potential therapeutic application of compound 13d in the management of leukemia.

New techniques and strategies in drug discovery

Great success has been witnessed in last decades,some new techniques and strategies have been widely used in drug discovery.In this roadmap,several representative techniques and strategies are highlighted to show recent advances in this filed.(A)A DOX protocol has been developed for accurate protein-ligand binding structure prediction,in which first principle method was used to rank the binding poses.Validation against crystal structures have found that DOX prediction achieved an impressive success rate of 99%,indicating significant improvement over molecular docking method.(B)Virtual target profiling is a compound-centric strategy enabling a parallel implementation of interrogating compounds against various targets in a single screen,which has been used in hit/lead identification,drug repositioning,and mechanism-of-action studies.Current and emerging methods for virtual target profiling are briefly summarized herein.(C)Research on targeted autophagy to treat diseases has received encouraging progress.However,due to the complexity of autophagy and disease,experimental and in silico methods should be performed synergistically for the entire process.This part focuses on in silico methods in autophagy research to promote their use in medicinal research.(D)Histone deacetylases(HDACs)play important roles in various biological functions through the deacetylation of lysine residues.Recent studies demonstrated that HDACs,which possess low deacetylase activities,exhibited more efficient defatty-acylase activities.Here,we review the defatty-acylase activity of HDACs and describe examples for the design of isoform selective HDAC inhibitor.(E)The FDA approval of three kinase allosteric inhibitors and some others entering clinical study has spurred considerable interests in this targeted drug discovery area.(F)Recent advances are reviewed in structure-based design of novel antiviral agents to combat drug resistance.(G)Since nitric oxide(NO)exerts anticancer activity depending on its concentration,optimal levels of NO in cancer cells is desirable.In this minireview,we briefly describe recent advances in the research of NO-based anticancer agents by our group and present some opinions on the future development of these agents.(H)The field of photoactivation strategies have been extensively developed for controlling chemical and biological processes with light.This review will summarize and provide insight into recent research advances in the understanding of photoactivatable molecules including photoactivatable caged prodrugs and photoswitchable molecules.

Effect of inhalation of nebulized NO donor substance on acute hypoxic lung injury in newborn piglets

Background Birth asphyxia may result in multiple organ dysfunction such as lung injury. Inhalation of nebulized nitric oxide precursor can selectively reduce pulmonary hypertension. However, it is unknown whether such precursors can alleviate lung injury induced by hypoxia. We evaluated the effect of inhalation of nebulized nitroglycerine and sodium nitroprusside on acute hypoxic lung injury in newborn piglets. Methods Acute hypoxic lung injury was induced by inspiring 10% 02 for 1 hour. Twenty-four anaesthetized and mechanically ventilated piglets （5-7 days old） were randomly divided into four groups： （1） group S, not hypoxic; （2） group C, nebulized saline after hypoxia; （3） group NTG, nebulized nitroglycerine after hypoxia; （4） group SNP, nebulized sodium nitroprusside after hypoxia, Respiratory dynamic compliance and resistance of respiratory system were recorded at baseline, 0.5 hour and 1 hour of hypoxia; then 0.5 hour, 1 hour, 3 hours and 5 hours following hypoxia. After nebulization, arterial blood was collected for measuring methaemoglobin and nitrate/nitrite levels. Right lung tissue, wet-dry ratio and myeloperoxidase level were determined. White blood cell count （WBC）, total surfactant phospholipids （TPL） and disaturated phosphatidyl choline （DSPC） of the bronchoalveolar lavage fluid （BALF） were calculated. Left lungs were used for examining pathological changes. Results No significant difference was observed in respiratory dynamic compliance, resistance of respiratory system, wet-dry ratio, levels of methaemoglobin and nitrate/nitrite after nebulization, TPL or DSPC/TPL among four groups. WBC in BALF in groups NTG and SNP significantly decreased as compared with group C： similarly for myeloperoxidase level in lung tissue. Lung histological findings showed infiltration of neutrophils in groups NTG and SNP decreased significantly as compared with group C. Conclusion Inhalation of nebulized nitroglycerine or sodium nitroprusside can alleviate the infiltration of neutrophils, while it affects neither the metabolism of phospholipids nor water content in the lungs.