Association of ABO, Rh-D and Kell blood groups with transfusion transmitted infections among blood donors from the Asir Region, Saudi Arabia: A retrospective observational study.

OBJECTIVES: To evaluate the association between transfusion-transmitted infections (TTIs) and ABO, Rh-D, and Kell blood systems among blood donors. METHODS: This was a retrospective study of 10,095 donors who visited the Blood Bank at Asir Hospital, Abha, Saudi Arabia. Data including demographic information, ABO, Rh-D, and Kell blood groups, and serological and molecular test results of TTIs (the TTIs were obtained from each donor's records). Chi-squared and Fisher's exact tests were employed to establish possible associations between blood groups and TTIs. RESULTS: The prevalence rate of TTIs among donors was 6.3%, with HBcAb (70%) being the most prevalent biomarker among positive donors. Donors with the O blood group were at a higher risk of contracting TTIs. Significant associations were observed between HIV and blood group A (χ2=6.30, p=0.01), HBsAg and group AB (χ2=17.3193, p=0.00003), malaria and group A (χ2=5.0567, p=0.02), and HBV-DNA and group AB (χ2=12.3163, p=0.0004). Also, Kell blood group was significantly associated with HIV (χ2=14.5, p=0.0001), HBcAb (χ2=78.51, p<0.0001), and syphilis (χ2=25.225, p<0.00001). CONCLUSION: ABO and Kell blood groups are associated with TTI markers. These findings highlight the need for improved strategies and approaches in screening and managing blood donations to minimize the risk of TTIs.

Chemical Profiling and Enzyme Inhibitory Activities of Essential Oil Isolated from Pistacia khinjuk Leaves: Insights On GC-MS Analysis and Skin Aging-Relevant Enzymes.

Pistacia khinjuk is a species of flowering plants belonging to family Anacardiaceae, with promising pharmacological activities like antioxidants, anti-inflammatory, antiviral, and antimicrobial. This study aimed to investigate the GC-MS chemical composition of essential oil isolated from Pistacia khinjuk leaves and its inhibitory properties against aging-relevant enzymes such a collagenase and elastase. The isolated oil showed predominance of ß-cadinene (15.34 %), γ-amorphene (8.50 %), α-cadinol (8.14 %), τ-cadinol (7.57 %), (E)-ß-caryophyllene (5.77 %), α-pinene (4.70 %), phytol (4.57 %), α-muurolene (3.30 %), (+)-epi-bicyclosesquiphellandrene (3.21 %), and cubenene (3.16 %). Further, it showed remarkable inhibitory activities against collagenase and elastase with IC50 values of 15.61±0.69 and 41.12±2.09 µg/mL, respectively compared to epigallocatechin gallate (IC50=29.52±1.3 µg/mL and 26.86±1.37 µg/mL). as a conclusion, the leaf oil is recommended for topical cosmetic preparations to retard skin aging symptoms such as wrinkles. However, the bioavailability assessment and toxicological profile should be considered in the future studies.

Low dose post-transplant cyclophosphamide and sirolimus induce mixed chimerism with CTLA4-Ig or lymphocyte depletion in an MHC-mismatched murine allotransplantation model.

Allogeneic hematopoietic cell transplantation (allo-HCT) offers a curative option for patients with certain non-malignant hematological diseases. High-dose post-transplant cyclophosphamide (PT-Cy) (200 mg/kg) and sirolimus (3 mg/kg), (HiC) synergistically induce stable mixed chimerism. Further, sirolimus and cytotoxic T lymphocyte-associated antigen-4 immunoglobulin (CTLA4-Ig), also known as Abatacept (Aba), promote immune tolerance and allograft survival. Here, in a major histocompatibility complex (MHC)-mismatched allo-HCT murine model, we combined Aba and/or T-cell depleting anti-Thy1.2 (Thy) with a lower dose of PT-Cy (50 mg/kg) and Sirolimus (3 mg/kg), (LoC). While mice in the LoC group showed graft rejection, the addition of Thy to LoC induced similar donor chimerism levels when compared to the HiC group. However, the addition of Aba to LoC led to graft acceptance only in younger mice. When Thy was added to the LoC+Aba setting, graft acceptance was restored in both age groups. Engrafted groups displayed significantly reduced frequencies of recipient-specific interferon-γ-producing T cells as well as an increased frequency in regulatory T cells (Tregs) except in the LoC+Aba group. Splenocytes from engrafted mice showed no proliferation upon restimulation with Balb/c stimulators. Collectively, in combination with Aba or Thy, LoC may be considered to reduce graft rejection in patients who undergo allo-HCT.

Sclareol exerts synergistic antidepressant effects with quercetin and caffeine, possibly suppressing GABAergic transmission in chicks.

This study evaluated the effects of sclareol (SCL) with or without caffeine (CAF) and quercetin (QUR) using in-vivo and in-silico studies. For this, 5-day-old chicks weighing between 45 and 48 g were randomly divided into five groups and treated accordingly. The chicks were monitored to compare the occurrence, latency, and duration of sleep as well as the loss and gain of righting reflex in response to SCL-10 mg/kg, CAF-10 mg/kg, and QUR-50 mg/kg using a thiopental sodium (TS)-induced sleeping model. Data were analyzed by one-way ANOVA followed by t-Student-Newman-Keuls' as a posthoc test at 95% confidence intervals with multiple comparisons. An in-silico study was also performed to investigate the possible antidepressant mechanisms of the test and/or standard drugs with different subunits of GABAA receptors. In comparison to the SCL, CAF, and QUR individual groups, SCL+CAF+QUR significantly increased the latency while decreasing the length of sleep. The incidence of loss and gain of the righting reflex was also modulated in the combination group. SCL showed better interaction with GABAA (α2 and α5) subunits than QUR with α2, α3, and α5. All these compounds showed stronger interactions with the GABAA receptor subunits than the standard CAF. Taken together, SCL, CAF, and QUR reduced the TS-induced righting reflex and sleeping time in the combination group more than in the individual treatments. SCL may show its antidepressant effects, possibly through interactions with GABAA receptor subunits.

Angiotensin Receptor Blockers Restore Skeletal Muscle in Patients with Chronic Obstructive Pulmonary Disease.

BACKGROUND: Age-related muscle decline, called sarcopenia, and hypertension are commonly observed in patients with chronic obstructive pulmonary disease (COPD). Angiotensin receptor blockers (ARBs) are common antihypertensive medications with muscle protective effects. However, the anti-sarcopenic potential and associated mechanisms of ARBs in hypertensive patients with COPD are unknown. OBJECTIVES: We aimed to investigate the potential contribution of neuromuscular junction (NMJ) stability as a driving mechanism of ARBs-induced muscle protection. METHODS: We categorized 236 patients with COPD into normotensive (n = 79) and hypertensive, based on treatment with ARB (n = 82), and other antihypertensive drugs (n = 75). Hypertensive patients with COPD were evaluated at two time points one year apart. Handgrip strength (HGS), body composition, short physical performance battery (SPPB), and plasma c-terminal agrin fragment-22 (CAF22) as a marker of NMJ degradation were measured. RESULTS: Patients with COPD exhibited reduced HGS and SPPB scores, and higher levels of CAF22 than controls, regardless of hypertension status. ARBs treatment improved HGS and gait speed and reduced plasma CAF22 levels in hypertensive patients with COPD (all p <0.05). ARBs also prevented the decline in SPPB components, including maintaining balance, gait speed, and the ability to rise from a chair in hypertensive patients with COPD (all p <0.05). We also found dynamic associations of plasma CAF22 with HGS, gait speed, and SPPB scores in hypertensive patients with COPD. CONCLUSIONS: Altogether, ARB treatment preserves skeletal muscle health and functional capacity in hypertensive patients with COPD by reducing plasma CAF22 and possibly repairing NMJs.

A leaky gut contributes to postural dysfunction in patients with Alzheimer's disease.

Background: Postural dysfunction is a common problem in patients with Alzheimer's disease (AD) and may lead to functional dependency and increasing morbidity and mortality. However, the pathophysiology of postural dysfunction in AD patients remains poorly understood. Objectives: Elevated intestinal permeability is an underlying contributor to multiple diseases, including AD. We aimed to investigate the association of elevated intestinal permeability with postural dysfunction in AD patients. Design Setting Participants Measurements: We conducted a cross-sectional, observational study on older adults, including controls and AD patients. We investigated the associations of postural balance with plasma zonulin, a marker of elevated intestinal permeability in geriatric controls (n = 74) and patients with mild (n = 71) and moderate (n = 66) AD. We used a standardized physical performance battery to measure balance in supine, tandem, and semi-tandem positions. We also measured handgrip strength (HGS), and gait speed as markers of physical capacity. Results: AD patients exhibited lower balance scores, HGS, and gait speed and higher plasma zonulin than in controls (all p < 0.05). Plasma zonulin levels demonstrated significant areas under the curves in diagnosing poor balance in AD patients (all p < 0.05). Moderate AD was associated with lower balance and physical capacity, and higher zonulin than mild AD (ALL P < 0.05). Poor scores on balance scale were associated with higher expressions of markers of inflammation, oxidative stress, and muscle damage providing a mechanistic link between increased intestinal permeability and postural dysfunction in AD patients. Conclusion: The results of our study show that plasma zonulin measurement may be used to diagnose postural dysfunction in AD patients. The study is relevant to non-ambulant and/or comatose AD patients with postural dysfunction. Our findings also highlight the therapeutic potential of repairing the intestinal leak to improve postural control and reduce the risk of falls in AD patients.

Anticancer Potential of the Plant-Derived Saponin Gracillin: A Comprehensive Review of Mechanistic Approaches.

With the increasing prevalence of cancer and the toxic side effects of synthetic drugs, natural products are being developed as promising therapeutic approaches. Gracillin is a naturally occurring triterpenoid steroidal saponin with several therapeutic activities. It is obtained as a major compound from different Dioscorea species. This review was designated to summarize the research progress on the anti-cancer activities of gracillin focusing on the underlying cellular and molecular mechanisms, as well as its pharmacokinetic features. The data were collected (up to date as of May 1, 2023) from various reliable and authentic literatures comprising PubMed, Springer Link, Scopus, Wiley Online, Web of Science, ScienceDirect, and Google Scholar. The findings demonstrated that gracillin displays promising anticancer effects through various molecular mechanisms, including anti-inflammatory effects, apoptotic cell death, induction of oxidative stress, cytotoxicity, induction of genotoxicity, cell cycle arrest, anti-proliferative effect, autophagy, inhibition of glycolysis, and blocking of cancer cell migration. Additionally, this review highlighted the pharmacokinetic features of gracillin, indicating its lower oral bioavailability. As a conclusion, it can be proposed that gracillin could serve as a hopeful chemotherapeutic agent. However, further extensive clinical research is recommended to establish its safety, efficacy, and therapeutic potential in cancer treatment.

Predictive value of ferritin, glucose, urea, and creatinine for COVID-19 severity and mortality in patients from Asir, Saudi Arabia.

OBJECTIVES: To correlate demographics, blood groupings, and laboratory characteristics of hospitalized COVID-19 patients with disease severity and outcomes. METHODS: This study included 294 COVID-19 patients. Data on patient age, gender, laboratory results, clinical severity, mortality, comorbidities, and blood group were obtained from medical records retrospectively. RESULTS: High levels of ferritin (p<0.01), urea (p<0.0001), and creatinine (p<0.05) were detected in intensive care unit (ICU)-admitted patients. Ferritin (p<0.05), glucose (p<0.0001), urea (p<0.0001), and creatinine (p<0.0001) were significantly higher in non-survivor compared to survivor COVID-19 patients. Predictors for ICU admission among patients were ferritin (odd ratio [OR]=0.999, p=0.0055) and urea (OR=0.991, p=0.0001). Predictors for mortality were: age (OR=0.963, p=0.0001), ferritin (OR=0.999, p=0.0149), glucose (OR=0.993, p=0.0001), urea (OR=0.976, p=0.0001), and creatinine (OR=0.556, p=0.0001). The most reliable laboratory parameters in predicting mortality were: age (area under the curve [AUC]=0.685, p<0.0001), ferritin (AUC=0.610, p<0.05), glucose (AUC=0.681, p<0.0001), urea (AUC=0.856, p<0.0001), and creatinine (AUC=0.823, p<0.0001). CONCLUSION: High ferritin, glucose, urea, and creatinine levels may predict poor outcomes in COVID-19 patients. These findings could help predict admissions to the ICU and mortality among such patients.

Estimating the prevalence of pediatric hematological malignancies in Al-Madinah Al-Munawwarah, Saudi Arabia.

OBJECTIVES: To provide an updated estimate to the prevalence of pediatric hematological malignancies (HMs) in the Al-Madinah Al-Munawwara, Saudi Arabia. METHODS: This is a retrospective study that was carried out between 2016 and 2022. The study population was comprised of 171 children under 16 who had been diagnosed with HMs. The data was compiled from King Salman Medical City's Maternity and Children's Hospital, Al-Madinah Al-Munawwarah, Saudi Arabia. RESULTS: Among the 171 HM patients (64% males and 36% females), 13 subtypes were identified, with B-cell acute lymphoblastic leukemia having the highest incidence (70.3%). Acute myelomonocytic leukemia (8.7%), T-cell acute lymphoblastic leukemia (4.7%), and acute promyelocytic leukemia (3.5%) were the next most common types of HMs. Other rare cases were also found. CONCLUSION: Prevalence rate can be utilized to monitor the progression of disease incidence. Here, HMs demonstrated a pattern of increasing incidence in males over a 7-year period, with a higher rate in early childhood. There were 13 types of HMs diagnosed, with B-acute lymphocytic leukemia having the highest incidence. Although juvenile cancer is rare, it is nonetheless a significant cause of mortality in children. A successful prognosis requires prompt and accurate diagnosis and treatment.

Anticancer Potentials of the Lignan Magnolin: A Systematic Review.

Magnolin is a naturally occurring, multi-bioactive lignan molecule with inherent anticancer effects. This study aims to summarize the botanical origins and anticancer properties of magnolin. For this, a recent (as of March 2023) literature review was conducted using various academic search engines, including PubMed, Springer Link, Wiley Online, Web of Science, Science Direct, and Google Scholar. All the currently available information about this phytochemical and its role in various cancer types has been gathered and investigated. Magnolin is a compound found in many different plants. It has been demonstrated to have anticancer activity in numerous experimental models by inhibiting the cell cycle (G1 and G2/M phase); inducing apoptosis; and causing antiinvasion, antimetastasis, and antiproliferative effects via the modulation of several pathways. In conclusion, magnolin showed robust anticancer activity against many cancer cell lines by altering several cancer signaling pathways in various non- and pre-clinical experimental models, making it a promising plant-derived chemotherapeutic option for further clinical research.

Prevalence, hematological parameters, and coagulation profiles: Cardiovascular diseases statistics in the Asir region, Saudi Arabia.

OBJECTIVES: To determine the prevalence of cardiovascular disease (CVD) types in the Asir region of Saudi Arabia and the importance of hematological testing for CVD patients in the context of disease management. METHODS: This retrospective study comprised 416 CVD patients, and samples were divided based the type of CVD. The Mann Whitney U test was used to compare patients' hematological markers and coagulation profiles to those of healthy controls. RESULTS: The rate of ischemic heart disease (IHD) was 80.7% that of other CVDs, and the rate of ST-elevation myocardial infarction (STEMI) was 37.3% the rate of CVD. Significant differences were observed in the hematological and coagulation parameters of CVD patients compared to the control group. White blood cells (WBC) were significantly higher in STEMI, non-ST-elevation myocardial infarction (NSTEMI), unstable angina (UA), and heart failure (HF) groups. Red blood cells (RBC) were significantly lower in STEMI, NSTEMI, UA, chronic coronary syndrome (CCS), HF, dilated cardiomyopathy (DCM), and ischemic cardiomyopathy (ICM). Red distribution width (RDW) was significantly greater in the HF, DCM, and ICM groups. Prothrombin time (PT) was significantly higher in the STEMI, HF, and DCM groups. CONCLUSION: ST-elevation myocardial infarction has a higher prevalence rate among CVD patients in the Asir region. Both coagulation and hematological indicators have high potential utility as CVD diagnostic and prognostic markers.

Computational modeling and in vitro evaluation identified natural product-Z218 as a novel Janus kinase 2 (JAK2) inhibitor to combat ß-thalassemia.

Aberrant activity of Janus kinase 2 (JAK2) is a known driver of several myeloproliferative disorders, including polycythemia vera, and thalassemia. Several inhibitors have been proposed to inhibit JAK2 activity in order to control the disease progression. Ruxolitinib and fedratinib that targets JAK2 kinase have been approved for use in myeloproliferative neoplasms patients. Experimental structures of JAK2 complexed with ruxolitinib provide insights into critical interactions of ruxolitinib. In this work, using a high-throughput virtual screening followed by experimental validations, we have identified a novel natural product from ZINC database that interacts with JAK2 in a manner similar to ruxolitinib and inhibits the activity of JAK2 kinase. Molecular dynamics simulations and MMPBSA method show binding dynamics and stability of our identified lead compound. Kinase inhibition assays show that our identified lead molecule inhibits JAK2 kinase at a nanomolar range, indicating a plausibility that the identified lead molecule can be further studied as natural product inhibitor of JAK2 kinase.

Computational and Preclinical Analysis of 2-(4-Methyl)benzylidene-4,7-dimethyl Indan-1-one (IPX-18): A Novel Arylidene Indanone Small Molecule with Anti-Inflammatory Activity via NF-κB and Nrf2 Signaling.

Background: The adverse effects of anti-inflammatory drugs urges the search for new anti-inflammatory agents. This study aims at the preclinical analysis of the in-house synthesized small molecule IPX-18. Human whole blood (HWB), peripheral blood mononuclear cells (PBMCs), and neutrophils were used. Rat basophil cells (RBL-2H3) were used to assess degranulation. Binding stability to NF-κB-p50 was predicted using computational docking and molecular dynamic simulations. Essential signaling proteins were evaluated through flow cytometry. Results: IPX-18 inhibited the release of TNF-α with an IC50 value of 298.8 nM and 96.29 nM in the HWB and PBMCs, respectively. The compound depicted an IC50 value of 217.6 nM in the HWB and of 103.7 nM in the PBMCs for IFN-γ inhibition. IL-2 release and IL-8 release were inhibited by IPX-18 in the HWB and PBMCs. The compound controlled the migration of and the elastase in the activated neutrophils. The IC50 value for basophil activation through the FcεRI receptor assay was found to be 91.63 nM. IPX-18 inhibited RBL-2H3-degranulation with an IC50 value of 98.52 nM. The computational docking analysis predicted that IPX-18 would effectively bind NF-κB-p50. NF-κB-phosphorylation in the activated RBL-2H3 cells was decreased, and the levels of nuclear factor erythroid 2-related factor 2 (Nrf2) were increased with IPX-18 treatment. Conclusions: IPX-18 demonstrated efficacy in mediating the effector cells' inflammatory responses through NF-κB/Nrf2 signaling.

Epithelial Cell Adhesion Molecule (EpCAM) Expression Can Be Modulated via NFκB.

The epithelial cell adhesion molecule (EpCAM) is considered an essential proliferation signature in cancer. In the current research study, qPCR induced expression of EpCAM was noted in acute lymphoblastic leukemia (ALL) cases. Costunolide, a sesquiterpene lactone found in crepe ginger and lettuce, is a medicinal herb with anticancer properties. Expression of EpCAM and its downstream target genes (Myc and TERT) wasdownregulated upon treatment with costunolide in Jurkat cells. A significant change in the telomere length of Jurkat cells was not noted at 72 h of costunolide treatment. An in silico study revealed hydrophobic interactions between EpCAM extracellular domain and Myc bHLH with costunolide. Reduced expression of NFκB, a transcription factor of EpCAM, Myc, and TERT in costunolide-treated Jurkat cells, suggested that costunolide inhibits gene expression by targeting NFκB and its downstream targets. Overall, the study proposes that costunolide could be a promising therapeutic biomolecule for leukemia.

Thrombospondin-1, Platelet Factor 4, and Galectin-1 Are Associated with Engraftment in Patients with Sickle Cell Disease who Underwent Haploidentical Hematopoietic Stem Cell Transplantation.

Sickle cell disease (SCD) is an inherited red blood cell disorder that leads to significant morbidity and early mortality. The most widely available curative approach remains allogeneic hematopoietic stem cell transplantation (HSCT). HLA-haploidentical (haplo) HSCT expands the donor pool considerably and is a practical alternative for these patients, but traditionally with an increased risk of allograft rejection. Biomarkers in patient plasma could potentially help predict HSCT outcome and allow treatment at an early stage to reverse or prevent graft rejection. Reliable, noninvasive methods to predict engraftment or rejection early after HSCT are needed. We sought to detect variations in the plasma proteomes of patients who engrafted compared with those who rejected their grafts. We used a mass spectrometry-based proteomics approach to identify candidate biomarkers associated with engraftment and rejection by comparing plasma samples obtained from 9 engrafted patients and 10 patients who experienced graft rejection. A total of 1378 proteins were identified, 45 of which were differentially expressed in the engrafted group compared with the rejected group. Based on bioinformatics analysis results, information from the literature, and immunoassay availability, 7 proteins-thrombospondin-1 (Tsp-1), platelet factor 4 (Pf-4), talin-1, moesin, cell division control protein 42 homolog (CDC42), galectin-1 (Gal-1), and CD9-were selected for further analysis. We compared these protein concentrations among 35 plasma samples (engrafted, n = 9; rejected, n = 10; healthy volunteers, n = 8; nontransplanted SCD, n = 8). ELISA analysis confirmed the significant up-regulation of Tsp-1, Pf-4, and Gal-1 in plasma samples from engrafted patients compared with rejected patients, healthy African American volunteers, and the nontransplanted SCD group (P < .01). By receiver operating characteristic analysis, these 3 proteins distinguished engrafted patients from the other groups (area under the curve, >0.8; P < .05). We then evaluated the concentration of these 3 proteins in samples collected pre-HSCT and at days +30, +60, +100, and +180 post-HSCT. The results demonstrate that Tsp-1 and Pf-4 stratified engrafted patients as early as day 60 post-HSCT (P < .01), and that Gal-1 was significantly higher in engrafted patients as early as day 30 post-HSCT (P < .01). We also divided the rejected group into those who experienced primary (n = 5) and secondary graft rejection (n = 5) and found that engrafted patients had significantly higher Tsp-1 levels compared with patients who developed primary graft rejection at days +60 and +100 (P < .05), as well as higher Pf-4 levels compared with patients who developed primary graft rejection at post-transplantation (PT) day 100. Furthermore, Tsp-1 levels were significantly higher at PT days 60 and 100 and Pf-4 levels were higher at PT day 100 in engrafted patients compared with those who experienced secondary graft rejection. Increased concentrations of plasma Gal-1, Tsp-1, and Pf-4 could reflect increased T regulatory cells, IL-10, and TGF-ß, which are essential players in the initiation of immunologic tolerance. These biomarkers may provide opportunities for preemptive intervention to minimize the incidence of graft rejection.

A Combined Chemical, Computational, and In Vitro Approach Identifies SBL-105 as Novel DHODH Inhibitor in Acute Myeloid Leukemia Cells.

Inhibition of the dihydroorotate dehydrogenase (DHODH) has been successful at the preclinical level in controlling myeloid leukemia. However, poor clinical trials warrant the search for new potent DHODH inhibitors. Herein we present a novel DHODH inhibitor SBL-105 effective against myeloid leukemia. Chemical characteristics were identified by 1H NMR, 13C NMR, and mass spectroscopy. Virtual docking and molecular dynamic simulation analysis were performed using the automated protocol with AutoDock-VINA, GROMACS program. Human-recombinant (rh) DHODH was used for enzyme inhibition study. THP-1, TF-1, HL-60, and SKM-1 cell lines were used. MTT assay was used to assess cell viability. Flow cytometry was employed for cell cycle, apoptosis, and differentiation analysis. Chemical analysis identified the compound to be 3-benzylidene-6,7-benz-chroman-4-one (SBL-105). The compound showed high binding efficacy toward DHODH with a Gbinding score of 10.9 kcal/mol. Trajectory analysis indicated conserved interactions of SBL-105DHODH to be stable throughout the 200-ns simulation. SBL-105 inhibited rh DHODH with an IC50 value of 48.48 nM. The GI50 values of SBL-105 in controlling THP-1, TF-1, HL-60, and SKM-1 cell proliferations were 60.66, 45.33, 73.98, and 86.01 nM, respectively. A dose-dependent increase in S-phase cell cycle arrest and total apoptosis was observed by SBL-105 treatment in both cell types, which were reversed in the presence of uridine. The compound also increased the differentiation marker CD11b-positive populations in both THP-1 and TF-1 cells, which were decreased under uridine influence. SBL-105, a novel DHODH inhibitor, identified using computational and in vitro analysis, was effective in controlling AML cells and needs attention for further preclinical developments.

Computational high-throughput screening and in vitro approaches identify CB-006-3; A novel PI3K-BRAFV600E dual targeted inhibitor against melanoma.

Malignant melanoma is characterized by both genetic and molecular alterations that activate phosphoinositide 3-kinase (PI3K), and RAS/BRAF pathways. In this work, through diversity-based high-throughput virtual screening we identified a lead molecule that selectively targets PI3K and BRAFV600E kinases. Computational screening, Molecular dynamics simulation and MMPBSA calculations were performed. PI3K and BRAFV600E kinase inhibition was done. A375 and G-361 cells were used for in vitro cellular analysis to determine antiproliferative effects, annexin V binding, nuclear fragmentation and cell cycle analysis. Computational screening of small molecules indicates compound CB-006-3 selectively targets PI3KCG (gamma subunit), PI3KCD (delta subunit) and BRAFV600E. Molecular dynamics simulation and MMPBSA bases binding free energy calculations predict a stable binding of CB-006-3 to the active sites of PI3K and BRAFV600E. The compound effectively inhibited PI3KCG, PI3KCD and BRAFV600E kinases with respective IC50 values of 75.80, 160.10 and 70.84 nM. CB-006-3 controlled the proliferation of A375 and G-361 cells with GI50 values of 223.3 and 143.6 nM, respectively. A dose dependent increase in apoptotic cell population and sub G0/G1 phase of cell cycle were also observed with the compound treatment in addition to observed nuclear fragmentation in these cells. Furthermore, CB-006-3 inhibited BRAFV600E, PI3KCD and PI3KCG in both melanoma cells. Collectively, based on the computational modeling and in vitro validations, we propose CB-006-3 as a lead candidate for selectively targeting PI3K and mutant BRAFV600E to inhibit melanoma cell proliferation. Further experimental validations, including pharmacokinetic evaluations in mouse models will identify the druggability of the proposed lead candidate for further development as a therapeutic agent for treating melanoma.

Early and late effects of therapeutic plasma exchange in patients with systemic lupus erythematosus and antineutrophil cytoplasmic antibody-associated vasculitis: A single-center experience.

Therapeutic plasma exchanges (TPE) is considered as one of the treatment modalities that is used in systemic autoimmune diseases. This study aimed to describe the early and late effect of TPE in patients with systemic lupus erythematosus (SLE) and antineutrophil cytoplasmic antibody-associated vasculitis (AAV) presented with acute kidney injury (AKI). Retrospective study comprised patients with SLE and AAV with AKI seen between January 2000 and June 2014 at King Faisal Specialist Hospital and Research Center in Riyadh. All patients underwent TPE. Retrospectively, all patients were assessed for early and late renal outcome at 12- month and 24-month intervals. Renal outcome was assessed according to serum creatinine level, glomerular filtration rate, active urine sediment, and proteinuria. P <0.05 was considered significant. A total of 68 patients were included, 58 patients (51 females) had SLE and 10 patients (7 females) had AAV completed TPE. All patients had active disease and had AKI. At the first 12 months, 18 patients (17 SLE and 1 AAV) showed complete response and 14 patients had partial response while 22 patients did not show therapeutic benefit. The nonresponders (22 patients) entered the late assessment interval (24 months) without any therapeutic response. Statistically, there was no significant difference between the patient's response to TPE at the first and second assessment intervals and the baseline serum creatinine level. TPE might be an alternative rescue treatment in lupus nephritis with AKI.

Outcome of adult Saudi patients with childhood-onset systemic lupus erythematosus.

OBJECTIVES: We aimed to describe the social, educational, employment and long-term clinical outcomes of adults with childhood-onset systemic lupus erythematosus (SLE) in a Saudi cohort. METHODS: All adult patients with childhood-onset SLE who were treated and had regular follow-up between 1990 and 2013 at King Faisal Specialist Hospital and Research Centre (KFSH-RC), Riyadh were included. The long-term outcome measures comprised SLE Disease Activity and Damage Indices at the last follow-up visit and death related to SLE. Social, educational and employment history were obtained via personal or phone interviews. RESULTS: Forty-eight patients (45 female) were included, whose mean age was 23.6±4 years and mean disease duration 15±4 years. At the last follow-up visit, 24 (50%) patients were found to have active disease with mean of accrual damage index of 2 (0-7). Forty patients (83%) had renal involvement, 7 (15%) of them progressed to end stage renal disease, 5 patients underwent renal transplant, 2 failed the transplant and are currently on haemodialysis. Sixteen patients had central nervous system involvement in the form of seizure disorder (6 patients), chorea (3 patients) and cerebrovascular accident (3 patients). Forty-three patients completed high school and 21 joined a college. Six patients were in employment. Eight patients got married and 5 of them had children. There were 3 deaths related to SLE (6.25%), mainly due to infection. CONCLUSIONS: Our cohort indicates that the outcome of adult Saudi patients with childhood-onset SLE was satisfactory and comparable to earlier reports.

Updated recommendations for the diagnosis and management of osteoporosis: a local perspective.

Postmenopausal osteoporosis and osteoporosis in elderly men are major health problems, with a significant medical and economic burden. Although osteopenia and osteoporosis are more common locally than in the West, fracture rates are generally less than in Western countries. Vitamin D deficiency is common in the region and contributes adversely to bone health. Vitamin D deficiency should be suspected and treated in all subjects with ostopenia or osteoporosis. The use of risk factors to determine fracture risk has been adopted by the World Health Organization and many international societies. Absolute fracture risk methodology improves the use of resources by targeting subjects at higher risk of fractures for screening and management. The King Faisal Specialist Hospital Osteoporosis Working Group recommends screening for women 65 years and older and for men 70 years and older. Younger subjects with clinical risk factors and persons with clinical evidence of osteoporosis or diseases leading to osteoporosis should also be screened. These guidelines provide recommendations for treatment for postmenopausal women and men older than 50 years presenting with osteoporotic fractures for persons having osteoporosis-after excluding secondary causes-or for persons having low bone mass and a high risk for fracture. The Working Group has suggested an algorithm to use at King Faisal Specialist Hospital that is based on the availability, cost, and level of evidence of various therapeutic modalities. Adequate calcium and vitamin D supplement are recommended for all. Weekly alendronate (in the absence of contraindications) is recommended as first-line therapy. Alternatives to alendronate are raloxifene or strontium ranelate. Second-line therapies are zoledronic acid intravenously once yearly, when oral therapy is not feasible or complicated by side effects, or teriparatide in established osteoporosis with fractures.