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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.

Environmental problems with chemical and biological water pollution have become a major concern for society. Providing people with safe and affordable water is a grand challenge of the 21st century. The study investigates the photocatalytic degradation capabilities of hydrothermally prepared pure and Cu-doped ZnO nanoparticles (NPs) for the elimination of dye pollutants. A simple, cost-effective hydrothermal process is employed to synthesize the Cu-doped ZnO NPs. The photocatalytic dye degradation activity of the synthesized Cu-doped ZnO NPs is tested by using methylene blue (MB) dye. In addition, the parameters that affect photodegradation efficiency, such as catalyst concentration, starting potential of hydrogen (pH), and dye concentration, were also assessed. The dye degradation is found to be directly proportional to the irradiation time, as 94% of the MB dye is degraded in 2 hrs. Similarly, the dye degradation shows an inverse relation to the MB dye concentration, as the degradation reduced from 94% to 20% when the MB concentration increases from 5 ppm to 80 ppm. The synthesized cost-effective and environmentally friendly Cu-doped ZnO NPs exhibit improved photocatalytic activity against MB dye and can therefore be employed in wastewater treatment materials.

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 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.

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.

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.

The marketability of pointed gourd fruit is drastically reduced after harvest due to moisture loss, chlorophyll degradation, yellowing of the skin, and shriveling. The present investigation studied the effect of exogenous salicylic acid (SA) treatment on senescence and fruit quality attributes of pointed gourd during storage under ambient conditions. Fruits were treated by immersing them in different concentrations of SA (1.0 mM, 2.0 mM, and 3.0 mM) and distilled water (control) for 5 minutes. The investigation showed beneficial effects of 3.0 mM SA treatment in lowering weight loss (16.8%), maintaining higher chlorophyll (32.8%) in the skin, and reducing lipid peroxidation (20.2%) compared to the control. SA (3.0 mM)-treated fruits retained 15.3% higher ascorbic acid and about 18% higher total phenol, flavonoids, and radical scavenging activity over pointed gourd fruits in the control group. However, significant difference in the total antioxidant capacity after 6 days of storage was not noted between SA-treated and control fruit. Thus, postharvest salicylic acid treatment can beneficially be used to extend marketability and delay quality deterioration of pointed gourd fruits stored under ambient conditions.

Kinesin super family protein 2A (KIF2A), an ATP-dependent microtubule (MT) destabilizer, regulates cell migration, axon elongation, and pruning in the developing nervous system. KIF2A mutations have recently been identified in patients with malformed cortical development. However, postnatal KIF2A is continuously expressed in the hippocampus, in which new neurons are generated throughout an individual's life in established neuronal circuits. In this study, we investigated KIF2A function in the postnatal hippocampus by using tamoxifen-inducible Kif2a conditional knockout (Kif2a-cKO) mice. Despite exhibiting no significant defects in neuronal proliferation or migration, Kif2a-cKO mice showed signs of an epileptic hippocampus. In addition to mossy fiber sprouting, the Kif2a-cKO dentate granule cells (DGCs) showed dendro-axonal conversion, leading to the growth of many aberrant overextended dendrites that eventually developed axonal properties. These results suggested that postnatal KIF2A is a key length regulator of DGC developing neurites and is involved in the establishment of precise postnatal hippocampal wiring. The brain contains billions of neurons that connect together to form ‘circuits’ that control behavior and process information. By the time we are born, most of the neurons in our brain have already formed and connected into these circuits. But there are some brain areas that continue to make new neurons throughout our lives. One such area is the hippocampus, a region of the brain involved in learning and memory. There, neurons called dentate granule cells keep their ability to divide, migrate to new locations, and develop new connections. Like most neurons, at the heart of each dentate granule cell is a cell body that contains the cell's nucleus and protein-making machinery. Attached to this are a set of small branch-like structures called dendrites that receive signals from surrounding neurons. Extending away from the cell body is another, longer branch called an axon, which transmits signals to other neurons. A protein called KIF2A plays several roles in the developing brain of mammals, including helping neurons to migrate to the right place and controlling how their axons form. Before birth, neurons across the brain make KIF2A. After birth this gradually changes until only the dentate granule cells in the hippocampus produce KIF2A. In humans, mutations that prevent KIF2A from working are thought to cause brain malformations. They may also lead to disorders such as schizophrenia, epilepsy and eye defects. To investigate the role of KIF2A in more detail, Homma et al. genetically engineered mice so that giving them a drug called tamoxifen would inactivate the gene that produces KIF2A. Mice that had this gene switched off three weeks after birth – when KIF2A levels in the hippocampus are normally at their highest – lost weight and became hyperactive. They also developed severe temporal lobe epilepsy. To find out why these problems ocurred, Homma et al. used a microscope to study sections of the brains of the mice. The neurons had divided and migrated to the correct location of the brain with no significant problems. However, dentate granule cells that lacked KIF2A looked unusual. They had too many dendrites, the dendrites were longer than they should be and they showed markers usually only found on axons. This suggests that KIF2A helps to control the length of axons and dendrites and the wiring of the hippocampus. At the moment, it's not known whether the same defects also occur in humans. If the results are reproducible in people, future work could help to diagnose and understand conditions linked to KIF2A, like schizophrenia and epilepsy.

Background The relationship between vitamin D (VitD) and insulin sensitivity and secretion in type 2 diabetes mellitus (T2D) has been shown to be different amongst different ethnic populations. In Saudi Arabia, where both T2D and VitD deficiency are highly prevalent health concerns, little is known about the relationship between VitD, insulin sensitivity, resistance and the relative importance of ethnicity. Our primary aim in this study was to investigate influence of ethnicity on VitD association with glycaemic profile and to measures of obesity as a secondary outcome, among multiethnic postmenopausal women with T2D in Saudi Arabia. Methods A cross-sectional study was conducted at King Fahad Medical Research Center, King Abdulaziz University, Jeddah, Saudi Arabia. Postmenopausal females ( n  = 173, age ≥ 50 years) with T2D were randomly selected in this study. Anthropometric measures and fasting blood samples were obtained for all study participants. Several biochemical parameters were measured including 25-hydroxyvitamin D (25(OH)D), glycosylated hemoglobin (HbA1c), insulin, glucose and c-peptide. Surrogate markers for insulin resistance were calculated using Homeostasis Model Assessment 2 for insulin resistance and beta cell activity (HOMA2-IR, HOMA2-β). Results Overall, 25(OH)D was inversely associated with fasting glucose ( r =-0.165, P  = 0.037), insulin ( r =-0.184, P  = 0.02), C-peptide ( r =-0.19, P  = 0.015) and HOMA2- IR C-peptide ( r =-0.23,  P  = 0.004). Additionally, serum 25 (OH)D showed a negative correlation with body weight ( r =-0.173 P  = 0.028), waist and hip circumferences ( r =-0.167, P  = 0.033; r =-0.22, P  = 0.004 respectively) but not with body mass index (BMI) or waist hip ratio (WHR). In the white ethnic group but not in black or Asian population groups, 25(OH)D level was also associated with only serum fasting C-peptide and HOMA2-IR C-peptide and BMI ( P  < 0.05). Conclusions Insulin resistance and obesity were associated with VitD status in T2D in this cohort. Our findings also suggest that these VitD associations in women from white ethnic background are different than in those from black/Asian ethnic backgrounds. Whether VitD supplements are able to improve either obesity and/or insulin sensitivity should be further investigated in different ethnic population groups.