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Journal of Translational Medicine Sep 2023Peritoneal dialysis (PD) remains limited due to dialysis failure caused by peritoneal fibrosis. Tamoxifen (TAM), an inhibitor of estrogen receptor 1 (ESR1), has been...
BACKGROUND
Peritoneal dialysis (PD) remains limited due to dialysis failure caused by peritoneal fibrosis. Tamoxifen (TAM), an inhibitor of estrogen receptor 1 (ESR1), has been reported to treat fibrosis, but the underlying mechanism remains unknown. In this study, we sought to explore whether tamoxifen played an anti-fibrotic role by affecting transcription factor ESR1.
METHODS
ESR1 expression was detected in the human peritoneum. Mice were daily intraperitoneally injected with 4.25% glucose PD dialysate containing 40 mM methylglyoxal for 2 weeks to establish PD-induced peritoneal fibrosis. Tamoxifen was administrated by daily gavage, at the dose of 10 mg/kg. Chromatin immunoprecipitation (ChIP) and dual-luciferase reporter assay were performed to validate ESR1 bound H19 promoter. Gain-of-function and loss-of-function experiments were performed to investigate the biological roles of H19 on the mesothelial-mesenchymal transition (MMT) of human peritoneal mesothelial cells (HPMCs). Intraperitoneal injection of nanomaterial-wrapped 2'-O-Me-modified small interfering RNA was applied to suppress H19 in the mouse peritoneum. RNA immunoprecipitation and RNA pull-down assays demonstrated binding between H19 and p300. Exfoliated peritoneal cells were obtained from peritoneal dialysis effluent to analyze the correlations between ESR1 (or H19) and peritoneal solute transfer rate (PSTR).
RESULTS
ESR1 was increased significantly in the peritoneum after long-term exposure to PD dialysate. Tamoxifen treatment ameliorated high glucose-induced MMT of HPMCs, improved ultrafiltration rate, and decreased PSTR of mouse peritoneum. Tamoxifen reduced the H19 level by decreasing the ESR1 transcription of H19. Depletion of H19 reversed the pro-fibrotic effect of high glucose while ectopic expression of H19 exacerbated fibrotic pathological changes. Intraperitoneal injection of nanomaterial-wrapped 2'-O-Me-modified siRNAs targeting H19 mitigated PD-related fibrosis in mice. RNA immunoprecipitation (RIP) and RNA pull-down results delineated that H19 activated VEGFA expression by binding p300 to the VEGFA promoter and inducing histone acetylation of the VEGFA promoter. ESR1 and H19 were promising targets to predict peritoneal function.
CONCLUSIONS
High glucose-induced MMT of peritoneal mesothelial cells in peritoneal dialysis via activating ESR1. In peritoneal mesothelial cells, ESR1 transcribed the H19 and H19 binds to transcription cofactor p300 to activate the VEGFA. Targeting ESR1/H19/VEGFA pathway provided new hope for patients undergoing peritoneal dialysis.
Topics: Animals; Humans; Mice; Dialysis Solutions; Fibrosis; Glucose; Peritoneum; RNA; Vascular Endothelial Growth Factor A; Tamoxifen
PubMed: 37697303
DOI: 10.1186/s12967-023-04470-3 -
Biomedicine & Pharmacotherapy =... Sep 2023Peritoneal dialysis is an efficient renal replacement therapy for patients with end-stage kidney disease. However, continuous exposure of the peritoneal membrane to... (Review)
Review
Peritoneal dialysis is an efficient renal replacement therapy for patients with end-stage kidney disease. However, continuous exposure of the peritoneal membrane to dialysate frequently leads to peritoneal fibrosis, which alters the function of the peritoneal membrane and results in withdrawal from peritoneal dialysis in patients. Among others, high glucose dialysate is considered as a predisposing factor for peritoneal fibrosis in patients on peritoneal dialysis. Glucose-induced inflammation, metabolism disturbance, activation of the renin-angiotensin-aldosterone system, angiogenesis and noninflammation-induced reactive oxygen species are implicated in the pathogenesis of high glucose dialysate-induced peritoneal fibrosis. Specifically, high glucose causes chronic inflammation and recurrent peritonitis, which could cause migration and polarization of inflammatory cells, as well as release of cytokines and fibrosis. High glucose also interferes with lipid metabolism and glycolysis by activating the sterol-regulatory element-binding protein-2/cleavage-activating protein pathway and increasing hypoxia inducible factor-1α expression, leading to angiogenesis and peritoneal fibrosis. Activation of the renin-angiotensin-aldosterone system and Ras-mitogen activated protein kinase signaling pathway is another contributing factor in high glucose dialysate-induced fibrosis. Ultimately, activation of the transforming growth factor-β1/Smad pathway is involved in mesothelial-mesenchymal transition or epithelial-mesenchymal transition, which leads to the development of fibrosis. Although possible intervention strategies for peritoneal dialysate-induced fibrosis by targeting the transforming growth factor-β1/Smad pathway have occasionally been proposed, lack of laboratory evidence renders clinical decision-making difficult. We therefore aim to revisit the upstream pathways of transforming growth factor-beta1/Smad and propose potential therapeutic targets for high glucose-induced peritoneal fibrosis.
Topics: Humans; Peritoneal Fibrosis; Dialysis Solutions; Transforming Growth Factor beta1; Peritoneum; Fibrosis; Inflammation; Glucose
PubMed: 37523983
DOI: 10.1016/j.biopha.2023.115246 -
Peritoneal Dialysis International :... Nov 2023When a patient on peritoneal dialysis (PD) presents with suspected PD-related peritonitis (e.g. cloudy PD fluid and abdominal pain), one of the most important initial... (Review)
Review
When a patient on peritoneal dialysis (PD) presents with suspected PD-related peritonitis (e.g. cloudy PD fluid and abdominal pain), one of the most important initial aspects of management is for the nephrology nurse/home dialysis nurse to collect PD effluent specimens for white blood cells count, Gram stain, culture and sensitivity for inspection and to send for laboratory testing before antibiotics are started. A review by seven members of the International Society for Peritoneal Dialysis (ISPD) Nursing Committee of all 133 questions posted to the ISPD website 'Questions about PD' over the last 4 years (January 2018-December 2021), revealed 97 posted by nephrology nurses from around the world. Of these 97 questions, 10 were noted to be related to best practices for PD effluent specimen collection. For our review, we focused on these 10 questions along with their responses by the members of the ISPD 'Ask The Experts Team', whereby existing best practice recommendations were considered, if available, relevant literature was cited and differences in international practice discussed. We revised the original responses for clarity and updated the references. We found that these 10 questions were quite varied but could be organised into four categories: how to collect PD effluent safely; how to proceed with PD effluent collection; how to collect PD effluent for assessment; and how to proceed with follow-up PD effluent collection after intraperitoneal antibiotics have been started. In general, we found that there was limited evidence in the PD literature to answer several of these 10 questions posted to the ISPD website 'Questions about PD' by nephrology nurses from around the world on this important clinical topic of best practices for PD effluent specimen collection. Some of these questions were also not addressed in the latest ISPD Peritonitis Guidelines. Moreover, when polling members of our ISPD Nursing Committee we found when answering a few of these questions, nursing practice varied within and among countries. We encourage PD nurses to conduct their own research on this important topic, focusing on areas where research evidence is lacking.
Topics: Humans; Peritoneal Dialysis; Anti-Bacterial Agents; Peritonitis; Dialysis Solutions
PubMed: 36475557
DOI: 10.1177/08968608221136389 -
Investigative Ophthalmology & Visual... Nov 2023The incidence of myopia has rapidly increased in recent decades, making it a growing public health concern worldwide. Interventions to suppress the progression of myopia...
PURPOSE
The incidence of myopia has rapidly increased in recent decades, making it a growing public health concern worldwide. Interventions to suppress the progression of myopia are needed; one suggested strategy is the prevention of choroidal thinning, which can improve choroidal blood perfusion (ChBP). Bunazosin hydrochloride (BH) is an alpha1-adrenergic blocker and commercialized glaucoma eye drop that increases in blood circulation in the eye. In this study, we evaluated the efficacy of BH in suppressing the progression of myopia in a lens-induced murine model.
METHODS
Lens-induced myopia was induced in 3-week-old C57BL/6 J mice with -30 diopter (D) lenses for three weeks. Refractive error, axial length, and choroidal thickness were evaluated at three and six weeks of age using an infrared photorefractor and a spectral domain optical coherence tomography (OCT) system. Moreover, ChBP and scleral thickness were evaluated using swept-source OCT and histological analysis.
RESULTS
Compared with the controls, the administration of BH eye drops suppressed the myopic shift of refractive error (mean difference ± standard error in the eye with -30 D lens, -13.65 ± 5.69 D vs. 2.55 ± 4.30 D; P < 0.001), axial elongation (0.226 ± 0.013 mm vs. 0.183 ± 0.023 mm; P < 0.05), choroidal thinning (-2.01 ± 1.80 µm vs. 1.88 ± 1.27 µm; P < 0.001), and scleral thinning (11.41 ± 3.91 µm vs. 19.72 ± 4.01 µm; P < 0.01) with myopia progression and increased ChBP (52.0% ± 4.1% vs. 59.5% ± 6.3%; P < 0.05). The suppressive effect of BH eye drops was dose-dependent and higher than that of other glaucoma eye drops and alpha1 blockers.
CONCLUSIONS
These results demonstrate the potential of BH eye drops in the treatment of myopia and support further investigation of their efficacy in humans. Further studies are needed to determine the mechanism of action and long-term safety of this treatment.
Topics: Humans; Animals; Mice; Mice, Inbred C57BL; Myopia; Refractive Errors; Glaucoma; Ophthalmic Solutions; Perfusion
PubMed: 37955611
DOI: 10.1167/iovs.64.14.15 -
The American Journal of Managed Care Nov 2023Dry eye disease (DED) is one of the most common ocular surface disorders. All DED involves an imbalance between tear production and evaporation. Most cases of DED are... (Review)
Review
Dry eye disease (DED) is one of the most common ocular surface disorders. All DED involves an imbalance between tear production and evaporation. Most cases of DED are driven by excessive evaporation, which is often associated with meibomian gland dysfunction (MGD). In evaporative DED, a deficient tear film lipid layer is believed to lead to increased tear evaporation, inflammation, and ocular surface damage. Most prescription treatments for DED address signs and symptoms by targeting tear production and/or inflammation, but they do not address excessive evaporation. Perfluorohexyloctane (PFHO) ophthalmic solution (MIEBO™; Bausch + Lomb) is a water-free, single-ingredient, preservative-free prescription eye drop that directly targets tear evaporation and is approved by the FDA to treat the signs and symptoms of DED. Results from preclinical studies indicate that PFHO has a high oxygen carrying capacity, may reduce friction on blinking, and spreads quickly over the tear film surface to form a monolayer that inhibits evaporation. These effects can lead to stabilization of the tear film to promote ocular surface healing. Further, PFHO was detected in tears for at least 6 hours in a rabbit pharmacokinetic study, and results indicate that it may improve lipid layer thickness and quality. In 2 pivotal phase 3 trials in patients with DED and clinical signs of MGD (GOBI [NCT04139798] and MOJAVE [NCT04567329]), treatment with PFHO consistently met primary efficacy end points related to DED signs and symptoms (total corneal fluorescein staining and eye dryness, respectively) and was well tolerated. Compared with use of hypotonic saline solution, instillation of PFHO led to significant improvements in signs and symptoms in as early as 2 weeks. In a long-term, open-label safety extension study, efficacy of PFHO was sustained over 12 months, and the safety profile was consistent with those of previous studies. Clinical trial results indicate that treatment with PFHO effectively and consistently reduces the signs and symptoms of DED.
Topics: Animals; Humans; Rabbits; Ophthalmic Solutions; Dry Eye Syndromes; Inflammation; Lipids
PubMed: 37930231
DOI: 10.37765/ajmc.2023.89464 -
Dermatitis : Contact, Atopic,... 2023Eyelid and periorbital dermatitis remains a distressing and recalcitrant disease. Contact dermatitis remains the most common cause of eyelid and periorbital dermatitis.... (Review)
Review
Eyelid and periorbital dermatitis remains a distressing and recalcitrant disease. Contact dermatitis remains the most common cause of eyelid and periorbital dermatitis. Ophthalmic solutions used in the treatment of ophthalmic conditions can often be the cause. This article is an update of our previous study, summarizing the contact allergens involved and the new test concentrations reported to investigate through patch testing. New insights found during the review are also documented.
Topics: Humans; Dermatitis, Allergic Contact; Allergens; Eyelids; Ophthalmic Solutions; Patch Tests
PubMed: 37327018
DOI: 10.1089/derm.2023.0033 -
Drug Delivery Dec 2023Immune ophthalmopathy is a collection of autoimmune eye diseases. Immunosuppressants are drugs that can inhibit the body's immune response. Considering drug side effects... (Review)
Review
Immune ophthalmopathy is a collection of autoimmune eye diseases. Immunosuppressants are drugs that can inhibit the body's immune response. Considering drug side effects such as hepatorenal toxicity and the unique structure of the eye, incorporating immunosuppressants into ophthalmic nanodrug delivery systems, such as microparticles, nanoparticles, liposomes, micelles, implants, and gels, has the advantages of improving solubility, increasing bioavailability, high eye-target specificity, and reducing side effects. This study reviews recent research and applications of this aspect to provide a reference for the development of an ophthalmic drug delivery system.
Topics: Humans; Administration, Ophthalmic; Drug Delivery Systems; Eye; Eye Diseases; Immunosuppressive Agents; Liposomes; Ophthalmic Solutions
PubMed: 36762580
DOI: 10.1080/10717544.2023.2175925 -
Clinical and Experimental Nephrology Sep 2023Encapsulating peritoneal sclerosis (EPS), a condition with a high mortality rate, is a serious complication of peritoneal dialysis (PD). In Japan, EPS became a central... (Review)
Review
Encapsulating peritoneal sclerosis (EPS), a condition with a high mortality rate, is a serious complication of peritoneal dialysis (PD). In Japan, EPS became a central issue in the clinical setting during the mid-90s and the beginning of this century. However, following the introduction of biocompatible neutral PD solutions containing lower levels of glucose degradation products, the incidence and clinical severity of EPS has been greatly lessened. During the past three decades, the etiology of EPS has been elucidated by findings obtained by peritoneal biopsy, laparoscopy, and surgical intervention. Accumulating findings suggest the need for a paradigm change on the nature of EPS pathophysiology; notably, EPS appears not to reflect peritoneal sclerosis per se, but rather the formation of a neo-membrane as a biological reaction to peritoneal injury. This narrative review looks back on the history of EPS in Japan, and discusses EPS pathophysiology, the impact of neutral PD solution on peritoneal protection, and a future novel diagnostic approach, ultra-fine endoscope, for the identification of patients at high risk of EPS.
Topics: Humans; Peritoneal Fibrosis; Japan; Peritoneal Dialysis; Peritoneum; Dialysis Solutions; Sclerosis
PubMed: 37278945
DOI: 10.1007/s10157-023-02360-y -
Molecular Aspects of Medicine Oct 2023Glaucoma is one of the leading causes of irreversible blindness. Progression is halted with a reduction in intraocular pressure (IOP), which is most often achieved with... (Review)
Review
Glaucoma is one of the leading causes of irreversible blindness. Progression is halted with a reduction in intraocular pressure (IOP), which is most often achieved with eye drops. A major challenge in the topical treatment of glaucoma patients is the many side effects and the resulting reduced adherence. Side effects may of course be due to the molecular properties of the active pharmaceutical ingredients (APIs). There are currently six different APIs available: prostaglandin analogues, β-adrenergic inhibitors, α-adrenergic agonists, carbonic anhydrase inhibitors, rho-kinase inhibitors and muscarinic 3 agonists. But the additives used in eye drops are also known to cause damage to the ocular surface and to some extent also to the deeper tissues. Said additives are considered inactive molecular components and are added to secure for instance viscosity and pH value, and to prevent contamination. There has been an increasing focus on the harmful effects of preservatives, with the most commonly used preservative benzalkonium chloride (BAK) being particularly controversial. BAK has long been recognized as a toxin that increases the risk of ocular discomfort. This can affect the adherence and ultimately result in lack of disease control. Other issues include the addition of certain buffers, such as phosphates, and varying pH values. This review will address the different molecular components of the IOP-lowering eye drops and what to be aware of when prescribing topical glaucoma treatment.
Topics: Humans; Glaucoma; Intraocular Pressure; Eye; Preservatives, Pharmaceutical; Ophthalmic Solutions
PubMed: 37459821
DOI: 10.1016/j.mam.2023.101195 -
Japanese Journal of Ophthalmology Sep 2023Understanding the practice patterns and costs of glaucoma care in real-world clinical settings is important for optimizing medical expenses. However, glaucoma treatment...
PURPOSE
Understanding the practice patterns and costs of glaucoma care in real-world clinical settings is important for optimizing medical expenses. However, glaucoma treatment trends and associated costs in Japan are unknown. We aimed to unveil glaucoma treatment trends and costs using a large administrative claims database in Japan.
STUDY DESIGN
Retrospective cohort study.
METHODS
We included patients diagnosed with glaucoma between April 2014 and March 2021 using the DeSC database. We calculated the frequencies and costs of antiglaucoma eyedrops, incisional or laser procedures, and ophthalmic examinations stratified by fiscal year and age. In the year-by-year analyses, the age distribution was standardized based on the 2020 distribution.
RESULTS
A total of 841,747 patient-years (429,051 patients) were included. The number of prescribed eyedrops significantly increased and the fixed-combination eyedrops proportion decreased with age. Trabeculectomy frequency decreased, and that of laser trabeculoplasty increased during the observation period. The frequencies of both incisional and laser procedures peaked in the 75-79 age group. In 2020, 16.1 bottles of eyedrops per patient-year were prescribed, and 15.9 incisional surgeries and 11.3 laser therapies were performed per 1000 patient-years. Intraocular pressure measurement and visual field testing were performed 6.5 times and 2.0 times per patient-year, respectively. The total direct cost of glaucoma treatment was 55,139 yen (US $399.5) per patient-year, of which medications accounted for 44.2%, ophthalmic examinations for 47.4%, and incisional or laser procedures for 8.4%.
CONCLUSION
These results may be useful for understanding glaucoma treatment trends and costs in Japan.
Topics: Humans; Intraocular Pressure; Japan; Retrospective Studies; Glaucoma; Trabeculectomy; Laser Therapy; Ophthalmic Solutions
PubMed: 37354251
DOI: 10.1007/s10384-023-01002-w