NEDD4L facilitates granulosa cell ferroptosis by promoting GPX4 ubiquitination and degradation

Background: Polycystic ovary syndrome (PCOS) is an androgen disorder and ovarian dysfunction disease in women of reproductive age. The cell death of granulosa cells (GCs) plays an important role in the development of PCOS. However, the mechanism of GC death is still unclear. Methods: In the current study, NEDD4L was found to be elevated in PCOS GEO (Gene Expression Omnibus) databases and mouse models. The cell viability was analyzed by CCK-8 and FDA staining. The expression of ferroptosis markers was assessed by ELISA and immunofluorescence. The direct interaction of GPX4 and NEDD4L was verified by co-immunoprecipitation assay. Result: Functionally, results from CCK-8 and FDA staining demonstrated that NEDD4L inhibited the cell viability of KGN cells and NEDD4L increased the levels of iron, malonyldialdehyde, and reactive oxygen species and decreased glutathione levels. Moreover, the cell death of KGN induced by NEDD4L was blocked by ferroptosis inhibitor, suggesting that NEDD4L regulates KGN cell ferroptosis. Mechanistically, NEDD4L directly interacts with GPX4 and promotes GPX4 ubiquitination and degradation. Conclusion: Taken together, our study indicated that NEDD4L facilitates GC ferroptosis by promoting GPX4 ubiquitination and degradation and contributes to the development of PCOS

Aza boron-pyridyl-isoindoline analogues

Several aza boron-pyridyl-isoindoline analogues are synthesized through a facile and scale-up two step reaction using 1,2-naphthalenedicarbonitrile as a starting material. These analogues show broad envelopes of intense vibrational bands in the absorption spectra with moderate fluorescence quantum yields in solution and the solid-state. An analysis of the structure–property relationships is described based on X-ray crystallography, optical spectroscopy, and theoretical calculations

Replication of British Rheumatoid Arthritis Susceptibility Loci in Two Unrelated Chinese Population Groups

Previous genome-wide association study by WTCCC identified many susceptibility loci of common autoimmune diseases in British, including rheumatoid arthritis (RA). Because of the genetic heterogeneity of RA, it is necessary to replicate these susceptibility loci in other populations. Here, three SNPs with strong RA association signal in the British were analyzed in Han Chinese, and two SNPs (rs6457617 and rs11761231) were genotyped in the test cohort firstly. The rs6457617 was significantly associated with RA in the test cohort. The individuals bearing the homozygous genotype CC had 0.39-fold risk than these bearing the wild-type genotype TT ( = 0.004, OR 0.39, [95% CI 0.21-0.74]). And the protective effect of allele C was confirmed in another validation cohort with 1514 samples ( / = 5.9 × 10 −10 , OR 0.34, [95% CI 0.24-0.48]). The rs6457617 can be used as a tagSNP of HLA-DQA1 * 03 which encoded MHC-II chain. Since MHC restriction is important for primary T-cells in positive selection and negative selection stages, MHC protein polymorphisms may be implicated in shaping the T-cell repertoire, including the emergence of a T-cell clone involved in the inflammatory arthritis

Replication of British Rheumatoid Arthritis Susceptibility Loci in Two Unrelated Chinese Population Groups

Previous genome-wide association study by WTCCC identified many susceptibility loci of common autoimmune diseases in British, including rheumatoid arthritis (RA). Because of the genetic heterogeneity of RA, it is necessary to replicate these susceptibility loci in other populations. Here, three SNPs with strong RA association signal in the British were analyzed in Han Chinese, and two SNPs (rs6457617 and rs11761231) were genotyped in the test cohort firstly. The rs6457617 was significantly associated with RA in the test cohort. The individuals bearing the homozygous genotype CC had 0.39-fold risk than these bearing the wild-type genotype TT (P=0.004, OR 0.39, [95% CI 0.21–0.74]). And the protective effect of allele C was confirmed in another validation cohort with 1514 samples (Pgenotye CC/TT=5.9   ×  10−10, OR 0.34, [95% CI 0.24–0.48]). The rs6457617 can be used as a tagSNP of HLA-DQA1*03 which encoded MHC-II α chain. Since MHC restriction is important for primary T-cells in positive selection and negative selection stages, MHC protein polymorphisms may be implicated in shaping the T-cell repertoire, including the emergence of a T-cell clone involved in the inflammatory arthritis

Association of gestational age at birth with subsequent suspected Developmental Coordination Disorder in early childhood

Importance. It remains unknown whether children born at different degrees of prematurity, early-term and post-term might have a higher risk of developing Developmental Coordination Disorder (DCD) compared to completely full-term children (39-40 gestational weeks). Objective. To differentiate between suspected DCD in children with different gestational ages based on a national representative sample in China. DESIGN, SETTING, AND PARTICIPANTS We conducted a retrospective cohort study in China from 2018 to 2019. A total of 152,433 children from 2,403 public kindergartens in 551 cities of China aged 3-5 years old were included in the final analysis. The association between gestational age and motor performance was investigated. A multi-level regression model was developed to determine the strength of association for different gestational ages associated with suspected DCD when considering kindergartens as clusters. Main outcomes and measures. Children’s motor performance was assessed using the Little Developmental Coordination Disorder Questionnaire (LDCDQ), completed by parents. Gestational age was determined according to the mother’s medical records. Results. Of the 152,433 children aged 3-5 years old, 80,370 (52.7%) were male, and 72,063 (47.3%) were female. There were 45,052 children aged 3 years old (29.6%), 59,796 aged 4 years old(39.2%), and 47,585 children aged 5 years old (31.2%). The LDCDQ total scores for very-preterm (β=-1.74, 95%CI: -1.98, 1.50; p<0.001), moderately-preterm (β=-1.24, 95%CI: -1.60, -0.89; p<0.001), late-preterm (β=-0.92, 95%CI: -1.08, -0.76; p<0.001), early-term (β=-0.36, 95%CI: -0.46, -0.25; p<0.001) and post-term children (β=-0.47, 95%CI: -0.67, -0.26; p<0.001) were significantly lower than full-term children when adjusting for child, family and maternal health characteristics. The very-preterm (OR=1.35, 95%CI: 1.23,1.48; p<0.001), moderately-preterm (OR=1.18, 95%CI: 1.02, 1.36; p<0.001), late-preterm (OR =1.24, 95%CI: 1.16,1.32; p<0.001), early-term (OR =1.11, 95%CI: 1.06,1.16; p<0.001) and post-term children (OR =1.167, 95%CI: 1.07, 1.27; p<0.001) were more likely to fall in the suspected Developmental Coordination Disorder (DCD) category on the LDCDQ compared with completely full-term children after adjusting for the same characteristics. The associations between different gestational ages and suspected DCD were stronger in boys and older (5 year old) children (each p<0.05). Conclusions and relevance. We found significant associations between every degree of prematurity at birth, early-term and post-term birth with suspected DCD when compared with full-term birth. Our findings have important implications for understanding motor development in children born at different gestational ages. Long-term follow-up and rehabilitation interventions should be considered for early- and post-term born children

Trans-ethnic and Ancestry-Specific Blood-Cell Genetics in 746,667 Individuals from 5 Global Populations

Most loci identified by GWASs have been found in populations of European ancestry (EUR). In trans-ethnic meta-analyses for 15 hematological traits in 746,667 participants, including 184,535 non-EUR individuals, we identified 5,552 trait-variant associations at p &lt; 5 × 10−9, including 71 novel associations not found in EUR populations. We also identified 28 additional novel variants in ancestry-specific, non-EUR meta-analyses, including an IL7 missense variant in South Asians associated with lymphocyte count in vivo and IL-7 secretion levels in vitro. Fine-mapping prioritized variants annotated as functional and generated 95% credible sets that were 30% smaller when using the trans-ethnic as opposed to the EUR-only results. We explored the clinical significance and predictive value of trans-ethnic variants in multiple populations and compared genetic architecture and the effect of natural selection on these blood phenotypes between populations. Altogether, our results for hematological traits highlight the value of a more global representation of populations in genetic studies. Delineation of the genetic architecture of hematological traits in a multi-ethnic dataset allows identification of rare variants with strong effects specific to non-European populations and improved fine mapping of GWAS variants using the trans-ethnic approach

Inhibitory Effect of a Novel Antirheumatic Drug T-614 on the IL-6-Induced RANKL/OPG, IL-17, and MMP-3 Expression in Synovial Fibroblasts from Rheumatoid Arthritis Patients

T-614 (also named as iguratimod), a novel antirheumatic drug, could attenuate joint inflammation and articular damage in rheumatoid arthritis (RA) patients, providing a new therapy for RA. Here, we tested the role T-614 on the IL-6-induced receptor activator of nuclear factor B ligand (RANKL)/osteoprotegerin (OPG), IL-17, and MMP-3 expression in synovial fibroblasts from rheumatoid arthritis (RASFs) patients. T-614 decreased RANKL expression and RANKL/OPG ratio in IL-6-induced RASFs. We confirmed this effect by a decrease of the mRNA and protein RANKL and mRNA RANKL/OPG in RASFs exposed in vitro to T-614 or MTX. Markedly decreased levels of IL-17, retinoid-related orphan receptor C (RORc), and MMP-3 mRNA expression were also observed in IL-6-induced RASFs in the presence of T-614 or MTX compared with those in its absence. Furthermore, T-614 blocked expression of p-ERK1/2 protein without affecting ERK1/2 expression, indicating that the way that T-614 regulated RANKL expression might be ERK1/2 pathway. Our results suggest that T-614 yields a strong improvement in arthritis via exact suppression of RANKL/OPG, IL-17, and MMP-3 expression in RASFs

Metabolomics Reveal That the High Application of Phosphorus and Potassium in Tea Plantation Inhibited Amino-Acid Accumulation but Promoted Metabolism of Flavonoid

As leaf-harvest plants, tea trees show unique nutrient requirements, different from those of corn and other field crops. However, the effects of nitrogen (N), phosphorus (P), and potassium (K) application on the accumulation of quality-related compounds and the mechanisms underlying how nutrients affect tea-leaf metabolism have not been well elucidated. Here, fertilizers with different N, P, K ratios were applied to tea plants in pot experiments, and metabolomics based on gas chromatography-mass spectrometry (GC-MS) combined with multivariate statistical and quantitative detections were conducted to assess the responses of quality-related compounds to NPK in tea leaves. An increased proportion of P and K was beneficial for the accumulation of carbohydrates and catechins in shoots, although the total carbon content did not increase significantly. In contrast, a high proportion of P and K input reduced the relative chlorophyll content in shoots, and the contents of free amino acids such as theanine and glutamic acid negatively correlated with P and K nutrient content. Moreover, the metabolism of malic acid in the tricarboxylic acid cycle was highly promoted by increasing the application of P and K. These results validate our suggestion that the application of high amounts of P and K in tea plantations induces the biased reallocation of photosynthates and carbohydrates to the catechin pathway by promoting malic acid metabolism in young tea shoots, which further affects tea quality. The results of this study provide theoretical ground for tea quality improvement by optimizing fertilization strategies

Exotic medicinal plants from the Silk Road promote the diversification of traditional Chinese medicines

Background: As a political, economic, and cultural exchange channel between ancient China and countries in Asia, Europe, and Africa, the Silk Road has promoted political, trade, and cultural exchanges between China and foreign countries in Chinese history and also promoted the development of traditional Chinese medicine. Methods: This article summarizes the introduction of medicinal materials from the Han to Qing Dynasties, spanning approximately 2000 years. Results: A total of 235 types of medicinal plant materials were imported. An analysis of 178 medicinal herbs of known origin, belonging to 72 families revealed their effectiveness in treating 20 diseases. The maximum number of medicinal herbs used to treat gastrointestinal and digestive disorders (GAS) was 122. The applications and origin of exotic medicinal materials, including draconis sanguis and olibanum have changed during the development of the Silk Road. Imported medicinal materials are affected by five factors, including local demand, adaptability, cultural exchange, scarcity, and medical theory. Five modes for introducing medicinal materials include the onshore Silk Road, the maritime Silk Road, diplomatic envoys and gifts, overseas Chinese, cultural exchange, and medical integration. The application of exotic medicinal materials expands the resources and application fields of traditional Chinese medicine, enriching the theory of traditional Chinese medicine. Conclusion: Traditional Chinese medicinal compounds introduced to China through the ancient Silk Road not only promoted their integration into foreign medicine but also had long-lasting impacts to date and over a wide range, thereby considerably affecting the pharmaceutical and general healthcare industries