Search

Leber's hereditary optic neuropathy (LHON) is a maternally inherited eye disease. X-linked nuclear modifiers were proposed to modify the phenotypic manifestation of LHON-associated mitochondrial DNA (mtDNA) mutations. By whole-exome sequencing, we identified the X-linked LHON modifier (c.157C>T, p.Arg53Trp) in PRICKLE3 encoding a mitochondrial protein linked to biogenesis of ATPase in 3 Chinese families. All affected individuals carried both ND4 11778G>A and p.Arg53Trp mutations, while subjects bearing only a single mutation exhibited normal vision. The cells carrying the p.Arg53Trp mutation exhibited defective assembly, stability, and function of ATP synthase, verified by PRICKLE3-knockdown cells. Coimmunoprecipitation indicated the direct interaction of PRICKLE3 with ATP synthase via ATP8. Strikingly, cells bearing both p.Arg53Trp and m.11778G>A mutations displayed greater mitochondrial dysfunction than those carrying only a single mutation. This finding indicated that the p.Arg53Trp mutation acted in synergy with the m.11778G>A mutation and deteriorated mitochondrial dysfunctions necessary for the expression of LHON. Furthermore, we demonstrated that Prickle3-deficient mice exhibited pronounced ATPase deficiencies. Prickle3-knockout mice recapitulated LHON phenotypes with retinal deficiencies, including degeneration of retinal ganglion cells and abnormal vasculature. Our findings provided new insights into the pathophysiology of LHON that were manifested by interaction between mtDNA mutations and X-linked nuclear modifiers.

In this report, we investigated the pathogenic mechanism underlying the deafness-associated mitochondrial(mt) tRNAAsp 7551A > G mutation. The m.7551A > G mutation is localized at a highly conserved nucleotide(A37), adjacent (3') to the anticodon, which is important for the fidelity of codon recognition and stabilization in functional tRNAs. It was anticipated that the m.7551A > G mutation altered the structure and function of mt-tRNAAsp The primer extension assay demonstrated that the m.7551A > G mutation created the m1G37 modification of mt-tRNAAsp Using cybrid cell lines generated by transferring mitochondria from lymphoblastoid cell lines derived from a Chinese family into mitochondrial DNA(mtDNA)-less (ρo) cells, we demonstrated the significant decreases in the efficiency of aminoacylation and steady-state level of mt-tRNAAsp in mutant cybrids, compared with control cybrids. A failure in metabolism of mt-tRNAAsp caused the variable reductions in mtDNA-encoded polypeptides in mutant cybrids. Impaired mitochondrial translation led to the respiratory phenotype in mutant cybrids. The respiratory deficiency lowed mitochondrial adenosine triphosphate production and increased the production of oxidative reactive species in mutant cybrids. Our data demonstrated that mitochondrial dysfunctions caused by the m.7551A > G mutation are associated with deafness. Our findings may provide new insights into the pathophysiology of maternally transmitted deafness that was manifested by altered nucleotide modification of mitochondrial tRNA.

A rapid analytical method for the simultaneous determination of 550 pesticide residues in vegetable samples was developed based on ultra-high performance liquid chromatography-tandem Q/Orbitrap high-resolution mass spectrometry (UPLC-Q/Orbitrap-HRMS). To investigate the risk of exposure to pesticide residues through vegetable consumption, 704 leafy vegetable samples from Shanghai were analysed for multiple residues using this method. A total of 54 pesticide residues were identified in these vegetable samples and 302 samples contained one or more pesticide residue. The levels of the detected pesticides did not pose a health risk in the long term and were acceptable according to the results of the chronic dietary risk assessment. Risk rankings displayed that most of the pesticides were low to medium risk. The findings of this study provide a reference for future pesticide monitoring programmes. [ABSTRACT FROM AUTHOR]

Introduction: The comparison of fluticasone propionate/formoterol (FP/FORM) with fluticasone propionate/salmeterol (FP/SAL) for paediatric asthma remains controversial., Aim: We conduct a systematic review and meta-analysis to explore the efficacy and safety of FP/FORM versus FP/SAL for paediatric asthma., Material and Methods: We have searched PubMed, Embase, Web of science, EBSCO, and Cochrane library databases through August 2019 for randomized controlled trials (RCTs) assessing the effect of FP/FORM versus FP/SAL for paediatric asthma. This meta-analysis is performed using the random-effects model., Results: Three RCTs are included in the meta-analysis. Overall for paediatric asthma, FP/FORM and FP/SAL demonstrate a comparable influence on FEVj (Std. MD = -0.01; 95% CI: -0.04 to 0.03; p = 0.62), FVC (Std. MD = 0; 95% CI: -0.07 to 0.06; p = 0.87), FEF25 (Std. MD = -1.69; 95% CI: -6.69 to 3.31; p = 0.51), FEF50 (Std. MD = 0.10; 95% CI: -0.12 to 0.33; p = 0.37), FEF75 (Std. MD = 0.01; 95% CI: -0.21 to 0.24; p = 0.91), asthma symptom scores (Std. MD = -0.03; 95% CI: -0.11 to 0.04; p = 0.43), sleep disturbance scores (Std. MD = 0.03; 95% CI: -0.19 to 0.24; p = 0.81) and adverse events (RR = 1.07; 95% CI: 0.83 to 1.38; p = 0.61)., Conclusions: FP/FORM and FP/SAL show a comparable efficacy for paediatric asthma., Competing Interests: The authors declare no conflict of interest., (Copyright: © 2021 Termedia Sp. z o. o.)

The 1555A→G mutation in mitochondrial 12S rRNA has been associated with aminoglycoside-induced and non-syndromic deafness in many individuals worldwide. Mitochondrial genetic modifiers are proposed to influence the phenotypic expression of m.1555A→G mutation. Here, we report that a deafness-susceptibility allele (m.4317A→G) in the tRNA Ile gene modulates the phenotype expression of m.1555A→G mutation. Strikingly, a large Han Chinese pedigree carrying both m.4317A→G and m.1555A→G mutations exhibited much higher penetrance of deafness than those carrying only the m.1555A→G mutation. The m.4317A→G mutation affected a highly conserved adenine at position 59 in the T-loop of tRNA Ile We therefore hypothesized that the m.4317A→G mutation alters both structure and function of tRNA Ile Using lymphoblastoid cell lines derived from members of Chinese families (three carrying both m.1555A→G and m.4317A→G mutations, three harboring only m.1555A→G mutation, and three controls lacking these mutations), we found that the cell lines bearing both m.4317A→G and m.1555A→G mutations exhibited more severe mitochondrial dysfunctions than those carrying only the m.1555A→G mutation. We also found that the m.4317A→G mutation perturbed the conformation, stability, and aminoacylation efficiency of tRNA Ile These m.4317A→G mutation-induced alterations in tRNA Ile structure and function aggravated the defective mitochondrial translation and respiratory phenotypes associated with the m.1555A→G mutation. Furthermore, mutant cell lines bearing both m.4317A→G and m.1555A→G mutations exhibited greater reductions in the mitochondrial ATP levels and membrane potentials and increasing production of reactive oxygen species than those carrying only the m.1555A→G mutation. Our findings provide new insights into the pathophysiology of maternally inherited deafness arising from the synergy between mitochondrial 12S rRNA and tRNA mutations., (© 2018 by The American Society for Biochemistry and Molecular Biology, Inc.)

Objective: To investigate neuroendocrine differentiation and Wilms' tumor protein-1 (WT-1) expression in breast mucinous carcinoma and their clinicopathological significance., Methods: The clinicopathological data of 65 patients with breast mucinous carcinoma, including 31 cases of mixed mucinous carcinoma, 23 cases of hypocellular pure mucinous carcinoma and 11 cases of hypercellular pure mucinous carcinoma, admitted in Taizhou Hospital from January 2010 to June 2015 were retrospectively reviewed. The expression of neuroendocrine markers and WT-1 was detected by immunohistochemistry staining in all cases., Results: The mixed mucinous carcinomas and hypercelluar pure mucinous carcinomas had higher incidence of axillary lymph node metastasis and human epidermal recepter 2 (HER-2) positive than hypocellular pure mucinous carcinoma (all (P<0.01). However, the difference was not significant between mixed mucinous carcinomas and hypercellular pure mucinous carcinomas (all P>0.05). The expression of neuroendocrine marker was stronger in hypercellular mucinous carcinoma than that in mixed mucinous carcinoma and hypocellular mucinous carcinoma (all (P<0.05), but the difference was not statistically significant between mixed mucinous carcinoma and hypocellular pure mucinous carcinoma (P>0.05). The expression of WT-1 was weaker in mixed mucinous carcinoma than that in hypercellular and hypocellular pure mucinous carcinoma(all (P<0.05), but the difference was not statistically significant between hypercellular and hypocellular pure mucinous carcinoma (P>0.05). The mucinous carcinomas with lymph node metastasis had lower expression of neuroendocrine markers than those without lymph node metastasis ((P<0.01). The expression of WT-1 in breast mucinous carcinoma with lymph node metastasis trended lower than that in those without lymph node metastasis, but the difference was not statistically significant (P>0.05)., Conclusion: Hypercellular pure mucinous breast carcinoma has higher rates of lymph node metastasis and HER-2 amplification than hypocellular pure mucinous carcinoma, the sub-classification of breast pure mucinous carcinoma should be considered. Neuroendocrine differentiation and WT-1 expression may be helpful in distinguishing the subtypes of breast mucinous carcinoma. Breast mucinous carcinoma with neuroendocrine differentiation trends to have less lymph node metastasis.

Hydroponics experiments were conducted to underpin the nature of interactions between Zn, an essential micronutrient and Pb, a nonessential element on plant growth and root morphology, as well as antioxidant adaptation in mined ecotype (ME) and nonmined ecotype (NME) of Elsholtzia argyi. Plants were exposed to 50 μM Pb having normal Zn (0.5 μM), and two other treatments of the same Pb with low (0.05 μM) and high (20 μM) Zn, respectively for 12 days. Application of Pb with normal Zn caused adverse effects on the overall growth and antioxidant capacity of both ecotypes, however; effects were more pronounced in NME. The addition of high Zn along with Pb improved the growth and antioxidant capacity of both the ecotypes, while low Zn failed to show significant changes in NME plants; however slightly aggravated the Pb toxicity in the plants of ME. Zinc antagonized Pb concentrations in root and stem of both ecotypes and leaf of ME, while no significant differences were noted in Pb concentrations of NME leaf. It is suggested that in E. argyi, mechanisms of Pb and Zn uptake and translocation as well as their interactions within the plant cell may be different for both ecotypes and need to be further investigated., (Copyright © 2010 Wiley Periodicals, Inc.)

Hydroponics studies were conducted to investigate the antioxidant adaptations, ascorbate and glutathione metabolism in hyperaccumulating ecotype of Sedum alfredii (HE) exposed to high Cd environment, when compared with its nonhyperaccumulating ecotype (NHE). Exposure to Cd induced a burst of oxidative stress in both ecotypes which was evident by the sharp increase in hydrogen peroxide (H(2)O(2)) contents and lipid peroxidation. Buthionine sulfoximine (BSO), an inhibitor of glutathione (GSH) synthesis, did not affect H(2)O(2) concentrations as well as growth of both ecotypes in the absence of Cd. However, compared with Cd application alone, BSO combined with Cd treatment caused a substantial augmentation of H(2)O(2) accumulation accompanied by a reduction in Cd concentrations in roots and leaves of HE at the end of treatment, which may rule out the possibility that GSH biosynthesis may play an important role as a signal of the stress regulation. No efficient and superior enzymatic antioxidant defense mechanisms against Cd-imposed oxidative stress existed in both NHE and HE, but the essential nonenzymatic components like ascorbic acid (AsA) and GSH played a prominent role in tolerance against Cd. Cadmium stimulated a notable rise in AsA concentration in both ecotypes soon after the application of treatment. A preferential Cd-stress response in HE was suggested to changes in the GSH pool, where acclimation was marked by increased GSH concentrations.