Prevalence of occult hepatitis B virus infection in Egypt: a systematic review with meta-analysis.

BACKGROUND: Occult hepatitis B virus (HBV) infection (OBI) is a major public health problem. The clinical importance of OBI stems from the fact that it can be transmitted to healthy individuals at extremely low viral load levels. Additionally, immunosuppression has the potential to trigger viral replication, which can result in life-threatening liver decompensation. Despite several studies examining the prevalence of OBI, the pooled prevalence of OBI in Egypt remains unknown, particularly among blood donors and high-risk individuals, to whom intervention should be targeted. METHODS: A comprehensive literature search of the following databases was conducted from inception to October 2022 using the following keywords: occult hepatitis B virus infection or occult HBV infection or OBI and Egypt in MEDLINE [PubMed], Scopus, Google Scholar, and Web of Science. The review was conducted following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) Statement. I-squared and Cochran's Q were used to measure the heterogeneity between the studies, and based on the random effects model, results were reported as proportions (%) with a 95% confidence interval (CI). Analyses of subgroup analyses were conducted based on the target population. Sensitivity analyses were conducted using the leave-one-out approach to test the robustness of the results. RESULTS: A total of 50 studies with 62 estimations of OBI were included, 19 in patients who were HBsAg-negative and anti-HBc-positive and 43 in patients who were HBsAg-negative. The highest prevalence (41%) was among multi-transfused patients according to  studies that report occult hepatitis B virus prevalence in an HBsAg-negative population, while the pooled prevalence of OBI among patients on hemodialysis, patients with chronic hepatitis C infection, patients with hepatocellular carcinoma (HCC), and patients with liver cirrhosis was 17%, 10%, 24%, and 13%, respectively. On the other hand, among studies that report OBI prevalence in HBsAg-negative and anti-HBc-positive individuals, the pooled prevalence of OBI among blood donors, patients with chronic hepatitis C infection, and patients with HCC was 12%, 15%, and 31%, respectively. Also, the majority of studies examining the genetic background of OBI have found that genotype D is the most prevalent. CONCLUSION:  This study highlights the high prevalence in OBI among blood donors and high-risk populations in Egypt. The implementation of HBV nucleic acid amplification testing (NAT) may increase the safety of blood transfusions by excluding all HBV DNA-positive donations. However, the cost-effectiveness of these tests should be investigated.

Bio-Guided Isolation of Antimalarial Metabolites from the Coculture of Two Red Sea Sponge-Derived Actinokineospora and Rhodococcus spp.

Coculture is a productive technique to trigger microbes' biosynthetic capacity by mimicking the natural habitats' features principally by competition for food and space and interspecies cross-talks. Mixed cultivation of two Red Sea-derived actinobacteria, Actinokineospora spheciospongiae strain EG49 and Rhodococcus sp. UR59, resulted in the induction of several non-traced metabolites in their axenic cultures, which were detected using LC-HRMS metabolomics analysis. Antimalarial guided isolation of the cocultured fermentation led to the isolation of the angucyclines actinosporins E (1), H (2), G (3), tetragulol (5) and the anthraquinone capillasterquinone B (6), which were not reported under axenic conditions. Interestingly, actinosporins were previously induced when the axenic culture of the Actinokineospora spheciospongiae strain EG49 was treated with signalling molecule N-acetyl-d-glucosamine (GluNAc); this finding confirmed the effectiveness of coculture in the discovery of microbial metabolites yet to be discovered in the axenic fermentation with the potential that could be comparable to adding chemical signalling molecules in the fermentation flask. The isolated angucycline and anthraquinone compounds exhibited in vitro antimalarial activity and good biding affinity against lysyl-tRNA synthetase (PfKRS1), highlighting their potential developability as new antimalarial structural motif.

New Cytotoxic Natural Products from the Red Sea Sponge Stylissa carteri.

Bioactivity-guided isolation supported by LC-HRESIMS metabolic profiling led to the isolation of two new compounds, a ceramide, stylissamide A (1), and a cerebroside, stylissoside A (2), from the methanol extract of the Red Sea sponge Stylissa carteri. Structure elucidation was achieved using spectroscopic techniques, including 1D and 2D NMR and HRMS. The bioactive extract's metabolomic profiling showed the existence of various secondary metabolites, mainly oleanane-type saponins, phenolic diterpenes, and lupane triterpenes. The in vitro cytotoxic activity of the isolated compounds was tested against two human cancer cell lines, MCF-7 and HepG2. Both compounds, 1 and 2, displayed strong cytotoxicity against the MCF-7 cell line, with IC50 values at 21.1 ± 0.17 µM and 27.5 ± 0.18 µM, respectively. They likewise showed a promising activity against HepG2 with IC50 at 36.8 ± 0.16 µM for 1 and IC50 30.5 ± 0.23 µM for 2 compared to the standard drug cisplatin. Molecular docking experiments showed that 1 and 2 displayed high affinity to the SET protein and to inhibitor 2 of protein phosphatase 2A (I2PP2A), which could be a possible mechanism for their cytotoxic activity. This paper spreads light on the role of these metabolites in holding fouling organisms away from the outer surface of the sponge, and the potential use of these defensive molecules in the production of novel anticancer agents.

Effect of a diet containing date pits on growth performance, diet digestibility, and economic evaluation of Japanese quail (Coturnix coturnix japonica).

This study was performed to investigate the effect of feeding different levels of date pits (DP) to growing Japanese quails on growth performance, diet digestibility, blood parameters, carcass traits, and economical value of the farm production. A total of 204 1-day-old quail chicks were randomly divided into 4 groups (three replicates each). DP was chemically analyzed and used as 0%, 2%, 4%, and 6% to formulate 4 balanced experimental diets (control, DP-2, DP-4, and DP-6, respectively). The feed and water were given ad libitum. Feed intake (FI) and body weight gain (BWG) were recorded weekly, and the feed conversion ratio (FCR) was calculated. A digestibility trial was conducted, and the digestion coefficient (DC) was calculated for diet dry matter (DM) and nutrients. At the end of the experiment, carcass traits were measured and blood samples were collected for blood picture analysis. Economical evaluation of the test diets was carried out to determine the net return (NR) of feeding DP to quails. Results showed significant (P < 0.05) change in FI and final body weight among treatments. FCR of DP-6 group was the best in all treatments. DC of diet DM and nutrients were reduced with increasing DP level except for nitrogen-free extract (NFE). Carcass traits and blood parameters were within the normal range with no adverse effects. From the economic point of view, quail selling return values were significantly higher (P < 0.05) for all the groups supplemented with DP than the control one. Total return (TR) and NR values showed insignificant (P > 0.05) differences among the experimental groups; they were higher for DP-fed groups compared with the control. The present results demonstrated a beneficial effect of DP inclusion in the diet of quails in terms of growth performance, blood profiles, carcass traits, and economic value.

New Antiproliferative Cembrane Diterpenes from the Red Sea Sarcophyton Species.

The combination of liquid chromatography coupled to high resolution mass spectrometry (LC-HRESMS)-based dereplication and antiproliferative activity-guided fractionation was applied on the Red Sea-derived soft coral Sarcophyton sp. This approach facilitated the isolation of five new cembrane-type diterpenoids (1-5), along with two known analogs (6 and 7), as well as the identification of 19 further, known compounds. The chemical structures of the new compounds were elucidated while using comprehensive spectroscopic analyses, including one-dimensional (1D) and two-dimensional (2D) NMR and HRMS. All of the isolated cembranoids (1-7) showed moderate in vitro antiproliferative activity against a human breast cancer cell line (MCF-7), with IC50 ranging from 22.39-27.12 µg/mL. This class of compounds could thus serve as scaffold for the future design of anticancer leads.

Differential leucocyte detection by flow cytometry improves the diagnosis of genital tract inflammation and identifies macrophages as proinflammatory cytokine-producing cells in human semen.

Genital tract inflammation is considered as a major cause of male infertility with leucocytospermia as widely used diagnostic marker. However, threshold of 10(6) leucocytes ml(-1) recommended by the WHO is a matter of debate. Moreover, leucocyte subpopulations and their impact cannot be identified by the routine peroxidase method (POM). Ejaculates of subfertile men (n = 47) were analysed by flow cytometry (FACS) using a bead-based method. Leucocytes were identified by CD18 and further divided into macrophages (HLA-Dr+/CD66abce-) and neutrophils (HLA-Dr-/CD66abce+). IL-1ß, TNF-α and IL-6 production was investigated in these subpopulations. It was found that CD18-positive cells correlated significantly with POM. However, only in samples with POM below 10(6) per millilitre, FACS detected significantly higher leucocyte numbers. Moreover, in 31% of these samples, FACS leucocyte detection reached threshold values greater than 1 × 10(6)  ml(-1) , fulfilling the criteria for diagnosis of leucocytospermia. Neutrophils were the predominating leucocyte population. Nevertheless, in 24% of samples, macrophages encountered more than 50% of leucocytes. Most interestingly, only macrophages produced significant amounts of IL-1ß, TNF-α and IL-6. It is concluded that FACS improves detection and functional differentiation of seminal leucocytes as one of the diagnostic hallmarks of male genital tract inflammation.

Semen quality and reproductive endocrinal function related to blood lead levels in infertile painters.

Lead causes male reproductive impairment among painters, but information is still limited. Therefore, the effect of lead on semen quality and reproductive endocrinal function in those patients was investigated. A case series of 27 infertile painters were subjected to semen analysis, measuring of blood lead level (PbB) and serum levels of endocrinal parameters including follicle-stimulating hormone (FSH), luteinising hormone (LH), testosterone (T) and prolactin (PRL). Significantly lower sperm count and motility were found in those with duration of exposure (≥ 15 years), but no significant difference was found for PbB and serum levels of FSH, LH, PRL and T. A significant negative correlation between PbB and spermatic count and motility was observed, while there was no significant correlation between PbB and all endocrinal parameters. Patients with PbB ≥ 20 µg dl(-1) showed a significant decrease in sperm motility and increase in testosterone alone among all measured hormones. But the observed decrease in sperm count did not reach a significant level. It is concluded that infertile painters are at risk of lead-related influence on semen quality, especially sperm motility and increased testosterone level without significant affection of other reproductive endocrinal parameters.

Effect of drilling process parameters on bearing strength of glass fiber/aluminum mesh reinforced epoxy composites.

The current study attempted to evaluate the impact of drilling parameters and delamination on the bearing strength of both neat GFRP (NG) and hybrid GFRP/aluminum (Al)-wire mesh with two various configurations, first with Al-mesh in the outer surface of specimen (AG) and the other with Al-mesh in the core of specimen (GA). Drilling procedure is carried out using [Formula: see text] 6 mm carbide twist drill with three different tip angles (90°, 120° and 135°), as well as Three different speeds and feeds (1000, 2000, and 3000 rpm) and (20, 40, and 60 mm/min), respectively. Taguchi and ANOVA analyses are used to analyze the influence of processing parameters. The findings showed that AG specimen experienced the least delamination damage. The maximum bearing strength refers to NG specimen, which is 9.6% and 8.7% more than AG and GA specimens, respectively. Drill point angle has the major effect on bearing strength for both AG and GA specimens, while for NG feed rate is of the major effect. The developed regression model displayed a high level of fitness with an average prediction error of less than 3%.

The effect of a thumb web spacer splint on hand function in children with hemiplegic cerebral palsy.

Objective: Many children with hemiplegic cerebral palsy (HCP) cannot maintain thumb abduction and experience obstruction caused by the thumb remaining in the palm. A web spacer splint maintains the thumb web space and opposition of the thumb for a more functional position. The aim of this study was to analyze the impact of a thumb web spacer as a functional splint on hand function in children with hemiplegic cerebral palsy. Methods: Thirty children with hemiplegic cerebral palsy (ages 4-7 years) were randomly divided into two groups (a control group and a study group). The treatment program for the control group was administered for 45 min three times/week for 8 successive weeks and the study group underwent the identical treatment regimen as the control group, as well as wearing a web spacer splint during the treatment program. Thereafter, the Peabody Developmental Motor Scale (PDMS-2) was used to assess hand function. Results: Post-treatment values in the study group demonstrated a substantial improvement in grasping and visual motor integration in the PDMS-2 when compared to the control group. Therefore, there was a significant improvement in total fine motor quotient when compared post-treatment (86.93 ± 8.94, 145.73 ± 15.04) in the control and study groups, respectively (p > 0.05). Conclusion: A web spacer splint can be a viable tool for improving hand function in children with HCP.

Subereamolline A as a potent breast cancer migration, invasion and proliferation inhibitor and bioactive dibrominated alkaloids from the Red Sea sponge Pseudoceratina arabica.

A new collection of several Red Sea sponges was investigated for the discovery of potential breast cancer migration inhibitors. Extracts of the Verongid sponges Pseudoceratina arabica and Suberea mollis were selected. Bioassay-directed fractionation of both sponges, using the wound-healing assay, resulted into the isolation of several new and known brominated alkaloids. Active fractions of the sponge Pseudoceratina arabica afforded five new alkaloids, ceratinines A-E (2-6), together with the known alkaloids moloka'iamine (1), hydroxymoloka'iamine (7) and moloka'iakitamide (8). The active fraction of the sponge Suberea mollis afforded the three known alkaloids subereamolline A (9), aerothionin (10) and homoaerothionin (11). Ceratinine B (3) possesses an unprecedented 5,7-dibrominated dihydroindole moiety with an epoxy ring on the side chain of a fully substituted aromatic moiety. Ceratinines D (5) and E (6) possess a terminal formamide moiety at the ethylamine side chain. Subereamolline A (9) potently inhibited the migration and invasion of the highly metastatic human breast cancer cells MDA-MB-231 at the nanomolar doses. Subereamolline A and related brominated alkaloids are novel scaffolds appropriate for further future use for the control of metastatic breast cancer.

Ultrastructure of the spermatozoon of Acanthostomum spiniceps (Digenea: Acanthostomidae), a parasite of Bagrus spp. (Siluriformes:Bagridae).

The present study describes, for the first time, the sperm ultrastructure of the parasite Acanthostomum spiniceps (Digenea: Acanthostomidae). The adult worms of this species were collected from the freshwater fishes, Bagrus bayad and Bagrus docmac, caught from the Damietta branch of the River Nile in Dakahlia Governorate, Egypt. Ultrastructure of the sperm of this species revealed that it can be differentiated into seven regions. It is characterized by its filiform shape, tapers anterior, and posterior ends; the two axonemes are in close contact with the plasma membrane and the presence of two mitochondria as one anterior and the other is posterior. The two mitochondria are parallel at a short distance enclosing the first part of nucleus in between. The nucleus is characteristically formed of unusual network of chromatin which is vacuolated. The spermatozoon of A. spiniceps is similar to that of most parasitic Platyhelminthes.

Synthesis and antioxidant and antitumor activity of novel pyridine, chromene, thiophene and thiazole derivatives.

2-Tosylacetonitrile (1) when reacted with α,ß-unsaturated nitriles 2a-c or a mixture of formaldehyde and 3-amino-2-substituted-pent-2-endinitriles 6a,b yielded pyridine derivatives 3a-c and 9a,b, respectively, while when subjected to react with salicylaldehyde yielded chromene derivatives 4 and 5, subsequently. The behavior of thiocarbamoyl derivative 10 derived from 1 towards some α-halogenated compounds have been investigated as well as its behavior towards elemental sulfur and phenyl isothiocyanate. Newly synthesized compounds were screened for their antioxidant activity, erythrocytes haemolysis and bleomycin-independent DNA damage. Some of the tested compounds exhibited promising activities.

Synthesis, reactions and antimicrobial activities of 8-ethoxycoumarin derivatives.

Condensation of 3-acetyl-8-ethoxycoumarin (3) with thiosemicarbazide gave ethylidenehydrazinecarbothioamide 5, which was transformed into the thiazolidin-4-one derivatives 6,7. Interaction of 3 with DMF/POCl(3) gave b-chloroacroline derivative 8. Treatment of 3 with malononitrile gave benzo[c]chromone and 2-aminobenzonitrile derivatives 9 and 10, respectively with respect to the reaction conditions. Condensation of 3-(2-bromoacetyl)-8-ethoxycoumarin (4) with o-phenylenediamine gave 3-(quioxaline-2-yl)-8-ethoxycoumarin hydrobromide (11), while 4 reacted with 2-aminopyridine to give chromenopyridopyrimidine derivative 12. Condensation of 4 with potassium thio-cyanate/methanol gave an unexpected derivative, 2H-chromeno-3-carboxy(methyl-carbonimidic)thioanhydride 16, which upon treatment with (NH(2))(2)·H(2)O gave 3-ethoxy-2-hydroxybenzaldehyde azine 19. Interaction of 4 with thiourea derivatives gave thiazole derivatives 20a-c. The structures of the newly synthesized compounds were confirmed by their spectra data. The newly synthesized compounds were also screened for their antimicrobial activity.

Biosorption as a Perfect Technique for Purification of Wastewater Contaminated with Ammonia.

Eichhornia crassipes root powder (ECRP) has been used to remove ammonia from aqueous solutions. The biosorption factors such as biosorbent dosage, pH, initial ammonia concentration, and contact time have been considered in batch conditions. The optimal conditions, at pH (6), sorbent dose 5 g/l, time (30 min) ammonia concentration (10 mg/l). Langmuir is better suited than Freundlich isotherm. The kinetic models Thomas, Yoon-Nelson, and Bohart-Adams were applied. These models showed that the adsorption capacity decreased with flow rate increases as follows: 32.57, 31.82, 31.25, and 30.17 mg/g, respectively, at a flow rate 10, 15, 20, and 25 ml/min. The root powder of Eichhornia crassipes was used to treat specific drainage wastewater obtained from the Sabal drain at Menoufia, Egypt. The average efficiency of ammonia removal was 87% per batch adsorption method at pH value = 7.5, sorbent dose 5 g/l, uptake period (30 min), and primary load 7.1 mg/l; however, ammonia removal by column continuous adsorption method exceeded 94%. In addition, ECRP is efficient in removing arsenic, sulfate, nitrates, nitrite, silica, iron, manganese, copper, zinc, aluminum, and lead from actual sewage wastewater, in addition to removing more than 75% COD.

Prevalence and Molecular Epidemiology of Cryptosporidium Infection in Clarias gariepinus Fish in Egypt.

PURPOSE: This study investigated the prevalence and molecular detection of Cryptosporidium spp. in catfish (Clarias gariepinus). METHODS: A total of 300 Carias gariepinus fish were collected from two freshwater sources: the Nile River (180) and drainage canals (120). The stomach and intestine epithelium of each individual fish sample were screened by modified Ziehl-Neelsen (mZN) staining technique for the detection of Cryptosporidium oocysts followed by the serological survey for detection of Cryptosporidium antibodies using Enzyme-Linked Immunosorbent Assay (ELISA) and molecular characterization using complemented DNA polymerase chain reaction (cPCR). RESULTS: ELISA showed higher prevalence of 69.3% than that prevalence obtained by mZN, 64% for the total examined Clarias gariepinus fish. Also, higher prevalence of Cryptosporidium infection 65.5% and 75.8% obtained by ELISA than 61.1% and 68.3% by mZN, in both fish groups from Nile River and Drainage canal, respectively. PCR analysis revealed the expected positive bands at 1056 bp. DNA sequencing and phylogenetic analysis proved that the positive-PCR Cryptosporidium isolate identified in the present study was Cryptosporidium molnari. CONCLUSION: Freshwater fishes (Clarias gariepinus) are subjected to a high infection rate with Cryptosporidium spp.; the drainage canals obtained fishes showed higher prevalence than that collected from Nile River which indicates an important public health problem and a potential risk of drainage canals in Egypt. ELISA showed higher prevalence of cryptosporidiosis than mZN, for the total examined Clarias gariepinus fish and phylogenetic analyses confirmed this protozoal organism to be a novel species of Cryptosporidium molnari.

Physico-analytical studies on some heterocyclic azo dyes and their metal complexes with some transition metals.

In this investigation, the azo dyes; 2-(3'-phenyl-5'-pyrazolyl azo) schaffer acid (la) and 2-(3'-phenyl-5'-pyrazolyl azo) resorcinol (Ib); were prepared through diazotizing 3-phenyl-5-aminopyrazole (PAP) and coupling the resulting diazonium salt with Schäffer acid and resorcinol respectively. The prepared azo dyes are characterized using both IR spectra and the elemental analysis (C, H, N and S). The prepared azo dyes are used as chromogenic reagents for the spectrophotometric determination of copper (II), nickel (II), cobalt (II) and zinc (II) ions. The conditional acid dissociation constants of these azo dyes (la and Ib) and the stability constants of its metal ion complexes have been determined by spectro-analytical methods. The effect of pH, time, organic solvent and the foreign ions on the spectrophotometric determination of these ions and their complexes with the azo dyes under study were studied. The stoichiometric ratio (M:L) of the formed complexes was also determined. The molar absorptivity, the Sandell's sensitivity values, the obeyance of Beers law and the stability constants of the formed complexes have been also determined and discussed.

LC/MS Profiling and Gold Nanoparticle Formulation of Major Metabolites from Origanum majorana as Antibacterial and Antioxidant Potentialities.

Origanum majoranum L. is a Lamiaceae medicinal plant with culinary and ethnomedical applications. Its biological and phytochemical profiles have been extensively researched. Accordingly, this study aimed to investigate the chemical composition and the antibacterial and antioxidant properties of O. majoranum high features, as well as to search for techniques for activity optimization. A metabolomics study of the crude extract of O. majoranum using liquid chromatography-high-resolution electrospray ionization mass spectrometry (LC ± HR ± ESI ± MS) was conducted. Five fractions (petroleum ether, dichloromethane, ethyl acetate, n-butanol, and aqueous) were derived from the total extract of the aerial parts. Different chromatographic methods and NMR analysis were utilized to purify and identify the isolated phenolics (high features). Moreover, the antimicrobial, antibiofilm, and antioxidant activity of phenolics were performed. Results showed that metabolomic profiling of the crude extract of O. majoranum aerial parts revealed the presence of a variety of phytochemicals, predominantly phenolics, resulting in the isolation and identification of seven high-feature compounds comprising two phenolic acids, rosmarinic and caffeic acids, one phenolic diterpene, 7-methoxyepirosmanol, in addition to four flavonoids, quercetin, hesperitin, hesperidin, and luteolin. On the other hand, 7-methoxyepirosmanol (OM1) displayed the most antimicrobial and antioxidant potential. Such a phenolic principal activity improvement seems to be established after loading on gold nanoparticles.

Synthesis and characterization of new diiodocoumarin derivatives with promising antimicrobial activities.

A series of 6,8-diiodocoumarin-3-N-carboxamides (4-11) were prepared. Treatment of ethyl 6,8-diiodocoumarin-3-carboxylate (1) with ethyl cyanoacetate/NH(4)OAc gave ethyl 2-(3-carbamoyl-6,8-diiodocoumarin-4-yl)-2-cyanoacetate (12) and 2-amino-4-hydroxy-7,9-diiodocoumarino[3,4-c]pyridine-1-carbonitrile (13), and treatment with acetone in the presence of NH(4)OAc or methylamine gave the ethyl 4-oxo-2,6-methano-2-methyl-3,4,5,6-tetrahydro-8,10-diiodobenzo[2,1-g]-2H-1,3-oxazocine-5-carboxylate derivatives 14a,b. All compounds were evaluated for their antimicrobial activity and the compounds 12-14a,b exhibited a pronounced effect on all tested microorganisms.

Endoscopic management of acute oesophageal variceal bleeding within 12 hours of admission is superior to 12-24 hours.

Background: Acute oesophageal variceal haemorrhage (AOVH) is a medical emergency. The American Association for the Study of Liver Diseases recommends endoscopy management as soon as possible and not more than 12 hours after presentation. The United Kingdom guidelines recommended endoscopy for unstable patients with severe acute upper gastrointestinal bleeding immediately after resuscitation and within 24 hours of admission. We aimed to evaluate the outcome of endoscopic management of AOVH in less than 12 hours compared to 12-24 hours post admission.Methods: 297 patients with AOVH were divided into groups depending on the timing of the endoscopic management: 180 within 12 h of admission and 117 patients at 12-24 hours of admission. Routine clinical and laboratory data were collected.Results: Compared to patients with endoscopic management at 12-24 hours (mean 16 hours), patients with endoscopic management within 12 hours (mean 8.3 hours) of admission had fewer hospital stay days (P = 0.001), significant reduction of ammonia levels (P < 0.0001) and significant improvement in associated hepatic encephalopathy grade 25 (p = 0.048). There were no major clinical events in the 12-hour group, but 8 events in the 12-24 hour group (p < 0.01).Conclusion: Endoscopic management of acute variceal bleeding within 12 hours of admission is superior to endoscopic management at 12-24 hours of admission regarding reduction of hospital stay, ammonia levels, correction of hepatic encephalopathy, re-bleeding and mortality rate, hence, reducing the cost of treatment benefiting patient satisfaction and improving hospital bed availability.

Redox-silent tocotrienol esters as breast cancer proliferation and migration inhibitors.

Tocotrienols are vitamin E members with potent antiproliferative activity against preneoplastic and neoplastic mammary epithelial cells with little or no effect on normal cell growth or functions. However, physicochemical and pharmacokinetic properties greatly limit their use as therapeutic agents. Tocotrienols' chemical instability, poor water solubility, NPC1L1-mediated transport, and rapid metabolism are examples of such obstacles which hinder the therapeutic use of these valuable natural products. Vitamin E esters like α-tocopheryl succinate were prepared to significantly improve chemical and metabolic stability, water solubility, and potency. Thus, 12 semisynthetic tocotrienol ester analogues 4-15 were prepared by direct esterification of natural tocotrienol isomers with various acid anhydrides or chlorides. Esters 4-15 were evaluated for their ability to inhibit the proliferation and migration of the mammary tumor cells +SA and MDA-MB-231, respectively. Esters 5, 9, and 11 effectively inhibited the proliferation of the highly metastatic +SA rodent mammary epithelial cells with IC(50) values of 0.62, 0.51, and 0.86µM, respectively, at doses that had no effect on immortalized normal mouse CL-S1 mammary epithelial cells. Esters 4, 6, 8-10, and 13 inhibited 50% of the migration of the human metastatic MDA-MB-231 breast cancer cells at a single 5µM dose in wound-healing assay. The most active ester 9 was 1000-fold more water-soluble and chemically stable versus its parent α-tocotrienol (1). These findings strongly suggest that redox-silent tocotrienol esters may provide superior therapeutic forms of tocotrienols for the control of metastatic breast cancer.