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10.1007/s004170050117 [PubMed] [CrossRef] [Google Scholar] 22. signaling during senescence, leading to the development of ARC. LM4 and its regulatory factors show potential as targets for drug development for prevention and treatment of ARC. Keywords: age-related cataract, anterior lens capsule, laminin 4, human lens epithelial cell, senescence, basement membrane Introduction Age-related cataract (ARC), characterized by lens opacity and visual impairment in the middle-aged and elderly, is responsible for nearly half of all blindness worldwide [1]. Previous studies have suggested that numerous risk factors, including age, sex, social status, ultraviolet radiation, smoking, and diabetes mellitus, may contribute to the development of ARC [2,3]. However, at present, mechanisms underlying the pathology of ARC remain unclear. Aside from surgery, there is a lack of effective treatments for curing ARC [3,4]. Oxidative stress caused by reactive oxygen species (ROS) has long been recognized as a major mechanism by which cells are damaged and cataracts are created [5C7]. Hydrogen peroxide (H2O2) is the main intracellular ROS in the aqueous humor that can cause protein oxidation and aggregation, lipid peroxidation, and DNA damage, and can decrease antioxidant levels in the lens, eventually accelerating the damage to the lens epithelial cells (LECs), resulting in subsequent cataract development [8C10]. With age, the lens undergoes several morphological, biochemical and physical changes [11], wherein thickness of the lens capsule as well as the accumulation of advanced glycation end products in the lens capsule increased [12C14], all of which may cause for the formation of ARC. Recent studies have reported that more senescent LECs were observed in the elderly ARC patients, thus oxidative stress induced cellular senescence may contribute to the development of ARC [15,16]. The lens capsule is usually a modified Praziquantel (Biltricide) basement membrane (BM) that completely surrounds the ocular lens. The normal lens capsule is mainly composed of laminin (LM) and type IV collagen [17C19]. Type I collagen is not detected in the capsule of normal lenses [20]. However, Type I collagen is usually expressed in cataractous lenses [21,22], and increases with Praziquantel (Biltricide) age in human lens capsules [23]. LMs are heterotrimers of , , and subunits drawn from a total of 5, 3, and 3 isoforms [24,25]. LM, which is the first BM component to appear during the early stages of embryonic development, promotes cell proliferation, migration, and differentiation [26,27]. In aged tissues, LM expression was decreased [28C30]; however, other studies have indicated that it was increased [31]. LM was highly expressed in the capsules of cataractous lenses [32,33]. Previous studies have demonstrated that this human adult lens capsule is composed of LM5-1, LM2-1, and LM1 Praziquantel (Biltricide) subunits [34]. The relationship between LM subunits and senescence was well analyzed in cells aside from LECs. One of our recent studies revealed that LM2, LM1, FKBP4 and LM1 were increased in senescent corneal endothelial cells [35]. LM1 was upregulated in senescent cardiac endothelial cells, while LM2 was downregulated [36]. LM1 and LM2 were found to be increased in the senescent cerebral vessels [37]. LM4 knockout mice displayed a senescent phenotype in skeletal neuromuscular junctions [38]. LM4 localization pattern was changed in senescent skeletal neuromuscular junctions, but its expression level was not reduced [39]. However, what LM subunits and how they contribute to the formation of cataract remains unclear. Matrix metalloproteinase-9 (MMP-9), a proteolytic enzyme, has been implicated in the progression of various kinds of cataracts, including anterior subcapsular cataract [40], posterior capsular opacification [41] and UVB-induced cataract [42]. MMP-9 could process LM and latent transforming growth factor-beta (TGF-). It promotes cell survival by degrading LMs in neuronal cells [43]. Furthermore, it increases the activation and transcription of TGF-1 during cardiac aging [44]. In addition, numerous LM peptides were able to induce MMP-9 expression [45,46]. LECs cultured on type I collagen-coated dishes exhibited high expression levels of the pro-form of MMP-9 [20]. However, there is currently no evidence that shows a potential role of MMP-9 in senescent LECs or in senescent lens capsules of ARC. TGF-1 is usually Praziquantel (Biltricide) involved in cell proliferation, migration, differentiation, and apoptosis as well as extracellular matrix accumulation in various cells [47,48]. It is present in the aqueous humor and vitreous, and is responsible for the induction of cataract and cell senescence at a relatively high concentration [49C53]. TGF-1 was highly expressed in LECs with kinds of cataracts, such anterior subcapsular cataract [54],.