Melatonin and vitamin D, two sides of the same coin, better to land on its edge to improve multiple sclerosis.

Previous studies revealed a latitudinal gradient of multiple sclerosis (MS) prevalence, increasing by moving from the equator to the poles. The duration and quality of an individual's exposure to sunlight vary with latitude. Skin exposure to sunlight activates vitamin D synthesis, while light absence, as perceived by the eyes, activates melatonin synthesis in the pineal gland. Vitamin D or melatonin deficiency/insufficiency or overdose can occur at any latitude due to specific lifestyles and diets. Moving away from the equator, especially beyond 37°, decreases vitamin D while raising melatonin. Furthermore, melatonin synthesis increases in cold habitats like northern countries. Since melatonin's beneficial role was shown in MS, it is expected that northern countries whose individuals have higher endogenous melatonin should show a lower MS prevalence; however, these are ranked with the highest scores. In addition, countries like the United States and Canada have uncontrolled over-the-counter usage. In high latitudes, vitamin D deficiency and a higher MS prevalence persist even though vitamin D is typically compensated for by supplementation and not sunlight. Recently, we found that prolonged darkness increased MS melatonin levels, mimicking the long-term increase in northern countries. This caused a reduction in cortisol and increased infiltration, inflammation, and demyelination, which were all rescued by constant light therapy. In this review, we explain melatonin and vitamin D's possible roles in MS prevalence. The possible causes in northern countries are then discussed. Finally, we suggest strategies to treat MS by manipulating vitamin D and melatonin, preferably with sunlight or darkness, not supplements.

Neurotrauma investigation through spatial omics guided by mass spectrometry imaging: Target identification and clinical applications.

Traumatic brain injury (TBI) represents one of the major public health concerns worldwide due to the increase in TBI incidence as a result of injuries from daily life accidents such as sports and motor vehicle transportation as well as military-related practices. This type of central nervous system trauma is known to predispose patients to several neurological disorders such as Parkinson's disease, Alzheimer's disease, chronic trauamatic encephalopathy, and age-related Dementia. Recently, several proteomic and lipidomic platforms have been applied on different TBI studies to investigate TBI-related mechanisms that have broadened our understanding of its distinct neuropathological complications. In this study, we provide an updated comprehensive overview of the current knowledge and novel perspectives of the spatially resolved microproteomics and microlipidomics approaches guided by mass spectrometry imaging used in TBI studies and its applications in the neurotrauma field. In this regard, we will discuss the use of the spatially resolved microproteomics and assess the different microproteomic sampling methods such as laser capture microdissection, parafilm assisted microdissection, and liquid microjunction extraction as accurate and precise techniques in the field of neuroproteomics. Additionally, we will highlight lipid profiling applications and their prospective potentials in characterizing molecular processes involved in the field of TBI. Specifically, we will discuss the phospholipid metabolism acting as a precursor for proinflammatory molecules such as eicosanoids. Finally, we will survey the current state of spatial neuroproteomics and microproteomics applications and present the various studies highlighting their findings in these fields.

The kinesin KIF1C transports APC-dependent mRNAs to cell protrusions.

RNA localization and local translation are important for numerous cellular functions. In mammals, a class of mRNAs localize to cytoplasmic protrusions in an APC-dependent manner, with roles during cell migration. Here, we investigated this localization mechanism. We found that the KIF1C motor interacts with APC-dependent mRNAs and is required for their localization. Live cell imaging revealed rapid, active transport of single mRNAs over long distances that requires both microtubules and KIF1C. Two-color imaging directly revealed single mRNAs transported by single KIF1C motors, with the 3'UTR being sufficient to trigger KIF1C-dependent RNA transport and localization. Moreover, KIF1C remained associated with peripheral, multimeric RNA clusters and was required for their formation. These results reveal a widespread RNA transport pathway in mammalian cells, in which the KIF1C motor has a dual role in transporting RNAs and clustering them within cytoplasmic protrusions. Interestingly, KIF1C also transports its own mRNA, suggesting a possible feedback loop acting at the level of mRNA transport.

Staphylococcus epidermidis biofilm assembly and self-dispersion: bacteria and matrix dynamics.

Staphylococcus epidermidis, despite being a commensal of human skin and mucosa, is a major nosocomial pathogen implicated in device-associated infections. The dissemination of infection to other body sites is related to biofilm dispersal. This study focused on the dispersion stage of S. epidermidis CIP 444 biofilm, with the assessment of biofilm matrix composition in a time-dependent experiment (7 days extended) with 3 independent repetitions, using confocal laser scanning microcopy (CLSM) in association with ZEN 3.4 blue edition, COMSTAT, and ImageJ software. SYTO-9, propidium iodide (PI), DID'OIL, FITC, and calcofluor white M2R (CFW) were used to stain biofilm components. The results indicated that the biomass of dead cells increased from 15.18 ± 1.81 µm3/µm2 (day 3) to 23.15 ± 6.075 µm3/µm2 (day 4), along with a decrease in alive cells' biomass from 22.75 ± 2.968 µm3/µm2 (day 3) to 18.95 ± 5.713 µm3/µm2 (day 4). When the intensities were measured after marking the biofilm components, in a 24-h-old biofilm, polysaccharide made up the majority of the investigated components (52%), followed by protein (18.9%). Lipids make up just 11.6% of the mature biofilm. Protein makes up the largest portion (48%) of a 4-day-old biofilm, followed by polysaccharides (37.8%) and lipids (7.27%). According to our findings, S. epidermidis CIP 444 dispersion occurred on day 4 of incubation, and new establishment of the biofilm occurred on day 7. Remarkable changes in biofilm composition will pave the way for a new approach to understanding bacterial strategies inside biofilms and finding solutions to their impacts in the medical field.

Fra-1 regulates its target genes via binding to remote enhancers without exerting major control on chromatin architecture in triple negative breast cancers.

The ubiquitous family of dimeric transcription factors AP-1 is made up of Fos and Jun family proteins. It has long been thought to operate principally at gene promoters and how it controls transcription is still ill-understood. The Fos family protein Fra-1 is overexpressed in triple negative breast cancers (TNBCs) where it contributes to tumor aggressiveness. To address its transcriptional actions in TNBCs, we combined transcriptomics, ChIP-seqs, machine learning and NG Capture-C. Additionally, we studied its Fos family kin Fra-2 also expressed in TNBCs, albeit much less. Consistently with their pleiotropic effects, Fra-1 and Fra-2 up- and downregulate individually, together or redundantly many genes associated with a wide range of biological processes. Target gene regulation is principally due to binding of Fra-1 and Fra-2 at regulatory elements located distantly from cognate promoters where Fra-1 modulates the recruitment of the transcriptional co-regulator p300/CBP and where differences in AP-1 variant motif recognition can underlie preferential Fra-1- or Fra-2 bindings. Our work also shows no major role for Fra-1 in chromatin architecture control at target gene loci, but suggests collaboration between Fra-1-bound and -unbound enhancers within chromatin hubs sometimes including promoters for other Fra-1-regulated genes. Our work impacts our view of AP-1.

Reduced melatonin levels may facilitate glioblastoma initiation in the subventricular zone.

There is increasing evidence that glioblastoma, a highly aggressive brain tumour, originates from a neural stem cell (NSC) located in the subventricular zone (SVZ) of the lateral cerebral ventricle. Using the most advanced in vivo imaging techniques, Gengatharan and colleagues recently identified a day/night difference in the adult SVZ-NSC division. They reported that the circadian melatonin rhythm and its receptor control the day/night difference in NSC division with high mitotic activity during the day and low activity at night. Expression of melatonin and its receptor diminishes during ageing, which eliminates the regulatory effect of melatonin on NSC mitosis. Moreover, the circadian melatonin rhythm is dampened by light-at-night with the potential of altering the circadian mitotic cycle of NSC in the SVZ. Also, men with a lower melatonin amplitude than women exhibit a 60% higher rate of glioblastoma incidence. Given that ageing contributes significantly to glioblastoma initiation and progression, we suggest that the decline in circadian melatonin synthesis and release as well as its receptors in the SVZ, which also diminish with an ageing act in concert with other factors to facilitate glioblastoma initiation and growth.

Inflammation and Microcalcification: A Never-Ending Vicious Cycle in Atherosclerosis?

Inflammatory cells and cytokines are known for long to worsen the development of atherosclerotic plaques in mice, and intense efforts are today devoted to develop anti-inflammatory therapeutic strategies to slow down plaque development. Increasing data indicate that plaque inflammation is intimately associated with microcalcifications, which exert harmful effects eventually culminating with plaque rupture. In this review article, we will first introduce microcalcification location, detection, and effects in atherosclerotic plaques. Then, we will present the numerous data suggesting that inflammatory cells and molecules are responsible for the formation of microcalcifications and the articles showing that microcalcifications stimulate macrophages and smooth muscle cells to produce more pro-inflammatory cytokines. Finally, we will discuss the possibility that microcalcifications might stimulate smooth muscle cells to produce larger and more stable calcifications to stabilize plaques, to exit the vicious cycle associating inflammation and microcalcification in atherosclerotic plaques.

Mesenchymal Stem Cells Ameliorate Cuprizone-Induced Demyelination by Targeting Oxidative Stress and Mitochondrial Dysfunction.

Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system. The main causes of MS disease progression, demyelination, and tissue damage are oxidative stress and mitochondrial dysfunction. Hence, the latter are considered as important therapeutic targets. Recent studies have demonstrated that mesenchymal stem cells (MSCs) possess antioxidative properties and are able to target mitochondrial dysfunction. Therefore, we investigated the effect of transplanting Wharton's jelly-derived MSCs in a demyelination mouse model of MS in which mice were fed cuprizone (CPZ) for 12 weeks. CPZ is a copper chelator that impairs the activity of cytochrome oxidase, decreases oxidative phosphorylation, and produces degenerative changes in oligodendrocytes, leading to toxic demyelination similar to those found in MS patients. Results showed that MSCs caused a significant increase in the percentage of myelinated areas and in the number of myelinated fibers in the corpus callosum of the CPZ + MSC group, compared to the CPZ group, as assessed by Luxol fast blue staining and transmission electron microscopy. In addition, transplantation of MSCs significantly increased the number of oligodendrocytes while decreasing astrogliosis and microgliosis in the corpus callosum of the CPZ + MSC group, evaluated by immunofluorescence. Moreover, the mechanism by which MSCs exert these physiological effects was found to be through abolishing the effect of CPZ on oxidative stress markers and mitochondrial dysfunction. Indeed, malondialdehyde significantly decreased while glutathione and superoxide dismutase significantly increased in CPZ + MSC mice group, in comparison witth the CPZ group alone. Furthermore, cell therapy with MSC transplantation increased the expression levels of mitochondrial biogenesis transcripts PGC1α, NRF1, MFN2, and TFAM. In summary, these results demonstrate that MSCs may attenuate MS by promoting an antioxidant response, reducing oxidative stress, and improving mitochondrial homeostasis.

A case-control study on factor V Leiden: an independent, gender-dependent risk factor for venous thromboembolism.

BACKGROUND: Activated protein C resistance (APCR) due to factor V Leiden (FVL) mutation (R506Q) is a major risk factor in patients with venous thromboembolism (VTE). The present study investigated the clinical manifestations and the risk of venous thromboembolism regarding multiple clinical, laboratory, and demographic properties in FVL patients. MATERIAL AND METHODS: A retrospective cross-sectional analysis was conducted on a total of 288 FVL patients with VTE according to APCR. In addition, 288 VET control samples, without FVL mutation, were also randomly selected. Demographic information, clinical manifestations, family and treatment history were recorded, and specific tests including t-test, chi-square and uni- and multi-variable regression tests applied. RESULTS: APCR was found to be 2.3 times significantly more likely in men (OR: 2.1, p < 0.05) than women. The risk of deep vein thrombosis (DVT) and pulmonary embolism (PE) in APCR patients was 4.5 and 3.2 times more than the control group, respectively (p < 0.05). However, APCR could not be an independent risk factor for arterial thrombosis (AT) and pregnancy complications. Moreover, patients were evaluated for thrombophilia panel tests and showed significantly lower protein C and S than the control group and patients without DVT (p < 0.0001). CONCLUSION: FVL mutation and APCR abnormality are noticeable risk factors for VTE. Screening strategies for FVL mutation in patients undergoing surgery, oral contraceptive medication, and pregnancy cannot be recommended, but a phenotypic test for activated protein C resistance should be endorsed in patients with VTE.

Mapping Spatiotemporal Microproteomics Landscape in Experimental Model of Traumatic Brain Injury Unveils a link to Parkinson's Disease.

Traumatic brain injury (TBI) represents a major health concerns with no clinically-approved FDA drug available for therapeutic intervention. Several genomics and neuroproteomics studies have been employed to decipher the underlying pathological mechanisms involved that can serve as potential neurotherapeutic targets and unveil a possible underlying relation of TBI to other secondary neurological disorders. In this work, we present a novel high throughput systems biology approach using a spatially resolved microproteomics platform conducted on different brain regions in an experimental rat model of moderate of controlled cortical injury (CCI) at a temporal pattern postinjury (1 day, 3 days, 7 days, and 10 days). Mapping the spatiotemporal landscape of signature markers in TBI revealed an overexpression of major protein families known to be implicated in Parkinson's disease (PD) such as GPR158, HGMB1, synaptotagmin and glutamate decarboxylase in the ipsilateral substantia nigra. In silico bioinformatics docking experiments indicated the potential correlation between TBI and PD through alpha-synuclein. In an in vitro model, stimulation with palmitoylcarnitine triggered an inflammatory response in macrophages and a regeneration processes in astrocytes which also further confirmed the in vivo TBI proteomics data. Taken together, this is the first study to assess the microproteomics landscape in TBI, mainly in the substantia nigra, thus revealing a potential predisposition for PD or Parkinsonism post-TBI.

Acriflavine targets oncogenic STAT5 signaling in myeloid leukemia cells.

Acriflavine (ACF) is an antiseptic with anticancer properties, blocking the growth of solid and haematopoietic tumour cells. Moreover, this compound has been also shown to overcome the resistance of cancer cells to chemotherapeutic agents. ACF has been shown to target hypoxia-inducible factors (HIFs) activity, which are key effectors of hypoxia-mediated chemoresistance. In this study, we showed that ACF inhibits the growth and survival of chronic myeloid leukaemia (CML) and acute myeloid leukaemia (AML) cell lines in normoxic conditions. We further demonstrated that ACF down-regulates STAT5 expression in CML and AML cells but activates STAT3 in CML cells in a HIF-independent manner. In addition, we demonstrated that ACF suppresses the resistance of CML cells to tyrosine kinase inhibitors, such as imatinib. Our data suggest that the dual effect of ACF might be exploited to eradicate de novo or acquired resistance of myeloid leukaemia cells to chemotherapy.

Genetic Depletion or Hyperresponsiveness of Natural Killer Cells Do Not Affect Atherosclerosis Development.

RATIONALE: Chronic inflammation is central in the development of atherosclerosis. Both innate and adaptive immunities are involved. Although several studies have evaluated the functions of natural killer (NK) cells in experimental animal models of atherosclerosis, it is not yet clear whether NK cells behave as protective or proatherogenic effectors. One of the main caveats of previous studies was the lack of specificity in targeting loss or gain of function of NK cells. OBJECTIVES: We used 2 selective genetic approaches to investigate the role of NK cells in atherosclerosis: (1) Ncr1iCre/+R26lsl-DTA/+ mice in which NK cells were depleted and (2) Noé mice in which NK cells are hyperresponsive. METHODS AND RESULTS: No difference in atherosclerotic lesion size was found in Ldlr-/- (low-density lipoprotein receptor null) mice transplanted with bone marrow (BM) cells from Ncr1iCreR26Rlsl-DTA , Noé, or wild-type mice. Also, no difference was observed in plaque composition in terms of collagen content, macrophage infiltration, or the immune profile, although Noé chimera had more IFN (interferon)-γ-producing NK cells, compared with wild-type mice. Then, we investigated the NK-cell selectivity of anti-asialoganglioside M1 antiserum, which was previously used to conclude the proatherogenicity of NK cells. Anti-asialoganglioside M1 treatment decreased atherosclerosis in both Ldlr-/- mice transplanted with Ncr1iCreR26Rlsl-DTA or wild-type bone marrow, indicating that its antiatherogenic effects are unrelated to NK-cell depletion, but to CD8+ T and NKT cells. Finally, to determine whether NK cells could contribute to the disease in conditions of pathological NK-cell overactivation, we treated irradiated Ldlr-/- mice reconstituted with either wild-type or Ncr1iCreR26Rlsl-DTA bone marrow with the viral mimic polyinosinic:polycytidylic acid and found a significant reduction of plaque size in NK-cell-deficient chimeric mice. CONCLUSIONS: Our findings, using state-of-the-art mouse models, demonstrate that NK cells have no direct effect on the natural development of hypercholesterolemia-induced atherosclerosis, but may play a role when an additional systemic NK-cell overactivation occurs.

Fertility and pregnancy in Iranian thalassemia patients: An update on transfusion complications.

BACKGROUND: Despite the significant advances in thalassemia pathobiology and efficacy of chelation regimens, complications of transfusion therapy have attenuated the reproductive health of thalassemia patients. Depending on clinical profiles, we aimed to assess the fertility status and stresses among thalassemia patients who desired to have children. MATERIAL AND METHODS: A total of 213 couples in reproductive ages were enrolled in this study in Tehran. Patients' demographic, clinical, fertility and spouse's health status were documented. We evaluated the pituitary-gonadal axis, serum ferritin, liver enzymes, and alloimmunization before planning a pregnancy and reported them as a function of spontaneous conception and transfusion dependency. RESULTS: Data showed that 131 patients (62%) had 228 spontaneous pregnancies leading to 198 (86.6%) successful pregnancies. A significant difference was observed in spontaneous pregnancy with respect to fertility complications and transfusion dependency. In addition, the clinical conditions of spouses in patients with any spontaneous pregnancy were more thalassemia carriers (P < .05). Moreover, serum ferritin levels had a significant negative correlation with the levels of Testosterone, Estradiol, luteinizing hormone, and follicle-stimulating hormone. Furthermore, a significant positive correlation was reported with the level of liver enzymes. Finally, alanine transaminase and aspartate transaminase had a significant negative correlation with pituitary hormones. CONCLUSION: We suggest that organised instruction in addition to good iron chelation, especially during the puberty period, would reduce the oxidative damage and related complications in thalassemia patients. Moreover, infertility seems to be attributed to iron deposition in various endocrine organs, pituitary, reproductive system and the liver, contributing to hormonal metabolism.

Calorie restriction promotes remyelination in a Cuprizone-Induced demyelination mouse model of multiple sclerosis.

Over the past few decades several attempts have been made to introduce a potential and promising therapy for Multiple sclerosis (MS). Calorie restriction (CR) is a dietary manipulation to reduce calorie intake which has been shown to improve neuroprotection and attenuate neurodegenerative disorders. Here, we evaluated the effect of 33% CR regimen for 4 weeks on the remyelination capacity of Cuprizone (CPZ) induced demyelination in a mouse model of MS. Results showed that CR induced a significant increase in motor coordination and balance performance in CPZ mice. Also, luxol fast blue (LFB) staining showed that CR regimen significantly improved the remyelination in the corpus callosum of CPZ + CR mice compared to the CPZ group. In addition, CR regimen significantly increased the transcript expression levels of BDNF, Sox2, and Sirt1 in the corpus callosum of CPZ mice, while decreasing the p53 levels. Moreover, CR regimen significantly decreased the apoptosis rate. Furthermore, astrogliosis (GFAP + astrocytes) and microgliosis (Iba-1 + microglia) were significantly decreased by CR regimen while oligodendrogenesis (Olig2+) and Sirt1 + cell expression were significantly increased in the corpus callosum of CPZ + CR mice compared to the CPZ group. In conclusion, CR regimen can promote remyelination potential in a CPZ-demyelinating mouse model of MS by increasing oligodendrocyte generation while decreasing their apoptosis.

Polyurethane/chitosan/hyaluronic acid scaffolds: providing an optimum environment for fibroblast growth.

OBJECTIVE: Biodegradable polymers can replace damaged tissue components using tissue engineering techniques. The objective of this study is to determine an optimum environment for polymer scaffolds to improve the proliferation of fibroblast cells capable of wound repair. METHOD: In this study, the addition of polysaccharides, such as chitosan (CH) or hyaluronic acid (HA), to a polyurethane (PU) polymer was evaluated using different methods to determine if they affect scaffold morphology and cell activity of fibroblasts prepared from human foreskin tissues. Mechanical properties, such as tensile strength, contact angle and swelling test, were used to check the physical and mechanical properties of the scaffold. Fibroblast growth was also measured at 24, 48 and 72 hours. RESULTS: Scanning electron microscopy (SEM) determined that a 3:1 ratio of PU/CH scaffold, developed by electrospinning, allowed the formation of a uniform structure in scaffold fibres. Physical mechanical tests showed that PU electrospun scaffolds were not modified by the addition of CH. The mean stretch and mean water absorption increased significantly using the PU/CH scaffold, compared with the PU scaffold. However, the mean tensile strength and the mean contact angle, used to study space and porosity, did not differ between scaffolds. Fourier transform infrared spectroscopy confirmed the functional groups (-OH, -NH and -C=O) in the PU/CH scaffold, compared with PU or CH chemical structures alone. HA was then added to CH and PU/CH scaffolds to evaluate the growth of fibroblast cells. Results showed that cell viability and the number of cells, using MTT and trypan blue exclusion assay, respectively, increased significantly at 24, 48 and 72 hours of culture in PU/CH/HA scaffold compared to HA, CH/HA, and PU/HA. Moreover, PU/HA at 48 and 72 hours also increased cell viability and cell numbers compared to HA and CH/HA scaffolds. However, scaffolds at 72 hours had limited space for cell growth. Moreover, SEM data demonstrated that fibroblasts were able to proliferate, penetrate, migrate and survive on PU/HA and PU/CH/HA three-dimensional scaffolds, especially during the first 48 hours. Furthermore, 4',6-diamidino-2-phenylindole (DAPI) staining confirmed that fibroblasts could penetrate PU scaffolds and showed higher cell viability and lower cellular damage in PU/CH/HA, compared to CH/HA and PU/HA scaffolds. Finally, flow cytometry using CD90 and CD105 surface markers revealed that >90% of cells isolated from the human dermis were fibroblasts. CONCLUSION: In summary, PU/HA and PU/CH/HA scaffolds were found to be biocompatible and provided a suitable environment for the growth and proliferation of fibroblasts, which filled and covered all pores between the fibres. The new scaffold used in this study, made of synthetic and natural polymers, is a good candidate for applications in tissue engineering. It is therefore recommended to use PU in grafts or in wound dressing.

VAS3947 Induces UPR-Mediated Apoptosis through Cysteine Thiol Alkylation in AML Cell Lines.

Nicotinamide adenine dinucleotide phosphate (NADPH) oxidases (NOX) involvement has been established in the oncogenic cell signaling of acute myeloid leukemia (AML) cells and in the crosstalk with their niche. We have shown an expression of NOX subunits in AML cell lines while NOX activity is lacking in the absence of exogenous stimulation. Here, we used AML cell lines as models to investigate the specificity of VAS3947, a current NOX inhibitor. Results demonstrated that VAS3947 induces apoptosis in AML cells independently of its anti-NOX activity. High-performance liquid chromatography (HPLC) and mass spectrometry analyses revealed that VAS3947 thiol alkylates cysteine residues of glutathione (GSH), while also interacting with proteins. Remarkably, VAS3947 decreased detectable GSH in the MV-4-11 cell line, thereby suggesting possible oxidative stress induction. However, a decrease in both cytoplasmic and mitochondrial reactive oxygen species (ROS) levels was observed by flow cytometry without disturbance of mitochondrial mass and membrane potential. Thus, assuming the consequences of VAS3947 treatment on protein structure, we examined its impact on endoplasmic reticulum (ER) stress. An acute unfolded protein response (UPR) was triggered shortly after VAS3947 exposure, through the activation of inositol-requiring enzyme 1α (IRE1α) and PKR-like endoplasmic reticulum kinase (PERK) pathways. Overall, VAS3947 induces apoptosis independently of anti-NOX activity, via UPR activation, mainly due to aggregation and misfolding of proteins.

Activation of the calcium-sensing receptor in human valvular interstitial cells promotes calcification.

INTRODUCTION AND AIMS: Calcific aortic valve disease (CAVD) is the most common heart valve disease in western countries. It has been reported that activation of the calcium-sensing receptor(CaSR) expressed by vascular smooth muscle cells prevents vascular calcification. However, to date, the CaSR's expression and function in cardiac valves have not been studied. The present study sought to evaluate the presence of the CaSR within human valvular interstitial cells (hVICs), assess the CaSR's functionality, and ascertain its involvement in hVIC calcification. METHODS AND RESULTS: Data from Western blot, flow cytometry and immunocytochemistry experiments demonstrated that primary hVICs express the CaSR. The receptor was functional, since the incubation of hVICs with the calcimimetic R-568 significantly increased Ca2+-induced ERK1/2 phosphorylation, and exposure to the calcilytic NPS2143 reduced ERK1/2 activation. A reduction in endogenous CaSR expression by hVICs (using siRNA) was associated with significantly lower levels of Ca2+-induced mineralization (quantified using Alizarin Red staining). Similar data were obtained after the pharmacological inhibition of CaSR activity by the calcilytic NPS2143. In contrast, overexpression of a functional CaSR amplified Ca2+-induced calcification. Pharmacological activation of the CaSR with the calcimimetic R-568 showed similar effects. CaSR's procalcific properties are associated with increased osteogenic transition (as characterized by elevated mRNA expression of bone morphogenetic protein 2 and osterix), and reduced the expression of the calcification inhibitor osteopontin. Histological analysis of 12 human aortic tricuspid valves showed that CaSR expression was greater in calcified areas than in non-calcified areas. These data were confirmed by Western blots. CONCLUSIONS: To the best of our knowledge, this study is the first to have demonstrated that hVICs express a functional CaSR. Taken as a whole, our data suggest that activation of the CaSR expressed by hVICs might be a key promoter of CAVD progression.

Chronic myeloid leukemia with complex karyotypes: Prognosis and therapeutic approaches.

OBJECTIVE AND BACKGROUND: Chronic myeloid leukemia (CML) is a neoplastic disease whose genetic and cytogenetic changes play important roles in prognosis and treatment strategies. Philadelphia (Ph) translocation t(9;22)(q34;q11) is a diagnostic and prognostic biomarker in CML. METHODS: Pubmed and Google Scholar databases were searched for English language articles from 1975 to 2017 containing the terms CML; Additional chromosomal abnormalities; Philadelphia translocation; Prognosis; and Treatment. DISCUSSION: Approximately 10-12% of CML patients exhibit additional chromosomal aberrations (ACAs) in chronic phase and blast crisis. ACAs emergence may cause different features in CML patients according to Ph pattern. For instance, deletion of chromosome 9 derivation is associated to patient's bad survival, whereas monosomy 7 develops myeloid dysplastic syndrome (MDS) or acute myeloid leukemia (AML) in CML patients with Ph-negative pattern. And ACAs in Ph-positive CML is considered as a failure in the management of CML with imatinib. CONCLUSION: CML classification using different features such as Ph and ACAs can play a decisive role in the evaluation of treatment responses in patients, for example, CML patients with Ph negative and monosomy 7 develop MDS or CML patient -Y and extra copy of Ph have a good response to tyrosine kinase inhibitors, therefore, classifications according to Ph and ACAs play an important role in choosing better treatment protocols and therapeutic strategies. Karyotype analysis in CML patients with complex karyotype shows unrandom pattern so ACAs can be great clue in medical guidelines.

Autophagy regulation and its role in normal and malignant hematopoiesis.

Autophagy, the molecular machinery of self-eating, plays a dual role of a tumor promoter and tumor suppressor. This mechanism affects different clinical responses in cancer cells. Autophagy is targeted for treating patients resistant to chemotherapy or radiation. Limited reports investigate the significance of autophagy in cancer therapy, the regulation of hematopoietic and leukemic stem cells and leukemia formation. In the current review, the role of autophagy is discussed in various stages of hematopoiesis including quiescence, self-renewal, and differentiation.

Matrix-Assisted Laser Desorption/Ionization-Mass Spectrometry Imaging of Lipids in Experimental Model of Traumatic Brain Injury Detecting Acylcarnitines as Injury Related Markers.

Identifying new lipid markers linked to traumatic brain injury (TBI) is of major importance in characterizing their central role in the regeneration process and inflammatory response in such an injury model. In the present study, an advanced lipidomics analysis using high spectral resolution matrix-assisted laser desorption/ionization-mass spectrometry imaging was performed on different brain regions in an experimental rat model of moderate controlled cortical impact (CCI) while considering different time points (1 day, 3 days, 7 days, and 10 days) assessing the acute and subacute phase after injury. Our results revealed a new family of lipids, the acylcarnitines, as TBI-lipid related markers, with maximum expression at 3 days after impact and main colocalization within resident microglia of the brain. Furthermore, our experiments highlighted the upregulation of these acylcarnitine lipids, secreted by microglia, in the ipsilateral substantia nigra, the main region in the brain affected in Parkinson's disease (PD).