The effects of Crocus sativus extract on inhaled paraquat-induced lung inflammation, oxidative stress, pathological changes and tracheal responsiveness in rats.

Paraquat is a green liquid toxin that is used in agriculture and can induce multi-organ including lung injury. Various pharmacological effects of Crocus sativus (C. sativus) were indicated in previous studies. In this research, the effects of C. sativus extract and pioglitazone on inhaled paraquat-induced lung inflammation, oxidative stress, pathological changes, and tracheal responsiveness were studied in rats. Eight groups of rats (n = 7 in each) including control (Ctrl), untreated paraquat aerosol exposed group (54 mg/m3, 8 times in alternate days), paraquat treated groups with dexamethasone (0.03 mg/kg/day, Dexa) as positive control, two doses of C. sativus extract (20 and 80 mg/kg/day, CS-20 and CS-80), pioglitazone (5 and 10 mg/kg/day, Pio-5 and Pio-10), and the combination of CS-20 + Pio-5 were studied. Total and differential WBC, levels of oxidant and antioxidant biomarkers in the BALF, lung tissue cytokine levels, tracheal responsiveness (TR), and pathological changes were measured. The levels of IFN-γ, IL-10, SOD, CAT, thiol, and EC50 were reduced, but MDA level, total and differential WBC count in the BALF and lung pathological changes were increased in the paraquat group (all, p < 0.001). The levels of IFN-γ, IL-10, SOD, CAT, thiol and EC50 were increased but BALF MDA level, lung pathological changes, total and differential WBC counts were reduced in all treated groups. The effects of C. sativus high dose and combination groups on measured parameters were equal or even higher than dexamethasone (p < 0.05 to p < 0.001). The effects of the combination of CS-20 + Pio-5 on most variables were significantly higher than CS-20 and Pio-5 alone (p < 0.05 to p < 0.001). C. sativus treatment improved inhaled paraquat-induced lung injury similar to dexamethasone and showed a synergistic effect with pioglitazone, suggesting possible PPAR-γ receptor-mediated effects of the plant.

Are the Cytotoxic Properties of Conjugated Unsaturated Ketones Inactivated by Thiols?

The focus of this study was to examine whether the conversion of cytotoxic conjugated unsaturated ketones (or enones) into the corresponding thiol adducts leads to a reduction or abolition of cytotoxic potencies. A number of enones and related thiol adducts were evaluated against human HCT116 and HT29 colon cancer cells. Some 63% of the IC50 values are less than 10 µM and several compounds are more toxic than 5-FU. The thiol adducts are either more potent or are equipotent with the corresponding enones. A number of compounds are far more toxic to HCT116 and HT29 neoplasms than non-malignant CRL1790 cells leading to impressive Selectivity Index figures. An additional positive feature of these compounds is that they have favorable ADME properties.

Use of thiols and implications for the use of inhaled corticosteroids in the presence of oxidative stress in COPD.

BACKGROUND: Oxidative stress and persistent airway inflammation are thought to be important contributors to the development of chronic obstructive pulmonary disease (COPD). This review summarizes the evidence for targeting oxidative stress and inflammation in patients with COPD with mucolytic/antioxidant thiols and inhaled corticosteroids (ICS), either alone or in combination. MAIN BODY: Oxidative stress is increased in COPD, particularly during acute exacerbations. It can be triggered by oxidant air pollutants and cigarette smoke and/or by endogenous reactive oxygen species (ROS) released from mitochondria and activated inflammatory, immune and epithelial cells in the airways, together with a reduction in endogenous antioxidants such as glutathione (GSH). Oxidative stress also drives chronic inflammation and disease progression in the airways by activating intracellular signalling pathways and the release of further inflammatory mediators. ICS are anti-inflammatory agents currently recommended for use with long-acting bronchodilators to prevent exacerbations in patients with moderate-to-severe COPD, especially those with eosinophilic airway inflammation. However, corticosteroids can also increase oxidative stress, which may in turn reduce corticosteroid sensitivity in patients by several mechanisms. Thiol-based agents such as erdosteine, N-acetyl L-cysteine (NAC) and S-carboxymethylcysteine (S-CMC) are mucolytic agents that also act as antioxidants. These agents may reduce oxidative stress directly through the free sulfhydryl groups, serving as a source of reducing equivalents and indirectly though intracellular GSH replenishment. Few studies have compared the effects of corticosteroids and thiol agents on oxidative stress, but there is some evidence for greater antioxidant effects when they are administered together. The current Global Initiative for Chronic Obstructive Lung Disease (GOLD) report supports treatment with antioxidants (erdosteine, NAC, S-CMC) in addition to standard-of-care therapy as they have been demonstrated to reduce COPD exacerbations. However, such studies have demonstrated that NAC and S-CMC reduced the exacerbation risk only in patients not treated with ICS, whereas erdosteine reduced COPD exacerbations irrespective of concomitant ICS use suggesting that erdosteine has additional pharmacological actions to ICS. CONCLUSIONS: Further clinical trials of antioxidant agents with and without ICS are needed to better understand the place of thiol-based drugs in the treatment of patients with COPD.

A novel thiol-saccharide mucolytic for the treatment of muco-obstructive lung diseases.

BACKGROUND: Mucin disulfide cross-links mediate pathologic mucus formation in muco-obstructive lung diseases. MUC-031, a novel thiol-modified carbohydrate compound, cleaves disulfides to cause mucolysis. The aim of this study was to determine the mucolytic and therapeutic effects of MUC-031 in sputum from patients with cystic fibrosis (CF) and mice with muco-obstructive lung disease (ßENaC-Tg mice). METHODS: We compared the mucolytic efficacy of MUC-031 and existing mucolytics (N-acetylcysteine (NAC) and recombinant human deoxyribonuclease I (rhDNase)) using rheology to measure the elastic modulus (G') of CF sputum, and we tested effects of MUC-031 on airway mucus plugging, inflammation and survival in ßENaC-Tg mice to determine its mucolytic efficacy in vivo. RESULTS: In CF sputum, compared to the effects of rhDNase and NAC, MUC-031 caused a larger decrease in sputum G', was faster in decreasing sputum G' by 50% and caused mucolysis of a larger proportion of sputum samples within 15 min of drug addition. Compared to vehicle control, three treatments with MUC-031 in 1 day in adult ßENaC-Tg mice decreased airway mucus content (16.8±3.2 versus 7.5±1.2 nL·mm-2, p<0.01) and bronchoalveolar lavage cells (73 833±6930 versus 47 679±7736 cells·mL-1, p<0.05). Twice-daily treatment with MUC-031 for 2 weeks also caused decreases in these outcomes in adult and neonatal ßENaC-Tg mice and reduced mortality from 37% in vehicle-treated ßENaC-Tg neonates to 21% in those treated with MUC-031 (p<0.05). CONCLUSION: MUC-031 is a potent and fast-acting mucolytic that decreases airway mucus plugging, lessens airway inflammation and improves survival in ßENaC-Tg mice. These data provide rationale for human trials of MUC-031 in muco-obstructive lung diseases.

Systemic oxidative stress associates with disease severity and outcome in patients with new-onset or worsening heart failure.

BACKGROUND: Oxidative stress may be a key pathophysiological mediator in the development and progression of heart failure (HF). The role of serum-free thiol concentrations, as a marker of systemic oxidative stress, in HF remains largely unknown. OBJECTIVE: The purpose of this study was to investigate associations between serum-free thiol concentrations and disease severity and clinical outcome in patients with new-onset or worsening HF. METHODS: Serum-free thiol concentrations were determined by colorimetric detection in 3802 patients from the BIOlogy Study to TAilored Treatment in Chronic Heart Failure (BIOSTAT-CHF). Associations between free thiol concentrations and clinical characteristics and outcomes, including all-cause mortality, cardiovascular mortality, and a composite of HF hospitalization and all-cause mortality during a 2-years follow-up, were reported. RESULTS: Lower serum-free thiol concentrations were associated with more advanced HF, as indicated by worse NYHA class, higher plasma NT-proBNP (P < 0.001 for both) and with higher rates of all-cause mortality (hazard ratio (HR) per standard deviation (SD) decrease in free thiols: 1.253, 95% confidence interval (CI): 1.171-1.341, P < 0.001), cardiovascular mortality (HR per SD: 1.182, 95% CI: 1.086-1.288, P < 0.001), and the composite outcome (HR per SD: 1.058, 95% CI: 1.001-1.118, P = 0.046). CONCLUSIONS: In patients with new-onset or worsening HF, a lower serum-free thiol concentration, indicative of higher oxidative stress, is associated with increased HF severity and poorer prognosis. Our results do not prove causality, but our findings may be used as rationale for future (mechanistic) studies on serum-free thiol modulation in heart failure. Associations of serum-free thiol concentrations with heart failure severity and outcomes.

Accurate 24-h urine cystine quantification for patients on cystine-binding thiol drugs.

Cystinuria is a rare disorder resulting in development of recurrent kidney stones, adversely affecting patient quality of life. The goal of cystinuria management is to reduce stone formation by increasing cystine solubility in urine, which includes lowering the urinary cystine level below its solubility limit. Treatment usually involves alkalinization of the urine and often requires initiating pharmacotherapy with a cystine-binding thiol drug (CBTD) such as tiopronin; however, proper dose adjustment requires accurate measurement of urinary cystine. The goal of this study was to validate a novel high-performance liquid chromatography tandem mass spectrometry (HPLC-MS/MS) method for quantification of cystine in the urine of patients with cystinuria receiving a CBTD. Urine samples were collected over 24 h from 24 patients and separated into 2 aliquots. Chromatographic separation of samples was conducted and separation of cystine from the cysteine-tiopronin drug complex was complete in < 3 min. The method was validated for accuracy, precision, linearity, limit of detection (LOD), and limit of quantification (LOQ). Mean accuracy range was 97.7-102.3%; intermediate precision was high with relative percent difference values calculated at 1.2-9.3%; the calibration curve resulted in a linear response throughout the concentration range (R2 = 0.998); and the LOD and LOQ were 0.002 and 0.005 mg/mL, respectively. Mean (range) cystine concentrations measured were 111.10 (51.31-179.46) and 242.21 (61.14-741.80) g/L in Aliquots A and B, respectively. The HPLC-MS/MS method presented here indicates that urine cystine can be reliably quantified in patients receiving a CBTD.

Anti-inflammatory, antioxidant, anti-fibrotic and schistosomicidal properties of plumbagin in murine schistosomiasis.

Schistosomiasis is still a major health problem affecting nearly 250 million people worldwide and causes approximately 280,000 deaths per year. The disease causes a serious granulomatous inflammatory response that produces significant mortality. Plumbagin reportedly displays anti-inflammatory, anti-fibrotic, antioxidant and anthelmintic properties. This study further elucidates these properties. Mice were infected with schistosomes and divided into five groups: non-infected untreated (C); infected untreated (IU); non-infected treated with plumbagin (P); infected treated with plumbagin (PI) and infected treated with praziquantel (PZ). Mice treated with 20 mg plumbagin/kg body weight showed reduction of 64.28% and 59.88% in male and female animals, respectively. Also, the number of eggs/g tissue was reduced 69.39%, 68.79% and 69.11% in liver, intestine and liver/intestine combined, respectively. Plumbagin alleviated schistosome-induced hepatosplenomegaly and reduced hepatic granuloma and liver collagen content by 62.5% and 35.26%, respectively while PZQ reduced hepatic granuloma and liver collagen content by 41.11% and 11.21%, respectively. Further, plumbagin treatment significantly (p < .001) reduced IL-4, IL-13, IL-17, IL-37, IFN-γ, TGF-ß and TNF-α levels and significantly (p < .001) upregulated IL-10. Plumbagin treatment restored hepatic enzymes activity to nearly normal levels and induced an increase in catalase, SOD, GSH, total thiol and GST in liver tissue homogenate. NO and LPO content was, however, decreased. Moreover, serum IgG levels significantly increased. The present study is the first to report immunomodulatory and schistosomicidal activities of plumbagin in schistosomiasis.

Oxidative stress and the importance of H. pylori eradication in patients with functional dyspepsia.

Background: To investigage the thiol and disulphide levels in Helicobacter pylori-positive patients with non-ulcer dyspepsia and investigate the change in these levels with eradication therapy. Methods: This is a prospective observational study. A total of 320 patients diagnosed with dyspepsia according to Rome IV criteria were included in the study. First, blood samples were drawn from patients to determine their serum thiol and disulphide levels. Endoscopic biopsy was performed on all patients and the biopsy specimens obtained were examined pathologically. Patients positive for H. pylori were administered eradication therapy. Blood samples were drawn from these patients for the second time, and their serum thiol and disulphide levels were measured. The thiol-disulfide levels of the patients who were successful in H. pylori eradication treatment, with those who were not, were compared before and after the treatment. Results: The mean plasma disulphide level decreased significantly from 14.0 ± 6.6 to 10.9 ± 5.9 µmol/L in H. pylori-positive patients that responded to the H. pylori eradication treatment (P = 0.033). On the other hand, there was an insignificant increase in the mean serum thiol level (341.4 ± 30.5 vs. 342.6 ± 29.8 µmol/L; P = 0.273) and an insignificant decrease in the mean serum disulphide level (15.2 ± 2.5 vs. 14.8 ± 2.3 µmol/L; P = 0.163) in H. pylori-positive patients that did not respond to the H. pylori eradication treatment. Conclusion: The inflammation caused by H. pylori shifted the thiol-disulphide equilibrium in the cell redox system towards the direction of disulphide. The study findings suggest that the restoration of the said hemostatic balance with eradication therapy relieved the organism from oxidative stress.

Anti-inflammatory, anti-oxidant and anti-apoptotic effects of olive leaf extract in cardiac tissue of diabetic rats.

OBJECTIVES: Inflammatory process and apoptosis are involved in the pathogenesis of cardiac injury and oxidative damage caused by diabetes mellitus. The cardioprotective effects of standardized aqueous ethanolic olive leaf extract (OLE), metformin (as a cardiovascular protective agent) and valsartan (as an angiotensin receptor blocker) in the streptozotocin-induced diabetic rats were evaluated. METHODS: Wistar rats divided into control, diabetic, OLE-treated (100, 200 and 400 mg/kg), metformin (300 mg/kg)-treated, valsartan (30 mg/kg)-treated and metformin/valsartan-treated diabetic groups. Biochemical parameters, including malondialdehyde (MDA) levels, superoxide dismutase (SOD) and catalase (CAT) activates, and the total contents of thiol were measured, and histopathological and gene expression studies were done on cardiac tissues. Fasting blood sugar (FBS) and cardiac injury markers were examined in serum. KEY FINDINGS: FBS; the serum levels of lactate dehydrogenase (LDH), creatine kinase-muscle/brain (CK-MB), aspartate aminotransferase (AST); and heart tissue MDA levels due to diabetes were significantly alleviated by OLE treatment (effect size; ηp2 = 0.934, 0.888, 0.848, 0.888 and 0.879, respectively), and SOD and CAT activity and the thiol content in heart tissue were significantly increased (effect size; ηp2 = 0.770, 0.749 and 0.753, respectively). Interleukin-1ß (IL-1ß), tumour necrosis factor-α (TNF-α) and the number of infiltrating inflammatory cells were reduced in cardiac tissues of OLE-treated groups compared with the diabetic rats (effect size; ηp2 = 0.969 and 0.949, respectively). OLE up-regulated BCL2 gene expression and down-regulated BAX gene expression in cardiac tissue (effect size; ηp2= 0.490 and 0.522, respectively). CONCLUSION: OLE in a dose-dependent manner ameliorates cardiac damage in diabetic cardiomyopathy, perhaps through attenuating inflammation, oxidative stress and apoptosis.

Diabetic cardiomyopathy was attenuated by cinnamon treatment through the inhibition of fibro-inflammatory response and ventricular hypertrophy in diabetic rats.

Diabetic cardiomyopathy (DCM) is a chronic complication of diabetes that emphasizes the urgency of developing new drug therapies. With an illustrious history in traditional medicine to improve diabetes, cinnamon has been shown to possess blood lipids lowering effects and antioxidative and anti-inflammatory properties. However, the extent to which it protects the diabetic heart has yet to be determined. Forty-eight rats were administered in the study and grouped as: control; diabetic; diabetic rats given 100, 200, or 400 mg/kg cinnamon extract, metformin (300 mg/kg), valsartan (30 mg/kg), or met/val (combination of both drugs), via gavage for six weeks. Fasting blood sugar (FBS) and markers of cardiac injury including creatine kinase-muscle/brain (CK-MB), aspartate aminotransferase (AST), and lactate dehydrogenase (LDH) were evaluated in blood samples. Malondialdehyde (MDA) levels, the total contents of thiol, superoxide dismutase (SOD), and catalase (CAT) activities were measured. Histopathology study and gene expression measurement of angiotensin II type 1 receptor (AT1), atrial natriuretic peptide (ANP), beta-myosin heavy chain (ß-MHC), and brain natriuretic peptide (BNP) were done on cardiac tissue. FBS and cardiac enzyme indicators were reduced in all treated groups. A reduction in MDA level and enhancement in thiol content alongside with increase of SOD and CAT activities were observed in extract groups. The decrease of inflammation and fibrosis was obvious in treated groups, notably in the high-dose extract group. Furthermore, all treated diabetic groups showed a lowering trend in AT1, ANP, ß-MHC, and BNP gene expression. Cinnamon extract, in addition to its hypoglycemic and antioxidant properties, can prevent diabetic heart damage by alleviating cardiac inflammation and fibrosis. PRACTICAL APPLICATIONS: This study found that cinnamon extract might protect diabetic heart damage by reducing inflammation and fibrosis in cardiac tissue, in addition to lowering blood glucose levels and increasing antioxidant activity. Our data imply that including cinnamon in diabetic participants' diets may help to reduce risk factors of cardiovascular diseases.

The therapeutic potential of γ-Al2O3 nanoparticle containing 5-fluorouracil in the treatment of colorectal cancer.

5-Fluorouracil (5-FU) is being used in the treatment of several malignancies, but side effects are often reported and include: diarrhea, vomiting, nausea, poor appetite, watery eyes, and photophobia. We have developed and tested the cytotoxic activity of nanocrystalline powder of γ-alumina (γ-Al2O3) containing 5-FU in two-dimensional and three-dimensional (3D) CRC cell culture. γ-Al2O3 was prepared using a facile sol-gel method. The physicochemical properties of nanoparticles were investigated by Fourier Transform Infrared (FTIR) analysis, Field Emission Scanning Electron Microscopy (FESEM) and Energy Dispersive X-ray Analysis (EDXA). Moreover, the particle size was monitored by Transmission Electron Microscopy (TEM). We used MTT and a scratch assay to assess the antiproliferative and anti-migratory of this agent. The effect of γ-Al2O3-5-FU on SOD, MDA, and total-thiols levels were evaluated. We assessed the expression of apoptotic markers in mRNA or proteins by RT-PCR and ELISA respectively. γ-Al2O3-5-FU inhibited cell growth in two-dimensional (2D) and three-dimensional (3D) cell culture and increased apoptosis as detected by DAPI stainning via modulation of caspases, BAx, BCl2 and cyclinD1. γ-Al2O3-5-FU also reduced the migratory activity of CRC cells relative to untreated controls. γ-Al2O3-5-FU increased the level of MDA, while reducing the level of SOD and total-thiols as well as inflamatory markers (e.g., TNF-s and IL-6). Our study demonstrated that γ-Al2O3-5-FU inhibited cell growth and migration, indicating its potential value in the treatment of colorectal cancer.

The effect of Cinnamomum cassia extract on oxidative stress in the liver and kidney of STZ-induced diabetic rats.

OBJECTIVES: Many diabetes-related complications are caused by oxidative stress. In the current study, the protective effect of Cinnamomum cassia against diabetes-induced liver and kidney oxidative stress was evaluated. METHODS: The male Wistar rats (n=48) were randomly divided into six groups including; control group received 500 µL normal saline orally for 42 days. Diabetes groups received intraperitoneally (i.p.) streptozotocin (STZ) as single-dose (60 mg/kg, i.p.). Cinnamon extract (100, 200, 400 mg/kg) and metformin (300 mg/kg) were orally administered to diabetic rats for 42 days. After the experiment period, the animals were anesthetized and the liver and kidney tissues were quickly removed and restored for oxidative stress evaluation. The levels of malondialdehyde (MDA), total thiol content, glutathione (GSH), nitric oxide (NO) metabolites, as well as, superoxide dismutase (SOD) and catalase (CAT) activities were measured in kidney and liver tissue. RESULTS: The level of MDA, SOD, and CAT activities increased significantly, while the total thiol content, and NO production were significantly reduced in diabetic animals compared to the control group (from p<0.05 to p<0.001). Treatment with cinnamon extract significantly decreased the MDA level, as well as, SOD and CAT activities in the liver and kidney of diabetic rats (from p<0.05 to p<0.001). In the liver and kidney of cinnamon treated groups, GSH and total thiol contents and NO production were significantly higher than diabetic group (from p<0.05 to p<0.001). CONCLUSIONS: Cinnamon extract due to its potent antioxidant property could be effective in decrease of diabetes-induced oxidative stress that plays a major role in renal and hepatic complications.

N-Acetyl Cysteine and Glutathione in Health and Cancer-Pharmacogenomics, Research, and Clinical Practice: Hypothesis and Review.

Context: Glutathione (GSH) is a major intracellular antioxidant capable of scavenging free radicals and detoxifying electrophiles from endogenous and exogenous sources via the free thiol group. GSH plays an important role in a multiple cellular process, including cell differentiation, proliferation, and apoptosis. Pharmacogenomics has demonstrated its important role as a key element in cellular health. Objective: The study intended to examine the benefits of using GSH pharmacogenomics as a therapy to prevent side effects and interactions with antineoplastic agents in the diagnosis and treatment of malignancies. Design: The research team performed a narrative review using the Google scholar and PubMed electronic databases. Conclusions: In summary, the involvement of GSH in the carcinogenesis and drug resistance of tumor cells is clear and well understood, but further studies, aimed at understanding the GSH-driven molecular pathways, might be crucial to designing new therapeutic strategies to fight cancer progression, overcoming chemoresistance, using in combination with immunotherapies, and preventing or minimizing their negative side effects.

Investigating Lipid-Modulating Agents for Prevention or Treatment of COVID-19: JACC State-of-the-Art Review.

Coronavirus disease-2019 (COVID-19) is associated with systemic inflammation, endothelial activation, and multiorgan manifestations. Lipid-modulating agents may be useful in treating patients with COVID-19. These agents may inhibit viral entry by lipid raft disruption or ameliorate the inflammatory response and endothelial activation. In addition, dyslipidemia with lower high-density lipoprotein cholesterol and higher triglyceride levels portend worse outcomes in patients with COVID-19. Upon a systematic search, 40 randomized controlled trials (RCTs) with lipid-modulating agents were identified, including 17 statin trials, 14 omega-3 fatty acids RCTs, 3 fibrate RCTs, 5 niacin RCTs, and 1 dalcetrapib RCT for the management or prevention of COVID-19. From these 40 RCTs, only 2 have reported preliminary results, and most others are ongoing. This paper summarizes the ongoing or completed RCTs of lipid-modulating agents in COVID-19 and the implications of these trials for patient management.

Design, Synthesis, and Biological Evaluation of a Novel Aminothiol Compound as Potential Radioprotector.

The risk of radiation damage has increased with the rapid development of nuclear technology and radiotherapy. Hence, research on radioprotective agents is of utmost importance. In the present study, a novel aminothiol compound 12, containing a linear alkylamino backbone and three terminal thiols, was synthesized. Owing to the appropriate capped groups in the chains, it has an improved permeability and oral bioavailability compared to other radioprotective agents. Oral administration of compound 12 improved the survival of mice that received lethal doses of γ-irradiation. Experimental results demonstrated that compound 12 not only mitigated total body irradiation-induced hematopoietic injury by increasing the frequencies of hematopoietic stem and progenitor cells but also prevented abdominal irradiation-induced intestinal injury by increasing the survival of Lgr5+ intestinal cells, lysozyme+ Paneth cells, and Ki67+ cells. In addition, compound 12 decreased oxidative stress by upregulating the expression of Nrf2 and NQO1 and downregulating the expression of NOX1. Further, compound 12 inhibited γ-irradiation-induced DNA damage and alleviated G2/M phase arrest. Moreover, compound 12 decreased the levels of p53 and Bax and increased the level of Bcl-2, demonstrating that it may suppress radiation-induced apoptosis via the p53 pathway. These results indicate that compound 12 has the possibility of preventing radiation injury and can be a potential radioprotector for clinical applications.

Cholesteryl ester transfer protein (CETP) as a drug target for cardiovascular disease.

Development of cholesteryl ester transfer protein (CETP) inhibitors for coronary heart disease (CHD) has yet to deliver licensed medicines. To distinguish compound from drug target failure, we compared evidence from clinical trials and drug target Mendelian randomization of CETP protein concentration, comparing this to Mendelian randomization of proprotein convertase subtilisin/kexin type 9 (PCSK9). We show that previous failures of CETP inhibitors are likely compound related, as illustrated by significant degrees of between-compound heterogeneity in effects on lipids, blood pressure, and clinical outcomes observed in trials. On-target CETP inhibition, assessed through Mendelian randomization, is expected to reduce the risk of CHD, heart failure, diabetes, and chronic kidney disease, while increasing the risk of age-related macular degeneration. In contrast, lower PCSK9 concentration is anticipated to decrease the risk of CHD, heart failure, atrial fibrillation, chronic kidney disease, multiple sclerosis, and stroke, while potentially increasing the risk of Alzheimer's disease and asthma. Due to distinct effects on lipoprotein metabolite profiles, joint inhibition of CETP and PCSK9 may provide added benefit. In conclusion, we provide genetic evidence that CETP is an effective target for CHD prevention but with a potential on-target adverse effect on age-related macular degeneration.

Advancing Beyond Failed High-density Lipoprotein Clinical Trials to Pharmacogenetic Studies of ADCY9 and Cholesterol Ester Transfer Protein Inhibition.

ABSTRACT: Atherosclerosis has been effectively avoided with many therapies that lower low-density lipoprotein cholesterol. However, significant cardiovascular burden remains. The effect of raising high-density lipoprotein (HDL) has been confounded by other factors (such as lowering triglycerides or LDL) and unsuccessful when attempting to solely increase HDL. Reviewing the available data, the failures of previous strategies may reflect the complexity of HDL in human metabolism and the heterogeneity of human genetics. dal-GenE (NCT02525939) represents the first large cardiovascular outcomes study to use a selective genomic test to identify the target population most likely to receive therapeutic benefit and uses a cholesterol ester transfer protein inhibitor, dalcetrapib. Both the cholesterol ester transfer protein target and the ADCY9 polymorphism identified by the diagnostic test are based on inheritance and an evolving understanding of inborn risk. Selective treatment of subpopulations may be the key to the conundrum of HDL as an actionable risk factor.

Role of Adenylate Cyclase 9 in the Pharmacogenomic Response to Dalcetrapib: Clinical Paradigm and Molecular Mechanisms in Precision Cardiovascular Medicine.

Following the neutral results of the dal-OUTCOMES trial, a genome-wide study identified the rs1967309 variant in the adenylate cyclase type 9 (ADCY9) gene on chromosome 16 as being associated with the risk of future cardiovascular events only in subjects taking dalcetrapib, a CETP (cholesterol ester transfer protein) modulator. Homozygotes for the minor A allele (AA) were protected from recurrent cardiovascular events when treated with dalcetrapib, while homozygotes for the major G allele (GG) had increased risk. Here, we present the current state of knowledge regarding the impact of rs1967309 in ADCY9 on clinical observations and biomarkers in dalcetrapib trials and the effects of mouse ADCY9 gene inactivation on cardiovascular physiology. Finally, we present our current model of the interaction between dalcetrapib and ADCY9 gene variants in the arterial wall macrophage, based on the intracellular role of CETP in the transfer of complex lipids from endoplasmic reticulum membranes to lipid droplets. Briefly, the concept is that dalcetrapib would inhibit CETP-mediated transfer of cholesteryl esters, resulting in a progressive inhibition of cholesteryl ester synthesis and free cholesterol accumulation in the endoplasmic reticulum. Reduced ADCY9 activity, by paradoxically leading to higher cyclic AMP levels and in turn increased cellular cholesterol efflux, could impart cardiovascular protection in rs1967309 AA patients. The ongoing dal-GenE trial recruited 6145 patients with the protective AA genotype and will provide a definitive answer to whether dalcetrapib will be protective in this population.

Phytochemicals in Gynecological Cancer Prevention.

Gynecological cancer confers an enormous burden among women worldwide. Accumulating evidence points to the role of phytochemicals in preventing cervical, endometrial, and ovarian cancer. Experimental studies emphasize the chemopreventive and therapeutic potential of plant-derived substances by inhibiting the early stages of carcinogenesis or improving the efficacy of traditional chemotherapeutic agents. Moreover, a number of epidemiological studies have investigated associations between a plant-based diet and cancer risk. This literature review summarizes the current knowledge on the phytochemicals with proven antitumor activity, emphasizing their effectiveness and mechanism of action in gynecological cancer.

Antifouling Coatings Generated from Unsymmetrical Partially Fluorinated Spiroalkanedithiols.

Biofouling negatively impacts modern society on a daily basis, especially with regard to the important industries of medicine, oil, and shipping. This manuscript describes the preparation and study of model antifouling coatings generated from the adsorption of unsymmetrical partially fluorinated spiroalkanedithiols on gold. The antifouling properties of the self-assembled monolayers (SAMs) derived from the spiroalkanedithiols were compared to SAMs derived from analogous monodentate partially fluorinated and nonfluorinated alkanethiols. The antifouling properties were evaluated using in situ surface plasmon resonance spectroscopy (SPR), ex situ electrochemical quartz crystal microbalance (QCM) measurements, and ex situ ellipsometric thickness measurements. The resistance to nonspecific protein adsorption of the SAMs was evaluated with proteins having a wide range of properties and applications including protamine, lysozyme, bovine serum albumin, and fibrinogen. The results from the SPR and the QCM measurements demonstrated that in most cases, the SAM coatings derived from the partially fluorinated spiroalkanedithiols having mixed hydrocarbon and fluorocarbon tail groups exhibited better antifouling performance when compared to the SAMs derived from their single-component monodentate counterparts. The studies also revealed that while the SPR and the QCM measurements in most cases were able to distinguish the adsorption trends for the SAMs and proteins examined, the ellipsometric thickness measurements were markedly less discriminating. On the whole, these studies validate the use of unsymmetrical partially fluorinated spiroalkanedithiols for generating effective antifouling coatings on metal substrates.