The eye represents a highly specialized organ, with its main function being to convert light signals into electrical impulses. Any damage or disease of the eye induces a local inflammatory reaction that could be harmful for the specialized ocular cells. Therefore, the eye developed several immunoregulatory mechanisms which protect the ocular structures against deleterious immune reactions. This protection is ensured by the production of a variety of immunosuppressive molecules, which create the immune privilege of the eye. In addition, ocular cells are potent producers of numerous growth and trophic factors which support the survival and regeneration of diseased and damaged cells. If the immune privilege of the eye is interrupted and the regulatory mechanisms are not sufficiently effective, the eye disease can progress and result in worsening of vision or even blindness. In such cases, external immunotherapeutic interventions are needed. One perspective possibility of treatment is represented by mesenchymal stromal/stem cell (MSC) therapy. MSCs, which can be administered intraocularly or locally into diseased site, are potent producers of various immunoregulatory and regenerative molecules. The main advantages of MSC therapy include the safety of the treatment, the possibility to use autologous (patient's own) cells, and observations that the therapeutic properties of MSCs can be intentionally regulated by external factors during their preparation. In this review, we provide a survey of the immunoregulatory and regenerative mechanisms in the eye and describe the therapeutic potential of MSC application for corneal damages and retinal diseases.
BACKGROUND: Extensive surgical resection of the thoracic aorta in patients with type A aortic dissection (TAAD) is thought to reduce the risk of late aortic wall degeneration and the need for repeat aortic operations. OBJECTIVES: We evaluated the early and late outcomes after aortic root replacement and supracoronary ascending aortic replacement in patients with TAAD involving the aortic root. DESIGN: Retrospective, multicenter cohort study. METHODS: The outcomes after aortic root replacement and supracoronary ascending aortic replacement in patients with TAAD involving the aortic root, that is dissection flap located at least in one of the Valsava segments, were herein evaluated. In-hospital mortality, neurological complications, dialysis as well as 10-year repeat proximal aortic operation, and mortality were the outcomes of this study. RESULTS: Supracoronary ascending aortic replacement was performed in 198 patients and aortic root replacement in 215 patients. During a mean follow-up of 4.0 ± 4.0 years, 19 patients underwent 22 repeat procedures on the aortic root and/or aortic valve. No operative death occurred after these reinterventions. The risk of proximal aortic reoperation was significantly lower in patients who underwent aortic root replacement (5.5% vs 12.9%, adjusted subdistributional hazard ratio (SHR) 0.085, 95% CI 0.022-0.329). Aortic root replacement was associated with higher rates of in-hospital (14.4% vs 12.1%, adjusted odds ratio 2.192, 95% CI 1.000-4.807) and 10-year mortality (44.5% vs 30.4%, adjusted hazard ratio 2.216, 95% CI 1.338-3.671). Postoperative neurological complications and dialysis rates were comparable in the study groups. CONCLUSION: Among patients with TAAD involving the aortic root, its replacement was associated with a significantly lower rate of repeat proximal aortic operation of any type compared to supracoronary aortic replacement. Still, aortic root replacement seems to be associated with an increased risk of mortality in these patients. UNLABELLED: ClinicalTrials.gov: NCT04831073 (https://clinicaltrials.gov/study/NCT04831073).
- MeSH
- aneurysma hrudní aorty * chirurgie mortalita diagnostické zobrazování MeSH
- časové faktory MeSH
- cévy - implantace protéz * škodlivé účinky mortalita MeSH
- disekce aorty * chirurgie mortalita MeSH
- dospělí MeSH
- hodnocení rizik MeSH
- lidé středního věku MeSH
- lidé MeSH
- mortalita v nemocnicích * MeSH
- pooperační komplikace * epidemiologie etiologie mortalita MeSH
- reoperace MeSH
- retrospektivní studie MeSH
- rizikové faktory MeSH
- senioři MeSH
- výsledek terapie MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- multicentrická studie MeSH
- srovnávací studie MeSH
INTRODUCTION: Mitochondrial dysfunction stands as a pivotal feature in neurodegenerative disorders, spurring the quest for targeted therapeutic interventions. This review examines Ubiquitin-Specific Protease 30 (USP30) as a master regulator of mitophagy with therapeutic promise in Alzheimer's disease (AD) and Parkinson's disease (PD). USP30's orchestration of mitophagy pathways, encompassing PINK1-dependent and PINK1-independent mechanisms, forms the crux of this exploration. METHOD: A systematic literature search was conducted in PubMed, Scopus, and Web of Science, selecting studies that investigated USP's function, inhibitor design, or therapeutic efficacy in AD and PD. Inclusion criteria encompassed mechanistic and preclinical/clinical data, while irrelevant or duplicate references were excluded. Extracted findings were synthesized narratively. RESULTS: USP30 modulates interactions with translocase of outer mitochondrial membrane (TOM) 20, mitochondrial E3 ubiquitin protein ligase 1 (MUL1), and Parkin, thus harmonizing mitochondrial quality control. Emerging novel USP30 inhibitors, racemic phenylalanine derivatives, N-cyano pyrrolidine, and notably, benzosulphonamide class compounds, restore mitophagy, and reduce neurodegenerative phenotypes across diverse models with minimal off-target effects. Modulation of other USPs also influences neurodegenerative disease pathways, offering additional therapeutic avenues. CONCLUSIONS: In highlighting the nuanced regulation of mitophagy by USP30, this work heralds a shift toward more precise and effective treatments, paving the way for a new era in the clinical management of neurodegenerative disorders.
- MeSH
- individualizovaná medicína metody MeSH
- lidé MeSH
- mitochondriální proteiny MeSH
- mitofagie * fyziologie účinky léků MeSH
- neurodegenerativní nemoci * farmakoterapie metabolismus MeSH
- specifické proteázy ubikvitinu metabolismus antagonisté a inhibitory MeSH
- thiolesterhydrolasy metabolismus MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
Infectious diseases, including bacterial, fungal, and viral, have once again gained urgency in the drug development pipeline after the recent COVID-19 pandemic. Tuberculosis (TB) is an old infectious disease for which eradication has not yet been successful. Novel agents are required to have potential activity against both drug-sensitive and drug-resistant strains of Mycobacterium tuberculosis (Mtb), the causative agent of TB. In this study, we present a series of 2-phenyl-N-(pyridin-2-yl)acetamides in an attempt to investigate their possible antimycobacterial activity, cytotoxicity on the HepG2 liver cancer cell line, and-as complementary testing-their antibacterial and antifungal properties against a panel of clinically important pathogens. This screening resulted in one compound with promising antimycobacterial activity-compound 12, MICMtb H37Ra = 15.625 μg/mL (56.26 μM). Compounds 17, 24, and 26 were further screened for their antiproliferative activity against human epithelial kidney cancer cell line A498, human prostate cancer cell line PC-3, and human glioblastoma cell line U-87MG, where they were found to possess interesting activity worth further exploration in the future.
- MeSH
- acetamidy * chemie farmakologie MeSH
- antifungální látky farmakologie chemie chemická syntéza MeSH
- antituberkulotika farmakologie chemie MeSH
- buňky Hep G2 MeSH
- lidé MeSH
- mikrobiální testy citlivosti * MeSH
- Mycobacterium tuberculosis * účinky léků MeSH
- nádorové buněčné linie MeSH
- proliferace buněk * účinky léků MeSH
- protinádorové látky farmakologie chemie MeSH
- pyridiny chemie farmakologie MeSH
- SARS-CoV-2 účinky léků MeSH
- vztahy mezi strukturou a aktivitou MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is an RNA virus responsible for coronavirus disease 2019 (COVID-19). While SARS-CoV-2 primarily targets the lungs and airways, it can also infect other organs, including the central nervous system (CNS). The aim of this study was to investigate whether the choroid plexus could serve as a potential entry site for SARS-CoV-2 into the brain. Tissue samples from 24 deceased COVID-19-positive individuals were analyzed. Reverse transcription real-time PCR (RT-qPCR) was performed on selected brain regions, including the choroid plexus, to detect SARS-CoV-2 viral RNA. Additionally, immunofluorescence staining and confocal microscopy were used to detect and localize two characteristic proteins of SARS-CoV-2: the spike protein S1 and the nucleocapsid protein. RT-qPCR analysis confirmed the presence of SARS-CoV-2 viral RNA in the choroid plexus. Immunohistochemical staining revealed viral particles localized in the epithelial cells of the choroid plexus, with the spike protein S1 detected in the late endosomes. Our findings suggest that the blood-cerebrospinal fluid (B-CSF) barrier in the choroid plexus serves as a route of entry for SARS-CoV-2 into the CNS. This study contributes to the understanding of the mechanisms underlying CNS involvement in COVID-19 and highlights the importance of further research to explore potential therapeutic strategies targeting this entry pathway.
- MeSH
- COVID-19 * virologie MeSH
- dospělí MeSH
- fosfoproteiny * metabolismus MeSH
- glykoprotein S, koronavirus * genetika metabolismus MeSH
- hematoencefalická bariéra * virologie MeSH
- internalizace viru MeSH
- koronavirové nukleokapsidové proteiny MeSH
- lidé středního věku MeSH
- lidé MeSH
- plexus chorioideus * virologie MeSH
- RNA virová * genetika MeSH
- SARS-CoV-2 * fyziologie MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
Prognostic significance of the timing in the cardiac cycle of the first (TP1) and second (TP2) systolic peak of the central aortic pulse wave is ill-defined. Incidence rates and standardized multivariable-adjusted hazard ratios (HRs) of adverse health outcomes associated with TP1 and TP2, estimated by the SphygmoCor software, were assessed in the International Database of Central Arterial Properties for Risk Stratification (IDCARS) (n = 5529). Model refinement was assessed by the integrated discrimination (ID) and net reclassification (NR) improvement. Over 4.1 years (median), 201 participants died and 248 and 159 patients experienced cardiovascular or cardiac endpoints. Mean TP1 and TP2, standardized for cohort, sex, age, and heart rate, were 103 and 228 ms. Shorter TP1 and TP2 were associated with higher mortality and shorter TP1 with a higher risk of cardiovascular and cardiac endpoints (trend p ≤ 0.004). The HRs relating total mortality and cardiovascular endpoints to TP2 were 0.82 (95% confidence interval [CI]: 0.72-0.94) and 0.87 (0.77-0.98), respectively. The HR relating cardiac endpoints to TP1 was 0.81 (0.68-0.97). For total mortality and cardiovascular endpoints in relation to TP2, NRI was significant (p ≤ 0.010), but not for cardiac endpoints in relation to TP1. Integrated discrimination improvement (IDI) was not significant for any endpoint. The HRs relating total mortality to TP2 were smaller (p ≤ 0.026) in women than men (0.67 vs. 0.95) and in older (≥ 60 years) versus younger (< 60 years) participants (0.80 vs. 0.88). Our study adds to the evidence supporting risk stratification based on aortic pulse analysis by showing that TP2 and TP1 carry prognostic information.
- MeSH
- analýza pulzové vlny * metody MeSH
- aorta patofyziologie MeSH
- hodnocení rizik metody statistika a číselné údaje MeSH
- hypertenze epidemiologie mortalita patofyziologie MeSH
- kardiovaskulární nemoci * mortalita epidemiologie MeSH
- lidé středního věku MeSH
- lidé MeSH
- prognóza MeSH
- rizikové faktory MeSH
- senioři MeSH
- srdeční frekvence fyziologie MeSH
- systola fyziologie MeSH
- tuhost cévní stěny fyziologie MeSH
- Check Tag
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
Pulmonary alveolar proteinosis (PAP) is a rare disease characterised by excessive accumulation of surfactant components in alveolar macrophages, alveoli, and peripheral airways. The accumulation of surfactant is associated with only a minimal inflammatory response but can lead to the development of pulmonary fibrosis. Three clinical forms of PAP are distinguished - primary, secondary and congenital. In recent years, significant findings have helped to clarify the ethiology and pathogenesis of the disease. Apart from impaired surfactant protein function, a key role in the development of PAP is played by signal pathway of granulocyte and macrophage colonies stimulating growth factor (GM-CSF) which is necessary for the functioning of alveolar macrophages and for surfactant homeostasis. Surfactant is partially degraded by alveolar macrophages that are stimulated by GM-CSF. The role of GM-CSF has been shown especially in primary PAP, which is currently considered an autoimmune disease involving the development of GM-CSF neutralising autoantibodies. Clinically, the disease may be silent or manifest with dyspnoeic symptoms triggered by exertion and cough. However, there is a 10 to 15% rate of patients who develop respiratory failure. Total pulmonary lavage is regarded as the standard method of treatment. In addition, recombinant human GM-CSF has been studied as a prospective therapy for the treatment of PAP.
- MeSH
- alveolární makrofágy * imunologie patologie MeSH
- faktor stimulující granulocyto-makrofágové kolonie * metabolismus MeSH
- lidé MeSH
- plicní alveolární proteinóza * patologie MeSH
- vzácné nemoci * patologie MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
BACKGROUND AND PURPOSE: The global burden of neurological diseases exceeds 43.1%, imposing a significant burden on patients, caregivers and society. This paper presents a roadmap to reduce this burden and improve brain health (BH) in Europe. METHODS: The roadmap is based on the European Academy of Neurology's (EAN) five-pillar BH strategy: advancing a global BH approach (P1), supporting policymaking (P2), fostering research (P3), promoting education (P4), and raising awareness of prevention and treatment (P5). It reviews current efforts, collaborations and future directions aligned with the WHO Intersectoral Global Action Plan (iGAP) for Neurological Disorders and suggests future initiatives and call for action. RESULTS: P1: Support WHO-iGAP through defined action points, international collaborations, in particular, the WHO BH Unit, and the EAN Brain Health Mission. P2: Collaborate with 48 national neurological societies to promote National Brain Plans (NBPs), addressing local needs, and improving access to care. P3: Advocate for more research funding; identify determinants of BH; develop preventive measures. P4: Provide educational opportunities for neurologists, public education programs, and advocacy training, including tools to educate the public. P5: Spearhead global awareness campaigns, organize public educational activities, and train BH advocates to contribute toward sustainable and long-term public health campaigns and policy engagement. CONCLUSIONS: The paper highlights the importance of a unified approach, integrating international collaborations and local initiatives, to improve BH outcomes based on the WHO-iGAP, and support sustainable development goals, in particular SDG 3: Good Health and Well-being and SDG 4: Quality Education.
Multiple myeloma is a plasma cell malignancy characterized by an abnormal increase in monoclonal immunoglobulins. Despite significant advances in treatment, some patients progress to more aggressive forms of multiple myeloma, including extramedullary disease or plasma cell leukemia. Although the exact molecular mechanisms are not known, several studies have confirmed the involvement of small extracellular vesicle-enriched microRNAs in multiple myeloma progression. Therefore, we performed expression profiling of these molecules in bone marrow plasma of multiple myeloma, extramedullary disease, and plasma cell leukemia patients using small RNA sequencing to identify novel molecules involved in disease pathogenesis. In total, 42 microRNAs were significantly dysregulated among analyzed subgroups. Independent validation by RT-qPCR confirmed elevated levels of miR-140-3p, miR-584-5p, miR-191-5p, and miR-143-3p in multiple myeloma patients compared to extramedullary disease and plasma cell leukemia patients. Subsequent statistical analysis revealed significant correlations between patient clinical characteristics or flow cytometry parameters and microRNA expression. These results indicate that dysregulation of microRNAs could contribute to multiple myeloma progression.
- Publikační typ
- časopisecké články MeSH
The Takeda G protein-coupled receptor 5 (TGR5), also known as GPBAR1 (G protein-coupled bile acid receptor), is a membrane-type bile acid receptor that regulates blood glucose levels and energy expenditure. These essential functions make TGR5 a promising target for the treatment of type 2 diabetes and metabolic disorders. Currently, most research on developing TGR5 agonists focuses on modifying the structure of bile acids, which are the endogenous ligands of TGR5. However, TGR5 agonists with nonsteroidal structures have not been widely explored. This study aimed at discovering new TGR5 agonists using bile acid derivatives as a basis for a computational approach. We applied a combination of pharmacophore-based, molecular docking, and molecular dynamic (MD) simulation to identify potential compounds as new TGR5 agonists. Through pharmacophore screening and molecular docking, we identified 41 candidate compounds. From these, five candidates were selected based on criteria including pharmacophore features, a docking score of less than 9.2 kcal/mol, and similarity in essential interaction patterns with a reference ligand. Biological assays of the five hits confirmed that Hit-3 activates TGR5 similarly to the bile acid control. This was supported by MD simulation results, which indicated that a hydrogen bond interaction with Tyr240 is involved in TGR5 activation. Hit-3 (CSC089939231) represents a new nonsteroidal lead that can be further optimized to design potent TGR5 agonists.
- MeSH
- lidé MeSH
- ligandy MeSH
- molekulární struktura MeSH
- objevování léků MeSH
- receptory spřažené s G-proteiny * agonisté metabolismus MeSH
- simulace molekulární dynamiky * MeSH
- simulace molekulového dockingu * MeSH
- vztahy mezi strukturou a aktivitou MeSH
- žlučové kyseliny a soli chemie metabolismus farmakologie MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
