Copyright (c) 2020 Edwin A Septory
This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.
Combination of Songga Wood Stem (Strychnos Lucida) and Act Is Associated to Cxcl12 and Parasitemia on Plasmodium Berghei Anka Infections
Corresponding Author(s) : Edwin A Septory
International Journal of Allied Medical Sciences and Clinical Research,
Vol. 8 No. 2 (2020): 2020 Volume 8- Issue -2
Abstract
Snake wood (Strychnos lucida) and Artemisinin-based-combined-therapy (ACT) possess antimalarial and immunomodulatory activity. Combination of these two therapies on parasitemia and CXCL12, which have protective properties toward Plasmodium berghei ANKA (PbA) infection, is still unknown. This research aims to prove the association between combination of ethanolic extract from songga wood stem (EESWS)-ACT treatment and decreasing parasitemia level-increasing production of CXCL12 on Swiss Webster mice that are susceptible to PbA infections.
Methods
This experimental laboratory research applied post test only control group design that distributed 25 female Swiss Webster mice into 5 groups. K1 group consisted of healthy mice, whereas K2, K3, P1, and P2 group consisted of mice infected with PbA at the dose of 107 and diagnosed as positive at the 3rd day following the infection. K2 group had no treatment; K3 group was treated with ACT (combination of dihydroartemisin (DHP) and piperaquine) at the dose of 0,819 mg/kg weight/day. Group P1 and P2 were treated with EESWS at preventive dose (0,15 mg/kg weight/day) for ten days and since day 4 of infection, the groups were treated with EESWS at therapeutic dose (0,3 mg/kg weight/day). As for P2, ACT treatment was also included. 14-days treatment was finalized with observation of parasitemia level and spleen cell culture. Difference and correlation test were performed using SPSS.
Result
One-way-ANOVA and post-hoc Bonferroni test on parasitemia level (p=0,0001) showed that P1 (mean±SD%; 4,68±1,94) and P2 (4,06±1,13) were not significally different from K3 (6,40±0,96;p=1,00 and p=0,88); as well as P2 that was not significantly different from P1 (p=1,00). Kruskal-Wallis and Mann-Whitney U test of CXCL12 level (p=0.001) showed that P1 (median(min-max))ng/mL 0,51(0,45–0,58)) and P2 (0,95(0,93-1,79)) were not significantly different from K1 (2,71(0,42-2.81);p=0,117 and p=0,116). Parasitemia was not proven to be associated with CXCL12 (Pearson test; r=0.311; p=0,131).
Conclusion
Treatment of EESWS and EESWS-ACT combination are associated with decreasing parasitemia level and normal production level of CXCXL12 in spleen.
Keywords
Strychnos lucida
Dihydroartemisinin
Piperaquine
References
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World Health Organisation. World Malaria Report 2018. World Health Organization.; 2018.
http://www.who.int/iris/handle/10665/275867.
[2]. Yusuf Y. Bukti munculnya malaria resisten artemisinin di asia. J Bionature. 14(2), 2011, 128-132.
[3]. Maslachah L, Dachlan YP, Nidom CA, Fitri LE. Profil Fenotipik Plasmodium falciparum Galur Papua 2300 Akibat Paparan Antimalaria Artemisinin in Vitro Phenotypic Profile of Plasmodium falciparum Papua 2300 Strain Exposed to in Vitro Antimalarial Artemisinin. 47(1), 2013, 1-9. doi:10.15395/mkb.v47n1.390
[4]. Hafid AF, Tyas MW, Widyawaruyanti A. Model Terapi Kombinasi Ekstrak Etanol 80 % Kulit Batang Cempedak ( Artocarpus Champeden Spreng .) dan Artesunat pada Mencit Terinfeksi Parasit Malaria. J Indones Med Assoc. 61(4), 2011, 161-167.
[5]. W. Syafii, R.K. Sari UC and LNA. Antimalarial Activity of the Fractions from Ethanol Extract of. Med Plant. 10(6-7), 2016, 403-408. doi:10.3923/rjmp.2016.403.408
[6]. Taek MM. Kandungan Fitokimia dan Aktivitas Antimalaria in-vivo Ekstrak Kayu Ular ( Strychnos ligustrina ). Nat Sains. 1(3), 2013, 102-106. doi:10.13140/RG.2.2.28502.91207
[7]. Rale SD. Aktivitas antioksidan dan penghambatan ? -glukosidase dari ekstrak etanol batang kayu ular (strychnos nitida g. Don) secara in vitro serta identifikasi senyawa aktif. 2018.
[8]. Choi E, Hwang J. Screening of Indonesian medicinal plants for inhibitor activity on nitric oxide production of RAW264 . 7 cells and antioxidant activity. 76, 2005, 194-203. doi:10.1016/j.fitote.2004.11.010
[9]. Sarmento C, Worachartcheewan A, Pingaew R, Nacional H, Valadares G, Leste T. Antimicrobial, antioxidant and anticancer activities of Strichnos lucida. Traditoonal Complement Altern Med. 12, 2015, 122-127.
[10]. Zubaidah A, Faidah KR, Samsundari S. Effectiveness of Strychnos ligustrina Bl . extract as feed supplementation to increase immune system of Nile Tilapia (Oreochromis niloticus) wich againts Streptococcus agalactiae. 1(1), 2018, 1-8.
[11]. Steen PE Van Den, Deroost K, Aelst I Van, et al. CXCR3 determines strain susceptibility to murine cerebral malaria by mediating T lymphocyte migration toward IFN- c -induced chemokines. EuroJ Immunol. 38, 2008, 1082-1095. doi:10.1002/eji.200737906
[12]. Ramos M, Trindade J. Stromal cell deri v ed factor 1 synthesis by spleen cells in rodent malaria , and the effects of in v i v o supplementation of SDF-1 a and CXCR4 receptor blocker. Immunol Lett. 83(v), 2002, 47-53.
[13]. Shadidi KR, Aarvak T, Henriksen JE, Natvig JB, Thompson KM. The Chemokines CCL5 , CCL2 and CXCL12 Play Significant Roles in the Migration of Th1 Cells into Rheumatoid Synovial Tissue. Scand J Immunol. 57, 2003, 192-198.
[14]. Wahyuniati N, Maulana R. Peran IL-10 pada infeksi malaria. 15(2), 2015, 96-103.
[15]. Lamb T, Spence P, Stephens R, et al. IL-27 Promotes IL-10 Production by Effector Th1 CD4 + T Cells: A Critical Mechanism for Protection from Severe Immunopathology during Malaria Infection´. 16, 2012.
doi:10.4049/jimmunol.1102755
[16]. Garnica MR. Supplementation of CXCL 12 ( CXCL 12 ) induces homing of CD 11 c + dendritic cells to the spleen and enhances control of Plasmodium berghei malaria in BALB / c mice. 12, 2005, 399-406.
doi:10.1111/j.1365-2567.2005.02178.x
[17]. Ghosh D, Brown SL, Stumhofer JS. IL-17 Promotes Differentiation of Splenic LSK ? Lymphoid Progenitors into B Cells following Plasmodium yoelii Infection. J Immunol. 199(5), 2017, 1783-1795.
doi:10.4049/jimmunol.1601972
[18]. Djamiatun K, Wijayahadi N, Utomo AW, Miranti IP, Nugroho D. Annona muricata increase IL-27 , CXCL12 levels and spleen- white-pulp-diameter in severe malaria. 2 nd Int Conf Transl Med Heal Sci conjunction with 4 th JAVA Int Nurs Conf 2018 Creat Better Futur Heal Care Partnersh Res Educ Clin Care. 66, 2018.
[19]. Ghosh D, Wikenheiser DJ, Kennedy B, et al. An Atypical Splenic B Cell Progenitor Population Supports Antibody Production during Plasmodium Infection in Mice. J Immunol. 197(5), 2016, 1788-1800.
doi:10.4049/jimmunol.1502199
[20]. Seemann S, Lupp A. Administration of a CXCL12 analog in endotoxemia is associated with anti-inflammatory, anti-oxidative and cytoprotective effects in vivo. PLoS One. 10(9), 2015, 1-22.
doi:10.1371/journal.pone.0138389
[21]. Tian X, Xie G, Xiao H, Ding F, Bao W, Zhang M. CXCR4 knockdown prevents inflammatory cytokine
Edwin A S et al / Int. J. of Allied Med. Sci. and Clin. Research Vol-8(2) 2020 [215-222]
222
expression in macrophages by suppressing activation of MAPK and NF-?B signaling pathways. Cell Biosci. 9(1), 2019, 1-8. doi:10.1186/s13578-019-0315-x
[22]. Sa L, Estecha A, Samaniego R, Sa S, Sa P. The chemokine CXCL12 regulates monocyte-macrophage differentiation and RUNX3 expression. Blood. 117(1), 2015, 88-98. doi:10.1182/blood-2009-12-258186.The
[23]. Chatterjee M, Von Ungern-Sternberg SNI, Seizer P, et al. Platelet-derived CXCL12 regulates monocyte function, survival, differentiation into macrophages and foam cells through differential involvement of CXCR4-CXCR7. Cell Death Dis. 6(11), 2015, 1-16. doi:10.1038/cddis.2015.233
[24]. Giri J, Das R, Nylen E, Chinnadurai R, Galipeau J. CCL2 and CXCL12 Derived from Mesenchymal Stromal Cells Cooperatively Polarize IL-10+ Tissue Macrophages to Mitigate Gut Injury. Cell Rep. 30(6), 2020, 1923-1934.e4. doi:10.1016/j.celrep.2020.01.047
[25]. Man S, Tucky B, Cotleur A, Drazba J, Takeshita Y, Ransohoff RM. CXCL12-induced monocyte-endothelial interactions promote lymphocyte transmigration across an in vitro blood-brain barrier. Sci Transl Med. 4(119), 2012. doi:10.1126/scitranslmed.3003197
[26]. Daniel SK, Seo YD, Pillarisetty VG. The CXCL12-CXCR4/CXCR7 axis as a mechanism of immune resistance in gastrointestinal malignancies. Semin Cancer Biol. 2020. doi:10.1016/j.semcancer. 12, 2019, 007
[27]. Meiron M, Zohar Y, Anunu R, Wildbaum G, Karin N. CXCL12 (SDF-1?) suppresses ongoing experimental autoimmune encephalomyelitis by selecting antigen-specific regulatory T cells. J Exp Med. 205(11), 2008, 2643-2655. doi:10.1084/jem.20080730
[28]. Wiatr M, Stump-Guthier C, Latorre D, et al. Distinct migratory pattern of naive and effector T cells through the blood-CSF barrier following Echovirus 30 infection. J Neuroinflammation. 16(1), 2019, 1-19.
doi:10.1186/s12974-019-1626-x
[29]. Vitiello L, Ferraro E, De Simone S, et al. CXCL12 prolongs naive CD4 + T lymphocytes survival via activation of PKA, CREB and Bcl2 and BclXl up-regulation. Int J Cardiol. 224, 2016, 206-212.
doi:10.1016/j.ijcard.2016.09.007
[30]. Zeng Y, Li B, Liang Y, et al. Dual blockade of CXCL12-CXCR4 and PD-1–PD-L1 pathways prolongs survival of ovarian tumor–bearing mice by prevention of immunosuppression in the tumor microenvironment. FASEB J. 33(5), 2019, 6596-6608. doi:10.1096/fj.201802067RR
[31]. Weinberg JB, Volkheimer AD, Rubach MP, et al. Monocyte polarization in children with falciparum malaria: Relationship to nitric oxide insufficiency and disease severity. Sci Rep. 6, 2016, 1-13. doi:10.1038/srep29151
[32]. Besnard AG, Guabiraba R, Niedbala W, et al. IL-33-Mediated Protection against Experimental Cerebral Malaria Is Linked to Induction of Type 2 Innate Lymphoid Cells, M2 Macrophages and Regulatory T Cells. PLoS Pathog. 11(2), 2015, 1-21. doi:10.1371/journal.ppat.1004607
[33]. Krishnegowda G, Hajjar AM, Zhu J, et al. Induction of proinflammatory responses in macrophages by the glycosylphosphatidylinositols of Plasmodium falciparum: Cell signaling receptors, glycosylphosphatidylinositol (GPI) structural requirement, and regulation of GPI activity. J Biol Chem. 280(9), 2005, 8606-8616. doi:10.1074/jbc.M413541200
[34]. Jaramillo M, Bellemare MJ, Martel C, et al. Synthetic Plasmodium-like hemozoin activates the immune response: A morphology - Function study. PLoS One. 4(9), 2009. doi:10.1371/journal.pone.0006957
[35]. Cai X, Chen R, Ma K, et al. Identification of the CXCL12–CXCR4/CXCR7 axis as a potential therapeutic target for immunomodulating macrophage polarization and foreign body response to implanted biomaterials. Appl Mater Today. 18, 2020, 100454. doi:10.1016/j.apmt.2019.100454
[36]. Das S, Mishra KP, Chanda S, Ganju L, Singh SB. CXCR7: A key neuroprotective molecule against alarmin HMGB1 mediated CNS pathophysiology and subsequent memory impairment. Brain Behav Immun. 82, 2019, 319-337. doi:10.1016/j.bbi.2019.09.003
[37]. Phillips R, Ager A. Activation of pertussis toxin-sensitive CXCL12 (SDF-1) receptors mediates transendothelial migration of T lymphocytes across lymph node high endothelial cells. Eur J Immunol. 32(3), 2002, 837-847. doi:10.1002/1521-4141(200203)32:3<837::AID-IMMU837>3.0.CO;2-Q.
References
World Health Organisation. World Malaria Report 2018. World Health Organization.; 2018.
http://www.who.int/iris/handle/10665/275867.
[2]. Yusuf Y. Bukti munculnya malaria resisten artemisinin di asia. J Bionature. 14(2), 2011, 128-132.
[3]. Maslachah L, Dachlan YP, Nidom CA, Fitri LE. Profil Fenotipik Plasmodium falciparum Galur Papua 2300 Akibat Paparan Antimalaria Artemisinin in Vitro Phenotypic Profile of Plasmodium falciparum Papua 2300 Strain Exposed to in Vitro Antimalarial Artemisinin. 47(1), 2013, 1-9. doi:10.15395/mkb.v47n1.390
[4]. Hafid AF, Tyas MW, Widyawaruyanti A. Model Terapi Kombinasi Ekstrak Etanol 80 % Kulit Batang Cempedak ( Artocarpus Champeden Spreng .) dan Artesunat pada Mencit Terinfeksi Parasit Malaria. J Indones Med Assoc. 61(4), 2011, 161-167.
[5]. W. Syafii, R.K. Sari UC and LNA. Antimalarial Activity of the Fractions from Ethanol Extract of. Med Plant. 10(6-7), 2016, 403-408. doi:10.3923/rjmp.2016.403.408
[6]. Taek MM. Kandungan Fitokimia dan Aktivitas Antimalaria in-vivo Ekstrak Kayu Ular ( Strychnos ligustrina ). Nat Sains. 1(3), 2013, 102-106. doi:10.13140/RG.2.2.28502.91207
[7]. Rale SD. Aktivitas antioksidan dan penghambatan ? -glukosidase dari ekstrak etanol batang kayu ular (strychnos nitida g. Don) secara in vitro serta identifikasi senyawa aktif. 2018.
[8]. Choi E, Hwang J. Screening of Indonesian medicinal plants for inhibitor activity on nitric oxide production of RAW264 . 7 cells and antioxidant activity. 76, 2005, 194-203. doi:10.1016/j.fitote.2004.11.010
[9]. Sarmento C, Worachartcheewan A, Pingaew R, Nacional H, Valadares G, Leste T. Antimicrobial, antioxidant and anticancer activities of Strichnos lucida. Traditoonal Complement Altern Med. 12, 2015, 122-127.
[10]. Zubaidah A, Faidah KR, Samsundari S. Effectiveness of Strychnos ligustrina Bl . extract as feed supplementation to increase immune system of Nile Tilapia (Oreochromis niloticus) wich againts Streptococcus agalactiae. 1(1), 2018, 1-8.
[11]. Steen PE Van Den, Deroost K, Aelst I Van, et al. CXCR3 determines strain susceptibility to murine cerebral malaria by mediating T lymphocyte migration toward IFN- c -induced chemokines. EuroJ Immunol. 38, 2008, 1082-1095. doi:10.1002/eji.200737906
[12]. Ramos M, Trindade J. Stromal cell deri v ed factor 1 synthesis by spleen cells in rodent malaria , and the effects of in v i v o supplementation of SDF-1 a and CXCR4 receptor blocker. Immunol Lett. 83(v), 2002, 47-53.
[13]. Shadidi KR, Aarvak T, Henriksen JE, Natvig JB, Thompson KM. The Chemokines CCL5 , CCL2 and CXCL12 Play Significant Roles in the Migration of Th1 Cells into Rheumatoid Synovial Tissue. Scand J Immunol. 57, 2003, 192-198.
[14]. Wahyuniati N, Maulana R. Peran IL-10 pada infeksi malaria. 15(2), 2015, 96-103.
[15]. Lamb T, Spence P, Stephens R, et al. IL-27 Promotes IL-10 Production by Effector Th1 CD4 + T Cells: A Critical Mechanism for Protection from Severe Immunopathology during Malaria Infection´. 16, 2012.
doi:10.4049/jimmunol.1102755
[16]. Garnica MR. Supplementation of CXCL 12 ( CXCL 12 ) induces homing of CD 11 c + dendritic cells to the spleen and enhances control of Plasmodium berghei malaria in BALB / c mice. 12, 2005, 399-406.
doi:10.1111/j.1365-2567.2005.02178.x
[17]. Ghosh D, Brown SL, Stumhofer JS. IL-17 Promotes Differentiation of Splenic LSK ? Lymphoid Progenitors into B Cells following Plasmodium yoelii Infection. J Immunol. 199(5), 2017, 1783-1795.
doi:10.4049/jimmunol.1601972
[18]. Djamiatun K, Wijayahadi N, Utomo AW, Miranti IP, Nugroho D. Annona muricata increase IL-27 , CXCL12 levels and spleen- white-pulp-diameter in severe malaria. 2 nd Int Conf Transl Med Heal Sci conjunction with 4 th JAVA Int Nurs Conf 2018 Creat Better Futur Heal Care Partnersh Res Educ Clin Care. 66, 2018.
[19]. Ghosh D, Wikenheiser DJ, Kennedy B, et al. An Atypical Splenic B Cell Progenitor Population Supports Antibody Production during Plasmodium Infection in Mice. J Immunol. 197(5), 2016, 1788-1800.
doi:10.4049/jimmunol.1502199
[20]. Seemann S, Lupp A. Administration of a CXCL12 analog in endotoxemia is associated with anti-inflammatory, anti-oxidative and cytoprotective effects in vivo. PLoS One. 10(9), 2015, 1-22.
doi:10.1371/journal.pone.0138389
[21]. Tian X, Xie G, Xiao H, Ding F, Bao W, Zhang M. CXCR4 knockdown prevents inflammatory cytokine
Edwin A S et al / Int. J. of Allied Med. Sci. and Clin. Research Vol-8(2) 2020 [215-222]
222
expression in macrophages by suppressing activation of MAPK and NF-?B signaling pathways. Cell Biosci. 9(1), 2019, 1-8. doi:10.1186/s13578-019-0315-x
[22]. Sa L, Estecha A, Samaniego R, Sa S, Sa P. The chemokine CXCL12 regulates monocyte-macrophage differentiation and RUNX3 expression. Blood. 117(1), 2015, 88-98. doi:10.1182/blood-2009-12-258186.The
[23]. Chatterjee M, Von Ungern-Sternberg SNI, Seizer P, et al. Platelet-derived CXCL12 regulates monocyte function, survival, differentiation into macrophages and foam cells through differential involvement of CXCR4-CXCR7. Cell Death Dis. 6(11), 2015, 1-16. doi:10.1038/cddis.2015.233
[24]. Giri J, Das R, Nylen E, Chinnadurai R, Galipeau J. CCL2 and CXCL12 Derived from Mesenchymal Stromal Cells Cooperatively Polarize IL-10+ Tissue Macrophages to Mitigate Gut Injury. Cell Rep. 30(6), 2020, 1923-1934.e4. doi:10.1016/j.celrep.2020.01.047
[25]. Man S, Tucky B, Cotleur A, Drazba J, Takeshita Y, Ransohoff RM. CXCL12-induced monocyte-endothelial interactions promote lymphocyte transmigration across an in vitro blood-brain barrier. Sci Transl Med. 4(119), 2012. doi:10.1126/scitranslmed.3003197
[26]. Daniel SK, Seo YD, Pillarisetty VG. The CXCL12-CXCR4/CXCR7 axis as a mechanism of immune resistance in gastrointestinal malignancies. Semin Cancer Biol. 2020. doi:10.1016/j.semcancer. 12, 2019, 007
[27]. Meiron M, Zohar Y, Anunu R, Wildbaum G, Karin N. CXCL12 (SDF-1?) suppresses ongoing experimental autoimmune encephalomyelitis by selecting antigen-specific regulatory T cells. J Exp Med. 205(11), 2008, 2643-2655. doi:10.1084/jem.20080730
[28]. Wiatr M, Stump-Guthier C, Latorre D, et al. Distinct migratory pattern of naive and effector T cells through the blood-CSF barrier following Echovirus 30 infection. J Neuroinflammation. 16(1), 2019, 1-19.
doi:10.1186/s12974-019-1626-x
[29]. Vitiello L, Ferraro E, De Simone S, et al. CXCL12 prolongs naive CD4 + T lymphocytes survival via activation of PKA, CREB and Bcl2 and BclXl up-regulation. Int J Cardiol. 224, 2016, 206-212.
doi:10.1016/j.ijcard.2016.09.007
[30]. Zeng Y, Li B, Liang Y, et al. Dual blockade of CXCL12-CXCR4 and PD-1–PD-L1 pathways prolongs survival of ovarian tumor–bearing mice by prevention of immunosuppression in the tumor microenvironment. FASEB J. 33(5), 2019, 6596-6608. doi:10.1096/fj.201802067RR
[31]. Weinberg JB, Volkheimer AD, Rubach MP, et al. Monocyte polarization in children with falciparum malaria: Relationship to nitric oxide insufficiency and disease severity. Sci Rep. 6, 2016, 1-13. doi:10.1038/srep29151
[32]. Besnard AG, Guabiraba R, Niedbala W, et al. IL-33-Mediated Protection against Experimental Cerebral Malaria Is Linked to Induction of Type 2 Innate Lymphoid Cells, M2 Macrophages and Regulatory T Cells. PLoS Pathog. 11(2), 2015, 1-21. doi:10.1371/journal.ppat.1004607
[33]. Krishnegowda G, Hajjar AM, Zhu J, et al. Induction of proinflammatory responses in macrophages by the glycosylphosphatidylinositols of Plasmodium falciparum: Cell signaling receptors, glycosylphosphatidylinositol (GPI) structural requirement, and regulation of GPI activity. J Biol Chem. 280(9), 2005, 8606-8616. doi:10.1074/jbc.M413541200
[34]. Jaramillo M, Bellemare MJ, Martel C, et al. Synthetic Plasmodium-like hemozoin activates the immune response: A morphology - Function study. PLoS One. 4(9), 2009. doi:10.1371/journal.pone.0006957
[35]. Cai X, Chen R, Ma K, et al. Identification of the CXCL12–CXCR4/CXCR7 axis as a potential therapeutic target for immunomodulating macrophage polarization and foreign body response to implanted biomaterials. Appl Mater Today. 18, 2020, 100454. doi:10.1016/j.apmt.2019.100454
[36]. Das S, Mishra KP, Chanda S, Ganju L, Singh SB. CXCR7: A key neuroprotective molecule against alarmin HMGB1 mediated CNS pathophysiology and subsequent memory impairment. Brain Behav Immun. 82, 2019, 319-337. doi:10.1016/j.bbi.2019.09.003
[37]. Phillips R, Ager A. Activation of pertussis toxin-sensitive CXCL12 (SDF-1) receptors mediates transendothelial migration of T lymphocytes across lymph node high endothelial cells. Eur J Immunol. 32(3), 2002, 837-847. doi:10.1002/1521-4141(200203)32:3<837::AID-IMMU837>3.0.CO;2-Q.
http://www.who.int/iris/handle/10665/275867.
[2]. Yusuf Y. Bukti munculnya malaria resisten artemisinin di asia. J Bionature. 14(2), 2011, 128-132.
[3]. Maslachah L, Dachlan YP, Nidom CA, Fitri LE. Profil Fenotipik Plasmodium falciparum Galur Papua 2300 Akibat Paparan Antimalaria Artemisinin in Vitro Phenotypic Profile of Plasmodium falciparum Papua 2300 Strain Exposed to in Vitro Antimalarial Artemisinin. 47(1), 2013, 1-9. doi:10.15395/mkb.v47n1.390
[4]. Hafid AF, Tyas MW, Widyawaruyanti A. Model Terapi Kombinasi Ekstrak Etanol 80 % Kulit Batang Cempedak ( Artocarpus Champeden Spreng .) dan Artesunat pada Mencit Terinfeksi Parasit Malaria. J Indones Med Assoc. 61(4), 2011, 161-167.
[5]. W. Syafii, R.K. Sari UC and LNA. Antimalarial Activity of the Fractions from Ethanol Extract of. Med Plant. 10(6-7), 2016, 403-408. doi:10.3923/rjmp.2016.403.408
[6]. Taek MM. Kandungan Fitokimia dan Aktivitas Antimalaria in-vivo Ekstrak Kayu Ular ( Strychnos ligustrina ). Nat Sains. 1(3), 2013, 102-106. doi:10.13140/RG.2.2.28502.91207
[7]. Rale SD. Aktivitas antioksidan dan penghambatan ? -glukosidase dari ekstrak etanol batang kayu ular (strychnos nitida g. Don) secara in vitro serta identifikasi senyawa aktif. 2018.
[8]. Choi E, Hwang J. Screening of Indonesian medicinal plants for inhibitor activity on nitric oxide production of RAW264 . 7 cells and antioxidant activity. 76, 2005, 194-203. doi:10.1016/j.fitote.2004.11.010
[9]. Sarmento C, Worachartcheewan A, Pingaew R, Nacional H, Valadares G, Leste T. Antimicrobial, antioxidant and anticancer activities of Strichnos lucida. Traditoonal Complement Altern Med. 12, 2015, 122-127.
[10]. Zubaidah A, Faidah KR, Samsundari S. Effectiveness of Strychnos ligustrina Bl . extract as feed supplementation to increase immune system of Nile Tilapia (Oreochromis niloticus) wich againts Streptococcus agalactiae. 1(1), 2018, 1-8.
[11]. Steen PE Van Den, Deroost K, Aelst I Van, et al. CXCR3 determines strain susceptibility to murine cerebral malaria by mediating T lymphocyte migration toward IFN- c -induced chemokines. EuroJ Immunol. 38, 2008, 1082-1095. doi:10.1002/eji.200737906
[12]. Ramos M, Trindade J. Stromal cell deri v ed factor 1 synthesis by spleen cells in rodent malaria , and the effects of in v i v o supplementation of SDF-1 a and CXCR4 receptor blocker. Immunol Lett. 83(v), 2002, 47-53.
[13]. Shadidi KR, Aarvak T, Henriksen JE, Natvig JB, Thompson KM. The Chemokines CCL5 , CCL2 and CXCL12 Play Significant Roles in the Migration of Th1 Cells into Rheumatoid Synovial Tissue. Scand J Immunol. 57, 2003, 192-198.
[14]. Wahyuniati N, Maulana R. Peran IL-10 pada infeksi malaria. 15(2), 2015, 96-103.
[15]. Lamb T, Spence P, Stephens R, et al. IL-27 Promotes IL-10 Production by Effector Th1 CD4 + T Cells: A Critical Mechanism for Protection from Severe Immunopathology during Malaria Infection´. 16, 2012.
doi:10.4049/jimmunol.1102755
[16]. Garnica MR. Supplementation of CXCL 12 ( CXCL 12 ) induces homing of CD 11 c + dendritic cells to the spleen and enhances control of Plasmodium berghei malaria in BALB / c mice. 12, 2005, 399-406.
doi:10.1111/j.1365-2567.2005.02178.x
[17]. Ghosh D, Brown SL, Stumhofer JS. IL-17 Promotes Differentiation of Splenic LSK ? Lymphoid Progenitors into B Cells following Plasmodium yoelii Infection. J Immunol. 199(5), 2017, 1783-1795.
doi:10.4049/jimmunol.1601972
[18]. Djamiatun K, Wijayahadi N, Utomo AW, Miranti IP, Nugroho D. Annona muricata increase IL-27 , CXCL12 levels and spleen- white-pulp-diameter in severe malaria. 2 nd Int Conf Transl Med Heal Sci conjunction with 4 th JAVA Int Nurs Conf 2018 Creat Better Futur Heal Care Partnersh Res Educ Clin Care. 66, 2018.
[19]. Ghosh D, Wikenheiser DJ, Kennedy B, et al. An Atypical Splenic B Cell Progenitor Population Supports Antibody Production during Plasmodium Infection in Mice. J Immunol. 197(5), 2016, 1788-1800.
doi:10.4049/jimmunol.1502199
[20]. Seemann S, Lupp A. Administration of a CXCL12 analog in endotoxemia is associated with anti-inflammatory, anti-oxidative and cytoprotective effects in vivo. PLoS One. 10(9), 2015, 1-22.
doi:10.1371/journal.pone.0138389
[21]. Tian X, Xie G, Xiao H, Ding F, Bao W, Zhang M. CXCR4 knockdown prevents inflammatory cytokine
Edwin A S et al / Int. J. of Allied Med. Sci. and Clin. Research Vol-8(2) 2020 [215-222]
222
expression in macrophages by suppressing activation of MAPK and NF-?B signaling pathways. Cell Biosci. 9(1), 2019, 1-8. doi:10.1186/s13578-019-0315-x
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