HTLV-I p30 inhibits multiple S phase entry checkpoints, decreases cyclin E-CDK2 interactions and delays cell cycle progression

<p>Abstract</p> <p>Background</p> <p>Human T-cell leukemia virus type I (HTLV-I) has efficiently adapted to its host and establishes a persistent infection characterized by low levels of viral gene expression and slow proliferation of HTLV-I infected cells over decades. We have previously found that HTLV-I p30 is a negative regulator of virus expression.</p> <p>Results</p> <p>In this study we show that p30 targets multiple cell cycle checkpoints resulting in a delayed entry into S phase. We found that p30 binds to cyclin E and CDK2 and prevents the formation of active cyclin E-CDK2 complexes. In turn, this decreases the phosphorylation levels of Rb and prevents the release of E2F and its transcriptional activation of genes required for G1/S transition. Our studies also show that HTLV-II p28 does not bind cyclin E and does not affect cell cycle progression.</p> <p>Conclusions</p> <p>In contrast to HTLV-I, the HTLV-II-related retrovirus is not oncogenic in humans. Here we report that the HTLV-I p30 delays cell cycle progression while its homologue, HTLV-II p28, does not, providing evidence for important differences between these two related retrovirus proteins.</p

Inducible nitric oxide synthase mediates DNA double strand breaks in Human T-Cell Leukemia Virus Type 1-induced leukemia/lymphoma

BACKGROUND: Adult T-cell leukemia/lymphoma (ATLL) is an aggressive and fatal malignancy of CD4(+) T-lymphocytes infected by the Human T-Cell Virus Type 1 (HTLV-1). The molecular mechanisms of transformation in ATLL have not been fully elucidated. However, genomic instability and cumulative DNA damage during the long period of latency is believed to be essential for HTLV-1 induced leukemogenesis. In addition, constitutive activation of the NF-κB pathway was found to be a critical determinant for transformation. Whether a connection exists between NF-κB activation and accumulation of DNA damage is not clear. We recently found that the HTLV-1 viral oncoprotein, Tax, the activator of the NF-κB pathway, induces DNA double strand breaks (DSBs). RESULTS: Here, we investigated whether any of the NF-κB target genes are critical in inducing DSBs. Of note, we found that inducible nitric oxide synthase (iNOS) that catalyzes the production of nitric oxide (NO) in macrophages, neutrophils and T-cells is over expressed in HTLV-1 infected and Tax-expressing cells. Interestingly, we show that in HTLV-1 infected cells, iNOS expression is Tax-dependent and specifically requires the activation of the classical NF-κB and JAK/STAT pathways. A dramatic reduction of DSBs was observed when NO production was inhibited, indicating that Tax induces DSBs through the activation of NO synthesis. CONCLUSIONS: Determination of the impact of NO on HTLV-1-induced leukemogenesis opens a new area for treatment or prevention of ATLL and perhaps other cancers in which NO is produced

Abnormality detection using graph matching for multi-task dynamics of autonomous systems

Self-learning abilities in autonomous systems are essential to improve their situational awareness and detection of normal/abnormal situations. In this work, we propose a graph matching technique for activity detection in autonomous agents by using the Gromov-Wasserstein framework. A clustering approach is used to discretise continuous agents' states related to a specific task into a set of nodes with similar objectives. Additionally, a probabilistic transition matrix between nodes is used as edges weights to build a graph. In this paper, we extract an abnormal area based on a sub-graph that encodes the differences between coupled of activities. Such sub-graph is obtained by applying a threshold on the optimal transport matrix, which is obtained through the graph matching procedure. The obtained results are evaluated through experiments performed by a robot in a simulated environment and by a real autonomous vehicle moving within a University Campus

Acute ST-segment elevation myocardial infarction in a young patient with essential thrombocythemia: a case with long-term follow-up report

Essential thrombocythemia (ET) is a neoplastic proliferation of mature myeloid cells - in particular, megakaryocytes - leading to persistently elevated platelet count. Usual clinical presentation is related to an increase in the risk of hemorrhage and/or thrombosis. Management of ET consists of antiplatelet therapies - mainly aspirin and cytoreductive therapies. Coronary involvement in patients with ET is rare. The optimal treatment strategies for ET patients presenting with acute myocardial infarction remains unclear. Acute interventions like intracoronary thrombolytic therapy, angioplasty, and coronary-artery bypass grafting have been reported in such patients. However, several questions remain unanswered about the acute and long-term management of these patients. Herein, we report the case of a 47-year-old female who presented with acute myocardial infarction as the first clinical sign of ET, and also present the long-term follow-up of this patient

CHEMICAL COMPOSITION, ANTIOXIDANT AND HEMOLYTIC ACTIVITIES OF SAGE (SALVIA FRUTICOSA MILLER) CULTIVATED IN LEBANON

As part of the efforts contributing towards encouraging the cultivation of commercially valuable medicinal and aromatic plants and the conservation of vulnerable wild species suffering from depletion due to destructive unsustainable harvesting from the wild, we set out to assess the in vitro antioxidant activity, decipher the phytochemical profile, and evaluate the hemolytic activity of Salvia fruticosa Miller cultivated at Beirut Arab University herbal garden in Bekaa, Eastern Lebanon. The chemical compositions of the methanolic, aqueous and essential oil extracts were assessed by GC-MS analysis. In addition, the total phenolic, total flavonoid, total carbohydrate and total protein contents were determined for the methanolic and aqueous extracts. The antioxidant activity of all samples was evaluated using the DPPH radical scavenging, β-carotene bleaching, superoxide radical scavenging, reducing power and metal chelating activity assays. The overall analysis of data revealed that the methanolic and aqueous extracts exhibited potent antioxidant activity while the essential oil showed weak activity. Furthermore, strong correlation was found between the antioxidant activities and phytochemicals content. Finally, the cytotoxicity of the essential oil and extracts against human erythrocytes was assessed using the hemolysis assay. The aqueous extract did not show any hemolytic effect within the used concentration range. On the other hand, the methanolic extract showed a weak hemolytic activity, while the essential oil showed high hemolytic activity at the highest concentration used. The collective analysis of the data offered an encouraging evidence for the cultivation of commercially valuable medicinal aromatic plants (MAPs) such as S. fruticosa Miller as a supportive measure for the Lebanese economy

Marjoram Relaxes Rat Thoracic Aorta Via a PI3-K/eNOS/cGMP Pathway.

Despite pharmacotherapeutic advances, cardiovascular disease (CVD) remains the primary cause of global mortality. Alternative approaches, such as herbal medicine, continue to be sought to reduce this burden. is recognized for many medicinal values, yet its vasculoprotective effects remain poorly investigated. Here, we subjected rat thoracic aortae to increasing doses of an ethanolic extract of (OME). OME induced relaxation in a dose-dependent manner in endothelium-intact rings. This relaxation was significantly blunted in denuded rings. N(ω)-nitro-l-arginine methyl ester (L-NAME) or 1H-[1,2,4]oxadiazolo[4,3,-a]quinoxalin-1-one (ODQ) significantly reduced the OME-induced vasorelaxation. Cyclic guanosine monophosphate (cGMP) levels were also increased by OME. Moreover, wortmannin or LY294002 significantly reduced OME-induced vasorelaxation. Blockers of ATP-sensitive or Ca2+-activated potassium channels such as glibenclamide or tetraethylamonium (TEA), respectively, did not significantly affect OME-induced relaxation. Similarly, verapamil, a Ca channel blocker, indomethacin, a non-selective cyclooxygenase inhibitor, and pyrilamine, a H1 histamine receptor blocker, did not significantly modulate the observed relaxation. Taken together, our results show that OME induces vasorelaxation via an endothelium-dependent mechanism involving the phosphoinositide 3-kinase (PI3-K)/ endothelial nitric oxide (NO) synthase (eNOS)/cGMP pathway. Our findings further support the medicinal value of marjoram and provide a basis for its beneficial intake. Although consuming marjoram may have an antihypertensive effect, further studies are needed to better determine its effects in different vascular beds

Modulation of Macrophage Function by Lactobacillus-Conditioned Medium

open access articleProbiotics are used as microbial food supplements for health and well-being. They are thought to have immunomodulatory effects although their exact physiological mechanism of action is not clear. This study investigated the influence of probiotic Lactobacillus rhamnosus GG conditioned media (LGG-CM) on macrophage phagocytosis of non-pathogenic Escherichia coli HfrC. The gentamicin protection assay was used to study the bacterial killing phases of phagocytosis. Macrophages co-incubated with E. coli for an hour allowed them to ingest bacteria and then the rate of E. coli killing was monitored for up to 300 min to determine the killing or digestion of the bacteria by recovering them from the macrophage lysate. We found that the LGG-CM significantly increased the bacterial killing by approximately 6-fold when compared with that of controls. By contrast, this killing process was found to be associated with enhanced free radical production via the activation of NADPH oxidase, stimulated by the LGG conditioned medium. We also found that the conditioned medium had small effect on nitric oxide (NO) generation, albeit to a lesser extent. This work suggests that LGG-CM may play an important role in suppressing the total microbial load within the macrophages and hence, the extent to which pro-inflammatory molecules such as free radicals and NO are generated. The modulation of inflammation-promoting signals by LGG-CM may be beneficial as it modulates bacterial killing, and thereby prevents any collateral damage to host

7-O-methylpunctatin, a novel homoisoflavonoid, inhibits phenotypic switch of human arteriolar smooth muscle cells

Remodeling of arterioles is a pivotal event in the manifestation of many inflammation-based cardio-vasculopathologies, such as hypertension. During these remodeling events, vascular smooth muscle cells (VSMCs) switch from a contractile to a synthetic phenotype. The latter is characterized by increased proliferation, migration, and invasion. Compounds with anti-inflammatory actions have been successful in attenuating this phenotypic switch. While the vast majority of studies investigating phenotypic modulation were undertaken in VSMCs isolated from large vessels, little is known about the effect of such compounds on phenotypic switch in VSMCs of microvessels (microVSMCs). We have recently characterized a novel homoisoflavonoid that we called 7-O-methylpunctatin (MP). In this study, we show that MP decreased FBS-induced cell proliferation, migration, invasion, and adhesion. MP also attenuated adhesion of THP-1 monocytes to microVSMCs, abolished FBS-induced expression of MMP-2, MMP-9, and NF-?B, as well as reduced activation of ERK1/2 and FAK. Furthermore, MP-treated VSMCs showed an increase in early (myocardin, SM-22?, SM-?) and mid-term (calponin and caldesmon) differentiation markers and a decrease in osteopontin, a protein highly expressed in synthetic VSMCs. MP also reduced transcription of cyclin D1, CDK4 but increased protein levels of p21 and p27. Taken together, these results corroborate an anti-inflammatory action of MP on human microVSMCs. Therefore, by inhibiting the synthetic phenotype of microVSMCs, MP may be a promising modulator for inflammation-induced arteriolar pathophysiology. - 2019 by the authors. Licensee MDPI, Basel, Switzerland.Funding: This work was supported by the American University of Beirut (Grant # MPP 320133 to A.E.), University of Petra (Grant #: 5/4/2019) to A.B., E.B., and A.E., and the National Council for Scientific Research (CNRS) to M.F.Scopu