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Fulltext Regulation of hepatic insulin signaling and glucose homeostasis by sphingosine kinase 2

Aji G, Huang Y, Ng ML, Wang W, Lan T, Li M, et al.

Proc Natl Acad Sci U S A, 2020 09 29;117(39):24434-24442.
PMID: 32917816 DOI: 10.1073/pnas.2007856117

Sphingolipid dysregulation is often associated with insulin resistance, while the enzymes controlling sphingolipid metabolism are emerging as therapeutic targets for improving insulin sensitivity. We report herein that sphingosine kinase 2 (SphK2), a key enzyme in sphingolipid catabolism, plays a critical role in the regulation of hepatic insulin signaling and glucose homeostasis both in vitro and in vivo. Hepatocyte-specific Sphk2 knockout mice exhibit pronounced insulin resistance and glucose intolerance. Likewise, SphK2-deficient hepatocytes are resistant to insulin-induced activation of the phosphoinositide 3-kinase (PI3K)-Akt-FoxO1 pathway and elevated hepatic glucose production. Mechanistically, SphK2 deficiency leads to the accumulation of sphingosine that, in turn, suppresses hepatic insulin signaling by inhibiting PI3K activation in hepatocytes. Either reexpressing functional SphK2 or pharmacologically inhibiting sphingosine production restores insulin sensitivity in SphK2-deficient hepatocytes. In conclusion, the current study provides both experimental findings and mechanistic data showing that SphK2 and sphingosine in the liver are critical regulators of insulin sensitivity and glucose homeostasis.

Matched MeSH terms: Mice, Knockout; Mice
Antimutagenic effects of aqueous fraction of Myristica fragrans (Houtt.) leaves on Salmonella typhimurium and Mus musculus

Akinboro A, Bin Mohamed K, Asmawi MZ, Yekeen TA

Acta Biochim. Pol., 2014;61(4):779-85.
PMID: 25520963

Natural plant extracts offer a promising hope in the prevention/treatment of cancer arising from genetic mutations. This study evaluated in vitro and in vivo mutagenic and antimutagenic effects of aqueous fraction of Myristica fragrans (AFMF) leaves on TA100 strain of Salmonella typhimurium and Mus musculus (Male Swiss albino mice), respectively. The antioxidant activity of AFMF against 2,2-diphenyl-1-picrylhydrazyl (DPPH), total phenolic and flavonoid contents were determined, followed by its phytochemical elucidation using the Ultra Performance Liquid Chromatography technique (UPLC). The mutagenicity of AFMF at 4, 20, 50, 100, 200, 500, and 1000 µg/well was <2.0 in S. typhimurium and the induced micronucleated polychromatic and normochromatic erythrocytes at 500, 1000, 2000, and 4000 mg/kg were not significantly different from the negative control (p≥0.05). The mutagenic activity of benzo[a]pyrene and cyclophosphamide was significantly suppressed above 50.0% throughout the tested concentrations. Fifty percent of the free radicals from DPPH were scavenged by AFMF at 0.11 mg/ml. Total phenolic and flavonoid contents of AFMF were 51.0 mg GAE/g and 27 mg QE/g, respectively. Rutin was elucidated by the UPLC technique, and thereby suspected to be the phytochemical responsible for the observed antimutagenic activity. Thus far, AFMF seems to contain a promising chemotherapeutic agent for the prevention of genetic damage that is crucial for cancer development.

Matched MeSH terms: Mice
Mutagenic and antimutagenic assessment of methanol leaf extract of Myristica fragrans (Houtt.) using in vitro and in vivo genetic assays

Akinboro A, Mohamed KB, Asmawi MZ, Othman AS, Ying TH, Maidin SM

Drug Chem Toxicol, 2012 Oct;35(4):412-22.
PMID: 22149219 DOI: 10.3109/01480545.2011.638300

The role of diets in causing cancers necessitates the ongoing search for natural antimutagens of promising anticancer therapeutics. This study determined the potential anticancer efficacy of the leaf extract of Myristica fragrans (Houtt.). Methanol leaf extract of M. fragrans (Houtt.) alone was screened for mutagenicity in the bacterial reverse mutation (Ames) test, using the Salmonella typhimurium TA100 strain, the Allium cepa, and the mouse in vivo bone marrow micronucleus tests. The antimutagenicity of this extract against benzo[a]pyrene- and cyclophosphamide-induced mutations was evaluated. An antioxidant test on the extract was performed with 2,2-diphenyl-1-picrylhydrazyl, using butylated hydroxyanisole (BHA) and butylated hydroxytoluene (BHT) as the standards, whereas its phytochemicals were elucidated by following the gas chromatography/mass spectrometry protocol. In S. typhimurium (TA100), the mutagenicity ratio at 200,500 and 1,000 µg/well was >2. Cell division in the A. cepa root tips and mouse bone marrow was significantly (P ≤ 0.05) inhibited at 2,000 and 4,000 mg/kg, whereas the observed chromosomal aberrations and micronucleated polychromatic erythrocytes were non-dose-related and were insignificantly (P ≥ 0.05) different from the negative control. Inhibition of benzo[a]pyrene- and cyclophosphamide-induced mutagenicity by this extract was above 40%. Half-maximal inhibitory concentration of the extract in the antioxidant test was lower than that of BHA and BHT. Phytochemical compounds, possessing antioxidant activity, may be responsible for the observed effects, suggesting a strong antimutagenic activity of the MeOH leaf extract of M. fragrans, a necessary characteristic of a promising anticancer agent.

Matched MeSH terms: Mice
Determination of betulinic acid from Orthosiphon stamineus leaf extract in rat plasma

Akowuah GA, Zhari I

Pharmazie, 2008 Nov;63(11):788-90.
PMID: 19069237

A simple high-performance liquid chromatography (HPLC) method to determine the content of betulinic acid (BA) in rat plasma collected at different times (0-8 h) after oral administration of Orthosiphon stamineus leaf extract was developed. The features of the assay include protein precipitation using acetonitrile and isocratic elution using reverse phase C-18 column with ultraviolet (UV) detection. The recovery of BA from plasma varied from 98.4 to 102.5%. The R.S.D of intra- and inter-day precision from rat plasma ranged from 4.2 to 9.8%. The maximum concentration of BA in the plasma was 1.2 +/- 0.3 microg/ml at 1 h after oral administration of the extract.

Matched MeSH terms: Mice
Generation of induced pluripotent stem cells by a polycistronic lentiviral vector in feeder- and serum- free defined culture

Al Abbar A, Nordin N, Ghazalli N, Abdullah S

Tissue Cell, 2018 Dec;55:13-24.
PMID: 30503056 DOI: 10.1016/j.tice.2018.09.004

Induced pluripotent stem cells (iPSCs) have great potentials for regenerative medicine. However, serious concerns such as the use of the viral-mediated reprogramming strategies and exposure of iPSCs to animal products from feeder cells and serum-containing medium have restricted the application of iPSCs in the clinics. Therefore, the generation of iPSCs with minimal viral integrations and in non-animal sourced and serum-free medium is necessary. In this report, a polycistronic lentiviral vector carrying Yamanaka's factors was used to reprogram mouse fibroblasts into iPSCs in feeder- and xeno-free culture environment. The generated iPSCs exhibited morphology and self-renewal properties of embryonic stem cells (ESCs), expression of specific pluripotent markers, and potentials to differentiate into the three-major distinct specialized germ layers in vitro. The iPSCs were also shown to have the potential to differentiate into neural precursor and neurons in culture, with greater than 95% expression of nestin, Pax6 and βIII-tubulin. This body of work describes an alternative method of generating iPSCs by using polycistronic lentiviral vector that may minimize the risks associated with viral vector-mediated reprogramming and animal derived products in the culture media.

Matched MeSH terms: Mice, Inbred C57BL
A new triterpenoid from Sapium baccatum (Euphorbiaceae)

Al Muqarrabun LM, Ahmat N, Aris SR, Norizan N, Shamsulrijal N, Yusof FZ, et al.

Nat Prod Res, 2014;28(13):1003-9.
PMID: 24697194 DOI: 10.1080/14786419.2014.903396

A new triterpene, malaytaraxerate (1), and four known compounds, taraxerol (2), taraxerone (3), docosyl isoferulate (4) and docosanoic acid 2',3'-dihydroxypropyl ester (5), were isolated from the acetone extract of Sapium baccatum stem bark. The structures of the isolated compounds were determined using several spectroscopic methods, including UV-Vis, FT-IR, 1D and 2D NMR, and mass spectrometry. Major isolated compounds were assayed for cytotoxicity. The chemotaxonomic significance of this plant was also studied.

Matched MeSH terms: Mice
Evaluation of the use of Cocos nucifera as antimalarial remedy in Malaysian folk medicine

Al-Adhroey AH, Nor ZM, Al-Mekhlafi HM, Amran AA, Mahmud R

J Ethnopharmacol, 2011 Apr 12;134(3):988-91.
PMID: 21277969 DOI: 10.1016/j.jep.2011.01.026

White flesh extract of Cocos nucifera (coconut) was studied to ascertain the ethnopharmacological standing of its antimalarial usage in Malaysian folk medicine.

Matched MeSH terms: Mice
Fulltext Antimalarial activity of methanolic leaf extract of Piper betle L

Al-Adhroey AH, Nor ZM, Al-Mekhlafi HM, Amran AA, Mahmud R

Molecules, 2010 Dec 28;16(1):107-18.
PMID: 21189459 DOI: 10.3390/molecules16010107

The need for new compounds active against malaria parasites is made more urgent by the rapid spread of drug-resistance to available antimalarial drugs. The crude methanol extract of Piper betle leaves (50-400 mg/kg) was investigated for its antimalarial activity against Plasmodium berghei (NK65) during early and established infections. The phytochemical and antioxidant potentials of the crude extract were evaluated to elucidate the possibilities of its antimalarial effects. The safety of the extract was also investigated in ICR mice of both sexes by the acute oral toxicity limit test. The leaf extract demonstrated significant (P < 0.05) schizonticidal activity in all three antimalarial evaluation models. Phytochemical screening showed that the leaf extract contains some vital antiplasmodial chemical constituents. The extract also exhibited a potent ability to scavenge the free radicals. The results of acute toxicity showed that the methanol extract of Piper betle leaves is toxicologically safe by oral administration. The results suggest that the Malaysian folklorical medicinal application of the extract of Piper betle leaf has a pharmacological basis.

Matched MeSH terms: Mice
Fulltext Median lethal dose, antimalarial activity, phytochemical screening and radical scavenging of methanolic Languas galanga rhizome extract

Al-Adhroey AH, Nor ZM, Al-Mekhlafi HM, Mahmud R

Molecules, 2010 Nov 16;15(11):8366-76.
PMID: 21081857 DOI: 10.3390/molecules15118366

The methanolic extract of Languas galanga rhizomes was investigated for antimalarial activity against Plasmodium berghei (NK65) infections in mice. The median lethal dose was determined to ascertain the safety of the extract in ICR mice of both sexes. The antimalarial activities during early and established infections, as well as the prophylactic activity were evaluated. Phytochemical screening and radical scavenging activity of the extract were also investigated to elucidate the possible mechanism of the antimalarial properties. The acute oral toxicity (LD₅₀) of Languas galanga extract in mice was established to be 4.998 mg/kg. The extract of Languas galanga rhizomes demonstrated significant antiplasmodial activity in all the three models of the antimalarial evaluations. Phytochemical screening revealed the presence of some vital antiplasmodial constituents such as terpenoids and flavonoids. The extract also exhibited a moderate capacity to scavenge the free radicals. The rhizome extract of Languas galanga thus possesses antimalarial activity, which explains the rational usage of this plant in traditional Malaysian medicine.

Matched MeSH terms: Mice, Inbred ICR; Mice
Fulltext The Effect of lead exposure of mice during pregnancy on the morphology of epididymal and testicular spermatozoa of their offspring

Al-Ani, I.M., al-Khfaji, I.N., Fakhrildin, M.B., Mangalo, H.H., Al-Obaidi, S.R.

International Medical Journal Malaysia, 2009;8(1):11-16.
MyJurnal

Introduction: The aims of this study were to assess the differences in the percentages of abnormal morphology between the epididymal and testicular spermatozoa of mature male offspring mice whose mothers were injected with various doses of lead acetate during gestation. Materials and Methods: Seventy two healthy female mice were divided into three major groups according to the number of injections involving 1, 2 or 3 injections at 8th day; 8th and 13th days; and 8th, 13th and 18th days of gestation period, respectively. Each major group was subdivided into four minor groups according to the dosage of lead administered (0, 25, 50 and 100) mg/Kg. Results: The percentages of abnormal morphology of epididymal and testicular spermatozoa were studied and the data were statistically analyzed. The results of this study proved that an increased number of injections and/or dose of lead acetate injected to the mothers during gestation cause an elevation in the percentage of abnormal morphology of both epididymal and testicular spermatozoa of the male mice offspring. Conclusion: In conclusion this study demonstrated that lead acetate when exposed prenatally have toxic effects on the sperm in the offspring male mice resulting in abnormal morphology of spermatozoa. The most likely causative factor is disturbances in the phase(s) of spermatogenesis and/or spermiogenesis.

Matched MeSH terms: Mice
Fulltext Assessing the Protective Role of Epigallocatechin Gallate (EGCG) against Water-Pipe Smoke-Induced Toxicity: A Comparative Study on Gene Expression and Histopathology

Al-Awaida W, Goh KW, Al-Ameer HJ, Gushchina YS, Torshin VI, Severin AE, et al.

Molecules, 2023 Nov 09;28(22).
PMID: 38005223 DOI: 10.3390/molecules28227502

Exposure to water-pipe smoking, whether flavored or unflavored, has been shown to instigate inflammation and oxidative stress in BALB/c mice. This consequently results in alterations in the expression of inflammatory markers and antioxidant genes. This study aimed to scrutinize the impact of Epigallocatechin gallate (EGCG)-a key active component of green tea-on inflammation and oxidative stress in BALB/c mice exposed to water-pipe smoke. The experimental setup included a control group, a flavored water-pipe smoke (FWP) group, an unflavored water-pipe smoke (UFWP) group, and EGCG-treated flavored and unflavored groups (FWP + EGCG and UFWP + EGCG). Expression levels of IL-6, IL1B, TNF-α, CAT, GPXI, MT-I, MT-II, SOD-I, SOD-II, and SOD-III were evaluated in lung, liver, and kidney tissues. Histopathological changes were also assessed. The findings revealed that the EGCG-treated groups manifested a significant decline in the expression of inflammatory markers and antioxidant genes compared to the FWP and UFWP groups. This insinuates that EGCG holds the capacity to alleviate the damaging effects of water-pipe smoke-induced inflammation and oxidative stress. Moreover, enhancements in histopathological features were observed in the EGCG-treated groups, signifying a protective effect against tissue damage induced by water-pipe smoking. These results underscore the potential of EGCG as a protective agent against the adverse effects of water-pipe smoking. By curbing inflammation and oxidative stress, EGCG may aid in the prevention or mitigation of smoking-associated diseases.

Matched MeSH terms: Mice
Fulltext Pharmacological inhibition of endoplasmic reticulum stress mitigates osteoporosis in a mouse model of hindlimb suspension

Al-Daghestani H, Qaisar R, Al Kawas S, Ghani N, Rani KGA, Azeem M, et al.

Sci Rep, 2024 Feb 27;14(1):4719.
PMID: 38413677 DOI: 10.1038/s41598-024-54944-7

Hindlimb suspension (HLS) mice exhibit osteoporosis of the hindlimb bones and may be an excellent model to test pharmacological interventions. We investigated the effects of inhibiting endoplasmic reticulum (ER) stress with 4-phenyl butyrate (4-PBA) on the morphology, physicochemical properties, and bone turnover markers of hindlimbs in HLS mice. We randomly divided 21 male C57BL/6J mice into three groups, ground-based controls, untreated HLS group and 4-PBA treated group (HLS+4PBA) (100mg/kg/day, intraperitoneal) for 21 days. We investigated histopathology, micro-CT imaging, Raman spectroscopic analysis, and gene expression. Untreated HLS mice exhibited reduced osteocyte density, multinucleated osteoclast-like cells, adipocyte infiltration, and reduced trabecular striations on micro-CT than the control group. Raman spectroscopy revealed higher levels of ER stress, hydroxyproline, non-collagenous proteins, phenylalanine, tyrosine, and CH2Wag as well as a reduction in proteoglycans and adenine. Furthermore, bone alkaline phosphatase and osteocalcin were downregulated, while Cathepsin K, TRAP, and sclerostin were upregulated. Treatment with 4-PBA partially restored normal bone histology, increased collagen crosslinking, and mineralization, promoted anti-inflammatory markers, and downregulated bone resorption markers. Our findings suggest that mitigating ER stress with 4-PBA could be a therapeutic intervention to offset osteoporosis in conditions mimicking hindlimb suspension.

Matched MeSH terms: Mice, Inbred C57BL; Mice
Fulltext Hepatic histopathological and ultrastructural alterations induced by 10 nm silver nanoparticles

Al-Doaiss A, Jarrar Q, Moshawih S

IET Nanobiotechnol, 2020 Jul;14(5):405-411.
PMID: 32691743 DOI: 10.1049/iet-nbt.2020.0039

Silver nanoparticles (Ag NPs) are invested in various sectors and are becoming more persistent in our ambient environment with potential risk on our health and the ecosystems. The current study aims to investigate the histological, histochemical and ultrastructural hepatic changes that might be induced by 10 nm silver nanomaterials. Male mice (BALB/C) were exposed for 35 injections of daily dose of 10 nm Ag NPs (2 mg/kg). Liver tissues were subjected to examination by light and electron microscopy for histological, histochemical and ultrastructural alterations. Exposure to Ag NPs induced Kupffer cells hyperplasia, sinusoidal dilatation, apoptosis, ground glass hepatocytes appearance, nuclear changes, inflammatory cells infiltration, hepatocytes degeneration and necrosis. In addition, 10 nm Ag NPs induced histochemical alterations mainly glycogen depletion with no hemosiderin precipitation. Moreover, these nanomaterials exhibited ultrastructure alterations including mitochondrial swelling and cristolysis, cytoplasmic vacuolation, apoptosis, multilammellar myelin figures formation and endoplasmic destruction and reduction. The findings revealed that Ag NPs can induce alterations in the hepatic tissues, the chemical components of the hepatocytes and in the ultrastructure of the liver. One may also conclude that small size Ag NPs, which are increasingly used in human products could cause various toxigenic responses to all hepatic tissue components.

Matched MeSH terms: Mice, Inbred BALB C; Mice
50% Ethanol extract of Orthosiphon stamineus modulates genotoxicity and clastogenicity induced by mitomycin C

Al-Dualimi DW, Shah Abdul Majid A, Al-Shimary SFF, Al-Saadi AA, Al Zarzour R, Asif M, et al.

Drug Chem Toxicol, 2018 Jan;41(1):82-88.
PMID: 28635332 DOI: 10.1080/01480545.2017.1317785

Herbal products contain a variety of compounds which may be useful in protecting against cellular damage caused by mutagens. Orthosiphon stamineus (O.s) also known as Cat whiskers. The herb has been shown anti-oxidative properties and can modulate key cellular proteins that have cytoprotective effect. The study aimed to evaluate the effects of different doses (250, 500 and 1000 mg kg-1) of 50% ethanol extract of O.s (Et. O.s) on micro-nucleated polychromatic erythrocytes (MNPCE), Polychromatic to normachromatic erythrocytes ratio (PCE/NCE), Mitotic index (MI), and Chromosomal aberration (CA) in Bab/c mice. Moreover, these parameters were used to evaluate the anti-genotoxic and clastogenic potencies of (Et. O.s) against mitomycin c (MMC) that interact with biological molecules and induce genotoxic and clastogenic disorders in non-tumor cells. MMC (4 mg kg-1) was injected intraperitoneally (i.p.) to the mice before and after treatment with three different doses of (Et. O.s). The results indicated that the extract at different doses did not show significant (p ≥ 0.05) differences in (MNPCE), (PCE/NCE) ratios, and (CA) values. The higher doses sowed high (MI) values compared with untreated control group. MMC showed significant increase (p ≤ 0.001) in (MNPCE), (CA) and reduce (PCE/NCE) and (MI) values compared with untreated control group. Treatment with (Et. O.s) at different doses before and after MMC injection showed to modulate MNPCE, PCE/NCE ratios, CA and MI values in mice bone marrow cells suggesting genoprotective potential of this plant extract.

Matched MeSH terms: Mice, Inbred BALB C
Fulltext Biosafety evaluation of culture-expanded human chondrocytes with growth factor cocktail: a preclinical study

Al-Masawa ME, Wan Kamarul Zaman WS, Chua KH

Sci Rep, 2020 12 09;10(1):21583.
PMID: 33299022 DOI: 10.1038/s41598-020-78395-y

The scarcity of chondrocytes is a major challenge for cartilage tissue engineering. Monolayer expansion is necessary to amplify the limited number of chondrocytes needed for clinical application. Growth factors are often added to improve monolayer culture conditions, promoting proliferation, and enhancing chondrogenesis. Limited knowledge on the biosafety of the cell products manipulated with growth factors in culture has driven this study to evaluate the impact of growth factor cocktail supplements in chondrocyte culture medium on chondrocyte genetic stability and tumorigenicity. The growth factors were basic fibroblast growth factor (b-FGF), transforming growth factor β2 (TGF β2), insulin-like growth factor 1 (IGF-1), insulin-transferrin-selenium (ITS), and platelet-derived growth factor (PD-GF). Nasal septal chondrocytes cultured in growth factor cocktail exhibited a significantly high proliferative capacity. Comet assay revealed no significant DNA damage. Flow cytometry showed chondrocytes were mostly at G0-G1 phase, exhibiting normal cell cycle profile with no aneuploidy. We observed a decreased tumour suppressor genes' expression (p53, p21, pRB) and no TP53 mutations or tumour formation after 6 months of implantation in nude mice. Our data suggest growth factor cocktail has a low risk of inducing genotoxic and tumorigenic effects on chondrocytes up to passage 6 with 16.6 population doublings. This preclinical tumorigenicity and genetic instability evaluation is crucial for further clinical works.

Matched MeSH terms: Mice, Nude; Mice
Fulltext Chemical Composition and Antioxidant, Antimicrobial, and Anti-Inflammatory Properties of Origanum compactum Benth Essential Oils from Two Regions: In Vitro and In Vivo Evidence and In Silico Molecular Investigations

Al-Mijalli SH, Mrabti NN, Ouassou H, Sheikh RA, Assaggaf H, Bakrim S, et al.

Molecules, 2022 Oct 28;27(21).
PMID: 36364152 DOI: 10.3390/molecules27217329

The purposes of this investigatory study were to determine the chemical composition of the essential oils (EOs) of Origanum compactum from two Moroccan regions (Boulemane and Taounate), as well as the evaluation of their biological effects. Determining EOs' chemical composition was performed by a gas chromatography-mass spectrophotometer (GC-MS). The antioxidant activity of EOs was evaluated using free radical scavenging ability (DPPH method), fluorescence recovery after photobleaching (FRAP), and lipid peroxidation inhibition assays. The anti-inflammatory effect was assessed in vitro using the 5-lipoxygenase (5-LOX) inhibition test and in vivo using the carrageenan-induced paw edema model. Finally, the antibacterial effect was evaluated against several strains using the disk-diffusion assay and the micro-dilution method. The chemical constituent of O. compactum EO (OCEO) from the Boulemane zone is dominated by carvacrol (45.80%), thymol (18.86%), and α-pinene (13.43%). However, OCEO from the Taounate zone is rich in 3-carene (19.56%), thymol (12.98%), and o-cymene (11.16%). OCEO from Taounate showed higher antioxidant activity than EO from Boulemane. Nevertheless, EO from Boulemane considerably inhibited 5-LOX (IC50 = 0.68 ± 0.02 µg/mL) compared to EO from Taounate (IC50 = 1.33 ± 0.01 µg/mL). A similar result was obtained for tyrosinase inhibition with Boulemane EO and Taounate EO, which gave IC50s of 27.51 ± 0.03 μg/mL and 41.83 ± 0.01 μg/mL, respectively. The in vivo anti-inflammatory test showed promising effects; both EOs inhibit and reduce inflammation in mice. For antibacterial activity, both EOs were found to be significantly active against all strains tested in the disk-diffusion test, but O. compactum EO from the Boulemane region showed the highest activity. Minimum inhibitory concentrations (MICs) and minimum bactericidal concentrations (MBCs) for O. compactum EO from the Boulemane region ranged from 0.06 to 0.25% (v/v) and from 0.15 to 0.21% (v/v) for O. compactum from the Taounate region. The MBC/MIC index revealed that both EOs exhibited remarkable bactericidal effects.

Matched MeSH terms: Mice
Fulltext Evaluation of immunomodulatory potential of probiotic conditioned medium on murine macrophages

Al-Najjar MAA, Abdulrazzaq SB, Alzaghari LF, Mahmod AI, Omar A, Hasen E, et al.

Sci Rep, 2024 Mar 26;14(1):7126.
PMID: 38531887 DOI: 10.1038/s41598-024-56622-0

Probiotics are a mixture of beneficial live bacteria and/or yeasts that naturally exist in our bodies. Recently, numerous studies have focused on the immunostimulatory effects of single-species or killed multi-species probiotic conditioned mediums on macrophages. This study investigates the immunostimulatory effect of commercially available active, multi-species probiotic conditioned medium (CM) on RAW264.7 murine macrophages. The probiotic CM was prepared by culturing the commercially available probiotic in a cell-culture medium overnight at 37 °C, followed by centrifugation and filter-sterilization to be tested on macrophages. The immunostimulatory effect of different dilution percentages (50%, 75%, 100%) of CM was examined using the MTT assay, proinflammatory cytokine (tumor necrosis factor TNF-alpha) production in macrophages, migration, and phagocytosis assays. For all the examined CM ratios, the percentages of cell viability were > 80%. Regarding the migration scratch, TNF-alpha and phagocytosis assays, CM demonstrated a concentration-dependent immunostimulatory effect. However, the undiluted CM (100%) showed a significant (p-value

Matched MeSH terms: Mice
Targeted delivery of paclitaxel drug using polymer-coated magnetic nanoparticles for fibrosarcoma therapy: in vitro and in vivo studies

Al-Obaidy R, Haider AJ, Al-Musawi S, Arsad N

Sci Rep, 2023 Feb 23;13(1):3180.
PMID: 36823237 DOI: 10.1038/s41598-023-30221-x

Fibrosarcoma is a rare type of cancer that affects cells known as fibroblasts that are malignant, locally recurring, and spreading tumor in fibrous tissue. In this work, an iron plate immersed in an aqueous solution of double added deionized water, supplemented with potassium permanganate solution (KMnO4) was carried out by the pulsed laser ablation in liquid method (PLAIL). Superparamagnetic iron oxide nanoparticles (SPIONs) were synthesized using different laser wavelengths (1064, 532, and 266 nm) at a fluence of 28 J/cm2 with 100 shots of the iron plate to control the concentration, shape and size of the prepared high-stability SPIONs. The drug nanocarrier was synthesized by coating SPION with paclitaxel (PTX)-loaded chitosan (Cs) and polyethylene glycol (PEG). This nanosystem was functionalized by receptors that target folate (FA). The physiochemical characteristics of SPION@Cs-PTX-PEG-FA nanoparticles were evaluated and confirmed by Fourier transform infrared spectroscopy (FTIR), scanning electron microscopy (SEM), transmission electron microscopy (TEM), X-Ray diffraction (XRD), atomic force microscopy (AFM), and dynamic light scattering (DLS) methods. Cell internalization, cytotoxicity assay (MTT), apoptosis induction, and gene expression of SPION@Cs-PTX-PEG-FA were estimated in fibrosarcoma cell lines, respectively. In vivo studies used BALB/c tumor-bearing mice. The results showed that SPION@Cs-PTX-PEG-FA exhibited suitable physical stability, spherical shape, desirable size, and charge. SPION@Cs-PTX-PEG-FA inhibited proliferation and induced apoptosis of cancer cells (P

Matched MeSH terms: Mice
Assembly of ligands interaction models for glutathione-S-transferases from Plasmodium falciparum, human and mouse using enzyme kinetics and molecular docking

Al-Qattan MN, Mordi MN, Mansor SM

Comput Biol Chem, 2016 10;64:237-249.
PMID: 27475235 DOI: 10.1016/j.compbiolchem.2016.07.007

BACKGROUND: Glutathione-s-transferases (GSTs) are enzymes that principally catalyze the conjugation of electrophilic compounds to the endogenous nucleophilic glutathione substrate, besides, they have other non-catalytic functions. The Plasmodium falciparum genome encodes a single isoform of GST (PfGST) which is involved in buffering the toxic heme, thus considered a potential anti-malarial target. In mammals several classes of GSTs are available, each of various isoforms. The human (human GST Pi-1 or hGSTP1) and mouse (murine GST Mu-1 or mGSTM1) GST isoforms control cellular apoptosis by interaction with signaling proteins, thus considered as potential anti-cancer targets. In the course of GSTs inhibitors development, the models of ligands interactions with GSTs are used to guide rational molecular modification. In the absence of X-ray crystallographic data, enzyme kinetics and molecular docking experiments can aid in addressing ligands binding modes to the enzymes.
METHODS: Kinetic studies were used to investigate the interactions between the three GSTs and each of glutathione, 1-chloro-2,4-dinitrobenzene, cibacron blue, ethacrynic acid, S-hexyl glutathione, hemin and protoporphyrin IX. Since hemin displacement is intended for PfGST inhibitors, the interactions between hemin and other ligands at PfGST binding sites were studied kinetically. Computationally determined binding modes and energies were interlinked with the kinetic results to resolve enzymes-ligands interaction models at atomic level.
RESULTS: The results showed that hemin and cibacron blue have different binding modes in the three GSTs. Hemin has two binding sites (A and B) with two binding modes at site-A depending on presence of GSH. None of the ligands were able to compete hemin binding to PfGST except ethacrynic acid. Besides bind differently in GSTs, the isolated anthraquinone moiety of cibacron blue is not maintaining sufficient interactions with GSTs to be used as a lead. Similarly, the ethacrynic acid uses water bridges to mediate interactions with GSTs and at least the conjugated form of EA is the true hemin inhibitor, thus EA may not be a suitable lead.
CONCLUSIONS: Glutathione analogues with bulky substitution at thiol of cysteine moiety or at γ-amino group of γ-glutamine moiety may be the most suitable to provide GST inhibitors with hemin competition.

Matched MeSH terms: Mice
Fulltext Anti-tumor activity of Eurycoma longifolia root extracts against K-562 cell line: in vitro and in vivo study

Al-Salahi OS, Ji D, Majid AM, Kit-Lam C, Abdullah WZ, Zaki A, et al.

PLoS One, 2014;9(1):e83818.
PMID: 24409284 DOI: 10.1371/journal.pone.0083818

Eurycoma longifolia Jack has been widely used in traditional medicine for its antimalarial, aphrodisiac, anti-diabetic, antimicrobial and anti-pyretic activities. Its anticancer activity has also been recently reported on different solid tumors, however no anti-leukemic activity of this plant has been reported. Thus the present study assesses the in vitro and in vivo anti-proliferative and apoptotic potentials of E. longifolia on K-562 leukemic cell line. The K-562 cells (purchased from ATCC) were isolated from patients with chronic myelocytic leukemia (CML) were treated with the various fractions (TAF273, F3 and F4) of E. longifolia root methanolic extract at various concentrations and time intervals and the anti-proliferative activity assessed by MTS assay. Flow cytometry was used to assess the apoptosis and cell cycle arrest. Nude mice injected subcutaneously with 10(7) K-562 cells were used to study the anti-leukemic activity of TAF273 in vivo. TAF273, F3 and F4 showed various degrees of growth inhibition with IC50 values of 19, 55 and 62 µg/ml, respectively. TAF273 induced apoptosis in a dose and time dependent manner. TAF273 arrested cell cycle at G1 and S phases. Intraperitoneal administration of TAF273 (50 mg/kg) resulted in a significant growth inhibition of subcutaneous tumor in TAF273-treated mice compared with the control mice (P = 0.024). TAF273 shows potent anti-proliferative activity in vitro and in vivo models of CML and therefore, justifies further efforts to define more clearly the potential benefits of using TAF273 as a novel therapeutic strategy for CML management.

Matched MeSH terms: Mice

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