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1.
J Refract Surg ; 40(7): e460-e467, 2024 Jul.
Article de Anglais | MEDLINE | ID: mdl-39007814

RÉSUMÉ

PURPOSE: To evaluate the clinical outcomes, rotational stability, and footplate position of the toric Implantable Collamer Lens (TICL) (STAAR Surgical) in eyes with low vault and analyze factors related to rotational stability. METHODS: This prospective observational study included 59 eyes of 59 patients with insufficient vault (< 250 µm). Postoperative rotation was defined as the difference between the achieved angle and the intraoperative fixation angle, and assessed with a digital anterior segment photograph after full mydriasis at 1 week and 1, 3, and 6 months postoperatively. Ultrasound biomicroscopy was used to determine the ciliary body morphology and position of the footplate. Correlation analysis was employed to identify the risk factors associated with TICL rotation at 6 months postoperatively. RESULTS: At 6 months postoperatively, the mean central vault was 137.4 ± 61.0 µm (range: 40 to 236 µm), and the mean efficacy and safety indices were 1.04 and 1.15, respectively. The mean manifest refractive astigmatism decreased from -1.67 ± 0.82 diopters (D) preoperatively to -0.43 ± 0.33 D postoperatively, and the mean absolute rotation was 4.50 ± 3.08 degrees (range: 0 to 12.50 degrees). The angle of rotation was correlated with the preoperative spherical power (r = -0.318, P = .014), the average value of TICL footplates position (r = 0.284, P = .029), and postoperative astigmatism (r = -.469, P⩽ .001). CONCLUSIONS: TICL implantation is predictable, safe, and effective in correcting myopic astigmatism in eyes with low vault. The rotational stability was acceptable and related to the malposition of the footplate and preoperative spherical power. [J Refract Surg. 2024;40(7):e460-e467.].


Sujet(s)
Astigmatisme , Pose d'implant intraoculaire , Myopie , Lentilles intraoculaires phaques , Réfraction oculaire , Acuité visuelle , Humains , Études prospectives , Mâle , Femelle , Adulte , Acuité visuelle/physiologie , Réfraction oculaire/physiologie , Myopie/chirurgie , Myopie/physiopathologie , Jeune adulte , Astigmatisme/physiopathologie , Astigmatisme/chirurgie , Microscopie acoustique , Rotation , Adulte d'âge moyen , Corps ciliaire/chirurgie , Corps ciliaire/imagerie diagnostique
2.
Future Med Chem ; 16(10): 983-997, 2024.
Article de Anglais | MEDLINE | ID: mdl-38910574

RÉSUMÉ

Aim: To design and synthesize a novel series of 1-aryldonepezil analogues. Materials & methods: The 1-aryldonepezil analogues were synthesized through palladium/PCy3-catalyzed Suzuki reaction and were evaluated for cholinesterase inhibitory activities and neuroprotective effects. In silico docking of the most effective compound was conducted. Results: The 4-tert-butylphenyl analogue exhibited good inhibitory potency against acetylcholinesterase and butyrylcholinesterase and had a favorable neuroprotective effect on H2O2-induced SH-SY5Y cell injury. Conclusion: The 4-tert-butylphenyl derivative is a promising lead compound for anti-Alzheimer's disease drug development.


[Box: see text].


Sujet(s)
Acetylcholinesterase , Maladie d'Alzheimer , Butyrylcholine esterase , Anticholinestérasiques , Conception de médicament , Simulation de docking moléculaire , Neuroprotecteurs , Maladie d'Alzheimer/traitement médicamenteux , Maladie d'Alzheimer/métabolisme , Humains , Anticholinestérasiques/pharmacologie , Anticholinestérasiques/synthèse chimique , Anticholinestérasiques/composition chimique , Neuroprotecteurs/pharmacologie , Neuroprotecteurs/synthèse chimique , Neuroprotecteurs/composition chimique , Acetylcholinesterase/métabolisme , Butyrylcholine esterase/métabolisme , Relation structure-activité , Pipéridines/composition chimique , Pipéridines/pharmacologie , Pipéridines/synthèse chimique , Structure moléculaire , Lignée cellulaire tumorale , Peroxyde d'hydrogène/pharmacologie , Peroxyde d'hydrogène/antagonistes et inhibiteurs , Indoles
3.
Invest Ophthalmol Vis Sci ; 65(5): 14, 2024 May 01.
Article de Anglais | MEDLINE | ID: mdl-38713483

RÉSUMÉ

Purpose: The purpose of this study was to assess the impact of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) on corneal stroma characteristics, ocular manifestations, and post-recovery refractive surgery outcomes after varying recovery durations. Methods: Fresh corneal lenticules from patients with post-coronavirus disease 2019 (COVID-19; recovered within 135 days) and healthy controls (HCs) after small incision lenticule extraction (SMILE) surgery were obtained for experimental validation of SARS-CoV-2 susceptibility, morphological changes, and immune response of the corneal stroma. Corneal optical density (CD) was measured using the Pentacam HR. Corneal epithelium thickness (ET) and endothelium parameters were evaluated by wide-field optical coherence tomography (OCT) and non-contact specular microscopy (SP-1P), respectively. All the patients were assessed after SMILE surgery until 3 month of follow-up. Results: The cornea was susceptible to SARS-CoV-2 with the presence of SARS-CoV-2 receptors (CD147 and ACE2) and spike protein remnants (4 out of 58) in post-recovery corneal lenticules. Moreover, SARS-CoV-2 infection triggered immune responses in the corneal stroma, with elevated IL-6 levels observed between 45 and 75 days post-recovery, which were then lower at around day 105. Concurrently, corneal mid-stromal nerve length and branching were initially higher in the 60D to 75D group and returned to control levels by day 135. A similar trend was observed in CD within zones 0 to 2 and 2 to 6 and in the hexagonal cells (HEX) ratio in endothelial cells, whereas ET remained consistent. Notably, these changes did not affect the efficacy, safety, or predictability of post-recovery SMILE surgery. Conclusions: SARS-CoV-2 induces temporal alterations in corneal stromal morphology and function post-recovery. These findings provided a theoretical basis for corneal health and refractive surgery management in the post-COVID-19 milieu.


Sujet(s)
COVID-19 , Stroma de la cornée , SARS-CoV-2 , Tomographie par cohérence optique , Humains , Stroma de la cornée/anatomopathologie , Stroma de la cornée/virologie , Mâle , Femelle , Adulte , Tomographie par cohérence optique/méthodes , Chirurgie de la cornée par laser/méthodes , Adulte d'âge moyen
4.
J Nat Prod ; 87(5): 1479-1486, 2024 May 24.
Article de Anglais | MEDLINE | ID: mdl-38728656

RÉSUMÉ

Bioinspired skeleton transformation of a tricyclic lathyrane-type Euphorbia diterpene was conducted to efficiently construct a tetracyclic tigliane diterpene on a gram scale via a key aldol condensation. The tigliane diterpene was then respectively converted into naturally rare ingenane and rhamnofolane diterpenes through a semipinacol rearrangement and a visible-light-promoted regioselective cyclopropane ring-opening reaction. This work provides a concise strategy for high-efficiency access to diverse polycyclic Euphorbia diterpene skeletons from abundant lathyrane-type natural products and paves the way for biological activity investigation of naturally rare molecules.


Sujet(s)
Diterpènes , Euphorbia , Diterpènes/composition chimique , Diterpènes/isolement et purification , Euphorbia/composition chimique , Structure moléculaire , Biomimétique , Produits biologiques/composition chimique
5.
Med Res Rev ; 2024 May 20.
Article de Anglais | MEDLINE | ID: mdl-38769656

RÉSUMÉ

Oncogenes and tumor suppressors are well-known to orchestrate several signaling cascades, regulate extracellular and intracellular stimuli, and ultimately control the fate of cancer cells. Accumulating evidence has recently revealed that perturbation of these key modulators by mutations or abnormal protein expressions are closely associated with drug resistance in cancer therapy; however, the inherent drug resistance or compensatory mechanism remains to be clarified for targeted drug discovery. Thus, dual-target drug development has been widely reported to be a promising therapeutic strategy for improving drug efficiency or overcoming resistance mechanisms. In this review, we provide an overview of the therapeutic strategies of dual-target drugs, especially focusing on pharmacological small-molecule compounds in cancer, including small molecules targeting mutation resistance, compensatory mechanisms, synthetic lethality, synergistic effects, and other new emerging strategies. Together, these therapeutic strategies of dual-target drugs would shed light on discovering more novel candidate small-molecule drugs for the future cancer treatment.

6.
Org Lett ; 26(22): 4818-4823, 2024 Jun 07.
Article de Anglais | MEDLINE | ID: mdl-38809781

RÉSUMÉ

We have successfully accomplished a catalytic asymmetric total synthesis of entecavir, a first-line antihepatitis B virus medication. The pivotal aspect of our strategy lies in the utilization of a Pd-catalyzed enyne borylative cyclization reaction, enabling the construction of a highly substituted cyclopentene scaffold with exceptional stereoselectivity. Additionally, we efficiently accessed the crucial 1,3-diol enyne system early in our synthetic route through a diarylprolinol organocatalyzed enantioselective cross-aldol reaction and Re-catalyzed allylic alcohol relocation. By strategically integrating these three catalytic protocols, we established a practical pathway for acquiring valuable densely heteroatom-substituted cyclopentene cores.


Sujet(s)
Antiviraux , Cyclopentanes , Guanine , Virus de l'hépatite B , Cyclopentanes/composition chimique , Cyclopentanes/synthèse chimique , Catalyse , Antiviraux/composition chimique , Antiviraux/synthèse chimique , Stéréoisomérie , Structure moléculaire , Guanine/composition chimique , Guanine/analogues et dérivés , Virus de l'hépatite B/effets des médicaments et des substances chimiques , Cyclisation , Palladium/composition chimique
7.
Eur J Ophthalmol ; : 11206721231223543, 2023 Dec 27.
Article de Anglais | MEDLINE | ID: mdl-38151004

RÉSUMÉ

PURPOSE: To assess the ocular anterior segment characteristics in myopic eyes intended for ICL surgery with horizontal ciliary sulcus-to-sulcus (STS) diameters being greater than vertical STS diameters. METHODS: This retrospective, comparative case study included 1230 eyes of patients who underwent ICL implantation for the treatment of myopia or myopic astigmatism at the Zhongshan Ophthalmic Center from September 2020 to November 2021. The myopic eyes were divided into two groups according to the relatively long diameter of the ciliary sulcus. General parameters and anterior chamber parameters were compared between the two groups. RESULTS: 1230 eyes of 694 patients were included. The proportion of myopic eyes with longer horizontal STS diameters was 4.63%. Horizontal STS distances exceeding vertical meridians in these eyes were mainly attributed to the shortening of vertical STS distances (horizontal STS: P = 0.112; vertical STS: P < 0.001). Eyes with longer horizontal meridians of the ciliary sulcus displayed larger steep keratometry value (P = 0.001), larger corneal volume (P = 0.002), larger corneal astigmatism (P < 0.001), larger ocular residual astigmatism (P = 0.017), worse visual acuity (logMAR UDVA: P = 0.021; logMAR CDVA: P = 0.001), and more iridociliary cysts (P = 0.017) compared to eyes with vertically oval shapes. CONCLUSION: Myopic eyes with longer horizontal STS diameters are commonly accompanied by a change in corneal morphology and more iridociliary cysts. The anatomical features of the ciliary sulcus should be given sufficient consideration to ICL size and placement selection, contributing to more personalized and precise surgery.

8.
Front Chem ; 11: 1282978, 2023.
Article de Anglais | MEDLINE | ID: mdl-38144888

RÉSUMÉ

A series of novel N-aryl-debenzeyldonepezil derivatives (1-26) were designed and synthesized as cholinesterase inhibitors by the modification of anti-Alzheimer's disease drug donepezil, using Palladium catalyzed Buchwald-Hartwig cross-coupling reaction as a key chemical synthesis strategy. In vitro cholinesterase inhibition studies demonstrated that the majority of synthesized compounds exhibited high selective inhibition of AChE. Among them, analogue 13 possessing a quinoline functional group showed the most potent AChE inhibition effect and significant neuroprotective effect against H2O2-induced injury in SH-SY5Y cells. Furthermore, Compound 13 did not show significant cytotoxicity on SH-SY5Y. These results suggest that 13 is a potential multifunctional active molecule for treating Alzheimer's disease.

9.
Eur J Med Chem ; 260: 115722, 2023 Nov 15.
Article de Anglais | MEDLINE | ID: mdl-37595546

RÉSUMÉ

Autophagy is well-known to be a lysosome-mediated catabolic process for maintaining cellular and organismal homeostasis, which has been established with many links to a variety of human diseases. Compared with the therapeutic strategy for inhibiting autophagy, activating autophagy seems to be another promising therapeutic strategy in several contexts. Hitherto, mounting efforts have been made to discover potent and selective small-molecule activators of autophagy to potentially treat human diseases. Thus, in this perspective, we focus on summarizing the complicated relationships between defective autophagy and human diseases, and further discuss the updated progress of a series of small-molecule activators targeting autophagy in human diseases. Taken together, these inspiring findings would provide a clue on discovering more small-molecule activators of autophagy as targeted candidate drugs for potential therapeutic purposes.


Sujet(s)
Autophagie , Systèmes de délivrance de médicaments , Humains , Homéostasie , Lysosomes
10.
Theranostics ; 13(11): 3689-3706, 2023.
Article de Anglais | MEDLINE | ID: mdl-37441592

RÉSUMÉ

Rationale: Microglia with a repertoire of functions are critical in pathological regulation of angiogenesis in the retina. However, retinal microglia with beneficial contributions and corresponding mechanisms during pathological neovascularization are poorly understood. Methods: We conducted a bioinformatic comparison of public single-cell RNA transcriptome data between retinal microglia from mice with oxygen-induced retinopathy (OIR) and an antiangiogenic microglial population named MG3 from the spine. The essential beneficial factor thrombospondin-1 (Tsp-1) from microglia was discovered and then validated in the retina of mice with OIR at P17. Exosomes were isolated from Tsp-1-knockout microglia (KO-Exos) and Tsp-1+ microglia (NT-Exos). Human umbilical vein endothelial cells (HUVEC) morphology studies, exosomes' miRNA sequencing, luciferase reporter assay, miRNA loss of function studies, and intravitreal injection were used to explore the mechanism of Tsp-1 and microglia-associated retinal angiogenesis. Results: The bioinformatic analyses of single-cell RNA-seq data indicated that a subtype of retinal microglia named RMG1 shares features with MG3 in regulating wound healing, cell adhesion, and angiogenesis. Remarkably, Tsp-1, an extracellular matrix protein with robust inhibition of angiogenesis, was especially expressed in both MG3 and RMG1. However, the scarcity of Tsp-1+ cells was observed in RMG1, which could be an obstacle to attenuating retinal neovascularization. Subsequently, we found that exosomes derived from Tsp-1+ microglia inhibit the migration and tube formation of HUVEC. Moreover, the knockout of Tsp-1 led to the enrichment of miR-27a-5p in exosomes from microglia and promoted angiogenesis compared to that of NT-Exos in vitro. Furthermore, in the luciferase reporter assay on the transcriptional activity of the promoter, we demonstrated that Tsp-1 negatively regulates miR-27a-5p expression. In addition, SMAD family member 3 (Smad3), a receptor-activated Smad protein that is conducive to vascular homeostasis, was defined as a functional target gene of miR-27a-5p. These data were consistently confirmed in vivo in the retina of mice with OIR. Conclusion: Collectively, the Tsp-1/miR-27a-5p/Smad3 axis is involved in microglia-related and exosome-mediated antiangiogenic regulation of the retina. Therefore, this study reveals a novel mechanism by which retinal microglia maintain vascular homeostasis, thereby providing a new therapeutic target for pathological neovascularization.


Sujet(s)
Exosomes , microARN , Néovascularisation rétinienne , Humains , Souris , Animaux , Néovascularisation rétinienne/métabolisme , Microglie/métabolisme , Exosomes/métabolisme , microARN/génétique , microARN/métabolisme , Néovascularisation pathologique/métabolisme , Cellules endothéliales de la veine ombilicale humaine/métabolisme
11.
J Asian Nat Prod Res ; 25(11): 1097-1109, 2023 Nov.
Article de Anglais | MEDLINE | ID: mdl-37098899

RÉSUMÉ

A series of arylated huperzine A (HPA) derivatives (1-24) were efficiently synthesized in good yields (45-88% yields) through the late-stage modification of structurally complex natural anti-Alzheimer's disease (AD) drug huperzine A (HPA), using the palladium-catalyzed Suzuki-Miyaura cross-coupling reaction. The acetylcholinesterase (AChE) inhibitory activity of all synthesized compounds was evaluated to screen the potential anti-AD bioactive molecules. The results showed that introducing the aryl groups to C-1 position of HPA resulted in the unsatisfactory AChE inhibitory activity. The present study demonstrably verifies pyridone carbonyl group could be the necessary and unchangeable pharmacophore for maintaining HPA's anti-AChE potency, and provides the helpful information on the further research for developing anti-AD HPA analogues.


Sujet(s)
Maladie d'Alzheimer , Anticholinestérasiques , Anticholinestérasiques/pharmacologie , Acetylcholinesterase , Palladium , Catalyse
12.
Invest Ophthalmol Vis Sci ; 64(3): 35, 2023 03 01.
Article de Anglais | MEDLINE | ID: mdl-37000125

RÉSUMÉ

Purpose: To explore the anti-inflammatory and neuroprotective effects of lithium chloride (LiCl) in LPS-induced retinal injury. Methods: In vitro, primary retinal microglia were pretreated with LiCl and stimulated with lipopolysaccharide (LPS). Pro-inflammatory cytokine production, microglial morphological changes, and inflammation-associated signaling pathways were measured by real-time PCR (RT-PCR), western blotting, and immunofluorescence. Primary retinal neurons were cultured with microglial-derived conditioned medium in the absence or presence of LiCl. Neurotoxicity was evaluated by Cell Counting Kit-8 (CCK-8), terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) assay, and γ-H2AX detection. In vivo, an endotoxin-induced uveitis mice model was established, and each animal was given intraperitoneal injection of LiCl or vehicle. The retinal inflammatory response was measured by hematoxylin and eosin and fluorescent staining, RT-PCR, western blotting, and TUNEL assay. Retinal thickness and function were evaluated by spectral-domain optical coherence tomography and electroretinography. Results: In vitro, LiCl exerted no obvious toxic effects on microglia and significantly decreased proinflammatory factor (inducible nitric oxide synthase, tumor necrosis factor α, interleukin 6) production, inhibited microglial activation in morphology, and suppressed nuclear factor kappa B (NF-κB), Akt, and phosphatidylinositol 3-kinase (PI3K) phosphorylation. Moreover, LiCl promoted retinal neuron survival and reduced cell apoptosis and the expression of γ-H2AX. In vivo, LiCl reduced inflammatory infiltrating cells in the vitreous cavity and decreased proinflammatory cytokine expression in retinas. LiCl suppressed LPS-induced microglial activation, proliferation, and migration. Additionally, LiCl reduced LPS-induced apoptosis of ganglion cells and retinal edema and rescued retinal functional damage. Conclusions: This study demonstrates that LiCl exerts anti-inflammatory and neuroprotective effects by inhibiting microglial activation via the PI3K/Akt/NF-κB pathway in LPS-induced retinal injury. LiCl provides a novel and promising option to treat retinal inflammatory diseases.


Sujet(s)
Neuroprotecteurs , Rétinopathies , Souris , Animaux , Lipopolysaccharides/toxicité , Facteur de transcription NF-kappa B/métabolisme , Microglie/métabolisme , Neuroprotecteurs/pharmacologie , Neuroprotecteurs/usage thérapeutique , Neuroprotecteurs/métabolisme , Chlorure de lithium/pharmacologie , Protéines proto-oncogènes c-akt/métabolisme , Phosphatidylinositol 3-kinases/métabolisme , Lignée cellulaire , Anti-inflammatoires/pharmacologie , Rétinopathies/anatomopathologie , Cytokines/génétique , Cytokines/métabolisme , Nitric oxide synthase type II/génétique , Nitric oxide synthase type II/métabolisme
13.
J Nat Prod ; 86(4): 939-946, 2023 04 28.
Article de Anglais | MEDLINE | ID: mdl-36808969

RÉSUMÉ

A series of new N-aryl galantamine analogues (5a-5x) were designed and synthesized by modification of galantamine, using Pd-catalyzed Buchwald-Hartwig cross-coupling reaction in good to excellent yields. The cholinesterase inhibitory and neuroprotective activities of N-aryl derivatives of galantamine were evaluated. Among the synthesized compounds, the 4-methoxylpyridine-galantamine derivative (5q) (IC50 = 0.19 µM) exhibited excellent acetylcholinesterase inhibition activity, as well as significant neuroprotective effect against H2O2-induced injury in SH-SY5Y cells. Molecular docking, staining, and Western blotting analyses were performed to demonstrate the mechanism of action of 5q. Derivative 5q would be a promising multifunctional lead compound for the treatment of Alzheimer's disease.


Sujet(s)
Maladie d'Alzheimer , Neuroblastome , Neuroprotecteurs , Humains , Galantamine/pharmacologie , Galantamine/usage thérapeutique , Acetylcholinesterase/métabolisme , Palladium , Anticholinestérasiques/pharmacologie , Anticholinestérasiques/usage thérapeutique , Simulation de docking moléculaire , Peroxyde d'hydrogène , Maladie d'Alzheimer/traitement médicamenteux , Neuroprotecteurs/pharmacologie , Neuroprotecteurs/usage thérapeutique , Catalyse , Relation structure-activité , Structure moléculaire
14.
J Org Chem ; 88(6): 3802-3807, 2023 Mar 17.
Article de Anglais | MEDLINE | ID: mdl-36822154

RÉSUMÉ

The organocatalytic asymmetric Morita-Baylis-Hillman (MBH) reaction of isatin derivatives with various vinyl sulfones is disclosed. Chiral sulfone-containing 3-hydroxyoxindoles were produced in good to high yields and with good to high ee's. This report displays an unprecedented example to apply activated alkenes with sulfone moiety other than carbonyl groups in asymmetric MBH reactions and provides an efficient strategy to incorporate the sulfone functional group for the synthesis of chiral 3-hydroxyoxindoles.

15.
Nat Commun ; 14(1): 138, 2023 01 10.
Article de Anglais | MEDLINE | ID: mdl-36627283

RÉSUMÉ

ß-Nucleosides and their analogs are dominant clinically-used antiviral and antitumor drugs. α-Nucleosides, the anomers of ß-nucleosides, exist in nature and have significant potential as drugs or drug carriers. Currently, the most widely used methods for synthesizing ß- and α-nucleosides are via N-glycosylation and pentose aminooxazoline, respectively. However, the stereoselectivities of both methods highly depend on the assisting group at the C2' position. Herein, we report an additive-controlled stereodivergent iodocyclization method for the selective synthesis of α- or ß-nucleosides. The stereoselectivity at the anomeric carbon is controlled by the additive (NaI for ß-nucleosides; PPh3S for α-nucleosides). A series of ß- and α-nucleosides are prepared in high yields (up to 95%) and stereoselectivities (ß:α up to 66:1, α:ß up to 70:1). Notably, the introduced iodine at the C2' position of the nucleoside is readily functionalized, leading to multiple structurally diverse nucleoside analogs, including stavudine, an FDA-approved anti-HIV agent, and molnupiravir, an FDA-approved anti-SARS-CoV-2 agent.


Sujet(s)
Agents antiVIH , COVID-19 , Humains , Nucléosides , Stéréoisomérie , Antiviraux/pharmacologie
16.
Org Lett ; 25(4): 597-602, 2023 02 03.
Article de Anglais | MEDLINE | ID: mdl-36662155

RÉSUMÉ

The biorelevant sulfur-containing Euphorbia diterpenes with scarce 5/7/6/3 premyrsinane- and 5/7/6 myrsinane-type backbones were easily constructed from naturally abundant lathyrane-type Euphorbia factor L3 by visible-light-triggered tandem thiol-ene click reaction/transannular cyclization and regioselective cyclopropane ring-opening. The selenide diterpene was also successfully obtained to verify the system universality. This concise synthesis route gives an efficient strategy for obtaining structurally diverse Euphorbia diterpenes under very mild conditions and provides a promising anti-HIV bioactive premyrsinane diterpene 3h.


Sujet(s)
Diterpènes , Euphorbia , Cyclisation , Structure moléculaire
17.
Genes (Basel) ; 13(11)2022 11 17.
Article de Anglais | MEDLINE | ID: mdl-36421815

RÉSUMÉ

Transforming growth factor ß (Tgf-ß), a pleiotropic cytokine, can enhance DNA repair in various cells, including cancer cells and neurons. The noncoding regulatory system plays an important role in Tgf-ß-mediated biological activities, whereas few studies have explored its role in DNA damage and repair. In this study, we suggested that Tgf-ß improved while its inhibitor LSKL impaired DNA repair and cell viability in UV-irradiated 661W cells. Moreover, RNA-seq was carried out, and a total of 106 differentially expressed (DE)-mRNAs and 7 DE-lncRNAs were identified between UV/LSKL and UV/ctrl 661W cells. Gene ontology and Reactome analysis confirmed that the DE-mRNAs were enriched in multiple DNA damaged- and repair-related biological functions and pathways. We then constructed a ceRNA network that included 3 lncRNAs, 19 miRNAs, and 29 mRNAs with a bioinformatics prediction. Through RT-qPCR and further functional verification, 2 Tgf-ß-mediated ceRNA axes (Gm20559-miR-361-5p-Oas2/Gbp7) were further identified. Gm20559 knockout or miR-361-5p mimics markedly impaired DNA repair and cell viability in UV-irradiated 661W cells, which confirms the bioinformatics results. In summary, this study revealed that Tgf-ß could reduce DNA damage in 661W cells, provided a Tgf-ß-associated ceRNA network for DNA damage and repair, and suggested that the molecular signatures may be useful candidates as targets of treatment for photoreceptor pathology.


Sujet(s)
microARN , ARN long non codant , ARN long non codant/génétique , ARN long non codant/métabolisme , Facteur de croissance transformant bêta/génétique , Réseaux de régulation génique , Transcriptome/génétique , microARN/génétique , microARN/métabolisme , ARN messager/génétique , Altération de l'ADN/génétique , Cellules photoréceptrices/métabolisme
18.
Invest Ophthalmol Vis Sci ; 63(11): 28, 2022 Oct 03.
Article de Anglais | MEDLINE | ID: mdl-36315123

RÉSUMÉ

Purpose: Retinoblastoma (RB) is the most common type of aggressive intraocular malignancy in children. The alteration of immunity during RB progression and invasion has not yet been well defined. This study investigated significantly altered immune-associated genes and cells related to RB invasion. Methods: The differentially expressed immune-related genes (IRGs) in noninvasive RB and invasive RB were identified by analysis of two microarray datasets (GSE97508 and GSE110811). Hub IRGs were further identified by real time PCR. The single-sample gene set enrichment analysis algorithm and Pearson correlation analysis were used to define immune cell infiltration and the relationships between hub IRGs and immune cells. Cell viability and migration were evaluated by CCK-8 and Transwell assays. A xenograft mouse model was used to verify the relationship between Src homology 3 (SH3) domain GRB2-like 2 (SH3GL2) expression and myeloid-derived suppressor cells (MDSCs). Results: Eight upregulated genes and six downregulated IRGs were identified in invasive RB. Seven IRGs were confirmed by real-time PCR. Moreover, the proportions of MDSCs were higher in invasive RB tissues than in noninvasive RB tissues. Furthermore, correlation analysis of altered immune genes and cells suggested that SH3GL2, Langerhans cell protein 1 (LCP1) and transmembrane immune signaling adaptor TYROBP have strong connections with MDSCs. Specifically, decreased SH3GL2 expression promoted the migration of RB cells in vitro, increased the tumor size and weight, and increased the numbers of MDSCs in the tumor and spleen in vivo. Conclusions: This study indicated that SH3GL2 and MDSCs play a critical role in RB progression and invasion and provide candidate targets for the treatment of RB.


Sujet(s)
Tumeurs de la rétine , Rétinoblastome , Animaux , Humains , Souris , Lignée cellulaire tumorale , Prolifération cellulaire/génétique , Biologie informatique , Régulation de l'expression des gènes tumoraux , Tumeurs de la rétine/anatomopathologie , Rétinoblastome/anatomopathologie , Cellules cancéreuses en culture
19.
Chem Commun (Camb) ; 58(77): 10869-10872, 2022 Sep 27.
Article de Anglais | MEDLINE | ID: mdl-36074791

RÉSUMÉ

A catalytic asymmetric total synthesis of avibactam and relebactam, two marketed diazabicyclooctane (DBO) ß-lactamase inhibitors (BLIs), has been accomplished. An important feature of this study is the creation of a stereogenic center by using Rh-catalysed asymmetric hydrogenation, affording the crucial α-amino acid ester derivative with high-level enantiocontrol (99% ee). Furthermore, the adoption of flow technologies for the assembly of a majority of intermediates significantly achieves a faster preparation and greater synthetic efficiency than corresponding batch procedures.


Sujet(s)
Antibactériens , Inhibiteurs des bêta-lactamases , Acides aminés , Antibactériens/composition chimique , Antibactériens/pharmacologie , Composés azabicycliques/composition chimique , Composés azabicycliques/pharmacologie , Esters , Tests de sensibilité microbienne , Inhibiteurs des bêta-lactamases/composition chimique , Inhibiteurs des bêta-lactamases/pharmacologie , bêta-Lactamases/composition chimique
20.
Acta Biomater ; 150: 154-167, 2022 09 15.
Article de Anglais | MEDLINE | ID: mdl-35896137

RÉSUMÉ

Substantial evidence has demonstrated the application of fresh and decellularized human corneal lenticules from increasing myopic surgeries. Further preservation of decellularized corneal lenticules would extend its clinical application. However, whether fresh and preserved decellularized lenticules have the same effects in vivo, including refractive correction, remains unclear. Here, we made comprehensive comparisons between fresh human lenticules (FHLs) and preserved decellularized human lenticules (DHLs). Another group of decellularized lenticules was combined with crosslinking for potential keratoconus therapy. Optical transparency, biomechanical properties, and fibrillar ultrastructure were analyzed to evaluate the DHLs and crosslinked DHLs (cDHLs) in vitro. The DHLs retained high transparency and regular ultrastructure, with genetic materials mostly being eliminated. The strength of lenticules in the cDHL group was markedly increased by crosslinking. Moreover, after storage in glycerol for 3 months, the lenticules were reimplanted into rabbit corneal lamellar pockets assisted by a femtosecond laser. The rabbits were followed for another 3 months. There were no obvious rejective complications in any of the three groups. From 1 week to 3 months postoperatively, the host corneas of the FHL group remained highly transparent, while slight hazes were observed in the DHL group. However, the corneas of the cDHL group displayed opacity throughout the 3-month postoperative period. Furthermore, all the lenticules could effectively induce corneal steepening and refractive changes. Taken together, our data indicated that FHLs are ideal inlay products, whereas preserved DHLs could be an alternative for intrastromal lamellar keratoplasty. Our study provides new insights into the clinical application of human lenticule recycling. STATEMENT OF SIGNIFICANCE: Currently, substantial evidence has demonstrated the application of fresh and decellularized human corneal lenticules from increasing myopic surgeries. Further preservation of decellularized lenticules would extend its clinical application. However, whether fresh and preserved decellularized lenticules have the same effects in vivo, including refractive correction, remains unclear. Herein, we decellularized human lenticules with or without mechanically strengthened crosslinking. After storage in glycerol for 3 months, the lenticules were reimplanted into rabbit corneas. Comprehensive comparisons were performed among fresh human lenticules (FHLs), decellularized human lenticules (DHLs) and crosslinked DHLs. Our study indicated that FHLs are ideal inlay products, whereas preserved DHLs could be an alternative for intrastromal lamellar keratoplasty. Our study provides new insights into the clinical application of human lenticule recycling.


Sujet(s)
Stroma de la cornée , Transplantation de cornée , Animaux , Cornée/chirurgie , Stroma de la cornée/chirurgie , Glycérol , Humains , Lasers , Lapins
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