Mesenchymal stem cells (MSCs) are a group of multipotent cells with key properties of multi-lineage differentiation, expressing a set of relatively specific surface markers and unique immunomodulatory functions. IDO1, a catabolic enzyme of tryptophan, represents a critical molecule mediating immunomodulatory functions of MSCs. However, the signaling pathways involved in regulating these key properties still remain elusive. To investigate the involvement of Notch signaling as well as other potential signaling pathway(s) in regulating these critical properties of MSCs, we treated human umbilical cord-derived mesenchymal stem cells (hUC-MSCs) with γ-secreatase inhibitor I (GSI-I), which inhibits both Notch signaling and ubiquitin-proteasome activities. It was shown that the GSI-I treatment resulted in apoptosis, reduced expression of surface markers CD73, CD90 and CD105, reduced osteogenic differentiation, and reduction of the hUC-MSCs-mediated suppression of Th1 lymphocyte proliferation and the IFN-γ-induced IDO1 expression. Through distinguishing the effects of GSI-I between Notch inhibition and proteasome inhibition, it was further observed that, whereas both Notch inhibition and proteasome inhibition were attributable to the reduced CD105 expression and osteogenic differentiation, but not to the induced apoptosis. However, Notch inhibition, but not proteasome inhibition, only contributed to the significant effect of GSI-I on Th1 proliferation probably through reducing IDO1 promoter activity. In conclusion, the Notch signaling may represent a very important cell signaling capable of regulating multiple critical properties, especially the immunomodulatory functions of MSCs.

BackgroundTo evaluate the distribution of biometric parameters and corneal astigmatism using the IOLMaster device before phacoemulsification in cataract patients in Central China.MethodsConsecutive cataract patients were recruited at the Central Hospital of Wuhan between January 2015 and June 2016. Ocular axial length (AL), keratometry values, anterior chamber depth (ACD) and horizontal corneal diameter (white to white [WTW]) of each cataract-affected eye were measured with the IOLMaster device.ResultsThe study evaluated 3209 eyes of 2821 cataract patients. The mean AL, ACD, and WTW were 24.38 ± 2.47 mm, 3.15 ± 0.48 mm, and 11.63 ± 0.43 mm, respectively. Corneal astigmatism of 0.51–1.00 diopters (D) was the most common range of values (34.96%). A total of 10.56% patients exhibited a corneal astigmatism greater than 2.0 D. The flat and steep keratometry values gradually increased with age. The mean ACD and WTW showed increasing trends as the AL increased (P < 0.001). When the AL was shorter than 26.0 mm, the keratometry decreased as AL increased. The against-the-rule (ATR) astigmatism proportion increased with age and the with-the-rule (WTR) astigmatism proportion decreased with age.ConclusionsThe profile of ocular biometric data and corneal astigmatism may help ophthalmologists improve their surgical procedures and make an appropriate IOL choice to gain a high quality of postoperative vision.

The transient receptor potential cation channel, subfamily V, member 5 (TRPV5) gene, which encodes the Ca 2ϩ channel in the apical membrane of distal convoluted tubule and connecting tubule of the kidney, exhibits an unusually high frequency of nonsynonymous single nucleotide polymorphisms (SNPs) among African Americans. To assess the functional impacts of the nonsynonymous SNP variations in TRPV5, these variants were analyzed with radiotracer 45 (15,16,27). Mice lacking Trpv5 resulted in a 6-to 10-fold increase in urinary Ca 2ϩ excretion, and ultimately in defects in bone mineralization (16).Urinary Ca 2ϩ excretion is an important factor for kidney stone formation and bone health. For instance, urine Ca 2ϩ excretion correlates with bone loss in calcium-stone-forming patients with idiopathic hypercalciuria (3). Interestingly, African Americans exhibit lower urinary Ca 2ϩ excretion than whites (8,25,29,34,35,40,45), and the risk of kidney stones in African American is lower than that in whites (32,36,38). Furthermore, African Americans have higher bone mass (5, 41) and lower incidence of osteoporosis-related fractures than whites (4, 6, 7). The mechanism underlying the lowered urinary Ca 2ϩ in African Americans is not well understood. A lower 25-hydroxyvitamin D concentration in African Americans could result in an increased parathyroid hormone level and in turn renal Ca 2ϩ conservation. However, Braun and colleagues (8) observed significantly lower urinary Ca 2ϩ excretion in adolescent African American girls than white girls in a wide range of controlled Ca 2ϩ intake, whereas the 25-hydroxyvitamin D, 1,25-dihydroxyvitamin D and parathyroid hormone values were not significantly different between the two groups. The difference in bone mass and urinary Ca 2ϩ excretion between blacks and whites is not restricted to Americans; a similar finding was reported in South Africa (10). Thus genetic rather than social and environmental factors may play a major role in the superior renal Ca 2ϩ conservation mechanism in African descendents.Because TRPV5 is a key protein that regulates Ca 2ϩ reabsorption, genetic variations of TRPV5 may influence urinary Ca 2ϩ excretion. Interestingly, TRPV5 gene is one of the four contiguous genes, including EPHB6, TRPV6, TRPV5, and KEL, in chromosome 7q34-35 with striking evidence of a recent selective sweep in European Americans based on the analysis on the single nucleotide polymorphisms (SNPs) of over 100 genes from 24 African Americans and 23 European Americans provided by SeattleSNPs program (1, 37). Akey and colleagues (2) further showed that the TRPV6 haplotype, defined by three nonsynonymous SNPs, is nearly fixed in populations outside Africa, suggesting that these variations may confer a selective advantage, e.g., efficiency in Ca 2ϩ absorption from dairy products or resistance to a pathogen, after early humans migrated out of Africa. The TRPV6 variant with the three nonsynonymous SNPs exhibited increased Ca 2ϩ transport ability and may play a role in absorptive hypercalciuria and ki...

TRPV5 is one of the two channels in the TRPV family that exhibit high selectivity to Ca(2+) ions. TRPV5 mediates Ca(2+) influx into cells as the first step to transport Ca(2+) across epithelia. The specialized distribution in the distal tubule of the kidney positions TRPV5 as a key player in Ca(2+) reabsorption. The responsiveness in expression and/or activity of TRPV5 to hormones such as 1,25-dihydroxyvitamin D3, parathyroid hormone, estrogen, and testosterone makes TRPV5 suitable for its role in the fine-tuning of Ca(2+) reabsorption. This role is further optimized by the modulation of TRPV5 trafficking and activity via its binding partners; co-expressed proteins; tubular factors such as calbindin-D28k, calmodulin, klotho, uromodulin, and plasmin; extracellular and intracellular factors such as proton, Mg(2+), Ca(2+), and phosphatidylinositol-4,5-bisphosphate; and fluid flow. These regulations allow TRPV5 to adjust its overall activity in response to the body's demand for Ca(2+) and to prevent kidney stone formation. A point mutation in mouse Trpv5 gene leads to hypercalciuria similar to Trpv5 knockout mice, suggesting a possible role of TRPV5 in hypercalciuric disorders in humans. In addition, the single nucleotide polymorphisms in Trpv5 gene prevalently present in African descents may contribute to the efficient renal Ca(2+) reabsorption among African descendants. TRPV5 represents a potential therapeutic target for disorders with altered Ca(2+) homeostasis.