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Title:	Kesan perencatan glikogen sintase kinase-3B (GSK3B) oleh kurkumin dan natrium tungstat dalam mencit terinfeksi- Burkholderia pseudomallei
Authors:	Anderson Tan (P67460)
Supervisor:	Hasidah Mohd Sidek, Prof. Madya Dr.
Keywords:	Burkholderia pseudomallei Glycogen synthase kinase-3
Issue Date:	29-May-2015
Description:	Infeksi Burkholderia pseudomallei, agen etiologi penyakit melioidosis, boleh menyebabkan respons pro-inflamasi yang keterlaluan pada hos dan mengakibatkan kejutan septik. Glikogen sintase kinase-3β (GSK3β), komponen hiliran dalam tapak jalan fosfotidilinositol-3-kinase/Akt (PI3K/Akt) mempunyai peranan penting dalam mengawalatur respons inflamasi hos semasa infeksi bakteria. Dilaporkan bahawa perencatan GSK3β oleh litium klorida (LiCl) memodulasi keseimbangan sitokin inflamasi hos dalam mencit terinfeksi-B. pseudomallei. Terdapat laporan yang menunjukkan pelbagai kesan farmakologi kurkumin diperantara sebahagian daripadanya melalui perencatan GSK3β. Justeru, kajian ini bertujuan untuk mengkaji kemungkinan penglibatan GSK3β dalam kesan anti-inflamasi kurkumin, sejenis imunomodulator dan komponen bioaktif daripada tumbuhan kunyit (Curcuma longa). Disamping itu, kajian ini juga mengkaji sama ada pengawalaturan aras sitokin inflamasi semasa infeksi melioidosis boleh diperantara melalui perencatan GSK3β- bersandaran Akt. Justeru kesan natrium tungstat (Na2WO4), yang merupakan pengaktif PI3K, terhadap respons sitokin inflamasi hos dalam mencit terinfeksi- B. pseudomallei turut dikaji. Kajian ini melibatkan penilaian kesan kurkumin dan Na2WO4 terhadap kemandirian mencit terinfeksi-B. pseudomallei, muatan bakteria, status pemfosfatan GSK3β dan aras sitokin inflamasi (TNF-α, IFN-γ dan IL-10) pada hepar, limpa dan serum mencit terinfeksi-B. pseudomallei. Perlakuan kurkumin (60 mg/kg b.w.) atau Na2WO4 (100 mg/kg b.w.) secara intraperitoneum meningkatkan kemandirian mencit terinfeksi-B. pseudomallei sebanyak 44.4% dan 33.3% masingmasing (P<0.05) berbanding dengan kumpulan kawalan mencit terinfeksi tanpa perlakuan. Muatan bakteria dalam hepar dan limpa mencit terinfeksi yang diberi perlakuan kurkumin atau Na2WO4 tidak berbeza secara signifikan berbanding dengan kumpulan kawalan terinfeksi tanpa perlakuan (P>0.05). Perlakuan kurkumin atau Na2WO4 menyebabkan peningkatan pemfosfatan GSK3β (Ser9) pada hepar dan limpa mencit terinfeksi-B. pseudomallei berbanding dengan kumpulan kawalan mencit terinfeksi tanpa perlakuan. Peningkatan pemfosfatan Akt pada hepar dan limpa mencit terinfeksi yang diberi perlakuan Na2WO4 juga dicerap. Secara keseluruhannya, perlakuan kurkumin atau Na2WO4 masing-masing menyebabkan pengurangan aras sitokin pro-inflamasi (TNF-α dan IFN-γ ) secara signifikan dalam hepar, limpa dan serum mencit terinfeksi, manakala aras sitokin anti-inflamasi (IL-10) menunjukkan peningkatan signifikan pada serum berbanding dengan kumpulan kawalan terinfeksi tanpa perlakuan. Secara keseluruhannya, hasil kajian ini menunjukkan bahawa perencatan GSK3β oleh kurkumin dan Na2WO4 memodulasi keseimbangan sitokin inflamasi hos. Disamping itu, hasil kajian ini juga mencadangkan bahawa kurkumin berpotensi sebagai imunomodulator semula jadi berasas tumbuhan yang mampu bertindak sebagai anti-infektif dalam menentang infeksi B. pseudomallei melalui pengawalaturan GSK3β.,Infection by Burkholderia pseudomallei, the etiologic agent of melioidosis, can cause overwhelming pro-inflammatory response and lead to septic shock. Glycogen synthase kinase-3β (GSK3β), a downstream component in the phosphotidylinositol-3- kinase/Akt (PI3K/Akt) pathway plays a central role in modulating host inflammatory response during bacterial infections. GSK3β inhibition by lithium chloride (LiCl) has previously been reported to modulate host inflammatory cytokine balance in mice experimentally infected with B. pseudomallei. Several reports suggest that the diverse pharmacological effects of curcumin are mediated in part via inhibition of GSK3β. Therefore, the present study aims to investigate the possible involvement of GSK3β in the anti-inflammatory effects of curcumin, an immunomodulator and bioactive component of the tumeric plant (Curcuma longa). In addition, the present study is also aimed to evaluate whether modulation of cytokine levels during melioidosis infection can be mediated through Akt-dependent inhibition of GSK3β. To this end, the effects of sodium tungstate (Na2WO4), a known activator of PI3K, on the host inflammatory cytokine response in B. pseudomallei-infected mice was investigated. The present study involved determination of the effects of curcumin and Na2WO4 on the survivability of B. pseudomallei-infected mice, bacterial loads, phosphorylation states of GSK3β as well as levels of inflammatory cytokines (TNF-α, IFN-γ and IL-10) in liver, spleen and serum of B. pseudomallei-infected mice. Intraperitoneal administration of curcumin (60 mg/kg b.w.) or Na2WO4 (100 mg/kg b.w.) each significantly (P<0.05) improved survivability of B. pseudomallei-mice by 44.4% and 33.3% respectively compared to non-treated infected controls. Bacterial loads in liver and spleen of curcumin or Na2WO4-treated infected mice were not significantly different from that in non-treated infected controls (P>0.05). Curcumin or Na2WO4 administration resulted in increased phosphorylation of GSK3β (Ser9) in both liver and spleen of mice infected with B. pseudomallei compared to non-treated infected control. Increased phosphorylation of Akt was also observed in both liver and spleen of Na2WO4-treated infected mice. Overall, curcumin and Na2WO4 treatment each significantly (P<0.05) decreased levels of pro-inflammatory cytokines (TNF-α and IFN-γ) in liver, spleen and serum samples from B. pseudomallei-infected mice whilst elevating anti-inflammatory cytokine levels (IL-10) in serum compared to non-treated infected control. Taken together, the results from the present study showed that inhibition of GSK3β caused by curcumin or Na2WO4 administration resulted in the modulation of host inflammatory cytokine balance. In addition, these findings provide scientific evidence that curcumin is a natural immunomodulator of plant origin and potentially useful as an anti-infective against B. pseudomallei infection through regulation of GSK3β.,Master/Sarjana
Pages:	156
Call Number:	QP606.P76A534 2015 tesis
Publisher:	UKM, Bangi
Appears in Collections:	Faculty of Science and Technology / Fakulti Sains dan Teknologi

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