Carnosol induces ROS-mediated beclin1-independent autophagy and apoptosis in triple negative breast cancer

Background: In this study we investigated the in vitro and in vivo anticancer effect of carnosol, a naturally occurring polyphenol, in triple negative breast cancer.Results: We found that carnosol significantly inhibited the viability and colony growth induced G2 arrest in the triple negative MDA-MB-231. Blockade of the cell cycle was associated with increased p21/WAF1 expression and downregulation of p27. Interestingly, carnosol was found to induce beclin1-independent autophagy and apoptosis in MDA-MB-231 cells. The coexistence of both events, autophagy and apoptosis, was confirmed by electron micrography. Induction of autophagy was found to be an early event, detected within 3 h post-treatment, which subsequently led to apoptosis. Carnosol treatment also caused a dose-dependent increase in the levels of phosphorylated extracellular signal-regulated kinase 1 and 2 (pERK1/2). Moreover, we show that carnosol induced DNA damage, reduced the mitochondrial potential and triggered the activation of the intrinsic and extrinsic apoptotic pathway. Furthermore, we found that carnosol induced a dose-dependent generation of reactive oxygen species (ROS) and inhibition of ROS by tiron, a ROS scavenger, blocked the induction of autophagy and apoptosis and attenuated DNA damage. To our knowledge, this is the first report to identify the induction of autophagy by carnosol.Conclusion: In conclusion our findings provide strong evidence that carnosol may be an alternative therapeutic candidate against the aggressive form of breast cancer and hence deserves more exploration.Scopu

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

Rare predicted loss-of-function variants of type I IFN immunity genes are associated with life-threatening COVID-19

Background: We previously reported that impaired type I IFN activity, due to inborn errors of TLR3- and TLR7-dependent type I interferon (IFN) immunity or to autoantibodies against type I IFN, account for 15–20% of cases of life-threatening COVID-19 in unvaccinated patients. Therefore, the determinants of life-threatening COVID-19 remain to be identified in ~ 80% of cases. Methods: We report here a genome-wide rare variant burden association analysis in 3269 unvaccinated patients with life-threatening COVID-19, and 1373 unvaccinated SARS-CoV-2-infected individuals without pneumonia. Among the 928 patients tested for autoantibodies against type I IFN, a quarter (234) were positive and were excluded. Results: No gene reached genome-wide significance. Under a recessive model, the most significant gene with at-risk variants was TLR7, with an OR of 27.68 (95%CI 1.5–528.7, P = 1.1 × 10−4) for biochemically loss-of-function (bLOF) variants. We replicated the enrichment in rare predicted LOF (pLOF) variants at 13 influenza susceptibility loci involved in TLR3-dependent type I IFN immunity (OR = 3.70[95%CI 1.3–8.2], P = 2.1 × 10−4). This enrichment was further strengthened by (1) adding the recently reported TYK2 and TLR7 COVID-19 loci, particularly under a recessive model (OR = 19.65[95%CI 2.1–2635.4], P = 3.4 × 10−3), and (2) considering as pLOF branchpoint variants with potentially strong impacts on splicing among the 15 loci (OR = 4.40[9%CI 2.3–8.4], P = 7.7 × 10−8). Finally, the patients with pLOF/bLOF variants at these 15 loci were significantly younger (mean age [SD] = 43.3 [20.3] years) than the other patients (56.0 [17.3] years; P = 1.68 × 10−5). Conclusions: Rare variants of TLR3- and TLR7-dependent type I IFN immunity genes can underlie life-threatening COVID-19, particularly with recessive inheritance, in patients under 60 years old

Non-linear state dependent differential Riccati states filter for wastewater treatment process

The most important issues relating to monitoring, quality control and prediction models for environmental protection in the treatment plant waste water are based on the amount of information and measures that are available. The key step in controlling and monitoring the plant is to obtain an accurate and robust estimate of the states model. The paper focuses on estimating non-measurable physical states of wastewater treatment system, which are unavailable because of difficulties techniques or the high cost of physical sensors. The developed filter is dealing with the non-linearity describing the system. The Activated Sludge Process (ASP) as the biological technique most commonly used wastewater treatment, attracts much attention the research community. We developed for this class of processes a robust non-linear estimator known as "state-dependent differential Riccati filter (SDDRF). The sensor software is simple to implement and has a computational cost relatively low. The results are compared with the extended Kalman filter (EKF) to demonstrate the improved performance of the filter SDDRF. The filter allows the online monitoring of process variables, which are not directly measurable. The simulation results prove the advantage of using this approach

Metatranscriptomic analysis of multiple environmental stresses identifies RAP2.4 gene associated with arabidopsis immunity to Botrytis cinerea

In this study, we aimed to identify common genetic components during stress response responsible for crosstalk among stresses, and to determine the role of differentially expressed genes in Arabidopsis-Botrytis cinerea interaction. Of 1,554 B. cinerea up-regulated genes, 24%, 1.4% and 14% were induced by biotic, abiotic and hormonal treatments, respectively. About 18%, 2.5% and 22% of B. cinerea down-regulated genes were also repressed by the same stress groups. Our transcriptomic analysis indicates that plant responses to all tested stresses can be mediated by commonly regulated genes; and protein-protein interaction network confirms the cross-interaction between proteins regulated by these genes. Upon challenges to individual or multiple stress(es), accumulation of signaling molecules (e.g. hormones) plays a major role in the activation of downstream defense responses. In silico gene analyses enabled us to assess the involvement of RAP2.4 (related to AP2.4) in plant immunity. Arabidopsis RAP2.4 was repressed by B. cinerea, and its mutants enhanced resistance to the same pathogen. To the best of our knowledge, this is the first report demonstrating the role of RAP2.4 in plant defense against B. cinerea. This research can provide a basis for breeding programs to increase tolerance and improve yield performance in crops

On estimation of unknown state variables in wastewater systems

This paper focuses on the estimation of the non-measurable physical states of wastewater systems when nonlinear models with uncertainties describe the processes. The activated sludge process (ASP), as the most commonly applied biological wastewater purification technique, attracts a great deal of attention from the research community. We developed for this class of processes a state dependent differential Riccati filter (SDDRF) for state estimation of nonlinear model describing the system. The resulting software sensor is simple to implement and has a relatively low computational cost. The results are compared with the extended Kalman filter (EKF) in order to demonstrate the better performance of the SDDRF filter. The filter allows the on-line tracking of process variables, which are not directly measurable. The simulation results point out to the advantage of using this approach