Cheminformatics approach for identification of N-HyMenatPimeMelly as a novel potential ligand against RAS and renal chloride channel.

Some angiotensin receptor (AR) blockers interfere with the renal chloride channel (ClC-K), which plays an important role in urine concentration. Identifying ligands targeting this channel, whether activating or blocking, is highly desirable because it could open the way for interventions that modulate their activity. In this study, the Asinex (BioDesign) complete library was screened to identify a compound with favorable physicochemical and pharmacokinetic properties, which have both AR blocking and ClC-Ka-modulating activities to present it as a novel potential oral candidate which could be useful for treatment of salt-sensitive hypertension without major ClC-K affection. A compound, N-{[4-Hydroxy-1-(2-methyl-1,6-naphthyridin-4-yl)-4-piperidinyl]methyl}-N-methyl-L-lysinamide (N-HyMenatPimeMelly) (Chem Spider ID 68416221), was identified as a potent potential oral ligand of the renin-angiotensin system (RAS) and ClC-Ka with docking scores ranging from -10.978 to -7.324 with the four selected proteins (4YAY: AR type 1, 2PFI: Cytoplasmic domain of ClC-Ka, 6JOD: AR type 2 and 6M0J: Angiotensin-converting enzyme 2). The protein-ligand complex was used to perform molecular dynamics (MD) simulation for 100 ns. The QikProp and SwissADME tools' results showed that the compound has ADME/T and drug-likeness properties, which are within the permissible ranges for 95% of known drugs. The density functional theory (DFT) analysis and MD simulation extended the study toward computational validation. Throughout the study, N-HyMenatPimeMelly has shown good interactions and stable performance in MD simulation and DFT analysis. The whole analysis has produced promising results, and N-HyMenatPimeMelly can be treated as a novel potential RAS and ClC-K oral ligand, however, experimental validation is needed before human use.Communicated by Ramaswamy H. Sarma.

Effect of eucalyptol on matrix metalloproteinase-9 and its tissue inhibitor in hypertensive rats.

Effects of eucalyptol, a key component of eucalyptus globules, on matrix metalloproteinase-9 (MMP-9) and its tissue inhibitor (TIMP-1), compared with lisinopril, were investigated in a model of hypertension induced by chronic intraperitoneal (IP) injection of low dose nicotine in rats. The hypertensive rats were randomly allocated to 4 groups (n=8): Positive control (PC, untreated), eucalyptol-treated group (1.0 mg/kg, IP), lisinopril-treated group (10 mg/kg, IP), and eucalyptol+lisinopril-treated group. Systolic blood pressure and plasma levels of MMP-9 and TIMP-1 were measured. All treatments decreased the elevated blood pressure and plasma levels of MMP-9 and TIMP-1 most significantly with the combination group which showed non-significant differences from the normal control group. Lisinopril reduced plasma levels of MMP-9 and TIMP-1 more significantly than eucalyptol. In conclusion, eucalyptol significantly decreased the increased plasma levels of MMP-9 and TIMP-1 in nicotine-induced hypertension in rats. Moreover, its combination with lisinopril exerted more significant effects compared to each drug alone. This makes this combination particularly useful in hypertension and related cardiovascular disorders where suppression of MMP-9 and TIMP-1 activities decreases the related complications and improves the overall morbidity and mortality. To our knowledge, the current data are novel, and may open the way for development of a co-delivery system of both drugs which could be beneficial in treatment of hypertension in chronic smokers.

Molecular docking analysis of AGTR1 antagonists.

Cardiovascular diseases (CVDs) are the leading cause of death and morbidity globally. The renin-angiotensin system is an important regulatory system for maintaining cardiovascular and renal function. Therefore, angiotensin-converting enzyme inhibitors and angiotensin receptor blockers have emerged as first-line treatments for conditions such as hypertension and heart failure. Currently available synthetic medications used to treat various CVDs have been linked with various adverse effects. Therefore, this study focuses on targeting type-1 angiotensin II receptor (AGTR1) by natural compounds. The ZINC database natural compounds and standard AGTR1 inhibitors have been screened against the AGTR1 active site. The results showed that five compounds, namely ZINC85625504, ZINC62001623, ZINC70666587, ZINC06624086, and ZINC95486187, had similar binding energies to established AGTR1 inhibitors. These compounds were found to interact with crucial AGTR1 residues, indicating their potential as AGTR1 inhibitors. Moreover, the hit compounds demonstrated favorable drug-like characteristics and warrant further investigation for their potential use in managing CVD.

Could Plasma CXCL12 Predict Ventricular Dysfunction in Patients with Severe Myocardial Infarction?

Plasma level of chemokine CXCL12 can predict adverse cardiovascular outcomes in patients with coronary artery disease, but data on its relationship with severity of coronary stenosis in cases of severe myocardial infarction (MI) are scarce and conflicting. The objective of this study was to investigate link between plasma CXCL12 levels and different grades of left ventricular ejection fraction (LVEF) in statin-treated and -untreated patients with severe MI. A total of 198 consecutive patients with first-time severe MI (ST-elevated myocardial infarction [STEMI], n = 121 and non-ST-elevated myocardial infarction [NSTEMI], n = 77) were recruited from Coronary Care Unit, King Abdulaziz University Hospital. They have one to two coronary arteries blocked ≥50%, or three arteries blocked 30 to 49%. Demographic and clinical criteria were collected and plasma CXCL12 level was measured. No correlations were detected between demographic and clinical criteria and CXCL12 level. While troponin peaks and LVEF significantly differed between STEMI and NSTEMI patients, CXCL12 level showed nonsignificant changes. Plasma CXCL12 levels decreased significantly in statin-treated patients compared with those untreated. From receiver operating characteristic (ROC) analysis, high CXCL12 levels were associated with no statin therapy. For STEMI and NSTEMI patients, area under the receiver operating characteristic curve for CXCL12 test were 0.685 and 0.820, while sensitivity and specificity values were 75.9 and 54.8%, and 73.1 and 84%, respectively. Plasma CXCL12 levels showed nonsignificant changes with different ranges of LVEF and troponin peaks. In patients with severe MI, irrespective of statin therapy, plasma CXCL12 showed no correlation with different ranges of LVEF suggesting that it cannot predict left ventricular dysfunction in these cases. However, cross-sectional design of this study is a limitation.

The Association Between Medication Non-Adherence and Early and Late Readmission Rates for Patients with Acute Coronary Syndrome.

Purpose: Unplanned hospital readmission forms costly, but preventable burdens on healthcare system. This study was designed to evaluate cardiovascular-related readmission rate after discharge of acute coronary syndrome (ACS) patients and its relationship with medication adherence at a university hospital, Saudi Arabia. Methods: A total of 370 consecutive patients presenting with ACS were involved. The inclusion criteria were clinical and coronary angiography diagnostic data of ACS. Exclusion criteria included heart valve disease, myocarditis, hepatic disease, and history of acute infection during the previous two weeks. Patients were divided into index admission group (n = 291) and unplanned readmission group (n = 79). Readmission and medication adherence rates were evaluated during 1-30, 31-180, 181-365, and 366-548 days post-ACS discharge. Medication adherence was estimated with a (yes/no) questionnaire. Results: The overall readmission rate was 21.4%; individual rates were 30.4%, 38.0%, 27.8%, and 3.8% and the overall medication adherence rate was 62.03%, while individual rates were 54.2%, 70.0%, 63.6%, and 33.3% during the four periods, respectively. There were strong correlations between medication non-adherence and readmission rates. Heart failure, ST-elevated myocardial infarction, unstable angina, cerebrovascular accident, and arrhythmia represented the top causes. Body mass index was higher in readmission group. There were significant correlations between smoking, hypertension, cerebrovascular accident, ischemic heart disease, previous stent, instent restenosis, and LDL-cholesterol as predictor factors and readmission rate. Conclusion: The cardiovascular-related unplanned readmission rate post-ACS discharge was 21.4%, and medication non-adherence rate was 37.97%. There were strong correlations between them in the time frames from 1-month to 1.5-year post-discharge. The individual rates decreased by time, but the first month showed lower rates than the following 5 months and this indicated the role of factors other than medication non-adherence in readmission. The rates are generally consistent with the international levels but utilizing technology can further improve medication adherence and reduce readmission rates.

Olmesartan medoxomil self-microemulsifying drug delivery system reverses apoptosis and improves cell adhesion in trinitrobenzene sulfonic acid-induced colitis in rats.

Olmesartan medoxomil (OM) is an angiotensin receptor blocker. This study aimed to investigate the effects of OM self-microemulsifying drug delivery system (OMS) in trinitrobenzene sulfonic acid (TNBS)-induced acute colitis in rats. Besides two control groups, five TNBS-colitic-treated groups (n = 8) were given orally sulfasalazine (100 mg/kg/day), low and high doses of OM (3.0 and 10.0 mg/kg/day) (OML and OMH) and of OMS (OMSL and OMSH) for seven days. A colitis activity score was calculated. The colon was examined macroscopically. Colonic levels of myeloperoxidase, tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), malondialdehyde, and reduced glutathione were measured. Plasma and colonic olmesartan levels were measured. Colonic sections were subjected to hematoxylin and eosin staining and immunohistochemical staining for E-cadherin, caspase-3, and matrix metalloproteinase-9 (MMP-9). Protein expression of E-cadherin, Bcl-2 associated X protein (Bax), and B-cell lymphoma 2 (Bcl-2), and cleaved caspase-3 by Western blot was done. TNBS-colitic rats showed increased colonic myeloperoxidase, TNF-α, IL-6, and malondialdehyde, decreased colonic glutathione, histopathological, immunohistochemical, and protein expression alterations. OMS, compared with OM, dose-dependently achieved higher colonic free olmesartan concentration, showed better anti-inflammatory, antioxidant, and anti-apoptotic effects, improved intestinal barrier, and decreased mucolytic activity. OMS more effectively up-regulated the reduced Bcl-2, Bcl-2/Bax ratio, and E-cadherin expression, and down-regulated the overexpressed Bax, cleaved caspase-3, and MMP-9. OMSL exerted effects comparable to OMH. Sulfasalazine exerted maximal colonic protective effects and almost completely reversed colonic damage, and OMSH showed nearly similar effects with non-significant differences in-between or compared with the normal control group. In conclusion, OMS could be a potential additive treatment for Crohn's disease colitis.

Interactions of selected cardiovascular active natural compounds with CXCR4 and CXCR7 receptors: a molecular docking, molecular dynamics, and pharmacokinetic/toxicity prediction study.

BACKGROUND: The chemokine CXCL12 and its two receptors (CXCR4 and CXCR7) are involved in inflammation and hematopoietic cell trafficking. This study was designed to investigate molecular docking interactions of four popular cardiovascular-active natural compounds; curcumin, resveratrol, quercetin, and eucalyptol; with these receptors and to predict their drug-like properties. We hypothesize that these compounds can modify CXCL12/CXCR4/CXCR7 pathway offering benefits for coronary artery disease patients. METHODS: Docking analyses were carried and characterized by Molecular Environment (MOE) software. Protein Data Bank ( http://www.rcsb.org/ ) has been retrieved from protein structure generation and crystal structures of CXCR4 and CXCR7 receptors (PDB code = 3ODU and 6K3F). The active sites of these receptors were evaluated and extracted from full protein and molecular docking protocol was done for compounds against them. The presented parameters included docking scores, ligand binding efficiency, and hydrogen bonding. The pharmacokinetic/toxic properties (ADME/T) were calculated using SwissADME, ProTox-II, and Pred-hERG softwares to predict drug-like properties of the compounds. The thermochemical and molecular orbital analysis, and molecular dynamics simulations were also done. RESULTS: All compounds showed efficient interactions with the CXCR4 and CXCR7 receptors. The docking scores toward proteins 3ODU of CXCR4 and 6K3F of CXCR7 were - 7.71 and - 7.17 for curcumin, - 5.97 and - 6.03 for quercetin, - 5.68 and - 5.49 for trans-resveratrol, and - 4.88 and - 4.70 for (1 s,4 s)-eucalyptol respectively indicating that all compounds, except quercetin, have more interactions with CXCR4 than with CXCR7. The structurally and functionally important residues in the interactive sites of docked CXCR4-complex and CXCR7-complex were identified. The ADME analysis showed that the compounds have drug-like properties. Only (1 s,4 s)-Eucalyptol has potential weak cardiotoxicity. The results of thermochemical and molecular orbital analysis and molecular dynamics simulation validated outcomes of molecular docking study. CONCLUSIONS: Curcumin showed the top binding interaction against active sites of CXCR4 and CXCR7 receptors, with the best safety profile, followed by quercetin, resveratrol, and eucalyptol. All compounds demonstrated drug-like properties. Eucalyptol has promising potential because it can be used by inhalation or skin massage. To our knowledge, this is the first attempt to find binding interactions of these natural agents with CXCR4 and CXCR7 receptors and to predict their druggability.

Isolation and drug susceptibility pattern of uropathogens in Saudi diabetic and non-diabetic patients with urinary tract infection.

Urinary tract infection (UTI), contribute substantially to healthcare burden. Diabetes predispose to UTI with high glycosuria being fertile medium for bacterial growth. With changing bacterial drug resistance patterns; the problem needs to be studied periodically to ensure a rational therapy, minimize adverse effects, and cost. Therefore, it is of interest to compare the profile and susceptibility pattern of uropathogens isolated from diabetic and non-diabetic patients with UTI. Mid-stream urine samples of 1100 patients (diabetic and non-diabetic), presenting with UTI symptoms were aseptically collected and inoculated into CLED medium. Colony counts of 105cfu/ml or 104cfu/ml and >5 pus cells per high power microscopic field were regarded as significant bacteriuria. Colonies from CLED were sub-cultured onto sheep blood agar and MacConkey agar. Bacterial identification was performed on the basis of colony morphology, gram staining, and series of biochemical tests though Analytical Profile Index (API) test strips. Drug susceptibility was done by standard Kirby-Bauer disk diffusion. Data was analyzed by SPSS ver. 25.Clinically significant bacteriuria was 32.8% and 19.2% in diabetics and non-diabetics respectively. The frequency of male and female patients was 153 and 208 in diabetic group; and 69 and 142 respectively in non-diabetic group. Diabetics were twice at risk of UTI; [Odds ratio; 2.04 (CI: 1.68-2.48, p<0.05)]. .Escherichia coli and klebsiella were most common gram-negative, while Staphylococcus aureus and Coagulase-negative staphylococci (CoNS) were most common gram-positive bacteria in both the groups. Most effective antibiotics against gram-negative bacteria were carbapenems, amikacin, colistin, and piperacillin/tazobactam; while ampicillin/amoxicillin, fluoroquinolones and cephalexin were least effective. For gram-positives, vancomycin, linezolid and tigecycline were most effective. No significant difference in bacterial profile and susceptibility pattern was found between diabetics and non-diabetics. However, diabetics were twice at risk of UTI compared to non-diabetics.

Development and Validation of an Arabic Version of the Drug Abuse Screening Test-10 (DAST-10) among Saudi Drug Abusers.

The Drug Abuse Screening Test-10 (DAST-10) is a valid and reliable screening tool for drug use-related problems, however there is no Arabic version. To our knowledge, this is the first study to develop and validate an Arabic DAST-10 version. Saudi young adults participated in the study as two groups; drug users (n=360) recruited from Alamal Complex for Mental Health, Jeddah, and drug non-users (n=100). Three measures were used: (1) Demographic and drug use description questionnaire, (2) Arabic DAST-10 version, and (3) Urine analysis for drug use. The developed Arabic DAST-10 version demonstrated adequate internal consistency. High correlations were shown between its scores and the two standard measures (urine analysis and self-reporting question) indicating good criterion validity. Sensitivity and specificity values were between 91.5 - 99.7% and 57 - 92.5% with different DAST-10 cutoff values. An optimal performance at a cutoff score of 3 or more was most likely to significantly identify drug users. Discriminant analysis showed that more than 90% of cases were correctly classified. Distribution of participants in categories of DAST-10 scores according to degree of problems was reasonable. It is concluded that the developed Arabic DAST-10 version is a reliable and valid screening tool for drug use-related problems in Arabic speakers.

Case report: A novel de novo loss of function variant in the DNA-binding domain of TBX2 causes severe osteochondrodysplasia.

Background: T-box family members are transcription factors characterized by highly conserved residues corresponding to the DNA-binding domain known as the T-box. TBX2 has been implicated in several developmental processes, such as coordinating cell fate, patterning, and morphogenesis of a wide range of tissues and organs, including lungs, limbs, heart, kidneys, craniofacial structures, and mammary glands. Methods: In the present study, we have clinically and genetically characterized a proband showing a severe form of chondrodysplasia with developmental delay. Whole-exome sequencing (WES), Sanger sequencing, and 3D protein modeling were performed in the present investigation. Results: Whole-exome sequencing revealed a novel nonsense variant (c.529A>T; p.Lys177*; NM_005994.4) in TBX2. 3D-TBX2 protein modeling revealed a substantial reduction of the mutated protein, which might lead to a loss of function (LOF) or nonsense-mediated decay (NMD). Conclusion: This study has not only expanded the mutation spectrum in the gene TBX2 but also facilitated the diagnosis and genetic counseling of related features in affected families.

Effect of sequential eradication therapy on serum osteoprotegerin levels in patients with Helicobacter pylori infection and co-existing inflammatory bowel disease.

OBJECTIVE: To investigate the effect of sequential Helicobacter pylori eradication therapy on serum osteoprotegerin levels in patients with H. pylori infection and co-existing inflammatory bowel disease (IBD). METHODS: Three groups of patients were involved in this observational cross-sectional study: IBD (n = 83), H. pylori infection (HP, n = 68), and H. pylori infection with co-existing IBD (HP + IBD, n = 52). These groups were compared with a normal control group (NC, n = 50). Serum osteoprotegerin, serum bone alkaline phosphatase (BALP), and fecal calprotectin (FC) levels were measured. RESULTS: Serum osteoprotegerin levels were significantly correlated with the simple endoscopic score for Crohn's disease and Mayo score for ulcerative colitis. The receiver operating characteristic analysis of osteoprotegerin revealed high values for the area under the curve, sensitivity, and specificity. Discriminant analysis illustrated that osteoprotegerin levels significantly differentiated patients with IBD from healthy controls. Osteoprotegerin and FC levels distinguished the IBD and HP + IBD groups from the NC and HP groups. CONCLUSIONS: Sequential eradication therapy did not affect serum osteoprotegerin levels in patients with H. pylori infection and co-existing IBD. Serum osteoprotegerin elevation might be a marker for IBD development in patients with past or current H. pylori infection.

Blood Levels of Glutamine and Nitrotyrosine in Patients with Chronic Viral Hepatitis.

PURPOSE: Oxidative stress is involved in pathogenesis of chronic viral hepatitis. Glutamine is an antioxidant, but there is a controversy about its risk-benefits. Nitrotyrosine is an oxidative stress marker. This observational cross-sectional study was designed to compare blood levels of glutamine and nitrotyrosine in treated versus untreated chronic viral hepatitis patients. PATIENTS AND METHODS: Five groups (n = 250) were included: hepatitis B untreated (HBV), hepatitis C untreated (HCV), HBV treated (HBVT), and HCV treated (HCVT) groups plus a normal control group. Liver function tests and blood levels of glutamine, nitrotyrosine, viral loads, and HBsAg were measured. RESULTS: Blood levels of glutamine and nitrotyrosine in all patient groups significantly increased compared with normal controls with non-significant differences in-between. Both tests showed significant large correlations with HBV-DNA or HCV-RNA test positivity, high accuracies, and cutoff scores with high sensitivities and specificities. The viral loads and HBsAg levels were significantly lower in treated versus untreated groups. However, they poorly correlated with levels of glutamine and nitrotyrosine in all patient groups. CONCLUSION: Blood levels of glutamine and nitrotyrosine significantly increased in treated and untreated chronic viral hepatitis B and C patients compared with normal controls. Both tests showed high accuracies and cutoff scores with high sensitivities and specificities. However, they did not differ significantly in treated versus untreated patients. To our knowledge, this is the first data showing elevation of glutamine and nitrotyrosine in treated and untreated chronic viral hepatitis. A prospective longitudinal study with repeated measurements of glutamine and nitrotyrosine is recommended to verify if they can predict response to treatment. Study of other oxidative stress markers is also advised to clarify if the elevated nitrotyrosine could be an oxidative stress marker in these patients, and whether the increased glutamine could act as an antioxidant or as a predictive agent for deleterious consequences.

Role and implications of the CXCL12/CXCR4/CXCR7 axis in atherosclerosis: still a debate.

Atherosclerosis is one of the leading causes of mortality and morbidity worldwide. Chemokines and their receptors are implicated in the pathogenesis of atherosclerosis. CXCL12 is a member of the chemokine family exerting a myriad role in atherosclerosis through its classical CXCR4 and atypical ACKR3 (CXCR7) receptors. The modulatory and regulatory functional spectrum of CXCL12/CXCR4/ACKR3 axis in atherosclerosis spans from proatherogenic, prothrombotic and proinflammatory to atheroprotective, plaque stabilizer and dyslipidemia rectifier. This diverse continuum is executed in a wide range of biological units including endothelial cells (ECs), progenitor cells, macrophages, monocytes, platelets, lymphocytes, neutrophils and vascular smooth muscle cells (VSMCs) through complex heterogeneous and homogenous coupling of CXCR4 and ACKR3 receptors, employing different downstream signalling pathways, which often cross-talk among themselves and with other signalling interactomes. Hence, a better understanding of this structural and functional heterogeneity and complex phenomenon involving CXCL12/CXCR4/ACKR3 axis in atherosclerosis would not only help in formulation of novel therapeutics, but also in elucidation of the CXCL12 ligand and its receptors, as possible diagnostic and prognostic biomarkers.Key messagesThe role of CXCL12 per se is proatherogenic in atherosclerosis development and progression.The CXCL12 receptors, CXCR4 and ACKR3 perform both proatherogenic and athero-protective functions in various cell typesDue to functional heterogeneity and cross talk of CXCR4 and ACKR3 at receptor level and downstream pathways, regional boosting with specific temporal and spatial modulators of CXCL12, CXCR4 and ACKR3 need to be explored.

Protective effect of 6-paradol in acetic acid-induced ulcerative colitis in rats.

BACKGROUND: Ulcerative colitis is a gut inflammatory disorder due to altered immune response to gut microbiome, with interplay of environmental and genetic factors. TNF-α activates inflammatory response through a cascade of immune responses, augmenting pro-inflammatory mediators and proteases, activating chemotaxis, and infiltration of inflammatory cells, leading to ulceration and haemorrhage through cytotoxic reactive oxygen species. 6-Paradol, a dietary component in several plants belonging to the Zingiberaceae family, has shown anti-inflammatory and antioxidant activities. Current study evaluates the effect of 6-paradol in amelioration of ulcerative colitis in rats for the first time. METHODS: 6-Paradol (95% purity) was obtained from seeds of Aframomum melegueta. Rats were divided randomly into six groups (n = 8). Group one was administered normal saline; group two was treated with the vehicle only; group three, sulfasalazine 500 mg/kg; and groups four, five, and six, were given 6-paradol (50, 100, 200, respectively) mg/kg orally through gastric gavage for 7 days. Colitis was induced on 4th day by intrarectal administration of 2 ml acetic acid (3%), approximately 3 cm from anal verge. On 8th day, rats were sacrificed, and distal one-third of the colon extending proximally up to 4 cm from anal orifice was taken for biochemical and gross examination. Two centimetres of injured mucosal portion was taken for histopathological investigations. SPSS (ver.26) was used for statistical analysis. RESULTS: Colonic and serum glutathione (GSH) levels decreased, while colonic and serum malondialdehyde (MDA), colonic myeloperoxidase (MPO) activity, serum interleukin-6 (IL-6), serum tumour necrosis factor-α (TNF-α) levels, and colon weight to length ratio were increased significantly in the colitis untreated group compared to normal control. Treatment with 6-paradol considerably improved all these parameters, especially at a dose of 200 mg/kg (p < 0.001), revealing non-significant differences with sulfasalazine 500 mg/kg and normal control (p = 0.998). Sulfasalazine and 6-paradol in a dose dependent manner also markedly reversed mucosal oedema, atrophy and inflammation, cryptic damage, haemorrhage, and ulceration. There were non-significant differences between low and medium doses and between medium and high doses of 6-paradol for IL-6 and serum MDA levels. CONCLUSION: 6-Paradol demonstrated protection against acetic acid-induced ulcerative colitis, probably by anti-inflammatory and antioxidant actions.

Telmisartan Self-Nanoemulsifying Drug Delivery System, Compared With Standard Telmisartan, More Effectively Improves Hepatic Fibrosis in Rats.

Background: This study was designed to examine effects of telmisartan; an angiotensin receptor blocker; self-nanoemulsifying drug delivery system (SNEDDS) in reversing already-established hepatic fibrosis. Method: Forty rats were given thioacetamide (200 mg/kg, intraperitoneally) twice/week for 8 weeks then divided into 5 groups (n = 8), PC and 4 treated groups. Treatments were given orally for another 2 months as follows: telmisartan low and high doses (TL and TH: 1.8 and 3.6 mg/kg/day) and telmisartan SNEDDS at the same doses (TLS and THS). At end of treatment, blood was obtained and liver was isolated. Results: Rats showed significant elevations of plasma ALT and AST and hepatic IL-6, TNF-α, and MDA, significant reductions of plasma albumin, hepatic GSH, and body weight, and hepatic histopathological damage. All treatments except for TL significantly reversed these thioacetamide-induced changes. THS group showed significant differences from all groups. Regarding ratio of free telmisartan concentration in hepatic homogenate to that of plasma, TH and TLS groups showed non-significant variation between each other while THS group showed significant differences from them. No significant changes were detected in blood pressure, hemoglobin, white blood cells, and platelets. Conclusion: Telmisartan SNEDDS, compared with telmisartan, more effectively reversed chronic hepatic fibrosis with good safety profile.

Improved histoarchitectural changes with angiotensin receptor blockers in early testicular and cauda toxicity in rats / Mejora de los cambios en la histoarquitectura con bloqueadores de receptores de angiotensina en la toxicidad precoz testicular y de cauda en ratas

SUMMARY: Reproductive dysfunction is a complication for many diseases and toxins. Its early diagnosis and treatment are immensely important. Here the morphological histoarchitecture changes in early testicular and cauda toxicity before and after treatment with angiotensin receptor blockers were evaluated. Low-grade testicular damage was induced using thioacetamide (TAA, 50 mg/kg/day) intraperitoneally for two weeks in rats. The rats were randomly divided into four groups (n = 8) treated daily orally for three weeks as follows: Normal control (distilled water), TAA (positive control), TAA+candesartan (0.2 mg/kg) and TAA+losartan (7.5 mg/kg). Serum testosterone and testicular malondialdehyde and glutathione were measured. The changes in histoarchitecture of testis and cauda epididymis were evaluated by hematoxylin and eosin for general structure, Masson's trichrome for collagen, periodic acid Schiff for basement membrane, and caspase-3 and proliferating cell nuclear antigen (PCNA) for immunohistochemical analysis. The TAA-rats showed decreases of serum testosterone and testicular glutathione, increases in testicular malondialdehyde, degenerative changes and apoptosis in germ cells, thickening of tubular basal lamina and increases in expression of caspase 3, and decreases in expression of PCNA. The ARBs (candesartan and losartan) significantly reversed these changes with non-significant differences in-between. Treatment with ARBs (candesartan and losartan) significantly reversed TAA-induced low-grade testicular and cauda toxicity in rats. This could be potentially useful for early treatment of male patients with occupational toxicant-induced reproductive dysfunction especially if they are using ARBs for other comorbidities.

RESUMEN: La disfunción reproductiva es una complicación por muchas enfermedades y toxinas. Su diagnóstico y tratamiento tempranos son inmensamente importantes. Aquí se evaluaron los cambios morfológicos en la histoarquitectura en la toxicidad precoz testicular y cauda antes y después del tratamiento con bloqueadores de receptores de angiotensina. Se indujo daño testicular de bajo grado usando tioacetamida (TAA, 50 mg / kg / día) por vía intraperitoneal durante dos semanas en ratas. Las ratas se dividieron aleatoriamente en cuatro grupos (n = 8) tratados diariamente por vía oral durante tres semanas de la siguiente manera: control normal (agua destilada), TAA (control positivo), TAA + candesartan (0,2 mg / kg) y TAA + losartán (7,5 mg / kg). Se midieron la testosterona sérica, el malondialdehído testicular y el glutatión. Los cambios en la histoarquitectura de los testículos y la epidermis de la cauda se evaluaron mediante Hematoxilina y Eosina para determinar la estructura general, con tricrómicro de Masson para el colágeno, ácido periódico de Schiff para la membrana basal y la caspasa-3 y el antígeno nuclear de células proliferantes (PCNA) para análisis inmunohistoquímico. Las ratas TAA mostraron disminución de la testosterona sérica y glutatión testicular, aumentos en el malondialdehído testicular, cambios degenerativos y apoptosis en células germinales, engrosamiento de la lámina basal tubular y aumentos en la expresión de la caspasa 3, y disminución en la expresión de PCNA. Los ARB (candesartán y losartán) revirtieron significativamente estos cambios con diferencias no significativas en el medio. El tratamiento con BRA (candesartán y losartán) revirtió significativamente la toxicidad testicular y cauda inducida por TAA en ratas. Esto podría ser potencialmente útil para el tratamiento temprano de pacientes con disfunción reproductiva inducida por tóxicos ocupacionales, especialmente si están usando BRA para otras comorbilidades.

Pharmacotherapy of schizophrenia: toward a metabolomic-based approach.

Approximately 20%-30% of schizophrenia patients are resistant to current standard pharmacotherapies. Recent schizophrenia research aims to identify specific pathophysiological abnormalities and novel targets in the disease, with the goals of identifying at-risk individuals, facilitating diagnosis, prompting early and personalized interventions, and helping predict response to treatment. Metabolomics involves the systematic study of the profile of biochemical alterations early in the course of a given disorder. Major aspects of the schizophrenia metabolome have been characterized, uncovering potential selective biomarkers for the disease that may change how the disorder is diagnosed, and how patients are stratified and treated. This review focuses on the most common metabolomic fingerprints of the different pathways involved in the pathophysiology of schizophrenia, and the potential development of novel metabolomic-related pharmacotherapies for improved treatment of schizophrenia and other related idiopathic psychotic disorders.

Adaptation of child oral health education leaflets for Arabic migrants in Australia: a qualitative study.

BACKGROUND: The purpose of this study was to gain an in-depth understanding of Arabic-speaking mothers views on the usefulness of existing oral health education leaflets aimed at young children and also to record their views on the tailored versions of these leaflets. METHODS: This qualitative study was nested within a large ongoing birth cohort study in South Western Sydney, Australia. Arabic-speaking mothers (n = 19) with young children were purposively selected and approached for a semi-structured interview. Two original English leaflets giving advice on young children's oral health were sent to mother's prior to the interview. On the day of interview, mothers were given simplified-English and Arabic versions of both the leaflets and were asked to compare the three versions. Interviews were audio-recorded, subsequently transcribed verbatim and analysed by thematic analysis. Ethical approval was obtained from Human Research Ethics Committees of the former Sydney South West Area Health Service, University of Sydney and Western Sydney University. RESULTS: Mothers reported that simplified English together with the Arabic version of the leaflets were useful sources of information. Although many mothers favoured the simplified version over original English leaflets, the majority favoured the leaflets in Arabic. Ideally, a "dual Arabic - simplified English leaflet" was preferred. The understanding of key health messages was optimised through a simple layout and visual images. CONCLUSIONS: There is a need to tailor oral health education leaflets for Arabic-speaking migrants. Producers of dental leaflets should also consider a "dual Arabic - simplified English leaflet" to improve oral health knowledge of Arabic-speaking migrants. The use of simple layout and pictures assists Arabic-speaking migrants to understand the content of dental leaflets.

Effect of genetic polymorphisms in SREBF-SCAP pathway on therapeutic response to rosuvastatin in Saudi metabolic syndrome patients.

AIM: Genetic variants contribute to statins' therapeutic variability. SREBF-SCAP pathway is a key player in lipid homeostasis. Hence, effect of SREBF-SCAP polymorphisms on therapeutic response was studied. PATIENTS & METHODS: Metabolic syndrome patients of either sex were prescribed rosuvastatin 10 mg for 24 weeks. Clinical, anthropometric and lipid measurements were done before and after treatment. Genotyping was done by pyrosequencing. RESULTS & CONCLUSION: No associations of SCAP and SREBF-1a genotypes with baseline lipids but significant associations with lipid reductions were observed. Significant effect of SCAP (GG; B = -8.16, p = 0.001); SREBF-1a (GG; B = -7.47, p = 0.001) and SREBF-1a (-delG; B = -7.42, p = 0.001) was observed on total cholesterol reduction. Additive trend was found between SCAP genotypes and lipid reductions. A total of 88% responders have SCAP 'G' allele (p = 0.001). Patients carrying SCAP (GG) and SREBF-1a (GG and -delG) have 9.5-, 8.6- and 14.6-times more likelihood of being responders (p < 0.05). 'G' allele in SCAP and SREBF-1a is significant predictor of rosuvastatin response.