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Pertinent clinical outcomes in pediatric survivors of pediatric acute respiratory distress syndrome (PARDS): a narrative review

Lee SW, Loh SW, Ong C, Lee JH

Ann Transl Med, 2019 Oct;7(19):513.
PMID: 31728366 DOI: 10.21037/atm.2019.09.32

The objectives of this review are to describe the limitations of commonly used clinical outcomes [e.g., mortality, ventilation parameters, need for extracorporeal membrane oxygenation (ECMO), pediatric intensive care unit (PICU) and hospital length of stay (LOS)] in pediatric acute respiratory distress syndrome (PARDS) studies; and to explore other pertinent clinical outcomes that pediatric critical care practitioners should consider in future clinical practice and research studies. These include long-term pulmonary function, risk of pulmonary hypertension (PHT), nutrition status and growth, PICU-acquired weakness, neurological outcomes and neurocognitive development, functional status, health-related quality of life (HRQOL)], health-care costs, caregiver and family stress. PubMed was searched using the following keywords or medical subject headings (MESH): "acute lung injury (ALI)", "acute respiratory distress syndrome (ARDS)", "pediatric acute respiratory distress syndrome (PARDS)", "acute hypoxemia respiratory failure", "outcomes", "pediatric intensive care unit (PICU)", "lung function", "pulmonary hypertension", "growth", "nutrition', "steroid", "PICU-acquired weakness", "functional status scale", "neurocognitive", "psychology", "health-care expenditure", and "HRQOL". The concept of contemporary measure outcomes was adapted from adult ARDS long-term outcome studies. Articles were initially searched from existing PARDS articles pool. If the relevant measure outcomes were not found, where appropriate, we considered studies from non-ARDS patients within the PICU in whom these outcomes were studied. Long-term outcomes in survivors of PARDS were not follow-up in majority of pediatric studies regardless of whether the new or old definitions of ARDS in children were used. Relevant studies were scarce, and the number of participants was small. As such, available studies were not able to provide conclusive answers to most of our clinical queries. There remains a paucity of data on contemporary clinical outcomes in PARDS studies. In addition to the current commonly used outcomes, clinical researchers and investigators should consider examining these contemporary outcome measures in PARDS studies in the future.
Fulltext Inhibition of euchromatic histone methyltransferase 1 and 2 sensitizes chronic myeloid leukemia cells to interferon treatment

Loh SW, Ng WL, Yeo KS, Lim YY, Ea CK

PLoS One, 2014;9(7):e103915.
PMID: 25079219 DOI: 10.1371/journal.pone.0103915

H3K9 methylation is one of the essential histone post-translational modifications for heterochromatin formation and transcriptional repression. Recently, several studies have demonstrated that H3K9 methylation negatively regulates the type I interferon response.
Fulltext A cell-based screening system for anti-influenza A virus agents

Wong WY, Loh SW, Ng WL, Tan MC, Yeo KS, Looi CY, et al.

Sci Rep, 2015;5:8672.
PMID: 25728279 DOI: 10.1038/srep08672

Emerging of drug resistant influenza A virus (IAV) has been a big challenge for anti-IAV therapy. In this study, we describe a relatively easy and safe cell-based screening system for anti-IAV replication inhibitors using a non-replicative strain of IAV. A nickel (II) complex of polyhydroxybenzaldehyde N4-thiosemicarbazone (NiPT5) was recently found to exhibit anti-inflammatory activity in vivo and in vitro. NiPT5 impedes the signaling cascades that lead to the activation of NF-κB in response to different stimuli, such as LPS and TNFα. Using our cell-based screening system, we report that pretreating cells with NiPT5 protects cells from influenza A virus (IAV) and vesicular stomatitis virus (VSV) infection. Furthermore, NiPT5 inhibits replication of IAV by inhibiting transcription and translation of vRNAs of IAV. Additionally, NiPT5 reduces IAV-induced type I interferon response and cytokines production. Moreover, NiPT5 prevents activation of NF-κB, and IRF3 in response to IAV infection. These results demonstrate that NiPT5 is a potent antiviral agent that inhibits the early phase of IAV replication.
Fulltext JMJD8 is a positive regulator of TNF-induced NF-κB signaling

Yeo KS, Tan MC, Wong WY, Loh SW, Lam YL, Tan CL, et al.

Sci Rep, 2016 Sep 27;6:34125.
PMID: 27671354 DOI: 10.1038/srep34125

TNF-induced signaling mediates pleiotropic biological consequences including inflammation, immunity, cell proliferation and apoptosis. Misregulation of TNF signaling has been attributed as a major cause of chronic inflammatory diseases and cancer. Jumonji domain-containing protein 8 (JMJD8) belongs to the JmjC family. However, only part of the family members has been described as hydroxylase enzymes that function as histone demethylases. Here, we report that JMJD8 positively regulates TNF-induced NF-κB signaling. Silencing the expression of JMJD8 using RNA interference (RNAi) greatly suppresses TNF-induced expression of several NF-κB-dependent genes. Furthermore, knockdown of JMJD8 expression reduces RIP ubiquitination, IKK kinase activity, delays IκBα degradation and subsequently blocks nuclear translocation of p65. In addition, JMJD8 deficiency enhances TNF-induced apoptosis. Taken together, these findings indicate that JMJD8 functions as a positive regulator of TNF-induced NF-κB signaling.
Fulltext Nickel(II) complex of polyhydroxybenzaldehyde N4-thiosemicarbazone exhibits anti-inflammatory activity by inhibiting NF-κB transactivation

Shawish HB, Wong WY, Wong YL, Loh SW, Looi CY, Hassandarvish P, et al.

PLoS One, 2014;9(6):e100933.
PMID: 24977407 DOI: 10.1371/journal.pone.0100933

BACKGROUND: The biological properties of thiosemicarbazone have been widely reported. The incorporation of some transition metals such as Fe, Ni and Cu to thiosemicarbazone complexes is known to enhance its biological effects. In this study, we incorporated nickel(II) ions into thiosemicarbazone with N4-substitution groups H3L (H; H3L1, CH3; H3L2, C6H5; H3L3 and C2H5; H3L4) and examined its potential anti-inflammatory activity.
METHODOLOGY/PRINCIPAL FINDINGS: Four ligands (1-4) and their respective nickel-containing complexes (5-8) were synthesized and characterized. The compounds synthesized were tested for their effects on NF-κB nuclear translocation, pro-inflammatory cytokines secretion and NF-κB transactivation activity. The active compound was further evaluated on its ability to suppress carrageenan-induced acute inflammation in vivo. A potential binding target of the active compound was also predicted by molecular docking analysis.
CONCLUSIONS/SIGNIFICANCE: Among all synthesized compounds tested, we found that complex [Ni(H2L1)(PPh3)]Cl (5) (complex 5), potently inhibited IκBα degradation and NF-κB p65 nuclear translocation in LPS-stimulated RAW264.7 cells as well as TNFα-stimulated HeLa S3 cells. In addition, complex 5 significantly down-regulated LPS- or TNFα-induced transcription of NF-κB target genes, including genes that encode the pro-inflammatory cytokines TNFα, IFNβ and IL6. Luciferase reporter assays confirmed that complex 5 inhibited the transactivation activity of NF-κB. Furthermore, the anti-inflammatory effect of complex 5 was also supported by its suppressive effect on carrageenan-induced paw edema formation in wild type C57BL/6 mice. Interestingly, molecular docking study showed that complex 5 potentially interact with the active site of IKKβ. Taken together, we suggest complex 5 as a novel NF-κB inhibitor with potent anti-inflammatory effects.