The prevalence of centenarians, people who lived 100 years and longer, is steadily growing in the last decades. This exceptional longevity is based on multifaceted processes influenced by a combination of intrinsic and extrinsic factors such as sex, (epi-)genetic factors, gut microbiota, cellular metabolism, exposure to oxidative stress, immune status, cardiovascular risk factors, environmental factors, and lifestyle behavior. Epidemiologically, the incidence rate of cardiovascular diseases is reduced in healthy centenarians along with late onset of age-related diseases compared with the general aged population. Understanding the mechanisms that affect vascular ageing in centenarians and the underlying factors could offer valuable insights for developing strategies to improve overall healthy life span in the elderly. This review discusses these key factors influencing vascular ageing and how their modulation could foster healthy longevity.

• MeSH
• dlouhověkost * fyziologie   MeSH
• kardiovaskulární nemoci patofyziologie   epidemiologie   MeSH
• lidé MeSH
• oxidační stres fyziologie   MeSH
• rizikové faktory MeSH
• senioři nad 80 let MeSH
• stárnutí * fyziologie   MeSH
• střevní mikroflóra fyziologie   MeSH
• zdravé stárnutí fyziologie   MeSH
• životní styl MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• senioři nad 80 let MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) main protease (Mpro) autocatalytically releases itself out of the viral polyprotein to form a fully active mature dimer in a manner that is not fully understood. Here, we introduce several tools to help elucidate differences between cis (intramolecular) and trans (intermolecular) proteolytic processing and to evaluate inhibition of precursor Mpro. We found that many mutations at the P1 position of the N-terminal autoprocessing site do not block cis autoprocessing but do inhibit trans processing. Notably, substituting the WT glutamine at the P1 position with isoleucine retains Mpro in an unprocessed precursor form that can be purified and further studied. We also developed a cell-based reporter assay suitable for compound library screening and evaluation in HEK293T cells. This assay can detect both overall Mpro inhibition and the fraction of uncleaved precursor form of Mpro through separable fluorescent signals. We observed that inhibitory compounds preferentially block mature Mpro. Bofutrelvir and a novel compound designed in-house showed the lowest selectivity between precursor and mature Mpro, indicating that inhibition of both forms may be possible. Additionally, we observed positive modulation of precursor activity at low concentrations of inhibitors. Our findings help expand understanding of the SARS-CoV-2 viral life cycle and may facilitate development of strategies to target precursor form of Mpro for inhibition or premature activation of Mpro.

• MeSH
• antivirové látky * farmakologie   chemie   MeSH
• farmakoterapie COVID-19 MeSH
• HEK293 buňky MeSH
• inhibitory proteas farmakologie   chemie   MeSH
• koronavirové proteasy 3C * metabolismus   antagonisté a inhibitory   chemie   genetika   MeSH
• lidé MeSH
• mutace MeSH
• objevování léků * metody   MeSH
• proteolýza MeSH
• SARS-CoV-2 * enzymologie   účinky léků   metabolismus   genetika   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH

MicroRNAs (miRNAs) have emerged as important regulators of gene expression in various biological processes, including cancer. miR-182-5p has gained attention for its potential implications in gynecologic cancers, including breast, ovarian, endometrial, and cervical cancers. miR-182-5p dysregulation has been associated with multiple facets of tumor biology in gynecologic cancers, including tumor initiation, progression, metastasis, and therapeutic response. Studies have highlighted its involvement in key signaling pathways and cellular processes that contribute to cancer development and progression. In addition, miR-182-5p has shown potential as a diagnostic and prognostic biomarker, with studies demonstrating its correlation with clinicopathological features and patient outcomes. Furthermore, the therapeutic potential of miR-182-5p is being explored in gynecologic cancers. Strategies such as miRNA mimics or inhibitors targeting miR-182-5p have shown promise in preclinical and early clinical studies. These approaches aim to modulate miR-182-5p expression, restoring normal cellular functions and potentially enhancing treatment responses. Understanding the biologic and clinical implications of miR-182-5p in gynecologic cancers is crucial for the development of targeted therapeutic strategies and personalized medicine approaches. Further investigations are needed to unravel the specific target genes and pathways regulated by miR-182-5p. It is important to consider the emerging biologic and clinical implications of miR-182-5p in gynecologic cancers.

• MeSH
• lidé MeSH
• mikro RNA * genetika   MeSH
• nádorové biomarkery genetika   MeSH
• nádory ženských pohlavních orgánů * genetika   terapie   MeSH
• prognóza MeSH
• regulace genové exprese u nádorů MeSH
• Check Tag
• lidé MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH

BACKGROUND: Modafinil is primarily used to treat narcolepsy but is also used as an off-label cognitive enhancer. Functional magnetic resonance imaging studies indicate that modafinil modulates the connectivity of neocortical networks primarily involved in attention and executive functions. However, much less is known about the drug's effects on subcortical structures. Following preliminary findings, we evaluated modafinil's activity on the connectivity of distinct cerebellar regions with the neocortex. We assessed the spatial relationship of these effects with the expression of neurotransmitter receptors/transporters. METHODS: Patterns of resting-state functional magnetic resonance imaging connectivity were estimated in 50 participants from scans acquired pre- and postadministration of a single (100 mg) dose of modafinil (n = 25) or placebo (n = 25). Using specific cerebellar regions as seeds for voxelwise analyses, we examined modafinil's modulation of cerebellar-neocortical connectivity. Next, we conducted a quantitative evaluation of the spatial overlap between the modulation of cerebellar-neocortical connectivity and the expression of neurotransmitter receptors/transporters obtained by publicly available databases. RESULTS: Modafinil increased the connectivity of crus I and vermis IX with prefrontal regions. Crus I connectivity changes were associated with the expression of dopaminergic D2 receptors. The vermis I-II showed enhanced coupling with the dorsal anterior cingulate cortex and matched the expression of histaminergic H3 receptors. The vermis VII-VIII displayed increased connectivity with the visual cortex, an activity associated with dopaminergic and histaminergic neurotransmission. CONCLUSIONS: Our study reveals modafinil's modulatory effects on cerebellar-neocortical connectivity. The modulation mainly involves crus I and the vermis and spatially overlaps the distribution of dopaminergic and histaminergic receptors.

• MeSH
• dospělí MeSH
• lidé MeSH
• magnetická rezonanční tomografie * MeSH
• mladý dospělý MeSH
• modafinil * farmakologie   aplikace a dávkování   MeSH
• mozeček * účinky léků   diagnostické zobrazování   metabolismus   MeSH
• neokortex účinky léků   metabolismus   diagnostické zobrazování   MeSH
• nervové dráhy účinky léků   metabolismus   MeSH
• stimulancia farmakologie   MeSH
• Check Tag
• dospělí MeSH
• lidé MeSH
• mladý dospělý MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• randomizované kontrolované studie MeSH

INTRODUCTION: The E3 ubiquitin ligase Cbl-b is a novel target in immune-oncology, with critical roles in regulating T-cell activation and signaling pathways. By facilitating the ubiquitination and degradation of key signaling proteins, Cbl-b modulates immune responses, maintaining immune homeostasis and preventing unwarranted T-cell proliferation. The therapeutic potential of Cbl-b as a cancer immunotherapy target is underscored by its contribution to an immunosuppressive tumor microenvironment, with efforts currently underway to develop small-molecule inhibitors. AREAS COVERED: We reviewed the small molecules, and antibody-drug conjugates targeting Cbl-b from 2018 to 2024. The patents were gathered through publicly available databases and analyzed with in-house developed cheminformatic workflow, described within the manuscript. EXPERT OPINION: Targeting Cbl-b presents a promising approach in immuno-oncology, offering a novel pathway to potentiate the immune system's ability to combat cancer beyond PDL1/PD1 inhibition. The development and clinical advancement of Cbl-b inhibitors, as evidenced by the ongoing trials, mark a significant step toward harnessing this target for therapeutic benefits. Overall, the strategic inhibition of Cbl-b holds substantial promise for improving cancer immunotherapy outcomes, heralding a new era in the fight against cancer.

• MeSH
• adaptorové proteiny signální transdukční MeSH
• cílená molekulární terapie * MeSH
• imunokonjugáty farmakologie   MeSH
• imunoterapie * metody   MeSH
• lidé MeSH
• nádorové mikroprostředí * imunologie   MeSH
• nádory * imunologie   farmakoterapie   MeSH
• patenty jako téma * MeSH
• protinádorové látky farmakologie   MeSH
• protoonkogenní proteiny c-cbl * imunologie   antagonisté a inhibitory   MeSH
• signální transdukce účinky léků   MeSH
• T-lymfocyty imunologie   účinky léků   MeSH
• vyvíjení léků * MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH

The sacroiliac joint (SIJ) exhibits significant variation in auricular surface morphology. This variation influences the mechanics of the SIJ, a central node for transmitting mechanical energy from upper body to lower limbs and vice versa. The impact of the auricular surface morphology on stress and deformation in the SIJ remains poorly understood to date. Computed tomography scans obtained from 281 individuals were included to extract the geometry of the pelvic ring. Then, the auricular surface area, SIJ cartilage thickness, and total SIJ cartilage volume were identified. Based on these reconstructions, 281 finite element models were created to simulate SIJ mechanical loading. It was found that SIJ cartilage thickness only weakly depended on age or laterality, while being strongly sex sensitive. Auricular surface area and SIJ cartilage volume depended weakly and non-linearly on age, peaking around menopause in females, but without significant laterality effect. Larger SIJs, characterized by greater auricular area and cartilage volume, exhibited reduced stress and deformation under loading. These findings highlight the significant role of SIJ morphology in its biomechanical response, suggesting a potential link between morphological variations and the risk of SIJ dysfunction. Understanding this relationship could improve diagnosis and targeted treatment strategies for SIJ-related conditions.

• MeSH
• analýza metodou konečných prvků MeSH
• biomechanika fyziologie   MeSH
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mechanický stres MeSH
• mladiství MeSH
• mladý dospělý MeSH
• počítačová rentgenová tomografie * MeSH
• sakroiliakální kloub * anatomie a histologie   fyziologie   diagnostické zobrazování   MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• mužské pohlaví MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH

This article provides an up-to-date review of the management of chronic pancreatitis, highlighting advancements in medical therapy, nutritional support, endoscopic and surgical approaches, and emerging treatments. Nutritional management accentuates addressing malabsorption and nutrient deficiencies. Advances in endoscopy and parenchyma-sparing surgical techniques have opened new avenues for improved patient outcomes, with total pancreatectomy and islet autotransplantation offering the only definitive solution for selected patients. Additionally, emerging therapies, including anti-inflammatory and immune-modulating agents, show promise for future treatment options. Emphasizing a multidisciplinary approach, this review aims to equip health care professionals with a comprehensive overview of current management strategies and future directions.

• MeSH
• chronická pankreatitida * terapie   MeSH
• lidé MeSH
• nutriční podpora * metody   MeSH
• pankreatektomie * metody   MeSH
• transplantace Langerhansových ostrůvků metody   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH

Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers with patients having unresectable or metastatic disease at diagnosis, with poor prognosis and very short survival. Given that genetic variation within autophagy-related genes influences autophagic flux and susceptibility to solid cancers, we decided to investigate whether 55,583 single nucleotide polymorphisms (SNPs) within 234 autophagy-related genes could influence the risk of developing PDAC in three large independent cohorts of European ancestry including 12,754 PDAC cases and 324,926 controls. The meta-analysis of these populations identified, for the first time, the association of the BIDrs9604789 variant with an increased risk of developing the disease (ORMeta = 1.31, p = 9.67 × 10-6). We also confirmed the association of TP63rs1515496 and TP63rs35389543 variants with PDAC risk (OR = 0.89, p = 6.27 × 10-8 and OR = 1.16, p = 2.74 × 10-5). Although it is known that BID induces autophagy and TP63 promotes cell growth, cell motility and invasion, we also found that carriers of the TP63rs1515496G allele had increased numbers of FOXP3+ Helios+ T regulatory cells and CD45RA+ T regulatory cells (p = 7.67 × 10-4 and p = 1.56 × 10-3), but also decreased levels of CD4+ T regulatory cells (p = 7.86 × 10-4). These results were in agreement with research suggesting that the TP63rs1515496 variant alters binding sites for FOXA1 and CTCF, which are transcription factors involved in modulating specific subsets of regulatory T cells. In conclusion, this study identifies BID as new susceptibility locus for PDAC and confirms previous studies suggesting that the TP63 gene is involved in the development of PDAC. This study also suggests new pathogenic mechanisms of the TP63 locus in PDAC.

• MeSH
• autofagie * genetika   MeSH
• běloši genetika   MeSH
• duktální karcinom slinivky břišní * genetika   patologie   MeSH
• forkhead transkripční faktory MeSH
• genetická predispozice k nemoci * MeSH
• hepatocytární jaderný faktor 3-alfa genetika   metabolismus   MeSH
• jednonukleotidový polymorfismus * MeSH
• kohortové studie MeSH
• lidé MeSH
• nádorové biomarkery * genetika   MeSH
• nádorové supresorové proteiny * genetika   MeSH
• nádory slinivky břišní * genetika   patologie   MeSH
• studie případů a kontrol MeSH
• transkripční faktory genetika   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• metaanalýza MeSH

The formation of memories is a complex, multi-scale phenomenon, especially when it involves integration of information from various brain systems. We have investigated the differences between a novel and consolidated association of spatial cues and amphetamine administration, using an in situ hybridisation method to track the short-term dynamics during the recall testing. We have found that remote recall group involves smaller, but more consolidated groups of neurons, which is consistent with their specialisation. By employing machine learning analysis, we have shown this pattern is especially pronounced in the VTA; furthermore, we also uncovered significant activity patterns in retrosplenial and prefrontal cortices, as well as in the DG and CA3 subfields of the hippocampus. The behavioural propensity towards the associated localisation appears to be driven by the nucleus accumbens, however, further modulated by a trio of the amygdala, VTA and hippocampus, as the trained association is confronted with test experience. Moreover, chemogenetic analysis revealed central amygdala as critical for linking appetitive emotional states with spatial contexts. These results show that memory mechanisms must be modelled considering individual differences in motivation, as well as covering dynamics of the process.

• MeSH
• amfetamin farmakologie   MeSH
• amygdala fyziologie   MeSH
• hipokampus * fyziologie   MeSH
• konsolidace paměti * fyziologie   MeSH
• krysa rodu rattus MeSH
• mozek fyziologie   MeSH
• neurony fyziologie   metabolismus   MeSH
• nucleus accumbens * fyziologie   MeSH
• odměna * MeSH
• paměť fyziologie   MeSH
• podněty MeSH
• prefrontální mozková kůra fyziologie   MeSH
• rozpomínání * fyziologie   MeSH
• strojové učení MeSH
• tegmentum mesencephali - area ventralis * fyziologie   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

Class A G protein-coupled receptors (GPCRs) continue to garner interest for their essential roles in cell signalling and their importance as drug targets. Although numerous drugs in the clinic target these receptors, over 60% GPCRs remain unexploited. Moreover, the adverse effects triggered by the available unbiased GPCR modulators, limit their use and therapeutic value. In this context, the elucidation of biased signalling has opened up new pharmacological avenues holding promise for safer therapeutics. Functionally selective ligands favour receptor conformations facilitating the recruitment of specific effectors and the modulation of the associated pathways. This review surveys the current drug discovery landscape of GPCR-biased modulators with a focus on recent advances. Understanding the biological effects of this preferential coupling is at different stages depending on the Class A GPCR family. Therefore, with a focus on individual GPCR families, we present a compilation of the functionally selective modulators reported over the past few years. In doing so, we dissect their therapeutic relevance, molecular determinants and potential clinical applications. LINKED ARTICLES: This article is part of a themed issue Complexity of GPCR Modulation and Signaling (ERNST). To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v182.14/issuetoc.

• MeSH
• lidé MeSH
• ligandy MeSH
• objevování léků * MeSH
• receptory spřažené s G-proteiny * metabolismus   agonisté   MeSH
• signální transdukce účinky léků   MeSH
• vyvíjení léků MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH