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Human immunodeficiency virus (HIV) infection is associated with B-cell malignancies in patients though HIV-1 is not able to infect B-cells. The rate of B-cell lymphomas in HIV-infected individuals remains high even under the combined antiretroviral therapy (cART) that reconstitutes the immune function. Thus, the contribution of HIV-1 to B-cell oncogenesis remains enigmatic. HIV-1 induces oxidative stress and DNA damage in infected cells via multiple mechanisms, including viral Tat protein. We have detected elevated levels of reactive oxygen species (ROS) and DNA damage in B-cells of HIV-infected individuals. As Tat is present in blood of infected individuals and is able to transduce cells, we hypothesized that it could induce oxidative DNA damage in B-cells promoting genetic instability and malignant transformation. Indeed, incubation of B-cells isolated from healthy donors with purified Tat protein led to oxidative stress, a decrease in the glutathione (GSH) levels, DNA damage and appearance of chromosomal aberrations. The effects of Tat relied on its transcriptional activity and were mediated by NF-κB activation. Tat stimulated oxidative stress in B-cells mostly via mitochondrial ROS production which depended on the reverse electron flow in Complex I of respiratory chain. We propose that Tat-induced oxidative stress, DNA damage and chromosomal aberrations are novel oncogenic factors favoring B-cell lymphomas in HIV-1 infected individuals., Graphical abstract fx1, Highlights • B-cells of HIV-infected individuals exhibit elevated levels of oxidative stress, DNA damage and chromosomal aberrations. • Purified HIV-1 Tat protein reproduces this effect and induces oxidative stress and DNA damage in B-cells. • HIV-1 Tat induces mitochondrial oxidative stress and activates NF-kB in B-cells. • This condition increases the risk of developing chromosomal abnormalities and translocations.

SETDB1 is a key histone lysine methyltransferase involved in gene silencing. The SETDB1 gene is amplified in human lung cancer, where the protein plays a driver role. Here, we investigated the clinical significance of SETDB1 expression in the two major forms of human non-small cell lung carcinoma (NSCLC), i.e., adenocarcinoma (ADC) and squamous cell carcinoma (SCC), by combining a meta-analysis of transcriptomic datasets and a systematic review of the literature. A total of 1140 NSCLC patients and 952 controls were included in the association analyses. Our data revealed higher levels of SETDB1 mRNA in ADC (standardized mean difference, SMD: 0.88, 95% confidence interval, CI: 0.73&ndash, 1.02, p &lt, 0.001) and SCC (SMD: 0.40, 95% CI: 0.13&ndash, 0.66, p = 0.003) compared to non-cancerous tissues. For clinicopathological analyses, 2533 ADC and 903 SCC patients were included. Interestingly, SETDB1 mRNA level was increased in NSCLC patients who were current smokers compared to non-smokers (SMD: 0.26, 95% CI: 0.08&ndash, 0.44, p = 0.004), and when comparing former smokers and non-smokers (p = 0.009). Furthermore, the area under the curve (AUC) given by the summary receiver operator characteristic curve (sROC) was 0.774 (Q = 0.713). Together, our findings suggest a strong foundation for further research to evaluate SETDB1 as a diagnostic biomarker and/or its potential use as a therapeutic target in NSCLC.

DUX4, a double homeobox transcription factor, has been mostly studied in facioscapulohumeral dystrophy (FSHD), a pathology linked to a deletion of subtelomeric repeats on chromosome 4q. More recently, however, the gene has been associated with various sarcomas and haematological malignancies. Drugs developed for FSHD could be tested on cancer cells to develop efficient treatment strategies for both pathologies.

Reactive oxygen species are at the origin of muscular fatigue and atrophy. They are also linked to muscular dystrophies, a group of human genetic diseases. Several studies point to the benefits of application of antioxidants and uncouplers of oxidative phosphorylation to improve the functional activity of normal and pathological muscles. Other studies point to potential dangers of these compounds. Aim. To study the effect of mitochondria-targeted antioxidants and uncouplers of oxidative phosphorylation on muscle differentiation. Methods. Muscle differentiation was induced by serum starvation and monitored by troponin T staining. Results. the mitochondria-targeted uncoupler of oxidative phosphorylation C12TPP, but not the mitochondria-targeted antioxidant SkQ1, inhibit fusion of primary myoblasts upon their differentiation, but do not affect the synthesis of troponin T, a protein marker of muscle differentiation. Conclusion. The effect of C12TPP could be at least partially mediated by inhibition of reactive oxygen species (ROS) production since antioxidant N-acetylcysteine at high doses also inhibited differentiation of myoblasts. Активні форми кисню (АФК) можуть викликати м'язову втому і атрофію м'язів. АФК також пов'язані з м'язовими дистрофії. Безліч досліджень вказує на позитивний вплив антиоксидантів і разобщітелей окисного фосфорилювання на функціональну активність м'язів в нормі та патології. Мета. Вивчити вплив мітохондріальної-спрямованих антиоксидантів і разобщітелей окисного фосфорилювання на диференціювання первинних міобластів людини. Методи. Результати. мітохондріальної-спрямований разобщитель окисного фосфорилювання C12TPP, але не мітохондріальної-спрямований антиоксидант SkQ1, пригнічує злиття міобластів при диференціюванні, при цьому не впливаючи на експресію тропонина Т, білкового маркера м'язової диференціювання. Висновки. Вплив C12TPP може бути частково викликано пригніченням АФК, так як високі концентрації класичного антиоксиданту N-ацетилцистеїну також інгібували диференціювання міобластів людини. Активные формы кислорода (АФК) могут вызывать мышечную усталость и атрофию мышц. АФК также связаны с мышечными дистрофиями. Множество исследований указывает на положительное влияние антиоксидантов и разобщителей окислительного фосфорилирования на функциональную активность мышц в норме и патологии. Цель. Изучить влияние митохондриально-направленных антиоксидантов и разобщителей окислительного фосфорилирования на дифференцировку первичных миобластов человека. Методы. Результаты. митохондриально-направленный разобщитель окислительного фосфорилирования C12TPP, но не митохондриально-направленный антиоксидант SkQ1, ингибирует слияние миобластов при дифференцировке, при этом не влияя на экспрессию тропонина Т, белкового маркера мышечной дифференцировки. Выводы. Влияние C12TPP может быть частично вызвано ингибированием АФК, так как высокие концентрации классического антиоксиданта N-ацетилцистеина также ингибировали дифференцировку миобластов человека.

Genome editing using engineered nucleases (meganucleases, zinc finger nucleases, transcription activator-like effector nucleases) has created many recent breakthroughs. Prescreening for efficiency and specificity is a critical step prior to using any newly designed genome editing tool for experimental purposes. The current standard screening methods of evaluation are based on DNA sequencing or use mismatch-sensitive endonucleases. They can be time-consuming and costly or lack reproducibility. Here, we review and critically compare standard techniques with those more recently developed in terms of reliability, time, cost, and ease of use.

Vascular aging is accompanied by increases in circulatory proinflammatory cytokines leading to inflammatory endothelial response implicated in early atherogenesis. To study the possible role of mitochondria-derived reactive oxygen species (ROS) in this phenomenon, we applied the effective mitochondria-targeted antioxidant SkQ1, the conjugate of plastoquinone with dodecyltriphenylp hosphonium. Eight months treatment of (CBAxC57BL/6) F1 mice with SkQ1 did not prevent age-related elevation of the major proinflammatory cytokines TNF and IL-6 in serum, but completely abrogated the increase in adhesion molecule ICAM1 expression in aortas of 24-month-old animals. In endothelial cell culture, SkQ1 also attenuated TNF-induced increase in IC AM1, VCAM, and E-selectin expression and secretion of IL-6 and IL-8, and prevented neutrophil adhesion to the endothelial monolayer. Using specific inhibitors to transcription factor NF-κB and stress-kinases p38 and JNK, we demonstrated that TNF-induced ICAM1 expression depends mainly on NF-κB activity and, to a lesser extent, on p38. SkQ1 had no effect on p3 8 phosphorylation (activation) but significantly reduced NF-κB activation by inhibiting phosphorylation and proteolytic cleavage of the inhibitory subunit IκBα. The data indicate an important role of mitochondrial reactive oxygen species in regulation of the NF-κB pathway and correspond ing age-related inflammatory activation of endothelium.