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Guidelines to Analyze Preclinical Studies Using Perinatal Derivatives
Get PDFThe last 18 years have brought an increasing interest in the therapeutic use of perinatal derivatives (PnD). Preclinical studies used to assess the potential of PnD therapy include a broad range of study designs. The COST SPRINT Action (CA17116) aims to provide systematic and comprehensive reviews of preclinical studies for the understanding of the therapeutic potential and mechanisms of PnD in diseases and injuries that benefit from PnD therapy. Here we describe the publication search and data mining, extraction, and synthesis strategies employed to collect and prepare the published data selected for meta-analyses and reviews of the efficacy of PnD therapies for different diseases and injuries. A coordinated effort was made to prepare the data suitable to make statements for the treatment efficacy of the different types of PnD, routes, time points, and frequencies of administration, and the dosage based on clinically relevant effects resulting in clear increase, recovery or amelioration of the specific tissue or organ function. According to recently proposed guidelines, the harmonization of the nomenclature of PnD types will allow for the assessment of the most efficient treatments in various disease models. Experts within the COST SPRINT Action (CA17116), together with external collaborators, are doing the meta-analyses and reviews using the data prepared with the strategies presented here in the relevant disease or research fields. Our final aim is to provide standards to assess the safety and clinical benefit of PnD and to minimize redundancy in the use of animal models following the 3R principles for animal experimentation
Exposure to Phosphates and Nitrites through Meat Products: Estimation of the Potential Risk to Pregnant Women
Get PDFDiet during pregnancy is one of the most important nutritional challenges associated with some risks for the mother and the fetus. For the first time, the study aims to estimate long-term (2018–2022) exposure to nitrate and phosphates in Serbian pregnant women, based on individual consumption data and accurate values measured in frequently consumed meat products. For this purpose, seven types of meat products, consisting of 3047 and 1943 samples, were collected from retail markets across Serbia, to analyze nitrites and phosphorus content, respectively. These data were combined with meat product consumption data from the Serbian National Food Consumption Survey to assess dietary intake of nitrites and phosphate. The results were compared with the acceptable daily intake (ADI) proposed by the European Food Safety Authority. The average dietary exposure (EDI) to phosphorus ranged from 0.733 mg/kg bw/day (liver sausage and pate) to 2.441 mg/kg bw/day (finely minced cooked sausages). Considering nitrite intake, the major sources were bacon (0.030 mg/kg bw/day) and coarsely minced cooked sausages (0.0189 mg/kg bw/day). In our study, average nitrite and phosphorus exposure in the Serbian pregnant women population are far below the EFSA recommendations (ADI 0.07 mg/kg bw/day and 40 mg/kg bw/day, respectively)
Integrated in vitro – in vivo – in silico studies in the pharmaceutical development of propranolol hydrochloride mucoadhesive buccal films
No full textIn order to exploit the advantage of drug delivery through the buccal mucosa, mucoadhesive buccal films with propranolol hydrochloride based on polyethylene oxide, hydroxypropyl methylcellulose, and polyvinyl alcohol have been developed. The aim of this study was the development, pharmaceutical-technological (uniformity of mass and drug content, film thickness, potential interactions between polymers and propranolol hydrochloride, in vitro drug permeation and drug release, mechanical and mucoadhesive properties), and biopharmaceutical characterization of prepared mucoadhesive buccal films through conducting in vivo study in spontaneously hypertensive rats and in silico modeling of intraoral and gastrointestinal drug absorption. For in vivo study formulation F2 (hydroxypropylmethyl cellulose 0.5%, polyethylene oxide 3.5%, polyvinyl alcohol 1.5%, propylene glycol 3%, and propranolol hydrochloride 2%) was selected, which showed the highest values of tensile strength and percentage of elongation, as well as the highest value of the force of adhesion. Results of pharmacokinetic in rats and in silico modeling confirmed the superiority of the mucoadhesive buccal films over immediate-release tablets (in rats: AUC0→24h 66.13 ± 18.03 vs. 24.61 ± 5.52 μg⋅h/mL, AUC0→∞ 111.82 ± 39.04 vs. 47.85 ± 11.67 μg⋅h/mL; in silico: AUC0→24h 200.17 vs.74.58 ng⋅h/mL, AUC0→∞ 204.04 vs. 75.64 ng⋅h/mL). Hemodynamic measurements have shown that mucoadhesive buccal films, compared to immediate-release tablets, provide a more pronounced decrease primarily in heart rate (28-51%), but also in diastolic pressure (up to 33%), as well as a longer heart rate reduction that was maintained for up to 12th h. Therefore, mucoadhesive buccal films increased the degree of absorbed drug and thus contributed to better therapeutic outcomes compared to immediate-release tablets for peroral administration
Sex Differences and Cytokine Profiles among Patients Hospitalized for COVID-19 and during Their Recovery: The Predominance of Adhesion Molecules in Females and Oxidative Stress in Males
Get PDFThe severity and mortality of coronavirus disease 2019 (COVID-19) are greater in males than in females, though the infection rate is the same in the two sexes. We investigated sex hormone differences associated with the hyperinflammatory immune response to SARS-CoV-2 on the basis of patients’ cytokine profiles and vaccination statuses. Clinical and laboratory data of 117 patients with COVID-19 were collected to examine sex differences associated with oxidative stress markers, neutrophil extracellular traps (NETs), and plasma cytokine levels up to 5 months from hospital admission. The testosterone and free testosterone levels were low in male patients with COVID-19 and returned to normal values after recovery from the disease. The dihydrotestosterone (DHT) levels were transiently reduced, while the sex hormone-binding globulin levels were decreased in post-COVID-19 male patients. The levels of the inflammatory cytokines interleukin-6 (IL-6) and IL-10 appeared generally increased at diagnosis and decreased in post-COVID-19 patients. In females, the concentration of tumor necrosis factor-alpha was increased by four times at diagnosis. The levels of the coagulation markers intercellular adhesion molecule-1 (ICAM-1) and E-selectin were consistently upregulated in post-COVID-19 female patients, in contrast to those of vascular cell adhesion molecule-1 (VCAM-1), P-selectin, and chemokine IL-8. DHT increased the levels of reactive oxygen species in the neutrophils of male patients, while estradiol decreased them in females. Markers for NET, such as circulating DNA and myeloperoxidase, were significantly more abundant in the patients’ plasma. Sex hormones have a potential protective role during SARS-CoV-2 infection, which is weakened by impaired testosterone synthesis in men
8-Iso-prostaglandin F2α as a potential biomarker in patients with unipolar and bipolar depression
Get PDFObjective: Previous studies have shown that the disturbance of redox homeostasis plays a role in the pathogenesis of mood disorders. It is currently unclear whether oxidative stress parameters can be used as biomarkers (state vs. trait). The aim of the present study was to investigate oxidative stress markers in patients with major depressive disorder (MDD) and bipolar disorder (BP) in acute depressive episodes and remission, and healthy individuals. Patients and methods: Thirty-two patients with a diagnosis of MDD, 32 patients with a diagnosis of BP and 32 matched healthy controls were included in the study. We measured the serum levels of markers of oxidative damage, including 8-hydroxy-2'-deoxyguanosine (8-OHdG), 8-Iso-prostaglandin F2α (8-iso-PGF2α; 8-isoprostane), and malondialdehyde (MDA), and also serum activities of superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPX), and glutathione reductase (GR) in both acute and remission phase, and in control group. Results: After controlling for the effects of age, sex, body mass index, and smoking status, serum 8-iso-PGF2α levels were significantly higher in both patient groups compared to controls, regardless of disease phase. The activities of GPX and GR were significantly lower in the acute phase in MDD patients compared to controls. Serum GR activity was lower in both acute and remission phase in MDD compared to BP. Conclusions: Our results suggest that both MDD and BP are associated with a disturbed redox balance with a particularly pronounced increase in serum 8-iso-PGF2α levels in both groups and the presence of glutathione metabolism disorders in MDD patients. Further research is needed to confirm the importance of oxidative stress parameters as potential biomarkers of MDD and BP
Toxoplasma gondii infection in pigs in Serbia
Get PDFToxoplasma gondii is a common zoonotic intracellular parasite in livestock raised forhuman consumption and is a public health concern. The mode of transmission is ingestion,and meat is considered to be a major vehicle for human and animal infection. AsT. gondii is environmentally transmissible, other important vehicles in particular foranimals include vegetation, soil and water. The seroprevalence of T. gondii infection inpigs is Serbia has been determined in several studies over the past two decades. It hasbeen established that it varies considerably, primarily based on husbandry, with strictlyto mostly indoor animals having a lower prevalence (below 20%) than animals raisedoutdoors, where prevalence exceeds 60%. Experimental data suggests that differentgenotypes of the parasite vary in virulence, but the significance of virulence in terms ofpathology and disease manifestations is still being investigated. Genotypes of T. gondiiisolated from pig tissues in Serbia to date are ToxoDB#1 (archetype II) and ToxoDB#2(archetype III). Archetype II is predominant and, based on historical reports and recentfindings, low to intermediately virulent. The virulence phenotype and mechanisms ofarchetype III, however, have not been extensively studied, but recent data suggests thatits virulence may vary considerably. This review will also summarize the current knowledgeregarding the virulence of archetypes II and III and evaluate it in the context ofthe pig host
Molecular screening of Borrelia miyamotoi and Tick-Borne Encephalitis Virus in ixodid ticks in urban green areas in Serbia
Get PDFIntroduction: Zoonotic tick-borne diseases (TBDs) represent an increasing threat in urban areas,
including city parks and green recreational areas. Borrelia miyamotoi is pathogenic to humans but
there is still little information about its circulation in nature and potential local impact on human health, while tick-borne encephalitis virus (TBEV) is endemic in many European countries and sporadic autochthonous cases in humans have been reported in Serbia.
The objective of our study was to determine the prevalence of two emerging zoonotic tick-borne
pathogens (TBPs) − B. miyamotoi and TBEV in urban areas in the city of Belgrade (24 localities),
four localities in Eastern Serbia, one in the province of the Vojvodina.
Methods: At 29 localities, a total of 480 ticks were collected from March to June 2021, and identified to the species level by using morphological keys. DNA and RNA were extracted from individual tick samples, while for molecular detection, probe-based qPCR and nested PCR were applied.Results: Among 480 ticks, 445 were identified as Ixodes ricinus (213 males, 176 females, 56 nymphs), 30 as Dermacentor reticulatus (18 females, 12 males), three Dermacentor marginatus females, one Haemaphysalis concinna female, and one Haemaphysalis punctata male. Using probe-based qPCR, the prevalence of B. miyamotoi in ticks was 1.04% (DNA was detected in five I. ricinus, two females and two males collected from three Belgrade localities and one male from Eastern Serbia), while sequencing was successful in samples of two I. ricinus females collected from two Belgrade localities and one male from Eastern Serbia. TBEV RNA was not detected in any sample. Conclusions: This is the first report on the presence of the emerging zoonotic pathogen B. miyamotoi in I. ricinus ticks in urban green areas in Serbia, indicating the risk of B. miyamotoi disease. Risk areas within cities should be identified and knowledge regarding TBPs and TBDs among the general population in urban areas should be increased
P1653: Inflammation mediated thrombus formation in lymphomas
Get PDFBackground: Patients with lymphomas increased the risk of thrombotic complications, especially in diagnosis and during chemotherapy treatment, in the range of 2.9-4.2%.
Aims: Our hypothesis is that inflammation and provoked immunity are responsible for generation of thrombus due to disturbed balance between coagulation and fibrinolysis.
Methods: Quantification of neutrophil extracellular traps (NETs) from peripheral blood of 80 patients with Hodgkin lymphoma (HL), diffuse large B-cell lymphoma (DLBCL), and follicular lymphoma (FL) measuring circulating cell-free DNA (cfDNA) and myeloperoxidase (MPO) activity. The inflammatory cytokines, coagulation factors and chemokines are measured by enzyme-linked immunosorbent assay (ELISA) and flow cytometry in peripheral blood, while fibrinolytic activity by fluorescent tissue-type plasminogen activator (tPA) and urokinase plasminogen activator (uPA) assays. Using a Boyden chamber, trans-endothelial migration of mononuclear cells (MNC) across a monolayer of human microvascular endothelial cells (HMEC-1) will be observed.
Results: The pro-inflammatory cytokines IL-1β and TNF-α were significantly increased in DLBCL and HL, but not the chemokines IL-8 and MCP-1. NETs were increased in the peripheral blood of patients with HL (p<0.05) as measured by cfDNA and MPO activity. In contrast, cfDNA was largely reduced in DLBCL with thrombosis (p<0.001). Trans-endothelial migration of MNC was decreased by IL-6, but increased by TNF-α (p<0.001) in DLBCL with thrombosis. In the absence of thrombosis, MNC of HL demonstrated increased trans-endothelial migration in the presence of pro-inflammatory IL-6 (p<0.01), while MNC of HL and DLBCL in the presence of TNF-α (p<0.05). Regarding coagulation, factor VIII was increased in HL (p<0.05), while tissue factor in non-Hodgkin lymphomas (DLBCL and FL, p<0.05). Adhesion molecule P-selectin was increased in lymphomas, mostly in non-Hodgkin lymphomas (p<0.0001), while TGF-β is only in FL (p<0.001). Fibrinogen was negatively correlated with cfDNA (p=0.021, r=-0.767) in HL, while in positive correlation with TNF-α (p=0.028, r=0.517), IL-8 (p=0.009, r=0.598) and MCP-1 (p=0.004, r=0.643) in FL and with TGF-β (p=0.007, r=0.748) in HL. In opposite to uPA, fibrinolytic activity was decreased in the plasma of patients with HL, DLBCL, and FL (p<0.05) as measured by tPA. The tPA was in negative correlation with MPO in HL (p=0.017, r=-0.783) and FL (p=0.006, r=-0.818), while positively correlated with cfDNA in DLBCL (p=0.034, r=0.402, Table 1). The uPA was in positive correlation with cfDNA (p=0.009, r=0.692) and fibrinogen (p=0.009, r=0.692) in FL. Tissue factor (CD142+) procoagulant microparticles derived from monocytes (CD14+: 7.49±0.2, p<0.001) and activated monocytes (CD14+/CD16+: 3.75±0.8%, p<0.05) were increased in DLBCL compared to healthy controls.
Summary/Conclusion: Chronic inflammation is present in the examined lymphomas where TNF-α, as an activator of the immune response, is linked with the initiation of thrombus formation. Moreover, augmented innate immunity is accompanied by procoagulants that mutually support thrombosis.
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Polyphenol-Rich Juices as a Potential Solution for Preventing Metabolic Syndrome and Related Obesity Disorders
Get PDFPutative Role of Neutrophil Extracellular Trap Formation in Chronic Myeloproliferative Neoplasms
Get PDFMyeloproliferative neoplasms (MPNs) are hematologic malignancies characterized by gene mutations that promote myeloproliferation and resistance to apoptosis via constitutively active signaling pathways, with Janus kinase 2-signal transducers and the activators of transcription (JAK-STAT) axis as a core part. Chronic inflammation has been described as a pivot for the development and advancement of MPNs from early stage cancer to pronounced bone marrow fibrosis, but there are still unresolved questions regarding this issue. The MPN neutrophils are characterized by upregulation of JAK target genes, they are in a state of activation and with deregulated apoptotic machinery. Deregulated neutrophil apoptotic cell death supports inflammation and steers them towards secondary necrosis or neutrophil extracellular trap (NET) formation, a trigger of inflammation both ways. NETs in proinflammatory bone marrow microenvironment induce hematopoietic precursor proliferation, which has an impact on hematopoietic disorders. In MPNs, neutrophils are primed for NET formation, and even though it seems obvious for NETs to intervene in the disease progression by supporting inflammation, no reliable data are available. We discuss in this review the potential pathophysiological relevance of NET formation in MPNs, with the intention of contributing to a better understanding of how neutrophils and neutrophil clonality can orchestrate the evolution of a pathological microenvironment in MPNs