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Retinal capillary cells undergo apoptosis before pathology characteristic of retinopathy can be observed, and the appearance of apoptotic capillary cell can predict the development of pathology. The purpose of this study is to investigate the effect of reversal of hyperglycemia on retinal capillary cell apoptosis, and identify the apoptosis encoding genes. Streptozotocin-diabetic rats were maintained either in poor glycemic control (PC, glycated hemoglobin, GHb >11%) or in good glycemic control (GC, GHb <6%) for 12 months, or allowed to be in PC for 6 months followed by GC for 6 additional months (PC–GC). Capillary cell apoptosis was determined in the trypsin-digested retinal microvasculature by TUNEL staining, and the genes encoding apoptosis were identified by Oligo GEArray rat apoptosis microarray that profiles 113 genes. Six months of good glycemic control that followed 6 months of poor control failed to attenuate the number of TUNEL-positive capillary cells in the retinal microvasculature. Twenty-three retinal genes, mainly from TNF ligand and receptor, caspase, Bcl-2 and death domain subfamilies that were upregulated by least a two-fold in PC rats remain upregulated after reversal of hyperglycemia. Thus, the continued activation of apoptosis plays a major role in the resistance of retinopathy to halt after re-institution of good glycemic control, and the regulation apoptosis machinery could help retard the progression of diabetic retinopathy. 相似文献
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Inhibition of autophagy has been daily served as a promising anti-cancer treatment strategies. AstragalosideII (ASII), a main compound isolated from traditional Chinese medicine Radix Astragali, has been demonstrated to inhibit autophagy and reverse multidrug resistance in human hepatic cancer cells Bel-7402/5-FU. In this study, we inspected the function and mechanisms of ASII and cisplatin on autophagy in human cancer cells, and assessed the effect of ASII on cisplatin-induced apoptosis. We found ASII increased LC3II protein level, p62 protein level and GFP-LC3 puncta accumulation in human cancer cells. Furthermore, we found that ASII downregulated the expression of lysosomal cathepsinB/L (CTSB/L) in EBSS medium and affected the lysosomal acidification. Finally, we demonstrated that cisplatin induced protective autophagy which was involved of PI3K/Akt/mTOR pathway. Moreover, ASII in conjunction with cisplatin significant reduced cell viability, arrested in S phase and increased apoptosis. In conclusion, these findings suggested that ASII served as autophagy inhibitor which restored chemosensitivity of anticancer agent cisplatin and enhanced tumor cell death. 相似文献
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Yang Gao Shixiong Tian Yanwei Sha Xiaomin Zha Huiru Cheng Anyong Wang Chunyu Liu Mingrong Lv Xiaoqing Ni Qiang Li Huan Wu Qing Tan Dongdong Tang Bing Song Ding Ding Jiangshan Cong Yuping Xu Ping Zhou Xiaojin He 《Reproductive biomedicine online》2021,42(5):963-972
Research questionMultiple morphological abnormalities of the flagella (MMAF) is characterized by excessive immotile spermatozoa with severe flagellar abnormalities in the ejaculate. Previous studies have reported a heterogeneous genetic profile associated with MMAF. What other genetic variants might explain the cause of MMAF?DesignWhole-exome sequencing was conducted in a cohort of 90 Chinese patients with MMAF. The pathogenicity of identified mutations was assessed through electron microscopy and immunofluorescent examinations.ResultsThree unrelated men with bi-allelic DNAH2 variants were identified. Sanger sequencing verified that the six novel variants originated from every parent. All these variants were located at the conserved domains of DNAH2 and predicted to be deleterious by bioinformatic tools. Haematoxylin and eosin staining and scanning electron microscopy revealed that spermatozoa harbouring DNAH2 variants displayed severely aberrant morphology mainly with absent and short flagella (≥78%). Moreover, transmission electron microscopy revealed the obvious absence of a central pair of microtubules and inner dynein arms in the spermatozoa with mutated DNAH2. Immunofluorescence data further validated these findings, showing reduced DNAH2 protein expression in the spermatozoa with DNAH2 variants, compared with normal spermatozoa. Intracytoplasmic sperm injection using spermatozoa from the three men with mutated DNAH2 resulted in blastocyst formation in all cases. Embryo transfer was carried out in two couples, both resulting in clinical pregnancy.ConclusionsThese experimental and clinical data suggest that bi-allelic DNAH2 variants might induce MMAF-associated asthenoteratozoospermia, which can be overcome through intracytoplasmic sperm injection. These findings contribute to the knowledge of the genetic landscape of asthenoteratozoospermia and clinical counselling of male infertility. 相似文献
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Objective
Traditional chemotherapy drugs have an obvious drawback of nonspecific biodistribution in treating ovarian cancer. Follicle-stimulating hormone receptor (FSHR), a G-protein coupled receptor which is mainly expressed in reproductive system, is an important drug target in developing novel therapeutics.Methods
Using a polypeptide of follicle-stimulating hormone (named as FSHP), a conjugated nanoparticle, FSHP-NP was developed to target FSHR in lymphatic metastasis of ovarian cancer. FSHP-NP was tested for recognition specificity and uptake efficiency on FSHR-expressing cells. A paclitaxel (PTX)-loaded FSHP-NP (FSHP-NP-PTX) was further developed and its anti-tumor effect was determined in vivo and in vitro.Results
Taking NuTu-19 cells as an example, FSHP-NP-PTX displayed significantly stronger anti-cell proliferative and anti-tumor effects in a dose- and time-dependent manner when compared with free PTX or naked PTX-loaded nanoparticles (NP-PTX) in vitro. In vivo examinations showed that the size and weight of the lymph nodes were reduced in the FSHP-NP-PTX group.Conclusion
FSHR as a novel therapeutic target in ovarian cancer and delivery of PTX via conjugated nanoparticle (FSHP-NP) might represent a new therapeutic approach in ovarian cancer. 相似文献10.
Weiwei Shan Chengcheng Ning Xuezhen Luo Qiongjie Zhou Chao Gu Zhenbo Zhang Xiaojun Chen 《Gynecologic oncology》2014