INTRODUCTION AND OBJECTIVES: With increases in obesity and metabolic syndrome because of lifestyle-related factors, the prevalence of non-alcoholic fatty liver disease (NAFLD) also is increasing worldwide. In a subset of patients with NAFLD, an inflammatory process arises in the steatotic liver, known as non-alcoholic steatohepatitis, that leads to liver fibrosis and liver cirrhosis. In selected patients with obesity, bariatric surgery, and bariatric endoscopy are important therapeutic options. MATERIALS AND METHODS: This prospective interventional pilot study was conducted to investigate two types of intragastric balloons (IGB). The IGBs were the Orbera and the Spatz3. Liver fibrosis changes were monitored non-invasively using point and 2D shear wave ultrasound elastography (SWE) and transient elastography that allowed for quantification of liver steatosis using the controlled attenuation parameter (CAP). Patients were followed for 12 months. RESULTS: Of 34 patients implanted with an IGB, 30 completed follow-up at month 12; results for one patient were excluded because of initiation of obesity pharmacotherapy. Fifteen patients received the Orbera IGB, and nineteen patients received the Spatz3 type. In month 12, total and excess weight loss was 7.88 % and 30.13 %. Elastography values decreased from baseline (3.88 kPa) to 3.61 kPa at month 12 (p 0.024). 2D SWE values decreased from baseline (5.42 kPa) to a value of 4.91 kPa at month twelve (p 0.135). Transient elastography values decreased from baseline (5.62 kPa) to a value of 4.17 kPa at month twelve (p 0.009). CONCLUSIONS: Bariatric endoscopy in the form of IGB implantation leads to weight reduction and improvement of liver fibrosis and steatosis. GOV REGISTRATION: NCT04895943.

• MeSH
• bariatrická chirurgie * MeSH
• časové faktory MeSH
• design vybavení MeSH
• dospělí MeSH
• elastografie MeSH
• hmotnostní úbytek MeSH
• jaterní cirhóza * etiologie   diagnostické zobrazování   diagnóza   MeSH
• lidé středního věku MeSH
• lidé MeSH
• nealkoholová steatóza jater * diagnostické zobrazování   diagnóza   etiologie   MeSH
• obezita * komplikace   chirurgie   diagnóza   MeSH
• pilotní projekty MeSH
• prospektivní studie MeSH
• výsledek terapie MeSH
• žaludeční balónek * MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• klinické zkoušky MeSH

The glycoprotein clusterin (CLU) is involved in cell proliferation and DNA damage repair and is highly expressed in tumor cells. Here, we aimed to investigate the effects of CLU dysregulation on two human astrocytic cell lines: CCF-STTG1 astrocytoma cells and SV-40 immortalized normal human astrocytes. We observed that suppression of CLU expression by RNA interference inhibited cell proliferation, triggered the DNA damage response, and resulted in cellular senescence in both cell types tested. To further investigate the underlying mechanism behind these changes, we measured reactive oxygen species, assessed mitochondrial function, and determined selected markers of the senescence-associated secretory phenotype. Our results suggest that CLU deficiency triggers oxidative stress-mediated cellular senescence associated with pronounced alterations in mitochondrial membrane potential, mitochondrial mass, and expression levels of OXPHOS complex I, II, III and IV, indicating mitochondrial dysfunction. This report shows the important role of CLU in cell cycle maintenance in astrocytes. Based on these data, targeting CLU may serve as a potential therapeutic approach valuable for treating gliomas.

• MeSH
• astrocyty * metabolismus   patologie   MeSH
• klusterin * metabolismus   genetika   MeSH
• lidé MeSH
• membránový potenciál mitochondrií * fyziologie   MeSH
• mitochondrie * metabolismus   MeSH
• nádorové buněčné linie MeSH
• oxidační stres fyziologie   MeSH
• oxidativní fosforylace MeSH
• poškození DNA MeSH
• proliferace buněk * MeSH
• reaktivní formy kyslíku metabolismus   MeSH
• stárnutí buněk * fyziologie   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH

BACKGROUND: Cell cycle progression and leukemia development are tightly regulated processes in which even a small imbalance in the expression of cell cycle regulatory molecules and microRNAs (miRNAs) can lead to an increased risk of cancer/leukemia development. Here, we focus on the study of a ubiquitous, multifunctional, and oncogenic miRNA-hsa-miR-155-5p (miR-155, MIR155HG), which is overexpressed in malignancies including chronic lymphocytic leukemia (CLL). Nonetheless, the precise mechanism of how miR-155 regulates the cell cycle in leukemic cells remains the subject of extensive research. METHODS: We edited the CLL cell line MEC-1 by CRISPR/Cas9 to introduce a short deletion within the MIR155HG gene. To describe changes at the transcriptome and miRNome level in miR-155-deficient cells, we performed mRNA-seq/miRNA-seq and validated changes by qRT-PCR. Flow cytometry was used to measure cell cycle kinetics. A WST-1 assay, hemocytometer, and Annexin V/PI staining assessed cell viability and proliferation. RESULTS: The limited but phenotypically robust miR-155 modification impaired cell proliferation, cell cycle, and cell ploidy. This was accompanied by overexpression of the negative cell cycle regulator p21/CDKN1A and Cyclin D1 (CCND1). We confirmed the overexpression of canonical miR-155 targets such as PU.1, FOS, SHIP-1, TP53INP1 and revealed new potential targets (FCRL5, ISG15, and MX1). CONCLUSIONS: We demonstrate that miR-155 deficiency impairs cell proliferation, cell cycle, transcriptome, and miRNome via deregulation of the MIR155HG/TP53INP1/CDKN1A/CCND1 axis. Our CLL model is valuable for further studies to manipulate miRNA levels to revert highly aggressive leukemic cells to nearly benign or non-leukemic types.

• MeSH
• chronická lymfatická leukemie * genetika   patologie   MeSH
• cyklin D1 genetika   metabolismus   MeSH
• inhibitor p21 cyklin-dependentní kinasy * genetika   metabolismus   MeSH
• kontrolní body buněčného cyklu * genetika   MeSH
• lidé MeSH
• mikro RNA * genetika   metabolismus   MeSH
• nádorové buněčné linie MeSH
• proliferace buněk genetika   MeSH
• proteiny teplotního šoku MeSH
• regulace genové exprese u leukemie MeSH
• transportní proteiny genetika   metabolismus   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH

PURPOSE: Genetic testing in consanguineous families advances the general comprehension of pathophysiological pathways. However, short stature (SS) genetics remain unexplored in a defined consanguineous cohort. This study examines a unique pediatric cohort from Sulaimani, Iraq, aiming to inspire a genetic testing algorithm for similar populations. METHODS: Among 280 SS referrals from 2018-2020, 64 children met inclusion criteria (from consanguineous families; height ≤ -2.25 SD), 51 provided informed consent (30 females; 31 syndromic SS) and underwent investigation, primarily via exome sequencing. Prioritized variants were evaluated by the American College of Medical Genetics and Genomics standards. A comparative analysis was conducted by juxtaposing our findings against published gene panels for SS. RESULTS: A genetic cause of SS was elucidated in 31 of 51 (61%) participants. Pathogenic variants were found in genes involved in the GH-IGF-1 axis (GHR and SOX3), thyroid axis (TSHR), growth plate (CTSK, COL1A2, COL10A1, DYM, FN1, LTBP3, MMP13, NPR2, and SHOX), signal transduction (PTPN11), DNA/RNA replication (DNAJC21, GZF1, and LIG4), cytoskeletal structure (CCDC8, FLNA, and PCNT), transmembrane transport (SLC34A3 and SLC7A7), enzyme coding (CYP27B1, GALNS, and GNPTG), and ciliogenesis (CFAP410). Two additional participants had Silver-Russell syndrome and 1 had del22q.11.21. Syndromic SS was predictive in identifying a monogenic condition. Using a gene panel would yield positive results in only 10% to 33% of cases. CONCLUSION: A tailored testing strategy is essential to increase diagnostic yield in children with SS from consanguineous populations.

• MeSH
• algoritmy MeSH
• dítě MeSH
• genetické testování * metody   MeSH
• lidé MeSH
• mladiství MeSH
• mutace genetika   MeSH
• nanismus genetika   diagnóza   MeSH
• pokrevní příbuzenství * MeSH
• poruchy růstu genetika   diagnóza   MeSH
• předškolní dítě MeSH
• rodokmen MeSH
• sekvenování exomu metody   MeSH
• tělesná výška genetika   MeSH
• Check Tag
• dítě MeSH
• lidé MeSH
• mladiství MeSH
• mužské pohlaví MeSH
• předškolní dítě MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• Geografické názvy
• Irák MeSH

During development, tooth germs undergo various morphological changes resulting from interactions between the oral epithelium and ectomesenchyme. These processes are influenced by the extracellular matrix, the composition of which, along with cell adhesion and signaling, is regulated by metalloproteinases. Notably, these include matrix metalloproteinases (MMPs), a disintegrin and metalloproteinases (ADAMs), and a disintegrin and metalloproteinases with thrombospondin motifs (ADAMTSs). Our analysis of previously published scRNAseq datasets highlight that these metalloproteinases show dynamic expression patterns during tooth development, with expression in a wide range of cell types, suggesting multiple roles in tooth morphogenesis. To investigate this, Marimastat, a broad-spectrum inhibitor of MMPs, ADAMs, and ADAMTSs, was applied to ex vivo cultures of mouse molar tooth germs. The treated samples exhibited significant changes in tooth germ size and morphology, including an overall reduction in size and an inversion of the typical bell shape. The cervical loop failed to extend, and the central area of the inner enamel epithelium protruded. Marimastat treatment also disrupted proliferation, cell polarization, and organization compared with control tooth germs. In addition, a decrease in laminin expression was observed, leading to a disruption in continuity of the basement membrane at the epithelial-mesenchymal junction. Elevated hypoxia-inducible factor 1-alpha gene (Hif-1α) expression correlated with a disruption to blood vessel development around the tooth germs. These results reveal the crucial role of metalloproteinases in tooth growth, shape, cervical loop elongation, and the regulation of blood vessel formation during prenatal tooth development.NEW & NOTEWORTHY Inhibition of metalloproteinases during tooth development had a wide-ranging impact on molar growth affecting proliferation, cell migration, and vascularization, highlighting the diverse role of these proteins in controlling development.

• MeSH
• faktor 1 indukovatelný hypoxií - podjednotka alfa metabolismus   genetika   MeSH
• inhibitory matrixových metaloproteinas farmakologie   MeSH
• kyseliny hydroxamové farmakologie   MeSH
• metaloproteasy metabolismus   genetika   MeSH
• moláry embryologie   růst a vývoj   metabolismus   enzymologie   MeSH
• morfogeneze MeSH
• myši inbrední C57BL MeSH
• myši MeSH
• odontogeneze * MeSH
• proliferace buněk * MeSH
• vývojová regulace genové exprese MeSH
• zubní zárodek embryologie   metabolismus   enzymologie   MeSH
• zvířata MeSH
• Check Tag
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

BACKGROUND: Many studies have demonstrated the association between low birth weight (LBW) and chronic kidney disease, estimated glomerular filtration rate (eGFR) and kidney volume (KV). However, studies on twins and those investigating numerous perinatal factors beyond LBW, and their associations with various kidney parameters are scarce. METHODS: A two-center cross-sectional study on five-year-old LBW children was conducted between 2021 and 2023. 110 children were enrolled (8 LBW, 58 very LBW (VLBW), 44 extremely LBW (ELBW)); 56 were twins. We examined associations between birth weight (BW), various prenatal, perinatal and postnatal factors, and eGFR, KV, tubular abnormalities and kidney ultrasound abnormalities, both in singletons and twins. RESULTS: In children with ELBW, eGFR correlated with BW (r = 0.55, P = 0.0018), while in those with BW ≥ 1000 g, eGFR remained constant. Other factors associated with decreased eGFR were hypertensive disorder of pregnancy (93.86 vs. 87.26 ml/min/1.73m2, P = 0.0285) in singletons, decreased growth velocity (β = 0.83, P = 0.0277) in twins, and lower total KV (tKV) and relative KV (rKV) in both singletons (r = 0.60, P < 0.0001 for tKV and r = 0.45, P = 0.0010 for rKV) and twins (β = 0.34, P < 0.0001 for tKV and β = 0.23, P = 0.0002 for rKV). Based on the multivariable models excluding KV, BW and gestational age were associated with eGFR in singletons, while male gender, BW, growth velocity, and coffee drinking during pregnancy were associated with eGFR in twins. However, in models that included KV, BW, gestational age and growth velocity were no longer significant. Total KV was associated with BW (r = 0.39, P = 0.0050 for singletons; β = 2.85, P < 0.0001 for twins), body mass index (r = 0.34, P = 0.0145 for singletons; β = 8.44, P < 0.0001 for twins), and growth velocity (β = 1.43, P = 0.0078). Twins born small for gestational age had lower tKV (70.88 vs 89.20 ml, P < 0.0001). Relative KV showed similar associations. Relative kidney volumes were significantly lower for both kidneys compared to the reference population (55.02 vs 65.42 ml/m2, P < 0.0001 for right kidney and 61.12 vs 66.25 ml/m2, P = 0.0015 for left kidney); however, only 8.6% of children had rKV below 10th percentile. CONCLUSION: Many factors affect eGFR and KV, some of them differ between twins and singletons. Based on multivariable models, eGFR seems to be better predicted by KV than by BW and gestational age in LBW children. Relative kidney volumes were significantly lower in our cohort compared to the reference population, but only 8.6% of rKV were below 10th percentile.

• MeSH
• chronická renální insuficience epidemiologie   etiologie   patofyziologie   MeSH
• dvojčata MeSH
• hodnoty glomerulární filtrace * MeSH
• ledviny * diagnostické zobrazování   patofyziologie   MeSH
• lidé MeSH
• novorozenec s nízkou porodní hmotností * MeSH
• novorozenec MeSH
• porodní hmotnost MeSH
• předškolní dítě MeSH
• průřezové studie MeSH
• rizikové faktory MeSH
• těhotenství MeSH
• velikost orgánu MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• novorozenec MeSH
• předškolní dítě MeSH
• těhotenství MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• multicentrická studie MeSH

The aim of the present study was to examine gender and age-specific effects on subjective daytime sleepiness (as measured by the Epworth Sleepiness Scale), body weight and eating behaviour in patients with central disorders of hypersomnolence. Based on the European Narcolepsy Network database, we compared 1035 patients with narcolepsy type I and 505 patients with other central disorders of hypersomnolence ("narcoleptic borderland"), including narcolepsy type II (N = 308) and idiopathic hypersomnia (N = 174), using logistic regression and general linear models. In the entire study population, the Epworth Sleepiness Scale was higher in women (N = 735, mean age = 30 years, mean Epworth Sleepiness Scale = 16.6 ± SD 3.9) than in men (N = 805, mean age = 32 years, mean Epworth Sleepiness Scale = 15.8 ± SD 4.4). In women with narcolepsy type I (N = 475), both Epworth Sleepiness Scale and body mass index increased in parallel with age. In women of the narcoleptic borderland (N = 260), the Epworth Sleepiness Scale markedly peaked in their early 30s, while body mass index only started to rise at that age. This rise in body mass index following the Epworth Sleepiness Scale peak cannot be explained by sleepiness-induced uncontrolled eating, as self-reported uncontrolled eating was negatively associated with the Epworth Sleepiness Scale in this group. We propose that the narcoleptic borderland harbours a unique cluster of women in their fertile years with an unexplored aetiology requiring further investigation towards tailored interventions.

• MeSH
• dospělí MeSH
• index tělesné hmotnosti * MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• narkolepsie * patofyziologie   MeSH
• poruchy nadměrné spavosti * patofyziologie   epidemiologie   MeSH
• sexuální faktory MeSH
• stravovací zvyklosti MeSH
• tělesná hmotnost MeSH
• věkové faktory MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH

A new group of potent histone deacetylase inhibitors (HDACis) capable of inhibiting cell growth and affecting cell-cycle progression in Tohoku Hospital Pediatrics-1 (THP-1) monocytic leukaemia cells was synthesized. The inhibitors belong to a series of hydroxamic acid derivatives. We designed and synthesized a series of 22 N-hydroxycinnamamide derivatives, out of which 20 are new compounds. These compounds contain various substituted anilides as the surface recognition moiety (SRM), a p-hydroxycinnamate linker, and hydroxamic acids as the zinc-binding group (ZBG). The whole series of synthesized hydroxamic acids inhibited THP-1 cell proliferation. Compounds 7d and 7p, which belong to the category of derivatives with the most potent antiproliferative properties, exert a similar effect on cell-cycle progression as vorinostat and induce apoptosis in THP-1 cells. Furthermore, compounds 7d and 7p were demonstrated to inhibit HDAC class I and II in THP-1 cells with comparable potency to vorinostat and increase acetylation of histones H2a, H2b, H3, and H4. Molecular modelling was used to predict the probable binding mode of the studied HDACis in class I and II histone deacetylases in terms of Zn2+ ion chelation by the hydroxamate group.

• MeSH
• apoptóza * účinky léků   MeSH
• buněčný cyklus účinky léků   MeSH
• histondeacetylasy metabolismus   MeSH
• inhibitory histondeacetylas * farmakologie   chemická syntéza   chemie   MeSH
• kyseliny hydroxamové * farmakologie   chemická syntéza   chemie   MeSH
• kyseliny kumarové * farmakologie   chemie   chemická syntéza   MeSH
• lidé MeSH
• molekulární struktura MeSH
• nádorové buněčné linie MeSH
• proliferace buněk účinky léků   MeSH
• protinádorové látky * farmakologie   chemická syntéza   chemie   MeSH
• screeningové testy protinádorových léčiv MeSH
• simulace molekulového dockingu MeSH
• THP-1 buňky MeSH
• vztah mezi dávkou a účinkem léčiva MeSH
• vztahy mezi strukturou a aktivitou MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH

Obezita a diabetes mellitus 2. typu (DM2T) sú významnými rizikovými faktormi rozvoja kognitívnej dysfunkcie a neurodegeneratívnych ochorení. Ich spoločný patofyziologický základ zahŕňa inzulínovú rezistenciu, chronický subklinický systémový zápal a neurozápal, poruchy mikrobiómu, hormonálnu dysreguláciu a štrukturálne zmeny mozgu. Tieto faktory vedú k zhoršeniu pamäte, exekutívnych funkcií a k akcelerácii neurodegenerácie. Pozitívne účinky úpravy životného štýlu – vrátane zníženia telesnej hmotnosti, zvýšenia fyzickej aktivity a úpravy výživy a stravovacích návykov – sa prejavujú zlepšením inzulínovej senzitivity v mozgu, zvýšením neurotrofických faktorov, redukciou systémového zápalu a neurozápalu a zlepšením metabolizmu. Kombinácia behaviorálnych a farmakologických intervencií môže spomaliť kognitívny pokles a znížiť riziko demencie u populácie s obezitou a poruchou metabolizmu glukózy.

Obesity and type 2 diabetes (T2D) are important risk factors for the development of cognitive dysfunction and neurodegenerative diseases. Their common pathophysiological substrate includes insulin resistance, chronic subclinical systemic inflammation, neuroinflammation, shifts in the intestinal microbiome composition, hormonal dysregulation, and structural changes of the brain. These factors lead to impaired memory, executive functions, and accelerated neurodegeneration. The positive effects of lifestyle modifications — including weight loss, increased physical activity, and improved dietary composition — are manifested by improved insulin sensitivity in the brain, increased neurotrophic factors, reduced systemic inflammation and neuroinflammation, and improved metabolism. A combination of behavioral and pharmacological interventions may slow cognitive decline and reduce the risk of dementia in patients with obesity, prediabetes and T2D.

• MeSH
• cvičení MeSH
• diabetes mellitus 2. typu komplikace   MeSH
• hmotnostní úbytek MeSH
• kognitivní poruchy * etiologie   MeSH
• lidé MeSH
• neurodegenerativní nemoci etiologie   MeSH
• obezita * komplikace   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• přehledy MeSH

Nárast obezity a problémy pri jej liečbe, motivácia a snaha ľudí o redukciu a kontrolu telesnej hmotnosti, ako aj intenzívny marketing, vytvárajú priaznivé podhubie pre hľadanie a používanie rôznych spôsobov ako dosiahnuť a udržať žiadanú telesnú hmotnosť. Práve výživové doplnky, prezentované ako prípravky na podporu chudnutia, si získali veľkú priazeň u spotrebiteľov, a to častokrát len na základe ľahkej dostupnosti a zjednodušenej interpretácie priaznivého pôsobenia látok, ktoré obsahujú. V klinickej praxi a pre odborníkov pretrváva nedostatok robustných randomizovaných, placebom kontrolovaných štúdií, ktoré by poskytli jednoznačné vedecké dôkazy o účinnosti a bezpečnosti týchto prípravkov. Napriek intenzívnemu a aj sľubnému výskumu biologicky aktívnych látok vo výživových doplnkoch, nedostatočné a nejednoznačné dôkazy neumožňujú ich zahrnutie do štandardných odporúčaní pre komplexný manažment (pre)obezity v klinickej praxi. Odborníci aj laická verejnosť by mali jednoznačne vnímať rozdiel medzi EBM (Evidence-Based Medicine) potvrdenými farmakologickými aj nefarmakologickými intervenciami pri redukcii telesnej hmotnosti a užívaním výživových doplnkov. Článok predkladá sumárne závery publikovaných prehľadových prác zaoberajúcich sa účinnosťou a bezpečnosťou výživových doplnkov pri redukcii telesnej hmotnosti.

The rise of obesity and the difficulties in its treatment, people’s motivation and desire to reduce and control weight, and intensive marketing, have created a favorable climate for finding and using different ways to achieve and maintain a desirable body weight. In particular, dietary supplements, presented as weight-loss products, have gained a great deal of favor with consumers, often on the basis of their easy availability and simplistic interpretation of the beneficial effects of the substances they contain. In clinical practice and for practitioners, there remains a lack of robust randomized, placebo-controlled trials that provide clear scientific evidence on the efficacy and safety of these products. Despite intensive and even promising research on biologically active substances in dietary supplements, insufficient and equivocal evidence does not allow their inclusion in standard recommendations for the comprehensive management of overweight and obesity in clinical practice. Both professionals and the public should clearly perceive the difference between EBM (Evidence-Based Medicine) validated pharmacological and non-pharmacological interventions for weight reduction and the use of dietary supplements. This article presents a summary of the findings of published reviews addressing the efficacy and safety of dietary supplements in weight reduction.

• MeSH
• bezpečnost MeSH
• hmotnostní úbytek MeSH
• klinická studie jako téma MeSH
• lidé MeSH
• metaanalýza jako téma MeSH
• obezita * terapie   MeSH
• potravní doplňky * MeSH
• výsledek terapie MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• přehledy MeSH