Inhibition of PARP1 improves cardiac function after myocardial infarction via up-regulated NLRC5.

The incidence and mortality rate of myocardial infarction are increasing per year in China. The polarization of macrophages towards the classically activated macrophages (M1) phenotype is of utmost importance in the progression of inflammatory stress subsequent to myocardial infarction. Poly (ADP-ribose) polymerase 1(PARP1) is the ubiquitous and best characterized member of the PARP family, which has been reported to support macrophage polarization towards the pro-inflammatory phenotype. Yet, the role of PARP1 in myocardial ischemic injury remains to be elucidated. Here, we demonstrated that a myocardial infarction mouse model induced cardiac damage characterized by cardiac dysfunction and increased PARP1 expression in cardiac macrophages. Inhibition of PARP1 by the PJ34 inhibitors could effectively alleviate M1 macrophage polarization, reduce infarction size, decrease inflammation and rescue the cardiac function post-MI in mice. Mechanistically, the suppression of PARP1 increase NLRC5 gene expression, and thus inhibits the NF-κB pathway, thereby decreasing the production of inflammatory cytokines such as IL-1ß and TNF-α. Inhibition of NLRC5 promote infection by effectively abolishing the influence of this mechanism discussed above. Interestingly, inhibition of NLRC5 promotes cardiac macrophage polarization toward an M1 phenotype but without having major effects on M2 macrophages. Our results demonstrate that inhibition of PARP1 increased NLRC5 gene expression, thereby suppressing M1 polarization, improving cardiac function, decreasing infarct area and attenuating inflammatory injury. The aforementioned findings provide new insights into the proinflammatory mechanisms that drive macrophage polarization following myocardial infarction, thereby introducing novel potential targets for future therapeutic interventions in individuals affected by myocardial infarction.

NLRP3 Inflammasome: A Potential Target in Isoflurane Pretreatment Alleviates Stroke-Induced Retinal Injury in Diabetes.

Ischemic stroke remains a devastating disease which is the leading cause of death worldwide. Visual impairment after stroke is a common complication which may lead to vision loss, greatly impacting life quality of patients. While ischemic stroke is traditionally characterized by a blockage of blood flow to the brain, this may coincide with reduced blood flow to the eye, resulting in retinal ischemia and leading to visual impairment. Diabetes increases the risk of ischemic stroke and induces diabetic retinopathy; the latter may be more sensitive to the ischemic retinal injury. In diabetic status, the underlying mechanism in stroke-induced retinal injury has not been fully clarified. The NLR pyrin domain containing 3 (NLRP3) inflammasome is an important activator of inflammation, which may play a critical role in catalyzing and forming certain pro-inflammatory cytokines in both cerebral and retinal ischemia. Isoflurane has been demonstrated to inhibit the activation of the NLRP3 inflammasome and show neuroprotective effects. In this study, we established a diabetic mouse model and performed the middle cerebral artery occlusion procedure to induce ischemic stroke. Our results revealed that cerebral ischemia-induced retinal injury in the diabetic model. Isoflurane pretreatment alleviated the cerebral and retinal injury after ischemic stroke. Of note, isoflurane pretreatment inhibited the NLRP3 inflammasome activation in the retina, indicating that isoflurane pretreatment may provide substantial retinal protection in stroke-induced retinal injury in diabetes.

Investigation of miR-490-3p Expression in Hepatocellular Carcinoma Based on Reverse Transcription-Polymerase Chain Reaction (RT-qPCR) and a Meta-Analysis of 749 Cases.

BACKGROUND miR-490-3p could play vital roles in multiple cancers. However, the role of miR-490-3p in hepatocellular carcinoma (HCC) remains uncertain. In this study, we sought to explore the underlying role of miR-490-3p in HCC. MATERIAL AND METHODS In this study, we explored the clinical role of miR-490-3p in HCC via quantitative reverse transcription-polymerase chain reaction (RT-qPCR) and The Cancer Genome Atlas (TCGA) database. Then, a meta-analysis was performed to evaluate the expression trend and diagnostic value of miR-490-3p in HCC. Furthermore, 12 miRNA prediction algorithms were applied to predict the potential target genes of miR-490-3p. The differentially expressed genes in HCC in the Gene Expression Profiling Interactive Analysis (GEPIA) database were also selected. Additionally, bioinformatics analyses were utilized to investigate the possible functions and pathways of the target genes. RESULTS miR-490-3p was clearly down-regulated in HCC based on RT-qPCR (P=0.002). Consistent with the results of RT-qPCR, miR-490 was more highly expressed in normal liver tissue than in HCC (P<0.001). Additionally, the meta-analysis confirmed the results from RT-qPCR and TCGA. Furthermore, based on the prediction algorithms and GEPIA, a total of 113 genes were selected. According to the bioinformatics analyses, we found that the most remarkably enriched functional terms included protein transport, poly(A) RNA binding, and intracellular organelle part. Additionally, the miR-490-3p target genes were significantly related to the pathways in cancer. CONCLUSIONS We found that miR-490-3p is down-regulated in HCC and is related to genes that have potential tumoral functions. However, the exact mechanism should be confirmed by functional experiments.

Reactive postural control deficits in patients with posterior parietal cortex lesions after stroke and the influence of auditory cueing.

OBJECTIVE: The purpose of this study was to investigate the ways in which stroke-induced posterior parietal cortex (PPC) lesions affect reactive postural responses and whether providing auditory cues modulates these responses. DESIGN: Seventeen hemiparetic patients after stroke, nine with PPC lesions (PPCLesion) and eight with intact PPCs (PPCSpared), and nine age-matched healthy adults completed a lateral-pull perturbation experiment under noncued and cued conditions. The activation rates of the gluteus medius muscle ipsilateral (GMi) and contralateral to the pull direction, the rates of occurrence of three types of GM activation patterns, and the GMi contraction latency were investigated. RESULTS: In noncued pulls toward the paretic side, of the three groups, the PPCLesion group exhibited the lowest activation rate (56%) of the GMi (P < 0.05), which is the primary postural muscle involved in this task, and the highest rate of occurrence (33%) of the gluteus medius muscle contralateral-activation-only pattern (P < 0.05), which is a compensatory activation pattern. In contrast, in cued pulls toward the paretic side, the PPCLesion group was able to increase the activation rate of the GMi to a level (81%) such that there became no significant differences in activation rate of the GMi among the three groups (P > 0.05). However, there were no significant differences in the GM activation patterns and GMi contraction latency between the noncued and cued conditions for the PPCLesion group (P > 0.05). CONCLUSIONS: The PPCLesion patients had greater deficits in recruiting paretic muscles and were more likely to use the compensatory muscle activation pattern for postural reactions than the PPCSpared patients, suggesting that PPC is part of the neural circuitry involved in reactive postural control in response to lateral perturbations. The auditory cueing used in this study, however, did not significantly modify the muscle activation patterns in the PPCLesion patients. More research is needed to explore the type and structure of cueing that could effectively improve patterns and speed of postural responses in these patients.

Synthesis and spectroscopic properties of some novel BODIPY dyes.

BODIPY dyes have some unique properties including high fluorescence quantum yield, large extinction coefficiency, narrow absorption and emission band. However, most of BODIPY dyes display short emission wavelength and small Stokes shift, which limits their applications in biosensing and bioimaging in vivo. For bioimaging application, a fluorescent dye with long emission wavelength and large Stokes shift is highly desired. To push the absorption and emission spectrum of BODIPY to red and even far-red region, a COOEt group was introduced to the meso position, and some aromatic group was attached to the 3, 5 position of BODIPY core. The structure of resulting compounds were comfirmed by 1H NMR, 13C NMR and HR-MS. Dye-1 displays a strong UV-Vis absorption band centered at 536 nm and a sharp emission band is located at 592 nm, which is significantly red-shifted (80 nm) compared to ordinary BODIPY analogs. In addition, the meso-COOEt substituted BODIPYs exhibit high quantum yield and red to far-red emission. Notably surprisingly, the meso-COOEt substituted BODIPYs display almost separated UV-Vis absorption and emission spectra with a large Stokes shift (-60 nm). Time-dependent density functional theory calculations were conducted to understand the structure-optical properties relationship, and it was revealed that the large Stokes shift was resulted from the geometric change from the ground state to the first excited singlet state. The spectroscopic properties of these BODIPY dyes display very subtle solvent-dependence effect. Furthermore, BODIPY was tested for its ability of imaging in living cells. The results indicate that Dye-1 is a water-soluble and membrane-permeable probe. Therefore, these BODIPYs are a new family dyes with excellent spectroscopic properties and can be good candidates for bioimaging in living cells.

Constitutional complex chromosomal rearrangements in azoospermic men--case report and literature review.

Complex chromosomal rearrangements are very rare and may lead to spermatogenic defect. We report on an infertile man with complex constitutional chromosomal rearrangements. The chromosomal breakpoints were located at 9p22, 13q22, and 21p11. This is the seventh case, to our knowledge, of complex chromosome rearrangements in a man presenting with a spermatogenic defect. The spermatogenic defect may be ascribed to disruption of sterile genes during chromosomal breakage or abnormal meiotic segregation of the rearranged chromosomes.

Expression patterns of the DAZ-associated protein DAZAP1 in rat and human ovaries.

OBJECTIVE: To evaluate the expression of DAZAP1 (deleted in azoospermia-associated protein 1) in rat and human ovaries. DESIGN: Experimental study. SETTING: University hospital. PATIENT(S): Twelve corpus luteum (CL) specimens were collected during operation, either by laparoscopic surgery for CL rupture or by laparotomy for benign gynecologic conditions. INTERVENTION(S): Surgical excision of 12 human CL. MAIN OUTCOME MEASURE(S): Proteins analyzed by immunohistochemical staining, Western blotting, and co-immunoprecipitation experiments. RESULT(S): DAZAP1 is expressed in rat and human luteal cells. Expression of DAZAP1 decreases with advancing stages of CL. Co-immunoprecipitation experiments show in vivo interaction of DAZ-like (DAZL) protein with DAZAP1 in the ovarian tissues. CONCLUSION(S): The expression patterns of DAZAP1 and DAZL are identical within rat and human ovaries. In mammalian species, DAZAP1 may be involved in diverse reproductive functions, ranging from cell cycle regulation and maturation of oocytes to differentiation of luteal cells.

Isochromosome of Yp in a man with Sertoli-cell-only syndrome.

OBJECTIVE: To address phenotype/genotype correlation in a man with i(Y)(p10). DESIGN: Case report. SETTING: University-based reproductive genetics laboratory. PATIENT(S): A 27-year-old azoospermic man with i(Y)(p10), relatively normal stature, and testicular Sertoli-cell-only syndrome. INTERVENTION(S): Testicular biopsy, cytogenetic study, Y-chromosome deletion mapping analysis, fluorescence in situ hybridization (FISH). MAIN OUTCOME MEASURE(S): Expression of Y-chromosome genes. RESULT(S): We have identified one azoospermic man with i(Y)(p10) of 312 Taiwanese men presenting with a severe spermatogenic defect. Y-chromosome deletion mapping analysis confirmed deletions of all Yq sequences, including a putative growth controlling gene. Fluorescence in situ hybridization (FISH) analysis showed duplication of Yp material. The patient had normal stature considering midparental height. He also had no germ cells in the testicular tissue (Sertoli-cell-only syndrome) resulting from the loss of azoospermia factor in Yq. CONCLUSION(S): Among structural rearrangements of the Y-chromosome, the isochromosome of Yp occurs very rarely. This case is the first reported case of an isochromosome Yp with a detailed description of testicular histology and body height.

Ring (Y) in two azoospermic men.

We have identified two azoospermic men with r(Y) in 312 infertile men presenting with non-obstructive azoospermia or oligozoospermia. Their karyotypes were 45,X [9]/46,X, r(Y)(p11q11) [11] (case 1), and 46,X,r(Y)(p11q11) (case 2), respectively. In both cases, the Yp breakpoints were located within the pseudoautosomal region. Both cases had extensive deletions of azoospermia factors (AZFs). Case 1 also had deletion of the putative growth controlling gene (GCY) and the Yq breakpoint was located between sY741 and USP9Y. The Yq breakpoint was located between sY105 and sY109 in case 2. Both cases did not have Turner stigmata except short stature in case 1. By a combination of cytogenetic and molecular genetic tools, we showed r(Y) arose from breakage in both arms of the chromosome with subsequent fusion of two broken ends of the centric fragment to form a continuous ring. Spermatogenic defects in men with r(Y) may result from deletion of Y-linked AZFs combined with synaptic failure.

Cytogenetic surveillance of mentally-retarded school children in southern Taiwan.

BACKGROUND AND PURPOSE: Mental retardation (MR), defined as having an IQ of less than 70, is present in approximately 2 to 3% of the population. Data on chromosomal abnormalities, an important cause of MR, are limited in the Taiwanese literature. This study evaluated the frequency and pattern of chromosomal abnormalities in school children with MR in southern Taiwan. METHODS: Peripheral blood samples of 419 children were collected from November 1999 to January 2003. Those with Prader-Willi syndrome (PWS), Angelman syndrome (AS) or fragile-X syndrome were excluded from the study. Metaphase chromosome preparations were obtained from peripheral blood cultures, and trypsin-giemsa (GTG) banded chromosomes were examined at the level of 500 to 600 bands. Fluorescence in situ hybridization was done for cases whose karyotypes could not be determined by conventional cytogenetic analysis. RESULTS: Of the 419 enrollees with MR, 10 had mild MR, while most had moderate to profound MR. Chromosomal abnormalities were found in 22.43% of the cases, with trisomy 21 being the major chromosomal abnormality, occurring in 77 cases (18.38%, 77/419 cases). Sex chromosome aneuploidies were found in 3 cases (0.72%, 3/419 cases). Structural abnormalities of autosomes were found in 13 cases (3.10%, 13/419 cases), including deletion, markers, unbalanced translocations, and inversions. One subject was found to have monosomy 20 mosaicism (0.24%, 1/419). CONCLUSIONS: Chromosomal abnormalities occurred in a high proportion of mentally retarded school children from southern Taiwan, with trisomy 21 being the most prevalent. These findings indicate the need for increased attention to prenatal, perinatal and postnatal screening in this population.

Placental sonolucency and pregnancy outcome in women with elevated second trimester serum alpha-fetoprotein levels.

BACKGROUND AND PURPOSE: Women with unexplained elevation of serum alpha-fetoprotein (AFP) are at increased risk for adverse pregnancy outcomes, including small for gestational age neonate, preterm labor, abruptio placentae, preeclampsia, intrauterine fetal death, and congenital malformations. This study investigated the association between placental sonolucency, elevation of maternal serum AFP, and pregnancy outcomes. METHODS: Singleton pregnancies (n = 168) with second trimester serum AFP level >/= 2.0 weight-adjusted multiples of the median (MoM) were recruited as the study group. Women with second trimester serum AFP level between 0.4 and 2.0 weight-adjusted MoM (n = 150) served as controls. A maternal Kleihauer-Betke stain was obtained for all participants. All participants were prospectively evaluated and the pregnancy complications were assessed by chart analysis after delivery. RESULTS: Compared with control subjects, women with placental sonolucent areas were not at increased risk for pregnancy complications, while women without sonolucent areas had higher risk of pregnancy complications. Singleton pregnancies with elevated serum AFP level had increased incidence of feto-maternal hemorrhage when placental sonolucency was observed. CONCLUSIONS: Our data suggest that feto-maternal hemorrhage may be the major factor contributing to elevated maternal serum AFP levels in pregnancies carrying placental sonolucencies. Screening for pregnancies with both elevated serum AFP and placental sonolucencies would help to identify the low-risk cases and facilitate cost-effective obstetric management.