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Aging poses a major risk factor for cardiovascular diseases, the leading cause of death in the aged population. However, the cell type-specific changes underlying cardiac aging are far from being clear. Here, we performed single-nucleus RNA-sequencing analysis of left ventricles from young and aged cynomolgus monkeys to define cell composition changes and transcriptomic alterations across different cell types associated with age. We found that aged cardiomyocytes underwent a dramatic loss in cell numbers and profound fluctuations in transcriptional profiles. Via transcription regulatory network analysis, we identified FOXP1, a core transcription factor in organ development, as a key downregulated factor in aged cardiomyocytes, concomitant with the dysregulation of FOXP1 target genes associated with heart function and cardiac diseases. Consistently, the deficiency of FOXP1 led to hypertrophic and senescent phenotypes in human embryonic stem cell-derived cardiomyocytes. Altogether, our findings depict the cellular and molecular landscape of ventricular aging at the single-cell resolution, and identify drivers for primate cardiac aging and potential targets for intervention against cardiac aging and associated diseases.
Subject(s)
Aged , Animals , Humans , Aging/genetics , Forkhead Transcription Factors/metabolism , Myocytes, Cardiac/metabolism , Primates/metabolism , Repressor Proteins/metabolism , Transcriptome , Macaca fascicularis/metabolismABSTRACT
OBJECTIVE@#To observe the clinical effect of acupuncture for glaucoma-induced optic atrophy.@*METHODS@#A total of 70 patients (89 affected eyes) with glaucoma-induced optic atrophy were randomized into an observation group and a control group, 35 cases in each group. The control group was given basic western medicine treatment. In the observation group, on the basis of the treatment in the control group, acupuncture was applied at main acupoints i.e. Baihui (GV 20), Shangjingming (Extra), Chengqi (ST 1), Fengchi (GB 20), Zusanli (ST 36), combined with supplementary acupoints based on syndrome differentiation, once every three days, twice a week. The treatment for 3 months was required in both groups. Before treatment, after treatment and in follow-up of 6 months after treatment, the best corrected visual acuity (BCVA), intraocular pressure (IOP), indexes of visual field (visual field index [VFI], mean deviation [MD], pattern standard deviation [PSD]) and mean thickness of retinal nerve fiber layer (RNFL) were observed in the two groups.@*RESULTS@#Compared before treatment, BCVA was decreased after treatment and in follow-up in the control group (P<0.05); in the follow-up, BCVA in the observation group was higher than that in the control group (P<0.05). On each time point before and after treatment, there was no significant difference within or between the two groups (P>0.05). After treatment and in the follow-up, the mean thickness of RNFL was larger than the control group (P<0.05).@*CONCLUSION@#On the basis of the basic western medicine treatment, acupuncture can delay the decline of vision and the thinning of retinal nerve fiber layer in patients with glaucoma-induced optic atrophy.
Subject(s)
Humans , Retinal Ganglion Cells , Glaucoma/therapy , Optic Atrophy/therapy , Intraocular Pressure , Acupuncture TherapyABSTRACT
Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a rare hereditary cerebrovascular disease caused by a NOTCH3 mutation. However, the underlying cellular and molecular mechanisms remain unidentified. Here, we generated non-integrative induced pluripotent stem cells (iPSCs) from fibroblasts of a CADASIL patient harboring a heterozygous NOTCH3 mutation (c.3226C>T, p.R1076C). Vascular smooth muscle cells (VSMCs) differentiated from CADASIL-specific iPSCs showed gene expression changes associated with disease phenotypes, including activation of the NOTCH and NF-κB signaling pathway, cytoskeleton disorganization, and excessive cell proliferation. In comparison, these abnormalities were not observed in vascular endothelial cells (VECs) derived from the patient's iPSCs. Importantly, the abnormal upregulation of NF-κB target genes in CADASIL VSMCs was diminished by a NOTCH pathway inhibitor, providing a potential therapeutic strategy for CADASIL. Overall, using this iPSC-based disease model, our study identified clues for studying the pathogenic mechanisms of CADASIL and developing treatment strategies for this disease.
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Purpose To detect the expression and the function of MCP-1 and its receptor CCR2 in wet agerelated macular degenerative (wAMD) model mouse retina. Methods C57BL/6J mouse were enrolled into the study. Model mouse of wAMD was induced with laser. Frozen sections were prepared for histopathological tests. Immunofluorescence study for MCP-1 and CCR2 was carried out. Co-expression study for CCR2/ CDllb or CCR2/CD68 was carried out. Total protein and total mRNA from the eyes of both wAMD and wild type mouse were extracted. The expression of mRNA and protein of MCP-1 and CCR2 in the eyes were determined by reverse transcription-poly-merase chain reaction (RT-PCR) and Western blots test, respectively. Results In wild type mouse, both MCP-1 and its receptor CCR2 were not detected in the retina. However in wAMD mouse, an obvious up-regulated MCP-1 and CCR2 expression was seen in the retinal pigment epithelium (RPE) cells accompanied with the increased expression of their mRNA and protein. The co-expression study showed that CCR2 co-ex-pressed with CDllb, but not with CD68. Conclusion MCP-1 and its receptor CCR2 may play a role in the wAMD through stimulation of microglia.
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Background Light stimulation at different wavelength influences the development of eyes.It has been showed that blue light can inhibit the growth of eyeball.To study whether blue light exposure can delay the extension of myopia is an interested research project.Objective This study was to investigate the effect of blue light with short wavelength on ocular growth in form deprived myopia (FDM) in guinea pigs and provide a new option for the prevention and treatment of myopia.Methods Thirty-six 2-week-old guinea pigs were reared in the environment of white light.The right eyes of the animals were occluded to establish the FDM models.The models were randomized into the deocclusion + blue light exposure group,simple deocclusion group and continuous occlusion group according to the random number table.The right eyes of the models were deoccluded for 1 hour per day to give the blue light (430 nm) irradiation in the deocclusion + blue light exposure group,and the right eyes were deoccluded for 1 hour per day only in the simple deocclusion group.In the continuous occlusion group,the right eyes of the models were occluded until the end of this experiment.Anterior chamber depth (ACD),lens thickness (LT) and vitreous cavity depth (VCD) were measured by A-type sonography.The binocular diopter of the guinea pigs was detected using retinoscopy in the mydriatic condition.In the fourth week after experiment,the retinal sections were prepared for the regular histopathological examination,and the scleral tissues next to 1 mm from optical nerve were exacted to obtain the dry weight of scleral tissues.Results In the right eyes of the animals,no significant differences were found in the diopter,ACD,LT and VCD before experiment among the 3 groups (all at P＞0.05).At the end of experiment,the refraction of right eye in the deocclusion + blue light exposure group,simple deocclusion group and continuous occlusion group was (+1.11±0.17)D,(+0.90±0.15)D and (-2.73±0.19)D respectively,with a significant difference among them (F=1 445.470,P=0.000).The VCD in the three groups was (3.70±0.09) mm,(3.78±0.11) mm and (3.91 ± 0.08) mm,respectively,showing a significant difference (F =13.243,P＜0.01).In addition,the dry weight of sclera tissues was (0.61 ±0.09)mg in the deocclusion + blue light exposure group,(0.54± 0.08)mg in the simple deocclusion group and (0.43 ± 0.07)mg in the continuous occlusion group,with a significant difference among the 3 groups (F=10.458,P＜0.01).However,there were no significant differences in the ACD and LT among the 3 groups (F=0.203,0.084,both at P＞0.05).Moreover,in the left eyes,no significant differences were found in the diopter,ACD,LT and VCD before experiment among the 3 groups (all at P＞0.05);while at the end of the experiment,the diopter of the continuous occlusion group was significantly lower than that of the deocclusion + blue light exposure group and simple deocclusion group (all at P＜0.05).No significant differences were seen in the ACD,LT,VCD and dry weight of sclera among the 3 groups (all at P＞0.05).Retinal structure was normal in the left eyes of various groups.However,the retinas were thinner in the right eyes of the deocclusion + blue light exposure group with clear layers; while atrophy of the outer segment of photoreceptor and disorder of cell arrangement were seen in the right eyes of the continuous occlusion group.Conclusions During sensitive period of visual development,blue light stimulation can arrest the extension of posterior sclera and elongation of vitreous cavity,which restrains development of myopia.This blue light at the wavelength of 430 nm is safe to retina.
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Background Various studies have suggested that inflammatory factors such as leucocytes and macrophages are involved in the occurrence and development of diabetic retinopathy (DR),and many cytokines promote the occurrence of DR.However,the relationship of aqueous and serum monocyte chemotactic protein-1 (MCP-1) and macrophage migration inhibitory factor (MIF) change with DR is unclear.Objective This study was to investigate the effects of MCP-1 and MIF in aqueous and serum during DR development.Methods Eighty patients with type 2 diabetes were enrolled from Beijing Shijitan Hospital.These patients received phacoemulsification or phacoemulsification and vitrectomy from September,2010 to June,2011.Twenty-six cataract patients in the same stage (without diabetes) who underwent phacoemulsification surgery served as controls.According to the clinical stage of the DR,the diabetic patients were classified as the non-DR group (NDR) (20 eyes),non-proliferative DR group (NPDR) (38 eyes) and proliferative DR group (PDR) (22 eyes).Aqueous humour and periphery blood samples were collected during the operation to detect MCP-1 and MIF using enzyme-linked immnunosorbent assay (ELISA).Written informed consent was obtained from each subject before any relevant medical examination.Results The average aqueous MCP-1 levels were(1660.78±562.98),(1463.26± 623.41),(686.76±186.16) and(494.35±148.59) ng/L in the PDR group,NPDR group,NDR group and control group,respectively,showing a significant difference among the 4 groups (F=37.968,P=0.000).No significant differences were found in the aqueous MCP-1 levels between the control group and NDR group (P=0.169),or between the NPDR group and PDR group (P=0.117).However,the aqueous MCP-1 levels were significantly elevated in the PDR group,NPDR group and NDR group compared with the control group (P=0.000).The average aqueous MIF levels were (6.85±1.99),(3.56±0.90),(1.10±0.48) and (0.86 ± 0.46) μg/L,respectively,with significant differences among them (F =144.502,P =0.000).Multiple comparisons between groups were found to be significantly different (P =0.000) according to the LSD-t test,except between the control group and NDR group (P =0.475).A significant positive correlation was seen between the aqueous MCP-1 level and MCP-1 level in all study participants (r =0.564,P =0.000).However,serum levels of MCP-1 and MIF were not statistically significantly different among the 4 groups (F =2.158,P＞0.05;F =0.813,P＞0.05).Conclusions The increase of the aqueous MIF and MCP-1 levels is associated with the progression of diabetic retinopathy.The results suggest that MIF and MCP-1 promote the occurrence of DR.
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BackgroundMonocyte chemotactic protein-1 (MCP-1)plays an important role in the tumor,inflammation,diabetic retinopathy and other neovascular disease,but the expression and the role of MCP-1 in the oxygen induced retinopathy(OIR) model have rarely been reported. Objective This study was to investigate the expression of MCP-1 in the retina development of newborn mouse and in mouse models with OIR.Methods C57BL/6J newborn mice were divided into two groups and 60 mice in each group.Mice in OIR group were exposed to 75％ oxygen for 5 days and then to room air.All mice in normal control group exposed to room air only.Ten mice in each group were randomly chosen and sacrificed at postnatal 5,7,12,14,17,21 days.The expression of MCP-1 in mouse retina was detected with the method of immunohistoehemistry and reverse transcription polymerase chain reaction(RT-PCR).Results MCP-1 positive cells were seen in normal mouse retina.Up-regulation of MCP-1 positive cells was detected both in 12 days in normal control group and in 14 days in OIR group.MCP-1 mRNA was detected in mouse retina at 5 days,and a transient up-regulation of MCP-1 mRNA was observed in 12 days in normal control group.MCP-1 mRNA in OIR group significantly increased in 14 days in comparison with the normal control group( P =0.028,P =0.001 ). Conclusions Expression of MCP-1 is detectable in whole retinal development procession of mice.A transient up-regulation of MCP-1 expression is detected in the critical period of retinal vascular development in mice models with OIR,which is closely related to the retinal vascular development and progression of retinal new vessels.