In II activity and by intercalating into the

In the present study, normal control animals showed gradual increase of 39.4% in body weight throughout the experiment duration (Archer et al., 2003) with decrease of 15.9% in BIL animals (Izumi et al., 2005;Papie? et al., 2016;Singh and Bansode, 2011).

This significant decrease in body weight (from 154.4±5.4 to 129.8 g, P<0.05) in BIL group confirming the development of leukemia in rats (Table 1).

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Administration of doxorubicin either in DOX group or in BIL/DOX group led to severe reduction of body weight amounted to 20.1% and 20.5% respectively compared to their initial weights. Similar findings were reported by (Hamza et al., 2016;Sheta et al., 2016;Su et al.

, 2015;Swamy et al., 2012). This decrease in body weight may be attributed to decline in food consumption (Kulkarni and Swamy, 2015).

In addition, decrease in body weight may be due to increased inhibition of DNA synthesis pathway, hence, doxorubicin is a cell cycle-nonspecific agent that acts by blocking topoisomerase II activity and by intercalating into the flat space between the bases of the DNA double helix, where it can act further to disrupt DNA replication and transcription (Thirumaran, Prendergast and Gilman, 2007). On the other hand, when doxorubicin was combined with Moringa Oleifera; enhanced results were manifested recording increase of 7.6% and 22% in DOX+MO and BIL/ DOX+MO groups respectively compared to their initial weights. Moreover, Moringa Oleifera administration alone in MO and BIL/MO groups showed continuous increase in body weights with the lapse of time amounted to 80.3% and 33.9% respectively compared to their initial weights. These results are in agreement with (Alabi et al.

, 2017;Nuhu, 2010;Osman, Shayoub and Babiker, 2012) who provided evidence that the positive effect of Moringa Oleifera in body weight may be due to the high crude protein content in it. Also, this increment in body weight might be as a result of the pharmacological chemical compounds (carbohydrates, saponins, cardiacglycosides, terpenes, steroids, flavonoids and alkaloids) present in the Moringa Oleifera extract as reported by (Furo and Ambali, 2013). Furthermore, leaves of Moraga oleifera are rich in carotenoids, vitamins, amino acids, alkaloids, flavonoids and minerals particularly iron (Anwar et al., 2007;Siddhuraju and Becker, 2003;Subadra, Monica and Dhabhai, 1997). Moreover,  the significant increase in body weights of rats might also be attributed to captivity, where energy spending is minimal (Fadi et al.

, 2010). In addition, (Khan et al., 2017) proved that supplementation of Moringa Oleifera leaf powder in diet promoted gut health through improved intestinal microarchitecture and cellular count.Leukocytosis was observed in the groups of benzene-induced leukemia rats as demonstrated in some other works (Olufemi, Terry and Kola, 2012;Quemener et al., 1996;Salven, Orpana and Joensuu, 1999) (Figure 1 and Table2).

Leukocytosis is usually associated with leukemia and was found to be restored or prevented in treated rats (Table 2). There was a significant decrease in WBCs count in BIL/DOX group when compare to BIL group either after two weeks or four weeks from treatment. However, doxorubicin is used as a wildly chemotherapeutic agent due to its ability to induce apoptosis. The apoptosis pathway is triggered when the attempt to repair the breaks in nuclear DNA fail and cellular growth is inhibited at phases G1 and G2 (Tacar, Sriamornsak and Dass, 2013). Also, (Ashley and Poulton, 2009) reported doxorubicin’s ability to intercalate with not only nuclear DNA, but also mitochondrial DNA. Other doxorubicin actions include free radical generation which causes further DNA damage, inhibition of macromolecule production, DNA separation and increase in alkylation (Minotti et al.

, 2004). Furthermore, doxorubicin can affect the cell membrane directly by binding to plasma proteins causing enzymatic electron reduction of doxorubicin. This can cause the formation of highly reactive species of hydroxyl free radicals (Tacar, Sriamornsak and Dass, 2013). Additionally, (Leung and Wang, 1999) explored that doxorubicin can decline antiapoptotic Bcl-2 with elevation in proapoptotic Bax in vitro studies on breast cancer cell line MCF-7.However, the main complication of chemotherapy is that it cannot maintain normal cells without damaging, due to it is blinded compounds have no ability to differentiate between tumor and normal cells. Doxorubicin induces apoptosis and necrosis in healthy tissue causing toxicity in the brain, liver, kidney and heart. This often impacts the efficacy of the therapy, making it impossible to cure patients suffered from cancer (Srivastava and Gupta, 2006).

In the present study, spleen and liver histological examinations demonstrate this toxic effect of doxorubicin. The present examination of spleen of DOX and BIL/DOX rats revealed degenerative changes in spleen cells; internal hemorrhage in red pulp with increase in fibrous tissues; hemorrhage and dilatation in sinusoids which increases after four weeks showing partial distortion of splenic architecture with necrotic areas (Figure 2). Also, the present examination of liver of DOX and BIL/DOX rats revealed degenerative changes in hepatocytes; necrosis; pyknosis and karyolysis in hepatic parenchymal cells which rises after four weeks displaying loss of hepatic architecture (Figure 3). These toxic effects are attributed to that doxorubicin-mediated redox cycling and therefore ROS and free radical generation is responsible for its toxicity (Dobson, Hohenhaus and Peaston, 2008;Lyu and Liu, 2012;Thorn et al.

, 2011).Because of these drugs adverse side effects, researches are focusing on phytomedicines that seem to have anti-cancer and immune system enhancing activity. Phytomedicines are believed to have benefits over conventional drugs and are regaining interest in current research (Al-Asmariet al., 2015).

Moringa Oleifera is considered to be a main medicinal plant (Bassey et al., 2013). Currently, there was a significant decrease in WBCs count in BIL/MO group when compare to BIL group either after two weeks or four weeks from treatment.

Moringa Oleifera has potent antiproliferative activity and apoptosis inducing capacity on tumor cell line. It also increases the cytotoxicity of chemotherapy on pancreatic cancer cells (Berkovich et al., 2013;Charoensin, 2014). The mechanisms of anticancer properties of Moringa Oleifera is still emerging. (Akanni, Adedeji and Oloke, 2014) conclude that enhanced apoptosis by increase expression of TNF-? is a possible mechanism of action Moringa Oleifera extract in rats bearing benzene-induced leukemia.  TNF-? activates and increases NK cytolytic function and can induce apoptosis through the activation of Type I receptors, which are considered part of an apoptotic cascade.

 Also, it was demonstrated that the antiproliferative activity of Moringa Oleifera may be attributable to the presence of kaempferol. Kaempferol, a compound found in Moringa Oleifera leaves, was reported to induce apoptosis in HCT116 colon cancer cells through induction of caspase-3 which is considered as a crucial component of the apoptotic machinery  (Li et al., 2009;Tragulpakseerojn et al., 2014)Moreover, (ACKLAND, VAN DE WAARSENBURG and Jones, 2005) proved that co-treatment with flavonoids; such as kaempferol  and quercetin showed inhibition of cell proliferation of human HuTu-80 duodenum adenocarcinoma cells, human Caco-2 colon cancer cells and human PMC42 breast cancer cells. Recently, Moringa Oleifera leaves and roots extracts act as anti-cancer agent by decreasing cell proliferation and exhibiting apoptosis-mediated cell death in liver HepG2, colon HCT 116 and Caco-2, and breast MCF7 cancer cell lines (Abd-Rabouet al., 2017).

Furthermore, polyphenols which are present in Moringa Oleifera leaves extract were shown to inhibit a specific protein found in bone marrow and which is responsible for cancer in bone and increased the production of antioxidants in the sperms (Abdou et al., 2012). However, the mechanisms of anticancer properties of Moringa Oleifera is still developing.

The current study supposed a new anticancer mechanism of Moringa Oleifera by decreasing myeloid derived suppressor cells (MDSCs). Myeloid-derived suppressor cells (MDSCs) are a heterogeneous population of immature myeloid cells that are constitute a unique constituent of the immune system that regulates immune responses in healthy individuals and suppress T cell immunity in tumor-bearing hosts. They are expanded in various disease states including cancer (Marvel and Gabrilovich, 2015;Ortizet al., 2014;Zhang et al., 2013). In the present study, flowcytometric analysis for MDSCs were performed at the end of the experiment. The percentage of MDSCs in BIL group is significantly increase comparing to control group.

After treatment, the percentage of MDSCs was significantly decrease comparing to BIL group (Figure 4).These results were in accordance with (Dolen et al., 2015) who verified that MDSCs numbers were expanded in peripheral blood and spleens of mammary tumor-bearing rats. Moreover, (Shen et al., 2014) elucidated that an increased population of MDSC in the peripheral blood of Hepatocellular carcinoma patients was observed. Additionally, it was identified that there is a significantly expanded MDSCs population in chronic myeloid leukemia patients (Giallongo et al., 2014). Also, (Zhanget al.

, 2013) substantiates the presence of increased immunosuppressive circulating and tumor-resident MDSCs in patients with colorectal cancers correlating with cancer stage and metastasis. And, (Van Valckenborgh et al., 2012) have demonstrated that immunosuppressive MDSC subsets are present and active in mice model of Multiple myeloma. MDSC are induced by tumor-secreted and host-secreted factors, this accumulation of MDSC down-regulate immune surveillance and antitumor immunity, thereby facilitating tumor growth (Ostrand-Rosenberg and Sinha, 2009). MDSCs express high levels of both arginase and iNOS. The increased activity of arginase in MDSCs leads to enhanced L-arginine catabolism, which lead to inhibition of T-cell proliferation (Rodríguez and Ochoa, 2008). Another important factor that contributes to the suppressive activity of MDSCs is ROS. Several known tumor-derived factors, such as TGF?, IL-10, IL-6, IL-3, platelet-derived growth factor and GM-CSF, can induce the production of ROS by MDSCs (Sauer, Wartenberg and Hescheler, 2001).

In addition, it has emerged that peroxynitrite (ONOO-) is a crucial mediator of MDSC-mediated suppression of T-cell function and one of the most powerful oxidants produced in the body. It was demonstrated that peroxynitrite production by MDSCs during direct contact with T cells results in nitration of the T-cell receptor (TCR) and CD8 molecules, which alters the specific peptide binding of the T cells and renders them unresponsive to antigen-specific stimulation (Gabrilovich and Nagaraj, 2009). More to the point, the ability of MDSCs to promote the de novo development of regulatory T cells in vivo has been described (Huang et al.

, 2006;Serafini et al., 2008). Further mechanisms of T cell inhibition mediated by MDSCs include the findings from the (Ku et al., 2016) group who demonstrated that MDSCs facilitate the downregulation of L-selectin (CD26L) in naive T and B cells resulting in an impaired homing of the cells to the lymph nodes, in tumor-bearing mice and therefore limiting the number of T cells responding to the presented antigen. Furthermore, they have demonstrated the ability of MDSC to induce T cell hyporesponsiveness in spleen and in blood.Regarding histological observations, spleen sections enhancement was designated in groups treated with MO.

This was marked in the form of minimal hemorrhage and degeneration in in red and white pulp cells was observed (Figure 2E) which is ameliorated after four weeks of MO administration (Figure 2H). In BIL/DOX+MO group, there was a great improvement in splenic architecture either after two weeks (Figure 2F) or after four weeks (Figure 2I) of treatment. In liver tissue, sinusoidal dilatation was observed (Figure 3D,3G). In BIL/DOX+MO group, there was an improvement in hepatic architecture after four weeks (Figure 3H) as compared to treatment with doxorubicin alone in BIL/DOX group (Figure 3F).

These improvements are due to neutralize the ROS and free radicals which are generated from doxorubicin therapy. Free radical scavenging represents one of the important characteristics of Moringa Oleifera leaves extract which is rich in antioxidants. Antioxidants provide protection or remediation by scavenging reactive oxidative species (ROS) that initiate diseases such as cancer (Sathya et al., 2010). Also, many components of Moringa Oleifera leaves extract such polyphenols and various carotenoids were observed to improve the immune system, scavenge of free radical and reduce the production of DNA mutations that were previously exposed to variety of oxidative conditions (Devaraj et al.

, 2008). In conclusion, our study reports the elevation of MDSCs in BIL and for the first time the suppressing effect of Moringa Oleifera therapy as a a possible mechanism of action Moringa Oleifera extract in rats bearing benzene-induced Leukemia. These findings suggest that MDSCs may play a role in benzene-induced Leukemia and more researches are needed to further learn about MDSCs as a potential future therapeutic target in Leukemia.


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