Association between CBS gene T833C, G919A and 844ins68 polymorphisms in the 8th exon region and coronary artery disease: a meta-analysis.

BACKGROUND: Several studies indicate that the cystathionine ß-synthase (CBS) gene T833C, G919A and 844ins68 polymorphisms in the 8th exon region may be correlated with coronary artery disease (CAD) susceptibility, but the results have been inconsistent and inconclusive. Thus, a meta-analysis was conducted to provide a comprehensive estimate of these associations. METHODS: On the basis of searches in the PubMed, EMBASE, Cochrane Library, Wanfang, VIP, and CNKI databases, we selected 14 case - control studies including 2123 cases and 2368 controls for this meta-analysis. Pooled odds ratios (ORs) with 95% confidence intervals (CIs) were calculated accordingly using a fixed-effect or random-effect model. RESULTS: The results indicated an increased risk between the CBS T833C gene polymorphisms and susceptibility to CAD under the dominant model (CC+CT vs. TT: OR = 1.92, 95% CI: 1.11 ~ 3.32), recessive model (CC vs. CT+TT: OR = 1.88, 95% CI: 1.17 ~ 3.03), and homozygous model (CC vs. TT: OR = 2.46, 95% CI: 1.04 ~ 5.83). In these three genetic models, no significant association was identified for CBS G919A (AA+AG vs. GG: OR = 1.48, 95% CI: 0.45 ~ 4.82),(AA vs. AG+GG: OR = 1.58, 95% CI: 0.93 ~ 2.70),(AA vs. GG: OR = 1.66, 95% CI: 0.40 ~ 6.92) or CBS 844ins68 (II+ID vs. DD: OR = 1.04, 95% CI: 0.80 ~ 1.35),(II vs. ID+DD: OR = 1.09, 95% CI: 0.51 ~ 2.36),(II vs. DD: OR = 1.10, 95% CI: 0.51 ~ 2.39). CONCLUSIONS: This meta-analysis suggests that the CBS T833C gene polymorphism is significantly associated with the risk of CAD and it shows a stronger association in Asian populations. Individuals with the C allele of the CBS gene T833C polymorphism might be particularly susceptible to CAD.

Record-Efficiency Printable Hole-Conductor-Free Mesoscopic Perovskite Solar Cells Enabled by the Multifunctional Schiff Base Derivative.

Tailoring multifunctional additives for performing interfacial modifications, improving crystallization, and passivating defects is instrumental for the fabrication of efficient and stable perovskite solar cells (PSCs). Here, a Schiff base derivative, (chloromethylene) dimethyliminium chloride (CDCl), is introduced as an additive to modify the interface between the mesoporous TiO2 electron transport layer and the MAPbI3 light absorber during the annealing process. CDCl chemically links to TiO2 and MAPbI3 through coordination and hydrogen bonding, respectively, and results in the construction of fast electron extraction channels. CDCl also optimizes the energy-level alignment of the TiO2/MAPbI3 heterojunction and improves the pore-filling and crystallization of MAPbI3 in the mesoscopic scaffold, which inhibits nonradiative recombination and eliminates open-circuit voltage losses. As a result, an impressive power conversion efficiency of 19.74%, which is the best one ever reported, is obtained for printable carbon-based hole-conductor-free PSCs based on MAPbI3.

Fetal bovine serum inhibits neomycin-induced apoptosis of hair cell-like HEI-OC-1 cells by maintaining mitochondrial function.

Aging and exposure to noise or ototoxic drugs are major causes of hair cell death leading to human hearing loss, and many agents have been developed to protect hair cells from apoptosis. Fetal bovine serum (FBS) is a fundamental ingredient in the culture medium of hair cell-like House Ear Institute Organ of Corti 1 (HEI-OC-1) cells, but there have been no reports about the function of FBS in HEI-OC-1 cell apoptosis. In this study, we found that FBS deprivation alone significantly increased HEI-OC-1 cell apoptosis in the absence of neomycin exposure and that the presence of FBS significantly inhibited HEI-OC-1 cell apoptosis after neomycin exposure compared to FBS-deprived cells. Further, we found that the protective effect of FBS was dose dependent and more effective than the growth factors B27, N2, EGF, bFGF, IGF-1, and heparan sulfate. We also found that FBS deprivation significantly disrupted the expression level of mitochondrial proteins, increased pro-apoptotic gene expression, decreased the mitochondrial membrane potential, and increased reactive oxygen species accumulation in HEI-OC-1 cells after neomycin exposure. These findings indicate that FBS is involved in maintaining the level of mitochondrial proteins, maintaining the balance of oxidant gene expression, and preventing the accumulation of ROS, and thus FBS maintains normal mitochondrial function and inhibits apoptosis in HEI-OC-1 cells after neomycin exposure.

Blebbistatin Inhibits Neomycin-Induced Apoptosis in Hair Cell-Like HEI-OC-1 Cells and in Cochlear Hair Cells.

Aging, noise, and ototoxic drug-induced hair cell (HC) loss are the major causes of sensorineural hearing loss. Aminoglycoside antibiotics are commonly used in the clinic, but these often have ototoxic side effects due to the accumulation of oxygen-free radicals and the subsequent induction of HC apoptosis. Blebbistatin is a myosin II inhibitor that regulates microtubule assembly and myosin-actin interactions, and most research has focused on its ability to modulate cardiac or urinary bladder contractility. By regulating the cytoskeletal structure and reducing the accumulation of reactive oxygen species (ROS), blebbistatin can prevent apoptosis in many different types of cells. However, there are no reports on the effect of blebbistatin in HC apoptosis. In this study, we found that the presence of blebbistatin significantly inhibited neomycin-induced apoptosis in HC-like HEI-OC-1 cells. We also found that blebbistatin treatment significantly increased the mitochondrial membrane potential (MMP), decreased ROS accumulation, and inhibited pro-apoptotic gene expression in both HC-like HEI-OC-1 cells and explant-cultured cochlear HCs after neomycin exposure. Meanwhile, blebbistatin can protect the synaptic connections between HCs and cochlear spiral ganglion neurons. This study showed that blebbistatin could maintain mitochondrial function and reduce the ROS level and thus could maintain the viability of HCs after neomycin exposure and the neural function in the inner ear, suggesting that blebbistatin has potential clinic application in protecting against ototoxic drug-induced HC loss.

Inner Ear Hair Cell Protection in Mammals against the Noise-Induced Cochlear Damage.

Inner ear hair cells are mechanosensory receptors that perceive mechanical sound and help to decode the sound in order to understand spoken language. Exposure to intense noise may result in the damage to the inner ear hair cells, causing noise-induced hearing loss (NIHL). Particularly, the outer hair cells are the first and the most affected cells in NIHL. After acoustic trauma, hair cells lose their structural integrity and initiate a self-deterioration process due to the oxidative stress. The activation of different cellular death pathways leads to complete hair cell death. This review specifically presents the current understanding of the mechanism exists behind the loss of inner ear hair cell in the auditory portion after noise-induced trauma. The article also explains the recent hair cell protection strategies to prevent the damage and restore hearing function in mammals.

Distinctive microRNA expression in early stage nasopharyngeal carcinoma patients.

The goal of this study was to investigate microRNAs (miRs) expression at different stages of nasopharyngeal carcinoma (NPC). MiR expression profiling at various stages of NPC was performed by miR array and further verified using quantitative real-time RT-PCR. Pathway enrichment analysis was carried out to identify the functional pathways regulated by the miRs. The expression of a selected group of identified miRs was verified in stage I NPC by in situ hybridization (ISH). A total of 449 miRs were identified with significantly different expressions between NPC tissues and normal pharyngeal tissues. Eighty-four miRs were dysregulated only in stage I NPC, among which 45 miRs were up-regulated and the other 39 were down-regulated. Pathway enrichment assay revleaed that three significantly down-regulated and three significantly up-regulated miRs involved in 12 pathways associating with tumour formation and progression. Quantitative RT-PCR confirmed the miR array result. In addition, the low expression levels of hsa-miR-4324, hsa-miR-203a and hsa-miR-199b-5p were further validated in stage I NPC by ISH. This present study identifed the miR signature in stage I NPC, providing the basis for early detection and treatment of NPC.

[The role of Th9, Th17 and Treg cells on pathogenesis of nasal polyps].

OBJECTIVE: To investigate the expression levels of Th9, Th17 and Treg cells in peripheral blood of patients with chronic rhinosinusitis with nasal polyps (CRSwNP), and explore the role of Th9, Th17 and Treg cells in the progression of CRSwNP. METHOD: Forty-six cases with CRSwNP served as an experimental group, while 22 cases with simple nasal bleeding or nasal septum deviation served as a control group. The peripheral blood of patients in both groups was collected and analyzed. (1) Using flow cytometry (FCM) to detect the expression rates of Th9, Th17 and Treg cells in peripheral blood. (2) Using qRT-PCR to detect the expression of relevant transcription factor of Th9, Th17 and Treg cells (IL-9mRNA, PU. 1, IRF-4, RoRc, and Foxp3). (3) Using SPSS16.0 to analyse the differentiations and the revelance among these three cells. RESULT: (1) The expression rates of Th9 and Th17 cells in patients with CRSwNP (1.29% ± 0.18%, 4.03% ± 0.69%) was higher than the control group (0.45% ± 0.14%, 1.35% ± 0.26%). But the expression rates of Treg cells in the experimental group (2.98% ± 0.13%) was significantly lower than the control group (5.44% ± 0.57%). The differences were statistically significant (P < 0.05). (2) The expression of revelant transcription factor (IL-9mRNA, PU.1, IRF-4, RoRc) in NP group was also higher than the control group. The expression of Foxp3 in the control group was higher than NP, the differences both were statistically significant (P < 0.05). (3) The difference between Th9 and Th17 in patients with NP was not significant (P > 0.05), and the negative correlation was found between Th17 and Treg (r = -0.549, P < 0.05). CONCLUSION: The high expression level of Th9 and Th17 cells might promote the development of NP, whereas the low expression level of Treg cells might further aggravate the occurrence of NP. The main function of the imbalance of Th17/Treg cells may be immune regulation in the pathogenesis of nasal polys.

Transcription factors in the development of inner ear hair cells.

Inner ear hair cells are the sensory receptors that detect and convert sound vibrations and head movements into neural signals. However, in humans, these cells are unable to regenerate if they are damaged or lost. Over thepast decade,there has been an exponential increase in interest and progress in understanding of the development of the inner ear and of hair cells, aiming to gain insights into hair cell repair or even regeneration. In hair cell development, various transcription factors have been found to be involved in the processes of hair cell proliferation, differentiation and survival. Among these transcription factors, Math1, Gata3, Sox2 and Atoh1 have been highlighted for their crucial role in the fate of hair cells. In this article, we will summarize the current understanding of the role of transcription factors in hair cell development, focusing on the role and possible mechanisms of Math1, Gata3, Sox2 and Atoh1.

FGF22 protects hearing function from gentamycin ototoxicity by maintaining ribbon synapse number.

Inner hair cell (IHC) ribbon synapses of cochlea play important role in transmitting sound signal into auditory nerve and are sensitive to ototoxicity. However, ototoxic damage of ribbon synapses is not understood clearly. Roles of fibroblast growth factor 22 (FGF22) on synapse formation were explored under gentamycin ototoxicity. 6-week-old mice were injected intraperitoneally once daily with 50-150 mg/kg gentamicin for 10 days. Immunostaining with anti- GluR2&3/CtBP2 was used to estimate the number of ribbon synapses in the cochlea. Expression of FGF22 and myocyte enhancer factor 2D (MEF2D) was assayed with RT-PCR. Expression and localization of FGF22 protein were visualized with anti-FGF22 immunostaining. Hearing thresholds were assessed using auditory brainstem responses. Gentamicin administration caused reduction in ribbon synapse number and hearing impairment without effect on hair cells in CBA/J mouse model. Immunohistochemistry showed that FGF22 protein was expressed in IHCs, but not OHCs of cochlea. Gentamycin attenuated expression of FGF22 but enhanced expression of MEF2D. Cochlear infusion of recombinant FGF22 inhibited expression of MEF2D, preserved ribbon synapses, and restored hearing function impaired by gentamycin. FGF22 restores hearing loss through maintaining ribbon synapse number, likely via inhibition of MEF2D. Activating FGF22 might provide the conceptual basis for the therapeutic strategies.

[The expression of IL-9, IL-17 and Foxp3 in nasal polyps].

OBJECTIVE: To observe the expression of IL-9, IL-17 and Foxp3 in nasal polyps,so that to explore the role of Th9, Th17/Treg cells imbalance in pathogenesis of nasal polyposis. METHOD: Forty cases of nasal polyps and 20 cases of normal middle turbinate mucosa (controls) were involved in this study. The expression patterns of IL-9, IL-17 and Foxp3 were detected by immunohistochemistry. RESULT: The positive rates of IL-9 and IL-17 in nasal polyps tissues were respectively 75.0% and 80.0%, which were both significantly higher than those in the controls (positive rates were 35.0% and 50.0%, respectively), but the Foxp3 expression was downregulated in nasal polyps tissues (37.5%) compared to the controls (80.0%), P < 0.05 respectively. CONCLUSION: The cytokines IL-9 and IL-17 are obviously involved in the occurrence and development of nasal polyposis, suggesting remarkable infiltration of Th9 and Th17/Treg imbalance exist in nasal polyps, both of which may play important roles in pathogenesis of nasal polyposis.

[The expression and correlation of inducible nitric oxide synthase, Bax and Bcl-2 in nasal polyps].

OBJECTIVE: To detect the expressions of inducible nitric oxide synthase (iNOS), apoptosis-related gene Bax, Bcl-2 in nasal polyps,and discuss the their relationship. METHOD: The apoptosis of 30 cases of nasal polyps was detected by TUNEL assay. The expressions of iNOS and Bax, Bcl-2 was detected by immunohistochemical SABC method. The expressions of iNOS and Bax, Bcl-2 was measured by western blot. RESULT: 1) The weakly positive stained apoptotic cells were detected at the surface epithelial cells and glandular epithelial cells of nasal polyps by TUNEL assay. 2) Immunohistochemical method revealed that positive stainings of iNOS, Bax, Bcl-2 located in the cytoplasm of epithelial cells, glandular epithelial cells, endothelial cells and infiltrating inflammatory cells in nasal polyps. The expression of Bax was weak, while the expressions of iNOS and Bcl-2 were strong. 3) iNOS, Bcl-2 and Bax was detected by western blot. The expressions of these proteins were significantly different (P<0.01). The expression of iNOS and Bcl-2 had a positive correlation (r=0.851, P<0.01), while the expression of iNOS and Bax had a negative correlation (r=-0.714, P<0.01). CONCLUSION: The pro-apoptotic and anti-apoptotic proteins are co-existed in the nasal polyps, iNOS may play an important role in the pathogens of nasal polyps through inhibition of apoptosis.

Sterol transfer by ABCG5 and ABCG8: in vitro assay and reconstitution.

ATP-binding cassette transporters G5 and G8 are half-transporters expressed on the apical membranes of enterocytes and hepatocytes that limit intestinal uptake and promote secretion of neutral sterols. Genetic defects that inactivate either half-transporter cause accumulation of cholesterol and plant sterols, resulting in premature coronary atherosclerosis. These observations suggest that G5 and G8 promote the translocation of sterols across membranes, but the primary transport substrate of the G5G8 complex has not been directly determined. Here we report the development of a sterol transfer assay using "inside-out" membrane vesicles from Sf9 cells expressing recombinant mouse G5 and G8. Radiolabeled cholesterol or sitosterol was transferred from donor liposomes to G5- and G8-containing membrane vesicles in an ATP-dependent and vanadate-sensitive manner; net transfer of cholesterol was associated with an increase in vesicular cholesterol mass. CTP, GTP, and UTP, as well as ATP, supported transfer but with lesser efficiency (ATP >> CTP > GTP > UTP). Transfer was specific for sterols and was stereoselective; minimal ATP-dependent and vanadate-sensitive transfer of cholesteryl oleate, phosphatidylcholine, or enantiomeric cholesterol was observed. These studies indicate that G5 and G8 are sufficient for reconstitution of sterol transfer activity in vitro and provide the first demonstration that sterols are direct transport substrates of the G5 and G8 heterodimer.

Effect of erythromycin on contractile response of uterine smooth muscle strips in non-pregnant rats.

OBJECTIVE: Erythromycin stimulates stomach smooth muscle contraction via action on motilin receptors, but the effects of erythromycin on non-pregnant uterine smooth muscle are unknown. The purpose of this study was to assess the effect of erythromycin on non-pregnant uterine smooth muscle and to examine the possible mechanism of its action. STUDY DESIGN: Uterine smooth muscle strips from rats were suspended in organ baths containing Krebs solution, and then isometric tension was measured. The response to erythromycin and the effect of hexamethonium, indomethacin, phentolamine, diphenhydramine, atropine, metoclopramide and verapamil on erythromycin-induced contraction were also assessed. RESULTS: The present study showed for the first time that erythromycin dose-dependently increased contractile frequency, and at a dose of 1.55 x 10(-3) mol/l it also increased contractile tension in non-pregnant uterine smooth muscle strips in rats. These actions were not affected by pretreatment with hexamethonium, indomethacin, phentolamine, atropine and metoclopramide, but histamine H1 receptor blocker diphenhydramine and calcium channel blocker verapamil inhibited both responses induced by erythromycin. CONCLUSION: Our results suggest that erythromycin could increase contractile frequency and tension of non-pregnant uterine smooth muscle via histamine H1 receptor and calcium channel.

Effects of Dangshen on isolated gastric muscle strips in rats.

AIM:To study the effects of Dangshen dried root of Codonopsis Pilosula (Franch) Nannf on contractile activity of isolated gastric muscle strips in rats and its possible mechanism involved.METHODS:Each isolated gastric muscle strip was put in a tissue chamber containing 5ml Krebs solution, constantly warmed by water jacket at 37?mgr; and supplied with a mixed gas of 95% O(2) and 5% CO(2). After incubating for 1h with 1g tension, Dangshen of varied concentration was added cumulatively in the tissue chamber at intervals of 2 minutes. The isometrical response was measured on ink-writing recorders.RESULTS:Dangshen dose dependence increased the resting tension of longitudinal muscle (LM) of fundus (r =0.96, P < 0.01), the mean contractile amplitude of circular muscle (CM) of the stomach body (r =0.87, P < 0.05) and CM of antrum (r =0.98, P < 0.01), and the motility index CM of pylorus(r =0.87, P < 0.05). Atropine (5 10( 8)mol/L) or Hexamethonium (10( 5)mol/L) or Indomethacin (5 10( 7)mol/L) was given 2 minutes before the administration of Dangshen, it did not abolish its dose related manner. Atropine apparently reduced the increasing action of 10% and 30% Dangshen on the resting tesion of LM of fundus (P < 0.05), 30%, 100% and 200% Dangshen on bodied strips (P < 0.05), 100% and 200% Dangshen on antral strips (P < 0.05).Hexamethonium reduced the increasing action of 10% and 30% Dangshen on the resting tesion of LM of fundus (P < 0.05 and P < 0.05), 30%, 100% and 200% Dangshen on bodied strips (P < 0.05), and 100% and 200% Dangshen on pyloric strips (P < 0.05). Indomethacin inhibited the effect of 10% Dangshen on the resting tesion of LM of fundus (P < 0.05), but did not affect the exciting action of Dangshen on strips of body, antrum and pylorus.CONCLUSION:The results showed that Dangshen possessed exciting action on the isolated gastric smooth muscle strips of the rat.The exciting action of Dangshen was partially mediated via cholinergic M and N receptors.