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Plumbagin (5-hydroxy-2-methyl-1,4-naphthoquinone) is a naphthoquinone derivative from the roots of plant Plumbago zeylanica and belongs to one of the largest and diverse groups of plant metabolites. The anticancer and antiproliferative activities of plumbagin have been observed in animal models as well as in cell cultures. Plumbagin exerts inhibitory effects on multiple cancer-signaling proteins, however, the binding mode and the molecular interactions have not yet been elucidated for most of these protein targets. The present study is the first attempt to provide structural insights into the binding mode of plumbagin to five cancer signaling proteins viz. PI3Kγ, AKT1/PKBα, Bcl-2, NF-κB, and Stat3 using molecular docking and (un)binding simulation analysis. We validated plumbagin docking to these targets with previously known important residues. The study also identified and characterized various novel interacting residues of these targets which mediate the binding of plumbagin. Moreover, the exact modes of inhibition when multiple mode of inhibition existed was also shown. Results indicated that the engaging of these important interacting residues in plumbagin binding leads to inhibition of these cancer-signaling proteins which are key players in the pathogenesis of cancer and thereby ceases the progression of the disease.

Background Breast cancer brain metastases (BCBM) develop in about 20–30% of breast cancer (BC) patients. BCBM are associated with dismal prognosis not at least due to lack of valuable molecular therapeutic targets. The aim of the study was to identify new molecular biomarkers and targets in BCBM by using complementary state-of-the-art techniques. Methods We compared array expression profiles of three BCBM with 16 non-brain metastatic BC and 16 primary brain tumors (prBT) using a false discovery rate (FDR) p  < 0.05 and fold change (FC) > 2. Biofunctional analysis was conducted on the differentially expressed probe sets. High-density arrays were employed to detect copy number variations (CNVs) and whole exome sequencing (WES) with paired-end reads of 150 bp was utilized to detect gene mutations in the three BCBM. Results The top 370 probe sets that were differentially expressed between BCBM and both BC and prBT were in the majority comparably overexpressed in BCBM and included, e.g. the coding genes BCL3 , BNIP3 , BNIP3P1 , BRIP1 , CASP14 , CDC25A , DMBT1 , IDH2 , E2F1 , MYCN , RAD51 , RAD54L , and VDR . A number of small nucleolar RNAs (snoRNAs) were comparably overexpressed in BCBM and included SNORA1 , SNORA2A , SNORA9 , SNORA10 , SNORA22 , SNORA24 , SNORA30 , SNORA37 , SNORA38 , SNORA52 , SNORA71A , SNORA71B , SNORA71C , SNORD13P2 , SNORD15A , SNORD34 , SNORD35A , SNORD41 , SNORD53 , and SCARNA22 . The top canonical pathway was entitled, role of BRCA1 in DNA damage response. Network analysis revealed key nodes as Akt, ERK1/2, NFkB, and Ras in a predicted activation stage. Downregulated genes in a data set that was shared between BCBM and prBT comprised, e.g. BC cell line invasion markers JUN, MMP3, TFF1, and HAS2. Important cancer genes affected by CNVs included TP53 , BRCA1 , BRCA2 , ERBB2 , IDH1 , and IDH2 . WES detected numerous mutations, some of which affecting BC associated genes as CDH1 , HEPACAM , and LOXHD1 . Conclusions Using complementary molecular genetic techniques, this study identified shared and unshared molecular events in three highly aberrant BCBM emphasizing the challenge to detect new molecular biomarkers and targets with translational implications. Among new findings with the capacity to gain clinical relevance is the detection of overexpressed snoRNAs known to regulate some critical cellular functions as ribosome biogenesis.

Autosomal recessive primary microcephaly (MCPH) is a neurodevelopmental disorder that is characterised by microcephaly present at birth and non-progressive mental retardation. Microcephaly is the outcome of a smaller but architecturally normal brain; the cerebral cortex exhibits a significant decrease in size. MCPH is a neurogenic mitotic disorder, though affected patients demonstrate normal neuronal migration, neuronal apoptosis and neural function. Twelve MCPH loci (MCPH1-MCPH12) have been mapped to date from various populations around the world and contain the following genes: Microcephalin , WDR62 , CDK5RAP2 , CASC5 , ASPM , CENPJ , STIL , CEP135 , CEP152 , ZNF335 , PHC1 and CDK6 . It is predicted that MCPH gene mutations may lead to the disease phenotype due to a disturbed mitotic spindle orientation, premature chromosomal condensation, signalling response as a result of damaged DNA, microtubule dynamics, transcriptional control or a few other hidden centrosomal mechanisms that can regulate the number of neurons produced by neuronal precursor cells. Additional findings have further elucidated the microcephaly aetiology and pathophysiology, which has informed the clinical management of families suffering from MCPH. The provision of molecular diagnosis and genetic counselling may help to decrease the frequency of this disorder.

Background Renal cell carcinoma (RCC) is a seventh ranked malignancy with poor prognosis. RCC is lethal at metastatic stage as it does not respond to conventional systemic treatments, and there is an urgent need to find out promising novel biomarkers for effective treatment. The goal of this study was to evaluate the biomarkers that can be potential therapeutic target and predict effective inhibitors to treat the metastatic stage of RCC. Methods We conducted transcriptomic profiling to identify differentially expressed genes associated with RCC. Molecular pathway analysis was done to identify the canonical pathways and their role in RCC. Tissue microarrays (TMA) based immunohistochemical stains were used to validate the protein expression of cyclinD1 (CCND1) and were scored semi-quantitatively from 0 to 3+ on the basis of absence or presence of staining intensity in the tumor cell. Statistical analysis determined the association of CCND1 expression with RCC. Molecular docking analyses were performed to check the potential of two natural inhibitors, rutin and curcumin to bind CCND1. Results We detected 1490 significantly expressed genes (1034, upregulated and 456, downregulated) in RCC using cutoff fold change 2 and p value < 0.05. Hes-related family bHLH transcription factor with YRPW motif 1 (HEY1), neuropilin 2 (NRP2), lymphoid enhancer-binding factor 1 (LEF1), and histone cluster 1 H3h (HIST1H3H) were most upregulated while aldolase B, fructose-bisphosphate (ALDOB), solute carrier family 12 (SLC12A1), calbindin 1 (CALB1) were the most down regulated genes in our dataset. Functional analysis revealed Wnt/β-catenin signaling as the significantly activated canonical pathway (z score = 2.53) involving cyclin D1 (CCND1). CCND1 was overexpressed in transcriptomic studies (FC = 2.26, p value = 0.0047) and TMA results also showed the positive expression of CCND1 in 53 % (73/139) of RCC cases. The ligands – rutin and curcumin bounded with CCND1 with good affinity. Conclusion CCND1 was one of the important upregulated gene identified in microarray and validated by TMA. Docking study showed that CCND1 may act as a potential therapeutic target and its inhibition could focus on the migratory, invasive, and metastatic potential of RCC. Further in vivo and in vitro molecular studies are needed to investigate the therapeutic target potential of CCND1 for RCC treatment.

Background Breast cancer incidence rates are increasing at an alarming rate among Saudi Arabian females. Most molecular genetic discoveries on breast cancer and other cancers have arisen from studies examining European and American patients. However, possibility of specific changes in molecular signature among cancer patients of diverse ethnic groups remains largely unexplored. We performed transcriptomic profiling of surgically-resected breast tumors from 45 patients based in the Western region of Saudi Arabia using Affymetrix Gene 1.0 ST chip. Pathway and biological function-based clustering was apparent across the tissue samples. Results Pathway analysis revealed canonical pathways that had not been previously implicated in breast cancer. Biological network analysis of differentially regulated genes revealed that Fatty acid binding protein 4, adipocyte ( FABP4 ), adiponectin ( ADIPOQ ), and retinol binding protein 4 ( RBP4 ) were most down regulated genes, sharing strong connection with the other molecules of lipid metabolism pathway. The marked biological difference in the signatures uncovered between the USA and Saudi samples underpins the importance of this study. Connectivity Map identified compounds that could reverse an observed gene expression signature Conclusions This study describes, to our knowledge, the first genome-wide profiling of breast cancer from Saudi ethnic females. We demonstrate the involvement of the lipid metabolism pathway in the pathogenesis of breast cancer from this region. This finding also highlights the need for strategies to curb the increasing rates of incidence of this disease by educating the public about life-style risk factors such as unhealthy diet and obesity.

Colorectal cancer (CRC) is a major health problem the world face currently and one of the leading causes of death worldwide. CRC is genetically heterogeneous and multiple genetic aberrations may appear on course of the disease throughout patient’s lifetime. Genetic biomarkers such as BRAF, KRAS, and NRAS may provide early precision treatment options that are crucial for patient survival and well-being. The aim of this study was to identify pathogenic mutations in the NRAS gene causing colorectal cancer in the Saudi population. We enrolled 80 CRC tumor tissue samples and performed molecular analyses to establish the mutation spectrum status in the western region of Saudi Arabia. We identified 5 different mutations in 10 patients, 4 of whom were reported previously (G10R, E37K, Q61K, and Q61*) in the literature while we discovered one novel lethal insertion mutation (E49R). A novel identified insertion mutation was present in the third codon of the NRAS gene [c.145 insA (p.Glu49ArgTer85)], causing a frameshift in the amino acid sequence of the protein, and leading to an aberrant and truncated protein of 85 amino acids. Subsequent bioinformatics analysis showed that the mutation was highly deleterious and affected protein function to a greater extent. This identification may further improve the prognosis of CRC and benefit subsequent treatment choices.

This work was aimed to develop a Curcuma oil-based self-nanoemulsifying drug delivery system (SNEDDS) 3D-printed polypills containing glimepiride (GMD) and rosuvastatin (RSV) for treatment of dyslipidemia in patients with diabetes as a model for metabolic syndrome (MS). Compartmentalized 3D printed polypills were prepared and studied in streptozotocin/poloxamer induced diabetic/dyslipidemic rats. The pharmacokinetic parameters of GMD and RSV in the prepared polypills were evaluated. Blood glucose level, lipid profile, antioxidant, and biochemical markers activities were investigated. Also, histopathological examination of the liver and pancreas was carried out. The atherosclerotic index, the area of islets of Langerhans, and liver steatosis lesion scores were calculated. The developed SNEDDS-loaded GMD/RSV polypills showed acceptable quality control characteristics with a high relative bioavailability of 217.16% and 224.28% for GMD and RSV, respectively, when compared with the corresponding non-SNEDDS pills. The prepared polypills showed dramatic lowering in blood glucose levels and substantial improvement in lipid profile and hepatic serum biomarkers as well as remarkable decrease in serum antioxidants in response to Poloxamer 407 intoxication. The prepared polypills decreased the risk of atherosclerosis and coronary disease by boosting the level of high-density lipoprotein and lowering both triglyceride and low-density lipoprotein. Microscopic examination showed normal hepatic sinusoids and high protection level with less detectable steatosis in the examined hepatocytes. Normal size pancreatic islets with apparently normal exocrine acini and pancreatic duct were also noticed. This formulation strategy clearly shows the potential of the developed polypills in personalized medicine for treatment of patients with MS.

Primary microcephaly (MCPH) is a rare developmental defect characterized by impaired cognitive functions, retarded neurodevelopment and reduced brain size. It is genetically heterogeneous and more than 17 genes so far have been identified that are associated with this disease. To study the genetic defect in a consanguineous Saudi family with primary microcephaly. Cross-sectional clinical genetics study of a Saudi family. Medical genomics research center. Blood samples collected from six members of a family of healthy consanguineous parents were analyzed by whole exome sequencing to identify the underlying pathogenic mutations in two members of the family (23-year-old female and 7-year-old male) who presented with primary microcephaly, intellectual disability, delayed psychomotor development and walking difficulty, speech impedi-ments and seizures. Detection of mutation in the WD repeat domain 62 (WDR62) gene in a family segregating autosomal recessive primary microcephaly. The exome variant analysis identified a novel missense mutation (c.3878C > A) in WDR62 gene in exon 30 resulting in amino acid change from alanine to aspartate (p.Ala1293Asp). Further validation in the affected patients and healthy members of family and 100 unrelated healthy persons as controls confirmed it to be pathogenic. Functional impairment of the WDR62 gene can lead to severe neurodevelopmental de-fects, brain malformations and reduced head size. A missense mutation of exon 30 changed alanine to aspartate in the WDR62 protein leading to the typical MCPH phenotype. Mutation was identified in a single family.

Background Polycystic ovary syndrome (PCOS) is a common endocrine disorder causing infertility in reproductive-age women. The cause of PCOS is not fully understood but it is thought to be influenced by environmental and genetic factors. Obesity is greatly related to PCOS and its reduction is one of the major aims in treating PCOS. Melanocortin 4 receptor ( MC4R ) gene polymorphisms were detected to be associated with different levels of obesity. Therefore, we aimed to determine the genotype and allele frequency of MC4R variants rs12970134 (A/G) and rs17782313 (C/T) in PCOS and investigate their association with PCOS and its clinical variables. Methods A case-control study was conducted on 189 women, consisting of 95 PCOS cases and 94 controls. Genotyping was performed by real-time polymerase chain reaction (PCR) using TaqMan™ Genotyping assays. Quantitative data were presented as (median ± interquartile range (IQR) whereas qualitative data were presented as frequencies. The chi-squared test was used to observe the difference between SNPs within the study groups (PCOS and control subjects). Multinomial logistic regression was used to test the risk of obesity and development of PCOS considering p  < 0.05 is statistically significant. Results Rs12970134 and rs17782313 are significantly associated with body mass index (BMI, kg/m 2 , p  < 0.0001) in PCOS women but not associated with PCOS itself. Risk alleles in our population are A in rs12970134 and C in rs17782313 that are associated with high BMI (> 30 kg/m 2 ) in obese women with PCOS (OR = 1.348, p  = 0.002 and OR = 1.364, p  = 0.002 respectively) in the homozygous state. In addition, we found that the other genotypes for non-obese PCOS group, AG/GG for rs12970134 and CT/TT for rs17782313, are associated with hirsutism, loss of hair, hyperandrogenism and anti-Müllerian hormone in PCOS. Conclusions These findings demonstrate that MC4R single nucleotide polymorphisms, rs12970134 and rs17782313, are correlated with elevated BMI in PCOS but are not causative factors for PCOS among women in the western region of Saudi Arabia. Moreover, the reverse genotypes are associated with major clinical variants in non-obese (< 30 kg/m 2 ) PCOS patients may demonstrate a poor prognosis for this group.

Oral squamous cell carcinoma (OSCC) is the most common epithelial tumor of the oral cavity. Gingival tumors, a unique type of OSCC, account for 10% of these malignant tumors. The antineoplastic properties of statins, including pitavastatin (PV), and the essential oil of the Pinus densiflora leaf (Pd oil) have been adequately reported. The goal of this investigation was to develop nanostructured lipid carriers (NLCs) containing PV combined with Pd oil and to determine their cytotoxicity against the cell line of human gingival fibroblasts (HGF-1). A central composite quadratic design was adopted to optimize the nanocarriers. The particle size and stability index of the nano-formulations were measured to evaluate various characteristics. TEM analysis, the entrapment efficiency, dissolution efficiency, and the cytotoxic efficiency of the optimized PV-loaded nanostructured lipid carrier drug delivery system (PV-Pd-NLCs) were evaluated. Then, the optimal PV-Pd-NLCs was incorporated into a Carbopol 940® gel base and tested for its rheological features and its properties of release and cell viability. The optimized NLCs had a particle size of 98 nm and a stability index of 89%. The gel containing optimum PV-Pd-NLCs had reasonable dissolution efficiency and acceptable rheological behavior and acquired the best cytotoxic activity against HGF-1 cell line among all the formulations developed for the study. The in vitro cell viability studies revealed a synergistic effect between PV and Pd oil in the treatment of gingival cancer. These findings illustrated that the gel containing PV-Pd-NLCs could be beneficial in the local treatment of gingival cancer.