BACKGROUND: Tick-borne encephalitis virus (TBEV) is a significant threat to human health. The virus causes potentially fatal disease of the central nervous system (CNS), for which no treatments are available. TBEV infected individuals display a wide spectrum of neuronal disease, the determinants of which are undefined. Changes to host metabolism and virus-induced immunity have been postulated to contribute to the neuronal damage observed in infected individuals. In this study, we evaluated the cytokine, chemokine, and metabolic alterations in the cerebrospinal fluid (CSF) of symptomatic patients infected with TBEV presenting with meningitis or encephalitis. Our aim was to investigate the host immune and metabolic responses associated with specific TBEV infectious outcomes. METHODS: CSF samples of patients with meningitis (n = 27) or encephalitis (n = 25) were obtained upon consent from individuals hospitalised with confirmed TBEV infection in Brno. CSF from uninfected control patients was also collected for comparison (n = 12). A multiplex bead-based system was used to measure the levels of pro-inflammatory cytokines and chemokines. Untargeted metabolomics followed by bioinformatics and integrative omics were used to profile the levels of metabolites in the CSF. Human motor neurons (hMNs) were differentiated from induced pluripotent stem cells (iPSCs) and infected with the highly pathogenic TBEV-Hypr strain to profile the role(s) of identified metabolites during the virus lifecycle. Virus infection was quantified via plaque assay. RESULTS: Significant differences in proinflammatory cytokines (IFN-α2, TSLP, IL-1α, IL-1β, GM-CSF, IL-12p40, IL-15, and IL-18) and chemokines (IL-8, CCL20, and CXCL11) were detected between neurological-TBEV and control patients. A total of 32 CSF metabolites differed in TBE patients with meningitis and encephalitis. CSF S-Adenosylmethionine (SAM), Fructose 1,6-bisphosphate (FBP1) and Phosphoenolpyruvic acid (PEP) levels were 2.4-fold (range ≥ 2.3-≥3.2) higher in encephalitis patients compared to the meningitis group. CSF urocanic acid levels were significantly lower in patients with encephalitis compared to those with meningitis (p = 0.012209). Follow-up analyses showed fluctuations in the levels of O-phosphoethanolamine, succinic acid, and L-proline in the encephalitis group, and pyruvic acid in the meningitis group. TBEV-infection of hMNs increased the production of SAM, FBP1 and PEP in a time-dependent manner. Depletion of the metabolites with characterised pharmacological inhibitors led to a concentration-dependent attenuation of virus growth, validating the identified changes as key mediators of TBEV infection. CONCLUSIONS: Our findings reveal that the neurological disease outcome of TBEV infection is associated with specific and dynamic metabolic signatures in the cerebrospinal fluid. We describe a new in vitro model for in-depth studies of TBEV-induced neuropathogenesis, in which the depletion of identified metabolites limits virus infection. Collectively, this reveals new biomarkers that can differentiate and predict TBEV-associated neurological disease. Additionally, we have identified novel therapeutic targets with the potential to significantly improve patient outcomes and deepen our understanding of TBEV pathogenesis.
- MeSH
- Cytokines cerebrospinal fluid MeSH
- Adult MeSH
- Encephalitis, Tick-Borne * cerebrospinal fluid metabolism MeSH
- Cells, Cultured MeSH
- Middle Aged MeSH
- Humans MeSH
- Metabolome * physiology MeSH
- Metabolomics MeSH
- Young Adult MeSH
- Neurons * metabolism virology MeSH
- Aged MeSH
- Encephalitis Viruses, Tick-Borne * MeSH
- Check Tag
- Adult MeSH
- Middle Aged MeSH
- Humans MeSH
- Young Adult MeSH
- Male MeSH
- Aged MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
1. vydání 352 stran : ilustrace (převážně barevné), portréty ; 22 cm
Publikace se zaměřuje na různá témata napříč lékařstvím, lidskou anatomií a kulturní antropologií. Určeno široké veřejnosti.; Vědění i veselí je možno sdílet různě. Konvenčně i nekonvenčně, písmem i obrazem, pojmy i pocity, suše i šťavnatěji. Podrobné informace lze nyní získat o kdečem snadno, zpravidla však nikoli je prožít s všetečnou radostí. Již Karel Havlíček (míněno Borovský) a mnozí s ním naznačili, že leccos podstatného lze popsat také v rýmu, jistě i obyčejnou rýmu, což prospívá vtipu a šprýmu. Za života se člověk až do smrti bez těla neobejde. A bez mysli to také nestojí za nic. Obojí může někdy pomoci udržovat medicína. Popsat nástroje života, smrti a medicíny po součástkách a v součástech jinak, než je běžné, se možná nesluší ve vědě, naopak vědění to prospívá. Autoři se desítky let věnují vědecké antropologii a klinické medicíně, ale po pracovní době sobě i vědě rádi odlehčí i jinak. Třeba touto přilnavou knížkou O životě, smrti a medicíně s humorem, která ke čtenáři přilne a nepustí, protože od něj neočekává mentální výkon, hledání smyslu života ani vážnost. Jak prolínat ironii s fakty a fakta s ironií, tím se zde moří dva profesoři a četní originální profíci, malíři a grafici. Navíc je nutno skromně poznamenat, že vše v knize uvedené je čirá pravda, čímž se liší od mnohých jiných. Knížka bude též skvělým dárkem, jimž dárce obdarovanému odhalí hloubku a jedinečnost své vlastní osobnosti. Překvapí nepřipravené, snad nepohorší, zcela jistě nikoho ani nezarmoutí. V dnešním digitálním světě umožní konkurovat umělé inteligenci pouhým člověčenstvím a imaginací. Učiňme se četbou uvolněnějšími a skvělejšími!
- MeSH
- Anatomy MeSH
- Anthropology, Cultural MeSH
- Medicine MeSH
- Death MeSH
- Life MeSH
- Publication type
- Monograph MeSH
- Popular Work MeSH
- Conspectus
- Lékařské vědy. Lékařství
- NML Fields
- lékařství
- antropologie
High-salt diets (HSDs) are known to impact blood pressure and cardiovascular health, but their effects on glucose metabolism, liver function, and gut microbiota remain poorly understood. This study investigates how long-term HSD affects these physiological processes and evaluates the potential therapeutic effects of ACE inhibitors (ACEIs) and angiotensin II receptor blockers (ARBs). Male Sprague-Dawley rats were fed a normal salt diet (0.3% NaCl), a moderate salt diet (2% NaCl), or a high-salt diet (8% NaCl) for 12 wk. Two subgroups in the HSD condition received telmisartan or enalapril. We assessed blood pressure, glucose homeostasis, liver inflammation, pancreatic function, and gut microbiota composition. HSD rats exhibited significantly higher blood pressure [130 ± 2 mmHg in normal diet (ND) vs. 144 ± 4 mmHg in HSD; P < 0.01], reduced fasting insulin (1.33 ± 0.14 ng/mL in ND vs. 0.60 ± 0.05 ng/mL in HSD; P < 0.01), and gut microbiota dysbiosis, with a 71% reduction in Ruminococcus species (P = 0.018). Liver inflammation, indicated by an increase in CD68+ macrophages, was also observed in the HSD group. Telmisartan treatment significantly reduced liver inflammation but did not fully restore metabolic homeostasis. HSD disrupts multiple physiological systems, including glucose metabolism and liver function, partly through gut microbiota alterations. ACEIs and ARBs provided partial protection, highlighting the need for multitargeted interventions to mitigate high-salt diet effects.NEW & NOTEWORTHY High-salt diet induces multisystem disruptions, including liver inflammation, reduced insulin levels, and gut microbiota imbalance. ACEIs and ARBs showed limited efficacy, highlighting the need for comprehensive therapeutic approaches.
- MeSH
- Angiotensin Receptor Antagonists * pharmacology MeSH
- Enalapril pharmacology MeSH
- Glucose * metabolism MeSH
- Angiotensin-Converting Enzyme Inhibitors * pharmacology MeSH
- Liver * drug effects metabolism MeSH
- Blood Glucose metabolism drug effects MeSH
- Blood Pressure drug effects MeSH
- Rats MeSH
- Sodium Chloride, Dietary * adverse effects MeSH
- Rats, Sprague-Dawley MeSH
- Gastrointestinal Microbiome * drug effects MeSH
- Telmisartan pharmacology MeSH
- Animals MeSH
- Check Tag
- Rats MeSH
- Male MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
Kontext: Infekční onemocnění covid-19 je spojeno s endotelovou dysfunkcí. Ověřuje se představa možnosti opravy endotelové buňky pomocí endotelových progenitorových buněk (endothelial progenitor cell, EPC) s použitím inhibitorů angiotenzin konvertujícího enzymu (ACEI); podle této představy by se tak mohla zlepšit angiogeneze EPC. Metody: Jedná se o skutečně experimentální in vitro studii s uspořádáním s kontrolní skupinou vytvořenou až po testu. Mononukleární buňky byly izolovány z periferní žilní krve pacienta s chronickým koronárním syndromem, který měl v anamnéze infekční onemocnění covid-19. Buňky byly kultivovány ve speciálním médiu po dobu sedmi dní a buňky EPC byly identifikovány imunocytochemicky pomocí protilátek proti buňkám CD34 radioaktivně značeným fluoresceinizothiocyanátem (FITC) s vyšetřením pod fluorescenčním mikroskopem. Buňky byly rozděleny do dvou skupin, kontrolní a do skupiny s aplikací lisinoprilu v dávce 50 μM. Morfologie a spojení tubulů byly zkoumány pomocí analyzátoru obrázků výrobce Wimasis. Koncentrace von Willebrandova faktoru (vWF) a CD31 byly měřeny metodou ELISA, následovanou statistickým srovnáním obou skupin, přičemž za statisticky významnou byla považována hodnota p < 0,05. Výsledky: Po 144hodinové kultivaci byly buňky EPC identifikovány pomocí světelné a fluorescenční mikroskopie. Parametry tvorby tubulů včetně pokryté plochy (29,6 ± 15,68 vs. 61,8 ± 25,41; p 0,13), celkového počtu tubulů 387 ± 101,55 vs. 382,67 ± 158,53; p 0,97), větvení (163 ± 72,52 vs. 179,66 ± 53,5; p 0,543) a celkového počtu kliček (40,66 ± 30,73 vs. 52,66 ± 5,77; p 0,543) nevykazovaly mezi kontrolní skupinou a skupinou s aplikací lisinoprilu žádný rozdíl. Pokud se týče sérologických biomarkerů, hodnoty CD31 se mezi kontrolami a skupinou s aplikací lisinoprilu statisticky významně nelišily (2 903,58 ± 578,08 vs. 3 361,89 ± 391,24; p 0,319), nicméně hodnoty vWF byly statisticky významně vyšší ve skupině s aplikací lisinoprilu (98,670 ± 3,240 vs. 91,181 ± 2,443; p 0,033). Závěr: U pacientů se stabilní ischemickou chorobou srdeční po prodělaném infekčním onemocnění covid-19 může lisinopril ovlivňovat angiogenezi buněk EPC, jak dokazuje zvyšování hodnot parametrů tvorby tubulů a statisticky významný nárůst koncentrace von Willebrandova faktoru.
Background: COVID-19 infection is associated with endothelial dysfunction. The concept of endothelial cell repair utilizing endothelial progenitor cells (EPCs) with the use of angiotensin-converting enzyme inhibitors (ACEIs) has been developing which is known for its potential for EPC's angiogenesis improvement. Methods: This is a true experimental in vitro study with post-test only control group design. Mononuclear cells were isolated from peripheral venous blood of patient with chronic coronary syndrome and history of COVID-19. The cells then cultured on special media for 7 days and EPC was identified using immunocytochemical examination with labelled anti-CD34 cells FITC-under fluorescence microscope examination. The cells were divided into two groups consisted of control group and 50 μM lisinopril-treated group. The morphology and tube connections were analyzed using Wimasis image analyzer. The von Willebrand factor (vWF) and CD31 concentrations were also measured by ELISA. Statistical comparison between both groups was performed and p-value < 0.05 was considered significant.
- MeSH
- Angiogenesis drug effects MeSH
- Antigens, CD34 MeSH
- COVID-19 complications MeSH
- Adult MeSH
- Endothelial Progenitor Cells * drug effects MeSH
- Microscopy, Fluorescence MeSH
- Immunohistochemistry methods instrumentation MeSH
- Coronary Disease drug therapy complications MeSH
- Humans MeSH
- Lisinopril * administration & dosage MeSH
- Statistics as Topic MeSH
- In Vitro Techniques MeSH
- Check Tag
- Adult MeSH
- Humans MeSH
- Male MeSH
- Publication type
- Clinical Study MeSH
- Research Support, Non-U.S. Gov't MeSH
Plants are subjected to a variety of abiotic stressors, including drought stress, that are fatal to their growth and ability to produce under natural conditions. Therefore, the present study was intended to investigate the drought tolerance potential of faba bean (Vicia faba L.) plants under the co-application of biochar and rhizobacteria, Cellulomonas pakistanensis (National Culture Collection of Pakistan (NCCP)11) and Sphingobacterium pakistanensis (NCCP246). The experiment was initiated by sowing the inoculated seeds with the aforementioned rhizobacterial strains in earthen pots filled with 3 kg of sand-mixed soil and 5% biochar. The morphology of biochar was observed with highly porous nature, along with the detection of various essential elements. The biochemical and physiological data showed that phenolic compounds and osmolytes were adversely affected by the induction of drought stress. However, the application of biochar and rhizobacteria boosted the level of flavonoids on average by 52.03%, total phenols by 50.67%, soluble sugar by 82.85%, proline by 76.81%, glycine betaine by 107.25%, and total protein contents by 89.18% in all co-treatments of biochar and rhizobacteria. In addition, stress indicator compounds, including malondialdehyde (MDA) contents and H2O2, were remarkably alleviated by 54.21% and 47.03%, respectively. Similarly, the amplitude of antioxidant enzymes including catalase, peroxidase, superoxide dismutase, ascorbate peroxidase, and guaiacol peroxidase was also enhanced by 63.80%, 80.95%, 37.87%, and 58.20%, respectively, in all co-treatments of rhizobacteria and biochar. Conclusively, biochar and rhizobacteria have a magnificent role in enhancing the drought tolerance potential of crop plants by boosting the physio-biochemical traits and enhancing the level of antioxidant enzymes.
- MeSH
- Antioxidants metabolism MeSH
- Charcoal * chemistry MeSH
- Phenols metabolism MeSH
- Flavonoids metabolism analysis MeSH
- Stress, Physiological * MeSH
- Plant Roots microbiology growth & development MeSH
- Malondialdehyde metabolism MeSH
- Droughts * MeSH
- Soil Microbiology MeSH
- Vicia faba * microbiology growth & development MeSH
- Publication type
- Journal Article MeSH
Various studies have correlated the mechanical properties of the aortic wall with its biochemical parameters and inner structure. Very few studies have addressed correlations with the cohesive properties, which are crucial for understanding fracture phenomena such as aortic dissection, i.e. a life-threatening process. Aimed at filling this gap, we conducted a comprehensive biochemical and histological analysis of human aortas (the ascending and descending thoracic and infrarenal abdominal aorta) from 34 cadavers obtained post-mortem during regular autopsies. The pentosidine, hydroxyproline and calcium contents, calcium/phosphorus molar ratio, degree of atherosclerosis, area fraction of elastin, collagen type I and III, alpha smooth muscle actin, vasa vasorum, vasa vasorum density, aortic wall thickness, thicknesses of the adventitia, media and intima were determined and correlated with the delamination forces in the longitudinal and circumferential directions of the vessel as determined from identical cadavers. The majority of the parameters determined did not indicate significant correlation with age, except for the calcium content and collagen maturation (enzymatic crosslinking). The main results concern differences between enzymatic and non-enzymatic crosslinking and those caused by the presence of atherosclerosis. The enzymatic crosslinking of collagen increased with age and was accompanied by a decrease in the delamination strength, while non-enzymatic crosslinking tended to decrease with age and was accompanied by an increase in the delamination strength. As the rate of calcification increased, the presence of atherosclerosis led to the formation of calcium phosphate plaques with higher solubility than the tissue without or with only mild signs of atherosclerosis. STATEMENT OF SIGNIFICANCE: This study presents a detailed biochemical and histological analysis of human aortic samples (ascending thoracic aorta, descending thoracic aorta and infrarenal abdominal aorta) taken from 34 cadavers. The contribution of this scientific study lies in the detailed biochemical comparison of the enzymatic and non-enzymatic glycosylation-derived crosslinks of vascular tissues and their influence on the delamination strength of the human aorta since, to the best of our knowledge, no such comprehensive studies exist in the literature. A further benefit concerns the notification of the limitations of the various analytical methods applied; an important factor that must be taken into account in such studies.
- MeSH
- Actins metabolism MeSH
- Aorta * metabolism MeSH
- Arginine analogs & derivatives MeSH
- Atherosclerosis metabolism pathology MeSH
- Adult MeSH
- Elastin metabolism MeSH
- Hydroxyproline metabolism MeSH
- Middle Aged MeSH
- Humans MeSH
- Lysine analogs & derivatives metabolism MeSH
- Aged, 80 and over MeSH
- Aged MeSH
- Aging * physiology MeSH
- Calcium metabolism MeSH
- Vasa Vasorum metabolism MeSH
- Check Tag
- Adult MeSH
- Middle Aged MeSH
- Humans MeSH
- Male MeSH
- Aged, 80 and over MeSH
- Aged MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
- Keywords
- Tislelizumab, tofersen, Danikopan,
- MeSH
- Aminopyridines pharmacology therapeutic use MeSH
- Amyotrophic Lateral Sclerosis drug therapy MeSH
- Renal Insufficiency, Chronic drug therapy MeSH
- Diabetes Mellitus drug therapy MeSH
- Insulin, Long-Acting pharmacology therapeutic use MeSH
- Antibodies, Monoclonal, Humanized pharmacology therapeutic use MeSH
- Humans MeSH
- Oligonucleotides pharmacology therapeutic use MeSH
- Hemoglobinuria, Paroxysmal drug therapy MeSH
- Proline pharmacology therapeutic use MeSH
- Registries * MeSH
- Drug Approval * MeSH
- Check Tag
- Humans MeSH
Daprodustat, also known under the trade name DUVROQ, is a small molecule developed by GlaxoSmithKline, which has become a promising drug in the field of anemia treatment in patients with chronic kidney disease. Daprodustat belongs to a group of drugs called hypoxia-inducible factor prolyl hydroxylase inhibitors. These drugs interfere with the regulation of erythropoietin, which is a key factor in the production of red blood cells. This drug was approved in Japan in June 2020 and clinical studies with it are ongoing in several countries around the world, where they focus on evaluating the effectiveness and safety in various populations of patients with chronic kidney disease.
Spontaneously hypertensive rats (SHR) are characterized by sympathetic hyperactivity and insufficient parasympathetic activity, and their high blood pressure (BP) can be lowered by long-term inhibition of the renin-angiotensin system. The aim of our study was to determine the influence of chronic inhibition of angiotensin converting enzyme (ACE) by captopril on cardiovascular regulation by the sympathetic and parasympathetic nervous system. Implanted radiotelemetric probes or arterial cannulas were used to measure mean arterial pressure (MAP), heart rate (HR), and arterial baroreflex in adult SHR and Wistar-Kyoto (WKY) rats under basal or stress conditions. MAP and the low-frequency component of systolic blood pressure variability (LF-SBPV, marker of sympathetic activity) were greater in SHR than in WKY rats. Under basal conditions chronic captopril treatment reduced both parameters more effectively in SHR, and the same was true during acute restraint stress. HR was similar in control rats of both strains, but WKY rats showed greater heart rate variability (HRV), indicating higher parasympathetic activity. Captopril administration increased HR in both strains, whereas HRV was decreased only in WKY. Chronic captopril treatment improved the impaired baroreflex-HR control in SHR by increasing the sensitivity but not the capacity of vagal arm of arterial baroreflex. Captopril treatment attenuated BP changes elicited by dimethylphenylpiperazinium (DMPP, agonist of nicotinic acetylcholine receptors), especially in SHR, indicating that sympathetic nerve transmission is facilitated by angiotensin II more in hypertensive than in normotensive animals. Thus, chronic ACE inhibition improves baroreflex sensitivity and lowers BP through both central and peripheral attenuation of sympathetic tone.
- MeSH
- Baroreflex * drug effects MeSH
- Hypertension drug therapy physiopathology enzymology MeSH
- Angiotensin-Converting Enzyme Inhibitors * pharmacology MeSH
- Captopril * pharmacology MeSH
- Blood Pressure * drug effects MeSH
- Rats MeSH
- Rats, Inbred SHR MeSH
- Rats, Inbred WKY MeSH
- Heart Rate * drug effects MeSH
- Sympathetic Nervous System * drug effects MeSH
- Animals MeSH
- Check Tag
- Rats MeSH
- Male MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
Nephrotoxicity as a cause of acute kidney injury (AKI) induced by cisplatin (CP), limits its usefulness as an anticancer agent. Diminazene, an angiotensin converting enzyme 2 activator, exhibited renoprotective properties on rat models of kidney diseases. This research aims to investigate the salutary effect of diminazene in comparison with lisinopril or valsartan in CP-induced AKI. The first and second groups of rats received oral vehicle (distilled water) for 9 days, and saline injection or intraperitoneal CP (6 mg/kg) on day 6, respectively. Third, fourth, and fifth groups received intraperitoneal injections of CP on day 6 and diminazene (15 mg/kg/day, orally), lisinopril (10 mg/kg/day, orally), or valsartan (30 mg/kg/day, orally), for 9 days, respectively. 24h after the last day of treatment, blood and kidneys were removed under anesthesia for biochemical and histopathological examination. Urine during the last 24 h before sacrificing the rats was also collected. CP significantly increased plasma urea, creatinine, neutrophil gelatinase-associated lipocalin, calcium, phosphorus, and uric acid. It also increased urinary albumin/creatinine ratio, N-Acetyl-beta-D-Glucosaminidase/creatinine ratio, and reduced creatinine clearance, as well the plasma concentrations of inflammatory cytokines [plasma tumor necrosis factor-alpha, and interleukin-1beta], and significantly reduced antioxidant indices [catalase, glutathione reductase , and superoxide dismutase]. Histopathologically, CP treatment caused necrosis of renal tubules, tubular casts, shrunken glomeruli, and increased renal fibrosis. Diminazine, lisinopril, and valsartan ameliorated CP-induced biochemical and histopathological changes to a similar extent. The salutary effect of the three drugs used is, at least partially, due to their anti-inflammatory and antioxidant effects. Keywords: Cisplatin, Diminazene, ACE2 activator, Lisinopril, Valsartan, Acute kidney injury.
- MeSH
- Acute Kidney Injury * chemically induced pathology metabolism prevention & control drug therapy MeSH
- Cisplatin * toxicity MeSH
- Diminazene * analogs & derivatives pharmacology therapeutic use MeSH
- Angiotensin-Converting Enzyme Inhibitors pharmacology MeSH
- Rats MeSH
- Kidney drug effects pathology metabolism MeSH
- Lisinopril * pharmacology MeSH
- Rats, Wistar * MeSH
- Antineoplastic Agents toxicity MeSH
- Valsartan * pharmacology MeSH
- Animals MeSH
- Check Tag
- Rats MeSH
- Male MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Comparative Study MeSH
