Fahad M. Almutairi

Inhibitors of apoptosis: clinical implications in cancer

Inhibitor of apoptosis (IAP) family comprises a group of endogenous proteins that function as main regulators of caspase activity and cell death. They are considered the main culprits in evasion of apoptosis, which is a fundamental hallmark of carcinogenesis. Overexpression of IAP proteins has been documented in various solid and hematological malignancies, rendering them resistant to standard chemotherapeutics and radiation therapy and conferring poor prognosis. This observation has urged their exploitation as therapeutic targets in cancer with promising pre-clinical outcomes. This review describes the structural and functional features of IAP proteins to elucidate the mechanism of their anti-apoptotic activity. We also provide an update on patterns of IAP expression in different tumors, their impact on treatment response and prognosis, as well as the emerging investigational drugs targeting them. This aims at shedding the light on the advances in IAP targeting achieved to date, and encourage further development of clinically applicable therapeutic approaches.

Cytochrome P450: Polymorphisms and Roles in Cancer, Diabetes and Atherosclerosis

Cytochromes P450s (CYPs) constitute a superfamily of enzymes that catalyze the metabolism of drugs and other substances. Endogenous substrates of CYPs include eicosanoids, estradiol, arachidonic acids, cholesterol, vitamin D and neurotransmitters. Exogenous substrates of CYPs include the polycyclic aromatic hydrocarbons and about 80% of currently used drugs. Some isoforms can activate procarcinogens to ultimate carcinogens. Genetic polymorphisms of CYPs may affect the enzyme catalytic activity and have been reported among different populations to be associated with various diseases and adverse drug reactions. With regard of drug metabolism, phenotypes for CYP polymorphism range from ultrarapid to poor metabolizers. In this review, we discuss some of the most clinically important CYPs isoforms (CYP2D6, CYP2A6, CYP2C19, CYP2C9, CYP1B1 and CYP1A2) with respect to gene polymorphisms and drug metabolism. Moreover, we review the role of CYPs in renal, lung, breast and prostate cancers and also discuss their significance for atherosclerosis and type 2 diabetes mellitus.

Induction of apoptosis by pyrazolo[3,4-d]pyridazine derivative in lung cancer cells via disruption of Bcl-2/Bax expression balance

In the rapidly expanding era of cancer target therapy, regulators of apoptosis are emerging as attractive therapeutic targets. X-linked inhibitor of apoptosis (XIAP) is of specific interest owing to its characteristic overexpression in a wide variety of neoplasms, with a resultant survival advantage for tumor cells and treatment resistance. In this study, we examined three pyrazolo [3,4-d] pyridazine derivatives (PPDs) through molecular modeling and studied their modes of interaction with XIAP-BIR3 domain. PPD-1, which possessed the highest binding affinity with XIAP, was tested on A549 (lung cancer cell line); HCT-116 (colorectal carcinoma cell line); HEPG2 (liver carcinoma cell line), HFB4 (normal human skin melanocyte cell line) and WI-38 (human embryonic lung fibroblasts). In comparison to cisplatin as a positive control, PPD-1 yielded remarkable cytotoxicity on all cancer cell lines, with the highest anti-tumor activity on A549 and a favorable therapeutic ratio. Flow cytometry studies concluded that PPD-1 treatment induces Sub G1 and G2/M cell cycle arrest and apoptosis. The percentage of apoptotic cells in PPD-1 treated A549 cells was considerably higher than that in untreated cells (10.06% vs 0.57%, respectively). To further investigate the mechanism of induction of apoptosis by PPD-1, Real time-PCR was used to quantify the expression levels of key apoptotic regulators. Significant overexpression of the effector capsase-3, pro-apoptotic bax and tumor suppressor gene p53 were noted as compared to untreated cells (7.19 folds, 7.28 folds, and 5.08 folds, respectively). Moreover, PPD-1 inhibited the expression of the anti-apoptotic bcl-2 gene to 0.22 folds. These findings demonstrate that PPD-1 treatment disrupts the Bcl-2/BAX balance in lung cancer cell lines, leading to apoptosis induction possibly through intrinsic mitochondria-dependent pathway. These novel insights elucidate the mechanism of PPD-1 cytotoxicity in lung cancer cell lines and offer a promising therapeutic approach that needs further study.

Biophysical insights into the interaction of clofazimine with human alpha 1-acid glycoprotein: A multitechnique approach

Alpha1-acid glycoprotein (AAG) is a major acute phase protein of human plasma. Binding of clofazimine to AAG is investigated using optical spectroscopy and molecular docking tools. We found significant quenching of intrinsic fluorescence of AAG upon the binding of clofazimine, binding mode is static with binding constant of 3.52 × 104at 298 K. The Gibbs free energy change is found to be negative for the interaction of clofazimine with AAG indicating spontaneity of the binding process. Binding of clofazimine induced ordered structure in protein and lead to molecular compaction. Molecular docking results indicate the binding site is located in the central beta barrel, hydrogen bonding and hydrophobic interactions are main bonding forces between AAG–clofazimine.

Urinary biomarkers for early detection of platinum based drugs induced nephrotoxicity

BackgroundNephrotoxicity is a major hazard complicating the use of platinum based drugs (PBD), which can hinder using higher doses protocols to maximize the therapeutic gain. Shortage of serum creatinine level as an accurate biomarker for acute kidney injuries (AKI) necessitates searching for novel biomarkers with better sensitivity and specificity in patients on PBD.MethodsIn a prospective cohort design, 132 patients receiving PBD were selected for the study. AKI was diagnosed by continuous follow up of serum creatinine level according to Kidney Disease: Improving Global Outcomes (KDIGO) guidelines 2012. Serum creatinine and urinary biomarkers (KIM-1, NGAL and cystatin C) was measured in the day of treatment and for 3xa0days after PBD cycle.ResultsAKI occurred in 35 patients (26.52% of patients). KIM-1, Cystatin C, and NGAL showed significant increase in samples collected in the day of AKI in comparison to their corresponding basal levels (Pu2009<u2009xa00.0001). In addition, significant increase in urinary levels of the biomarkers in samples collected 1xa0day before AKI in comparison to their basal levels (Pu2009<u2009xa00.0001, Pu2009<u2009xa00.0001, and Pu2009=u20090.013 for KIM-1, NGAL and Cystatin C respectively). Furthermore KIM-1 data showed a significant increase 2xa0days before serum creatinine rise in comparison to the corresponding KIM-1 levels in patients who developed AKI (Pu2009=u20090.001).ConclusionsUrinary KIM-1, Cystatin C and NGAL can predict PBD induced AKI in earlier stages than serum createnine. KIM-1 is the most sensitive biomarker for early detection of AKI in patients receiving PBD.

Analysis of patients with end-stage renal disease on dialysis in Tabuk City, Saudi Arabia: A single-center, three-year retrospective study

This study was performed to analyze various demographic data such as age, gender, nationality, status of the patients, and the causes of end-stage renal disease (ESRD) of 349 patients who were undergoing hemodialysis (HD) during the period from January 2013 to December 2015 at the Dialysis Center of King Khalid Hospital in Tabuk City. One hundred and fifty-two patients (43.6%) were on HD in 2015. Age of the patients ranged from 9 to 93 years and the mean age was 51.3 ± 17.6 years. Majority of the patients, i.e., 140 (40.1%) were in the age group of 40-59 years, followed by the age group of 60-79 years by 27.8% (97 patients). Saudis constituted 84.2% (294) and non-Saudis accounted 15.8% (55) of the patients over the years studied. There were 198 males (56.7%) and 151 females (43.3%). The death rate in 2014 was 6.2%, whereas it increased in 2015 to 10.5%. The high escape rate (10.3%) of patients was in 2014. Diabetic nephropathy was the most common cause of ESRD, accounting for 30.4% of all cases, followed by unknown etiologies accounting for 25.2%. Nearly 22.6% of all ESRD cases had hypertension. Primary glomerular disease was seen in 8.9% and obstructive uropathy in 3.7%. Other causes constituted 7.4% of the cases. The data of ERSD patients in Tabuk City are comparable with that of other regions of the Kingdom of Saudi Arabia. We conclude that analysis studies of HD centers help to understand the problems and the needs of the patients, find the solutions, and create a connection between the consumers and health-care providers.

Certain investigations on water treatment processes for healthy life-review

To live in the world, water is an essential need to everyone. On other hand, to have a healthy life purified water is required for all. In connection with that, this paper has presented a novel survey about the membrane filtration technologies which is using for purifying the water and treating the waste water. MWTS (Membrane Water Treatment Systems) is mainly used for purifying the water, in terms of removing microorganisms, particulates and natural organic materials that foul waters taste and purification. The paper is segregated into four divisions that, Micro Filtration (MF), Ultra Filtration (UF), Nano Filtration (NF) and Reverse osmosis (RO).

Aspects of the Analytical Ultracentrifuge Determination of the Molar Mass Distribution of Polysaccharides

Molar mass or ‘molecular weight’ is one of the most fundamental parameters describing a macromolecule. Because of their polydisperse nature, polysaccharides are usually described by distributions of molar mass. SEC-MALS (size exclusion chromatography coupled to multi-angle light scattering) is often a convenient method of choice, but there are many instances where it is unsuitable. Modern AUC (analytical ultracentrifuge) methods provide a valuable alternative – now easier to use than before – and, after briefly reviewing some older procedures, we highlight two recently published and complementary methods, namely, the ‘Extended Fujita’ approach for the analysis of sedimentation velocity data and SEDFIT-MSTAR for the analysis of sedimentation equilibrium data. Nonideality needs to be considered and can be dealt with in a standard way. These methods can also indicate if associative phenomena are present, which can then be quantified using more complex AUC algorithms.