Identification of copy number variations among fetuses with isolated ultrasound soft markers in pregnant women not of advanced maternal age.

BACKGROUND: Pathogenic (P) copy number variants (CNVs) may be associated with second-trimester ultrasound soft markers (USMs), and noninvasive prenatal screening (NIPS) can enable interrogate the entire fetal genome to screening of fetal CNVs. This study evaluated the clinical application of NIPS for detecting CNVs among fetuses with USMs in pregnant women not of advanced maternal age (AMA). RESULTS: Fetal aneuploidies and CNVs were identified in 6647 pregnant women using the Berry Genomics NIPS algorithm.Those with positive NIPS results underwent amniocentesis for prenatal diagnosis. The NIPS and prenatal diagnosis results were analyzed and compared among different USMs. A total of 96 pregnancies were scored positive for fetal chromosome anomalies, comprising 37 aneuploidies and 59 CNVs. Positive predictive values (PPVs) for trisomy 21, trisomy 18, trisomy 13, and sex chromosome aneuploidies were 66.67%, 80.00%, 0%, and 30.43%, respectively. NIPS sensitivity for aneuploidies was 100%. For CNVs, the PPVs were calculated as 35.59% and false positive rate of 0.57%. There were six P CNVs, two successfully identified by NIPS and four missed, of which three were below the NIPS resolution limit and one false negative. The incidence of aneuploidies was significantly higher in fetuses with absent or hypoplastic nasal bone, while that of P CNVs was significantly higher in fetuses with aberrant right subclavian artery (ARSA), compared with other groups. CONCLUSIONS: NIPS yielded a moderate PPV for CNVs in non-AMA pregnant women with fetal USM. However, NIPS showed limited ability in identifying P CNVs. Positive NIPS results for CNVs emphasize the need for further prenatal diagnosis. We do not recommend the use of NIPS for CNVs screening in non-AMA pregnant women with fetal USM, especially in fetuses with ARSA.

Maternal, neonatal, pregnancy outcome characteristics of pregnant women with high plasma cell-free DNA concentration in non-invasive prenatal screening: a retrospective analysis.

Objective: Cell-free DNA (cfDNA) is a useful biomarker in various clinical contexts. Herein, we aimed to identify maternal characteristics and pregnancy outcomes associated with a failed NIPS test due to high cfDNA concentrations. Methods: A retrospective study of cases with high plasma cfDNA concentration in pregnant women in which NIPS test was performed (from 174,318 cases). We reported the detection of 126 cases (118 with complete clinical information) in which the high amount of cfDNA did not allow the performance of NIPS and study the possible causes of this result. Results: 622 (0.35%) of 174,318 pregnant women had failed the NIPS test, including 126 (20.3%) cases with high plasma cfDNA concentrations. The failed NIPS due to high plasma cfDNA concentrations was associated with maternal diseases and treatment with low-molecular-weight heparin (LMWH). Further follow-up of the 118 pregnant women in the case group revealed that the pregnancy outcomes included 31 premature deliveries, 21 abortions. The cfDNA concentrations of pregnant women with preterm deliveries were 1.15 (0.89, 1.84), which differed significantly from those who had full-term deliveries. Conclusions: Among pregnant women with high cfDNA concentrations, systemic autoimmune diseases, pregnancy complications and LMWH were associated with increased incidence of failed NIPS test. High maternal cfDNA concentrations may not be associated with chromosomal abnormalities in the fetus. However, they should be alerted to the possibility of preterm births and stillbirths. Further clinical studies on pregnant women with high cfDNA concentrations are required.

Maternal and fetal factors influencing fetal fraction: A retrospective analysis of 153,306 pregnant women undergoing noninvasive prenatal screening.

Background: Genetic factors are important causes of birth defects. Noninvasive prenatal screening (NIPS) is widely used for prenatal screening of trisomy 21, trisomy 18, and trisomy 13, which are the three most common fetal aneuploidies. Fetal fraction refers to the proportion of cell-free fetal DNA in maternal plasma, which can influence the accuracy of NIPS. Elucidating the factors that influence fetal fraction can provide guidance for the interpretation of NIPS results and genetic counseling. However, there is currently no broad consensus on the known factors that influence fetal fraction. Objective: The study aimed to explore the maternal and fetal factors influencing fetal fraction. Methods: A total of 153,306 singleton pregnant women who underwent NIPS were included. Data on gestational age; maternal age; body mass index (BMI); z-scores for chromosomes 21, 18, and 13; and fetal fraction in NIPS were collected from the study population, and the relationships between fetal fraction and these factors were examined. The relationship between fetal fraction and different fetal trisomy types was also analyzed. Results: The results showed that the median gestational age, maternal age, and BMI of the pregnant women were 18 (16, 20) weeks, 29 (25, 32) years, and 22.19 (20.40, 24.24) kg/m2, respectively. The median fetal fraction was 11.62 (8.96, 14.7)%. Fetal fraction increased with gestational age and decreased with maternal age and BMI (P < 0.001). Fetal fraction of fetuses with trisomies 21, 18, and 13 was similar to that of the NIPS-negative group. The z-scores of pregnant women with trisomy 21 and 18 fetuses were positively correlated with fetal fraction, but not with that of the trisomy 13 cases. Conclusions: The factors that influence fetal fraction need to be taken into consideration before NIPS for quality control and after NIPS for result interpretation.

Large-scale assessment of exposure to legacy and emerging per- and polyfluoroalkyl substances in China's shorebirds.

Emerging per- and polyfluoroalkyl substances (PFAS) have become more widely applied, whereas legacy PFAS such as PFOS continue to distribute ubiquitously in the environment. Large-scale assessment of wildlife exposure to both emerging and legacy PFAS plays a key role in effective biomonitoring to better discriminate regional contamination patterns and provide early warnings. Using eggs of two closely-related shorebird species collected across China during the breeding season in 2021, we constructed contrasting PFAS levels and profiles in coastal versus inland populations. The highest ∑PFAS concentrations were found in two Kentish plover (Charadrius alexandrinus) populations from the Bohai Sea, a semi-enclosed shallow bay located in northeast China. These two populations showed exceptionally high PFOA concentrations (mean: 94 and 121 ng/g wet weight; West and North Bohai Sea, respectively) dominating the overall PFAS profile (66% for both). This pattern is characteristic, compared to that of other seabird eggs worldwide. By comparison, PFAS profile in the white-faced plover (Charadrius dealbatus) population at the South China Sea coast was dominated by PFOS (46%), which showed similar levels to those at the North Bohai Sea coast (mean: 29 and 20 ng/g, respectively). PFAS concentrations of Kentish plovers from the remote Qinghai Lake were lower compared to the three coastal populations, and were dominated by PFNA (mean: 2.6 ng/g, 29%) and PFOS (mean: 2.5 ng/g, 27%). None of the eggs analyzed in the present study exceeded estimated toxicity reference values for PFOS or PFOA. Additionally, the emerging 6:2 Cl-PFESA was detected in eggs from all regions, while its concentrations were highest in the Bohai Sea populations, and short-chain PFBS was only detected in the North Bohai Sea population. Our results indicate intensive local emissions of PFOA and emerging PFAS at the Bohai Sea region, and warrant further investigation and monitoring.

Global ocean contamination of per- and polyfluoroalkyl substances: A review of seabird exposure.

Per- and polyfluoroalkyl substances (PFAS) have been extensively produced and used as surfactants and repellents for decades. To date, the global contamination pattern of PFAS in marine biota has seldomly been reviewed. Seabirds are ideal biomonitoring tools to study environmental contaminants and their effects. Here, we compiled and synthesized reported PFAS concentrations in various seabird species to reflect spatiotemporal patterns and exposure risks of major PFAS on a global ocean scale. Perfluorooctane sulfonic acid (PFOS) was the most studied PFAS in seabirds, which showed the highest level in eggs of common guillemots (U. aalge) from the Baltic Sea, followed by great cormorants (P. carbo) from the North Sea and double-crested cormorants (P.auritus) from the San Francisco Bay, whereas the lowest were those reported for Antarctic seabirds. The temporal pattern showed an overall higher level of PFOS in the late 1990s and early 2000s, consistent with the phase-out of perfluorooctane sulfonyl fluoride-based products. Maximum liver PFOS concentrations in several species such as cormorants and fulmars from Europe and North America exceeded the estimated toxicity reference values. Systematic evaluations using representative species and long time-series are necessary to understand contamination patterns in seabirds in South America, Africa, and Asia where information is lacking. In addition, limited research has been conducted on the identification and toxic effects of novel substitutes such as fluorotelomers and ether PFAS (F-53B, Gen-X etc.) in seabirds. Further research, including multi-omics analysis, is needed to comprehensively characterize the exposure and toxicological profiles of PFAS in seabirds and other wildlife.

Long-read Oxford nanopore sequencing reveals a de novo case of complex chromosomal rearrangement involving chromosomes 2, 7, and 13.

BACKGROUND: Complex chromosomal rearrangements (CCRs) are associated with high reproductive risk, infertility, abnormalities in offspring, and recurrent miscarriage in women. It is essential to accurately characterize apparently balanced chromosome rearrangements in unaffected individuals. METHODS: A CCR young couple who suffered two spontaneous abortions and underwent labor induction due to fetal chromosomal abnormalities was studied using long-read sequencing(LRS), single-nucleotide polymorphism (SNP) array, G-banding karyotype analysis (550-band resolution), and Sanger sequencing. RESULTS: SNP analysis of the amniotic fluid cells during the third pregnancy revealed a 9.9-Mb duplication at 7q21.11q21.2 and a 24.8-Mb heterozygous deletion at 13q21.1q31.1. The unaffected female partner was a carrier of a three-way CCR [46,XX,? ins(7;13)(q21.1;q21.1q22)t(2;13)(p23;q22)]. Subsequent LRS analysis revealed the exact breakpoint locations on the derivative chromosomes and the specific method of chromosome rearrangement, indicating that the CCR carrier was a more complex structural rearrangement comprising five breakpoints. Furthermore, LRS detected an inserted fragment of chromosome 13 in chromosome 7. CONCLUSIONS: LRS is effective for analyzing the complex structural variations of the human genome and may be used to clarify the specific CCRs for effective genetic counseling and appropriate intervention.

Evaluation of the effects of Ipomoea staphylina on ovarian cancer cell line.

Ovarine cancer is a common woman malignancy in the world. Majority of the ovarian cancers are originated in the epithelial region which are lack of symptomps and this type of cancer is often get localized, when the tumour has spread outside the pelvis. Based on this context, the present study evaluated the effects of both aqueous and ethanolic extracts of Ipomoea staphylina leaves on ovarian cancer cell line. The SKOV-3 ovarian cancer cell line was used for evaluation of the effects of both extracts. Both extracts showed IC50 effects on ovarian cancer cell lines as sensitivity index (SI) for both extracts were recorded to above 1.iFurther, ethanol extract was more effective in the moderation of gene expressions of matrix metalloproteinase-2 (MMP-2) and matrix metalloproteinase-9 (MMP-9) in comparison to aqueous extract. Further, morphological changes of SKOV-3 cells after treatment with both extracts also confirmed the results. The study, therefore, concludes that the ethanolic extract of Ipomoea staphylina leaves is more effective against ovarian cancer cell line.

Performance of noninvasive prenatal screening in twin pregnancies: a retrospective study of 5469 twin pregnancies.

OBJECTIVES: To evaluate the performance of noninvasive prenatal screening (NIPS) for the fetal common aneuploidy screening in twin pregnancies. METHODS: The data of 5469 women with twin pregnancies were collected in this retrospective observational study between January 2017 and December 2018. Patients underwent NIPS as first-line screening or after standard serum screening for fetal aneuploidy. The performance of NIPS was examined, and a regression analysis was performed to investigate testing failure in cases of low fetal fraction. RESULTS: In this study, 2231 (40.8%) patients opted for NIPS as the primary prenatal screening test, and 3238 (59.2%) opted for serum screening, including 440 patients who opted for NIPS after serum screening. Among the 2671 pregnancies with available NIPS outcomes, 11 cases of aneuploidy were identified, seven of trisomy 21 and four of sex chromosome aneuploidy (SCA). The sensitivity and specificity for trisomy 21 were 100% (95% CI, 56.1-100.0%) and 100% (95% CI, 99.8-100.0%), respectively. The positive predictive value (PPV) for SCA was 40.0% (95% CI, 13.7-72.6%). No false negatives were found, with a negative predictive value (NPV) of 100% (95% CI, 99.8-100.0%) in total. In 32 pregnancies who failed NIPS test without available NIPS outcomes due to low fetal fraction, the regression analysis demonstrated that increasing BMI and assisted reproductive technology treatment were significant independent predictors. CONCLUSIONS: NIPS is a high-performing routine primary prenatal screening test in twin pregnancies, with a high PPV and low false positive rate for detecting trisomy 21. It is also useful to identify common sex chromosome aneuploidies in twin pregnancies, with similar performance to that reported in singleton pregnancy.

Dysregulation of Circulating miR-24-3p in Children with Obesity and Its Predictive Value for Metabolic Syndrome.

INTRODUCTION: Obesity is a major risk factor for metabolic disorders in children. Therefore, it is particularly important to study the abnormal regulation of circulating miR-24-3p in obese children and its predictive value for metabolic syndrome. METHODS: Serum samples were obtained from children with obesity (n = 45), obese children with metabolic syndrome (n = 52), and healthy controls (n = 50). The expression levels of miR-24-3p were detected by reverse transcription quantitative PCR. The ROC curve was used to evaluate the diagnostic value of miR-24-3p. Pearson's correlation analysis was performed to evaluate the relationship between serum miR-24-3p and different clinical parameters. Logistic regression analysis was used to evaluate the relationship between miR-24-3p and obesity with metabolic syndrome in children. RESULTS: The expression of miR-24-3p was the highest in obese children with metabolic syndrome. ROC results showed that miR-24-3p had the ability to distinguish healthy individuals from obese children (area under the curve [AUC] = 0.951) and can predict the occurrence of metabolic syndrome for obese children (AUC = 0.890). The expression level of miR-24-3p was positively correlated with body mass index (r = 0.817, p < 0.001), fasting blood glucose (r = 0.798, p < 0.001), triglycerides (r = 0.773, p < 0.001), systolic blood pressure (r = 0.746, p < 0.001), and diastolic blood pressure (r = 0.623, p < 0.001), respectively. Logistic regression analysis showed that miR-24-3p was an independent influence factor for the occurrence of metabolic syndrome in obese children. DISCUSSION/CONCLUSION: MiR-24-3p is a potential noninvasive marker for children with obesity and has predictive value for the occurrence of metabolic syndrome.

Follow-up in Patients With Non-invasive Prenatal Screening Failures: A Reflection on the Choice of Further Prenatal Diagnosis.

BACKGROUND: Our aim was to provide a theoretical basis for clinicians to conduct genetic counseling and choose further prenatal diagnosis methods for pregnant women who failed non-invasive prenatal screening (NIPS). METHODS: A retrospective analysis was performed on pregnant women who had failed NIPS tests. RESULTS: Among the 123,291 samples, 394 pregnant women did not obtain valid results due to test failures. A total of 378 pregnant women were available for follow-up, while 16 patients were lost to follow-up. Of these 378, 135 pregnant women chose further prenatal diagnosis through amniocentesis, and one case of dysplasia was recalled for postpartum chromosome testing. The incidence rate of congenital chromosomal abnormalities in those who failed the NIPS was 3.97% (15/378), which was higher than that of the chromosomal abnormalities in the common population (1.8%). Among the pregnant women who received prenatal diagnosis, the positive rates of chromosomal abnormalities in the chromosomal microarray analysis/copy number variation sequencing (CMA/CNV-seq) group and in the karyotyping group were 15.28 and 4.76%, respectively. CONCLUSION: Prenatal diagnosis should be strongly recommended in posttest genetic counseling for pregnant women with NIPS failures. Further, high-resolution detection methods should be recommended for additional prenatal diagnoses.

Regio- and Enantioselective Ni-Catalyzed Formal Hydroalkylation, Hydrobenzylation, and Hydropropargylation of Acrylamides to α-Tertiary Amides.

The development of enantioselective alkyl-alkyl cross-couplings with coinstantaneous formation of a stereogenic center without the use of sensitive organometallic species is attractive yet challenging. Herein, we report the intermolecular regio- and enantioselective formal hydrofunctionalizations of acrylamides, forging a stereogenic center α-position to the newly formed Csp3 -Csp3 bond for the first time. The use of a newly developed chiral ligand enables the electronically-reversed formal hydrofunctionalizations, including hydroalkylation, hydrobenzylation, and hydropropargylation, offering an efficient way to access diverse enantioenriched amides with a tertiary α-stereogenic carbon center which is facile to racemize. This operationally simple protocol allows for the anti-Markovnikov enantioselective hydroalkylation, and unprecedented hydrobenzylation, hydropropargylation under mild conditions with excellent functional group compatibility, delivering a wide range of amides with excellent levels of enantioselectivity.

Noninvasive Prenatal Screening Based on Second-Trimester Ultrasonographic Soft Markers in Low-Risk Pregnant Women.

Background: We aimed to assess the clinical application of noninvasive prenatal screening (NIPS) based on second-trimester ultrasonographic soft markers (USMs) in low-risk pregnant women. Methods: Data of pregnant women between April 2015 and December 2019 were retrospectively analyzed. Pregnant women [age at expected date of confinement (EDC) of <35 years; low risks for trisomy 21 (T21) and trisomy 18 (T18) based on maternal serum screening; presenting second-trimester USMs (7 types)] who successfully underwent NIPS and had available follow-up information were included in our study. Cases with positive NIPS results were prenatally diagnosed. All patients were followed up for 6 months to 2 years after NIPS, and their clinical outcomes were obtained. Subgroup analyses were performed according to the different USMs. Results: NIPS suggested that among a total of 10,023 cases, 37 (0.37%) were at high risk of aneuploidy, including 4 T21, 6 trisomy 13 (T13), and 27 sex chromosome abnormalities (SCA). Ten cases with aneuploidy (0.10%) were confirmed by prenatal diagnosis, consisting of two T21 and eight SCA. The eight fetuses with SCA consisted of one monosomy X, two XXY, one XXXY, one XXX, one XYY, and two mosaicisms. T21 was detected in one fetus with absent or hypoplastic nasal bone and one fetus with echogenic intracardiac focus (EICF). SCA was detected in five fetuses with EICF, two fetuses with multiple soft markers, and one fetus with echogenic bowel. The positive rate of chromosomal aneuploidy was significantly higher in fetuses with absent or hypoplastic nasal bone (6.25 vs. 0.10%, p = 0.017), echogenic bowel (3.7 vs. 0.10%, p = 0.029), and multiple soft markers (0.678 vs. 0.10%, p = 0.045) than in the total fetuses. The positive predictive values (PPVs) of NIPS in these three groups were 100%, 50%, and 100%, respectively. EICF accounted for 93.25% (9,346/10,023) of the study population, whereas the PPV of NIPS was only 20%. Conclusion: NIPS is an advanced screening test for low-risk pregnant women. In the 10,023 pregnant women sampled, SCA were more common than autosomal trisomy, and EICF was the most frequent USM but the least predictive aneuploidy. Further aneuploidy evaluation is suggested for low-risk pregnant women whose ultrasound indicates absent or hypoplastic nasal bone, echogenic bowel, or multiple soft markers. NIPS can serve as a second-line complementary screening for these women.

Clinical Selection of Prenatal Diagnostic Techniques Following Positive Noninvasive Prenatal Screening Results in Southwest China.

Background: This study aims to evaluate prenatal diagnosis methods following positive noninvasive prenatal screening (NIPS) results. Methods: According to the positive noninvasive prenatal screening results, 926 pregnant women were divided into three groups: main target disease group (high risk for trisomy 21, trisomy 18, or trisomy 13), sex chromosome aneuploidy (SCA) group, and other chromosomal abnormalities group [abnormal Z-scores for chromosomes other than trisomy (T)21/T18/T13 or SCAs]. The verification methods and results were then retrospectively analysed. Results: In the main target disease group, the positive rate of chromosomal abnormalities confirmed by quantitative fluorescence polymerase chain reaction (QF-PCR) was 75.18% (212/282), which was not significantly different from that by karyotyping (79.36%, 173/218) and copy number variation (CNV) detection methods (71.43%, 65/91). The positive rate of additional findings confirmed by karyotyping and copy number variation detection methods in main target disease group was 0.46% (1/218) and 8.79% (8/91), respectively. The positive rate of chromosomal abnormalities confirmed by karyotyping and CNV detection methods were 27.11% (45/166) and 38.46% (95/247) in the SCA group and 4.17% (1/24) and 20% (36/180) in the other chromosomal abnormalities group, respectively. Fetal sex chromosome mosaicism was detected in 16.13% (20/124) of the confirmed SCA cases. There were no significant differences in the detection rates of chromosomal microarray analysis (CMA) and CNV sequencing (CNVseq) among the three groups (p > 0.05). Conclusion: QF-PCR can quickly and accurately identify aneuploidies following NIPS-positive results for common aneuploidy, and in combination with karyotyping and CNV detection techniques can provide more comprehensive results. With the NIPS-positive results for SCA or other abnormalities, CMA and CNVseq may have the same effect on increasing the detection rate. The addition of fluorescence in situ hybridization assay may help to identify true fetal mosaicism.

Rhein alleviates renal interstitial fibrosis by inhibiting tubular cell apoptosis in rats.

BACKGROUND: Ureteral obstruction causes injury of the renal tissues and can irreversibly progress to renal fibrosis, with atrophy and apoptosis of tubular cells. The goal of the current study was to examine the effects of rhein on the apoptosis o renal tubular cells as well as renal fibrosis using a rodent model of unilateral ureteral obstruction (UUO). METHODS: UUO was induced through ureteral ligation, then animals received treatments with rhein or vehicle. The control rats only received sham operation. The renal tissue was harvested 1 week after surgery for assessment of kidney fibrosis. RESULTS: The expressions of collagen I and α-smooth muscle actin (α-SMA), as well as the severity of renal tubular apoptosis and fibrosis were time-dependently increased following UUO. Treatments with rhein partially inhibited such responses. Renal interstitial fibrosis was associated with STAT3 (signal transducer and activator of transcription 3) phosphorylation as well as altered expressions of Bax and Bcl2, both apoptosis-related proteins. Treatment with rhein also partly blocked these responses. CONCLUSION: These findings demonstrated that rhein mitigated apoptosis of renal tubular cell as well as renal fibrosis in a UUO rodent model. This curative effect is likely mediated via suppression of STAT3 phosphorylation.

Clinical application of noninvasive prenatal screening for sex chromosome aneuploidies in 50,301 pregnancies: initial experience in a Chinese hospital.

To evaluate the clinical performance of noninvasive prenatal screening (NIPS) for fetal sex chromosome aneuploidies (SCAs), pregnant women were recruited in this retrospective observational study. The NIPS test was undertaken using high-throughput gene sequencing. In total,50,301 pregnant women were analysed for demographic characteristics and medical history. Of them, 308 women (0.61%) had high risk for fetal SCAs, including 138 for 45,X, 111 for 47,XXY, 42 for 47,XXX, and 17 for 47,XYY. After the pre-test counselling, 182 participants chose to undergo invasive prenatal diagnosis, confirming 59 positive cases. The combined positive predictive value of NIPS was 32.42% (59/182), 18.39% (16/87), 44.4% (12/27), 39.29% (22/56), and 75% (9/12) for detecting SCAs, 45,X, 47,XXX, 47,XXY, and 47,XYY, respectively. NIPS can be a useful method to detect the fetal SCAs using high-throughput gene sequencing, though accuracy can still be improved, especially for 45,X. Although the value of NIPS compare favorably with those seen in traditional screening approaches for SCAs, it is important to highlight the limitations of NIPS while educating clinicians and patients.

Nudel involvement in the high-glucose-induced epithelial-mesenchymal transition of tubular epithelial cells.

Nudel is a newly discovered factor related to cell migration. The tubular epithelial-mesenchymal transition (EMT) includes four steps: the loss of the adhesive properties of epithelial cells, the acquisition of a mesenchymal cell phenotype, the destruction of the tubular basal membrane, and the migration into the renal interstitium. The purpose of this study was to investigate the role of Nudel in the high-glucose-induced EMT of tubular epithelial cells. Human renal proximal tubular epithelial cells (HKCs) were treated with Nudel shRNA to clarify the role and mechanism of Nudel in tubular EMT induced by high glucose. We found that Nudel was expressed at a high level in high-glucose-stimulated HKCs, and the expression of Nudel was associated with the activation of signal transducer and activator of transcription 3. After transfection with Nudel shRNA, we detected the expression levels of E-cadherin, α-smooth muscle actin (α-SMA), and the Wiskott-Aldrich syndrome family of proteins (including WASP, N-WASP, WAVE1, WAVE2, and WAVE3) via assay. Cell migration was analyzed by the scratching method. The results showed that high glucose downregulated E-cadherin expression, upregulated α-SMA expression, and promoted the migration of HKCs. The expression levels of N-WASP, WAVE1, and WAVE2 were also elevated in HKCs treated with high glucose. All changes induced by high glucose were ameliorated by Nudel depletion. We conclude that Nudel participates in the transition and the migration of tubular epithelial cells via the regulation of WASP family proteins.

Rhein alleviates renal interstitial fibrosis by inhibiting tubular cell apoptosis in rats

BACKGROUND: Ureteral obstruction causes injury of the renal tissues and can irreversibly progress to renal fibrosis, with atrophy and apoptosis of tubular cells. The goal of the current study was to examine the effects of rhein on the apoptosis o renal tubular cells as well as renal fibrosis using a rodent model of unilateral ureteral obstruction (UUO). METHODS: UUO was induced through ureteral ligation, then animals received treatments with rhein or vehicle. The control rats only received sham operation. The renal tissue was harvested 1 week after surgery for assessment of kidney fibrosis. RESULTS: The expressions of collagen I and α-smooth muscle actin (α-SMA), as well as the severity of renal tubular apoptosis and fibrosis were time-dependently increased following UUO. Treatments with rhein partially inhibited such responses. Renal interstitial fibrosis was associated with STAT3 (signal transducer and activator of transcription 3) phosphorylation as well as altered expressions of Bax and Bcl2, both apoptosis-related proteins. Treatment with rhein also partly blocked these responses. CONCLUSION: These findings demonstrated that rhein mitigated apoptosis of renal tubular cell as well as renal fibrosis in a UUO rodent model. This curative effect is likely mediated via suppression of STAT3 phosphorylation.

TLR2 Plays a Critical Role in HMGB1-Induced Glomeruli Cell Proliferation Through the FoxO1 Signaling Pathway in Lupus Nephritis.

The objective of this study was to examine the role and possible mechanisms of toll-like receptor 2 (TLR2) in high-mobility group box chromosomal protein 1 (HMGB1)-induced mouse mesangial cell (MMC) proliferation and glomeruli proliferation of MRL/Fas(lpr) mice. First, the expression of proliferating cell nuclear antigen (PCNA), TLR2 and Forkhead box protein O1 (FoxO1) messenger RNA (mRNA) and protein in the glomeruli of MRL/Fas(lpr) mice was quantified, and the correlation with cell proliferation of glomeruli was analyzed. Then, lipopolysaccharide (LPS), TLR2 neutralization antibody, and small hairpin TLR2 (shTLR2) were used to confirm the role of TLR2 in HMGB1-induced MMC proliferation. Furthermore, wild-type FoxO1 (WT-FoxO1) vector was used to investigate the effect of FoxO1 pathway on HMGB1-induced MMC proliferation. Finally, electroporation was used to knockdown TLR2 in the glomeruli of MRL/Fas(lpr) mice, and renal function, FoxO1, and PCNA expression were detected. The results showed that the TLR2 expression was upregulated and FoxO1 expression was decreased in the glomeruli of MRL/Fas(lpr) mice, and these effects were significantly correlated with cell proliferation of the glomeruli. In vitro, the TLR2 neutralization antibody and the WT-FoxO1 vector, both reduced the MMC proliferation levels induced by HMGB1. The TLR2 neutralization antibody also blocked the HMGB1-dependent activation of the FoxO1 pathway and cell proliferation. In addition, transfection with shTLR2 decreased the proliferation levels and PCNA expression induced by HMGB1. In vivo, treatment with shTLR2 significantly reduced the PCNA expression in the glomeruli of MRL/Fas(lpr) mice and improved renal function. In addition, treatment with shTLR2 or blocking of TLR2 also reduced the translocation of FoxO1. Thus, TLR2 plays a critical role in HMGB1-induced glomeruli cell proliferation through the FoxO1 signaling pathway in lupus nephritis.

PTEN Inhibits High Glucose-Induced Phenotypic Transition in Podocytes.

Accumulating evidence has suggested that podocytes undergo epithelial-mesenchymal transition (EMT) in diabetic nephropathy (DN). However, the underlying mechanisms of EMT in podocyte are not well understood. PI3K/Akt pathway is involved in the progression of DN. In the present study, we demonstrated that PI3K/Akt pathway was activated in podocytes exposed to high glucose conditions, accompanied by down-regulation of the podocalyxin (PCX) and nephrin expression and up-regulation of the desmin and α-smooth muscle actin (α-SMA) expression. Inhibition of PI3K/Akt pathway by chemical LY294002 or Phosphase and tensin homology deleted on chromosome ten (PTEN) prevented the phenotypic transition. These findings indicate that PTEN/PI3K/Akt pathway mediates high glucose-induced phenotypic transition in podocytes.