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Inhibition of proinflammatory signaling impairs fibrosis of bone marrow mesenchymal stromal cells in myeloproliferative neoplasms
Get PDFAlthough bone marrow-derived mesenchymal stromal cells (BM-MSCs) have been identified as a major cellular source of fibrosis, the exact molecular mechanism and signaling pathways involved have not been identified thus far. Here, we show that BM-MSCs contribute to fibrosis in myeloproliferative neoplasms (MPNs) by differentiating into αSMA-positive myofibroblasts. These cells display a dysregulated extracellular matrix with increased FN1 production and secretion of profibrotic MMP9 compared to healthy donor cells. Fibrogenic TGFβ and inflammatory JAK2/STAT3 and NFκB signaling pathway activity is increased in BM-MSCs of MPN patients. Moreover, coculture with mononuclear cells from MPN patients was sufficient to induce fibrosis in healthy BM-MSCs. Inhibition of JAK1/2, SMAD3 or NFκB significantly reduced the fibrotic phenotype of MPN BM-MSCs and was able to prevent the development of fibrosis induced by coculture of healthy BM-MSCs and MPN mononuclear cells with overly active JAK/STAT signaling, underlining their involvement in fibrosis. Combined treatment with JAK1/2 and SMAD3 inhibitors showed synergistic and the most favorable effects on αSMA and FN1 expression in BM-MSCs. These results support the combined inhibition of TGFβ and inflammatory signaling to extenuate fibrosis in MPN
Probing the role of the posterior parietal cortex in conflict processing – a transcranial electrical stimulation (tES) study
No full textThe fronto-parietal network (FPN) has a substantial role in cognitive control, conflict processing, and goal-directed behavior. Transcranial electrical stimulation (tES) is increasingly establishing as a promising tool for cognitive neuromodulation. It has been already demonstrated that tES over frontal areas can modulate processes of conflict processing. However, there is a lack of empirical evidence whether tES over the parietal cortex has similar effects. Forty-two healthy right-handed volunteers (26 f, age M=24.7 SD=3.71 y) participated in a cross-over sham-controlled experiment. In four experimental sessions participants received stimulation for 20 min over the left posterior parietal cortex PPC (P3, 10-20 International EEG system) in a counterbalanced order: 1) tDCS (constant 1.5mA), 2) otDCS (1.5mA ± 0.5mA) oscillating at previously determined individual theta frequency (ITF, 4-8 Hz), 3) tACS at ITF (0±1mA) or 4) sham (placebo). To tap conflict processing, we administered the Simon task during the stimulation. The word “left” or “right” was sequentially presented at the left or right position of the computer screen. Participants were instructed to react as fast as possible by pressing the left or the right key according to the presented word, regardless of its position on the screen. In the congruent trials, position and word were matched while in incongruent trials they were mismatched. Difference RT scores were used as a dependent variable. Simon effect was significant only in the first [t(41) = -3.633, p = .001] and the third [t(41) = -2.098, p = .042] session, regardless of the experimental condition. No effects of tES protocols were observed on differential scores [F(3,123) = .730, p = .536, ηp2 = .017], global mean RT [F(3,123) = 1.716, p = .167, ηp2 = .040], incongruent trials RT [F(3,123) = 1.051, p = .372, ηp2 = .025], nor significant contrasts of active stimulations and sham (mean-centered for a session order). The absence of a consistent Simon effect indicates that the task was not demanding enough for the participants, thus limiting the conclusions about tES effects on conflict processing. The null effects of parietal tES in this context can be interpreted in a line of the previous study showing no parietal effects on simple RT or tasks that pose low cognitive demand
Immunohistochemical expression of heme oxygenase-1, 4-hydroxynonenal and hypoxia inducible factors (1α, 1β, 2α) after HBO preconditioning in postischemic acute kidney injury induced in spontaneously hypertensive
Get PDFAndrogen Dependence in Thrombosis of Patients With COVID-19
Get PDFBackground. A vascular system inflammation is a risk of venous thromboembolism
and can result in widespread microangiopathy with microvascular thrombosis.
Methods. We performed laboratory clinical follow-up of patients with COVID-19 to
compare gender differences. To study the sex difference in COVID-19 outcome we
will measure estradiol and androgens: dihydrotestosterone (DHT) and sex hormone
binding globulin (SHBP) in plasma of 63 COVID-19 patients, analyzed by ELISA. Their
levels will be correlated to the adhesion molecules: soluble intercellular adhesion
molecule 1 (sICAM-1), soluble vascular adhesion molecule 1 (sVCAM-1), sE-selectin,
and sP-selectin as biomarkers for inflammation and thrombosis.
Results. DHT was increased (1.9 fold) in male COVID-19 patients compared to healthy
male volunteers. SHBP was significantly increased in COVID-19 patients compared
to healthy volunteers (p<0.05) as well as female vs. male COVID-19 patients (p<0.001,
2.5 fold). sVCAM-1 and sICAM-1 were increased in female COVID-19 patients compared
to male COVID-19 patients and female volunteers, respectively (p<0.05). The
sP-selection was significantly (p<0.01) increased in male vs. female COVID-19 patients.
SHBP was in negative correlation with sP-selectin (p<0.05). DHT was in positive
correlation with sVCAM-1 (p<0.05). Ferritin had 3-fold higher levels in male than
female COVID-19 patients (p<0.001).
Conclusions. Upregulation of androgen hormones and thrombotic biomarkers in
COVID-19 patients demonstrate sex dependence
Occurence and genetic diversity of Giardia intestinalis, Cryptosporidium spp. and Toxoplazma gondii in surface waters in Serbia
Get PDFVoda je neophodan resurs za ljudsko društvo, stoga je važno da ona bude i bezbedna za upotrebu. Usled rasta potrebe za vodom, često se pribegava i upotrebi vode koja nije hemijski i bakteriološki ispravna. Predmet ovog istraživanja jesu parazitske protozoe Giardia intestinalis, Cryptosporidium spp. i Toxoplasma gondii i detekcija njihovih životnih oblika u površinskim vodama u Srbiji. Da bi se utvrdilo prisustvo parazita u vodotokovima, kao i stepen kontaminacije, analizirana su vodna tela propisana programom mera Agencije za zaštitu životne sredine koja se nalaze u 19 okruga, uključujući i grad Beograd. Uzorkovanje vode započeto je krajem 2018. godine i trajalo je do jula 2021. godine, i tom prilikom je sakupljeno 48 uzoraka vode iz površinskih voda različite kategorije. Za detekciju (oo)cista G. intestinalis i Cryptosporidium spp. korišćena je metodologija US EPA 1623 dok je detekcija oocista T. gondii vršena PCR metodom uz prethodno koncentrisanje uzorka. Od ukupno 48 uzoraka, u 24 (50%, 24/48) detektovana je barem jedna od tri ispitivane protozoe. Rezultati testa imunofluorescencije (IFA) pokazali su prisustvo cista G. intestinalis u 14 uzoraka (29,2%, 14/48), prisustvo oocista Cryptosporidium spp. u pet (10,4%, 5/48), dok su ciste i oociste oba parazita detektovane u tri uzorka (6,25%, 3/48). PCR metodom amplifikacije β-giardin gena prisustvo gDNK G. intestinalis detektovano je u osam uzoraka (16,6%, 8/48), dok amplifikacija nijednog od četiri gena korišćena u detekciji Cryptosporidium spp. nije bila uspešna. U četiri uzorka (8,3%, 4/48) detektovana je gDNK T. gondii, pri čemu je u detekciji prvo korišćen 529 bp repetitivni fragment, nakon čega su za potvrdu korišćeni geni GRA6 i SAG2. Tipizacija asemblaža G. intestinalis bila je uspešna u tri uzorka. U jednom uzorku detektovana je asemblaža A, dok je u preostala dva uzorka detektovana asemblaža B. Statističkom obradom podataka o hidromorfološkom kvalitetu voda nije se ustanovila povezanost tih parametara i prisustva parazita u vodi. Takođe, korišćenjem qGIS softvera, lokacije na kojima je vršeno uzorkovanje, kao i njihov status u odnosu na detekciju parazita, prikazani su na mapi Republike Srbije. Na osnovu toga zapaženo je veće prisustvo protozoa u vodama u Mačvanskom i Sremskom okrugu u zapadnoj Srbiji, kao i Pomoravskom i Šumadijskom okrugu u centralnoj Srbiji.Rezultati ove doktorske disertacije po prvi put u Srbiji ukazali su na postojanje kontaminacije vodotokova parazitskim protozoama G. intestinalis, Cryptosporidium spp. i T. gondii. Podaci dobijeni ovim istraživanjem mogu se iskoristiti za pravljenje strategije za zaštitu zdravlja ljudi i životinja i sprečavanje hidričnih epidemija, a takođe predstavljaju uvod u dalja, opsežnija istraživanja u ovoj oblasti koja bi pomogla boljem razumevanju kontaminacije i distribucije parazitskih protozoa u površinskim vodama Srbije.Since water is such an important resource for human society, it must be safe to use. Due to the rising demand for water, it is becoming increasingly common to use water that is neither chemically nor bacteriologically suitable. This research focused on the parasitic protozoa Giardia intestinalis, Cryptosporidium spp. and Toxoplasma gondii, and the detection of their life forms in surface waters in Serbia. Water bodies designated as economically or strategically significant for the country by the Serbian Environmental Protection Agency, in 19 administrative districts, were analysed to determine the occurrence of parasites as well as the degree of contamination. Water sampling began at the end of 2018 and continued through July 2021; during that time, 48 water samples were collected from various types of surface waters. The US EPA 1623 methodology was used to detect (oo)cysts of G. intestinalis and Cryptosporidium spp., while the detection of T. gondii was performed by PCR with prior concentration of the sample. According to the results of immunofluorescence assays, evidence of at least one of the three protozoa were found in 24 of the 48 samples (50%, 24/48). G. intestinalis cysts were found in 14 samples (29.2%, 14/48), Cryptosporidium spp. oocysts in five (10.4%, 5/48), while cysts and oocysts of both parasites were found in three samples (6.25%, 3/48). G. intestinalis β-giardin gene was detected by PCR amplification in eight (16.6%, 8/48) samples, but the attempts to amplify any of the four genes used to detect Cryptosporidium spp. remained unsuccessful. T. gondii gDNK was detected in four samples (8.3%, 4/48), firstly by amplification of the 529 bp repetitive fragment and then confirmed by detection of the GRA6 and SAG2 gene sequences. Typing of G. intestinalis assemblages was successful in three samples. Assemblage A was detected in one, and assemblage B in the remaining two samples. There was no association of hydro-morphological water quality with the presence of parasites in water. Also, using qGIS software, the locations where the sampling was performed as well as their status in relation to sample positivity were shown on the map of the Republic of Serbia. Based on that, a greater presence of protozoa was observed in the waters in the Mačva and Srem districts in Western Serbia, as well as in the Pomoravlje and Šumadija districts in Central Serbia. Results of this Dissertation showed, for the first time in this country, that parasitic protozoa G. intestinalis, Cryptosporidium spp. and T. gondii contaminate Serbian watercourses. These findings could be used to establish a prevention and control strategy for protecting human and animal health, primarily by preventing waterborne epidemics. Also they laid a foundation for further research in this area that could improve the understanding of the scope and precise distribution of parasitic protozoa contamination in Serbian surface waters
Upotreba reperfuzione terapije u zemljama tranzicije bez potpuno primenljive farmakoinvazivne strategije
Get PDFBackground/Aim.The pharmacoinvasive (PI) therapy is a recommended strategy in patients (pts) with ST elevation myocardial infarction (STEMI) unable to undergo timely primary percutaneous coronary intervention (p-PCI). The aim of the study was to find out the cohorts of pts who are not treated by any reperfusion therapy (RT) as well to determine the outcome of the pts treated with RT in a transition country without fully applicable PI therapy. Methods. The study analyzed data from the Hospital National Registry for Acute Coronary Syndrome of Serbia (HORACS). Results. The significant predictors of the withdrawing of the application of any RT in the model [c 75.6%, SE 0.004, 95% CI 0.748-0.761)] were age (≥ 65 years), heart failure (Killip II-IV), diabetes mellitus, and the time to first medical contact (FMC) (> 360 min). In patients without RT, mortality was 15.7%, in pts treated with fibrinolytic therapy (FT) was 10.5%, and in pts treated with pPCI, it was 6.2% (p 360min). Kod bolesnika koji nisu bili lečeni RT, mortalitet je bio 15,7%, kod bolesnika lečenih fibrinolitičkom terapijom (FT) iznosio je 10,5%, a kod bolesnika lečenih p-PCI 6,2% ( p <0,000). U grupi bolesnika koji su do PMK stizali za 3 sata, mortalitet lečenih pomoću FT bio je veći od mortaliteta bolesnika lečenih p-PCI (FT 8,7% vs p-PCI 4,3%). Bolesnici lečeni pomoću FT bili su stariji, sa više komorbiditeta i sa učestalijim znacima srčane insuficijencije. Ipak, posle primenjenog propensity skora, sa ciljem da se izbegnu razlike između dve grupe bolesnika, mortalitet u FT grupi ostao je veći, alibez statistički značajne razlike u odnosu na bolesnike lečene p-PCI (FT 8,8%. vs p-PCI 6,4%). Zaključak. Primena RT, uz postignuti idealan balans potrošnje i koristi, teško je izvodljiva u zemljama u tranziciji. Mogućnosti za blagovremenu primenu p-PCI, kao i FIterapije, posebno su ograničene kod visoko rizičnih, starijih bolesnika, kod bolesnika sa znacima srčane insuficijencije, komorbiditetima i dijabetesom melitusom
Nelinearna laserska skenirajuća mikroskopija hemoglobina i eritrocita
Get PDFOslikavanje eritrocita bez obeležavanja pomoću konfokalne ili epifluorescentne mikroskopije je praktično nemoguće jer se fluorescencija od hemoglobina (Hb) ne može detektovati zbog brzih neradijativnih raspada koji su dominantni u odnosu na spontanu emisiju. Sa druge strane, demonstrirana je značajna dvofotonska apsorptivnost Hb u infracrvenoj oblasti1 kao i dvofotonski pobuđena fluorescencija (TPEF) od novoformiranog fotoprodukta2 nakon interakcije ultrakratkih laserskih impulsa sa Hb. TPEF mikroskopija je korišćena u brojnim studijama za oslikavanje Hb i eritrocita bez obeležavanja.3 U ovom radu prikazane su fotofizičke osobine i potencijalne primene novoformiranog fotoprodukta. Kreirane su fluorescentne mikrostrukture pomoću direktnog laserskog upisivanja na tankim Hb slojevima (micropatterning). Fotoprodukt je okarakterisan pomoću različitih (mikro)spektroskopskih tehnika: emisije nakon vofotonske apsorpcije, UV-VIS apsorpcije i spektralnog oslikavanja. Razmatrane su spektroskopske osobine protoporfirina IX (PpIX) pošto je on strukturni deo Hb i potencijalno može biti prekursor za formiranje fotoprodukta. Takođe, Hb je tretiran vodonik peroksidom da bi se uočila optička i spektroskopska sličnost tako dobijenog jedinjenja i fotoprodukta. Potvrđena je dugovremena fotostabilnost fotoprodukta u periodima od nekoliko meseci. Na osnovu toga što je fotoprodukt moguće dobiti na prostorno i vremenski kontrolisan način, izvršeno je fotoobeležavanje i praćenje kretanja pojedinačnih eritrocita u humanoj punoj krvi zdravog donora
The Polymorphisms of Genes Encoding Catalytic Antioxidant Proteins Modulate the Susceptibility and Progression of Testicular Germ Cell Tumor
Get PDFThe simultaneous analysis of redox biomarkers and polymorphisms encoding for regulatory and catalytic antioxidant proteins was performed in order to evaluate their potential role in the development of testicular germ cell tumor (GCT), as well as the progression of the disease. NRF2 (rs6721961), GSTM3 (rs1332018), SOD2 (rs4880) and GPX3 (rs8177412) polymorphisms were assessed in 88 patients with testicular GCT (52 with seminoma) and 88 age-matched controls. The plasma levels of 8-hydroxy-2′-deoxyguanosine (8-OHdG), thiol groups and the plasma activity of glutathione peroxidase were measured. A significant association between variant GPX3*TC+CC genotype and risk of overall testicular GCT, as well as seminoma development, was found. Moreover, carriers of variant SOD2*TT genotype were at almost 3-fold increased risk of seminoma development. Interestingly, combined SOD2*TT/GPX3*TC+CC genotype conferred a 7-fold higher risk for testicular GCT development. Finally, variant GSTM3*AC+CC genotype was associated with a higher risk for the development of advanced diseased. The presence of assessed genetic variants was not associated with significantly higher levels of redox biomarkers in both testicular GCT patients, as well as in those diagnosed with seminoma. In conclusion, the polymorphic expression of certain antioxidant enzymes might affect susceptibility toward testicular GCT development, as well as the progression of the disease
Seasonal differences in the intensity of acute phase response in dogs infected with Babesia canis
No full textThe highest number of acute Babesia canis cases in dogs is recorded over the February-May (Feb-May) period, which also represents the optimal climate conditions for tick activity in Belgrade, Serbia. A possibility that the acute phase response is more intense in dogs developing the disease in the Feb-May period compared with the response in other time periods of the year was tested. A total of 63 client-owned dogs with acute B. canis infection were enrolled and the routine hematology and biochemistry parameters-serum amyloid A (SAA), IgG against B. canis, level of parasitemia, ceruloplasmin (CER), paraoxonase-1 (PON-1), and fibrinogen-were measured. Acute phase indexes (API) were calculated as (SAA×CER)/(Iron×PON-1) and (SAA×CER)/(Albumin×Iron). Statistics included Kruskal-Wallis test and logistic regression analysis. The results showed that in the Feb-May period, the following parameters were lower: creatinine, albumin, iron, and level of parasitemia. Furthermore, increased API values were more probable in the Feb-May than in the other periods. Together, higher acute phase response intensity and presumptive hemodilution in the Feb-May period indicate a more acute course of B. canis infection than in other time periods of the year