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Sandra Rizk
Department of Natural Sciences, Lebanese American University, Byblos, Lebanon

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Journal article
Published: 02 June 2021 in Biomedicine & Pharmacotherapy
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Annonaceae family has broad uses in herbal medicine for treatment of several diseases, whether through seeds’ or leaves’ extracts. The present study investigates the antiproliferative and antitumor activity of Annona cherimola aqueous leaf (AAL) extract/infusion in acute myeloid leukemia (AML) cell lines in vitro. High-resolution LC-MS was first used to analyze the composition of the aqueous extract. Cell proliferation assay, Annexin V staining, cell cycle analysis, dual Annexin V/PI staining, cell death quantification by ELISA, ROS level detection and Western Blotting were then performed to elucidate the therapeutic effects of AAL extract. The results obtained revealed a potent antioxidant activity of AAL extract. Moreover, the extract exhibited dose- and time-dependent antiproliferative effects on AML cell lines by decreasing cell viability with an IC50 of 5.03% (v/v) at 24 h of treatment of KG-1 cells. This decrease in viability was accompanied with a significant increase in apoptotic cell death with cell cycle arrest and flipping of the phosphatidylserine from the inner to the outer leaflet of the cell membrane. The respective overexpression and downregulation of proapoptotic proteins like cleaved caspase-8, cleaved PARP-1 and Bax and antiapoptotic proteins like Bcl-2 further validated the apoptotic pathway induced by AAL on AML cells. Finally, LC-MS revealed the presence of several compounds like fatty acids, terpenes, phenolics, cinnamic acids and flavonoids that could contribute to the antioxidant and anti-cancer effects of this herbal infusion. In addition to the generally known nutritional effects of the Annona cherimola fruit and leaves, the presented data validates the antioxidant and anti-cancerous effects of the leaf infusion on AML cell lines, proposing its potential therapeutic use against acute myeloid leukemia with future in vivo and clinical trials.

ACS Style

Tony Haykal; Maria Younes; Marianne El Khoury; Carl Ammoury; Stephanie Tannous; Mohammad H. Hodroj; Rita Sarkis; Natalia Gasilova; Laure Menin; Sandra Rizk. The pro-apoptotic properties of a phytonutrient rich infusion of A. cherimola leaf extract on AML cells. Biomedicine & Pharmacotherapy 2021, 140, 111592 .

AMA Style

Tony Haykal, Maria Younes, Marianne El Khoury, Carl Ammoury, Stephanie Tannous, Mohammad H. Hodroj, Rita Sarkis, Natalia Gasilova, Laure Menin, Sandra Rizk. The pro-apoptotic properties of a phytonutrient rich infusion of A. cherimola leaf extract on AML cells. Biomedicine & Pharmacotherapy. 2021; 140 ():111592.

Chicago/Turabian Style

Tony Haykal; Maria Younes; Marianne El Khoury; Carl Ammoury; Stephanie Tannous; Mohammad H. Hodroj; Rita Sarkis; Natalia Gasilova; Laure Menin; Sandra Rizk. 2021. "The pro-apoptotic properties of a phytonutrient rich infusion of A. cherimola leaf extract on AML cells." Biomedicine & Pharmacotherapy 140, no. : 111592.

Journal article
Published: 29 January 2021 in Nutrients
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Rosa canina L. is a natural polyphenol-rich medicinal plant that exhibits antioxidant and anti-inflammatory activities. Recent in vivo studies have demonstrated that a methanol extract of Rosa canina L. (RCME) has reversed an inflammatory bowel disease (IBD)-like phenotype that has been triggered by dextran sulfate sodium (DSS) in mice. In the current study, we investigated the effects of RCME on perturbations of cellular mechanisms induced by DSS-treatment of intestinal Caco-2 cells, including stress response in the endoplasmic reticulum (ER), protein trafficking and sorting as well as lipid rafts integrity and functional capacities of an intestinal enzyme. 6 days post-confluent cells were treated for 24 h with DSS (3%) or simultaneously with DSS (3%) and RCME (100 µg/mL) or exclusively with RCME (100 µg/mL) or not treated. The results obtained demonstrate the ability of RCME to counteract the substantial increase in the expression levels of several ER stress markers in DSS-treated cells. Concomitantly, the delayed trafficking of intestinal membrane glycoproteins sucrase-isomaltase (SI) and dipeptidyl peptidase 4 (DPP4) induced by DSS between the ER and the Golgi has been compromised by RCME. Furthermore, RCME restored the partially impaired polarized sorting of SI and DPP4 to the brush border membrane. An efficient sorting mechanism of SI and DPP4 is tightly associated with intact lipid rafts structures in the trans-Golgi network (TGN), which have been distorted by DSS and normalized by RCME. Finally, the enzymatic activities of SI are enhanced in the presence of RCME. Altogether, DSS treatment has triggered ER stress, impaired trafficking and function of membrane glycoproteins and distorted lipid rafts, all of which can be compromised by RCME. These findings indicate that the antioxidants in RCME act at two major sites in Caco-2 cells, the ER and the TGN and are thus capable of maintaining the membrane integrity by correcting the sorting of membrane-associated proteins.

ACS Style

Dalanda Wanes; Mohamad Toutounji; Hichem Sebai; Sandra Rizk; Hassan Naim. Rosa canina L. Can Restore Endoplasmic Reticulum Alterations, Protein Trafficking and Membrane Integrity in a Dextran Sulfate Sodium-Induced Inflammatory Bowel Disease Phenotype. Nutrients 2021, 13, 441 .

AMA Style

Dalanda Wanes, Mohamad Toutounji, Hichem Sebai, Sandra Rizk, Hassan Naim. Rosa canina L. Can Restore Endoplasmic Reticulum Alterations, Protein Trafficking and Membrane Integrity in a Dextran Sulfate Sodium-Induced Inflammatory Bowel Disease Phenotype. Nutrients. 2021; 13 (2):441.

Chicago/Turabian Style

Dalanda Wanes; Mohamad Toutounji; Hichem Sebai; Sandra Rizk; Hassan Naim. 2021. "Rosa canina L. Can Restore Endoplasmic Reticulum Alterations, Protein Trafficking and Membrane Integrity in a Dextran Sulfate Sodium-Induced Inflammatory Bowel Disease Phenotype." Nutrients 13, no. 2: 441.

Communication
Published: 22 December 2020 in Nutrients
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Congenital sucrase-isomaltase deficiency (CSID) is a rare metabolic intestinal disorder with reduced or absent activity levels of sucrase-isomaltase (SI). Interestingly, the main symptoms of CSID overlap with those in irritable bowel syndrome (IBS), a common functional gastrointestinal disorder with unknown etiology. Recent advances in genetic screening of IBS patients have revealed rare SI gene variants that are associated with IBS. Here, we investigated the biochemical, cellular and functional phenotypes of several of these variants. The data demonstrate that the SI mutants can be categorized into three groups including immature, mature but slowly transported, and finally mature and properly transported but with reduced enzymatic activity. We also identified SI mutant phenotypes that are deficient but generally not as severe as those characterized in CSID patients. The variable effects on the trafficking and function of the mutations analyzed in this study support the view that both CSID and IBS are heterogeneous disorders, the severity of which is likely related to the biochemical phenotypes of the SI mutants as well as the environment and diet of patients. Our study underlines the necessity to screen for SI mutations in IBS patients and to consider enzyme replacement therapy as an appropriate therapy as in CSID.

ACS Style

Diab M. Husein; Sandra Rizk; Hassan Y. Naim. Differential Effects of Sucrase-Isomaltase Mutants on Its Trafficking and Function in Irritable Bowel Syndrome: Similarities to Congenital Sucrase-Isomaltase Deficiency. Nutrients 2020, 13, 9 .

AMA Style

Diab M. Husein, Sandra Rizk, Hassan Y. Naim. Differential Effects of Sucrase-Isomaltase Mutants on Its Trafficking and Function in Irritable Bowel Syndrome: Similarities to Congenital Sucrase-Isomaltase Deficiency. Nutrients. 2020; 13 (1):9.

Chicago/Turabian Style

Diab M. Husein; Sandra Rizk; Hassan Y. Naim. 2020. "Differential Effects of Sucrase-Isomaltase Mutants on Its Trafficking and Function in Irritable Bowel Syndrome: Similarities to Congenital Sucrase-Isomaltase Deficiency." Nutrients 13, no. 1: 9.

Journal article
Published: 13 November 2020 in BMC Complementary Medicine and Therapies
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Background Herbal medicines have been a major target for numerous studies through the past years as an alternative treatment for cancer, mainly due to their minimal effects on normal healthy cells. Annona cherimola, popularly known as Cherimoya, is an edible natural fruit rich in phytochemical components and known to possess various biological activities. Previous studies have reported the anti-cancerous effect of A. cherimola ethanolic leaf extract (AELE) on leukemia. This study aims at studying the potential anti-cancer activity of this extract in vitro in two different breast cancer cell lines, namely MDA-MB-231 and MCF-7, in addition to investigating its toxicity on normal mesenchymal stem cells. Methods The anti-proliferative effect of AELE was evaluated via cell viability assay. Propidium iodide staining, Cell Death Detection ELISA and flow cytometry analysis of Annexin V binding were used to assess cell cycle progression, DNA fragmentation and apoptosis induction, respectively. Protein expression was determined via Western Blot analysis to decipher the underlying apoptotic molecular mechanism induced upon AELE treatment. Results The anti-proliferative effect of the extract was found to be selective on the triple-negative breast cancer cell line (MDA-MB-231) in a time- and dose-dependent manner with an IC50 of 390.2 μg/mL at 48 h, with no cytotoxic effects on normal murine mesenchymal stem cells. The pro-apoptotic effect was confirmed by the increase in cellular and DNA fragmentation, flipping of the phosphatidylserine moiety to the outer leaflet, and the increase in Annexin V binding. The underlying molecular mechanism revealed the involvement of the mitochondrial pathway, as shown by alterations in mitochondrial permeability and the upregulation of cytochrome c expression. Conclusion All the data presented in our study suggest that AELE exhibits a selective anti-proliferative and pro-apoptotic effect on the chemo-resistant MDA-MB-231 breast cancer cells, providing evidence for the anti-tumor effects of A. cherimola.

ACS Style

Maria Younes; Carl Ammoury; Tony Haykal; Leah Nasr; Rita Sarkis; Sandra Rizk. The selective anti-proliferative and pro-apoptotic effect of A. cherimola on MDA-MB-231 breast cancer cell line. BMC Complementary Medicine and Therapies 2020, 20, 1 -10.

AMA Style

Maria Younes, Carl Ammoury, Tony Haykal, Leah Nasr, Rita Sarkis, Sandra Rizk. The selective anti-proliferative and pro-apoptotic effect of A. cherimola on MDA-MB-231 breast cancer cell line. BMC Complementary Medicine and Therapies. 2020; 20 (1):1-10.

Chicago/Turabian Style

Maria Younes; Carl Ammoury; Tony Haykal; Leah Nasr; Rita Sarkis; Sandra Rizk. 2020. "The selective anti-proliferative and pro-apoptotic effect of A. cherimola on MDA-MB-231 breast cancer cell line." BMC Complementary Medicine and Therapies 20, no. 1: 1-10.

Journal article
Published: 17 October 2020 in Biomedicine & Pharmacotherapy
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Flaxseeds have been known for their anti-cancerous effects due to the high abundance of lignans released upon ingestion. The most abundant lignan, secoisolariciresinol diglucoside (SDG), is ingested during the dietary intake of flax, and is then metabolized in the gut into two mammalian lignan derivatives, Enterodiol (END) and Enterolactone (ENL). These lignans were previously reported to possess anti-tumor effects against breast, colon, and lung cancer. This study aims to investigate the potential anti-cancerous effect of the flaxseed lignans SDG, END and ENL on acute myeloid leukemia cells (AML) in vitro and to decipher the underlying molecular mechanism. AML cell lines, (KG-1 and Monomac-1) and a normal lymphoblastic cell line were cultured and treated with the purified lignans. ENL was found to be the most promising lignan, as it exhibits a significant selective dose- and time-dependent cytotoxic effect in both AML cell lines, contrary to normal cells. The cytotoxic effects observed were attributed to apoptosis induction, as revealed by an increase in Annexin V staining of AML cells with increasing ENL concentrations. The increase in the percentage of cells in the pre-G phase, in addition to cell death ELISA analysis, validated cellular and DNA fragmentation respectively. Analysis of protein expression using western blots confirmed the activation of the intrinsic apoptotic pathway upon ENL treatment. This was also accompanied by an increase in ROS production intracellularly. In conclusion, this study demonstrates that ENL has promising anti-cancer effects in AML cell lines in vitro, by promoting DNA fragmentation and the intrinsic apoptotic pathway, highlighting the protective health benefits of flax seeds in leukemia.

ACS Style

Stephanie Tannous; Tony Haykal; Jana Dhaini; Mohammad Hassan Hodroj; Sandra Rizk. The anti-cancer effect of flaxseed lignan derivatives on different acute myeloid leukemia cancer cells. Biomedicine & Pharmacotherapy 2020, 132, 110884 .

AMA Style

Stephanie Tannous, Tony Haykal, Jana Dhaini, Mohammad Hassan Hodroj, Sandra Rizk. The anti-cancer effect of flaxseed lignan derivatives on different acute myeloid leukemia cancer cells. Biomedicine & Pharmacotherapy. 2020; 132 ():110884.

Chicago/Turabian Style

Stephanie Tannous; Tony Haykal; Jana Dhaini; Mohammad Hassan Hodroj; Sandra Rizk. 2020. "The anti-cancer effect of flaxseed lignan derivatives on different acute myeloid leukemia cancer cells." Biomedicine & Pharmacotherapy 132, no. : 110884.

Journal article
Published: 01 September 2020 in Journal of Complementary and Integrative Medicine
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Background Colorectal cancer (CRC) is a major public health problem, with almost 1.8 million newly diagnosed cases and about 881,000 deaths annually. Chamomile (Matricaria chamomilla) is a well-documented medicinal herb that possesses anti-inflammatory and anti-carcinogenic properties. This study aimed to unravel the effect of aqueous chamomile extract against 1,2-dimethylhydrazine(DMH)-induced CRC in mice. Methods Male Balb/c mice received a weekly intraperitoneal injection of DMH (20 mg/kg body weight) for 12 weeks. Chamomile extract (150 mg/kg body weight/5 days/week p.o.) was administered at the initiation and post-initiation stages of carcinogenesis. Polyps count, histopathological analysis, real-time polymerase chain reaction (RT-PCR) analysis of Wnt signaling genes, ELISA of cyclooxygenase-2 (COX-2), and enzyme assay for inducible nitric oxide synthase (iNOS) were performed. Results Chamomile extract modulated the Wnt pathway in colonic tissues, where it significantly downregulated Wnt5a, β-catenin, T cell factor (Tcf4), lymphoid enhancer factor 1 (Lef1), c-Myc and Cyclin D1 expression levels, while it upregulated adenomatous polyposis coli (APC) and glycogen synthase kinase (GSK3β) expression levels. This extract significantly reduced COX-2 levels and iNOS activities. Polyps count and histopathological analysis provided supportive evidence for the biochemical and molecular analyses. Conclusions Chamomile can act as a potent dietary chemopreventive agent against DMH-induced CRC.

ACS Style

Manal M. El Joumaa; Robin Taleb; Sandra Rizk; Jamilah M. Borjac. Protective effect of Matricaria chamomilla extract against 1,2-dimethylhydrazine-induced colorectal cancer in mice. Journal of Complementary and Integrative Medicine 2020, 17, 1 .

AMA Style

Manal M. El Joumaa, Robin Taleb, Sandra Rizk, Jamilah M. Borjac. Protective effect of Matricaria chamomilla extract against 1,2-dimethylhydrazine-induced colorectal cancer in mice. Journal of Complementary and Integrative Medicine. 2020; 17 (3):1.

Chicago/Turabian Style

Manal M. El Joumaa; Robin Taleb; Sandra Rizk; Jamilah M. Borjac. 2020. "Protective effect of Matricaria chamomilla extract against 1,2-dimethylhydrazine-induced colorectal cancer in mice." Journal of Complementary and Integrative Medicine 17, no. 3: 1.

Journal article
Published: 28 August 2020 in Nutrients
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Urtica dioica (UD), commonly known as “stinging nettle”, is a herbaceous flowering plant that is a widely used agent in traditional medicine worldwide. Several formulations of UD leaf extract have been reported to exhibit anti-inflammatory and antioxidant properties, with anticancer potential. The current study investigated the possible anticancer properties of nettle tea, prepared from Urtica dioica leaves, on acute myeloid leukemia (AML) cell lines, and deciphered the underlying molecular mechanisms. Treatment of AML cell lines (U-937 and KG-1) with UD aqueous leaf extract resulted in a dose- and time-dependent inhibition of proliferation, an increase in apoptotic hallmarks such as phosphatidylserine flipping to the outer membrane leaflet, and DNA fragmentation as revealed by cell-death ELISA and cell-cycle analysis assays. Apoptosis induction in U937 cells involves alterations in the expression of Bax and Bcl-2 upon exposure to nettle tea. Furthermore, the chemical composition of UD aqueous extract indicated the presence of multiple chemical agents, such as flavonoids and phenolics, mainly patuletin, m/p-hydroxybenzoic acid, and caffeic acid, among others, to which the pro-apoptotic and anti-tumor effects may be attributed.

ACS Style

Mohammad Hassan Hodroj; Nour Al Hoda Al Bast; Robin I. Taleb; Jamilah Borjac; Sandra Rizk. Nettle Tea Inhibits Growth of Acute Myeloid Leukemia Cells In Vitro by Promoting Apoptosis. Nutrients 2020, 12, 2629 .

AMA Style

Mohammad Hassan Hodroj, Nour Al Hoda Al Bast, Robin I. Taleb, Jamilah Borjac, Sandra Rizk. Nettle Tea Inhibits Growth of Acute Myeloid Leukemia Cells In Vitro by Promoting Apoptosis. Nutrients. 2020; 12 (9):2629.

Chicago/Turabian Style

Mohammad Hassan Hodroj; Nour Al Hoda Al Bast; Robin I. Taleb; Jamilah Borjac; Sandra Rizk. 2020. "Nettle Tea Inhibits Growth of Acute Myeloid Leukemia Cells In Vitro by Promoting Apoptosis." Nutrients 12, no. 9: 2629.

Journal article
Published: 21 August 2020 in Chemosphere
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In this study, the acute toxicological impacts associated with electronic cigarettes consumption were determined using a novel dynamic exposure methodology. The methodology was deployed to test various e-cigarette generated aerosols in A549 cell cultures. The e-liquid chemical profiling was achieved using GC-MS analysis while toxicity of diluted e-liquids aerosols was reported using numerous cytotoxicity assays. The presented findings pointed to acute aerosol exposure (thirty puffs at 40 W of power and higher) inducing significant cytotoxic, genotoxic, and apoptotic induction in exposed cells. These findings highlighted the significant risks posed by e-cigarette usage. The proposed methodology proved to be a useful tool for future screening of e-liquids generated aerosols toxicity. Future research is needed to establish the chronic toxicity resulting from long-term e-cigarette consumption.

ACS Style

Christian Khalil; Joe Braham Chahine; Tony Haykal; Cynthia Al Hageh; Sandra Rizk; Rony S. Khnayzer. E-cigarette aerosol induced cytotoxicity, DNA damages and late apoptosis in dynamically exposed A549 cells. Chemosphere 2020, 263, 127874 .

AMA Style

Christian Khalil, Joe Braham Chahine, Tony Haykal, Cynthia Al Hageh, Sandra Rizk, Rony S. Khnayzer. E-cigarette aerosol induced cytotoxicity, DNA damages and late apoptosis in dynamically exposed A549 cells. Chemosphere. 2020; 263 ():127874.

Chicago/Turabian Style

Christian Khalil; Joe Braham Chahine; Tony Haykal; Cynthia Al Hageh; Sandra Rizk; Rony S. Khnayzer. 2020. "E-cigarette aerosol induced cytotoxicity, DNA damages and late apoptosis in dynamically exposed A549 cells." Chemosphere 263, no. : 127874.

Journal article
Published: 15 April 2020 in International Journal of Molecular Sciences
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A key morphological feature of inflammatory bowel disease (IBD) is the loss of the barrier function of intestinal epithelial cells. The present study investigates endoplasmic reticulum (ER) stress in addition to alterations in protein and membrane trafficking in a dextran sulfate sodium (DSS)-induced IBD-like phenotype of intestinal Caco-2 cells in culture. DSS treatment significantly reduced the transepithelial electric resistance (TEER) and increased the epithelial permeability of Caco-2 cells, without affecting their viability. This was associated with an alteration in the expression levels of inflammatory factors in addition to an increase in the expression of the ER stress protein markers, namely immunoglobulin-binding protein (BiP), C/EBP homologous protein (CHOP), activation transcription factor 4 (ATF4), and X-box binding protein (XBP1). The DSS-induced ER-stress resulted in impaired intracellular trafficking and polarized sorting of sucrase-isomaltase (SI) and dipeptidyl peptidase-4 (DPPIV), which are normally sorted to the apical membrane via association with lipid rafts. The observed impaired sorting was caused by reduced cholesterol levels and subsequent distortion of the lipid rafts. The data presented confirm perturbation of ER homeostasis in DSS-treated Caco-2 cells, accompanied by impairment of membrane and protein trafficking resulting in altered membrane integrity, cellular polarity, and hence disrupted barrier function.

ACS Style

Mohamad Toutounji; Dalanda Wanes; Mohammad El-Harakeh; Marwan El-Sabban; Sandra Rizk; Hassan Y. Naim. Dextran Sodium Sulfate-Induced Impairment of Protein Trafficking and Alterations in Membrane Composition in Intestinal Caco-2 Cell Line. International Journal of Molecular Sciences 2020, 21, 2726 .

AMA Style

Mohamad Toutounji, Dalanda Wanes, Mohammad El-Harakeh, Marwan El-Sabban, Sandra Rizk, Hassan Y. Naim. Dextran Sodium Sulfate-Induced Impairment of Protein Trafficking and Alterations in Membrane Composition in Intestinal Caco-2 Cell Line. International Journal of Molecular Sciences. 2020; 21 (8):2726.

Chicago/Turabian Style

Mohamad Toutounji; Dalanda Wanes; Mohammad El-Harakeh; Marwan El-Sabban; Sandra Rizk; Hassan Y. Naim. 2020. "Dextran Sodium Sulfate-Induced Impairment of Protein Trafficking and Alterations in Membrane Composition in Intestinal Caco-2 Cell Line." International Journal of Molecular Sciences 21, no. 8: 2726.

Mini review article
Published: 15 April 2020 in Frontiers in Molecular Biosciences
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Heat shock protein 60 (HSP60) is a mitochondrial chaperone that is implicated in physiological and pathological processes. For instance, it contributes to protein folding and stability, translocation of mitochondrial proteins, and apoptosis. Variations in the expression levels of HSP60 have been correlated to various diseases and cancers, including hepatocellular carcinoma (HCC). Unlike other HSPs which clearly increase in some cancers, data about HSP60 levels in HCC are controversial and difficult to interpret. In the current review, we summarize and simplify the current knowledge about the role of HSP60 in HCC. In addition, we highlight the possibility of its targeting, using chemical compounds and/or genetic tools for treatment of HCC.

ACS Style

Abdullah Hoter; Sandra Rizk; Hassan Y. Naim. Heat Shock Protein 60 in Hepatocellular Carcinoma: Insights and Perspectives. Frontiers in Molecular Biosciences 2020, 7, 60 .

AMA Style

Abdullah Hoter, Sandra Rizk, Hassan Y. Naim. Heat Shock Protein 60 in Hepatocellular Carcinoma: Insights and Perspectives. Frontiers in Molecular Biosciences. 2020; 7 ():60.

Chicago/Turabian Style

Abdullah Hoter; Sandra Rizk; Hassan Y. Naim. 2020. "Heat Shock Protein 60 in Hepatocellular Carcinoma: Insights and Perspectives." Frontiers in Molecular Biosciences 7, no. : 60.

Journal article
Published: 09 April 2020 in Biomolecules
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Studies on tocotrienols have progressively revealed the benefits of these vitamin E isoforms on human health. Beta-tocotrienol (beta-T3) is known to be less available in nature compared to other vitamin E members, which may explain the restricted number of studies on beta-T3. In the present study, we aim to investigate the anti-proliferative effects and the pro-apoptotic mechanisms of beta-T3 on two human breast adenocarcinoma cell lines MDA-MB-231 and MCF7. To assess cell viability, both cell lines were incubated for 24 and 48 h, with different concentrations of beta-T3 and gamma-T3, the latter being a widely studied vitamin E isoform with potent anti-cancerous properties. Cell cycle progression and apoptosis induction upon treatment with various concentrations of the beta-T3 isoform were assessed. The effect of beta-T3 on the expression level of several apoptosis-related proteins p53, cytochrome C, cleaved-PARP-1, Bax, Bcl-2, and caspase-3, in addition to key cell survival proteins p-PI3K and p-GSK-3 α/β was determined using western blot analysis. Beta-tocotrienol exhibited a significantly more potent anti-proliferative effect than gamma-tocotrienol on both cell lines regardless of their hormonal receptor status. Beta-T3 induced a mild G1 arrest on both cell lines, and triggered a mitochondrial stress-mediated apoptotic response in MDA-MB-231 cells. Mechanistically, beta-T3′s anti-neoplastic activity involved the downregulation of phosphorylated PI3K and GSK-3 cell survival proteins. These findings suggest that vitamin E beta-T3 should be considered as a promising anti-cancer agent, more effective than gamma-T3 for treating human breast cancer and deserves to be further studied to investigate its effects in vitro and on other cancer types.

ACS Style

Maya Idriss; Mohammad Hassan Hodroj; Rajaa Fakhoury; Sandra Rizk. Beta-Tocotrienol Exhibits More Cytotoxic Effects than Gamma-Tocotrienol on Breast Cancer Cells by Promoting Apoptosis via a P53-Independent PI3-Kinase Dependent Pathway. Biomolecules 2020, 10, 577 .

AMA Style

Maya Idriss, Mohammad Hassan Hodroj, Rajaa Fakhoury, Sandra Rizk. Beta-Tocotrienol Exhibits More Cytotoxic Effects than Gamma-Tocotrienol on Breast Cancer Cells by Promoting Apoptosis via a P53-Independent PI3-Kinase Dependent Pathway. Biomolecules. 2020; 10 (4):577.

Chicago/Turabian Style

Maya Idriss; Mohammad Hassan Hodroj; Rajaa Fakhoury; Sandra Rizk. 2020. "Beta-Tocotrienol Exhibits More Cytotoxic Effects than Gamma-Tocotrienol on Breast Cancer Cells by Promoting Apoptosis via a P53-Independent PI3-Kinase Dependent Pathway." Biomolecules 10, no. 4: 577.

Journal article
Published: 19 March 2020 in International Journal of Molecular Sciences
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Niemann-Pick Type C (NPC) is an autosomal recessive lysosomal storage disease leading to progressive neurodegeneration. Mutations in the NPC1 gene, which accounts for 95% of the cases, lead to a defect in intra-lysosomal trafficking of cholesterol and an accumulation of storage material including cholesterol and sphingolipids in the endo-lysosomal system. Symptoms are progressive neurological and visceral deterioration, with variable onset and severity of the disease. This study investigates the influence of two different NPC1 mutations on the biochemical phenotype in fibroblasts isolated from NPC patients in comparison to healthy, wild type (WT) cells. Skin derived fibroblasts were cultured from one patient compound-heterozygous for D874V/D948Y mutations, which presented wild-type like intracellular trafficking of NPC1, and a second patient compound- heterozygous for I1061T/P887L mutations, which exhibited a more severe biochemical phenotype as revealed in the delayed trafficking of NPC1. Biochemical analysis using HPLC and TLC indicated that lipid accumulations were mutation-dependent and correlated with the trafficking pattern of NPC1: higher levels of cholesterol and glycolipids were associated with the mutations that exhibited delayed intracellular trafficking, as compared to their WT-like trafficked or wild type (WT) counterparts. Furthermore, variations in membrane structure was confirmed in these cell lines based on alteration in lipid rafts composition as revealed by the shift in flotillin-2 (FLOT2) distribution, a typical lipid rafts marker, which again showed marked alterations only in the NPC1 mutant showing major trafficking delay. Finally, treatment with N-butyldeoxynojirimycin (NB-DNJ, Miglustat) led to a reduction of stored lipids in cells from both patients to various extents, however, no normalisation in lipid raft structure was achieved. The data presented in this study help in understanding the varying biochemical phenotypes observed in patients harbouring different mutations, which explain why the effectiveness of NB-DNJ treatment is patient specific.

ACS Style

Graham Brogden; Hadeel Shammas; Friederike Walters; Katia Maalouf; Anibh M. Das; Hassan Y. Naim; Sandra Rizk. Different Trafficking Phenotypes of Niemann-Pick C1 Gene Mutations Correlate with Various Alterations in Lipid Storage, Membrane Composition and Miglustat Amenability. International Journal of Molecular Sciences 2020, 21, 2101 .

AMA Style

Graham Brogden, Hadeel Shammas, Friederike Walters, Katia Maalouf, Anibh M. Das, Hassan Y. Naim, Sandra Rizk. Different Trafficking Phenotypes of Niemann-Pick C1 Gene Mutations Correlate with Various Alterations in Lipid Storage, Membrane Composition and Miglustat Amenability. International Journal of Molecular Sciences. 2020; 21 (6):2101.

Chicago/Turabian Style

Graham Brogden; Hadeel Shammas; Friederike Walters; Katia Maalouf; Anibh M. Das; Hassan Y. Naim; Sandra Rizk. 2020. "Different Trafficking Phenotypes of Niemann-Pick C1 Gene Mutations Correlate with Various Alterations in Lipid Storage, Membrane Composition and Miglustat Amenability." International Journal of Molecular Sciences 21, no. 6: 2101.

Journal article
Published: 13 February 2020 in Cancers
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Malva pseudolavatera Webb & Berthel. is a plant from the Malvaceae family that has long been included in the human diet due to its various curative effects. Many plant leaf extracts from the various species of Malva genus have been reported to possess anti-cancer properties, however, studies on M. pseudolavatera Webb & Berthel. leaves have documented anti-inflammatory and anti-oxidant effects with no emphasis on their possible anti-cancer potential. The present study explores the anti-cancer properties of Malva pseudolavatera Webb & Berthel. leaf extract on acute myeloid leukemia (AML) cell lines in vitro and deciphers the underlying molecular mechanism. Treatment of AML cell lines with M. pseudolavatera methanolic leaf extract showed a dose- and time-dependent inhibition of proliferation and a dose-dependent increase in apoptotic hallmarks such as an increase in phosphatidylserine on the outer membrane leaflet and membrane leakage in addition to DNA fragmentation. The pro-apoptotic effect was induced by reactive oxygen species (ROS) as well as an upregulation of cleaved poly(ADP-ribose) polymerase (PARP), increase in Bax/Bcl-2 ratio, andrelease of cytochrome-c from the mitochondria. Major compounds of the extract included methyl linolenate, phytol, γ-sitosterol, and stigmasterol as revealed by gas chromatography coupled with mass spectrometry, and amino acids, amino acid derivatives, tiliroside, 13-hydroxyperoxyoctadecadienoic, and quercitrin as detected by liquid chromatography coupled to mass spectrometry.

ACS Style

Marianne El Khoury; Tony Haykal; Mohammad H. Hodroj; Sonia Abou Najem; Rita Sarkis; Robin I. Taleb; Sandra Rizk. Malva pseudolavatera Leaf Extract Promotes ROS Induction Leading to Apoptosis in Acute Myeloid Leukemia Cells In Vitro. Cancers 2020, 12, 435 .

AMA Style

Marianne El Khoury, Tony Haykal, Mohammad H. Hodroj, Sonia Abou Najem, Rita Sarkis, Robin I. Taleb, Sandra Rizk. Malva pseudolavatera Leaf Extract Promotes ROS Induction Leading to Apoptosis in Acute Myeloid Leukemia Cells In Vitro. Cancers. 2020; 12 (2):435.

Chicago/Turabian Style

Marianne El Khoury; Tony Haykal; Mohammad H. Hodroj; Sonia Abou Najem; Rita Sarkis; Robin I. Taleb; Sandra Rizk. 2020. "Malva pseudolavatera Leaf Extract Promotes ROS Induction Leading to Apoptosis in Acute Myeloid Leukemia Cells In Vitro." Cancers 12, no. 2: 435.

Journal article
Published: 12 December 2019 in BMC Complementary and Alternative Medicine
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Background The edible fruit Annona cherimola has previously shown many nutritional and medicinal properties. The current study evaluates the anti-cancer and anti-proliferative properties of Annona cherimola ethanolic leaf extract (AELE) on Acute Myeloid Leukemia (AML) cell lines cultured in vitro (Monomac-1 and KG-1). Methods The anti-proliferative effect of A. cherimola ethanolic leaf extract was evaluated via cell viability assay. Its pro-apoptotic effect was assessed through Cell Death ELISA and dual Annexin V/PI staining. To further investigate the molecular mechanism by which the extract promoted apoptosis and inhibited the proliferation of the AML cells used, apoptotic protein expression was determined through western blots. Extract composition was elucidated by Gas Chromatography-Mass Spectrometry (GC-MS). Results Our results showed that the treatment with A. cherimola ethanolic leaf extract exhibited an inhibitory effect on the proliferation of both cancer cell lines used in a dose- and time-dependent manner, with no toxic effects on normal mononuclear cells (MNCs) isolated from human bone marrow. This effect was mediated by DNA fragmentation and apoptosis, as revealed by Cell Death ELISA and dual Annexin V/PI staining. Western blot analysis revealed a Bax/Bcl2 dependent mechanism of apoptosis, as well as PARP cleavage, confirming the apoptotic results observed previously. These effects may be attributed to the presence of terpenes which constitute a large component of the leafy extract, as revealed via GC-MS. Conclusion All the data presented in our study show that the terpene-rich A. cherimola ethanolic leaf extract exhibits an anti-proliferative and pro-apoptotic effect on the AML cell lines used.

ACS Style

Carl Ammoury; Maria Younes; Marianne El Khoury; Mohammad H. Hodroj; Tony Haykal; Peter Nasr; Marilyne Sily; Robin I. Taleb; Rita Sarkis; Rana Khalife; Sandra Rizk. The pro-apoptotic effect of a Terpene-rich Annona cherimola leaf extract on leukemic cell lines. BMC Complementary and Alternative Medicine 2019, 19, 1 -10.

AMA Style

Carl Ammoury, Maria Younes, Marianne El Khoury, Mohammad H. Hodroj, Tony Haykal, Peter Nasr, Marilyne Sily, Robin I. Taleb, Rita Sarkis, Rana Khalife, Sandra Rizk. The pro-apoptotic effect of a Terpene-rich Annona cherimola leaf extract on leukemic cell lines. BMC Complementary and Alternative Medicine. 2019; 19 (1):1-10.

Chicago/Turabian Style

Carl Ammoury; Maria Younes; Marianne El Khoury; Mohammad H. Hodroj; Tony Haykal; Peter Nasr; Marilyne Sily; Robin I. Taleb; Rita Sarkis; Rana Khalife; Sandra Rizk. 2019. "The pro-apoptotic effect of a Terpene-rich Annona cherimola leaf extract on leukemic cell lines." BMC Complementary and Alternative Medicine 19, no. 1: 1-10.

Journal article
Published: 21 November 2019 in Cells
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Atypical epigenetic processes including histone acetylation and DNA methylation have been identified as a fundamental theme in hematologic malignancies. Such mechanisms modify gene expression and prompt, in part at least, the initiation and progression of several malignancies including acute myeloid leukemia. In the current study we determined the effects of treating KG-1 and U937 acute myeloid leukemia (AML) cells, in vitro, with the HDAC inhibitor, suberoylanilide hydroxamic acid (SAHA), or with a DNMT inhibitor, decitabine (DAC), or their combination, on cell proliferation, cell cycle progression, apoptosis, and expression of apoptosis-related proteins. Each of SAHA and DAC attenuated cell proliferation and induced cell cycle arrest and apoptotic cell death of KG-1 and U937 cell lines. Besides, their sequential combination improved the obtained anti-neoplastic effect: significant augmentation of growth inhibition and apoptosis induction as compared to cells treated with either drug alone. This effect was featured by the upregulated expression of Bax, cytochrome c1, p21, and cleaved caspases 8, 9, and 3, signifying the activation of both the intrinsic and extrinsic pathways of apoptosis. The sequential combination of SAHA and DAC causes a profound antitumorigenic effect in AML cell lines by inducing the expression of tumor suppressor genes.

ACS Style

Sonia Abou Najem; Ghada Khawaja; Mohammad Hassan Hodroj; Patil Babikian; Sandra Rizk; Abou Najem; Rizk. Adjuvant Epigenetic Therapy of Decitabine and Suberoylanilide Hydroxamic Acid Exerts Anti-Neoplastic Effects in Acute Myeloid Leukemia Cells. Cells 2019, 8, 1480 .

AMA Style

Sonia Abou Najem, Ghada Khawaja, Mohammad Hassan Hodroj, Patil Babikian, Sandra Rizk, Abou Najem, Rizk. Adjuvant Epigenetic Therapy of Decitabine and Suberoylanilide Hydroxamic Acid Exerts Anti-Neoplastic Effects in Acute Myeloid Leukemia Cells. Cells. 2019; 8 (12):1480.

Chicago/Turabian Style

Sonia Abou Najem; Ghada Khawaja; Mohammad Hassan Hodroj; Patil Babikian; Sandra Rizk; Abou Najem; Rizk. 2019. "Adjuvant Epigenetic Therapy of Decitabine and Suberoylanilide Hydroxamic Acid Exerts Anti-Neoplastic Effects in Acute Myeloid Leukemia Cells." Cells 8, no. 12: 1480.

Journal article
Published: 17 November 2019 in Nutrients
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Acute myeloid leukemia (AML) is a blood cancer characterized by the formation of faulty defective myelogenous cells with morphological heterogeneity and cytogenic aberrations leading to a loss of their function. In an attempt to find an effective and safe AML treatment, vitamin E derivatives, including tocopherols were considered as potential anti-tumor compounds. Recently, other isoforms of vitamin E, namely tocotrienols have been proposed as potential potent anti-cancerous agents, displaying promising therapeutic effects in different cancer types. In this study we evaluated the anti-cancerous effects of γ-tocotrienol, on AML cell lines in vitro. For this purpose, AML cell lines incubated with γ-tocotrienol were examined for their viability, cell cycle status, apoptotic cell death, DNA fragmentation, production of reactive oxygen species and expression of proapoptotic proteins. Our results showed that γ-tocotrienol exhibits time and dose-dependent anti-proliferative, pro-apoptotic and antioxidant effects on U937 and KG-1 cell lines, through the upregulation of proteins involved in the intrinsic apoptotic pathway.

ACS Style

Paola Ghanem; Annalise Zouein; Maya Mohamad; Mohammad H. Hodroj; Tony Haykal; Sonia Abou Najem; Hassan Y. Naim; Sandra Rizk. The Vitamin E Derivative Gamma Tocotrienol Promotes Anti-Tumor Effects in Acute Myeloid Leukemia Cell Lines. Nutrients 2019, 11, 2808 .

AMA Style

Paola Ghanem, Annalise Zouein, Maya Mohamad, Mohammad H. Hodroj, Tony Haykal, Sonia Abou Najem, Hassan Y. Naim, Sandra Rizk. The Vitamin E Derivative Gamma Tocotrienol Promotes Anti-Tumor Effects in Acute Myeloid Leukemia Cell Lines. Nutrients. 2019; 11 (11):2808.

Chicago/Turabian Style

Paola Ghanem; Annalise Zouein; Maya Mohamad; Mohammad H. Hodroj; Tony Haykal; Sonia Abou Najem; Hassan Y. Naim; Sandra Rizk. 2019. "The Vitamin E Derivative Gamma Tocotrienol Promotes Anti-Tumor Effects in Acute Myeloid Leukemia Cell Lines." Nutrients 11, no. 11: 2808.

Journal article
Published: 15 October 2019 in Current Molecular Pharmacology
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Background:Colorectal Cancer (CRC) is a common cause of oncological deaths worldwide. Alterations of the epigenetic landscape constitute a well-documented hallmark of CRC phenotype. The accumulation of aberrant DNA methylation and histone acetylation plays a major role in altering gene activity and driving tumor onset, progression and metastasis.Objective:In this study, we evaluated the effect of Suberoylanilide Hydroxamic Acid (SAHA), a panhistone deacetylase inhibitor, and Decitabine (DAC), a DNA methyltransferase inhibitor, either alone or in combination, on Caco-2 human colon cancer cell line in vitro.Results:Our results showed that SAHA and DAC, separately, significantly decreased cell proliferation, induced apoptosis and cell cycle arrest of Caco-2 cell line. On the other hand, the sequential treatment of Caco-2 cells, first with DAC and then with SAHA, induced a synergistic anti-tumor effect with a significant enhancement of growth inhibition and apoptosis induction in Caco-2 cell line as compared to cells treated with either drug alone. Furthermore, the combination therapy upregulates protein expression levels of pro-apoptotic proteins Bax, p53 and cytochrome c, downregulates the expression of antiapoptotic Bcl-2 protein and increases the cleavage of procaspases 8 and 9; this suggests that the combination activates apoptosis via both the intrinsic and extrinsic pathways. Mechanistically, we demonstrated that the synergistic anti-neoplastic activity of combined SAHA and DAC involves an effect on PI3K/AKT and Wnt/β-catenin signaling.Conclusion:In conclusion, our results provide evidence for the profound anti-tumorigenic effect of sequentially combined SAHA and DAC in the CRC cell line and offer new insights into the corresponding underlined molecular mechanism.

ACS Style

Sonia Abou Najem; Ghada Khawaja; Mohammad Hassan Hodroj; Sandra Rizk. Synergistic Effect of Epigenetic Inhibitors Decitabine and Suberoylanilide Hydroxamic Acid on Colorectal Cancer In vitro. Current Molecular Pharmacology 2019, 12, 281 -300.

AMA Style

Sonia Abou Najem, Ghada Khawaja, Mohammad Hassan Hodroj, Sandra Rizk. Synergistic Effect of Epigenetic Inhibitors Decitabine and Suberoylanilide Hydroxamic Acid on Colorectal Cancer In vitro. Current Molecular Pharmacology. 2019; 12 (4):281-300.

Chicago/Turabian Style

Sonia Abou Najem; Ghada Khawaja; Mohammad Hassan Hodroj; Sandra Rizk. 2019. "Synergistic Effect of Epigenetic Inhibitors Decitabine and Suberoylanilide Hydroxamic Acid on Colorectal Cancer In vitro." Current Molecular Pharmacology 12, no. 4: 281-300.

Journal article
Published: 30 August 2019 in Toxins
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Annona cherimola Mill is a large green fruit with black seeds widely known to possess toxic properties due to the presence of Annonaceous acetogenins. The present study investigates the anti-cancer properties of an Annona cherimola Mill ethanolic seed extract on Acute Myeloid Leukemia (AML) cell lines in vitro and elucidates the underlying cellular mechanism. The anti-proliferative effects of the extract on various AML cell lines and normal mesenchymal cells (MSCs) were assessed using WST-1 viability reagent. The pro-apoptotic effect of the extract was evaluated using Annexin V/PI staining and Cell Death ELISA. The underlying mechanism was deciphered by analyzing the expression of various proteins using western blots. Treatment with an A. cherimola seed ethanolic extract promotes a dose- and time-dependent inhibition of the proliferation of various AML cell lines, but not MSCs. Positive Annexin V staining, as well as DNA fragmentation, confirm an increase in apoptotic cell death by upregulating the expression of pro-apoptotic proteins which control both intrinsic and extrinsic pathways of apoptosis. GC/MS analysis revealed the presence of phytosterols, in addition to other bioactive compounds. In conclusion, Annona cherimola Mill seed extract, previously known to possess a potent toxic activity, induces apoptosis in AML cell lines by the activation of both the extrinsic and the intrinsic pathways.

ACS Style

Tony Haykal; Peter Nasr; Mohammad H. Hodroj; Robin I. Taleb; Rita Sarkis; Marvy Nadine El. Moujabber; Sandra Rizk. Annona cherimola Seed Extract Activates Extrinsic and Intrinsic Apoptotic Pathways in Leukemic Cells. Toxins 2019, 11, 506 .

AMA Style

Tony Haykal, Peter Nasr, Mohammad H. Hodroj, Robin I. Taleb, Rita Sarkis, Marvy Nadine El. Moujabber, Sandra Rizk. Annona cherimola Seed Extract Activates Extrinsic and Intrinsic Apoptotic Pathways in Leukemic Cells. Toxins. 2019; 11 (9):506.

Chicago/Turabian Style

Tony Haykal; Peter Nasr; Mohammad H. Hodroj; Robin I. Taleb; Rita Sarkis; Marvy Nadine El. Moujabber; Sandra Rizk. 2019. "Annona cherimola Seed Extract Activates Extrinsic and Intrinsic Apoptotic Pathways in Leukemic Cells." Toxins 11, no. 9: 506.

Review
Published: 16 August 2019 in Cancers
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Prostate cancer (PCa) is one of the most common cancer types in men worldwide. Heat shock proteins (HSPs) are molecular chaperones that are widely implicated in the pathogenesis, diagnosis, prognosis, and treatment of many cancers. The role of HSPs in PCa is complex and their expression has been linked to the progression and aggressiveness of the tumor. Prominent chaperones, including HSP90 and HSP70, are involved in the folding and trafficking of critical cancer-related proteins. Other members of HSPs, including HSP27 and HSP60, have been considered as promising biomarkers, similar to prostate-specific membrane antigen (PSMA), for PCa screening in order to evaluate and monitor the progression or recurrence of the disease. Moreover, expression level of chaperones like clusterin has been shown to correlate directly with the prostate tumor grade. Hence, targeting HSPs in PCa has been suggested as a promising strategy for cancer therapy. In the current review, we discuss the functions as well as the role of HSPs in PCa progression and further evaluate the approach of inhibiting HSPs as a cancer treatment strategy.

ACS Style

Abdullah Hoter; Sandra Rizk; Hassan Y. Naim; Rizk; Naim; And Hassan Y. Naim. The Multiple Roles and Therapeutic Potential of Molecular Chaperones in Prostate Cancer. Cancers 2019, 11, 1194 .

AMA Style

Abdullah Hoter, Sandra Rizk, Hassan Y. Naim, Rizk, Naim, And Hassan Y. Naim. The Multiple Roles and Therapeutic Potential of Molecular Chaperones in Prostate Cancer. Cancers. 2019; 11 (8):1194.

Chicago/Turabian Style

Abdullah Hoter; Sandra Rizk; Hassan Y. Naim; Rizk; Naim; And Hassan Y. Naim. 2019. "The Multiple Roles and Therapeutic Potential of Molecular Chaperones in Prostate Cancer." Cancers 11, no. 8: 1194.

Review article
Published: 19 June 2019 in Frontiers in Genetics
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To cope with the extreme heat stress and drought of the desert, the Arabian camel (Camelus dromedarius) has developed exceptional physiological and biochemical particularities. Previous reports focused mainly on the physiological features of Arabian camel and neglected its cellular and molecular characteristics. Heat shock proteins are suggested to play a key role in the protein homeostasis and thermotolerance. Therefore, we aim by this review to elucidate the implication of camel HSPs in its physiological adaptation to heat stress and compare them with HSPs in related mammalian species. Correlation of these molecules to the adaptive mechanisms in camel is of special importance to expand our understanding of the overall camel physiology and homeostasis.

ACS Style

Abdullah Hoter; Sandra Rizk; Hassan Y. Naim. Cellular and Molecular Adaptation of Arabian Camel to Heat Stress. Frontiers in Genetics 2019, 10, 588 .

AMA Style

Abdullah Hoter, Sandra Rizk, Hassan Y. Naim. Cellular and Molecular Adaptation of Arabian Camel to Heat Stress. Frontiers in Genetics. 2019; 10 ():588.

Chicago/Turabian Style

Abdullah Hoter; Sandra Rizk; Hassan Y. Naim. 2019. "Cellular and Molecular Adaptation of Arabian Camel to Heat Stress." Frontiers in Genetics 10, no. : 588.