Sildenafil prevents chronic psychosocial stress-induced working memory impairment: Role of brain-derived neurotrophic factor.

Background: Psychosocial stress, a common feature in modern societies, impairs cognitive functions. It is suggested that stress hormones and elevated excitatory amino acids during stress are responsible for stress-induced cognitive deficits. Reduced brain-derived neurotrophic factor (BDNF) levels, increased oxidative stress, and alteration of synaptic plasticity biomarkers are also possible contributors to the negative impact of stress on learning and memory. Sildenafil citrate is a selective phosphodiesterase type 5 (PDE5) inhibitor and the first oral therapy for the treatment of erectile dysfunction. It has been shown that sildenafil improves learning and memory and possesses antioxidant properties. We hypothesized that administering sildenafil to stressed rats prevents the cognitive deficit induced by chronic psychosocial stress. Methods: Psychosocial stress was generated using the intruder model. Sildenafil 3 mg/kg/day was administered intraperitoneally to animals. Behavioral studies were conducted to test spatial learning and memory using the radial arm water maze. Then, the hippocampal BDNF level and several antioxidant markers were assessed. Results: This study revealed that chronic psychosocial stress impaired short-term but not long-term memory. The administration of sildenafil prevented this short-term memory impairment. Chronic psychosocial stress markedly reduced the level of hippocampal BDNF (P˂0.05), and this reduction in BDNF was normalized by sildenafil treatment. In addition, neither chronic psychosocial stress nor sildenafil significantly altered the activity of measured oxidative parameters (P > 0.05). Conclusion: Chronic psychosocial stress induces short-term memory impairment. The administration of sildenafil citrate prevented this impairment, possibly by normalizing the level of BDNF.

Cardiovascular medications used for comorbid diseases in patients with atrial fibrillation. The JoFib study.

PURPOSE: Many atrial fibrillation (AF) patients use cardiovascular medications for indications other than AF. These medications can affect morbidity and mortality. We aim to investigate the characteristics of AF patients who use different medication classes and their clinical course. METHODS: We collected data from the prospective, multicenter registry, JoFib study. We identified classes of non-AF medications (medications not used for rate control, rhythm control, or anticoagulation), described demographic and clinical characteristics, and investigated AF-related outcomes according to these medication classes. RESULTS: From a total of 2020 patients, five classes of cardiovascular non-AF medications were identified, aspirin, P2Y12 inhibitors, ACE inhibitors/ARBs, statins, and diuretics. The most commonly used non-AF medications were diuretics and ACE inhibitors/ARBs (39.2%, and 39%, respectively). 51% of AF patients took more than one non-AF medication. Multivariable Cox regression analysis demonstrated that ACE inhibitor/ARB therapy independently reduced the risks of all-cause mortality and cardiovascular mortality (aHR 0.50, 95%CI 0.37-0.68; aHR 0.51, 95%CI 0.34-0.75, respectively) and that statin therapy reduced the risk of cardiovascular mortality (aHR 0.68, 95%CI 0.48-0.98) in AF patients. Multivariable logistic regression analysis demonstrated a protective effect of statin therapy against the secondary outcome, clinically relevant non-major bleeding (CRNMB) (adjusted OR 0.62 95%CI 0.42-0.94). CONCLUSION: Our findings suggest a protective effect of ACE inhibitors/ARBs against all-cause and cardiovascular mortality, statins against cardiovascular mortality, and CRNMB in patients with AF. Accordingly, these medications should be encouraged in patients with AF when indicated. Additionally, future research should explore whether these medications should be offered to AF patients more routinely. The study was registered with Clinicaltrials.gov (unique identifier number: NCT03917992, Registration date:14/4/2019).

Patterns of adverse drug reactions in Jordan: a retrospective analysis of the National Pharmacovigilance Data Registry (2015-2021).

BACKGROUND: Post-marketing surveillance of drugs is a cornerstone of pharmacovigilance. This study was conducted to characterize patterns of adverse drug reactions (ADRs) reported in Jordan. RESEARCH DESIGN AND METHODS: ADR reports submitted to the pharmacovigilance database of the Jordan Food and Drug Administration during 2015-2021 were retrospectively analyzed. The most commonly reported drugs, drug classes, ADRs, and ADRs consequences were explored. Logistic regression identified possible predictors of reporting serious ADRs. RESULTS: A total of 2744 ADR reports were included, among which 28.4% were classified as serious. An annual increase in ADR reporting was observed. The most commonly implicated drug classes were antineoplastic and immunomodulating agents (24.0%), anti-infectives for systemic use (14.2%), and alimentary tract and metabolism (12.1%). Covid-19 vaccination was the most reported drug (22.8%). Fatigue (6.3%), injection site pain (6.1%), and headache (6.0%) were the top three common ADRs. Among ADRs with outcome information, 4.7% were fatal. Patient's age and intravenous medication use largely predicted reporting serious ADRs. CONCLUSIONS: This study provides contemporary insights into the post-marketing surveillance of drugs in Jordan. The findings are foundational for future studies exploring drug-ADRs causality relationships. Efforts that promote pharmacovigilance concepts should be sustained and enhanced at the national level.

Reporting Antimicrobial-Related Adverse Drug Events in Jordan: An Analysis from the VigiBase Database.

This study aims to assess the reporting of antimicrobial-related adverse drug events (ADEs) in Jordan between 2003 and 2022. Data regarding the antimicrobial-related ADEs were extracted from the WHO's global database (VigiBase) by the Rational Drug Use and Pharmacovigilance Department at the Jordan Food and Drug Administration (JFDA). A total of 279 Individual Case Safety Reports (ICSRs) were recorded. The number of ICSRs increased from 2019 onwards (219 out of 279 cases). This increase in the reported ADEs was influenced by the actions of the JFDA, including the introduction of electronic reporting forms, updating the national pharmacovigilance guidelines, which encouraged adverse drug reactions reporting, the implementation of the AMR-national action plan, the encouragement to report due to COVID-19 vaccine, and the continuous awareness campaigns and training programs. Skin and subcutaneous tissue disorders (n = 105; 19.48%) were the most reported antimicrobial-related ADEs. The highest number of ADEs was reported for tetracyclines (n = 101; 18.74%) followed by fluoroquinolones (n = 54; 10.02%), third-generation cephalosporines (n = 48; 8.9%), and carbapenems (n = 42; 7.79%). From the top 10 consumed antibiotics, the number of ADEs in patients who consumed Watch group antibiotics (97 ADEs) was higher than those who consumed Access group antibiotics (28 ADEs). The findings highlight the need to monitor and rationalize the use of Watch antibiotics. Enhanced reporting of antimicrobial-related adverse drug reactions is needed to inform antimicrobial stewardship and improve the pharmacovigilance system in Jordan.

Preparation of Modified Chitosan-based Nanoparticles for Efficient Delivery of Doxorubicin and/or Cisplatin to Breast Cancer Cells.

PURPOSE: The aim is to develop a novel pH-responsive modified chitosan-based nanoparticles system for active loading of doxorubicin (DOX) and triggered intracellular release. METHODS: Nanoparticles were formed in an aqueous medium via ionic interaction between negatively charged chitosan derivative and positively charged DOX at neutral pH and then transformed in situ into cisplatin (CIS) cross-linked nanoparticles through cross-linking the formed micelles via chelation interaction between the negatively charged polymeric carrier and cisplatin. Nanoparticles were characterized in terms of particle size and zeta potential using DLS and TEM. Drug loading efficiency and encapsulation efficiency were determined based on the physio-chemical proprieties of the polymer and the amount of the cross-linking agent. In vitro release studies were performed using the dialysis method at different pHs. Finally, the cytotoxic effects of these nanoparticles were performed against the MCF-7 BrCA cell line under different pHs. RESULTS: The average particle size of polymer alone and DOX nanoparticles was 277.401 ± 13.50 nm and 290.20 ± 17.43 nm, respectively. The zeta potential was -14.6 ± 1.02 mV and -13.2 ± 0.55 mV, respectively, with a low polydispersity index. Drug loading and encapsulation deficiencies were determined, dependent on the amount of the cross-linking agent. In vitro release studies showed that the release of DOX from these nanoparticles was pH-dependent. Moreover, results showed that the cytotoxicity magnitude of DOX-loaded nanoparticles against MCF-7 BrCA cells was higher compared with free DOX. CONCLUSION: These novel pH-sensitive nanoparticles proved to be a promising Nano-drug delivery for tumor-targeted delivery of DOX.

The Protective Effects of Pioglitazone Against Cognitive Impairment Caused by L-methionine Administration in a Rat Model.

PURPOSE: Accumulating evidence indicates that elevated levels of methionine are associated with cognitive decline, including loss of memory. The exact mechanisms behind this observation are not completely understood but could be related to an increase in oxidative stress markers in hippocampal tissues. The above increase in oxidative stress could be directly caused by an increase in the blood levels of methionine (hypermethioninemia) or one of its metabolites, such as homocysteine. Pioglitazone is a drug primarily used for the treatment of type 2 diabetes mellitus. Several reports showed that using pioglitazone protects against cognitive decline observed in Alzheimer's disease. Pioglitazone has antioxidant properties independent of its hypoglycemic effects. Taken together, we hypothesized that pioglitazone protects against memory loss triggered by elevated levels of methionine through lowering oxidative stress in the hippocampus. METHODS: To test this hypothesis, we used chronic administration of L-methionine in a rat model. Spatial learning and memory were evaluated in the model using a radial arm water maze (RAWM). The levels of several markers related to oxidative stress were measured in hippocampal tissues recovered from experimental rats. RESULTS: Current results showed that administration of L-methionine was associated with a significant loss of short- and long-term memory and an increase in blood homocysteine levels. The above memory changes were associated with an increase in lipid peroxidation and a decrease in the activity of catalase and glutathione peroxidase antioxidant enzymes in the hippocampus. The combined treatment of pioglitazone with L-methionine protected rat model from memory loss. It also prevented changes observed in lipid peroxidation and changes in the activity of catalase and glutathione peroxidase enzymes. CONCLUSION: Current findings indicate that pioglitazone is a viable therapeutic option that protects against cognitive changes observed upon administration of L-methionine.

Knowledge and perceptions of pharmacists' readiness during coronavirus pandemic: the case of United Arab Emirates.

BACKGROUND: With the outbreak of Coronavirus infection (COVID-19), pharmacists play an important role in supporting local health during this emergency. AIM: To assess the knowledge and to identify information sources regarding COVID-19 used by pharmacists, to investigate the active and public perceived roles of pharmacists, to explore the role of the pharmacy facilities and health authorities, and to identify barriers that would hinder pharmacists from performing their duties optimally in the United Arab Emirates. METHODS: This descriptive cross-sectional online study was conducted in the UAE during the COVID-19 outbreak, from 18 May to 20 June 2020. A validated online questionnaire addressing participants' current knowledge about pandemics and COVID-19, source of information, and their perspectives of their role was used. Participants were licensed pharmacists practising in community and hospital pharmacies in UAE, academics, and pharmacy students. RESULTS: Almost two-thirds of the participants (71.2%) were aged 18-30 years, with 76.2% females. Only 57.5% of participants believed that they got enough education about pandemics, and 88.3% of them followed on the latest coronavirus updates regarding treatments, and that is mainly from the World Health Organization reports (53.9%), followed by health authorities (44.8%). Two-thirds of participants (69.7%) had good/very good current knowledge regarding COVID-19. Knowledge of pharmacy students compared to pharmacists was significantly higher (p < 0.001). CONCLUSION: The majority of pharmacists and pharmacy students reported that they have a major role in managing pandemics executed through the community pharmacies and that it is their role to ensure the availability of key medications. Policymakers and health authorities are called upon to train pharmacists in advance of emerging situations, supporting and helping them to optimally fulfill their role.

Anticancer and antimutagenic activity of Silybum marianum L. and Eucalyptus camaldulensis Dehnh. against skin cancer induced by DMBA: In vitro and in vivo models.

The current study investigated the prospective effect of Silybum marianum L. and Eucalyptus camaldulensis Dehnh extracts against skin cancer. Skin cancer was induced by 7,12-dimethylbenz(a) anthracene (DMBA) in young Balb/c mice. Plant extracts were administered to animals orally, once/day (100mg/kg, 5 days/week) for the 20 weeks. Anticancer activity was examined via tumor progression, where antimutagenic activity was measured using 8-OHdG and sister chromatid exchange (SCE) levels. Eucalyptus camaldulensis Dehnh. leaves extract and Silybum marianum L. leaves extract significantly reduced 8-OHdG in cultured human lymphocytes in a dose-response manner (P<0.05). Similarly, the leave extracts of both plants significantly reduced chromosomal damage as measured by SCE levels (P<0.05). In the skin painting assay, the leave extracts of both plants significantly delayed the onset of tumors compared to DMBA treated group (P<0.05). The Silybum marianum leaves extract significantly reduced tumor incidence (P<0.01) and papilloma frequency (P<0.01) induced by DMBA. The Eucalyptus camaldulensis leaves extract significantly reduced the number of tumors per animal (P<0.05) and incidence of tumors (P<0.001). The in vitro and in vivo findings showed that leaves of Silybum marianum L. and Eucalyptus camaldulensis Dehnh. extracts might be a promising source for anticancer and antimutagenic agents against human cancer.

Effect of metformin on irinotecan-induced cell cycle arrest in colorectal cancer cell lines HCT116 and SW480.

OBJECTIVES: Metformin is widely used for the treatment of type 2 diabetes mellitus and found to have a crucial rule in the induction of apoptosis in several cancer types including pancreatic cell carcinoma, epithelial ovarian cancer, breast cancer, and renal cell carcinoma. In this study, we propose to explore the potential role of metformin as an adjuvant of irinotecan to target colorectal cancer (CRC) cell lines, exploring the effects underlying the anticancer properties of metformin on CRC cell lines. METHODS: HCT116 and SW480 cell lines were treated with metformin, irinotecan and their combination. The effect of metformin on cell viability was evaluated using MTT assay. Flow cytometry technique was used to analyze apoptosis and cell cycle progression. While, detection of protein expression was analyzed by Western blot. RESULTS: Metformin was found to inhibit growth in both HCT1116 and SW480 cell lines. On combination with irinotecan, it has been revealed that metformin sensitized CRC cells to irinotecan-induced cytotoxicity. Flow cytometry analysis showed that metformin did not induce apoptosis, but blocked cell cycle in G1 and S phases. This blockage was accompanied by decreased cyclin E and Cdk2 levels and increased p21 level. CONCLUSION: Combination of metformin with irinotecan may be an effective treatment strategy for targeting colorectal cancer that are resistant to irinotecan monotherapy.

An Assessment of the Impact of Coronavirus Disease (COVID-19) Pandemic on National Antimicrobial Consumption in Jordan.

Coronavirus disease 2019 (COVID-19) has overlapping clinical characteristics with bacterial respiratory tract infection, leading to the prescription of potentially unnecessary antibiotics. This study aimed at measuring changes and patterns of national antimicrobial use for one year preceding and one year during the COVID-19 pandemic. Annual national antimicrobial consumption for 2019 and 2020 was obtained from the Jordan Food and Drug Administration (JFDA) following the WHO surveillance methods. The WHO Access, Watch, and Reserve (AWaRe) classification was used. Total antibiotic consumption in 2020 (26.8 DDD per 1000 inhabitants per day) decreased by 5.5% compared to 2019 (28.4 DDD per 1000 inhabitants per day). There was an increase in the use of several antibiotics during 2020 compared with 2019 (third generation cephalosporins (19%), carbapenems (52%), macrolides (57%), and lincosamides (106%)). In 2020, there was a marked reduction in amoxicillin use (-53%), while the use of azithromycin increased by 74%. National antimicrobial consumption of the Access group decreased by 18% from 2019 to 2020 (59.1% vs. 48.1% of total consumption). The use of the Watch group increased in 2020 by 26%. The study highlighted an increase in the use of certain antibiotics during the pandemic period that are known to be associated with increasing resistance. Efforts to enhance national antimicrobial stewardship are needed to ensure rational use of antimicrobials.

Awareness of pharmacy researchers about the national research code of ethics: A study from Jordan.

OBJECTIVE: In Jordan, research ethics have been subject to increasingly formal regulations and structuring. Recently the Ministry of Higher Education and Research Published the National Research Code of Ethics. However, little is known about the awareness of pharmacology researchers of this code and the extent of its applicability to their research. METHODS: Purposeful sampling through institutions' websites was used to identify staff members with excellent profiles from 20 Faculties of Pharmacy in Jordan. After obtaining the required approvals, in-depth interviews were conducted, recorded, transcribed, and analyzed using NVivo 11 Software. The interviews followed a previously prepared and validated interview guide that covered various aspects of education, research, and training. KEY FINDINGS: Eighteen members of staff agreed to take part in the study. Qualitative analysis revealed three main themes each concerning respondents' awareness of the National Code of Research Ethics in Jordan. The emerging themes were: the lack of awareness regarding the code of ethics, the need for clear guidelines for pharmacology research in Jordan, and the need for further workshops and training courses for pharmacology researchers. CONCLUSION: This study highlights a lack of awareness regarding the presence of the National Research Ethics Code among pharmacology researchers in Jordan. This might have negative implications on medical research. It was thought that the code of ethics should be incorporated in postgraduate pharmacy education, training courses for pharmacy researchers, and workshops for pharmacy academic staff.

Positive COVID19-PCR patients as negative controls for COVID19 antibody tests.

COVID-19 serological antibody tests are recently needed for a relatively quick, affordable, and valuable assessment of the immunity toward COVID-19 infection. Furthermore, they can help with evaluating the sufficiency of the vaccination process and its longevity. There are limitations in the current approach of choosing the positive and negative control samples for the validation of those tests. Herein, we are proposing the use of blood samples from positive COVID-19 patients, at the beginning of the disease course, as negative control blood samples for the antibody tests. For more precision, both the negative and the positive control samples can be obtained from the same patients where the accuracy of the test will depend on its ability to detect the seroconversion, from negative to positive antibodies detection, within the same patient. Furthermore, when the validation of the test is accompanied by detecting/sequencing the viral genome in those COVID-19 patients, this can also aid in determining the accuracy of the test in detecting the immune response to specific viral variants. The latter notion is needed for the proper management of the COVID-19 crisis, new vaccines' manufacturing, and evaluating the vaccines' efficiencies. Finally, this approach could be requested/formulated by the regulatory agencies as part of the tests' validation and can be "in-house" obtained by health facilities before its clinical use.

Correlation Between BCL2 and Mcl1 Single Nucleotide Polymorphisms and Chemotherapy Response in Jordanian Patients with Colorectal Cancer.

BACKGROUND: Colorectal cancer is one of the most common types of cancer worldwide and a leading cause of death in Jordan. BCL-2 and MCL-1 are anti-apoptotic proteins that inhibit programmed cell death and their over-expression has been shown to be associated with reduced sensitivity to chemotherapy and poor survival in cancer patients. OBJECTIVES: In the present study, three SNPs in the promoter region of antiapoptotic genes were investigated in an effort to inspect the occurrences of SNPs (rs2279115, rs4987852) in the promoter region of BCL2 and SNP (rs9803935) in the promoter region of MCL1 in Jordanian patients with CRC, and investigate correlations between BCL2 and MCL1 SNPs and clinical outcomes. METHODS: PCR-restriction fragment length polymorphism (RFLP)-based analysis was used for samples genotyping. RESULTS: The BCL2 rs2279115 and MCL1 rs9803935 SNPs showed significant distribution where mutant and hetero genotypes are more prominent in CRC patients. Additionally, the rs2279115 genotypes and alleles were associated with stages of disease, its recurrence and metastasis. The MCL1 rs9803935 genotypes were associated disease metastasis. However, for BCL2 rs4987852 SNP, there was no association of genotypes or alleles with any of the disease variables. CONCLUSION: The BCL2 SNPs (rs2279115) and MCL1 SNP (rs9803935) present as important determinants of the progress of CRC in Jordanian patients.

High levels of leptin and non-high molecular weight-adiponectin in patients with colorectal cancer: Association with chemotherapy and common genetic polymorphisms.

Colorectal cancer (CRC) is the third most frequently diagnosed cancer worldwide. Leptin and adiponectin are hormones produced by adipose tissues, which exhibit opposing effects on tumor growth. Leptin promotes tumor development and metastasis, whereas adiponectin attenuates this. The aim of the present study was to assess the possible association between leptin and adiponectin [both high molecular weight (HMW) and non-HMW factions] levels with CRC, CRC response to chemotherapy, and to study the relationship between LEPR (rs6588147), ADIPO (rs266729), LEP (rs2167270), and ADIPO (rs822369) polymorphisms and CRC. A total of 32 blood samples collected from CRC patients were analyzed to identify the serum levels of leptin and adiponectin, and the presence of CRC related polymorphisms. A total of 25 healthy subjects were recruited in the control group. Serum levels of leptin and adiponectin were detected using ELISA whereas DNA from patients and controls was amplified and analyzed using PCR-restriction fragment length polymorphism assay. The results showed that the levels of leptin and non-HMW adiponectin were significantly higher in CRC patients compared with the controls (P<0.05). In addition, HMW adiponectin was significantly higher in patients receiving chemotherapy. The association between LEPR (rs6588147), ADIPO (rs266729), LEP (rs2167270) and ADIPO (rs822369) polymorphisms and CRC was not significant (P>0.05). In conclusion, higher leptin and non-HMW adiponectin levels may be associated with increased CRC. Chemotherapy may positively influence the levels of HMW adiponectin. No association between LEPR (rs6588147), ADIPO (rs266729), LEP (rs2167270) and ADIPO (rs822369) polymorphisms with CRC was found.

Primary health care policy and vision for community pharmacy and pharmacists in Jordan.

Jordan is considered a low middle-income country with a population of 9.956 million in 2018. It is considered the training center for healthcare professions in the region, as the Jordanian healthcare sector has seen remarkable development. In 2017, the expenditure on health as a percentage of Gross Domestic Product (GDP) was estimated to be around 8%. The healthcare sector is divided into two main sectors; the public and the private sector with both including hospitals, primary care clinics and pharmacies. The Jordanian government has a strong commitment to health and educational programs; hence, an increase in the number of pharmacy schools and pharmacy graduates has occurred in the past few years. Health authorities, such as the Jordan Food and Drug Association (JFDA) and the Jordan Pharmaceutical Association (JPA) have played an important role in ensuring the availability and affordability of medications, and has influenced the practice of pharmacists. Protecting the pharmaceutical market and professional interests, preserving pharmacists' rights, building needed cooperation with the internal federation, and maintaining professional ethics are some of the objectives for the JPA. Hence, the integration of community pharmacists into the primary healthcare system is considered vital to the different health authorities in Jordan, emphasizing the fact that community pharmacists are the most trusted, accessible, and affordable healthcare providers in the country. There have been many developments in the pharmacy practice in the past recent years, including the establishment of 'Good Pharmacy Practice', new curricular development based on the international accreditation (the ACPE), a new immunization program, and health services research aimed to save patients' lives, influence expenses, and improve patients' quality of life. Although these developments in pharmacy practice are promising, challenges continue to exist, specifically the establishment of an evidence base for pharmaceutical care services such as the medication management review service.

Chitosan Nanoparticles as a Novel Drug Delivery System: A Review Article.

Natural polymers, particularly polysaccharide, have been used as drug delivery systems for a variety of therapeutic agents such as peptides, proteins, vaccines, DNA, and drugs for parenteral and non-parenteral administration. Chitosan, the second most abundant naturally occurring polysaccharide after cellulose, is a biocompatible and biodegradable mucoadhesive polymer that is extensively used in the preparation of nanoparticles (NPs). Chitosan NPs loaded with drugs were found to be stable, permeable and bioactive. In this review, the importance of chitosan and its derivatives in drug delivery is illustrated, different methods of preparation of chitosan and chitosan derivatives NPs and their physio- chemical properties are addressed. Moreover, the desirable characteristics of successful NPs based drug delivery systems, as well as the pharmaceutical applications of these NPs are also clearly explored.

Ligand Based Pharmacophore Modeling Followed by Biological Screening Lead to Discovery of Novel PDK1 Inhibitors as Anticancer Agents.

BACKGROUND: Phosphoinositide-Dependent Kinase-1 (PDK1) is a serine/threonine kinase, which belongs to AGC kinase family required by cancer cells. METHODS: Pharmacophoric space of 86 PDK1 inhibitors using six diverse sets of inhibitors was explored to identify high-quality pharmacophores. The best combination of pharmacophoric models and physicochemical descriptors was selected by genetic algorithm-based QSAR analysis that can elucidate the variation of bioactivity within the training inhibitors. Two successful orthogonal pharmacophores emerged in the optimum QSAR equation (r2 69 = 0.90, r2 LOO= 0.86, F= 51.92, r2 PRESS against 17 test inhibitors = 0.79). Receiver Operating Characteristic (ROC) curve analyses were used to estimate the QSAR-selected pharmacophores. RESULTS: 5 out of 11 compounds tested had shown potential intracellular PDK1 inhibition with the highest inhibition percent for compounds 92 and 93 as follows; 90 and 92% PDK1 inhibition, respectively. CONCLUSION: PDK1 inhibitors are potential anticancer agents that can be discovered by combination method of ligand based design with QSAR and ROC analysis.

Investigation of Binding Characteristics of Phosphoinositide-dependent Kinase-1 (PDK1) Co-crystallized Ligands Through Virtual Pharmacophore Modeling Leading to Novel Anti-PDK1 Hits.

BACKGROUND: 3-Phosphoinositide Dependent Protein Kinase-1 (PDK1) is being lately considered as an attractive and forthcoming anticancer target. A Protein Data Bank (PDB) cocrystallized crystal provides not only rigid theoretical data but also a realistic molecular recognition data that can be explored and used to discover new hits. OBJECTIVE: This incited us to investigate the co-crystallized ligands' contacts inside the PDK1 binding pocket via a structure-based receptor-ligand pharmacophore generation technique in Discovery Studio 4.5 (DS 4.5). METHODS: Accordingly, 35 crystals for PDK1 were collected and studied. Every single receptorligand interaction was validated and the significant ones were converted into their corresponding pharmacophoric features. The generated pharmacophores were scored by the Receiver Operating Characteristic (ROC) curve analysis. RESULTS: Consequently, 169 pharmacophores were generated and sorted, 11 pharmacophores acquired good ROC-AUC results of 0.8 and a selectivity value above 8. Pharmacophore 1UU3_2_01 was used in particular as a searching filter to screen NCI database because of its acceptable validity criteria and its distinctive positive ionizable feature. Several low micromolar PDK1 inhibitors were revealed. The most potent hit illustrated anti-PDK1 IC50 values of 200 nM with 70% inhibition against SW480 cell lines. CONCLUSION: Eventually, the active hits were docked inside the PDK1 binding pocket and the recognition points between the active hits and the receptor were analyzed that led to the discovery of new scaffolds as potential PDK1 inhibitors.

Simvastatin enhances irinotecan-induced apoptosis in prostate cancer via inhibition of MCL-1.

Prostate cancer is one of the most common malignant tumors around the world. Hyperlipidemia is considered as one of the most important risk factors for the development of prostate cancer. Simvastatin is widely used for the treatment of hyperlipidemia and was previously shown to induce apoptosis in several cancer types including lung, colon, pancreas, breast, and prostate cancer. In this study we aimed to explore the potential role of simvastatin in enhancing irinotecan-induced apoptosis in prostate cancer cells. In addition, the underlying molecular mechanisms driving this potential effect of simvastatin were also explored. PC3 cells were treated with simvastatin, irinotecan or combination. Cell viability was assessed by 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) colorimetric assay. Flow cytometry technique was used to analyze apoptosis and cell cycle progression. Western blot was used for detection of protein expression. Results showed that simvastatin has a significant anti-proliferative activity on PC3 cells. Combined treatment of simvastatin with irinotecan exhibited a significant inhibition of PC3 cell growth compared to each treatment alone. Flow cytometry analysis showed that PC3 cell treatment with simvastatin and irinotecan combination demonstrated a remarkable increase in the percentage of apoptotic cells and those accumulated at G0/G1 phase when compared to each treatment alone. Moreover, induction of apoptosis was caspase-independent. Western blot showed that apoptosis was accompanied by upregulation of GRP-78 level and downregulation of Mcl-1 levels in a time-dependent manner. The results of this study demonstrated that combined treatment of simvastatin with chemotherapeutic agents such as irinotecan resulted in enhancement of growth inhibition and induction of prostate cancer cell apoptosis.

Caffeine Prevents Memory Impairment Induced by Hyperhomocysteinemia.

L-Methionine chronic administration leads to impairment of memory. This impairment is due to the increase in the body oxidative stress, which damages neurons and prevents their firing. On the other hand, caffeine has antioxidant and neuroprotective effects that could prevent impairment of memory induced by L-methionine chronic administration. In the current study, this hypothesis was evaluated. L-methionine (1.7 g/kg/day) was orally administered to animals for 4 weeks and caffeine (0.3 g/L) treatment was added to the drinking water. The radial arm water maze (RAWM) was used to test spatial learning and memory. Antioxidant biomarkers were assessed in the hippocampus tissues using biochemical assay methods. Chronic L-methionine administration induced (short- and long-) term memory impairment (P < 0.05), while caffeine treatment prevented such effect. Additionally, L-methionine treatment reduced catalase and glutathione peroxidase (GPx") enzymatic activities, and reduced glutathione (GSH) to oxidized glutathione (GSSG) ratio. These effects were normalized by caffeine treatment. Activity of superoxide dismutase (SOD) was unchanged by either L-methionine or caffeine treatments. In conclusion, L-methionine induces impairment of memory, and caffeine treatment prevented this impairment probably through affecting hippocampus antioxidant mechanisms.