Active Nucleosome Displacement: A Theoretical Approach

AbstractThree-quarters of eukaryotic DNA are wrapped around protein cylinders forming so-called nucleosomes that block the access to the genetic information. Nucleosomes need therefore to be repositioned, either passively (by thermal fluctuations) or actively (by molecular motors). Here we introduce a theoretical model that allows us to study the interplay between a motor protein that moves along DNA (e.g., an RNA polymerase) and a nucleosome that it encounters on its way. We aim at describing the displacement mechanisms of the nucleosome and the motor protein on a microscopic level to understand better the intricate interplay between the active step of the motor and the nucleosome-repositioning step. Different motor types (Brownian ratchet versus power-stroke mechanism) that perform very similarly under a constant load are shown to have very different nucleosome repositioning capacities

Relationship between Vitamin D Receptor Gene Polymorphisms and Migraine without Aura in an Iranian Population

Background. Inflammation has a key role in migraine pathophysiology. Vitamin D is an effective anti-inflammatory agent. The aim of this study was to investigate the association between migraine and two vitamin D receptor (VDR) polymorphisms (TaqI and FokI) and also the relationship between VDR polymorphisms and headache severity. Methods. In this case-control study we assessed 103 patients with newly diagnosed migraine without aura and 100 healthy subjects. Patients filled headache impact test-6 (HIT-6) as a tool to assess headache severity. Results. Genotype frequencies of VDR were significantly different between control and migraine patients. Heterozygote genotypes (Ff and Tt) were statistically more frequent in the migraine patients than the control subjects both for TaqI gene ( = 0.018; OR = 1.81, 95% CI = 1.03-3.18) and FokI gene polymorphisms ( = 0.001; OR = 2.91, 95% CI = 1.47-5.77). Also f and t alleles were more frequent in the migraine patients. Total HIT-6 score was significantly different between FokI heterozygote and homozygote patients (60.32 ± 1.87 versus 49.87 ± 2.69, resp., = 0.004). Conclusions. In conclusion our results showed that TaqI and FokI gene polymorphisms are associated with migraine without aura in Iranians patients. Also headache severity in FokI heterozygote patients was significantly greater than in the homozygote patients

The dysbiosis signature of Fusobacterium nucleatum in colorectal cancer-cause or consequences? A systematic review

Colorectal cancer (CRC) is the third most common cause of cancer globally and the fourth attributable cause of mortality and morbidity due to cancer. An emerging factor contributing to CRC is the gut microbiota and the cellular changes associated with it. Further insights on this may help in the prevention, diagnosis and new therapeutic approaches to colorectal cancer. In most cases of CRC, genetic factors appear to contribute less to its aetiology than environmental and epigenetic factors; therefore, it may be important to investigate these environmental factors, their effects, and the mechanisms that may contribute to this cancer. The gut microbiota has recently been highlighted as a potential risk factor that may affect the structural components of the tumor microenvironment, as well as free radical and enzymatic metabolites directly, or indirectly. Many studies have reported changes in the gut microbiota of patients with colorectal cancer. What is controversial is whether the cancer is the cause or consequence of the change in the microbiota. There is strong evidence supporting both possibilities. The presence of Fusobacterium nucleatum in human colorectal specimens has been demonstrated by RNA-sequencing. F. nucleatum has been shown to express high levels of virulence factors such as FadA, Fap2 and MORN2 proteins. Our review of the published data suggest that F. nucleatum may be a prognostic biomarker of CRC risk, and hence raises the potential of antibiotic treatment of F. nucleatum for the prevention of CRC

The global burden of cancer attributable to risk factors, 2010-19 : a systematic analysis for the Global Burden of Disease Study 2019

Background Understanding the magnitude of cancer burden attributable to potentially modifiable risk factors is crucial for development of effective prevention and mitigation strategies. We analysed results from the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2019 to inform cancer control planning efforts globally. Methods The GBD 2019 comparative risk assessment framework was used to estimate cancer burden attributable to behavioural, environmental and occupational, and metabolic risk factors. A total of 82 risk-outcome pairs were included on the basis of the World Cancer Research Fund criteria. Estimated cancer deaths and disability-adjusted life-years (DALYs) in 2019 and change in these measures between 2010 and 2019 are presented. Findings Globally, in 2019, the risk factors included in this analysis accounted for 4.45 million (95% uncertainty interval 4.01-4.94) deaths and 105 million (95.0-116) DALYs for both sexes combined, representing 44.4% (41.3-48.4) of all cancer deaths and 42.0% (39.1-45.6) of all DALYs. There were 2.88 million (2.60-3.18) risk-attributable cancer deaths in males (50.6% [47.8-54.1] of all male cancer deaths) and 1.58 million (1.36-1.84) risk-attributable cancer deaths in females (36.3% [32.5-41.3] of all female cancer deaths). The leading risk factors at the most detailed level globally for risk-attributable cancer deaths and DALYs in 2019 for both sexes combined were smoking, followed by alcohol use and high BMI. Risk-attributable cancer burden varied by world region and Socio-demographic Index (SDI), with smoking, unsafe sex, and alcohol use being the three leading risk factors for risk-attributable cancer DALYs in low SDI locations in 2019, whereas DALYs in high SDI locations mirrored the top three global risk factor rankings. From 2010 to 2019, global risk-attributable cancer deaths increased by 20.4% (12.6-28.4) and DALYs by 16.8% (8.8-25.0), with the greatest percentage increase in metabolic risks (34.7% [27.9-42.8] and 33.3% [25.8-42.0]). Interpretation The leading risk factors contributing to global cancer burden in 2019 were behavioural, whereas metabolic risk factors saw the largest increases between 2010 and 2019. Reducing exposure to these modifiable risk factors would decrease cancer mortality and DALY rates worldwide, and policies should be tailored appropriately to local cancer risk factor burden. Copyright (C) 2022 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license.Peer reviewe

Evaluation of CD52 positive sperms in subfertile human semen samples: Is there any relationship with main semen parameters?

Background: Sperm maturation and sperm membrane integration are the most important elements in male fertility. CD52 is one of the antigens. CD52 is a GPI (glycosylphosphatidylinositol) anchored that express on lymphocytes and epididymal cells. This antigen bind to sperm membrane during transition sperm from epididymal duct as well as its relationship with semenogelins in human seminal plasma. The aim of this study was to obtain any association between the percentage of CD52 positive sperms with main semen parameters such as percentage of motile sperms, percentage of sperm with normal morphology, and the presence of normal viscosity. Materials and Methods: Semen samples from subfertile men were analyzed, the samples totally were 45 that divided according to their motility into three groups, first one, more than 40%, second one 10-40%, and the third one under 10% total motility. Fifteen samples in each group were evaluated by semen analysis according to WHO 2010 guidelines for infertility laboratory. Sperms were washed by Ham′s F-10 and immunostaining with the monoclonal antibody CAMPATH-1G and then analyzed by flow cytometry. We compared each of the groups based on their motility and the data were analyzed by SPSS 20. Results: Correlation between CD52 labeling and sperm motility was negatively significant, in the second group (r = -0.592, P = 0.020) and in the third group (r = -0.805, P = 0.00). Conclusion: Our results showed that the correlation between CD52 labeling and sperm motility was negatively significant, but we did not observe any relation with other semen parameters, such as sperm normal morphology, sperm concentration, and semen viscosity

Role of peroxisome proliferator-activated receptor alpha and gamma in antiangiogenic effect of pomegranate peel extract

Objective(s): Herbal medicines are promising cancer preventive candidates. It has been shown that Punica granatum L. could inhibit angiogenesis and tumor invasion. In this study, we investigated whether the anti-angiogenic effect of pomegranate peel extract (PPE) is partly attributable to Peroxisome proliferator-activated receptors (PPARs) activation in the Human Umbilical Vein Endothelial Cells (HUVECs). Materials and Methods: Ethanol extract from PPE was prepared. HUVECs were treated in four groups (with PPE (10 μg/ml) alone, PPE with or without PPARγ (T0070907) and α (GW6471) antagonists, and control group). The possible effect of PPARs on angiogenic regulation was checked by Matrigel assay. The mRNA expression levels of vascular endothelial growth factor (VEGF) was detected by Quantitative reverse transcription-polymerase chain reaction (QRT-PCR).  Results: PPE significantly inhibited both tube formation (size, length, and junction of tubes) and VEGF mRNA expression (

Fluvoxamine inhibits some inflammatory genes expression in LPS/stimulated human endothelial cells, U937 macrophages, and carrageenan-induced paw edema in rat

Objective(s): Fluvoxamine is a well-known selective serotonin reuptake inhibitor (SSRI); Despite its anti-inflammatory effect, little is known about the precise mechanisms involved. In our previous work, we found that IP administration of fluvoxamine produced a noticeable anti-inflammatory effect in carrageenan-induced paw edema in rats. In this study, we aimed to evaluate the effect of fluvoxamine on the expression of some inflammatory genes like intercellular adhesion molecule (ICAM1), vascular cell adhesion molecule (VCAM1), cyclooxygenases2 (COX2), and inducible nitric oxide synthase (iNOS). Materials and Methods: An in vitro model of LPS stimulated human endothelial cells and U937 macrophages were used. Cells were pretreated with various concentrations of fluvoxamine, from 10-8 M to 10-6 M. For in vivo model, fluvoxamine was administered IP at doses of 25 and 50 mg/kg-1, before injection of carrageenan. At the end of experiment, the expression of mentioned genes were measured by quantitative real time (RT)-PCR in cells and in paw edema in rat. Results: The expression of ICAM1, VCAM1, COX2, and iNOS was significantly decreased by fluvoxamine in endothelial cells, macrophages, and in rat carrageenan-induced paw edema. Our finding also confirmed that IP injection of fluvoxamine inhibits carrageenan-induced inflammation in rat paw edema. Conclusion: The results of present study provide further evidence for the anti-inflammatory effect of fluvoxamine. This effect appears to be mediated by down regulation of inflammatory genes. Further studies are needed to evaluate the complex cellular and molecular mechanisms of immunomodulatory effect of fluvoxamine

In vitro and in vivo modulation of LPS and carrageenan-induced expression of inflammatory genes by amitriptyline

Context: Amitriptyline, a tricyclic antidepressant is used for the management of psychological disorders and various types of pain. In the previous work, it is founded that amitriptyline inhibited the migration of polymorphonuclear (PMN) into the site of inflammation. Aims: To evaluate the effect of amitriptyline on the expression of some inflammatory mediators such as intercellular adhesion molecule (ICAM-1), vascular cell adhesion molecule (VCAM-1), cyclooxygenase 2 (COX2) and inducible nitric oxide synthase (iNOS). Methods: An in vitro model system of LPS-stimulated human endothelial cells and U937 macrophages and also in vivo model of carrageenan-induced paw edema in rat were used. The expression of inflammatory mediator genes was determined by qRT-Real-time PCR. In endothelial cells, soluble forms of ICAM-1 and VCAM-1 were quantified by ELISA. Results: The expression of ICAM-1, VCAM-1, COX2, iNOS, sICAM-1 and sVCAM-1 significantly decreased by amitriptyline. The finding of this study also confirmed that intraperitoneal (i.p.) injection of amitriptyline inhibited carrageenan-induced inflammation in rat paw edema. Conclusions: The results of the present study provide further evidence for the anti-inflammatory effect of amitriptyline. This effect appears to be mediated by down-regulation of inflammatory genes

Evaluation of the Effect of Antidepressant Drug, Fluvoxamine, on Cyclooxygenase-2 Protein Expression in Lipopolysaccharide-stimulated Macrophages

Background: Fluvoxamine, a well-known selective serotonin reuptake inhibitor, is used for the management of mental disorders and various types of chronic pain. In our previous study, we found the inhibitory effect of fluvoxamine on inflammatory mediator's expression. In the line of the indicated study, we sought to evaluate the effect of fluvoxamine on the expression of some inflammatory mediators such as cyclooxygenase-2 (COX-2). Materials and Methods: An in vitro model system of lipopolysaccharide-stimulated human U937 macrophages was used. The expression of COX-2 protein was measured by flow cytometry. Results: The expression of COX-2 significantly decreased by fluvoxamine in U937 macrophages. Conclusion: The results of the present study provide further evidence for the anti-inflammatory effect of fluvoxamine. This effect appears to be mediated by the downregulation of inflammatory genes. Further studies are needed to evaluate the complex cellular and molecular mechanisms of fluvoxamine