pathogenesis Dotaz Zobrazit nápovědu
Existence syndromu časného normoglykemického zhoršení byla dlouhou dobu předmětem sporů. V současné době je tento syndrom široce akceptován pod zkratkou EWDR. Jeho podstatou je rychlá kompenzace subkompenzovaného až dekompenzovaného diabetu, která vede k progresi diabetické retinopatie. Významnou roli v jeho patogenezi hrají vysoké hladiny růstového faktoru. V kazuistice upozorňujeme na současný přístup v prevenci této závažné komplikace.
The existence of normoglycaemic re-entry phenomenon has long been a matter of controversy. Currently, this syndrome is widely accepted under the acronym EWDR. Its essence is rapid compensation of subcompensated to decompensated diabetes, which leads to progression of diabetic retinopathy. High levels of growth factor play a significant role in its pathogenesis. In the case report, we draw attention to the current approach to the prevention of this serious complication.
Alzheimer's disease (AD), a leading cause of dementia worldwide, is a multifactorial neurodegenerative disorder characterized by amyloid-beta plaques, tauopathy, neuronal loss, neuro-inflammation, brain atrophy, and cognitive deficits. AD manifests as familial early-onset (FAD) with specific gene mutations or sporadic late-onset (LOAD) caused by various genetic and environmental factors. Numerous transgenic rodent models have been developed to understand AD pathology development and progression. The TgF344-AD rat model is a double transgenic model that carries two human gene mutations: APP with the Swedish mutation and PSEN-1 with delta exon 9 mutations. This model exhibits a complete repertoire of AD pathology in an age-dependent manner. This review summarizes multidisciplinary research insights gained from studying TgF344-AD rats in the context of AD pathology. We explore neuropathological findings; electrophysiological assessments revealing disrupted synaptic transmission, reduced spatial coding, network-level dysfunctions, and altered sleep architecture; behavioral studies highlighting impaired spatial memory; alterations in excitatory-inhibitory systems; and molecular and physiological changes in TgF344-AD rats emphasizing their age-related effects. Additionally, the impact of various interventions studied in the model is compiled, underscoring their role in bridging gaps in understanding AD pathogenesis. The TgF344-AD rat model offers significant potential in identifying biomarkers for early detection and therapeutic interventions, providing a robust platform for advancing translational AD research. Key words Alzheimer's disease, Transgenic AD models, TgF344-AD rats, Spatial coding.
- MeSH
- Alzheimerova nemoc * genetika patologie metabolismus MeSH
- amyloidový prekurzorový protein beta genetika metabolismus MeSH
- krysa rodu rattus MeSH
- lidé MeSH
- modely nemocí na zvířatech * MeSH
- mozek patologie metabolismus MeSH
- potkani inbrední F344 MeSH
- potkani transgenní * MeSH
- presenilin-1 genetika MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
Lipoblastoma, a rare benign tumor composed of immature fat cells, typically arises in the first 3 years of life. Although commonly found in the extremities and trunk, occurrences on the scalp are exceedingly rare. We present a case report of a lipoblastoma located on the scalp of a 5-year-old female patient. The patient presented with a painless, gradually enlarging mass over a 6-month period. Clinical and radiological evaluation confirmed the presence of a well-defined, lobulated lesion with adipose density. Surgical excision was performed, and histopathologic examination revealed characteristic features of lipoblastoma, including lipoblast-like cells and lobules of adipose tissue, separated by fibrous connective tissue septae of varying thickness surrounded by a fibrocartilaginous capsule. To our knowledge, this is the fourth documented case of lipoblastoma originating in the scalp region in a pediatric patient. Given the rarity of lipoblastoma in this location, this case highlights the importance of considering lipoblastoma as a differential diagnosis when evaluating scalp masses in children. Awareness of atypical presentations and histopathologic features can aid in accurate diagnosis and appropriate management, which usually involves complete surgical resection. Further studies are warranted to explore the genetic and molecular underpinnings of these unique cases, contributing to a better understanding of the pathogenesis of lipoblastomas in various anatomical sites.
- Publikační typ
- časopisecké články MeSH
- kazuistiky MeSH
Východiska: Signální dráha UPR (unfolded protein response, tj. odpověď na chybně složené proteiny) pomáhá myelomovým buňkám vyrovnat se se stresovými podmínkami vzniklými v důsledku nadměrné proteosyntézy, a představuje tak pro myelomové buňky prostředek umožňující jejich přežití. Extramedulární onemocnění je agresivnější forma mnohočetného myelomu, při které myelomové buňky ztrácí svoji závislost na mikroprostředí kostní dřeně a mohou infiltrovat jiné tkáně a orgány. Patogeneze vzniku extramedulárního onemocnění není dosud zcela objasněna. Cílem této studie bylo zjistit, zda existuje rozdíl v expresi genů spjatých s UPR mezi plazmatickými buňkami kostní dřeně od pacientů s mnohočetným myelomem a extramedulárním onemocněním. Materiál a metody: Pomocí reverzní transkripce ve spojení s kvantitativní polymerázovou řetězovou reakcí byla analyzována exprese šesti genů spjatých s UPR (ERN1, DDIT3, EIF2AK3, TUSC3, XBP1, HSPA5). Použito bylo celkem 76 vzorků plazmatických buněk kostní dřeně, z toho 44 bylo od pacientů s mnohočetným myelomem a 32 od pacientů s extramedulárním onemocněním. Výsledky: Byl pozorován statisticky významný rozdíl v expresi genů HSPA5, DDIT3, EIF2AK3 a ERN1 mezi skupinou mnohočetného myelomu a extramedulárního onemocnění; exprese byla ve všech případech vyšší u vzorků od pacientů s extramedulárním onemocněním. V případě genů XBP1 a TUSC3 nebyl pozorován statisticky významný rozdíl. Prokázáno bylo také několik statisticky významných korelací mezi hladinou exprese analyzovaných genů a klinickými daty pacientů. Závěr: Výsledky poukazují na možný význam signální dráhy UPR v patogenezi extramedulárního onemocnění. UPR se jeví jako vhodný směr dalšího výzkumu.
Background: The unfolded protein response (UPR) enables myeloma cells to overcome the stress conditions arising from excessive proteosynthesis and thus provides a survival advantage for myeloma cells. Extramedullary disease is a more aggressive form of multiple myeloma in which myeloma cells lose their dependence on the bone marrow microenvironment and are able to infiltrate other tissues and organs. The pathogenesis of extramedullary disease is not fully elucidated yet. The aim of this study was to determine whether there is a difference in the expression of UPR-related genes between bone marrow plasma cells from multiple myeloma and extramedullary disease patients. Materials and methods: Gene expression of six genes involved in UPR (ERN1, DDIT3, EIF2AK3, TUSC3, XBP1, HSPA5) was analyzed by quantitative reverse transcription polymerase chain reaction. In total, 76 bone marrow plasma cell samples were used, of which 44 were from patients with multiple myeloma and 32 from patients with extramedullary disease. Results: A statistically significant difference was observed between the multiple myeloma and extramedullary disease groups regarding the expression of HSPA5, DDIT3, EIF2AK3, and ERN1 genes. However, in the case of XBP1 and TUSC3 genes, no statistically significant difference in the expression was found. Several statistically significant correlations between the expression levels of the analyzed genes and the clinical data of the patients were observed as well. Conclusion: Our results suggest the importance of UPR in the pathogenesis of extramedullary disease. UPR appears to be a promising avenue for further research.
Glomerulonephritis (GN) encompasses a diverse group of immune-mediated diseases that damage the glomerular component of the nephron. While kidney biopsy remains the gold standard for diagnosis, it often fails to provide adequate insight into the underlying etiology of GN. Current classification systems have limited our understanding of the disease's pathophysiology and hinder the development of targeted therapies. Immunosuppressive treatments, such as glucocorticoids, calcineurin inhibitors, cyclophosphamide, and rituximab, remain the mainstay of therapy, though many patients fail to achieve remission or experience significant adverse effects. Moreover, the complex and multifactorial nature of GN pathogenesis calls for more refined therapeutic approaches. In recent years, multitarget therapies-combining different immunosuppressive agents targeting distinct immune pathways-have emerged as promising alternatives. Evidence suggests that multitarget therapy may offer superior outcomes compared to standard treatments. Despite early success, further studies are needed to optimize these regimens, reduce toxicity, and extend benefits to a broader range of GN patients. The development of personalized, biomarker-driven treatments, potentially leveraging innovative drug delivery systems and targeted biologics, holds promise for transforming GN care in the future.
- Publikační typ
- časopisecké články MeSH
The FGF signaling pathway plays an important role in the regulation of limb development, controlling cell migration, proliferation, differentiation, and apoptosis. Sprouty proteins act as antagonists of the FGF pathway and control the extent of FGF signaling as part of a negative feedback loop. Sprouty2/4 deficient mice evince defects in endochondral bone formation and digit patterning in their forelimbs, with pathogenesis recently related to ciliopathies. To understand the mechanisms behind these pathologies, the limb defects in Sprouty2+/-;Sprouty4-/- male and female mice were characterized and correlated to the dynamic expression patterns of Sprouty2 and Sprouty4, and the impact on the main signaling centers of the limb bud was assessed. Sprouty2 and Sprouty4 exhibited dynamic expressions during limb development. Interestingly, despite similar expression patterns in all limbs, the hindlimbs did not evince any obvious alterations in development, while the forelimbs showed consistent phenotypes of variable severity. Prenatally as well as postnatally, the left forelimb was significantly more severely affected than the right one. A broad variety of pathologies was present in the autopodium of the forelimb, including changes in digit number, size, shape, and number of bones, hand clefts, and digit fusions. Ectopic ossification of bones and abnormal bone fusions detected in micro-CT scans were frequently observed in the digital as well as in the carpal and metacarpal areas. Sprouty2+/-;Sprouty4-/- limb buds showed patchy loss of Fgf8 expression in the apical ectodermal ridge, and a loss of tissue underlying these regions. The zone of polarizing activity was also impacted, with lineage analysis highlighting a change in the contribution of Sonic hedgehog expressing cells. These findings support the link between Sproutys and Hedgehog signaling during limb development and highlight the importance of Sprouty2 and Sprouty4 in controlling early signaling centers in the limb.
- Publikační typ
- časopisecké články MeSH
Pulmonary tumor thrombotic microangiopathy (PTTM) is a rare paraneoplastic syndrome associated with various adenocarcinomas, most commonly gastric adenocarcinoma. This condition can progressively worsen pulmonary arterial hypertension, leading to acute or subacute pulmonary heart failure and respiratory insufficiency. This paper examines the pathogenesis, clinical presentation, diagnosis, treatment, and prognosis of PTTM. Given PTTM's poor prognosis, we emphasize treatment strategies. PTTM in adenocarcinoma patients can mimic other pulmonary diseases, causing diagnostic delays. Current PTTM treatment strategies primarily focus on managing the underlying malignancy and addressing thrombotic complications. Anti-angiogenic therapy with bevacizumab and the platelet-derived growth factor receptor antagonist imatinib have shown promise in multiple cases. Further research is needed to develop more effective and targeted therapies for this challenging condition. The precise mechanisms underlying this association remain to be fully elucidated.
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
This study aimed to establish a rat model of chronic wounds to observe the effects of hyperbaric oxygen (HBO) on chronic wound repair and pyroptosis and explore the potential role of pyroptosis in the pathogenesis of chronic wounds. Sprague-Dawley (SD) rats were randomly divided into acute wound group (control group), chronic wound group (model group), chronic wound + HBO treatment group (HBO group), and chronic wound + VX-765 (IL-converting enzyme/Caspase-1 inhibitor) treatment group (VX-765 group). After 7 days of respective interventions, the wound healing status was observed, and wound tissue specimens were collected. Hematoxylin and eosin (HE) staining was used to observe the pathological changes in wound tissues. Transmission electron microscopy was used to observe the changes in cellular ultrastructure. Immunofluorescence was used to observe the expression and localization of vascular endothelial growth factor A (VEGF-A) and the N-terminal domain of gasdermin D (GSDMD-N). Western blot was conducted to detect the expression of nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3), cysteine-requiring aspartate protease-1 (Caspase-1), VEGF-A, and GSDMD-N proteins in wound tissues. Real-time quantitative reverse transcription polymerase chain reaction (qRT-PCR) was used to detect the expression of NLRP3, Caspase-1, and GSDMD genes. Enzyme-linked immunosorbent assay (ELISA) was performed to observe the expression of the inflammatory cytokines interleukin-1 beta (IL-1beta) and IL-18. The results showed that the HBO group had a faster wound healing rate and better pathology improvement compared to the model group. The expression level of VEGF-A was higher in the HBO group compared to the model group, while the expression levels of NLRP3, Caspase-1, GSDMD, IL-1beta, and IL-18 were lower than those in the model group. HBO can effectively promote the healing of chronic wounds, and the regulation of pyroptosis may be one of its mechanisms of action. Keywords: Hyperbaric oxygen, Pyroptosis, Chronic wounds, Inflammatory.
- MeSH
- chronická nemoc MeSH
- gasderminy MeSH
- hojení ran * fyziologie MeSH
- hyperbarická oxygenace * metody MeSH
- krysa rodu rattus MeSH
- potkani Sprague-Dawley * MeSH
- protein NLRP3 metabolismus MeSH
- proteiny vázající fosfáty metabolismus MeSH
- pyroptóza * fyziologie MeSH
- vaskulární endoteliální růstový faktor A metabolismus genetika MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- mužské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
Diabetic kidney disease (DKD) is the leading cause of end-stage renal disease. Therefore, understanding the molecular regulatory mechanisms underlying the pathogenesis of DKD is imperative. In this study, we aimed to explore the molecular mechanisms of tubule region endothelial dysfunction in early DKD. Early-stage DKD model was established in 16-week-old female db/db mice for 16 weeks. Body weight, glucose level, and urine albumin-to-creatinine ratio (UACR) were measured. Hematoxylin and eosin (H&E) and periodic acid-Schiff (PAS) staining were performed to evaluate pathological lesions. RNA sequencing data of the kidneys and integrated publicly available single-cell and spatial transcriptome datasets were used to investigate the mechanism of endothelial dysfunction. There was a significant increase in body weight (p = 0.001), glucose levels (p=0.0008), and UACR (p=0.006) in db/db mice compared with db/m mice. H&E and PAS staining showed that vacuolar lesions and protein casts of tubules were the major histopathological changes observed in early-stage DKD mice. The apoptotic pathway in endothelial cells was notably activated in DKD, and Thbs1 was identified as the central gene involved in this apoptotic process. Deconvolution of the cell composition in the RNA sequencing data showed a decrease in the proportion of endothelial cells in the DKD mice. Further analysis of the activity and regulatory network of transcription factors showed that Creb1 was activated in both mouse and human early-stage DKD, suggesting that Creb1 activation may be involved in early kidney injury. The endothelial cell apoptotic pathway is activated in DKD, and the proportion of endothelial cells was reduced in the DKD mice, which is significantly associated with Thbs1. Keywords: Diabetic kidney disease, Endothelial dysfunction, RNA sequencing,Thbs1, Creb1.
- MeSH
- apoptóza MeSH
- diabetické nefropatie * patologie metabolismus patofyziologie genetika MeSH
- endoteliální buňky metabolismus patologie MeSH
- ledvinové kanálky patologie metabolismus MeSH
- myši inbrední C57BL MeSH
- myši MeSH
- progrese nemoci * MeSH
- protein vázající cAMP responzivní element metabolismus genetika MeSH
- thrombospondin 1 metabolismus genetika MeSH
- zvířata MeSH
- Check Tag
- myši MeSH
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
An excessive increase in reactive oxygen species (ROS) levels is one of the main causes of mitochondrial dysfunction. However, when ROS levels are maintained in balance with antioxidant mechanisms, ROS fulfill the role of signaling molecules and modulate various physiological processes. Recent advances in mitochondrial bioenergetics research have revealed a significant interplay between mitochondrial peroxiredoxins (PRDXs) and monoamine oxidase-A (MAO-A) in regulating ROS levels. Both proteins are associated with hydrogen peroxide (H2O2), MAO-A as a producer and PRDXs as the primary antioxidant scavengers of H2O2. This review focuses on the currently available knowledge on the function of these proteins and their interaction, highlighting their importance in regulating oxidative damage, apoptosis, and metabolic adaptation in the heart. PRDXs not only scavenge excess H2O2, but also act as regulatory proteins, play an active role in redox signaling, and maintain mitochondrial membrane integrity. Overexpression of MAO-A is associated with increased oxidative damage, leading to mitochondrial dysfunction and subsequent progression of cardiovascular diseases (CVD), including ischemia/reperfusion injury and heart failure. Considering the central role of oxidative damage in the pathogenesis of many CVD, targeting PRDXs activation and MAO-A inhibition may offer new therapeutic strategies aimed at improving cardiac function under conditions of pathological load related to oxidative damage. Keywords: Mitochondria, Peroxiredoxin, Monoamine oxidase-A, Reactive oxygen species, Cardioprotective signaling.
- MeSH
- lidé MeSH
- monoaminoxidasa * metabolismus MeSH
- oxidační stres MeSH
- peroxiredoxiny * metabolismus MeSH
- reaktivní formy kyslíku * metabolismus MeSH
- signální transdukce * MeSH
- srdeční mitochondrie metabolismus enzymologie MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
