Asian Pacific Journal of Tropical Biomedicine

94-103

Authors: Noreafifah Semail, Nik Mohd Noor Nik Zuraina, Yasmin Khairani Muhammad Ismadi, Nurul Iman Mohamad, Azian Harun, Ismail Aziah, Zakuan Zainy Deris

Burkholderia pseudomallei is a causative agent of melioidosis that can infect humans and animals in endemic countries, specifically in Southeast Asia and tropical Australia. A fundamental component for the pathogenesis of Burkholderia pseudomallei is the capability of the bacterium to enter, survive, replicate, and cause disease in a host cell by inducing the host cell fusion. Cell fusion results in multinucleated-giant cell formation, thus enabling the dissemination of Burkholderia pseudomallei intracellularly. cGAS reacts to Burkholderia pseudomallei infection by activating the cGAS-STING pathway and subsequently limiting host’s aberrant cell division and cellular replication by inducing autophagic cell death. In this review, we discuss the host-pathogen interactions between the type Ⅵ secretion system 5 (T6SS-5) of Burkholderia pseudomallei and human cGAS pathway in melioidosis infections. Since T6SS-5 is a main virulent factor in Burkholderia pseudomallei and the cGAS pathway is vital for host immune response, elucidating their functions is important for better understanding the pathogenesis of Burkholderia pseudomallei.

112-120

Authors: Wen-Da Wang, Gang Chen

Objective: To evaluate the antiviral activity of pure compounds against herpes simplex virus type 1 (HSV-1) from the rhizome of Anemarrhena asphodeloides. Methods: Bioassay-guided isolation was conducted to separate the active compound and its chemical structure was elucidated by spectral analysis. In vitro antiviral efficacy of active compound was detected by Cell Counting Kit-8 assay, plaque reduction assay, and fluorescence observation. RT-PCR was used to determine the viral load and the cytokine-related gene expression after HSV-1 infection. In vivo study was also conducted to further determine antiviral efficacy of an active compound against HSV-1. Results: An active compound was isolated and elucidated as mangiferin. Mangiferin significantly inhibited the replication of HSV-1 in Vero cells with a half maximal inhibitory concentration (IC50) of 64.0 mg/L. Time-of-addition and time-of-removal assays demonstrated that mangiferin could effectively inhibit the replication of HSV-1 in the early stage (8 h). UL12, UL42, and UL54 gene expression levels of HSV-1 in the 64 mg/L mangiferin-treated group were markedly reduced as compared with the HSV-1 group (P<0.01). Fluorescence observation showed that mangiferin attenuated the mitochondrial damage maintaining ΔΨm induced by HSV-1 in Vero cells. The expression of inflammatory factors TNF-α, IL- 1β, and IL-6 was remarkably increased in the virus-infected group as compared with that in the normal group (P<0.05), the levels of these inflammatory factors dropped after treatment with mangiferin. Mangiferin significantly decreased the viral load and attenuated the HSV-1-induced up-regulation of TNF-α, IL1β, and IL-6. The relative protection rate of HSV-1-infected mice could reach up to 55.5% when the concentration of mangiferin was 4 g/kg. Conclusions: Mangiferin exhibits promising antiviral activity against HSV-1 in vitro and in vivo and could be a potential antiviral agent for HSV-1.

131-138

Authors: Naglaa M El-Lakkany, Hadeel H Elkattan, Alaa E Elsisi

Objective: To evaluate the efficacy of ponatinib plus gossypol against colorectal cancer HCT-116 and Caco-2 cells. Methods: Cells were treated with ponatinib and/or gossypol at increasing concentrations to evaluate synergistic drug interactions by combination index. Cell viability, FGF19/FGFR4, and apoptotic and autophagic cell death were studied. Results: Ponatinib (1.25-40 μM) and gossypol (2.5-80 μM) monotherapy inhibited HCT-116 and Caco-2 cell viability in a dose- and time-dependent manner. The combination of ponatinib and gossypol at a ratio of 1 to 2 significantly decreased cell viability (P<0.05), with a > 2- and > 4-fold reduction in IC50, respectively, after 24 h and 48 h, as compared to the IC50 of ponatinib. Lower combined concentrations showed greater synergism (combination index<1) with a higher ponatinib dose reduction index. Moreover, ponatinib plus gossypol induced morphological changes in HCT-116 and Caco-2 cells, increased beclin-1 and caspase-3, and decreased FGF19, FGFR4, Bcl-2 and p-Akt as compared to treatment with drugs alone. Conclusions: Gossypol enhances ponatinib's anticancer effects against colorectal cancer cells through antiproliferative, apoptotic, and autophagic mechanisms. This may open the way for the future use of ponatinib at lower doses with gossypol as a potentially safer targeted strategy for colorectal cancer treatment.