Shinichi Fukuda

Bio: Shinichi Fukuda is an academic researcher from University of Tsukuba. The author has contributed to research in topics: Optical coherence tomography & Cornea. The author has an hindex of 17, co-authored 42 publications receiving 915 citations. Previous affiliations of Shinichi Fukuda include University of Virginia & University of Kentucky.

cGAS drives noncanonical-inflammasome activation in age-related macular degeneration

Abstract: Geographic atrophy is a blinding form of age-related macular degeneration characterized by retinal pigmented epithelium (RPE) death; the RPE also exhibits DICER1 deficiency, resultant accumulation of endogenous Alu-retroelement RNA, and NLRP3-inflammasome activation. How the inflammasome is activated in this untreatable disease is largely unknown. Here we demonstrate that RPE degeneration in human-cell-culture and mouse models is driven by a noncanonical-inflammasome pathway that activates caspase-4 (caspase-11 in mice) and caspase-1, and requires cyclic GMP-AMP synthase (cGAS)-dependent interferon-β production and gasdermin D-dependent interleukin-18 secretion. Decreased DICER1 levels or Alu-RNA accumulation triggers cytosolic escape of mitochondrial DNA, which engages cGAS. Moreover, caspase-4, gasdermin D, interferon-β, and cGAS levels were elevated in the RPE in human eyes with geographic atrophy. Collectively, these data highlight an unexpected role of cGAS in responding to mobile-element transcripts, reveal cGAS-driven interferon signaling as a conduit for mitochondrial-damage-induced inflammasome activation, expand the immune-sensing repertoire of cGAS and caspase-4 to noninfectious human disease, and identify new potential targets for treatment of a major cause of blindness.

Vision-related quality of life and visual function after vitrectomy for various vitreoretinal disorders.

Abstract: Purpose To investigate vision-related quality of life (VR-QOL) in patients undergoing vitrectomy for various vitreoretinal disorders and to evaluate the relationship between VR-QOL and visual function. Methods The study included 100 normal control subjects and 299 patients with various vitreoretinal disorders including proliferative diabetic retinopathy (PDR), diabetic macular edema (DME), branch retinal vein occlusion (BRVO), central retinal vein occlusion (CRVO), macular hole (MH), epiretinal membrane (ERM), and rhegmatogenous retinal detachment (RD). The 25-item National Eye Institute Visual Function Questionnaire (VFQ-25) was answered by the patients with vitreoretinal disorders before and 3 months after pars plana vitrectomy, as well as by the normal control subjects. Clinical data were collected, including visual acuity, contrast sensitivity, and severity of metamorphopsia. Results Vitrectomy significantly improved the VFQ-25 composite score in all vitreoretinal disorders. Preoperative VFQ-25 composite scores in MH and ERM were significantly higher than those in PDR, DME, and BRVO. Postoperative VFQ-25 composite scores were significantly higher in MH, ERM, and RD than in PDR, DME, BRVO, and CRVO. A greater improvement in the VFQ-25 composite score was observed in ERM than in DME. Multiple regression analysis revealed that changes in contrast sensitivity had a significant correlation with changes in the VFQ-25 composite score in PDR and DME. Changes in metamorphopsia were significantly associated with changes in the VFQ-25 composite score in MH and ERM. Conclusions Vitrectomy significantly improved VR-QOL in various vitreoretinal disorders. The largest improvement in VR-QOL was observed in ERM and smallest improvement in DME. The visual function parameters associated with VR-QOL are different depending on vitreoretinal disorders.

Birefringence measurement of cornea and anterior segment by office-based polarization-sensitive optical coherence tomography

Abstract: We present a case series of cornea and anterior segment disorders investigated by an office-based polarization-sensitive optical coherence tomography (PS-OCT). Blebs of glaucoma patients treated by trabeculectomy, and corneas of keratoconus and keratoplasty patients were measured by PS-OCT. Birefringence formations in trabeculectomy bleb were measured in 1 control eye and 3 eyes of trabeculectomy model rabbits. Polarization insensitive scattering OCT and the depth-resolved birefringence were measured simultaneously by PS-OCT. Abnormal birefringence was observed in keratoconus cases with advanced thinning and with a rupture of Descemet’s membrane. The graft-host interface of the keratoplasty case showed abnormal birefringence. The appearance of abnormal birefringence in the cornea was likely to be an indication of cross-linking of collagen fibrils. The measurement of rabbit showed abnormal birefringence in the scarring eyes. Wide regions of strong birefringence were observed in the eyes of trabeculectomy patients who had high intraocular pressure. Visualization of scarring in bleb by PS-OCT may be useful for the planning of secondary surgery. PS-OCT showed promising for the study and diagnosis diseases related to abnormal fibrous tissues of the cornea and anterior eye segment.

Vision-Related Quality of Life and Visual Function in Patients undergoing Vitrectomy, Gas tamponade, and Cataract Surgery for Macular Hole

Abstract: Aim: To evaluate the relationship between vision-related quality of life (VR-QOL) and visual function in patients undergoing vitrectomy, gas tamponade and cataract surgery for macular hole (MH). Methods: The 25-item National Eye Institute Visual Function Questionnaire (VFQ-25) was self-administered by 32 patients with MH (age 66.2 (SD 5.4) years) preoperatively and at 3 months postoperatively. Clinical data were collected, including logarithm of minimum angle of resolution (logMAR) best corrected visual acuity (BCVA), severity of metamorphopsia and letter contrast sensitivity. The severity of metamorphopsia was evaluated by the M-Charts. MH index was measured using optical coherence tomography. The presence and severity of cataract were graded using the Lens Opacities Classification System III reference standards. Multiple regression analysis was performed to investigate the relationship between various explanatory variables and VFQ-25 questionnaire scores. Explanatory variables tested were the severity of metamorphopsia, visual acuity, letter contrast sensitivity, MH index and grade of cataract. Results: Vitrectomy for MH significantly improved VFQ-25 composite score as well as subscale scores, including general vision, near activities, distance activities, social functioning, mental health and dependency (p Conclusion: Vitrectomy for MH significantly improved VR-QOL. The severity of metamorphopsia was significantly associated with both preoperative and postoperative VR-QOL.

The NLRP3 inflammasome: molecular activation and regulation to therapeutics

Abstract: NLRP3 (NOD-, LRR- and pyrin domain-containing protein 3) is an intracellular sensor that detects a broad range of microbial motifs, endogenous danger signals and environmental irritants, resulting in the formation and activation of the NLRP3 inflammasome. Assembly of the NLRP3 inflammasome leads to caspase 1-dependent release of the pro-inflammatory cytokines IL-1β and IL-18, as well as to gasdermin D-mediated pyroptotic cell death. Recent studies have revealed new regulators of the NLRP3 inflammasome, including new interacting or regulatory proteins, metabolic pathways and a regulatory mitochondrial hub. In this Review, we present the molecular, cell biological and biochemical bases of NLRP3 activation and regulation and describe how this mechanistic understanding is leading to potential therapeutics that target the NLRP3 inflammasome.

DAMP-sensing receptors in sterile inflammation and inflammatory diseases

Abstract: The innate immune system has the capacity to detect ‘non-self’ molecules derived from pathogens, known as pathogen-associated molecular patterns, via pattern recognition receptors. In addition, an increasing number of endogenous host-derived molecules, termed damage-associated molecular patterns (DAMPs), have been found to be sensed by various innate immune receptors. The recognition of DAMPs, which are produced or released by damaged and dying cells, promotes sterile inflammation, which is important for tissue repair and regeneration, but can also lead to the development of numerous inflammatory diseases, such as metabolic disorders, neurodegenerative diseases, autoimmune diseases and cancer. Here we examine recent discoveries concerning the roles of DAMP-sensing receptors in sterile inflammation and in diseases resulting from dysregulated sterile inflammation, and then discuss insights into the cross-regulation of these receptors and their ligands. Host-derived molecules, the so-called damage-associated molecular patterns (DAMPs), can induce sterile inflammation. This Review provides an overview of DAMP-sensing receptors, discusses the crosstalk between these receptors and explores their role in disease.

The cGAS-cGAMP-STING pathway connects DNA damage to inflammation, senescence, and cancer.

Abstract: Detection of microbial DNA is an evolutionarily conserved mechanism that alerts the host immune system to mount a defense response to microbial infections. However, this detection mechanism also poses a challenge to the host as to how to distinguish foreign DNA from abundant self-DNA. Cyclic guanosine monophosphate (GMP)-adenosine monophosphate (AMP) synthase (cGAS) is a DNA sensor that triggers innate immune responses through production of the second messenger cyclic GMP-AMP (cGAMP), which binds and activates the adaptor protein STING. However, cGAS can be activated by double-stranded DNA irrespective of the sequence, including self-DNA. Although how cGAS is normally kept inactive in cells is still not well understood, recent research has provided strong evidence that genomic DNA damage leads to cGAS activation to stimulate inflammatory responses. This review summarizes recent findings on how genomic instability and DNA damage trigger cGAS activation and how cGAS serves as a link from DNA damage to inflammation, cellular senescence, and cancer.

DNA sensing by the cGAS–STING pathway in health and disease

Abstract: The detection of pathogens through nucleic acid sensors is a defining principle of innate immunity. RNA-sensing and DNA-sensing receptors sample subcellular compartments for foreign nucleic acids and, upon recognition, trigger immune signalling pathways for host defence. Over the past decade, our understanding of how the recognition of nucleic acids is coupled to immune gene expression has advanced considerably, particularly for the DNA-sensing receptor cyclic GMP-AMP synthase (cGAS) and its downstream signalling effector stimulator of interferon genes (STING), as well as the molecular components and regulation of this pathway. Moreover, the ability of self-DNA to engage cGAS has emerged as an important mechanism fuelling the development of inflammation and implicating the cGAS-STING pathway in human inflammatory diseases and cancer. This detailed mechanistic and biological understanding is paving the way for the development and clinical application of pharmacological agonists and antagonists in the treatment of chronic inflammation and cancer.