Association of diabetic retinopathy on all-cause and cause-specific mortality in older adults with diabetes: National Health and Nutrition Examination Survey, 2005-2008.

To evaluate the effect of diabetic retinopathy (DR) status or severity on all-cause and cause-specific mortality among diabetic older adults in the United States using the most recent National Health and Nutrition Examination Survey (NHANES) follow-up mortality data. The severity of DR was graded according to the Early Treatment Diabetic Retinopathy Study (ETDRS) grading scale. Multiple covariate-adjusted Cox proportional hazards regression models, Fine and Gray competing risk regression models, and propensity score matching (PSM) methods were used to assess the risk of all-cause and cause-specific mortality in individuals with diabetes. All analyses adopted the weighted data and complex stratified design approach proposed by the NHANES guidelines. Time to death was calculated based on the time between baseline and date of death or December 31, 2019, whichever came first. Ultimately 1077 participants, representing 3,025,316 US non-hospitalized individuals with diabetes, were included in the final analysis. After a median follow-up of 12.24 years (IQR, 11.16-13.49), 379 participants were considered deceased from all-causes, with 43.90% suffering from DR, including mild DR (41.50%), moderate to severe DR (46.77%), and proliferative DR (PDR) (67.21%). DR was associated with increased all-cause, cardiovascular disease (CVD) and diabetes mellitus (DM)-specific mortality, which remained consistent after propensity score matching (PSM). Results of DR grading assessment suggested that the presence of mild, moderate to severe NPDR was significantly associated with increased risk of all-cause and CVD-specific mortality, while the presence and severity of any DR was associated with increased DM-specific mortality, with a positive trend. The presence of DR in elderly individuals with diabetes is significantly associated with the elevated all-cause and CVD mortality. The grading or severity of DR may reflect the severity of cardiovascular disease status and overall mortality risk in patients with diabetes.

Epithelial cells derived exosomal miR-203a-3p facilitates stromal inflammation of type IIIA chronic prostatitis/chronic pelvic pain syndrome by targeting DUSP5 and increasing MCP-1 generation.

Increased proinflammatory cytokines and infiltration of inflammatory cells in the stroma are important pathological features of type IIIA chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS-A), and the interaction between stromal cells and other cells in the inflammatory microenvironment is closely related to the inflammatory process of CP/CPPS-A. However, the interaction between stromal and epithelial cells remains unclear. In this study, inflammatory prostate epithelial cells (PECs) released miR-203a-3p-rich exosomes and facilitated prostate stromal cells (PSCs) inflammation by upregulating MCP-1 expression. Mechanistically, DUSP5 was identified as a novel target gene of miR-203a-3p and regulated PSCs inflammation through the ERK1/2/MCP-1 signaling pathway. Meanwhile, the effect of exosomes derived from prostatic fluids of CP/CPPS-A patients was consistent with that of exosomes derived from inflammatory PECs. Importantly, we demonstrated that miR-203a-3p antagomirs-loaded exosomes derived from PECs targeted the prostate and alleviated prostatitis by inhibiting the DUSP5-ERK1/2 pathway. Collectively, our findings provide new insights into underlying the interaction between PECs and PSCs in CP/CPPS-A, providing a promising therapeutic strategy for CP/CPPS-A.

HuR promotes castration-resistant prostate cancer progression by altering ERK5 activation via posttranscriptional regulation of BCAT1.

BACKGROUND: Castration-resistant prostate cancer (CRPC) is refractory to hormone treatment, and the underlying mechanism has not been fully elucidated. This study aimed to clarify the role and mechanism of Human antigen R (HuR) as a therapeutic target for CRPC progression. METHODS: HuR was knocked out by Cas9 or inhibited by the HuR-specific inhibitor KH-3 in CRPC cell lines and in a mouse xenograft model. The effects of HuR inhibition on tumour cell behaviors and signal transduction were examined by proliferation, transwell, and tumour xenograft assays. Posttranscriptional regulation of BCAT1 by HuR was determined by half-life and RIP assays. RESULTS: HuR knockout attenuated the proliferation, migration, and invasion of PC3 and DU145 cells in vitro and inhibited tumour progression in vivo. Moreover, BCAT1 was a direct target gene of HuR and mediated the oncogenic effect of HuR on CRPC. Mechanistically, HuR directly interacted with BCAT1 mRNA and upregulated BCAT1 expression by increasing the stability and translation of BCAT1, which activated ERK5 signalling. Additionally, the HuR-specific inhibitor KH-3 attenuated CRPC progression by disrupting the HuR-BCAT1 interaction. CONCLUSIONS: We confirmed that the HuR/BCAT1 axis plays a crucial role in CRPC progression and suggest that inhibiting the HuR/BCAT1 axis is a promising therapeutic approach for suppressing CRPC progression.

Metabotropic glutamate receptor 5 promotes blood-brain barrier recovery after traumatic brain injury.

Blood-brain barrier (BBB) impairment and glutamate release are two pathophysiological features of traumatic brain injury (TBI), contributing to secondary brain damage and neuroinflammation. However, our knowledge of BBB integrity damage and dysfunction are still limited due to the diverse and fluctuating expression of glutamate receptors after trauma. Here, we confirmed the downregulation of metabotropic glutamate receptor 5 (mGluR5) on microvascular endothelial cell within the acute phase of TBI, and the recovered mGluR5 levels on BBB was positively associated with blood perfusion and neurological recovery. In whole body mGluR5-knockout mice, BBB dysfunction and neurological deficiency were exacerbated after TBI compared with wild type mice. In terms of mechanism, the amino acid sequence 201-259 of cytoskeletal protein Alpha-actinin-1 (ACTN1) interacted with mGluR5, facilitating mGluR5 translocation from cytoplasmic compartment to plasma membrane in endothelial cells. Activation of plasma membrane mGluR5 triggers the PLC/PKCµ/c-Jun signaling pathway, leading to increased expression of the tight junction-actin cytoskeleton connecting protein zonula occludens-1 (ZO-1). Our findings uncover a novel mechanism mediated by membrane and cytoplasmic mGluR5 in endothelial cell integrity maintenance and repair, providing the potential therapeutic target for TBI treatment targeting at mGluR5 and mGluR5/ACTN1 complex in BBB.

MiR-216a-3p inhibits the proliferation and invasion of fibroblast-like synoviocytes by targeting dual-specificity phosphatase 5.

Dual-specificity phosphatase 5 (DUSP5) is a novel anti-inflammatory modulator in many inflammatory diseases. However, the role of DUSP5 in fibroblast-like synoviocytes (FLS) of rheumatoid arthritis (RA) remains unknown. In this study, we aimed to explore the biological function and regulation of DUSP5 in FLS. We found that lower DUSP5 expression level was detected in collagen-induced arthritis (CIA) and synoviocyte MH7A. Overexpression of DUSP5 markedly decreased the proliferation, migration, and invasion of MH7A, which correlated with suppressing the phosphorylation of extracellular signal-regulated kinase (ERK). Moreover, DUSP5 was identified as a novel target gene of miR-216a-3p, which was upregulated in FLS. Therefore, DUSP5 expression was negatively regulated by miR-216a-3p, and the effect of DUSP5 overexpression on FLS was reversed by miR-216a-3p mimics. Overall, our study demonstrates that DUSP5 is a miR-216a-3p target gene and its anti-inflammatory function in FLS via inactivation of ERK. These results revealed that the miR-216a-3p/DUSP5 pathway may play a crucial role in the malignant behavior of FLS, which may serve as a new target for the treatment of RA.

Upregulated miR-194-5p suppresses retinal microvascular endothelial cell dysfunction and mitigates the symptoms of hypertensive retinopathy in mice by targeting SOX17 and VEGF signaling.

BACKGROUND: Hypertensive retinopathy (HR) is a retinal disease that may lead to vision loss and blindness. Sex-determining region Y (SRY)-box (SOX) family transcription factors have been reported to be involved in HR development. In this study, the role and upstream mechanism of SRY-box transcription factor 17 (SOX17) in HR pathogenesis were investigated. METHODS: SOX17 and miR-194-5p levels in Angiotensin II (Ang II)-stimulated human retinal microvascular endothelial cells (HRMECs) and retinas of mice were detected by RT-qPCR. SOX17 protein level as well as levels of tight junction proteins and vascular endothelial growth factor (VEGF) signaling-associated proteins were quantified by western blotting. Tube formation assays were performed to evaluate angiogenesis in HRMECs. The structure of mouse retinal tissues was observed by H&E staining. The interaction between miR-194-5p and SOX17 was confirmed by a luciferase reporter assay. RESULTS: SOX17 was upregulated in HRMECs treated with Ang II. SOX17 knockdown inhibited angiogenesis in Ang II-stimulated HRMECs and increased tight junction protein levels. Mechanically, SOX17 was targeted by miR-194-5p. Moreover, miR-194-5p upregulation restrained angiogenesis and increased tight junction protein levels in Ang II-treated HRMECs, and the effect was reversed by SOX17 overexpression. MiR-194-5p elevation inactivated VEGF signaling via targeting SOX17. miR-194-5p alleviated pathological symptoms of HR in Ang II-treated mice, and its expression was negatively correlated with SOX17 expression in the retinas of model mice. CONCLUSIONS: MiR-194-5p upregulation suppressed Ang II-stimulated HRMEC dysfunction and mitigates the symptoms of HR in mice by regulating the SOX17/VEGF signaling.

The emerging role of neutrophils in autoimmune-associated disorders: effector, predictor, and therapeutic targets.

Neutrophils are essential components of the immune system and have vital roles in the pathogenesis of autoimmune disorders. As effector cells, neutrophils promote autoimmune disease by releasing cytokines and chemokines cascades that accompany inflammation, neutrophil extracellular traps (NETs) regulating immune responses through cell-cell interactions. More recent evidence has extended functions of neutrophils. Accumulating evidence implicated neutrophils contribute to tissue damage during a broad range of disorders, involving rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), primary sjögren's syndrome (pSS), multiple sclerosis (MS), crohn's disease (CD), and gout. A variety of studies have reported on the functional role of neutrophils as therapeutic targets in autoimmune diseases. However, challenges and controversies in the field remain. Enhancing our understanding of neutrophils' role in autoimmune disorders may further advance the development of new therapeutic approaches.

Silencing microRNA­29b­3p expression protects human trabecular meshwork cells against oxidative injury via upregulation of RNF138 to activate the ERK pathway.

In recent years, the potential involvement of numerous microRNAs (miRNAs) in glaucoma has been widely reported. However, the role of microRNA­29b­3p (miR­29b­3p) in the pathogenesis of glaucoma remains unknown. This study aimed to explore the biological role and regulatory mechanism of miR­29b­3p in the oxidative injury of human trabecular meshwork (HTM) cells induced by H2O2 stimulation. By establishing a glaucoma rat model, the effects of miR­29­3p in glaucoma were detected in vivo. Our findings demonstrated that miR­29b­3p was upregulated in a glaucoma model and antagomiR­29b­3p alleviated the symptoms of glaucoma. In vitro assays revealed that miR­29b­3p expression was significantly upregulated in HTM cells with H2O2 stimulation. Knockdown of miR­29b­3p alleviated H2O2 ­induced oxidative injury in HTM cells by promoting cell viability, and inhibiting cell apoptosis, reactive oxygen species generation and extracellular matrix production. Subsequently, it was found that E3 ubiquitin­protein ligase RNF138 (RNF138) was a downstream target of miR­29b­3p. RNF138 expression was downregulated in HTM cells with H2O2 stimulation. RNF138 knockdown significantly rescued the protective effect of miR­29b­3p inhibitor on HTM cells under oxidative injury. Additionally, miR­29b­3p silencing activated the ERK pathway via upregulating RNF138. Collectively, silencing of miR­29b­3p protected HTM cells against oxidative injury by upregulation of RNF138 to activate the ERK pathway.

Efficacy and safety of high-dose ultrasound cyclo-plasty procedure in refractory glaucoma.

AIM: To evaluate the efficacy and safety of high-dose ultrasound cyclo-plasty (UCP) for the treatment of refractory glaucoma in Chinese patients. METHODS: In this 6-month retrospective study, 37 eyes of 37 patients suffering from severe glaucoma with uncontrolled intraocular pressure (IOP) of ≥21 mm Hg underwent 8-s ultrasonic cyclocoagulation with ten active piezoelectric elements. A complete ophthalmic examination was performed before and at 1d, 1, 3, 6mo after UCP. Therapeutic success was defined as IOP reduction from baseline ≥20% and IOP ≥5 mm Hg without adding new glaucoma medication compare to baseline at the 6-month follow-up visit. In addition to mean IOP at each follow-up visit, medications used and complications were also detected and compared to baseline. RESULTS: After UCP procedure, the mean IOP was significantly reduced (P<0.01) from the preoperative 44.1±11.9 mm Hg to postoperative 26.7±11.8 mm Hg at 3mo, and 30.4±14.5 mm Hg at 6mo. The overall mean IOP reductions achieved at 3 and 6mo were 39% and 31% compared to baseline IOP. Sixty-one percent of patients responded well to UCP treatment with a mean IOP reduction of 48% at 3mo and 42% at 6mo. Ocular pain in most of patients were alleviated. No serious intraoperative or postoperative complications occurred. CONCLUSION: High-dose UCP treatment is an effective and safe procedure to reduce IOP in Chinese patients with severe glaucoma.

Parameters of ocular fundus on spectral-domain optical coherence tomography for glaucoma diagnosis.

In this review, we summarize the progression of several parameters assessed by spectral-domain optical coherence tomography (SD-OCT) in recent years for the detection of glaucoma. Monitoring the progression of defects in the retinal nerve fiber layer (RNFL) thickness is essential. Imaging and analysis of retinal ganglion cells (RGCs) and inner plexiform layer (IPL), respectively, have been of great importance. Optic nerve head (ONH) topography obtained from 3D SD-OCT images is another crucial step. Other important assessments involve locating the Bruch's membrane opening (BMO), estimating the optic disc size and rim area, and measuring the lamina cribrosa displacement. Still other parameters found in the past three years for glaucoma diagnosis comprise central retinal artery resistive index, optic disc perfusion in optical coherence tomography angiography (OCTA) study, peripapillary choroidal thickness, and choroidal area in SD-OCT. Recently, several more ocular fundus parameters have been found, and compared with the earlier parameters to judge the accuracy of diagnosis. While a few of these parameters have been widely used in clinical practice, a fair number are still in the experimental stage.

New two-point scleral-fixation technique for foldable intraocular lenses with four hollow haptics.

The study was to report a new two-point scleral-fixation technique for foldable intraocular lenses with four haptics. Lenses were slid into the anterior chamber from a 2.8 mm corneal incision and fixed under two sclera flaps at two opposite points. The postoperative best-corrected visual acuities (BCVAs) of all patients were significantly better than their preoperative BCVA. The results demonstrate that two-point, scleral fixations of foldable, intraocular lenses might be practicable and effective.

Spectroscopic studies on the interaction of Phacolysin and bovine serum albumin.

The interaction between Phacolysin (PCL) and bovine serum albumin (BSA) under imitated physiological conditions was investigated by spectroscopic (fluorescence, UV-Vis absorption and Circular dichroism) techniques. The experiments were conducted at different temperatures (294K, 302K, 306K and 310K) and the results showed that the PCL caused the fluorescence quenching of BSA through a static quenching procedure. The binding constant (Ka), binding sites (n) were obtained. The corresponding thermodynamic parameters (ΔH, ΔS and ΔG) of the interaction system were calculated at different temperatures. The results revealed that the binding process was spontaneous and the acting force between PCL and BSA were mainly hydrogen bonding and van der Waals forces. According to Förster non-radiation energy transfer theory, the binding distance between PCL and BSA was calculated to be 2.41nm. What is more, both synchronous fluorescence and Circular dichroism spectra confirmed the interaction, which indicated the conformational changes of BSA.

The investigation of the interaction between Tropicamide and bovine serum albumin by spectroscopic methods.

The fluorescence and ultraviolet-visible (UV-Vis) spectroscopy were explored to study the interaction between Tropicamide (TA) and bovine serum albumin (BSA) at three different temperatures (292, 301 and 310K) under imitated physiological conditions. The experimental results showed that the fluorescence quenching mechanism between TA and BSA was static quenching procedure. The binding constant (Ka), binding sites (n) were obtained. The corresponding thermodynamic parameters (ΔH, ΔS and ΔG) of the interaction system were calculated at different temperatures. The results revealed that the binding process is spontaneous, hydrogen binds and vander Waals were the main force to stabilize the complex. According to Förster non-radiation energy transfer theory, the binding distance between TA and BSA was calculated to be 4.90 nm. Synchronous fluorescence spectroscopy indicated the conformation of BSA changed in the presence of TA. Furthermore, the effect of some common metal ions (Mg(2+), Ca(2+), Cu(2+), and Ni(2+)) on the binding constants between TA and BSA were examined.

A highly porous 4,4-paddlewheel-connected NbO-type metal-organic framework with a large gas-uptake capacity.

A highly porous 4,4-paddlewheel-connected NbO-type metal-organic framework (HNUST-2, HNUST represents Hunan University of Science and Technology) has been designed and synthesized by self-assembling [Cu2(COO)4] SBUs with a nanosized tetracarboxylate ligand prolonged by alkyne groups, 5,5'-(naphthalene-1,4-diylbis(ethyne-2,1-diyl))diisophthalic acid (H4NDED). HNUST-2 exhibits high structural stability, a porous non-interpenetration framework with open metal sites and excellent gas-uptake capacity. This MOF material possesses a high BET surface area of 2366 m² g⁻¹, a large unsaturated excess and total H2 uptake of 4.57 wt% and 5. 20 wt% at 20 bar and 77 K, respectively. Meanwhile, HNUST-2 also exhibits an excellent adsorption capacity for CO2 (18.07 mmol g⁻¹ at 20 bar and 298 K) and CH4 (85.6 cm³ cm⁻³ at 20 bar and 298 K) with a high selectivity for CO2 over N2 (22.9) and CH4 (4.9) at 298 K.

Spectroscopic studies on the interaction of carteolol hydrochloride and urea-induced bovine serum albumin.

The interaction of carteolol hydrochloride, to 0.2 mol L(-1) urea-induced bovine serum albumin in aqueous solution has been first investigated by fluorescence spectra and ultraviolet-visible (UV-vis) spectra at pH 7.40. The quenching mechanism, binding parameter and sites (n), the binding mode (ΔG, ΔH, and ΔS) as well as the binding distance (r) have been obtained according to the experimental results. We also use the synchronous fluorescence method to study the effect of CTL on the conformation change of urea-induced BSA.

The investigation of the interaction between Oxymetazoline hydrochloride and mucin by spectroscopic approaches.

The fluorescence and ultraviolet spectroscopy were explored to study the interaction between Oxymetazoline hydrochloride (OMZH) and mucin under imitated physiological condition. The results demonstrated that the fluorescence quenching mechanism between OMZH and mucin is a combined quenching process. The binding constants (K(a)), binding sites (n) and the corresponding thermodynamic parameters (ΔG, ΔH, and ΔS) of the interaction system were calculated at different temperatures. The hydrogen bonds and van der Waals forces play a major role in the interaction between OMZH and mucin. According to Förster non-radiation energy transfer theory, the binding distance between OMZH and mucin was calculated.