Microbial dysbiosis and microbiota–gut–retina axis: The lesson from brain neurodegenerative diseases to primary open-angle glaucoma pathogenesis of autoimmunity

In recent years, microbiota-associated neurodegenerative diseases have been exploited and provided new insight into disease pathogenesis. However, primary open-angle glaucoma (POAG), known as a complex neurodegenerative disease resulting from retinal ganglion cell death and optic nerve damage, can cause irreversible blindness and visual field loss. POAG, which shares several similarities with Parkinson’s disease (PD) and Alzheimer’s disease (AD), has limited studies and slow progression in the understanding of pathogenesis when compared to PD and AD. In this review, we summarized the current knowledge of POAG and commensal microbiota, combined with several lines of evidence in PD and AD to propose a possible hypothesis for POAG pathogenesis: microorganisms cause glaucoma via gut–retina axis, resulting in autoantibodies and autoreactive T cells that lead to autoimmunity. Furthermore, dual-hit hypothesis, an example of a commensal pathogen that causes PD, was partially exported in POAG. Finally, future perspectives are suggested to expand understanding of POAG

Roles of Toll-Like Receptor 4 for Cellular Pathogenesis in Primary Open-Angle Glaucoma: A potential therapeutic strategy

In recent years, glaucoma has been proposed as an autoimmune disease and an understanding immune-regulation concept has been applied for novel glaucoma therapy. Current evidence suggests an innate immunity is a keystone step for primary open angle glaucoma (POAG) pathogenesis resulting from trabecular meshwork (TM) cell fibrosis and retinal ganglion cell (RGC) death. Toll-like receptor 4 (TLR4) is a common player in the innate immunity, which appears on the TM and RGC of POAG. The activation of TLR4 regulates several molecules involving both fibrosis and cell death. Inhibition of TLR4 decreases TGF-β2-induced fibrosis in TM cells and enhances cell survival of RGC in both optic nerve crush and ischemia models. In this review, we will summarize the molecular mechanisms of TLR4 related to POAG pathogenesis. An understanding of this mechanism may provide novel development of therapeutic strategies for POAG. Keywords: Primary open angle glaucoma (POAG), Trabecular meshwork (TM), Retinal ganglion cells (RGC), Toll-like receptor 4 (TLR4), Innate immunit

The association of toll-like receptor 4 gene polymorphisms with primary open angle glaucoma susceptibility: a meta-analysis

Abstract Primary open angle glaucoma (POAG) and normal tension glaucoma (NTG) cause irreversible blindness while current medications cannot completely inhibit disease progression. An understanding of immunopathogenesis is thus a keystone to develop novel drug targets and genetic markers are still required for early diagnosis. Toll-like receptor 4 (TLR4) is an essential player in inflammation in various diseases. However, the TLR4 polymorphisms have not been completely elucidated in both types of glaucoma. The aim of the present study was to identify the association between TLR4 polymorphism and glaucoma (POAG and NTG) via the use of a comprehensive review and meta-analysis. The relevant studies were collected from PubMed, Excerpta Medica Database (EMBASE), and Web of Science to identify eight included articles, assessed for quality by a modified Newcastle-Ottawa Scale (NOS) for gene association study. A meta-analysis was applied to calculate the pooled odds-ratio and 95% confidence intervals (CIs) to evaluate the association between TLR4 polymorphism and glaucoma. The results revealed that TLR4 rs1927911 A/G, rs12377632 C/T, and rs2149356 G/T significantly decrease the risk of POAG and NTG in allele contrast models 0.71-, 0.71-, and 0.67-fold, respectively. Moreover, rs4986790 A/G and rs4986791 C/T showed a stringent association with POAG in allele contrast, heterozygous, recessive, and overdominant models. In conclusion, this meta-analysis represented a significant correlation between TLR4 polymorphisms and both types of glaucoma suggesting that TLR4 might be involved in the pathogenesis of glaucoma and may be applied as a genetic marker for disease screening.</jats:p

Microbial dysbiosis and microbiota–gut–retina axis: The lesson from brain neurodegenerative diseases to primary open-angle glaucoma pathogenesis of autoimmunity

In recent years, microbiota-associated neurodegenerative diseases have been exploited and provided new insight into disease pathogenesis. However, primary open-angle glaucoma (POAG), known as a complex neurodegenerative disease resulting from retinal ganglion cell death and optic nerve damage, can cause irreversible blindness and visual field loss. POAG, which shares several similarities with Parkinson’s disease (PD) and Alzheimer’s disease (AD), has limited studies and slow progression in the understanding of pathogenesis when compared to PD and AD. In this review, we summarized the current knowledge of POAG and commensal microbiota, combined with several lines of evidence in PD and AD to propose a possible hypothesis for POAG pathogenesis: microorganisms cause glaucoma via gut–retina axis, resulting in autoantibodies and autoreactive T cells that lead to autoimmunity. Furthermore, dual-hit hypothesis, an example of a commensal pathogen that causes PD, was partially exported in POAG. Finally, future perspectives are suggested to expand understanding of POAG.</jats:p

Correction: Prevalence and associated factors for self-reported symptoms of dry eye among Thai school children during the COVID-19 outbreak.

[This corrects the article DOI: 10.1371/journal.pone.0284928.]

Polymorphisms of the <it>pfmdr1 </it>but not the <it>pfnhe-1 </it>gene is associated with <it>in vitro </it>quinine sensitivity in Thai isolates of <it>Plasmodium falciparum</it>

Abstract Background The emergence of Plasmodium falciparum resistance to most currently used anti-malarial drugs is a major problem in malaria control along the Thai-Myanmar and Thai-Cambodia borders. Quinine (QN) with tetracycline/doxycycline has been used as the second-line treatment for uncomplicated falciparum malaria. In addition, QN monotherapy has been the first-line treatment for falciparum malaria in pregnant women. However, reduced in vitro and in vivo responses to QN have been reported. To date, a few genetic markers for QN resistance have been proposed including Plasmodium falciparum chloroquine resistance transporter (pfcrt), P. falciparum multidrug resistance 1 (pfmdr1), and P. falciparum Na+/H+ exchanger (pfnhe-1). This study was to investigate the role of the pfmdr1 and pfnhe-1 gene on in vitro QN sensitivity in Thai isolates of P. falciparum. Methods Eighty-five Thai isolates of P. falciparum from the Thai-Myanmar and Thai-Cambodia borders from 2003-2008 were determined for in vitro QN sensitivity using radioisotopic assay. Polymorphisms of the pfmdr1 and pfnhe-1 gene were determined by PCR-RFLP and sequence analysis. Associations between the in vitro QN sensitivity and the polymorphisms of the pfmdr1 and pfnhe-1 gene were evaluated. Results The mean QN IC50 was 202.8 nM (range 25.7-654.4 nM). Only four isolates were QN resistant when the IC50 of >500 nM was used as the cut-off point. Significant associations were found between the pfmdr1 mutations at codons N86Y and N1042D and in vitro QN sensitivity. However, no associations with the number of DNNND, DDNNNDNHNDD, and NHNDNHNNDDD repeats in the microsatellite ms4760 of the pfnhe-1 gene were identified. Conclusion Data from the present study put doubt regarding the pfnhe-1 gene as to whether it could be used as the suitable marker for QN resistance in Thailand. In contrast, it confirms the influence of the pfmdr1 gene on in vitro QN sensitivity.</p