TY  - JOUR
A1  - Fathy, Moustafa
A1  - Okabe, Motonori
A1  - Othman, Eman M.
A1  - Saad Eldien, Heba M.
A1  - Yoshida, Toshiko
T1  - Preconditioning of adipose-derived mesenchymal stem-like cells with eugenol potentiates their migration and proliferation in vitro and therapeutic abilities in rat hepatic fibrosis
JF  - Molecules
N2  - Mesenchymal stem cells (MSCs) have considerable therapeutic abilities in various disorders, including hepatic fibrosis. They may be affected with different culture conditions. This study investigated, on molecular basics, the effect of pretreatment with eugenol on the characteristics of adipose tissue-derived MSCs (ASCs) in vitro and the implication of eugenol preconditioning on the in vivo therapeutic abilities of ASCs against CCl\(_4\)-induced hepatic fibrosis in rats. The effect of eugenol on ASCs was assessed using viability, scratch migration and sphere formation assays. Expressions of genes and proteins were estimated by immunofluorescence or qRT-PCR. For the in vivo investigations, rats were divided into four groups: the normal control group, fibrotic (CCl\(_4\)) group, CCl\(_4\)+ASCs group and CCl\(_4\) + eugenol-preconditioned ASCs (CCl\(_4\)+E-ASCs) group. Eugenol affected the viability of ASCs in a concentration- and time-dependent manner. Eugenol improved their self-renewal, proliferation and migration abilities and significantly increased their expression of c-Met, reduced expression 1 (Rex1), octamer-binding transcription factor 4 (Oct4) and nanog genes. Furthermore, E-ASCs showed more of a homing ability than ASCs and improved the serum levels of ALT, AST, albumin, total bilirubin and hyaluronic acid more efficient than ASCs in treating CCl\(_4\)-induced hepatic fibrosis, which was confirmed with histopathology. More interestingly, compared to the CCl\(_4\)+ASCs group, CCl\(_4\)+E-ASCs group showed a lower expression of inducible nitric oxide synthase (iNOS), monocyte chemoattractant protein-1 (MCP-1), cluster of differentiation 163 (CD163) and tumor necrosis factor-α (TNF-α) genes and higher expression of matrix metalloproteinase (MMP)-9 and MMP-13 genes. This study, for the first time, revealed that eugenol significantly improved the self-renewal, migration and proliferation characteristics of ASCs, in vitro. In addition, we demonstrated that eugenol-preconditioning significantly enhanced the therapeutic abilities of the injected ASCs against CCl\(_4\)-induced hepatic fibrosis.
KW  - adipose tissue-derived MSCs
KW  - eugenol
KW  - migration
KW  - self-renewal
KW  - hepatic fibrosis
KW  - CCl\(_4\)
Y1  - 2020
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-203662
SN  - 1420-3049
VL  - 25
IS  - 9
ER  - 
TY  - JOUR
A1  - Abdel-Latif, Rania
A1  - Fathy, Moustafa
A1  - Anwar, Hend Ali
A1  - Naseem, Muhammad
A1  - Dandekar, Thomas
A1  - Othman, Eman M.
T1  - Cisplatin-induced reproductive toxicity and oxidative stress: ameliorative effect of kinetin
JF  - Antioxidants
N2  - Cisplatin is a commonly used chemotherapeutic agent; however, its potential side effects, including gonadotoxicity and infertility, are a critical problem. Oxidative stress has been implicated in the pathogenesis of cisplatin-induced testicular dysfunction. We investigated whether kinetin use at different concentrations could alleviate gonadal injury associated with cisplatin treatment, with an exploration of the involvement of its antioxidant capacity. Kinetin was administered in different doses of 0.25, 0.5, and 1 mg/kg, alone or along with cisplatin for 10 days. Cisplatin toxicity was induced via a single IP dose of 7 mg/kg on day four. In a dose-dependent manner, concomitant administration of kinetin with cisplatin significantly restored testicular oxidative stress parameters, corrected the distorted sperm quality parameters and histopathological changes, enhanced levels of serum testosterone and testicular StAR protein expression, as well as reduced the up-regulation of testicular TNF-α, IL-1β, Il-6, and caspase-3, caused by cisplatin. It is worth noting that the testicular protective effect of the highest kinetin dose was comparable/more potent and significantly higher than the effects of vitamin C and the lowest kinetin dose, respectively. Overall, these data indicate that kinetin may offer a promising approach for alleviating cisplatin-induced reproductive toxicity and organ damage, via ameliorating oxidative stress and reducing inflammation and apoptosis.
KW  - cytokinins
KW  - kinetin
KW  - cisplatin
KW  - reproductive toxicity
Y1  - 2022
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-271223
SN  - 2076-3921
VL  - 11
IS  - 5
ER  - 
TY  - JOUR
A1  - Naseem, Muhammad
A1  - Othman, Eman M.
A1  - Fathy, Moustafa
A1  - Iqbal, Jibran
A1  - Howari, Fares M.
A1  - AlRemeithi, Fatima A.
A1  - Kodandaraman, Geema
A1  - Stopper, Helga
A1  - Bencurova, Elena
A1  - Vlachakis, Dimitrios
A1  - Dandekar, Thomas
T1  - Integrated structural and functional analysis of the protective effects of kinetin against oxidative stress in mammalian cellular systems
JF  - Scientific Reports
N2  - Metabolism and signaling of cytokinins was first established in plants, followed by cytokinin discoveries in all kingdoms of life. However, understanding of their role in mammalian cells is still scarce. Kinetin is a cytokinin that mitigates the effects of oxidative stress in mammalian cells. The effective concentrations of exogenously applied kinetin in invoking various cellular responses are not well standardized. Likewise, the metabolism of kinetin and its cellular targets within the mammalian cells are still not well studied. Applying vitality tests as well as comet assays under normal and hyper-oxidative states, our analysis suggests that kinetin concentrations of 500 nM and above cause cytotoxicity as well as genotoxicity in various cell types. However, concentrations below 100 nM do not cause any toxicity, rather in this range kinetin counteracts oxidative burst and cytotoxicity. We focus here on these effects. To get insights into the cellular targets of kinetin mediating these pro-survival functions and protective effects we applied structural and computational approaches on two previously testified targets for these effects. Our analysis deciphers vital residues in adenine phosphoribosyltransferase (APRT) and adenosine receptor (A2A-R) that facilitate the binding of kinetin to these two important human cellular proteins. We finally discuss how the therapeutic potential of kinetin against oxidative stress helps in various pathophysiological conditions.
KW  - cytokinins
KW  - 6-benzylaminopurine
Y1  - 2020
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-231317
VL  - 10
ER  - 
TY  - JOUR
A1  - Othman, Eman M.
A1  - Fathy, Moustafa
A1  - Bekhit, Amany Abdlrehim
A1  - Abdel-Razik, Abdel-Razik H.
A1  - Jamal, Arshad
A1  - Nazzal, Yousef
A1  - Shams, Shabana
A1  - Dandekar, Thomas
A1  - Naseem, Muhammad
T1  - Modulatory and toxicological perspectives on the effects of the small molecule kinetin
JF  - Molecules
N2  - Plant hormones are small regulatory molecules that exert pharmacological actions in mammalian cells such as anti-oxidative and pro-metabolic effects. Kinetin belongs to the group of plant hormones cytokinin and has been associated with modulatory functions in mammalian cells. The mammalian adenosine receptor (A2a-R) is known to modulate multiple physiological responses in animal cells. Here, we describe that kinetin binds to the adenosine receptor (A2a-R) through the Asn253 residue in an adenosine dependent manner. To harness the beneficial effects of kinetin for future human use, we assess its acute toxicity by analyzing different biochemical and histological markers in rats. Kinetin at a dose below 1 mg/kg had no adverse effects on the serum level of glucose or on the activity of serum alanine transaminase (ALT) or aspartate aminotransferase (AST) enzymes in the kinetin treated rats. Whereas, creatinine levels increased after a kinetin treatment at a dose of 0.5 mg/kg. Furthermore, 5 mg/kg treated kinetin rats showed normal renal corpuscles, but a mild degeneration was observed in the renal glomeruli and renal tubules, as well as few degenerated hepatocytes were also observed in the liver. Kinetin doses below 5 mg/kg did not show any localized toxicity in the liver and kidney tissues. In addition to unraveling the binding interaction between kinetin and A2a-R, our findings suggest safe dose limits for the future use of kinetin as a therapeutic and modulatory agent against various pathophysiological conditions.
KW  - cytokinin kinetin
KW  - modulatory effects
KW  - in vivo toxicity
KW  - A2a-R receptor
Y1  - 2021
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-223064
SN  - 1420-3049
VL  - 26
IS  - 3
ER  - 
TY  - JOUR
A1  - Fathy, Moustafa
A1  - Saad Eldin, Sahar M.
A1  - Naseem, Muhammad
A1  - Dandekar, Thomas
A1  - Othman, Eman M.
T1  - Cytokinins: wide-spread signaling hormones from plants to humans with high medical potential
JF  - Nutrients
N2  - Nature is a rich source of biologically active novel compounds. Sixty years ago, the plant hormones cytokinins were first discovered. These play a major role in cell division and cell differentiation. They affect organogenesis in plant tissue cultures and contribute to many other physiological and developmental processes in plants. Consequently, the effect of cytokinins on mammalian cells has caught the attention of researchers. Many reports on the contribution and potential of cytokinins in the therapy of different human diseases and pathophysiological conditions have been published and are reviewed here. We compare cytokinin effects and pathways in plants and mammalian systems and highlight the most important biological activities. We present the strong profile of the biological actions of cytokinins and their possible therapeutic applications.
KW  - cytokinins
KW  - phytohormones
KW  - biological activities
KW  - plant system
KW  - mammalian system
Y1  - 2022
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-271017
SN  - 2072-6643
VL  - 14
IS  - 7
ER  - 
TY  - JOUR
A1  - Fathy, Moustafa
A1  - Fawzy, Michael Atef
A1  - Hintzsche, Henning
A1  - Nikaido, Toshio
A1  - Dandekar, Thomas
A1  - Othman, Eman M.
T1  - Eugenol exerts apoptotic effect and modulates the sensitivity of HeLa cells to cisplatin and radiation
JF  - Molecules
N2  - Eugenol is a phytochemical present in different plant products, e.g., clove oil. Traditionally, it is used against a number of different disorders and it was suggested to have anticancer activity. In this study, the activity of eugenol was evaluated in a human cervical cancer (HeLa) cell line and cell proliferation was examined after treatment with various concentrations of eugenol and different treatment durations. Cytotoxicity was tested using lactate dehydrogenase (LDH) enzyme leakage. In order to assess eugenol’s potential to act synergistically with chemotherapy and radiotherapy, cell survival was calculated after eugenol treatment in combination with cisplatin and X-rays. To elucidate its mechanism of action, caspase-3 activity was analyzed and the expression of various genes and proteins was checked by RT-PCR and western blot analyses. Eugenol clearly decreased the proliferation rate and increased LDH release in a concentration- and time-dependent manner. It showed synergistic effects with cisplatin and X-rays. Eugenol increased caspase-3 activity and the expression of Bax, cytochrome c (Cyt-c), caspase-3, and caspase-9 and decreased the expression of B-cell lymphoma (Bcl)-2, cyclooxygenase-2 (Cox-2), and interleukin-1 beta (IL-1β) indicating that eugenol mainly induced cell death by apoptosis. In conclusion, eugenol showed antiproliferative and cytotoxic effects via apoptosis and also synergism with cisplatin and ionizing radiation in the human cervical cancer cell line.
KW  - eugenol
KW  - HeLa cells
KW  - cisplatin
KW  - radiation
KW  - apoptosis
Y1  - 2019
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-193227
SN  - 1420-3049
VL  - 24
IS  - 21
ER  - 
TY  - JOUR
A1  - Fathy, Moustafa
A1  - Darwish, Mostafa A.
A1  - Abdelhamid, Al-Shaimaa M.
A1  - Alrashedy, Gehad M.
A1  - Othman, Othman Ali
A1  - Naseem, Muhammad
A1  - Dandekar, Thomas
A1  - Othman, Eman M.
T1  - Kinetin ameliorates cisplatin-induced hepatotoxicity and lymphotoxicity via attenuating oxidative damage, cell apoptosis and inflammation in rats
JF  - Biomedicines
N2  - Though several previous studies reported the in vitro and in vivo antioxidant effect of kinetin (Kn), details on its action in cisplatin-induced toxicity are still scarce. In this study we evaluated, for the first time, the effects of kinetin in cisplatin (cp)- induced liver and lymphocyte toxicity in rats. Wistar male albino rats were divided into nine groups: (i) the control (C), (ii) groups 2,3 and 4, which received 0.25, 0.5 and 1 mg/kg kinetin for 10 days; (iii) the cisplatin (cp) group, which received a single intraperitoneal injection of CP (7.0 mg/kg); and (iv) groups 6, 7, 8 and 9, which received, for 10 days, 0.25, 0.5 and 1 mg/kg kinetin or 200 mg/kg vitamin C, respectively, and Cp on the fourth day. CP-injected rats showed a significant impairment in biochemical, oxidative stress and inflammatory parameters in hepatic tissue and lymphocytes. PCR showed a profound increase in caspase-3, and a significant decline in AKT gene expression. Intriguingly, Kn treatment restored the biochemical, redox status and inflammatory parameters. Hepatic AKT and caspase-3 expression as well as CD95 levels in lymphocytes were also restored. In conclusion, Kn mitigated oxidative imbalance, inflammation and apoptosis in CP-induced liver and lymphocyte toxicity; therefore, it can be considered as a promising therapy.
KW  - cisplatin
KW  - hepatotoxicity
KW  - lymphotoxicity
KW  - oxidative stress
KW  - AKT
KW  - CD95
KW  - caspase-3
Y1  - 2022
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-281686
SN  - 2227-9059
VL  - 10
IS  - 7
ER  -