Sigma-1 receptor (σ ₁R) has become a focus point of drug discovery for central nervous system (CNS) diseases. A series of novel 1-phenylethan-1-one O-(2-aminoethyl) oxime derivatives were synthesized. In vitro biological evaluation led to the identification of 1a, 14a, 15d and 16d as the most high-affinity (K _i < 4 nmol/L) and selective σ ₁R agonists. Among these, 15d, the most metabolically stable derivative exhibited high selectivity for σ ₁R in relation to σ ₂R and 52 other human targets. In addition to low CYP450 inhibition and induction, 15d also exhibited high brain permeability and excellent oral bioavailability. Importantly, 15d demonstrated effective antipsychotic potency, particularly for alleviating negative symptoms and improving cognitive impairment in experimental animal models, both of which are major challenges for schizophrenia treatment. Moreover, 15d produced no significant extrapyramidal symptoms, exhibiting superior pharmacological profiles in relation to current antipsychotic drugs. Mechanistically, 15d inhibited GSK3β and enhanced prefrontal BDNF expression and excitatory synaptic transmission in pyramidal neurons. Collectively, these in vivo proof-of-concept findings provide substantial experimental evidence to demonstrate that modulating σ ₁R represents a potential new therapeutic approach for schizophrenia. The novel chemical entity along with its favorable drug-like and pharmacological profile of 15d renders it a promising candidate for treating schizophrenia.

BACKGROUND: As one of the early discovered long non-coding RNAs (lncRNA), taurine upregulation gene 1 ( TUG1 ) has been widely expressed in a variety of tumors. Moreover, it promotes cell proliferation, differentiation, apoptosis, and migration. However, our understanding of its importance in the pathogenesis of cataracts remains limited. This study aimed to explore the mechanism by which lncRNA TUG1 mediates lens epithelial cell apoptosis in age-related cataracts (ARC) by regulating the microRNAs (miR-29b)/second mitochondria-derived activator of caspases axis, and to identify more non-surgical strategies for cataract treatment. METHODS: The messenger RNA expression levels of TUG1 , miR-29b, and Smac were detected using quantitative real-time polymerase chain reaction in vivo and in vitro . The expression of the Smac protein was analyzed by Western blotting and immunofluorescence. Flow cytometry and cell counting kit-8 assays were used to detect the cell apoptosis and proliferation rates, respectively. The targeted regulatory relationship between lncRNA TUG1 , miR-29b, and Smac was verified by viral vector construction, co-transfection, nuclear and cytoplasmic separation, luciferase reporter assays, and RNA immunoprecipitation. RESULTS: TUG1 and Smac were expressed at high levels in ARC and HLE-B3 cells treated with 200 μmol/L H 2 O 2 , whereas miR-29b expression was decreased. In vitro cell experiments confirmed that down-regulation of TUG1 could inhibit the apoptosis of lens epithelial cells. Mechanistically, Smac expression was negatively regulated by miR-29b. TUG1 competitively inhibited miR-29b expression and caused greater release of Smac. In addition, miR-29b partially reversed the effects of TUG1 on human lens epithelial cell line cells. CONCLUSIONS lncRNA TUG1 increases Smac expression and promotes apoptosis of lens epithelial cells in ARC by competitively inhibiting miR-29b. This mechanism is the cytological basis for ARC formation. Based on these results, the lncRNA TUG1/miR29b/Smac axis may be a new molecular pathway that regulates ARC development.

Humans ; Botulinum Toxins, Type A/therapeutic use* ; Esotropia/drug therapy* ; Neuromuscular Agents ; Injections ; Treatment Outcome ; Oculomotor Muscles

The syndrome of dampness stagnancy due to spleen deficiency (DSSD) is relatively common globally. Although the pathogenesis of DSSD remains unclear, evidence has suggested that the gut microbiota might play a significant role. Radix Astragali, used as both medicine and food, exerts the effects of tonifying spleen and qi. Astragalus polysaccharide (APS) comprises a macromolecule substance extracted from the dried root of Radix Astragali, which has many pharmacological functions. However, whether APS mitigates the immune disorders underlying the DSSD syndrome via regulating gut microbiota and the relevant mechanism remains unknown. Here, we used DSSD rats induced by high-fat and low-protein (HFLP) diet plus exhaustive swimming, and found that APS of moderate molecular weight increased the body weight gain and immune organ indexes, decreased the levels of interleukin-1β (IL-1β), IL-6, and endotoxin, and suppressed the Toll-like receptor 4/nuclear factor-‍κB (TLR4/NF-‍κB) pathway. Moreover, a total of 27 critical genera were significantly enriched according to the linear discriminant analysis effect size (LEfSe). APS increased the diversity of the gut microbiota and changed its composition, such as reducing the relative abundance of Pseudoflavonifractor and Paraprevotella, and increasing that of Parasutterella, Parabacteroides, Clostridium XIVb, Oscillibacter, Butyricicoccus, and Dorea. APS also elevated the contents of short-chain fatty acids (SCFAs). Furthermore, the correlation analysis indicated that 12 critical bacteria were related to the body weight gain and immune organ indexes. In general, our study demonstrated that APS ameliorated the immune disorders in DSSD rats via modulating their gut microbiota, especially for some bacteria involving immune and inflammatory response and SCFA production, as well as the TLR4/NF-κB pathway. This study provides an insight into the function of APS as a unique potential prebiotic through exerting systemic activities in treating DSSD.
Rats ; Animals ; NF-kappa B/metabolism* ; Spleen ; Gastrointestinal Microbiome ; Toll-Like Receptor 4 ; Polysaccharides/pharmacology* ; Astragalus Plant/metabolism* ; Immune System Diseases/drug therapy* ; Body Weight

Objective:To assess the effectiveness of Vision Therapy System 4 (VTS4) combined with traditional comprehensive training for ametropic amblyopia.Methods:A non-randomized controlled clinical study was performed.A total of 168 children aged 4-10 years with ametropic amblyopia were enrolled in The First Affiliated Hospital of Zhengzhou University from January 2018 to March 2021.The children were assigned to conventional comprehensive training combined with Vision Therapy System 4 group (conventional+ VTS4 group) and conventional group according to the preference of their guardian.Patients in conventional+ VTS4 group (84 children) received conventional comprehensive training combined VTS4 and patients in conventional group (84 children) were treated with conventional comprehensive training only, and the intervention was continuously used for over a year.Best corrected visual acuity (BCVA) of the patients converted to the logarithm of the minimum angle of resolution (LogMAR) units was examined by international standard visual acuity chart before and after therapy.Spherical equivalent of the patients was detected by optometry under cycloplegic conditions and skiascopy.Binocular and fusion vision was examined with a synoptiscope.The stereopsis was evaluated using Titmus Stereogram.The ocular axial length (AL) and mean keratometry (Km) were measured with the IOLMaster 500.The basic cure rate, BCVA, reconstruction rate of stereopsis, △SE, △AL and △Km following training were compared to evaluate the effectiveness and myopic shift between two groups.The patients in conventional+ VTS4 group were divided into 4-5 years old group and 6-10 years old group, with 42 cases in each group, and the basic cure rate, BCVA, reconstruction rate of stereopsis were compared to evaluate the therapeutic effect between the two groups.The basic cure was defined as acuity improved to ≥0.9, with reduced myopic diopter and stable therapy outcome over 6 months.This study adhered to the Declaration of Helsinki.The study protocol was approved by an Ethics Committee of The First Affiliated Hospital of Zhengzhou University (No.2021-KY-0891-002). Written informed consent was obtained from guardians prior to any medical examination.Results:The basic cure rate of conventional+ VTS4 group was 58.33%(49/84), which was significantly higher than 40.48%(34/84) of conventional group ( χ2=5.358, P=0.021). The BCVA in the conventional+ VTS4 group was better than that in conventional group, showing a statistically significant difference ( Z=-2.537, P=0.011). The recovery rates of binocular vision, fusion vision and stereo vision were 87.93%(51/58), 78.33%(47/60) and 70.77%(46/65) in conventional+ VTS4 group, which were higher than 65.57%(40/61), 57.81%(37/64) and 52.86%(37/70) in conventional group, respectively, with significant differences between them ( χ2=8.259, 5.968, 4.566; all at P<0.05). No significant difference was found in △SE, △AL, and △Km between conventional group and conventional+ VTS4 group (all at P>0.05). The basic cure rate was 69.05%(29/42) in the children aged 4-5 years group, which was higher than 47.62%(20/42) in 6-10 years group, respectively, showing a significant difference ( χ2=3.967, P=0.046). Both BCVA and the stereo vision recovery rate in the 4-5 years old group were better than those in the 6-10 years old group ( Z=-2.046, P=0.041; χ2=4.624, P=0.032). Conclusions:A combination therapy of VTS4 and conventional comprehensive training can improve the visual acuity and reconstruct the fusion and stereopsis of children with ametropic amblyopia, without causing additional myopic drift.

Objective:To observe the 5-year outcomes and complications after cataract extraction combined with intraocular lens implantation in children with bilateral congenital cataract.Methods:An observational case series study was performed.A total of 72 children (144 eyes), aged 2 to 7 years, who received intraocular lens (IOL) implantation combined with posterior continuous curvilinear capsulorhexies and anterior vitrectomy after cataract extraction for bilateral congenital cataract in The First Affiliated Hospital of Zhengzhou University from January 2007 to January 2012 were enrolled.All the patients underwent refractive correction and amblyopia training two weeks after the second operative eye underwent surgery.The patients were divided into 2-3 years old group (64 eyes), 4-5 years old group (48 eyes) and 6-7 years old group (32 eyes) according to their age at surgery.The preoperative and postoperative best corrected visual acuity (BCVA), refraction, axial length, corneal curvature, binocular visual function and postoperative complications were observed during the 5-year follow-up period.The influence of age at surgery on postoperative BCVA in one eye at the final follow-up visit was analyzed.This study adhered to the Declaration of Helsinki.The study protocol was approved by the Ethics Committee of The Affiliated First Hospital of Zhengzhou University (No.2020-KY-219), and written informed consent was obtained from guardians of the subjects before treatment.Results:The mean myopic shift was -2.10(-2.90, -1.90), -1.73(-2.50, -2.10) and-0.52(-2.00, -0.28)D in the 2-3 years old group, 4-5 years old group and 6-7 years old group, respectively, and the axial elongation in the three groups was (1.41±0.32), (0.96±0.51), and (0.52±0.26)mm, respectively, and the differences among the three groups were statistically significant ( H=19.85, P<0.01; F=13.24, P<0.05).There was no statistically significant difference in preoperative and postoperative corneal curvature among the three groups (all at P>0.05).The BCVA was significantly improved in all the eyes after operation, and a certain binocular visual function was obtained, and the visual function in the 2-3 years old group was better than that of 4-5 years old group and 6-7 years old group (all at P<0.05).The BCVA at the end of following-up was 0.3 or better in 116 eyes (80.56%), and was better than 0.8 in 28 eyes (19.44%).The regression analysis results showed that children younger at surgery had better visual outcome (postoperative BCVA=0.959-0.104 operative age of patient; R2=0.539, P<0.01). Conclusions:The recovery of visual function in children with binocular congenital cataract is related to the age at operation.The younger the age at operation is, the better the recovery of visual function will be.Timely, systematic and standardized refractive correction, amblyopia treatment and binocular visual function training after operation are helpful to the development and reconstruction of visual function.

Objective:To observe the clinical effect of medium and long term visual quality after regional refractive multifocal intraocular lens (MIOL) implantation and compared with that of single focal intraocular lens (SMOL) implantation.Methods:A cohort study was conducted with 108 patients (141 eyes) who had undergone MIOL and SIOL implantation in First Affiliated Hospital of Zhengzhou University from August 2016 to August 2017.According to the implanted IOL, the patients were divided into the MIOL group (55 patients 76 eyes) and the SIOL group (53 patients 65 eyes). At 2 years after operation, the parameters of uncorrected far, intermediate and near vision, as well as corrected distant vision were assessed; the spherical equivalen was checked; the defocus curve of the operation eye was drawn; the high order aberrations (HOAs), Strehl ratio and modulation transfer function (MTF) were measured by i-Trace visual quality analyzer; contrast sensitivity of eyes was evaluated by a CSV-1000 contrast sensitivity instrument; visual quality between the two groups was compared by using the Chinese version of the American questionnaire on quality of Life after MIOL.This study was approved by the Ethics Committee of the First Affiliated Hospital of Zhengzhou University.Written informed consent was obtained from each patient prior to any medical examination. Results:The uncorrected intermediate and near visual acuity in the MIOL group was better than that in the SIOL group, with statistically significant difference(both at P<0.05). Two years after operation, the average defocus curve showed that there were two peaks at 0.0 D and -3.0 D in the MIOL group, and formed a wide platform between 0.0 and -3.0 D, and the downward trend was gentle.Under the pupil diameter of 5 mm, HOAs, coma, trefoil and secondary astigmatism in the MIOL group were higher than those in the SIOL group (all at P<0.05). Strehl ratio in the MIOL group was significantly lower than that in the SIOL group, with statistically significant difference ( P<0.05). Under the pupil diameter of 5 mm, MTF values of spatial frequencies of 5, 10, 15, 20, 25 and 30 c/d in the MIOL group were slightly lower than those in the SIOL group, without statistically significant differences (all at P>0.05). There was no significant difference in contrast sensitivity (3, 6, 12 and 18 c/d) between the two groups under photopic or mesopic conditions and with or without glare (all at P>0.05). The proportion of glasses removed in the MIOL group was 98.18%, which was significantly higher than that in the SIOL group (52.83%) by questionnaire ( χ2=30.37, P<0.01). The incidence of visual interference symptoms, such as glare and halo was 7.27% (4/55) in the MIOL group and 1.89% (1/53) in the SIOL group, respectively, with no statistically significant difference ( χ2=0.76, P=0.382). The satisfaction scores of vision at near distance vision, medium distance vision and overall visual acuity in the MIOL group were higher than that in the SIOL group, with statistically significant differences (all at P<0.05). Conclusions:Compared with SIOL implantation, regional refraction MIOL implantation can provide better and more stable mediate and near vision, a better contrast sensitivity, a lower incidence of optical interference and a higher postoperative satisfaction.

Objective To investigate the changes of the axial length,corneal curvature and refractive power in infants with monocular congenital cataract.Methods A retrospective cohort study was carried out.The clinical data of 105 eyes of 105 cases with monocular congenital cataract who were received cataract extraction during January 2015 to December 2017 were collected in the First Affiliated Hospital of Zhengzhou University.According to the initial operation age,the infants were assigned to 3-6 month old group,7-12 month old group and 13-18 month old group.The patients were followed-up for 12 months.Axial length,corneal curvature and refractive power were recorded in 3,6 and 12 months after surgery.This study followed the Declaration of Helsinki,and written informed consent was obtained from each guardian prior to any medical examination.Results The increasing value of axial length in 3-6 month old group was larger than that in 7-12 month old group,and increasing value in 7-12 month old group was larger than that in 13-18 month old group (all at P＜0.001).The increasing value of axial length of operated eyes was larger than that of fellow eyes in both 3-6 month old group and 7-12 month old group during following-up,and so was in the 13-18 month old group at 6 months and 12 months after surgery (all at P＜0.001).The ocular axial length of operated eyes was significantly shorter than that of the fellow eyes in three groups before operation (t =-10.420,P＜0.001;t=-32.288,P＜0.001;t =-2.370,P =0.024),and at 12 months after operation,the axial length of operated eyes was longer than that of the fellow eyes in the 13-18 month old group (t =18.513,P＜0.001).No significant difference was found in the axial length between operated eyes and fellow eyes in both 3-6 month old group and 7-12month old group (P =0.051,0.062).The pre-operative corneal curvature was significantly larger than that of fellow eyes in both 3-6 month old group and 7-12 month old group (both at P＜0.01),and was not significantly different in 13-18 month old group (P =0.433).There were not significant differences in corneal curvature in the three groups at 12 months after surgery (all at P＞0.05).The change value of refractive power was gradually increased as aging at 12 months after surgery (all at P＜0.001).The surgical eye amplitude of change in refractive diopter was higher than healthy eye,with significant difference between them (P＜0.001).Conclusions The developing process of axial length and corneal curvature are interacted and coordinated in bilateral eyes in infants who received extraction surgery of monocular congenital cataract.It is better to remove the cataract as early as possible in infants.Refraction of bilateral eyes still has a trend to myopia,and the shifting amplitude of myopic power decreases with aging.

OBJECTIVETo identify the disease-causing gene mutations in three Chinese pedigrees affected with congenital inherited cataract, in ordre to provide genetic counseling and prenatal diagnosis.

METHODSUsing exons combined target region capture sequencing chip to screen the candidate disease-causing mutations, Sanger sequencing was used to confirm the disease-causing mutations.

RESULTSFamily 1 was polymorphic cataract, family 2 was cerulean cataract, family 3 was coralliform cataract. The inheritance mode of the three pedigrees consisted with autosomal dominant inheritance. In family 1, a nonsense mutation of CRYβB2 gene c.463C>T in exon 6 result in a p.Q155X amino acid change. In family 2, a missense mutation of of CRYGD gene c.43C>T in exon 2 result in a p.R14C amino acid change. In family 3, a missense mutation of CRYGD gene c.70C>A in exon 2 result in a p.P23T amino aid change. No above-mentioned mutations were found in normal individuals.

CONCLUSIONThe nonsense mutation c.463C>T (p.Q155X) of CRYβB2 gene, the heterozygous mutations c.43C>T(p.R14C) of CRYGD gene and c.70C>A( p.P23T) of CRYGD gene was the disease-causing gene mutation in family 1, 2 and 3 respectively, our results provid genetic counseling and prenatal diagnosis for these three families.

Cataract ; genetics ; Genetic Counseling ; Humans ; Mutation ; Pedigree ; Prenatal Diagnosis ; beta-Crystallin B Chain ; genetics ; gamma-Crystallins ; genetics

Objective To observe the long-term visual quality and clinical effect of aspheric diffractive multifocal intraocular lens (IOL) implantation for congenital and developmental cataracts in childhood.Methods A retrospective cohort study on multifocal IOL implantation for congenital and developmental cataracts in childhood (aged 8 to 14 years) was performed in the First Affiliated Hospital of Zhengzhou University from August 2013 to January 2015.The clinical data of 67 eyes from 46 congenital cataract patients who received phacoemulsification with IOL implantation were collected.The AMO (ZMB00) IOL was implanted in 34 eyes of 24 patients in the multifocal IOL group,and Bausch & Lomb (MI60) IOL was implanted in 33 eyes of 22 patients in the monofocal IOL group.The distance,intermediate and near vision acuity were analyzed in 3,6 and 12 months after surgery,including uncorrected visual acuity (UCVA) and best corrected visual acuity (BCVA).The wavefront aberrations,modulation transfer functions (MTF) and stereopsis were obtained with iTrace Analysis System,Optec-6500 Visual Functional Analyzer and Titmus Stereo Test Chart,respectively in 12 months after surgery.The near additional degree,removing glasses rate and myopic shift were compared between the two groups in postoperative 12 months.Results The intermediate and near UCVA in the multifocal IOL group were obviously better than those in the monofocal IOL group 3,6 and 12 months after surgery (intermediate:Z=-3.74,-4.36,-3.66;all at P=0.00.near:Z=-2.67,-2.50,-2.33;all at P＜0.05).There were no significant differences between the two groups in total aberration,high and low order total aberrations,comatic aberration,trefoil aberration,spherical aberration and secondary astigmatism under the 5.0 mm optical zone in 12 months after surgery (all at P＞0.05).The MTFs under the 5.0 mm optical zone and 5,10,15,20,25,30 c/d in the multifocal IOL group were insignificantly lower than those in the monofocal IOL group (all at P＞0.05).In addition,the near stereopsis,near additional degree and myopic shift (AD) were reduced in the multifocal IOL group compared with monofocal IOL group (both at P＜0.05).The glasses removing rate was 93.3％ in the multifocal IOL group,which was significantly higher than 33.3％ in the monofocal IOL group (x2 =23.25,P =0.00).No significant difference in the incidence of posterior capsular opacification was found between the two groups (P＞0.05).The myopic shifting rates were 16.7％ and 83.3％ in the multifocal IOL group and monofocal IOL group,with a significant difference between the two groups (x2=15.02,P=0.00).Conclusions The aspheric multifical IOL implantation can achieve good and stable distance,intermediate and near visual acuities,provide better near stereopsis,reduce postoperative dependence on spectacles and decrease the incidence of myopic shift in child cataract patients.