Tinospora cordifolia Aqueous Extract Alleviates Cyclophosphamide- Induced Immune Suppression, Toxicity and Systemic Candidiasis in Immunosuppressed Mice: In vivo Study in Comparison to Antifungal Drug Fluconazole

Author(s): Faris Alrumaihi, Khaled S. Allemailem, Ahmad Almatroudi, Mohammed A. Alsahli, Arif Khan, Masood A. Khan*.

Journal Name: Current Pharmaceutical Biotechnology

Volume 20 , Issue 12 , 2019

Become EABM
Become Reviewer

Graphical Abstract:


Abstract:

Objective: The present study was aimed to evaluate the effect of the aqueous extract of Tinospora cordifolia (AETC) against cyclophosphamide-induced immunosuppression and systemic Candida albicans infection in a murine model.

Methods: The protective effect of AETC against cyclophosphamide-induced leukopenia was evaluated by quantitative and qualitative analysis of the leukocytes. The immune-stimulating potential of AETC on macrophages was assessed by determining the levels of secreted cytokines. To determine the direct antifungal activity, AETC or fluconazole was administered to C. albicans infected mice. The efficacy of treatment was assessed by determining the survival rate, kidney fungal burden, the organ index and liver inflammation parameters.

Results: Cyclophosphamide administration resulted in substantial depletion of leukocytes, whereas AETC treatment induced the recovery of leukocytes in cyclophosphamide-injected mice. Moreover, AETC treatment of macrophages resulted in enhanced secretion of IFN-γ, TNF-α and IL-1β. C. albicans infected mice treated with AETC at the doses of 50 and 100 mg/kg exhibited 40% and 60% survival rate, whereas the mice treated with fluconazole at a dose of 50 mg/kg showed 20% survival rate. Like survival data, the fungal load was found to be the lowest in the kidney tissues of mice treated with AETC at a dose of 100 mg/kg. Interestingly, mice infected with C. albicans demonstrated improvement in the organ indices and liver functioning after AETC treatment.

Conclusion: These results suggest that AETC may potentially be used to rejuvenate the weakened immune system and eliminate systemic candidiasis in mice.

Keywords: Alternative medicines, Tinospora cordifolia, Candida albicans, immunosuppression, toxicity, AETC.

[1]
Alekshun, M.N. New advances in antibiotic development and discovery. Expert Opin. Investig. Drugs, 2005, 14(2), 117-134.
[http://dx.doi.org/10.1517/13543784.14.2.117] [PMID: 15757391]
[2]
Edmond, M.B.; Wallace, S.E.; McClish, D.K.; Pfaller, M.A.; Jones, R.N.; Wenzel, R.P. Nosocomial bloodstream infections in United States hospitals: a three-year analysis. Clin. Infect. Dis., 1999, 29(2), 239-244.
[http://dx.doi.org/10.1086/520192] [PMID: 10476719]
[3]
Khan, M.A.; Firoz, A.; Jabeen, R.; Mohammad, O. Prophylactic role of immunomodulators in treatment of systemic candidiasis in leukopenic mice. J. Drug Target., 2004, 12(7), 425-433.
[http://dx.doi.org/10.1080/10611860412331285215] [PMID: 15621667]
[4]
Conly, J.; Rennie, R.; Johnson, J.; Farah, S.; Hellman, L. Disseminated candidiasis due to amphotericin B-resistant Candida albicans. J. Infect. Dis., 1992, 165(4), 761-764.
[http://dx.doi.org/10.1093/infdis/165.4.761] [PMID: 1285732]
[5]
Tujios, S.; Fontana, R.J. Mechanisms of drug-induced liver injury: from bedside to bench. Nat. Rev. Gastroenterol. Hepatol., 2011, 8(4), 202-211.
[http://dx.doi.org/10.1038/nrgastro.2011.22] [PMID: 21386809]
[6]
Khan, M.A.; Owais, M. Toxicity, stability and pharmacokinetics of amphotericin B in immunomodulator tuftsin-bearing liposomes in a murine model. J. Antimicrob. Chemother., 2006, 58(1), 125-132.
[http://dx.doi.org/10.1093/jac/dkl177] [PMID: 16709592]
[7]
Chapman, S.W.; Sullivan, D.C.; Cleary, J.D. In search of the holy grail of antifungal therapy. Trans. Am. Clin. Climatol. Assoc., 2008, 119, 197-215.
[PMID: 18596853]
[8]
Alsuhaibani, S.; Khan, M.A. Immune-stimulatory and therapeutic activity of Tinospora cordifolia: Double-edged sword against Salmonellosis. J. Immunol. Res., 2017.20171787803
[http://dx.doi.org/10.1155/2017/1787803] [PMID: 29318160]
[9]
Panchabhai, T.S.; Kulkarni, U.P.; Rege, N.N. Validation of therapeutic claims of Tinospora cordifolia: A review. Phytother. Res., 2008, 22(4), 425-441.
[http://dx.doi.org/10.1002/ptr.2347] [PMID: 18167043]
[10]
Maurya, R.; Wazir, V.; Kapil, A.; Kapil, R.S. Cardifoliosides A and B, two new phenylpropene disaccharides from Tinospora cordifolia possessing immunostimulant activity. Nat. Prod. Lett., 1996, 8, 7-10.
[http://dx.doi.org/10.1080/10575639608043231]
[11]
Sharma, U.; Bala, M.; Kumar, N.; Singh, B.; Munshi, R.K.; Bhalerao, S. Immunomodulatory active compounds from Tinospora cordifolia. J. Ethnopharmacol., 2012, 141(3), 918-926.
[http://dx.doi.org/10.1016/j.jep.2012.03.027] [PMID: 22472109]
[12]
Desai, V.R.; Ramkrishnan, R.; Chintalwar, G.J.; Sainis, K.B. G1-4A, an immunomodulatory polysaccharide from Tinospora cordifolia, modulates macrophage responses and protects mice against lipopolysaccharide induced endotoxic shock. Int. Immunopharmacol., 2007, 7(10), 1375-1386.
[http://dx.doi.org/10.1016/j.intimp.2007.06.004] [PMID: 17673153]
[13]
Thatte, U.M.; Kulkarni, M.R.; Dahanukar, S.A. Immunotherapeutic modification of Escherichia coli peritonitis and bacteremia by Tinospora cordifolia. J. Postgrad. Med., 1992, 38(1), 13-15.
[PMID: 1512717]
[14]
Mishra, A.; Kumar, S.; Bhargava, A.; Sharma, B.; Pandey, A.K. Studies on in vitro antioxidant and antistaphylococcal activities of some important medicinal plants. Cell. Mol. Biol., 2011, 57(1), 16-25.
[PMID: 21366958]
[15]
Gupta, P.K.; Chakraborty, P.; Kumar, S.; Singh, P.K.; Rajan, M.G.; Sainis, K.B.; Kulkarni, S. G1-4A, a Polysaccharide from Tinospora cordifolia inhibits the survival of Mycobacterium tuberculosis by modulating host immune responses in TLR4 dependent manner. PLoS One, 2016, 11(5)e0154725
[http://dx.doi.org/10.1371/journal.pone.0154725] [PMID: 27148868]
[16]
Akhtar, S. Use of Tinospora cordifolia in HIV infection. Indian J. Pharmacol., 2010, 42(1), 57.
[http://dx.doi.org/10.4103/0253-7613.62402] [PMID: 20606842]
[17]
Banerjee, N.; Saha, B.; Mukhopadhyay, S. Intracellular ROS generated in chikungunya patients with persisting polyarthralgia can be reduced by Tinospora cordifolia leaf extract. Virusdisease, 2018, 29(3), 375-379.
[http://dx.doi.org/10.1007/s13337-018-0465-1] [PMID: 30159374]
[18]
Kritikos, A.; Manuel, O. Bloodstream infections after solid-organ transplantation. Virulence, 2016, 2,7(3), 329-340.
[http://dx.doi.org/10.1080/21505594.2016.1139279]
[19]
Wiederhold, N.P. Antifungal resistance: Current trends and future strategies to combat. Infect. Drug Resist., 2017, 10, 249-259.
[http://dx.doi.org/10.2147/IDR.S124918] [PMID: 28919789]
[20]
Khan, M.A.; Aljarbou, A.N.; Khan, A.; Younus, H. Liposomal thymoquinone effectively combats fluconazole-resistant Candida albicans in a murine model. Int. J. Biol. Macromol., 2015, 76, 203-208.
[http://dx.doi.org/10.1016/j.ijbiomac.2015.02.015] [PMID: 25709021]
[21]
Khan, M.A.; Aljarbou, A.; Khan, A.; Owais, M. Immune stimulating and therapeutic potential of tuftsin-incorporated nystatin liposomes against Cryptococcus neoformans in leukopenic BALB/C mice. FEMS Immunol. Med. Microbiol., 2012, 66(1), 88-97.
[http://dx.doi.org/10.1111/j.1574-695X.2012.00992.x] [PMID: 22612788]
[22]
Khan, M. A.; Aldebasi, Y. H.; Alsuhaibani, S. A.; AlSahli, M. A.; Alzohairy, M. A.; Khan, A.; Younus, H. Therapeutic potential of thymoquinone liposomes against the systemic infection of Candida albicans in diabetic mice PLoS One, 2018, 27,13(12)e0208951
[23]
Laskar, A.A.; Khan, M.A.; Rahmani, A.H.; Fatima, S.; Younus, H. Thymoquinone, an active constituent of Nigella sativa seeds, binds with bilirubin and protects mice from hyperbilirubinemia and cyclophosphamide-induced hepatotoxicity. Biochimie, 2016, 127, 205-213.
[http://dx.doi.org/10.1016/j.biochi.2016.05.020] [PMID: 27265787]
[24]
Ahlmann, M.; Hempel, G. The effect of cyclophosphamide on the immune system: Implications for clinical cancer therapy. Cancer Chemother. Pharmacol., 2016, 78(4), 661-671.
[http://dx.doi.org/10.1007/s00280-016-3152-1] [PMID: 27646791]
[25]
Khan, M.A. Immune potentiating and antitoxic effects of camel milk against cyclophosphamide-induced toxicity in BALB/C mice. Int. J. Health Sci. (Qassim), 2017, 11(4), 18-22.
[PMID: 29085263]
[26]
Newman, S.L.; Bhugra, B.; Holly, A.; Morris, R.E. Enhanced killing of Candida albicans by human macrophages adherent to type 1 collagen matrices via induction of phagolysosomal fusion. Infect. Immun., 2005, 73(2), 770-777.
[http://dx.doi.org/10.1128/IAI.73.2.770-777.2005] [PMID: 15664915]
[27]
Ohta, H.; Tanimoto, T.; Taniai, M.; Taniguchi, M.; Ariyasu, T.; Arai, S.; Ohta, T.; Fukuda, S. Regulation of Candida albicans morphogenesis by tumor necrosis factor-alpha and potential for treatment of oral candidiasis. In Vivo, 2007, 21(1), 25-32.
[PMID: 17354610]
[28]
Lilic, D.; Gravenor, I.; Robson, N.; Lammas, D.A.; Drysdale, P.; Calvert, J.E.; Cant, A.J.; Abinun, M. Deregulated production of protective cytokines in response to Candida albicans infection in patients with chronic mucocutaneous candidiasis. Infect. Immun., 2003, 71(10), 5690-5699.
[http://dx.doi.org/10.1128/IAI.71.10.5690-5699.2003] [PMID: 14500490]
[29]
Rocha, F.A.C.; Alves, A.M.C.V.; Rocha, M.F.G.; Cordeiro, R.A.; Brilhante, R.S.N.; Pinto, A.C.M.D.; Nunes, R.M.; Girão, V.C.C.; Sidrim, J.J.C. Tumor necrosis factor prevents Candida albicans biofilm formation. Sci. Rep., 2017, 7(1), 1206.
[http://dx.doi.org/10.1038/s41598-017-01400-4] [PMID: 28446778]


Rights & PermissionsPrintExport Cite as

Article Details

VOLUME: 20
ISSUE: 12
Year: 2019
Page: [1055 - 1063]
Pages: 9
DOI: 10.2174/1389201019666190722151126
Price: $58

Article Metrics

PDF: 19
HTML: 1