Cupressus sempervirens L. flavonoids as potent inhibitors to xanthine oxidase: in vitro, molecular docking, ADMET and PASS studies.

Excessive intake of purine-rich foods such as seafood and red meat leads to excess xanthine oxidase activity and provokes gout attacks. The aim of this paper is to evaluate in vitro and in silico, the inhibition effect of Cupressus sempervirens plant extracts (flavonoids (Cae) and alkaloids (CaK)) and its six derivative compounds on bovine xanthine oxidase (BXO). The in silico study consists of molecular docking with GOLD v4.0 based on the best PLPchem score (PLP) and prediction of biological activity with the PASS server tool. The inhibitors used were lignan (cp1), Amentoflavone (cp2), Cupressuflavone (cp3), Isocryptomerin (cp4), Hinokiflavone (cp5), and Neolignan (cp6). The in vitro results showed that CaK gives an IC50 of 3.52 ± 0.04 µg/ml. Similarly, Cae saved an IC50 of 8.46 ± 1.98 µg/ml compared with the control (2.82 ± 0.10 µg/ml). The in silico results show that cp1 was the best inhibitor model (PLP of 88.09) with approved pharmacokinetics. These findings suggest that cp1 and cp2 may offer good alternatives for the treatment of hyperuricemia; cp3 was moderate, while the others (cp4 to cp6) were considered weak inhibitors according to their PLP.Communicated by Ramaswamy H. Sarma.

Association of Plasma Fibrinogen Level with Insulin Resistance in Angiographically Confirmed Coronary Artery Disease Patients.

Fibrinogen is an important coagulation factor that plays a key role in thrombus formation. The co-existence of CAD, insulin resistance (IR) and coagulation incongruity are believed to exacerbate the existing condition towards more lethal pathological events.The purpose of current study was to find out a possible association between fibrinogen and IR in CAD patients. The study population consist of 135 participants; 82 angiographically confirmed CAD patients who visited the outpatient department at King Abdulaziz University Hospital (KAUH), Jeddah and 53 healthy control individuals. Peripheral blood samples were collected from CAD patients and healthy control individuals. Various biochemical parameters such as complete blood count, C-reactive protein (CRP), glycosylated hemoglobin (HbA1c), insulin, C-peptide, lipid profile, platelet, partial thromboplastin time (PTT), fibrinogen and D-dimer levels were measured by the use of different analytical methods. Calculation of homeostasis model assessment (HOMA) and non-HDL were done by using online tools. Among the studied parameters, majority of the conventional risk factors were found to be significantly increased in CAD patients compared with control individuals. Different coagulation components such as fibrinogen (223.8 vs. 394 mg/dL), D-dimer (0.25 vs. 0.63 mg/L), platelet (222.9 vs. 245.9 K/uL) and PTT (27.6 vs. 29.6 seconds) were also found to be significantly enhanced in CAD patients. Based on the severity of IR [HOMA index up to 3 and ≥ 3], comparison with different parameters such as fibrinogen, D-dimer, C-peptide and insulin in CAD groups were also made. As per HOMA index, fibrinogen level was found to be significantly increased in below and above 3 categories. Moreover, C-peptide (P < 0.01) and insulin (P < 0.001) levels also showed significant association with both HOMA groups. Our study provides an insight towards the association of fibrinogen and IR in CAD patients with respect to severity.

Ethnicity and skin autofluorescence-based risk-engines for cardiovascular disease and diabetes mellitus.

Skin auto fluorescence (SAF) is used as a proxy for the accumulation of advanced glycation end products (AGEs) and has been proposed to stratify patients into cardiovascular disease (CVD) and diabetes mellitus (DM) risk groups. This study evaluates the effects of seven different ethnicities (Arab, Central-East African, Eastern Mediterranean, European, North African, South Asian and Southeast Asian) and gender on SAF as well as validating SAF assessment as a risk estimation tool for CVD and DM in an Arabian cohort. SAF data from self-reported healthy 2,780 individuals, collated from three independent studies, has been linear modelled using age and gender as a covariate. A cross-study harmonized effect size (Cohens'd) is provided for each ethnicity. Furthermore, new data has been collected from a clinically well-defined patient group of 235 individuals, to evaluate SAF as a clinical tool for DM and CVD-risk estimation in an Arab cohort. In an Arab population, SAF-based CVD and/or DM risk-estimation can be improved by referencing to ethnicity and gender-specific SAF values. Highest SAF values were observed for the North African population, followed by East Mediterranean, Arab, South Asian and European populations. The South Asian population had a slightly steeper slope in SAF values with age compared to other ethnic groups. All ethnic groups except Europeans showed a significant gender effect. When compared with a European group, effect size was highest for Eastern Mediterranean group and lowest for South Asian group. The Central-East African and Southeast Asian ethnicity matched closest to the Arab and Eastern Mediterranean ethnicities, respectively. Ethnic and gender-specific data improves performance in SAF-based CVD and DM risk estimation. The provided harmonized effect size allows a direct comparison of SAF in different ethnicities. For the first time, gender differences in SAF are described for North African and East Mediterranean populations.

Assessment of IL-18 Serum Level and Its Promoter Polymorphisms in the Saudi Coronary Artery Disease (CAD) Patients.

The purpose of the current study was to find out the possible changes polymorphic site at the promoter region of IL-18 gene in Saudi CAD patients. We have also measured serum IL-18 level to find out, the likely association between its level and polymorphic site. The present study included total 197 subjects (98 confirmed CAD patients both men and women and 99 healthy control individuals). Serum concentration of IL-18 was measured by enzyme linked immuno-sorbent assay. For SNPs analysis, sanger method of DNA sequencing was followed. We observed variable numbers of SNPs at -137 C/G, -607 A/C, and -656 T/G promoter sites in our studied samples. However, the observed changes in the number of SNP hotspots were found to be non-significant compared with control. IL-18 level was found to be significantly (P < 0.001) elevated in CAD patients compared with control individuals. The highest rise of around 36% (P < 0.001) in IL-18 level was recorded in unstable angina (UA) patients. Moreover, the group belonging to UA and non-ST segment elevation myocardial infarction (NSTEMI) showed only 6% rise. On the basis of our result, inflammation seems to have a role in the pathogenesis of CAD but not leading to the significant changes at the genetic level. J. Cell. Biochem. 118: 1849-1854, 2017. © 2017 Wiley Periodicals, Inc.

Assessment of genetic diversity in IL-6 and RANTES promoters and their level in Saudi coronary artery disease patients.

BACKGROUND: The present study consisted of a total of 200 subjects (100 confirmed coronary artery disease (CAD) patients), both men and women, and 100 healthy control individuals. METHODS: Serum concentration of IL-6 and RANTES were measured by enzyme-linked immunosorbent assay kit. For SNPs analysis, sanger method of DNA sequencing was followed. RESULTS: We observed variable numbers of SNP sites at -174 G/C, -572 G/C, and -597 G/A in IL-6 and -28 C/G and -109 C/T in RANTES promoters in CAD patients compared with control individuals. However, the observed changes in the number of SNPs were found to be non-significant compared with control individuals. The IL-6 level was found to be significantly (P<.001) elevated in CAD patients compared with control. Moreover, RANTES serum level did not show any significant change in CAD patients. CONCLUSION: Based on our result, it is quite clear that inflammation has a role in the pathogenesis of CAD but does not lead to significant changes at the genetic level in our population. As far as our knowledge goes, this is the first report that shows the genetic diversity in IL-6 and RANTES promoters and their respective levels in Saudi CAD patients.

Denaturation induced aggregation in α-crystallin: differential action of chaotropes.

α-Crystallin is a member of small heat shock proteins and is believed to play an exceptional role in the stability of eye lens proteins. The disruption or denaturation of the protein arrangement or solubility of the crystallin proteins can lead to vision problems including cataract. In the present study, we have examined the effect of chemical denaturants urea and guanidine hydrochloride (GdnHCl) on α-crystallin aggregation, with special emphasis on protein conformational changes, unfolding, and amyloid fibril formation. GdnHCl (4 M) induced a 16 nm red shift in the intrinsic fluorescence of α-crystallin, compared with 4 nm shift by 8 M urea suggesting a major change in α-crystallin structure. Circular dichroism analysis showed marked increase in the ellipticity of α-crystallin at 216 nm, suggesting gain in ß-sheet structure in the presence of GdnHCl (0.5-1 M) followed by unfolding at higher concentration (2-6 M). However, only minor changes in the secondary structure of α-crystallin were observed in the presence of urea. Moreover, 8-anilinonaphthalene-1-sulfonic acid fluorescence measurement in the presence of GdnHCl and urea showed changes in the hydrophobicity of α-crystallin. Amyloid studies using thioflavin T fluorescence and congo red absorbance showed that GdnHCl induced amyloid formation in α-crystallin, whereas urea induced aggregation in this protein. Electron microscopy studies further confirmed amyloid formation of α-crystallin in the presence of GdnHCl, whereas only aggregate-like structures were observed in α-crystallin treated with urea. Our results suggest that α-crystallin is susceptible to unfolding in the presence of chaotropic agents like urea and GdnHCl. The destabilized protein has increased likelihood to fibrillate. Copyright © 2016 John Wiley & Sons, Ltd.

A synopsis on the linkage between age-related dementias and vascular disorders.

The concept of age-related dementias and vascular disorders has now been recognized for over a century. In the present review, we have emphasized on the causes, consequences and the true bases for the treatment and prevention of these disorders. Systematic efforts have been put together to identify the aetiology in each case. Increased efforts have been targeted towards the concept and genetic factors responsible for vascular cognitive impairment and post-stroke dementia in relation with Alzheimer's disease, which is a consequence of age-related dementia, especially as they hold promise for early prevention and treatment. It has now been well accepted that vascular dementia is not a single disease but a group of conditions with different pathological correlations and pathophysiological mechanisms. The present review represents an amalgamation of several pathophysiological mechanisms producing a very heterogeneous clinical presentation for developing such consequences. We suggest current diagnostic categories and describe clinical parameters according to recently reported studies that document the demographic data in a standardized manner for age-related dementia disorders.

Current Updates on Therapeutic Advances in the Management of Cardiovascular Diseases.

Despite the significant advances in the medical research and treatment methods, the rate of mortality associated with cardiovascular disease (CVD) is continuously rising and it remains the leading cause of death worldwide. There are several treatment methods for CVD and associated complications that have been considered till now. The current treatment methods cannot produce rapid cure, but could prevent or reduce the progression of this devastating disease. In the current article, we have summarized the use of various pharmacological agents viz. HMG-CoA reductase inhibitors (statins), antihypertensive, thrombolytic and anticoagulation agents that are currently being used for the management of CVD which targets different biochemical or molecular events. Based on our article, more research in this field is advocated which will provide the rapid and effective treatment methods in order to avoid fatal complications associated with CVD.

Neopterin: An immune biomarker of coronary artery disease and its association with other CAD markers.

Neopterin has been considered as an important marker of cellular inflammation. The primary objective of the current study was to determine the role of neopterin in cardiovascular disease and its association with other well known cardiac markers. The study was composed of total 200 subjects (100 confirmed coronary artery disease (CAD) patients, 50 recently diagnosed, and 50 managed CAD patients) both men and women and 100 healthy control individuals of matching age and weight. Serum neopterin analysis was done using commercial available ELISA kits. Other cardiac markers viz. troponin, creatine kinase (CK), CK MB isoenzyme (CKMB), lactate dehydrogenase (LDH), fibrinogen, C-reactive protein (CRP), alanine aminotransferase (ALT), and aspartate aminotransferase (AST) estimation was done by standard routine biochemical methods. Neopterin level was found to be remarkably enhanced by 150% and 513% in the recently diagnosed and managed CAD patients, respectively. CK level also showed a significant rise by 62% in the managed patients. However, recently diagnosed patients did not show any significant change. Moreover, cross correlation study showed statistically significant (P < 0.01) change in neopterin and CK levels between recently and managed patients. In the other studied CAD markers such as CKMB, fibrinogen and LDH also showed a significant increase in both categories of patients. CRP level was also found to be significantly enhanced by 357% (P < 0.01) and 341% (P < 0.05) in recently diagnosed and managed patients respectively. Because of cost effectiveness, easy and quick analysis of neopterin in the serum sample, we propose neopterin as the prognostic as well as diagnostic biomarker of CAD before other markers could be tested especially in Saudi population.

Alzheimer's and type 2 diabetes treatment via common enzyme targeting.

Alzheimer's disease (AD) and type 2 diabetes mellitus (T2DM) are two devastating diseases that are currently incurable. Epidemiological, clinical and pathological evidence has confirmed the co-existence of these two disorders. Moreover, there has been promising progress made in the identification of the pathological linkage between T2DM and AD in the last decade. Hence, developing common treatment strategies for these diseases is important. Currently, enzyme targeting is a potential strategy to cure many diseases. In this communication, we tried to summarize the single enzymetargeted therapeutic approach for the treatment of AD and T2DM. This field of research continues to be active and progressive in identifying many promising enzymes that are involved in both diseases. Based on this review article, we also believe that enzyme inhibition is a promising and reliable strategy for the treatment of many incurable diseases. In the future, we expect that the scientific community will be able to develop common enzyme inhibitors for the treatment of both AD and T2DM.