Cdc42: Role in Cancer Management

Contribution of Cdc42, a member of Rho family, has been characterized for the beginning of variety of cellular responses including cellular transformation, cell division, cell invasion, migration, invadopodia formation, enzyme activity, filopodia formation, and cell polarity in cells. Deregulation of Cdc42 can alter the normal functioning of the cells, responsible for the initiation of signaling pathways and is correlated with several pathogenic processes such as cancer. Therefore, maintaining the level of Cdc42 and its effectors in cells, tumor progression can be controlled. Therefore, it can be suggested that deeper understanding about the Cdc42 contribution in cancer cell progression at molecular level can approach to the development of Cdc42 inhibitors in cancer management.     

A Novel Nicotinamide Adenine Dinucleotide Correction Method for Mitochondrial Ca2+ Measurement with FURA-2-FF in Single Permeabilized Ventricular Myocytes of Rat

Fura-2 analogs are ratiometric fluoroprobes that are widely used for the quantitative measurement of [Ca²⁺]. However, the dye usage is intrinsically limited, as the dyes require ultraviolet (UV) excitation, which can also generate great interference, mainly from nicotinamide adenine dinucleotide (NADH) autofluorescence. Specifically, this limitation causes serious problems for the quantitative measurement of mitochondrial [Ca²⁺], as no available ratiometric dyes are excited in the visible range. Thus, NADH interference cannot be avoided during quantitative measurement of [Ca²⁺] because the majority of NADH is located in the mitochondria. The emission intensity ratio of two different excitation wavelengths must be constant when the fluorescent dye concentration is the same. In accordance with this principle, we developed a novel online method that corrected NADH and Fura-2-FF interference. We simultaneously measured multiple parameters, including NADH, [Ca²⁺], and pH/mitochondrial membrane potential; Fura-2-FF for mitochondrial [Ca²⁺] and TMRE for Ψ_m or carboxy-SNARF-1 for pH were used. With this novel method, we found that the resting mitochondrial [Ca²⁺] concentration was 1.03 µM. This 1 µM cytosolic Ca²⁺ could theoretically increase to more than 100 mM in mitochondria. However, the mitochondrial [Ca²⁺] increase was limited to ~30 µM in the presence of 1 µM cytosolic Ca²⁺. Our method solved the problem of NADH signal contamination during the use of Fura-2 analogs, and therefore the method may be useful when NADH interference is expected.     

Folate-mediated mitochondrial targeting with doxorubicin-polyrotaxane nanoparticles overcomes multidrug resistance

Resistance to treatment with anticancer drugs is a significant obstacle and a fundamental cause of therapeutic failure in cancer therapy. Functional doxorubicin (DOX) nanoparticles for targeted delivery of the classical cytotoxic anticancer drug DOX to tumor cells, using folate-terminated polyrotaxanes along with dequalinium, have been developed and proven to overcome this resistance due to specific molecular features, including a size of approximately 101 nm, a zeta potential of 3.25 mV and drug-loading content of 18%. Compared with free DOX, DOX hydrochloride, DOX nanoparticles, and targeted DOX nanoparticles, the functional DOX nanoparticles exhibited the strongest anticancer efficacy in vitro and in the drug-resistant MCF-7/ Adr (DOX) xenograft tumor model. More specifically, the nanoparticles significantly increased the intracellular uptake of DOX, selectively accumulating in mitochondria and the endoplasmic reticulum after treatment, with release of cytochrome C as a result. Furthermore, the caspase-9 and caspase-3 cascade was activated by the functional DOX nanoparticles through upregulation of the pro-apoptotic proteins Bax and Bid and suppression of the antiapoptotic protein Bcl-2, thereby enhancing apoptosis by acting on the mitochondrial signaling pathways. In conclusion, functional DOX nanoparticles may provide a strategy for increasing the solubility of DOX and overcoming multidrug-resistant cancers.     

线粒体神经胃肠型脑肌病的临床和病理分析

目的 探讨线粒体神经胃肠型脑肌病(Mitochondrial Neurogastrointestinal Encephalopathy Disease,MNGIE)的临床和病理特点.方法 通过1例临床确诊为线粒体神经胃肠型脑肌病病例的临床表现、影像学检查及病理检查,系统回顾线粒体神经胃肠型脑肌病的发病机制、临床表现、病理特点.结果 该患有长期的腹痛、腹泻史,神经系统首发症状为听力障碍,此后出现头晕、走路不稳、记忆力逐渐下降.神经系统检查有眼外肌麻痹、听力障碍、周围神经损害.肌电图:广泛神经源性损害.头部MRI表现为广泛的白质脑病.肌肉活检为HE染色中出现嗜碱的肌纤维,在GT染色中为典型和不典型的RRF,在NADH染色和SDH染色中深染.结论 线粒体神经胃肠型脑肌病是一种特殊类型的线粒体肌病,具有上述临床及影像学特点,加上血及(或)脑脊液乳酸水平升高,肌肉活检示组织学线粒体肌病的表现.如果发现血清白细胞中胸苷磷酸化酶活性降低或基因检测发现胸苷磷酸化酶(thymidine phosphorylase,TYMP)基因位点突变更能进一步确诊.     

阿尔茨海默病治疗的研究进展

阿尔茨海默病（AD）是一种隐匿性起病,进行性恶化的神经退行性疾病,临床最初表现为认知功能障碍,并有可能在5～10年内完全衰退。患者往往伴随严重的记忆力丧失、精神行为异常、人格改变、言语功能障碍,无法独立生活,最终近乎于植物状态。Ferri等采用DISMOD软件在全球60岁以上人群中估计,全球的痴呆患者人数到2040年将达到8llO万左右。     

消旋羟蛋氨酸钙对人肾系膜细胞增殖影响及其机制研究

【目的】体外观察消旋羟蛋氨酸钙对人肾系膜细胞（HMC）的影响。【方法】10mM消旋羟蛋氨酸钙对HMC体外干预，检测干预后转化生长因子-β1（TGF-β1）和乳酸脱氢酶（LDH）的变化，并采用MTT和流式细胞仪检测细胞增殖、凋亡和细胞周期。【结果】10mM消旋羟蛋氨酸钙干预HMC，实验组与对照组相比，TGFB1含量增加；细胞LDH表达水平没有改变；同时细胞出现增殖抑制。细胞流式分析发现，实验组干预后出现了细胞周期G1期阻滞并观测到了细胞凋亡。【结论】10mM的消旋羟蛋氨酸钙可以诱导TGF-β1的表达增加；同时诱导细胞周期G1阻滞并伴随细胞凋亡。     

ARX-associated infantile epileptic-dyskinetic encephalopathy with responsiveness to valproate for controlling seizures and reduced activity of muscle mitochondrial complex IV

BackgroundARX genetic defect is associated with a spectrum of neurodevelopmental disorders that exhibit a high degree of phenotypic heterogeneity.MethodsWe studied a family with a 13-year old Chinese boy and his two elder brothers presented with infantile epileptic-dyskinetic encephalopathy and clarified the unknown genetic etiology of the youngest brother by whole exome sequencing.ResultsThe youngest brother of this family presented with developmental regression, dystonia, epilepsy, microcephaly, visual impairment and oromotor dysfunction. Hyperlactataemia, raised alanine and muscle complex IV deficiency indicated that he had mitochondrial dysfunction. Likely pathogenic hemizygous missense ARX variants (c.989G > A; p.Arg330His) located in conserved nuclear localization sequence was identified. The variant was carried by his asymptomatic mother and not found in his asymptomatic third elder brother. The intractable seizures showed complete but transient responsiveness to pyridoxal phosphate and finally controlled by valproate treatment.ConclusionThis is the first case of ARX-associated encephalopathy showing mitochondrial dysfunction and transient responsiveness to pyridoxal phosphate treatment.     

The maternal inheritance of Alto Paraná revealed by full mitogenome sequences

Most studies on maternal lineages of South America populations are restricted to control region (CR) markers and, for some geographical regions, the number of studied samples does not adequately represent the existing diversity. This is the case of mitochondrial DNA (mtDNA) studies on Paraguay that are limited to two Native ethnic groups. To overcome this deficiency, we analysed the mitogenomes from 105 individuals living in Alto Paraná, the second most populated department of the country. Using the Precision ID mtDNA Whole Genome Panel, the molecule was sequenced on Ion S5. The majority of the haplotypes belong to the Native American lineages A, B, C and D. Analyses of maximum parsimony using mitogenome data retrieved from publications and in The 1000 Genomes Project showed a high number of new native American subclades in Paraguay. Also, none of the haplotypes found in Alto Paraná match the remaining South American samples, which include admixed populations from Colombia, Peru and Ecuador, and natives from Colombia and Ecuador. F_ST genetic distance analysis showed that the native genetic background of Alto Paraná has an intermediate position between the Amazonian groups and the admixed populations from Peru and Ecuador, supporting the theory about the Amazonian origin of the Tupi-Guarani and, at the same time, showing the influence of other linguistic groups.     

Taurine supplementation associated with exercise increases mitochondrial activity and fatty acid oxidation gene expression in the subcutaneous white adipose tissue of obese women

Taurine supplementation only increased the expression of fat oxidation genes (ACO2 and ACOX1). Exercise increased energy metabolism and the expression of fat oxidation genes in the subcutaneous white adipose tissue. The association between taurine supplementation and exercise promoted additional effects to exercise by increasing energy expenditure, and upregulating mitochondrial respiratory capacity and the expression of genes related to mitochondrial metabolism and fat oxidation in the subcutaneous adipose tissue (scWAT) of obese women.

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