Multifactorial Effects Research Articles

Epidemiology of Severe Cutaneous Adverse Drug Reaction and Its HLA Association among Pediatrics.

Severe cutaneous adverse drug reaction (SCAR) is considered to be a multifactorial drug side effect. This study was designed to investigate the epidemiology and human leukocyte antigen (HLA)-A and -B gene polymorphisms in pediatric patients with SCAR admitted in tertiary referral center, southwestern of Iran from 2013 to 2017. Demographic data, past allergy and autoimmune history, clinical presentations, drugs confirmed to be the cause of SCAR as well as its therapy were reviewed for each patient. HLA-A and -B allele frequencies were determined in 40 of the patients using polymerase chain reaction based on sequence specific primers (PCR-SSP) and compared with 40 healthy individuals as control group. Sixty-one patients with mean age of 6 years old and boy to girl ratio was 1.2/1 in this study. The most common type of SCAR in our patients was Steven Johnson Syndrome (SJS)/Toxic Epidermal Necrosis (TEN) mainly caused by beta-lactam antibiotics. Carbamazepine was the second cause of drug-induced SCAR. Moreover, HLA-A*02:01 and A*51:01 were related to the increased risk of SCAR while A*11:01 seemed to be protective against SCAR. HLA-A*02:01, HLA-A*24:02, and HLA-B*51:01 showed associations to the increased risk of SJS. Based on our results, beta-lactam antibiotics and antiepileptic drugs are the most common causes of severe adverse drug reaction in southwestern Iranian pediatric patients. Moreover, some HLA-A alleles can influence risk of SCAR.

ГИГИЕНИЧЕСКИЕ ОСНОВЫ ОЦЕНКИ РИСКА РАЗВИТИЯ РЕПРОДУКТИВНЫХ НАРУШЕНИЙ У ЖЕНЩИН-ВРАЧЕЙ АКУШЕРОВ-ГИНЕКОЛОГОВ В СВЯЗИ С УСЛОВИЯМИ ТРУДА

Background. Women doctors obstetrician-gynecologists belong to the professional group that is the most susceptible to the multifactorial effects of harmful occupational factors. The aim of the study is to assess the occupational risks for development of reproductive disorders among women doctors obstetrician-gynecologists. Material and methods. The professional risk assessment was carried out on the basis of a comprehensive hygienic assessment of working conditions. Results. It has been established that factors of biological, psychophysiological and chemical (in stationary conditions) nature made a significant contribution to the formation of harmful working conditions in working places of women doctors obstetrician-gynecologists (class 3.2 – in the antenatal clinics, class 3.3 – in the obstetric-gynecological hospitals). Conclusion. The working conditions of women doctors obstetrician-gynecologists determine the «average» and «high» degree of risk for reproductive health disorders that requires the development of a set of appropriate preventive measures.

Центральное Черноземье: военное сословие и его роль в региональном развитии

We consider the multifactorial effects of the military class, including the soldiers of the Russian army and their families, as well as indefinite, spare and retired soldiers, military disabled, on the social and cultural, ethnic and confessional, social and class development of the Central Black Earth Region. Included in it Voronezh, Kursk, Orel and Tambov Governorates were the largest densely populated, agricultural regions, traditionally used by the government for military procurement, cantonment of troops and other military mobilization activities in the Russian Em-pire in the 18th – early 20th century. The military factor had almost continuous impact on all as-pects of life of the Central Black Earth Region population, forming in its inhabitants a special character, endurance and stamina, which allowed to be quite successful in a peaceful, “non-military” life. We give the evaluation of historiographical approaches and interpretation of sources on the role of the military class in the Center Black Earth Region development in domestic and foreign historiography. We pay special attention to the impact of recruitment on the daily life of the population in the cities of the region and rural areas. We reveal the historical and legal aspects of changes in the legal status of male and female representatives of the “military class” in the agrarian society in the Imperial Russia. We clarify military and statistical indicators of military class representation in the social structure of the provincial society during the period of conscript obligation and in post-reform Russia, as well as the complexity of accounting for family members of military servicemen during the service and after retirement. The involvement of archival docu-ments, statistical and other published materials allowed for a successful reconstruction of the so-cial and legal regulation and the position of the military class in the Center Black Earth Region of the considered chronological period. We draw conclusions about the prospects of studying the post-reform ethnic and social, social and cultural, class and legal features of the military class life in a non-belligerent provincial society. We prove that the military class was a special social institu-tion in the Russian province of the Imperial period of Russian history.

Clinical and morphological aspects of myocardial damage and cardioprotection in patients with leukemia

Myocardial damage in the background of leukemia is considered as a manifestation of the disease and various types of therapy. It is noted that myocardial damage in this category of patients is the result of multifactorial effects on the myocardium in the oncohematologic patient. The problem of cardioprotection is quite actively studied in order to develop effective prophylaxis and reduce the cardiotoxicity of the most common groups of cytostatic drugs. Purpose — to investigate the features of myocardial damage in patients with leukemia and the prospects of therapeutic intervention. A comprehensive clinical and laboratory study was conducted for 92 patients with leukemia who were on examination and treatment in the hematological department of the Vinnitsa Regional Clinical Hospital named after M.I. Pirogov and received cytostatic therapy in accordance with the nosology and protocol of medical care of the Ministry of Health of Ukraine. Additionally, patients were screened for quality of life indicators according to the methods proposed by us. The statistical processing of the obtained results was carried out in the license package “STATISTICA 6.1” with the use of nonparametric methods for evaluating the obtained results. Evaluated the correctness of the distribution of characteristics for each of the variation series received, the mean of each studied feature, and the standard quadratic deviation. The reliability of the difference between independent quantitative values was determined using the Man-Whitney U-criterion. Signs of myocardial damage were detected in all patients prior to cytostatic therapy. The analysis of medical correction of myocardial damage in patients is carried out. All patients received metabolic therapy in the form of Meldonium, Arginine, Tivortin and aspartic acid. However, these appointments were not standardized, which did not allow to assess the effectiveness of their appointment. Therapy for heart failure was performed by metabolic, diuretic, accompanied by clinical and laboratory improvement. Prospects of standardization of pharmacological cardioprotection in patients with leukemia are considered.

DEFECTS IN METAL DURING PLASMA AND TIG SURFACING (REVIEW)

In the process of exploitation, such property of articles as working capacity most often depends on the quality and condition of the surface layer. Therefore, a complex approach that includes a multifactorial effect on phase formation and structure formation in metal systems with the use of modern equipment is of particular relevance. The quality of products, determined by a number of its mechanical properties, can be significantly reduced by the occurrence and spreading of defects in products in surfacing, welding and additive technologies that are associated with the use of highly concentrated energy sources, which is a significant problem.Preventing the occurrence of defects during surfacing is a priority and urgent task in modern machine-building production. The solution to this problem can be the selection of optimal deposition modes in accordance with the requirements for the quality of the welded layer, the mechanical properties of the material of the parts and the quality of the products as a whole.

Mangiferin: An effective therapeutic agent against several disorders (Review).

Mangiferin (1,3,6,7‑tetrahydroxyxanthone‑C2‑β‑D‑glucoside) is a bioactive ingredient predominantly isolated from the mango tree, with potent antioxidant activity and multifactorial pharmacological effects, including antidiabetic, antitumor, lipometabolism regulating, cardioprotective, anti‑hyperuricemic, neuroprotective, antioxidant, anti‑inflammatory, antipyretic, analgesic, antibacterial, antiviral and immunomodulatory effects. Therefore, it possesses several health‑endorsing properties and is a promising candidate for further research and development. However, low solubility, mucosal permeability and bioavailability restrict the development of mangiferin as a clinical therapeutic, and chemical and physical modification is required to expand its application. This review comprehensively analyzed and collectively summarized the primary pharmacological actions of mangiferin that have been demonstrated in the literature, to support the potential future development of mangiferin as a novel therapeutic drug.

Experimental and computational studies of the interactions between carbon nanotubes and ionic liquids used for detection of acetaminophen

The interactions between multi-walled carbon nanotubes and different amounts of an ionic liquid (IL), as well as the interactions between this system (used as electrochemical sensor) and acetaminophen (ACOP), were investigated through both experimental and theoretical methodologies. Experiments indicated that there is an optimal concentration of ionic liquid for ACOP detection. A host of techniques and model systems were employed to investigate the adsorption and oxidation processes. To investigate the source of the increased electrochemical current in the presence of an IL, we computed the adsorption energy values of ACOP in the nanotube – IL system via Monte Carlo simulations and Density Functional Theory (DFT). DFT allowed us to explore the changes in adsorption energy due to oxidation. Our theoretical results support the experimental findings that moderate amounts of IL modulates ACOP/ACOP+ adsorption, pointing to a cooperative effect that tends to wane with increasing amounts of IL pairs. We observed that the IL favors desorption of the oxidized species and facilitates charge transfer from the ACOP to the nanotube. Therefore, our studies point towards multifactorial effects with clear physical basis that modulates binding leading to an optimal ratio to promote ACOP detection.

Remote ischemic conditioning as a cytoprotective strategy in vasculopathies during hyperhomocysteinemia: An emerging research perspective.

Higher levels of nonprotein amino acid homocysteine (Hcy), that is, hyperhomocysteinemia (HHcy) (~5% of general population) has been associated with severe vasculopathies in different organs; however, precise molecular mechanism(s) as to how HHcy plays havoc with body's vascular networks are largely unknown. Interventional modalities have not proven beneficial to counter multifactorial HHcy's effects on the vascular system. An ancient Indian form of exercise called 'yoga' causes transient ischemia as a result of various body postures however the cellular mechanisms are not clear. We discuss a novel perspective wherein we argue that application of remote ischemic conditioning (RIC) could, in fact, deliver anticipated results to patients who are suffering from chronic vascular dysfunction due to HHcy. RIC is the mechanistic phenomenon whereby brief episodes of ischemia-reperfusion events are applied to distant tissues/organs; that could potentially offer a powerful tool in mitigating chronic lethal ischemia in target organs during HHcy condition via simultaneous reduction of inflammation, oxidative and endoplasmic reticulum stress, extracellular matrix remodeling, fibrosis, and angiogenesis. We opine that during ischemic conditioning our organs cross talk by releasing cellular messengers in the form of exosomes containing messenger RNAs, circular RNAs, anti-pyroptotic factors, protective cytokines like musclin, transcription factors, small molecules, anti-inflammatory, antiapoptotic factors, antioxidants, and vasoactive gases. All these could help mobilize the bone marrow-derived stem cells (having tissue healing properties) to target organs. In that context, we argue that RIC could certainly play a savior's role in an unfortunate ischemic or adverse event in people who have higher levels of the circulating Hcy in their systems.

Bulk tank milk ELISA to detect IgG1 prevalence and clustering to determine spatial distribution and risk factors of Fasciola hepatica-infected herds in Mexico.

Fasciola hepatica is a helminth parasite that causes huge economic losses to the livestock industry worldwide. Fasciolosis is an emerging foodborne zoonotic disease that affects both humans and grazing animals. This study investigated the associations between climatic/environmental factors (derived from satellite data) and management factors affecting the spatial distribution of this liver fluke in cattle herds across different climate zones in three Mexican states. A bulk-tank milk (BTM) IgG1 enzyme-linked immunosorbent assay (ELISA) test was used to detect F. hepatica infection levels of 717 cattle herds between January and April 2015. Management data were collected from the farms by questionnaire. The parasite's overall herd prevalence and mean optical density ratio (ODR) were 62.76% and 0.67, respectively. The presence of clustered F. hepatica infections was studied using the spatial scan statistic. Three marked clusters in the spatial distribution of the parasite were observed. Logistic regression was used to test three models of potential statistical association from the ELISA results using climatic, environmental and management variables. The final model based on climatic/environmental and management variables included the following factors: rainfall, elevation, proportion of grazed grass in the diet, contact with other herds, herd size, parasite control use and education level as significant predictors. Geostatistical kriging was applied to generate a risk map for the presence of parasites in dairy herds in Mexico. In conclusion, the spatial distribution of F. hepatica in Mexican cattle herds is influenced by multifactorial effects and should be considered in developing regionally adapted control measures.

Menopausal hormone treatments and risk of cardiovascular diseases: modern view

Estrogens have a multifactorial protective effect on various components of the cardiovascular system, and postmenopause in women is associated with an increased incidence of cardiovascular disease. Admission of menopausal hormone therapy helps to reduce the risk of cardiovascular events, but the perceived benefit far outweighs the risks in cases where women begin treatment no later than at the age of 60 or 10 years after menopause. Studies have shown that the combination of estradiol and drospirenone is effective and safe in terms of preventing cardiovascular diseases. The antiandrogenic effect of drospirenone has additional metabolic effects that may be preferable in certain groups of postmenopausal patients.

Evaluation of renal and cardiovascular protection mechanisms of SGLT2 inhibitors: model-based analysis of clinical data.

The mechanisms of cardiovascular and renal protection observed in clinical trials of sodium-glucose cotransporter 2 (SGLT2) inhibitors (SGLT2i) are incompletely understood and likely multifactorial, including natriuretic, diuretic, and antihypertensive effects, glomerular pressure reduction, and lowering of plasma and interstitial fluid volume. To quantitatively evaluate the contribution of proposed SGLT2i mechanisms of action on changes in renal hemodynamics and volume status, we coupled a mathematical model of renal function and volume homeostasis with clinical data in healthy subjects administered 10 mg of dapagliflozin once daily. The minimum set of mechanisms necessary to reproduce observed clinical responses (urinary sodium and water excretion, serum creatinine and sodium) was determined, and important unobserved physiological variables (glomerular pressure, blood and interstitial fluid volume) were then simulated. We further simulated the response to SGLT2i in diabetic virtual patients with and without renal impairment. Multiple mechanisms were required to explain the observed response: 1) direct inhibition of sodium and glucose reabsorption through SGLT2, 2) SGLT2-driven inhibition of Na+/H+ exchanger 3 sodium reabsorption, and 3) osmotic diuresis coupled with peripheral sodium storage. The model also showed that the consequences of these mechanisms include lowering of glomerular pressure, reduction of blood and interstitial fluid volume, and mild blood pressure reduction, in agreement with clinical observations. The simulations suggest that these effects are more significant in diabetic patients than healthy subjects and that while glucose excretion may diminish with renal impairment, improvements in glomerular pressure and blood volume are not diminished at lower glomerular filtration rate, suggesting that cardiorenal benefits of SGLT2i may be sustained in renally impaired patients.

The multifactorial effects of dispersal on biodiversity in environmentally forced metacommunities

AbstractDisentangling the effects of dispersal and environmental heterogeneity on biodiversity is a central goal in ecology. Although metacommunity structure can be partitioned into spatial and environmental fractions, it remains unclear whether these statistical results can be used to infer the relative importance of dispersal limitation (spatial fraction) and environmental forcing (environmental fraction). Using an environmentally forced, spatially explicit metacommunity model, we show that the distinct effects of the mean (advection) and the standard deviation (diffusion) of the dispersal kernel on biodiversity are not easily detectable via variation partitioning alone. Although increasing dispersal ultimately leads to a decrease in the spatial fraction due to reduced dispersal limitation and greater species sorting, the magnitude of the spatial fraction depends on the complex interplay between the nature of dispersal and the type of boundary conditions in the metacommunity. Indeed, metacommunities characterized by either high or low dispersal can exhibit a small spatial fraction. A case study of a marine metacommunity experiencing strong alongshore transport is consistent with these findings, as the size of the spatial fraction is not associated with dispersal. Overall, our results suggest that accounting for the nature of environmental forcing as well as the multifactorial effects of dispersal is critical for understanding how ecological and environmental processes give rise to biodiversity across spatial scales.

Disruption of microglia histone acetylation and protein pathways in mice exhibiting inflammation-associated depression-like symptoms

BackgroundPeripheral immune challenge can elicit microglia activation and depression-related symptoms. The balance of inflammatory signals in the tryptophan pathway can skew the activity of indoleamine-pyrrole 2,3 dioxygenase (IDO1) towards the metabolization of tryptophan into kynurenine (rather than serotonin), and towards neuroprotective or neurotoxic metabolites. The proteome changes that accompany inflammation-associated depression-related behaviors are incompletely understood. MethodsThe changes in microglia protein abundance and post-translational modifications in wild type (WT) mice that exhibit depression-like symptoms after recovery from peripheral Bacille Calmette-Guerin (BCG) challenge were studied. This WT_BGG group was compared to mice that do not express depression-like symptoms after BCG challenge due to IDO1 deficiency by means of genetic knockout (BCG_KO group), and to WT Saline-treated (Sal) mice (WT_Sal group) using a mass spectrometry-based label-free approach. ResultsThe comparison of WT_BCG relative to WT_Sal and KO_BCG mice uncovered patterns of protein abundance and acetylation among the histone families that could influence microglia signaling and transcriptional rates. Members of the histone clusters 1, 2 and 3 families were less abundant in WT_BCG relative to WT_Sal whereas members in the H2A family exhibited the opposite pattern. Irrespective of family, the majority of the histones were less abundant in WT_BCG relative to KO_BCG microglia. Homeostatic mechanisms may temper the potentially toxic effects of high histone levels after BCG challenge to levels lower than Sal. Histone acetylation was highest in WT_BCG and the similar levels observed in WT_Sal and KO_BCG. This result suggest that histone acetylation levels are similar between IDO1 deficient mice after immune challenge and unchallenged WT mice. The over-abundance of tyrosine 3-monooxygenase/tryptophan 5-monooxygenase activation proteins (14-3-3 series) in WT_BCG relative to KO_BCG is particularly interesting because these proteins activate another rate-limiting enzyme in the tryptophan pathway. The over-representation of alcoholism and systemic lupus erythematosus pathways among the proteins exhibiting differential abundance between the groups suggest that these disorders share microglia activation pathways with BCG challenge. The over-representation of phagosome pathway among proteins differentially abundant between WT_BCG and KO_BCG microglia suggest an association between IDO1 deficiency and phagocytosis. Likewise, the over-representation of the gap junction pathway among the differentially abundant proteins between KO_BCG and WT_Sal suggest a multifactorial effect of BCG and IDO1 deficiency on cell communication. ConclusionsThe present study of histone acetylation and differential protein abundance furthers the understanding of the long lasting effects of peripheral immune challenges. Our findings offer insights into target proteins and mechanisms that provide clues for therapies to ameliorate inflammation-associated depression-related behaviors.

Chromatin assembly factor-1 (CAF-1) chaperone regulates Cse4 deposition into chromatin in budding yeast.

Correct localization of the centromeric histone variant CenH3/CENP-A/Cse4 is an important part of faithful chromosome segregation. Mislocalization of CenH3 could affect chromosome segregation, DNA replication and transcription. CENP-A is often overexpressed and mislocalized in cancer genomes, but the underlying mechanisms are not understood. One major regulator of Cse4 deposition is Psh1, an E3 ubiquitin ligase that controls levels of Cse4 to prevent deposition into non-centromeric regions. We present evidence that Chromatin assembly factor-1 (CAF-1), an evolutionarily conserved histone H3/H4 chaperone with subunits shown previously to interact with CenH3 in flies and human cells, regulates Cse4 deposition in budding yeast. yCAF-1 interacts with Cse4 and can assemble Cse4 nucleosomes in vitro. Loss of yCAF-1 dramatically reduces the amount of Cse4 deposited into chromatin genome-wide when Cse4 is overexpressed. The incorporation of Cse4 genome-wide may have multifactorial effects on growth and gene expression. Loss of yCAF-1 can rescue growth defects and some changes in gene expression associated with Cse4 deposition that occur in the absence of Psh1-mediated proteolysis. Incorporation of Cse4 into promoter nucleosomes at transcriptionally active genes depends on yCAF-1. Overall our findings suggest CAF-1 can act as a CenH3 chaperone, regulating levels and incorporation of CenH3 in chromatin.

P-257 - Evaluation of the anti-cancer property of Toluquinol, a marine fungus derived natural product

Marine derived novel anti-cancer natural products are in high demand because of its multifactorial and lesser side effects. Toluquinol, a methylhydroquinone, isolated from marine fungus of Penicillium sps. is a known AKT inhibitor, a major player in cancer progression. The present study investigates the anticancer property of toluquinol in human lung cancer cell line NCI-H520 as compared to normal immortalized lung cells, L -132. Cytotoxicity of the compound was assessed through MTT assay and doses were decided according to its IC50. Soft agar, Colony formation and Wound healing assays revelaed its potent anticancer activity in a dose-dependent manner. The compound also possesses apoptotic properties as confirmed by DNA fragmentation, AO/PI staining and mRNA levels of key pro/anti-apoptotic genes. Toluquinol also showed potent free radical scavenging activity in cell-free assays – ABTS, CUPRAC, DPPH indicating its antioxidant property. In-silico docking analysis also showed stable strong interactions of Toluquinol with EGFR and AKT with high LibDock Score, which makes toluquinol a potent inhibitor to be used in future. Hence toluquinol shows enormous potential as a potent anti-cancer marine derived drug and a novel therapeutic molecule.

P-120 - MiRNome of epileptic children suggests the involvement of antioxidant pathways in the neuroprotective role of ketogenic diet

Ketogenic diet (KD) has been used as treatment for refractory epilepsy in children since the 1920s. However, the neuroprotective mechanism of this diet is still unknown. Recent evidence points to a multifactorial effect of KD that involves a decrease of oxidative stress. Mononuclear cells from 14 children with refractory epilepsy, from the Paediatric Hospital “Nino Jesus” in Madrid, were obtained before and after treatment with a ketogenic diet for 6 months. A global analysis of miRNA expression (miRNome) indicates that there are 230 miRNAs which are expressed differently before and after the treatment with KD. If additionally, we restrict the miRNAs with a fold change > |1.3|we obtain 11 relevant miRNAs: miR-3978, miR-6726-3p, miR-130a-3p, miR-4758, miR- 6745, miR-532, miR-185-5p (downregulated after the ketogenic treatment) and miR-4538, miR-602, miR-330-5p, miR-4673 (upregulated after the treatment). Many of these miRNAs are involved in antioxidant pathways. For instance, miR-185 upregulation impairs an efficient antioxidant response in human [doi: 10.1186/s12933-016-0390-9], whereas in our patients treated with KD this miRNA is down-regulated. These findings support the role of the prevention of oxidative stress in the neuroprotective effects of the ketogenic diet.

Kinetic Analysis of PRMT1 Reveals Multifactorial Processivity and a Sequential Ordered Mechanism

BACKGROUNDProtein arginine N‐methyltransferases (PRMTs) are responsible for the transfer of one or two methyl groups from the methyl donor S‐adenosyl‐L‐methionine (SAM) to produce mono‐ or dimethylated arginine residues and the spent cofactor S‐adenosyl‐L‐homocysteine (SAH). Methylated arginines in eukaryotic cells are involved in several crucial biological processes, including transcription control, DNA damager repair, and RNA processing. However, contrasting findings for two major questions in the field have generated debate regarding PRMT mechanisms. The purpose of this research was to elucidate the PRMT1 mechanism and answer these two highly debated questions: do PRMTs dimethylate their substrates processively or distributively, and do PRMTs bind their substrates using a random or sequential method of substrate binding?METHODSTo explore these mechanisms, we assayed PRMT1 with well‐characterized peptide substrates. We used tandem mass spectrometry to quantitate the ratios of mono‐ and dimethylarginine species produced to assess PRMT1 processivity. We determined the mechanism of bisubstrate binding using radioactive SAM in enzyme assays to measure methyl transfer to a target peptide in the presence of various concentrations of product inhibitors.RESULTSWe demonstrate that PRMT1 processivity differs depending on the substrate sequence, which is congruent with previous reports. However, we show for the first time that as cofactor and/or enzyme concentration increases, the ratio of dimethylarginine to monomethylarginine substantially increases, suggesting the enzyme becomes more processive. Further, the steady‐state inhibition patterns favour a sequential ordered mechanism over a random mechanism, indicating that for catalysis to occur, SAM binding must precede peptide binding.CONCLUSIONSThe degree of PRMT1 processivity is a multifactorial effect that is heavily influenced by experimental design considerations, so previous conclusions about processivity may require reassessment. We also find that PRMT1 uses a sequential ordered substrate binding mechanism, in contrast with recent findings. Use of nonlinear regression and presentation of our data using three linear plots strengthens our conclusions. Considering the conserved active sites within the human PRMT family, we anticipate that our results regarding PRMT1 kinetic and processive mechanisms may extend to other human PRMTs.Support or Funding InformationThis work was supported by the Natural Sciences and Engineering Research Council of Canada (NSERC) RGPIN‐2015–04450 Discovery Grant (A.F.), NSERC CGS‐M (J.I.B.), the Shaughnessy Hospital Volunteer Society Fellowship in Health Care (J.I.B.), and the Walter C. Koerner Fellowship (J.I.B.). Additional support provided by Utrecht University and the Netherlands Organization for Scientific Research is acknowledged (T.K., J.v.S., and N.I.M.).This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Herbal Medicine in Ischemic Stroke: Challenges and Prospective.

Herbal medicines, mainly of plant source, are invaluable source for the discovery of new therapeutic agents for all sorts of human ailments. The complex pathogenesis of stroke and multifactorial effect of herbal medicine and their active constituents may suggest the promising future of natural medicine for stroke treatment. Anti-oxidant, anti-inflammatory, anti-apoptotic, neuroprotective and vascular protective effect of herbal medicines are believed to be efficacious in stroke treatment. Herbs typically have fewer reported side effects than allopathic medicine, and may be safer to use over longer period of time. Herbal medicines are believed to be more effective for the longstanding health complaints, such as stroke. Several medicinal plants and their active constituents show the promising results in laboratory research. However failure in transformation of laboratory animal research to the clinical trials has created huge challenge for the use of herbal medicine in stroke. Until and unless scientifically comprehensive evidence of the efficacy and safety of herbal medicine in ischemic stroke patients is available, efforts should be made to continue implementing treatment strategies of proven effectiveness. More consideration should be paid to natural compounds that can have extensive therapeutic time windows, perfect pharmacological targets with few side effects. Herbal medicine has excellent prospective for the treatment of ischemic stroke, but a lot of effort should be invested to transform the success of animal research to human use.

Chromatin assembly factor-1 (CAF-1) chaperone regulates Cse4 deposition into chromatin in budding yeast.

Correct localization of the centromeric histone variant CenH3/CENP-A/Cse4 is an important part of faithful chromosome segregation. Mislocalization of CenH3 could affect chromosome segregation, DNA replication and transcription. CENP-A is often overexpressed and mislocalized in cancer genomes, but the underlying mechanisms are not understood. One major regulator of Cse4 deposition is Psh1, an E3 ubiquitin ligase that controls levels of Cse4 to prevent deposition into non-centromeric regions. We present evidence that Chromatin assembly factor-1 (CAF-1), an evolutionarily conserved histone H3/H4 chaperone with subunits shown previously to interact with CenH3 in flies and human cells, regulates Cse4 deposition in budding yeast. yCAF-1 interacts with Cse4 and can assemble Cse4 nucleosomes in vitro. Loss of yCAF-1 dramatically reduces the amount of Cse4 deposited into chromatin genome-wide when Cse4 is overexpressed. The incorporation of Cse4 genome-wide may have multifactorial effects on growth and gene expression. Loss of yCAF-1 can rescue growth defects and some changes in gene expression associated with Cse4 deposition that occur in the absence of Psh1-mediated proteolysis. Incorporation of Cse4 into promoter nucleosomes at transcriptionally active genes depends on yCAF-1. Overall our findings suggest CAF-1 can act as a CenH3 chaperone, regulating levels and incorporation of CenH3 in chromatin.

Treatment with 5-azacitidine delay growth of glioblastoma xenografts: a potential new treatment approach for glioblastomas.

Glioblastoma multiforme (GBM) is the most lethal primary brain tumor in adults. The epigenetically active ribonucleoside analog 5-azacitidine is a new therapy option that changes tumor cell chromatin, which is frequently modified by methylation and deacetylation in malignant gliomas. In vitro, we analyzed cell viability, cell apoptosis, and migration of human GBM cells. In vivo, we established subcutaneous and intracerebral GBM mouse models originating from U87MG, U373MG, and primary GBM cells as well as one patient-derived xenograft. Xenografts were treated with 5-azacitidine as well as valproic acid, bevacizumab, temozolomide, and phosphate buffered saline. The tumor sizes and Ki67 proliferation indices were determined. Glioma angiogenesis was examined immunohistochemically by expression analysis of endothelial cells (CD31) and pericytes (PDGFRβ). In vitro, 5-azacitidine treatment significantly reduced human glioblastoma cell viability, increased cellular apoptosis, and reduced cellular migration. In vivo, 5-azacitidine significantly reduced growth in two intracerebral GBM models. Notably, this was also shown for a xenograft established from a patient surgery sample; whereas, epigenetically acting valproic acid did not show any growth reduction. Highly vascularized tumors responded to treatment, whereas low-vascularized xenografts showed no response. Furthermore, intracerebral glioblastomas treated with 5-azacitidine showed a clearly visible reduction of tumor angiogenesis and lower numbers of endothelial cells and tumor vessel pericytes. Our data show significant growth inhibition as well as antiangiogenic effects in intracerebral as well as patient-derived GBM xenografts. This encourages to investigate in detail the multifactorial effects of 5-azacitidine on glioblastomas.