Harnessing the Potential of Electron Donor-Acceptor Complexes and N-Centered Radicals: Expanding the Frontiers of Isoquinoline Derivative Synthesis.

Research on synthesizing nitrogen-containing heterocyclic scaffolds is important because these structures are commonly found in Nature, such as in the alkaloids' family. In our study, we propose a new method to synthesize the isoquinoline core using an electron donor-acceptor (EDA) complex strategy. Our mechanistic investigations have confirmed that our synthesis process operates through an EDA mechanism, which is not extensively discussed in the literature, particularly regarding its applications on alkynyl substrates. This EDA strategy has proven to be a simple and straightforward way to produce isoquinoline scaffolds and their derivatives without the need for metal catalysts.

Synthesis of Isoquinolines and Related Heterocycles under Visible-Light Conditions.

Visible-light catalysis is now widely acknowledged as a potent approach for efficiently constructing various types of frameworks, particularly bioactive compounds, with high yields. However, there is still a strong need for further advancements in these methods because certain delicate compounds cannot be synthesized due to structural sensitivity. In this context, a seamless reaction pathway toward 6-membered ring nitrogen-containing heterocycles is presented here, offering access to isoquinoline derivatives and related heterocycles.

Improvement of platelet preservation by inhibition of TRPC6.

BACKGROUND: The preservation of platelets (PLTs) by room temperature (RT) oscillation limits their shelf life to between 4 and 7 days because of the decrease in PLT function. TRPC6 is a non-selective mechanically sensitive cation channel that has been shown to mediate Ca2+ signalling, implying a role in PLT activation during preservation by RT oscillation. OBJECTIVES: This study was designed to investigate whether inhibition of TRPC6 can improve the RT preservation of PLTs and the possible underlying mechanism. METHODS: Human PLTs from whole blood were stored at 22 ± 2°C with oscillation in plasma or M-sol (mixture of solutions). BI-749327, a specific TRPC6 inhibitor, was administered throughout the preservation period. PLT distribution width (PDW), mean platelet volume (MPV), maximum platelet aggregation rate (MAR) and average aggregation rate (AAR) were measured. The MTT method was used to assess the relative viability of PLTs. Flow cytometry was used to measure the changes of Ca2+ concentration in PLTs and phosphatidylserine (PS) exposure on the PLT surface, and western blotting was used to assess the expression changes of platelet TRPC6 and CD62P proteins. RESULTS: Compared with the control group, inhibition of TRPC6 with BI-749327 significantly reduced the PDW, MPV and Ca2+ concentration, the MAR and AAR were significantly increased, the expression of TRPC6 and CD62P protein was significantly down-regulated in PLTs, and the PS exposure was significantly reduced on the PLT surface. However, these effects were all reversed by activation of TRPC6. CONCLUSION: Inhibition of TRPC6 improves the quality of PLT preservation by inhibiting the Ca2+ signal mediated by TRPC6.

Cytokines possibly involved in idiopathic epiretinal membrane progression after uncomplicated cataract surgery.

Epiretinal membrane (ERM) is a common retinal fibrotic disorder disease causing visual impairment and metamorphopsia. Recently, increasing attention has been devoted to ERM progression after uncomplicated cataract surgery. Cytokines, which play a role in diverse physiological and pathological activities in eyes, are suggested to be involved in these postoperative changes. However, few studies have investigated the post-cataract surgery cytokine expression changes in ERM eyes and their roles in the postoperative changes. The purpose of this study was to evaluate the aqueous levels of cytokines in eyes with idiopathic epiretinal membrane (iERM) both pre- and post-cataract surgery, and their correlations with postoperative iERM progression. In this study, aqueous humor (AH) samples were collected from iERM eyes (n = 25) and non-iERM eyes (n = 23) from 48 patients (48 eyes) undergoing uncomplicated cataract surgery preoperatively and 20 h postoperatively. Samples were analyzed for 48 cytokines with multiplex bead-based immunoassay. Correlations between cytokine level changes (postoperation vs. preoperation) and three-month postoperative best-corrected visual acuity (BCVA) and optical coherence tomography measure changes were evaluated in iERM eyes. We found that in iERM eyes, the levels of 4 cytokines exhibited significant elevations when compared with those in the controls (all p ≤ 0.0015) preoperatively. Postoperatively, the concentrations of 21 cytokines were higher than the preoperative levels in iERM eyes (all p ≤ 0.0015), among which GRO-α, IL-8, and MCP-3 levels showed more pronounced changes than the controls. Additionally, in iERM eyes, IL-4 level changes showed moderate positive correlations with MV (r = 0.492, p = 0.028) and MT (r = 0.481, p = 0.032) changes. LogMAR changes were positively correlated with IL-1α (r = 0.553, p = 0.011), IL-12(P40) (r = 0.544, p = 0.013), and MCP-3 (r = 0.588, p = 0.006) level changes. No significant cytokine-level-change differences were found between eyes with and without postoperative cystoid macular edema development. In conclusion, cataract surgery will bring great alterations to the specific intraocular cytokine microenvironment inherently in eyes with iERM. Many fibrotic and inflammatory cytokines showing elevated levels or relationships with clinical characteristics are suggested to be involved in the pathogenesis and post-cataract surgery progression of iERM; however, further investigations are needed to discern their real roles.

Influence of angle alpha on visual quality after implantation of extended depth of focus intraocular lenses.

BACKGROUND: To assess postoperative changes in angle alpha, and to evaluate the postoperative visual quality of patients with different angle alpha values after implantation of extended depth of focus (EDOF) intraocular lenses (IOLs). METHODS: Seventy-nine eyes of 79 patients who had phacoemulsification with EDOF IOLs implantation were enrolled. A cut-off value of 0.3 mm, 0.4 mm, and 0.5 mm in preoperative angle alpha was chosen to divide eyes into groups. Distance, intermediate, and near visual acuities, modulation transfer function (MTF), and aberrations were recorded during a 6-month follow-up. A patient questionnaire was completed. RESULTS: There were no significant differences in angle alpha postoperatively compared to preoperatively. No significant differences were found in visual acuity and MTF between all groups. With 5 mm pupil diameter, there were significant differences of higher-order aberrations and spherical aberration in ocular aberration and internal aberration between angle alpha<0.4 mm and angle alpha≥0.4 mm. Additionally, significant differences of coma were also added in cut-off value of 0.5 mm. When the value of angle alpha is 0.4 mm or higher, there were significant differences in the score of halos and glare. CONCLUSIONS: Angle alpha did not affect visual acuity, but the value of 0.4 mm or higher in angle alpha affected the visual quality under scotopic conditions and occurrence of halos and glare. For patients with 0.4 mm or higher in angle alpha, the choice to implant a EDOF IOL should be carefully considered.

Comparison of preoperative angle kappa measurements in the eyes of cataract patients obtained from Pentacam Scheimpflug system, optical low-coherence reflectometry, and ray-tracing aberrometry.

BACKGROUND: Angle kappa plays a vital role in the implantation of multifocal intraocular lens (MIOL). Large angle kappa is related to a higher risk of postoperative photic phenomena. This study aims to compare preoperative angle kappa in the eyes of cataract patients obtained from the Pentacam Scheimpflug system (Pentacam), optical low-coherence reflectometry (Lenstar), and ray-tracing aberrometry (iTrace). METHODS: One hundred thirteen eyes of 113 patients with cataracts were included. Each eye was examined 3 times using all devices to obtain angle kappa and pupil diameter. When considering dependent eyes for one individual, angle kappa in both right eyes and left eyes should be analysed separately. The repeatability and reproducibility were evaluated using the within-subject standard deviation (Sw), repeatability (2.77 Sw), and intraclass correlation coefficient (ICC). The difference, correlation, and agreement between devices were evaluated by paired t-tests, Pearson tests, and Bland-Altman analysis, respectively. RESULTS: Intraoperator repeatability and interoperator and intersession reproducibility of angle kappa showed an Sw of less than 0.05 mm, a 2.77 Sw of 0.14 mm or less, and an ICC of more than 0.96. Angle kappa was not significantly different between Pentacam and Lenstar (P > 0.05), while angle kappa was significantly different between Pentacam and iTrace and between Lenstar and iTrace (P < 0.05). There was a strong correlation between Pentacam and Lenstar for angle kappa (r =0.907 to 0.918) and a weak or moderate correlation between Pentacam and iTrace and between Lenstar and iTrace (r =0.292 to 0.618). There were narrow 95% limits of agreement (LoA) between Pentacam and Lenstar for angle kappa and wide 95% LoA between Pentacam and iTrace and between Lenstar and iTrace. No significant differences in pupil diameter were found between Pentacam and Lenstar in either eye (P > 0.05). Positive angle kappa (nasal light reflex) was found in most cataract patients (79.25% to 84.91%) through 3 different devices in both eyes. CONCLUSIONS: The 3 devices provided high intraoperator repeatability and interoperator and intersession reproducibility for angle kappa measurements. The measurement of preoperative angle kappa in the eyes of patients with cataracts by Pentacam and Lenstar has good agreement.

Successful conservative treatment of intestinal perforation in VLBW and ELBW neonates: a single centre case series and review of the literature.

BACKGROUND: The current standard treatment of neonates with intestinal perforation is surgery. However, the mortality rate after surgical treatment for intestinal perforation is very high for very low birth weight (VLBW) and extremely low birth weight (ELBW) neonates. In this review, conservative treatment of pneumoperitoneum among VLBW and ELBW neonates is investigated. METHODS: Between January 2015 and December 2017, data from all of the VLBW and ELBW neonates with pneumoperitoneum who survived without surgical treatment were collected from Shenzhen Maternity and Child Healthcare Hospital in Guangdong, China. Twenty-two neonates with birth weight less than 1500 g were diagnosed with pneumoperitoneum. Following careful evaluation and discussion, eleven were treated conservatively and this was successful in eight. Details of the eight neonates including birth weight, gestational age, gender, risk factors, time of the perforation, treatment and prognosis were retrospectively recorded. A literature review was performed of previously reported cases that had used conservative treatment. RESULTS: The median gestational age and birth weight of the eight neonates were 27+ 1 weeks (range 24w+ 3 to 31w+ 6) and 855 g (range 650 g to 1440 g), respectively. Pneumoperitoneum was confirmed by X-ray in all at a median of 8 days of life. They received full parenteral support for a median of 22 days. All eight neonates received a combination of piperacillin-tazobactam and meropenem as first-choice antibiotics, two of them also received fluconazole as anti-fungal medication. Median duration of hospitalisation was 80 days. CONCLUSIONS: Conservative treatment with careful surveillance may be a practical choice for the VLBW and ELBW neonates with intestinal perforation. Further studies are needed for confirmation.

Pro-Fibrotic Role of Interleukin-4 in Influencing Idiopathic Epiretinal Membrane in Cataract Patients: Analysis From Clinical-Experimental Approaches.

Purpose: To evaluate the role of interleukin-4 in influencing idiopathic epiretinal membrane (iERM) formation and early progression post cataract surgery (PCS) from clinical and experimental perspectives. Methods: We quantified levels of IL-4 in aqueous humor (AH) samples from 22 iERM patients and 31 control subjects collected before and 20 hours after cataract surgeries using ELISA. After a 3-month follow-up, the association between IL-4 levels and iERM progression measurements was identified. In addition, in vitro studies were conducted to investigate the effects of IL-4 on primary rat retinal Müller glia proliferation, migration, and glial-mesenchymal transition (GMT). Results: Concentrations of IL-4 were significantly higher in preoperative AH samples from iERM patients versus controls (P = 0.006). Postoperatively, although IL-4 levels were elevated in both groups compared to their respective preoperative levels, they were even more obviously so in the iERM group (P < 0.001). Multivariate linear regression analyses revealed that, postoperatively, IL-4 level elevation was positively associated with macular volume and thickness increase (both P < 0.05) in iERM patients. However, no correlations were observed between IL-4 level (changes) and clinical characters in the controls. In vitro studies demonstrated that IL-4 promoted Müller glia proliferation and migration and increased the expression of GMT-related markers in a manner independent of transforming growth factor-ß1 (TGF-ß1). Conclusions: IL-4 plays a crucial pro-fibrotic role in iERM formation and early progression 3 months PCS possibly by stimulating Müller glia proliferation, migration, and GMT in a TGF-ß1-independent manner. Translational Relevance: The current study suggests the potential of IL-4 as a novel therapeutic target for iERM.

XRCC5 downregulated by TRIM25 is susceptible for lens epithelial cell apoptosis.

Exposure of the lens to UVB can lead to oxidative stress, which would result in age-related cataract (ARC) formation. In this study, we investigate the regulatory mechanism of tripartite motif containing 25 (TRIM25) in ARC. The protein level of TRIM25 was elevated in ARC specimens and UVB-exposed SRA01/04 cells. Bioinformatic analysis indicated that X-ray repair cross complementing 5 (XRCC5) might interact with TRIM25, and the interaction was validated via immunoprecipitation. TRIM25 interacted with XRCC5 and ubiquitinated it for degradation. Further studies showed that XRCC5 overexpression notably repressed UVB-induced apoptosis, while XRCC5 knockdown promoted apoptosis. Of note, ubiquitination of XRCC5 mediated by TRIM25 overexpression facilitated apoptosis. Attenuation of XRCC5 ubiquitination by mutant with substitution of lysine residues with arginine residues rescued its anti-apoptosis effect. Moreover, we observed that TRIM25-mediated XRCC5 degradation was reversed by proteasome inhibitor MG-132 or lysosome inhibitor 3-MA. In conclusion, TRIM25 mediates ubiquitination of XRCC5 to regulate the function and degradation of XRCC5, suggesting that interventions targeting TRIM25 might be a promising therapeutic strategy for ARC.

Effect of Anterior Chamber Instability during Phacoemulsification Combined with Intraocular Lens Implantation.

PURPOSE: To determine the incidence of anterior chamber (AC) instability during phacoemulsification (phaco) combined with intraocular lens implantation and investigate its effect on intraocular tissues. METHODS: Among the 248 enrolled eyes, 121 and 127 eyes were categorized into the irrigation and nonirrigation groups, respectively, depending on the use of a self-made anterior chamber maintainer (ACM) during phaco. AC stability was evaluated using operating microscopy and intraoperative optical coherence tomography (iOCT). Slit-lamp examination of AC flare and cells was performed 1 day postoperatively. Corrected distance visual acuity (CDVA), intraocular pressure (IOP), endothelial cell density (ECD), central corneal thickness (CCT), posterior vitreous detachment (PVD), and central foveal thickness (CFT) were evaluated preoperatively and at 1 week, 1 month, and 3 months postoperatively. RESULTS: There was good consistency in AC stability evaluation between operating microscopy and iOCT. The incidence of AC instability was significantly different between groups after the phaco and irrigation/aspiration tips were withdrawn from the AC (P < 0.001). At 1 day postoperatively, after excluding eyes in which the AC could not be visualized, AC cell grades were significantly lower in the irrigation group (P = 0.014). There was no significant difference in CDVA, IOP, ECD, and CCT between groups during the 3-month follow-up (P > 0.05). At 1 month and 3 months postoperatively, PVD occurred in 8 (16.3%) and 14 (28.6%) eyes and in 22 (40.7%) and 37 (68.5%) eyes in the irrigation and nonirrigation groups, respectively (P = 0.006 and P < 0.001). CFT was significantly higher in the nonirrigation group at 1 and 3 months postoperatively (P = 0.018 and P = 0.010). CONCLUSIONS: Both operating microscopy and iOCT are efficient for AC stability evaluation. When the phaco and I/A tips were withdrawn from the AC, there was frequent instability. Intraoperative AC instability can increase surgery-induced inflammation and lead to postoperative complications such as PVD, retinal detachment, and macular edema. The self-made ACM can effectively reduce the incidence of intraoperative AC instability and these complications.

Evolution of Cracks in Nano-CaCO3 Modified Pre-Disintegrated Carbonaceous Mudstone Under Cyclic Wetting and Drying.

To explore the evolution of cracks in the pre-disintegrated carbonaceous mudstone, wetting-drying tests were carried out on nano-CaCO3 modified pre-disintegrated carbonaceous mudstone samples. The samples were prepared with aqueous solutions of different pH values. Scanning electron microscopy (SEM) was performed to clarify the mechanism of crack evolution of pre-disintegrated carbonaceous mudstone modified by nano-CaCO3. The results showed that development of shrinkage and cracks was basically divided into three stages, i.e., the gestation stage, the rapid development stage and the stable stage. For the samples without nano-CaCO3, the final crack rates and pore sizes of samples with pH = 3 and pH = 11 were larger than corresponding values of the sample with pH= 7. Moreover, final crack rate and pore size significantly decreased with the addition of nano-CaCO3 suggesting that nano-CaCO3 can effectively improve cracking resistance of pre-disintegrated carbonaceous mudstone.