Pinocytosis as the Biological Mechanism That Protects Pgp Function in Multidrug Resistant Cancer Cells and in Blood–Brain Barrier Endothelial Cells

Cancer is the second leading cause of death worldwide. Chemotherapy has shown reasonable success in treating cancer. However, multidrug resistance (MDR), a phenomenon by which cancerous cells become resistant to a broad range of functionally and structurally unrelated chemotherapeutic agents, is a major drawback in the effective use of chemotherapeutic agents in the clinic. Overexpression of P-glycoprotein (Pgp) is a major cause of MDR in cancer as it actively effluxes a wide range of structurally and chemically unrelated substrates, including chemotherapeutic agents. Interestingly, Pgp is also overexpressed in the endothelial cells of blood–brain barrier (BBB) restricting the entry of 98% small molecule drugs to the brain. The efficacy of Pgp is sensitive to any impairment of the membrane structure. A small increase of 2% in the membrane surface tension, which can be caused by a very low drug concentration, is enough to block the Pgp function. We demonstrate in this work by mathematical equations that the incorporation of drugs does increase the surface tension as expected, and the mechanism of endocytosis dissipates any increase in surface tension by augmenting the internalisation of membrane per unit of time, such that an increase in the surface tension of about 2% can be dissipated within only 4.5 s

Biodesulfurizing Microbes in the Petroleum Refinery Areas of Saudi Arabia

Gordonia sp., Rhodococcus, Paenibaccilus, Mycobacterium and many other desulfurizing strains have shown good potential for dibenzothiophene (DBT), 4, 6-Dimethyldibenzothiophene (4-6-Dimethyl dibenzothiophene) and other organosulfur biodesulfurization. These are microbes which have 4S pathway to remove S from remaining calcitarant organosulfur compounds even after deep desulfurization. Sulfur compounds present in crude oils, diesel and petrol when combust in engines they emerge out in the form of elemental Sulfur, which causes environmental and health problems. Therefore, efforts are going to remove this Sulfur compounds by Hydrodesulfurization (HDS) treatment. Some organosulfur compounds remain there even after HDS, which can only remove by highly evolved microbes residing nearby petroleum-contaminated areas in refineries zone. Nature has such adopted and evolved microbes for the bioremediation of such toxic substances. Here we have isolated and characterized highly evolved and adopted Biodesulfurizing microbes present around oil refineries in Kingdom of Saudi Arabia and prepare the culture collection of such highly evolved and adopted biodesulfurization microorganisms for future application of applied Industrial petroleum refineries, which can reduce the Sulfur load in the petroleum products. The several (10 different types) microbes have been reported in these soils to grow in sulfur compounds. Out of these microbes one microbe desulfurizes by 4S pathway. It was identified to be Rhodococcus erythropolis type named as Rhodococcus erythroplis KAU10. They show good potential for various organosulfur compounds (DBT, 2,4,6-Trimethyl Benzothiophene, Benzothiophene, Dibenzyl sulfide, Benzonaphthothiophene, Dibenzothiophene sulfone, along with crude oil and Petrol and Diesel. Isolated strain Rhodococcus erythroplis KAU10 have good potential for Biodesulfurization

Possible hypocholesterolemic effect of ginger and rosemary oils in rats

Background: Hypercholesterolemia is a major risk factor for development of atherosclerosis. The present study was conducted to evaluate the potential effect of ginger oil alone or combined with rosemary oil as hypocholesterolemic agent in rats fed high fat diet.Materials and methods: Healthy female albino rats (n=80) weighting about (150-180 g) were included in this study divided into two equal groups; Group (I): were fed on the basal diet. Group (I) were divided into 4 subgroups each 10: Group (Ia): negative control. Group (Ib): Rats received i.p 2.5 g/Kg b.w of ginger oil. Group (Ic): rats received i.p 2.5 g/Kg b.w of rosemary oil. Group (Id): Rats received i.p 5 g/Kg b.w mixture of ginger oil and rosemary oil (1:1). The second main groups; Group (II): high fat diet (HFD) were fed on the basal diet plus cholesterol (1%), bile salt (0.25%) and animal fat (15%) to induce hypercholesterolemia for six weeks. Group (II) was divided into 4subgroups: Group (IIa): HFD. Group (IIb): HFD were treated with i.p 2.5 g/Kg b.w ginger oil. Group (IIc): (n=10) HFD were treated with i.p 2.5 g/Kg b.w rosemary oil. Group (IId): (n=10) HFD were treated with i.p 5 g/Kg b.w mixture of oils.Results: It was found that HFD rats showed a significant elevation in glucose, total cholesterol, triglyceride, GOT, GPT, alkaline phosphatase and a reduction in serum HDL-c compared with negative control. Treatment with ginger oil, rosemary oil and their mixture modulated the elevation of these parameters. Histopathological examination of the liver tissue of HFD rats showed a lipid deposition and macrophage infiltration and stenosis of hepatic vein. Treatment with mixture oils preserves normal structure of liver.Conclusion: It was concluded that, hypocholesterolemic effect was related to the active oil content as Rosemary oil contain - α-pinene, Camphor, cineole, borneol and Ginger oil contain Linalool, Terpineol ,Borneol , Eucalyptol.Keywords: Ginger Oil, Rosemary Oil, Rats, Hypocholesterolemi

POSSIBLE HYPOCHOLESTEROLEMIC EFFECT OF GINGER AND ROSEMARY OILS IN RATS

Background: Hypercholesterolemia is a major risk factor for development of atherosclerosis. The present study was conducted to evaluate the potential effect of ginger oil alone or combined with rosemary oil as hypocholesterolemic agent in rats fed high fat diet. Materials and methods: Healthy female albino rats (n=80) weighting about (150-180 g) were included in this study divided into two equal groups; Group (I): were fed on the basal diet. Group (I) were divided into 4 subgroups each 10: Group (Ia): negative control. Group (Ib): Rats received i.p 2.5 g/Kg b.w of ginger oil. Group (Ic): rats received i.p 2.5 g/Kg b.w of rosemary oil. Group (Id): Rats received i.p 5 g/Kg b.w mixture of ginger oil and rosemary oil (1:1). The second main groups; Group (II): high fat diet (HFD) were fed on the basal diet plus cholesterol (1%), bile salt (0.25%) and animal fat (15%) to induce hypercholesterolemia for six weeks. Group (II) was divided into 4subgroups: Group (IIa): HFD. Group (IIb): HFD were treated with i.p 2.5 g/Kg b.w ginger oil. Group (IIc): (n=10) HFD were treated with i.p 2.5 g/Kg b.w rosemary oil. Group (IId): (n=10) HFD were treated with i.p 5 g/Kg b.w mixture of oils. Results: It was found that HFD rats showed a significant elevation in glucose, total cholesterol, triglyceride, GOT, GPT, alkaline phosphatase and a reduction in serum HDL-c compared with negative control. Treatment with ginger oil, rosemary oil and their mixture modulated the elevation of these parameters. Histopathological examination of the liver tissue of HFD rats showed a lipid deposition and macrophage infiltration and stenosis of hepatic vein. Treatment with mixture oils preserves normal structure of liver. Conclusion: It was concluded that, hypocholesterolemic effect was related to the active oil content as Rosemary oil contain - α-pinene, Camphor, cineole, borneol and Ginger oil contain Linalool, Terpineol ,Borneol , Eucalyptol

Co-Occurrence of β-Lactam and Aminoglycoside Resistance Determinants among Clinical and Environmental Isolates of Klebsiella pneumoniae and Escherichia coli: A Genomic Approach

The presence of antimicrobial-resistance genes (ARGs) in mobile genetic elements (MGEs) facilitates the rapid development and dissemination of multidrug-resistant bacteria, which represents a serious problem for human health. This is a One Health study which aims to investigate the co-occurrence of antimicrobial resistance determinants among clinical and environmental isolates of K. pneumoniae and E. coli. Various bioinformatics tools were used to elucidate the bacterial strains’ ID, resistome, virulome, MGEs, and phylogeny for 42 isolates obtained from hospitalized patients (n = 20) and environmental sites (including fresh vegetables, fruits, and drinking water) (n = 22). The multilocus sequence typing (MLST) showed that K. pneumoniae belonged to ten sequence types (STs) while the E. coli belonged to seventeen STs. Multidrug-resistant isolates harbored β-lactam, aminoglycoside resistance determinants, and MGE were detected circulating in the environment (drinking water, fresh vegetables, and fruits) and in patients hospitalized with postoperative infections, neonatal sepsis, and urinary tract infection. Four K. pneumoniae environmental isolates (7E, 16EE, 1KE, and 19KE) were multidrug-resistant and were positive for different beta-lactam and aminoglycoside resistance determinants. blaCTX-M-15 in brackets of ISEc 9 and Tn 3 transposases was detected in isolates circulating in the pediatrics unit of Soba hospital and the environment. This study documented the presence of bacterial isolates harboring a similar pattern of antimicrobial resistance determinants circulating in hospitals and environments. A rapid response is needed from stakeholders to initiate a program for infection prevention and control measures to detect such clones disseminated in the communities and hospitals

Genomic Analysis of Multidrug-Resistant Hypervirulent (Hypermucoviscous) Klebsiella pneumoniae Strain Lacking the Hypermucoviscous Regulators (rmpA/rmpA2)

Hypervirulent K. pneumoniae (hvKP) strains possess distinct characteristics such as hypermucoviscosity, unique serotypes, and virulence factors associated with high pathogenicity. To better understand the genomic characteristics and virulence profile of the isolated hvKP strain, genomic data were compared to the genomes of the hypervirulent and typical K. pneumoniae strains. The K. pneumoniae strain was isolated from a patient with a recurrent urinary tract infection, and then the string test was used for the detection of the hypermucoviscosity phenotype. Whole-genome sequencing was conducted using Illumina, and bioinformatics analysis was performed for the prediction of the isolate resistome, virulome, and phylogenetic analysis. The isolate was identified as hypermucoviscous, type 2 (K2) capsular polysaccharide, ST14, and multidrug-resistant (MDR), showing resistance to ciprofloxacin, ceftazidime, cefotaxime, trimethoprim-sulfamethoxazole, cephalexin, and nitrofurantoin. The isolate possessed four antimicrobial resistance plasmids (pKPN3-307_type B, pECW602, pMDR, and p3K157) that carried antimicrobial resistance genes (ARGs) (blaOXA-1,blaCTX-M-15, sul2, APH(3″)-Ib, APH(6)-Id, and AAC(6′)-Ib-cr6). Moreover, two chromosomally mediated ARGs (fosA6 and SHV-28) were identified. Virulome prediction revealed the presence of 19 fimbrial proteins, one aerobactin (iutA) and two salmochelin (iroE and iroN). Four secretion systems (T6SS-I (13), T6SS-II (9), T6SS-III (12), and Sci-I T6SS (1)) were identified. Interestingly, the isolate lacked the known hypermucoviscous regulators (rmpA/rmpA2) but showed the presence of other RcsAB capsule regulators (rcsA and rcsB). This study documented the presence of a rare MDR hvKP with hypermucoviscous regulators and lacking the common capsule regulators, which needs more focus to highlight their epidemiological role

Thymoquinone-Induced Reactivation of Tumor Suppressor Genes in Cancer Cells Involves Epigenetic Mechanisms

The epigenetic silencing of tumor suppressor genes (TSGs) is a common finding in several solid and hematological tumors involving various epigenetic readers and writers leading to enhanced cell proliferation and defective apoptosis. Thymoquinone (TQ), the major biologically active compound of black seed oil, has demonstrated anticancer activities in various tumors by targeting several pathways. However, its effects on the epigenetic code of cancer cells are largely unknown. In the present study, we performed RNA sequencing to investigate the anticancer mechanisms of TQ-treated T-cell acute lymphoblastic leukemia cell line (Jurkat cells) and examined gene expression using different tools. We found that many key epigenetic players, including ubiquitin-like containing plant homeodomain (PHD) and really interesting new gene (RING) finger domains 1 ( UHRF1), DNMT1,3A,3B, G9A, HDAC1,4,9, KDM1B , and KMT2A,B,C,D,E , were downregulated in TQ-treated Jurkat cells. Interestingly, several TSGs, such as DLC1, PPARG, ST7, FOXO6, TET2, CYP1B1, SALL4 , and DDIT3 , known to be epigenetically silenced in various tumors, including acute leukemia, were upregulated, along with the upregulation of several downstream pro-apoptotic genes, such as RASL11B, RASD1, GNG3, BAD , and BIK . Data obtained from RNA sequencing were confirmed using quantitative reverse transcription polymerase chain reaction (RT-qPCR) in Jurkat cells, as well as in a human breast cancer cell line (MDA-MB-468 cells). We found that the decrease in cell proliferation and in the expression of UHRF1, DNMT1, G9a , and HDAC1 genes in both cancer cell (Jurkat cells and MDA-MB-468 cells) lines depends on the TQ dose. Our results indicate that the use of TQ as an epigenetic drug represents a promising strategy for epigenetic therapy for both solid and blood tumors by targeting both DNA methylation and histone post-translational modifications