Ebola virus disease: Recent advancs in diagnostics and therapeutics

Ebola virus disease (EVD) is associated with haemorrhagic fever in humans and nonhuman primates, with a high rate of fatality (up to 90%). Some outbreaks in human history have proven the lethality of EVD. The recent epidemic of 2014 and 2015 in West Africa was the deadliest of all time (11 284 deaths). To understand the transmission dynamics, we have reviewed the epidemiology of EVD to date. The absence of any licensed vaccines or approved drugs against Ebola virus (EBOV) further highlights the severity and crisis level of EVD. Some organizations (public and private) are making considerable efforts to develop novel therapeutic approaches or vaccines to contain the outbreak of EBOV shortly. Here, we summarized the various potential drugs and vaccines (undergoing multiple phases of clinical trials) that have arisen as an alternative against EBOV, and we highlighted the numerous issues and limitations hindering this process. Alternatively, an increasing focus on strengthening the medical and civic health structure could provide speedy benefits in containing the spread of EVD, as well as offer a resilient foundation for the deployment of novel drugs and vaccines to the affected countries, once such drugs and vaccines become available.

Ebola virus disease: Recent advancs in diagnostics and therapeutics

Ebola virus disease (EVD) is associated with haemorrhagic fever in humans and nonhuman primates, with a high rate of fatality (up to 90%). Some outbreaks in human history have proven the lethality of EVD. The recent epidemic of 2014 and 2015 in West Africa was the deadliest of all time (11 284 deaths). To understand the transmission dynamics, we have reviewed the epidemiology of EVD to date. The absence of any licensed vaccines or approved drugs against Ebola virus (EBOV) further highlights the severity and crisis level of EVD. Some organizations (public and private) are making considerable efforts to develop novel therapeutic approaches or vaccines to contain the outbreak of EBOV shortly. Here, we summarized the various potential drugs and vaccines (undergoing multiple phases of clinical trials) that have arisen as an alternative against EBOV, and we highlighted the numerous issues and limitations hindering this process. Alternatively, an increasing focus on strengthening the medical and civic health structure could provide speedy benefits in containing the spread of EVD, as well as offer a resilient foundation for the deployment of novel drugs and vaccines to the affected countries, once such drugs and vaccines become available.

Lysophosphatidic acid enhances breast cancer cells-mediated osteoclastogenesis

Lysophosphatidic acid (LPA) is known to play a critical role in breast cancer metastasis to bone. In this study, we tried to investigate any role of LPA in the regulation of osteoclastogenic cytokines from breast cancer cells and the possibility of these secretory factors in affecting osteoclastogenesis. Effect of secreted cytokines on osteoclastogenesis was analyzed by treating conditioned media from LPA-stimulated breast cancer cells to differentiating osteoclasts. Result demonstrated that IL-8 and IL-11 expression were upregulated in LPA-treated MDA-MB-231 cells. IL-8 was induced in both MDA-MB-231 and MDA-MB-468, however, IL-11 was induced only in MDA-MB-231, suggesting differential LPARs participation in the expression of these cytokines. Expression of IL-8 but not IL-11 was suppressed by inhibitors of PI3K, NFkB, ROCK and PKC pathways. In the case of PKC activation, it was observed that PKCδ and PKCμ might regulate LPA-induced expression of IL-11 and IL-8, respectively, by using specific PKC subtype inhibitors. Finally, conditioned Medium from LPA-stimulated breast cancer cells induced osteoclastogenesis. In conclusion, LPA induced the expression of osteolytic cytokines (IL-8 and IL-11) in breast cancer cells by involving different LPA receptors. Enhanced expression of IL-8 by LPA may be via ROCK, PKCu, PI3K, and NFkB signaling pathways, while enhanced expression of IL-11 might involve PKCδ signaling pathway. LPA has the ability to enhance breast cancer cells-mediated osteoclastogenesis by inducing the secretion of cytokines such as IL-8 and IL-11.

Micro-environmental signature of the interactions between druggable target protein, dipeptidyl peptidase-IV, and anti-diabetic drugs

Objective: Druggability of a target protein depends on the interacting micro-environment between the target protein and drugs. Therefore, a precise knowledge of the interacting micro-environment between the target protein and drugs is requisite for drug discovery process. To understand such micro-environment, we performed in silico interaction analysis between a human target protein, Dipeptidyl Peptidase-IV [DPP-4], and three anti-diabetic drugs [saxagliptin, linagliptin and vildagliptin]

Materials and Methods: During the theoretical and bioinformatics analysis of micro-environmental properties, we performed drug-likeness study, protein active site predictions, docking analysis and residual interactions with the protein-drug interface. Micro-environmental landscape properties were evaluated through various parameters such as binding energy, intermolecular energy, electrostatic energy, van der Waals'+H-bond+desolvo energy [EVHD] and ligand efficiency [LE] using different in silico methods. For this study, we have used several servers and software, such as Molsoft prediction server, CASTp server, AutoDock software and LIGPLOT server

Results: Through micro-environmental study, highest log P value was observed for linagliptin [1.07]. Lowest binding energy was also observed for linagliptin with DPP-4 in the binding plot. We also identified the number of H-bonds and residues involved in the hydrophobic interactions between the DPP-4 and the anti-diabetic drugs. During interaction, two H-bonds and nine residues, two H-bonds and eleven residues as well as four H-bonds and nine residues were found between the saxagliptin, linagliptin as well as vildagliptin cases and DPP-4, respectively

Conclusion: Our in silico data obtained for drug-target interactions and micro-environmental signature demonstrates linagliptin as the most stable interacting drug among the tested anti-diabetic medicines

Quercetin induces apoptosis and cell cycle arrest in triple-negative breast cancer cells through modulation of Foxo3a activity

Quercetin, a plant-derived flavonoid found in fruits, vegetables and tea, has been known to possess bioactive properties such as anti-oxidant, anti-inflammatory and anti-cancer. In this study, anti-cancer effect of quercetin and its underlying mechanisms in triple-negative breast cancer cells was investigated. MTT assay showed that quercetin reduced breast cancer cell viability in a time and dose dependent manner. For this, quercetin not only increased cell apoptosis but also inhibited cell cycle progression. Moreover, quercetin increased FasL mRNA expression and p51, p21 and GADD45 signaling activities. We also observed that quercetin induced protein level, transcriptional activity and nuclear translocation of Foxo3a. Knockdown of Foxo3a caused significant reduction in the effect of quercetin on cell apoptosis and cell cycle arrest. In addition, treatment of JNK inhibitor (SP 600125) abolished quercetin-stimulated Foxo3a activity, suggesting JNK as a possible upstream signaling in regulation of Foxo3a activity. Knockdown of Foxo3a and inhibition of JNK activity reduced the signaling activities of p53, p21 and GADD45, triggered by quercetin. Taken together, our study suggests that quercetin induces apoptosis and cell cycle arrest via modification of Foxo3a signaling in triple-negative breast cancer cells.

Anti-inflammatory effects of traditional mixed extract of medicinal herbs (MEMH) on monosodium urate crystal-induced gouty arthritis / 中国天然药物

Korean oriental medicine prescription is widely used for the treatment of gouty diseases. In the present study, we investigated anti-inflammatory effects of modified Korean herbal formulation, mixed extract of medicinal herbs (MEMH), and its modulatory effects on inflammatory mediators associated with gouty arthritis. Both in vitro and in vivo studies were carried out to assess the anti-inflammatory efficacy of MEMH on monosodium urate (MSU) crystals-induced gouty inflammation. MSU crystals stimulated human chondrosarcoma cell line, SW1353, and human primary chondrocytes were treated with MEMH in vitro. The expression levels of pro-inflammatory mediators and metalloproteases were analyzed. The effect of MEMH on NFκB signaling pathway in SW1353 cells was examined. Effect of MEMH on the mRNA expression level of pro-inflammatory mediators and chemotactic factor from human monocytic cell line, THP-1, was also analyzed. The probable role of MEMH in the differentiation process of osteoblast like cells, SaOS-2, after MSU treatment was also observed. To investigate the effects of MEMH in vivo, MSU crystals-induced ankle arthritic model was established. Histopathological changes in affected joints and plasma levels of pro-inflammatory mediators (IL-1β and TNFα) were recorded. MEMH inhibited NFκB signaling pathway and COX-2 protein expression in chondrocytes. MSU-induced mRNA expressions of pro-inflammatory mediators and chemotactic cytokines were suppressed by MEMH. In MSU crystals-induced ankle arthritic mouse model, administration of MEMH relieved inflammatory symptoms and decreased the plasma levels of IL-1β and TNFα. The results indicated that MEMH can effectively inhibit the expression of inflammatory mediators in gouty arthritis, demonstrating its potential for treating gouty arthritis.