Mechanisms of muscular electrophysiological and mitochondrial dysfunction following exposure to malathion, an organophosphorus pesticide

Muscle dysfunction in acute organophosphorus (OP) poisoning is a cause of death in human. The present study was conducted to identify the mechanism of action of OP in terms of muscle mitochondrial dysfunction. Electromyography (EMG) was conducted on rats exposed to the acute oral dose of malathion (400 mg/kg) that could inhibit acetylcholinesterase activity up to 70%. The function of mitochondrial respiratory chain and the rate of production of reactive oxygen species (ROS) from intact mitochondria were measured. The bioenergetic pathways were studied by measurement of adenosine triphosphate (ATP), lactate, and glycogen. To identify mitochondrial-dependent apoptotic pathways, the messenger RNA (mRNA) expression of bax and bcl-2, protein expression of caspase-9, mitochondrial cytochrome c release, and DNA damage were measured. The EMG confirmed muscle weakness. The reduction in activity of mitochondrial complexes and muscular glycogen with an elevation of lactate was in association with impairment of cellular respiration. The reduction in mitochondrial proapoptotic stimuli is indicative of autophagic process inducing cytoprotective effects in the early stage of stress. Downregulation of apoptotic signaling may be due to reduction in ATP and ROS, and genotoxic potential of malathion. The maintenance of mitochondrial integrity by means of artificial electron donors and increasing exogenous ATP might prevent toxicity of OPs

Induction of androgenesis and production of haploid embryos in anther cultures of borage (Borago officinalis L.)

[EN] Borage (Borago officinalis L.) is an important medicinal plant with different culinary, pharmaceutical and industrial properties. Unfortunately, there are no published reports on the establishment of protocols to produce DHs in this species up to now. In this work, we show for the first time the induction of borage microspores to become embryogenic calli, from which haploid embryos are produced. In addition, we evaluated the effect of using different flower bud sizes, carbon sources, concentrations of 2,4-D and BAP, cold (4 A degrees C) pretreatments and heat shock treatments. Production of total calli, embryogenic calli and callus-derived embryos was differently affected by the different parameters studied. Our results showed that the use of 5-7 mm-long flower buds, a cold (4 A degrees C) pretreatment during 4 days, a 32 A degrees C heat shock for 3 days, and the addition of 3 % maltose and 2 mgl(-1) 2,4-D and 1 mgl(-1) BAP to the culture medium, was beneficial for embryo production. Overall, this work demonstrates that DH technology is possible in borage, and opens the door for future improvements needed to finally obtain borage DH plants.Eshaghi, ZC.; Abdollahi, MR.; Moosavi, SS.; Deljou, A.; Seguí-Simarro, JM. (2015). Induction of androgenesis and production of haploid embryos in anther cultures of borage (Borago officinalis L.). Plant Cell, Tissue and Organ Culture. 122:321-329. doi:10.1007/s11240-015-0768-5S321329122Abdollahi MR, Moieni A, Javaran MJ (2004) Interactive effects of shock and culture density on embryo induction in isolated microspore culture of Brassica napus L. cv. 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In: Mazza G (ed) Functional foods, biochemical and processing aspects. Technomic Publ Co. Inc, Lancaster, pp 265–291Ozkum D, Tipirdamaz R (2002) The effects of cold treatment and charcoal on the in vitro androgenesis of pepper (Capsicum annuum L.). Turk J Bot 26:131–139Parra-Vega V, González-García B, Seguí-Simarro JM (2013a) Morphological markers to correlate bud and anther development with microsporogenesis and microgametogenesis in pepper (Capsicum annuum L.). Acta Physiol Plant 35:627–633Parra-Vega V, Renau-Morata B, Sifres A, Seguí-Simarro JM (2013b) Stress treatments and in vitro culture conditions influence microspore embryogenesis and growth of callus from anther walls of sweet pepper (Capsicum annuum L.). Plant Cell Tissue Organ Cult 112:353–360Raquin C (1983) Utilization of different sugars as carbon sources for in vitro cultures of Petuina. 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Archon Books, Hamden, CTSkrzypek E, Czyczyło-Mysza I, Marcińska I, Wędzony M (2008) Prospects of androgenetic induction in Lupinus spp. Plant Cell Tissue Organ Cult 94(2):131–137Snape JW (1989) Doubled haploid breeding: theoretical basis and practical applications. In: Mujeeb-Kazi A, Sitch LA (eds) Review of advances in plant biotechnology, 1985–1988: 2nd international symposium genetic manipulation in crops. Mexico and Manila, CIMMYT and IRRI, pp 19–30Tipirdamaz R, Ellialtioğlu Ş (1998) The effects of cold treatments and activated charcoal on ABA contents of anthers and in vitro androgenesis in eggplant (Solanum melongena L.). In: Tsekos I, Moustakas M (eds) Progress in botanical research, Proceedings of the 1st Balkan botanical congress. Kluwer Academic Publishers, The NetherlandsVagera J, Havranek P (1985) In vitro induction of androgenesis in Capsicum annuum L. and its genetic aspests. 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DNA Double-Strand Breaks Induced by Cavitational Mechanical Effects of Ultrasound in Cancer Cell Lines

Ultrasonic technologies pervade the medical field: as a long established imaging modality in clinical diagnostics; and, with the emergence of targeted high intensity focused ultrasound, as a means of thermally ablating tumours. In parallel, the potential of [non-thermal] intermediate intensity ultrasound as a minimally invasive therapy is also being rigorously assessed. Here, induction of apoptosis in cancer cells has been observed, although definitive identification of the underlying mechanism has thus far remained elusive. A likely candidate process has been suggested to involve sonochemical activity, where reactive oxygen species (ROS) mediate the generation of DNA single-strand breaks. Here however, we provide compelling new evidence that strongly supports a purely mechanical mechanism. Moreover, by a combination of specific assays (neutral comet tail and staining for γH2AX foci formation) we demonstrate for the first time that US exposure at even moderate intensities exhibits genotoxic potential, through its facility to generate DNA damage across multiple cancer lines. Notably, colocalization assays highlight that ionizing radiation and ultrasound have distinctly different signatures to their respective γH2AX foci formation patterns, likely reflecting the different stress distributions that initiated damage formation. Furthermore, parallel immuno-blotting suggests that DNA-PKcs have a preferential role in the repair of ultrasound-induced damage

Transforming growth factor β receptor 1 is a new candidate prognostic biomarker after acute myocardial infarction

<p>Abstract</p> <p>Background</p> <p>Prediction of left ventricular (LV) remodeling after acute myocardial infarction (MI) is clinically important and would benefit from the discovery of new biomarkers.</p> <p>Methods</p> <p>Blood samples were obtained upon admission in patients with acute ST-elevation MI who underwent primary percutaneous coronary intervention. Messenger RNA was extracted from whole blood cells. LV function was evaluated by echocardiography at 4-months.</p> <p>Results</p> <p>In a test cohort of 32 MI patients, integrated analysis of microarrays with a network of protein-protein interactions identified subgroups of genes which predicted LV dysfunction (ejection fraction ≤ 40%) with areas under the receiver operating characteristic curve (AUC) above 0.80. Candidate genes included transforming growth factor beta receptor 1 (TGFBR1). In a validation cohort of 115 MI patients, TGBFR1 was up-regulated in patients with LV dysfunction (P < 0.001) and was associated with LV function at 4-months (P = 0.003). TGFBR1 predicted LV function with an AUC of 0.72, while peak levels of troponin T (TnT) provided an AUC of 0.64. Adding TGFBR1 to the prediction of TnT resulted in a net reclassification index of 8.2%. When added to a mixed clinical model including age, gender and time to reperfusion, TGFBR1 reclassified 17.7% of misclassified patients. TGFB1, the ligand of TGFBR1, was also up-regulated in patients with LV dysfunction (P = 0.004), was associated with LV function (P = 0.006), and provided an AUC of 0.66. In the rat MI model induced by permanent coronary ligation, the TGFB1-TGFBR1 axis was activated in the heart and correlated with the extent of remodeling at 2 months.</p> <p>Conclusions</p> <p>We identified TGFBR1 as a new candidate prognostic biomarker after acute MI.</p

Functional polymorphisms in genes of the Angiotensin and Serotonin systems and risk of hypertrophic cardiomyopathy: AT1R as a potential modifier

<p>Abstract</p> <p>Background</p> <p>Angiotensin and serotonin have been identified as inducers of cardiac hypertrophy. DNA polymorphisms at the genes encoding components of the angiotensin and serotonin systems have been associated with the risk of developing cardiovascular diseases, including left ventricular hypertrophy (LVH).</p> <p>Methods</p> <p>We genotyped five polymorphisms of the <it>AGT</it>, <it>ACE</it>, <it>AT1R</it>, <it>5-HT2A</it>, and <it>5-HTT </it>genes in 245 patients with Hypertrophic Cardiomyopathy (HCM; 205 without an identified sarcomeric gene mutation), in 145 patients with LVH secondary to hypertension, and 300 healthy controls.</p> <p>Results</p> <p>We found a significantly higher frequency of <it>AT1R </it>1166 C carriers (CC+AC) among the HCM patients without sarcomeric mutations compared to controls (p = 0.015; OR = 1.56; 95%CI = 1.09-2.23). The <it>AT1R </it>1166 C was also more frequent among patients who had at least one affected relative, compared to sporadic cases. This allele was also associated with higher left ventricular wall thickness in both, HCM patients with and without sarcomeric mutations.</p> <p>Conclusions</p> <p>The 1166 C <it>AT1R </it>allele could be a risk factor for cardiac hypertrophy in patients without sarcomeric mutations. Other variants at the <it>AGT</it>, <it>ACE</it>, <it>5-HT2A </it>and <it>5-HTT </it>did not contribute to the risk of cardiac hypertrophy.</p

The global distribution of fatal pesticide self-poisoning: Systematic review

<p>Abstract</p> <p>Background</p> <p>Evidence is accumulating that pesticide self-poisoning is one of the most commonly used methods of suicide worldwide, but the magnitude of the problem and the global distribution of these deaths is unknown.</p> <p>Methods</p> <p>We have systematically reviewed the worldwide literature to estimate the number of pesticide suicides in each of the World Health Organisation's six regions and the global burden of fatal self-poisoning with pesticides. We used the following data sources: Medline, EMBASE and psycINFO (1990–2007), papers cited in publications retrieved, the worldwide web (using Google) and our personal collections of papers and books. Our aim was to identify papers enabling us to estimate the proportion of a country's suicides due to pesticide self-poisoning.</p> <p>Results</p> <p>We conservatively estimate that there are 258,234 (plausible range 233,997 to 325,907) deaths from pesticide self-poisoning worldwide each year, accounting for 30% (range 27% to 37%) of suicides globally. Official data from India probably underestimate the incidence of suicides; applying evidence-based corrections to India's official data, our estimate for world suicides using pesticides increases to 371,594 (range 347,357 to 439,267). The proportion of all suicides using pesticides varies from 4% in the European Region to over 50% in the Western Pacific Region but this proportion is not concordant with the volume of pesticides sold in each region; it is the pattern of pesticide use and the toxicity of the products, not the quantity used, that influences the likelihood they will be used in acts of fatal self-harm.</p> <p>Conclusion</p> <p>Pesticide self-poisoning accounts for about one-third of the world's suicides. Epidemiological and toxicological data suggest that many of these deaths might be prevented if (a) the use of pesticides most toxic to humans was restricted, (b) pesticides could be safely stored in rural communities, and (c) the accessibility and quality of care for poisoning could be improved.</p

Therapeutic management of intestinal fibrosis induced by radiation therapy: from molecular profiling to new intervention strategies et vice et versa

Chronic toxicities of locoregional and systemic oncological treatments commonly develop in long-term cancer survivors. Amongst these toxicities, post-radiotherapeutic complications alter patient's quality of life. Reduction of exposure of normal tissues can be achieved by optimization of radiotherapy. Furthermore, understanding of the fibrogenic mechanisms has provided targets to prevent, mitigate, and reverse late radiation-induced damages. This mini-review shows how (i) global molecular studies using gene profiling can provide tools to develop new intervention strategies and (ii) how successful clinical trials, conducted in particular with combined pentoxifylline-vitamin E, can take benefice of biological and molecular evidences to improve our understanding of fibrogenic mechanisms, enhance the robustness of proposed treatments, and lead ultimately to better treatments for patient's benefice

MiR-218 Inhibits Invasion and Metastasis of Gastric Cancer by Targeting the Robo1 Receptor

MicroRNAs play key roles in tumor metastasis. Here, we describe the regulation and function of miR-218 in gastric cancer (GC) metastasis. miR-218 expression is decreased along with the expression of one of its host genes, Slit3 in metastatic GC. However, Robo1, one of several Slit receptors, is negatively regulated by miR-218, thus establishing a negative feedback loop. Decreased miR-218 levels eliminate Robo1 repression, which activates the Slit-Robo1 pathway through the interaction between Robo1 and Slit2, thus triggering tumor metastasis. The restoration of miR-218 suppresses Robo1 expression and inhibits tumor cell invasion and metastasis in vitro and in vivo. Taken together, our results describe a Slit-miR-218-Robo1 regulatory circuit whose disruption may contribute to GC metastasis. Targeting miR-218 may provide a strategy for blocking tumor metastasis

Systemic inhibition of tumour angiogenesis by endothelial cell-based gene therapy

Angiogenesis and post-natal vasculogenesis are two processes involved in the formation of new vessels, and both are essential for tumour growth and metastases. We isolated endothelial cells from human blood mononuclear cells by selective culture. These blood outgrowth cells expressed endothelial cell markers and responded correctly to functional assays. To evaluate the potential of blood outgrowth endothelial cells (BOECs) to construct functional vessels in vivo, NOD-SCID mice were implanted with Lewis lung carcinoma cells subcutaneously (s.c.). Blood outgrowth endothelial cells were then injected through the tail vein. Initial distribution of these cells occurred throughout the lung, liver, spleen, and tumour vessels, but they were only found in the spleen, liver, and tumour tissue 48 h after injection. By day 24, they were mainly found in the tumour vasculature. Tumour vessel counts were also increased in mice receiving BOEC injections as compared to saline injections. We engineered BOECs to deliver an angiogenic inhibitor directly to tumour endothelium by transducing them with the gene for human endostatin. These cells maintained an endothelial phenotype and decreased tumour vascularisation and tumour volume in mice. We conclude that BOECs have the potential for tumour-specific delivery of cancer gene therapy