Association between tear meniscus dimensions and higher-order aberrations in patients with surgically treated lacrimal passage obstruction.

PURPOSE: To analyze the relationship between tear meniscus dimensions and higher-order aberrations (HOAs) in patients with lacrimal passage obstruction using anterior segment optical coherence tomography (AS-OCT). METHODS: This study was a retrospective observational study of 71 eyes of 49 patients with lacrimal passage obstruction. These patients received sheath-guided dacryoendoscopic probing and bicanalicular intubation (SG-BCI) at Toyama University Hospital between August 2020 and October 2021. Using AS-OCT, tear meniscus height (TMH), tear meniscus area (TMA), and total corneal HOAs values were measured before and after surgery. RESULTS: Surgical success was achieved in 69 eyes (97.1%). At the final observation, 62 eyes showed lacrimal patency (89.8%). The preoperative TMH, TMA, and HOAs values were 1.55 ± 0.96 mm, 0.11 ± 0.14 mm2, and 0.37 ± 0.27 µm, respectively, and the final postoperative TMH, TMA, and HOAs values were 0.97 ± 0.74 mm (p < 0.0001), 0.06 ± 0.11 mm2 (p = 0.02), and 0.29 ± 0.16 µm (p = 0.001), respectively. The results showed a significant improvement. The changes in HOAs before and after surgery were positively correlated with the changes in TMH (r = 0.3476, p = 0.0241) and TMA (r = 0.3653, p = 0.0174). CONCLUSION: SG-BCI for lacrimal passage obstruction resulted in a significant decrease in measured HOAs. The decrease in HOAs was correlated with decreases in tear meniscus dimensions.

Visual field changes in glaucoma patients after blepharoptosis surgery.

PURPOSE: To examine changes in parameters of the visual field test before and after blepharoptosis surgery in patients with glaucoma. METHODS: Twenty-three eyes of 14 glaucoma patients who underwent blepharoptosis surgery at Toyama University Hospital between July 2015 and September 2020 were included in this study. Pre- and post-operative values for the mean deviation (MD), pattern standard deviation (PSD) and total deviation (TD) of the upper or lower hemi-visual field in the Humphrey visual field test, best-corrected visual acuity (BCVA), intraocular pressure (IOP), and margin reflex distance (MRD)-1 were compared. RESULTS: MRD-1 showed a significant improvement after blepharoptosis surgery (preoperative MRD-1: 1.0 ± 0.82 mm, postoperative MRD-1: 3.26 ± 0.66 mm, p < 0.001). There were no significant differences in BCVA, IOP, MD and PSD values before and after surgery. On the other hand, there was a significant improvement in the superior TD (preoperative: -11.29 ± 6.57 dB, postoperative: -9.88 ± 7.31 dB, p = 0.044) although no significant difference was detected in the inferior TD postoperatively. The preoperative parameters of 2 groups (improvement and non-improvement groups of postoperative superior TD) were compared. Preoperative MD and superior TD were significantly lower in the improvement group (p = 0.03, p = 0.004, respectively), although there was no significant difference in preoperative PSD and inferior TD between the two groups. CONCLUSION: In glaucoma patients, blepharoptosis may interfere with accurate visual field assessment, especially of superior TD.

Bisphenol AF as an Inducer of Estrogen Receptor ß (ERß): Evidence for Anti-estrogenic Effects at Higher Concentrations in Human Breast Cancer Cells.

Bisphenols are endocrine disruptors that are widely found in the environment. Accumulating experimental evidence suggests an adverse interaction between bisphenols and estrogen signaling. Most studies have performed experiments that focused on estrogen receptor (ER) engagement by bisphenols. Therefore, the effects of bisphenols on the expression of ERα (ESR1) and ERß (ESR2) remain largely unknown. In the present study, we examined the effects of four bisphenols: bisphenol A (BPA), bisphenol B (BPB), bisphenol S (BPS), and bisphenol AF (BPAF), on estrogen signaling in two human breast cancer cell lines (MCF-7 and SK-BR-3). Among these bisphenols, BPAF up-regulated the expression of ERß, and this was coupled with the abrogation of estrogen response element (ERE)-mediated transcriptional activities as well as the down-regulation of Cdc2 expression in MCF-7 cells, without influencing the expression of ERα. BPAF functioned as an agonist of ERα at lower concentrations (nanomolar order), but did not exhibit any modulatory action on ERα transiently expressed in SK-BR-3 cells in the presence or absence of 17ß-estradiol (E2) at higher concentrations (micromolar order). The introduction of ERß cDNA resulted in greater reductions in MCF-7 cell viability than with BPAF alone. Since ERß is a suppressive molecule of ERα function, these results provide rational evidence for BPAF functioning as an anti-estrogenic compound via the induction of ERß at higher concentrations.

Bongkrekic acid as a selective activator of the peroxisome proliferator-activated receptor γ (PPARγ) isoform.

Bongkrekic acid (BKA), an antibiotic isolated from Pseudomonas cocovenans, is an inhibitory molecule of adenine nucleotide translocase. Since this translocase is a core component of the mitochondrial permeability transition pore (MPTP) formed by apoptotic stimuli, BKA has been used as a tool to abrogate apoptosis. However, the other biochemical properties of BKA have not yet been resolved. Although the definition of a fatty acid is a carboxylic acid (-COOH) with a long hydrocarbon chain (tail), when focused on the chemical structure of BKA, the molecule was revealed to be a branched unsaturated tricarboxylic acid that resembled the structure of polyunsaturated fatty acids (PUFAs). Peroxisome proliferator-activated receptors (PPARs) consist of a subfamily of three isoforms: α, ß, and γ, the ligands of which include PUFAs. Using completely synthesized BKA together with simplified BKA derivatives (purity: > 98%), we herein demonstrated the utility of BKA as a selective activator of the human PPARγ isoform, which may not be associated with the anti-apoptotic nature of BKA. We also discussed the possible usefulness of BKA.

Decreased calcitonin gene-related peptide expression in the dorsal root ganglia of TNF-deficient mice in a monoiodoacetate-induced knee osteoarthritis model.

BACKGROUND: The detailed mechanisms of knee osteoarthritis (OA) pain have not been clarified, but involvement of inflammatory cytokines such as tumor necrosis factor-alpha (TNF) has been suggested. The present study aimed to investigate the more detailed neurological involvement of TNF in joint pain using a TNF-knockout mouse OA model. METHODS: The right knees of twelve-week-old C57BL/6J wild and TNF-deficient knockout (TNF-ko) mice (n=15, each group) were given a single intra-articular injection of 10 µg monoiodoacetate in 10 mL sterile saline. The left knees were only punctured as the control. Evaluations were performed immediately after the injection (baseline) and at 7, 14, and 28 days after the injection with a subsequent intra-articular injection of neurotracer into both knees. The animals were evaluated for immunofluorescence of the lumbar dorsal root ganglia (DRG) innervating the knee joints. The injected knees were observed macroscopically and mouse pain-related behaviors were scored. RESULTS: Macroscopic observation showed similar knee OA development in both wild and TNF-ko mice. Calcitonin gene-related peptide (CGRP, a neuropeptide identified as a inflammatory pain-related biomarker) was significantly increased in DRG neurons innervating OA-induced knee joints with significantly less CGRP expression in TNF-ko animals. Pain-related behavior scoring showed a significant increase in pain in OA-induced joints, but there was no significant difference in pain observed between the wild and TNF-ko mice. CONCLUSIONS: The result of the present study indicates the possible association of TNF-alpha in OA pain but not OA development.

Δ(9)-THC modulation of fatty acid 2-hydroxylase (FA2H) gene expression: possible involvement of induced levels of PPARα in MDA-MB-231 breast cancer cells.

We recently reported that Δ(9)-tetrahydrocannabinol (Δ(9)-THC), a major cannabinoid component in Cannabis Sativa (marijuana), significantly stimulated the expression of fatty acid 2-hydroxylase (FA2H) in human breast cancer MDA-MB-231 cells. Peroxisome proliferator-activated receptor α (PPARα) was previously implicated in this induction. However, the mechanisms mediating this induction have not been elucidated in detail. We performed a DNA microarray analysis of Δ(9)-THC-treated samples and showed the selective up-regulation of the PPARα isoform coupled with the induction of FA2H over the other isoforms (ß and γ). Δ(9)-THC itself had no binding/activation potential to/on PPARα, and palmitic acid (PA), a PPARα ligand, exhibited no stimulatory effects on FA2H in MDA-MB-231 cells; thus, we hypothesized that the levels of PPARα induced were involved in the Δ(9)-THC-mediated increase in FA2H. In support of this hypothesis, we herein demonstrated that; (i) Δ(9)-THC activated the basal transcriptional activity of PPARα in a concentration-dependent manner, (ii) the concomitant up-regulation of PPARα/FA2H was caused by Δ(9)-THC, (iii) PA could activate PPARα after the PPARα expression plasmid was introduced, and (iv) the Δ(9)-THC-induced up-regulation of FA2H was further stimulated by the co-treatment with L-663,536 (a known PPARα inducer). Taken together, these results support the concept that the induced levels of PPARα may be involved in the Δ(9)-THC up-regulation of FA2H in MDA-MB-231 cells.

Neutral cysteine protease bleomycin hydrolase is essential for the breakdown of deiminated filaggrin into amino acids.

Filaggrin is a component of the cornified cell envelope and the precursor of free amino acids acting as a natural moisturizing factor in the stratum corneum. Deimination is critical for the degradation of filaggrin into free amino acids. In this study, we tried to identify the enzyme(s) responsible for the cleavage of deiminated filaggrin in vitro. First, we investigated citrulline aminopeptidase activity in the extract of newborn rat epidermis by double layer fluorescent zymography and detected strong activity at neutral pH. Monitoring the citrulline-releasing activity, we purified an enzyme of 280 kDa, comprised of six identical subunits of 48 kDa. The NH(2) terminus of representative tryptic peptides perfectly matched the sequence of rat bleomycin hydrolase (BH). The enzyme released various amino acids except Pro from beta-naphthylamide derivatives and hydrolyzed citrulline-beta-naphthylamide most effectively. Thus, to break down deiminated filaggrin, another protease would be required. Among proteases tested, calpain I degraded the deiminated filaggrin effectively into many peptides of different mass on the matrix-assisted laser desorption/ionization-time of flight mass spectrum. We confirmed that various amino acids including citrulline were released by BH from those peptides. On the other hand, caspase 14 degraded deiminated filaggrin into a few peptides of limited mass. Immunohistochemical analysis of normal human skin revealed co-localization of BH and filaggrin in the granular layer. Collectively, our results suggest that BH is essential for the synthesis of natural moisturizing factors and that calpain I would play a role as an upstream protease in the degradation of filaggrin.