The 26S proteasome degrades the majority of cellular proteins and affects all aspects of cellular life. Therefore, the 26S proteasome abundance, proper assembly, and activity in different life contexts need to be precisely controlled. Impaired proteasome activity is considered a causative factor in several serious disorders. Recent advances in proteasome biology have revealed that the proteasome can be activated by different factors or small molecules. Thus, activated ubiquitin-dependent proteasome degradation has effects such as extending the lifespan in different models, preventing the accumulation of protein aggregates, and reducing their negative impact on cells. Increased 26S proteasome-mediated degradation reduces proteotoxic stress and can potentially improve the efficacy of engineered degraders, such as PROTACs, particularly in situations characterized by proteasome malfunction. Here, emerging ideas and recent insights into the pharmacological activation of the proteasome at the transcriptional and posttranslational levels are summarized.

• Publication type
• Journal Article MeSH
• Review MeSH

INTRODUCTION: Plantar fasciitis (PF) is one of the most common running-related injuries. PURPOSE: The aim of this prospective study was to determine the incidence of PF and identify potential risk or protective factors for PF in runners and non-runners. METHODS: Data from 1206 participants from the 4HAIE cohort study (563 females/643 males; 715 runners/491 non-runners; 18-65 yr of age) were included in the analysis. We collected biomechanical data during overground running using a three-dimensional motion capture system at the baseline and running distance data via retrospective questionnaires and followed the participants for 12 months following the baseline data collection. Participants were asked weekly about any sports-related injury (including PF). A binary logistic regression was performed to reveal potential associations between running distance and biomechanical risk factors and PF while controlling for running distance, sex, and age. RESULTS: The total incidence of PF was 2.3% (28 PF from 1206 participants), 2.5% in runners and 2.0% in non-runners ( P = 0.248). Runners who ran more than 40 km·wk -1 had six times higher odds of suffering PF than individuals who ran 6-20 km·wk -1 ( P = 0.009). There was a significant association between maximal ankle adduction and PF; that is, runners with a lower abduction angle during the stance period had higher risk of PF ( P = 0.024). No other biomechanical variables indicated significant associations with PF. CONCLUSIONS: Regular running with a moderate weekly volume and more toeing out of the foot relative to the shank may reduce the risk against PF in runners, which may be useful for researchers, runners, coaches, and health professionals to minimize PF injury risk.

• MeSH
• Running * physiology   injuries   MeSH
• Biomechanical Phenomena MeSH
• Adult MeSH
• Fasciitis, Plantar * epidemiology   physiopathology   MeSH
• Incidence MeSH
• Middle Aged MeSH
• Humans MeSH
• Adolescent MeSH
• Young Adult MeSH
• Prospective Studies MeSH
• Risk Factors MeSH
• Aged MeSH
• Check Tag
• Adult MeSH
• Middle Aged MeSH
• Humans MeSH
• Adolescent MeSH
• Young Adult MeSH
• Male MeSH
• Aged MeSH
• Female MeSH
• Publication type
• Journal Article MeSH

The extracellular matrix (ECM)-and its mechanobiology-regulates key cellular functions that drive tumor growth and development. Accordingly, mechanotherapy is emerging as an effective approach to treat fibrotic diseases such as cancer. Through restoring the ECM to healthy-like conditions, this treatment aims to improve tissue perfusion, facilitating the delivery of chemotherapies. In particular, the manipulation of ECM is gaining interest as a valuable strategy for developing innovative treatments based on nanoparticles (NPs). However, further progress is required; for instance, it is known that the presence of a dense ECM, which hampers the penetration of NPs, primarily impacts the efficacy of nanomedicines. Furthermore, most 2D in vitro studies fail to recapitulate the physiological deposition of matrix components. To address these issues, a comprehensive understanding of the interactions between the ECM and NPs is needed. This review focuses on the main features of the ECM and its complex interplay with NPs. Recent advances in mechanotherapy are discussed and insights are offered into how its combination with nanomedicine can help improve nanomaterials design and advance their clinical translation.

• MeSH
• Extracellular Matrix * metabolism   MeSH
• Humans MeSH
• Neoplasms * therapy   MeSH
• Nanoparticles * chemistry   MeSH
• Nanomedicine * methods   MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Review MeSH

Cancer immunotherapy is increasingly used in clinical practice, but its success rate is reduced by tumor escape from the immune system. This may be due to the genetic instability of tumor cells, which allows them to adapt to the immune response and leads to intratumoral immune heterogeneity. The study investigated spatial immune heterogeneity in the tumor microenvironment and its possible drivers in a mouse model of tumors induced by human papillomaviruses (HPV) following immunotherapy. Gene expression was determined by RNA sequencing and mutations by whole exome sequencing. A comparison of different tumor areas revealed heterogeneity in immune cell infiltration, gene expression, and mutation composition. While the mean numbers of mutations with every impact on gene expression or protein function were comparable in treated and control tumors, mutations with high or moderate impact were increased after immunotherapy. The genes mutated in treated tumors were significantly enriched in genes associated with ECM metabolism, degradation, and interactions, HPV infection and carcinogenesis, and immune processes such as antigen processing and presentation, Toll-like receptor signaling, and cytokine production. Gene expression analysis of DNA damage and repair factors revealed that immunotherapy upregulated Apobec1 and Apobec3 genes and downregulated genes related to homologous recombination and translesion synthesis. In conclusion, this study describes the intratumoral immune heterogeneity, that could lead to tumor immune escape, and suggests the potential mechanisms involved.

• MeSH
• Immunotherapy * methods   MeSH
• Papillomavirus Infections immunology   virology   MeSH
• Humans MeSH
• Disease Models, Animal * MeSH
• Mutation * MeSH
• Mice, Inbred C57BL MeSH
• Mice MeSH
• Tumor Microenvironment * immunology   MeSH
• Gene Expression Regulation, Neoplastic MeSH
• Exome Sequencing MeSH
• Tumor Escape genetics   MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Mice MeSH
• Female MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH

The endorsement of conspiracy theories may be increased by subjectively perceived stress. Yet, it is not known whether this correlation is caused by the effects of the acute stress reaction on the brain or other psychological, social, or methodological factors. The effect of an experimentally induced acute stress reaction on conspiracy thinking was tested on a sample (n = 115) of students of medicine. Although the stress procedure caused a substantial increase in salivary cortisol, there was no significant effect on endorsing conspiracy theories or adopting conspiracy interpretations of novel information. The results confirmed no effect of the acute stress reaction on conspiracy thinking, suggesting it may be absent or weaker than expected. The study demonstrated the viability of psychophysiological experimental design in conspiracy research and may inspire further examination of the physiological mechanisms underlying susceptibility to conspiracy theories.

• MeSH
• Adult MeSH
• Hydrocortisone analysis   metabolism   MeSH
• Humans MeSH
• Young Adult MeSH
• Stress, Psychological * psychology   MeSH
• Saliva chemistry   MeSH
• Check Tag
• Adult MeSH
• Humans MeSH
• Young Adult MeSH
• Male MeSH
• Female MeSH
• Publication type
• Journal Article MeSH

BACKGROUND: Over the past two decades, the global incidence of gout has markedly increased, affecting people worldwide. Considering the side effects of xanthine oxidase (XO) inhibitor drugs (e.g. allopurinol and febuxostat) used in the treatment of hyperuricemia and gout, the potential application of phytochemicals has been widely studied. In addition, XO also takes part in the elimination of certain drugs, including 6-mercaptopurine. In the current explorative study, we aimed to examine the potential effects of tea catechins, resveratrol, silymarin flavonolignans and some of their conjugated metabolites on XO-catalyzed xanthine and 6-mercaptopurine oxidation, applying in vitro assays and modeling studies. RESULTS: Catechins, resveratrol and resveratrol conjugates exerted no or only weak inhibitory effects on XO. Silybin A, silybin B and isosilybin A were weak, silychristin was a moderate, while 2,3-dehydrosilychristin was a potent inhibitor of the enzyme. Sulfate metabolites of silybin A, silybin B and isosilybin A were considerably stronger inhibitors compared to the parent flavonolignans, and the sulfation of 2,3-dehydrosilychristin slightly increased its inhibitory potency. Silychristin was the sole flavonolignan tested, where sulfate conjugation decreased its inhibitory effect. CONCLUSION: 2,3-Dehydrosilychristin seems to be a promising candidate for examining its in vivo antihyperuricemic effects, because both the parent compound and its sulfate conjugate are highly potent inhibitors of XO. © 2024 The Author(s). Journal of the Science of Food and Agriculture published by John Wiley & Sons Ltd on behalf of Society of Chemical Industry.

• MeSH
• Enzyme Inhibitors * chemistry   pharmacology   MeSH
• Catalysis MeSH
• Catechin * chemistry   analogs & derivatives   pharmacology   MeSH
• Humans MeSH
• Mercaptopurine * chemistry   pharmacology   metabolism   MeSH
• Oxidation-Reduction * MeSH
• Resveratrol * chemistry   pharmacology   MeSH
• Silymarin * pharmacology   chemistry   MeSH
• Xanthine chemistry   metabolism   pharmacology   MeSH
• Xanthine Oxidase * antagonists & inhibitors   metabolism   chemistry   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH

The precise measurement of cell temperature and an in-depth understanding of thermogenic processes are critical in unraveling the complexities of cellular metabolism and its implications for health and disease. This review focuses on the mechanisms of local temperature generation within cells and the array of methods developed for accurate temperature assessment. The contact and noncontact techniques are introduced, including infrared thermography, fluorescence thermometry, and other innovative approaches to localized temperature measurement. The role of thermogenesis in cellular metabolism, highlighting the integral function of temperature regulation in cellular processes, environmental adaptation, and the implications of thermogenic dysregulation in diseases such as metabolic disorders and cancer are further discussed. The challenges and limitations in this field are critically analyzed while technological advancements and future directions are proposed to overcome these barriers. This review aims to provide a consolidated resource for current methodologies, stimulate discussion on the limitations and challenges, and inspire future innovations in the study of cellular thermodynamics.

• MeSH
• Humans MeSH
• Temperature MeSH
• Thermogenesis * physiology   MeSH
• Thermography * methods   MeSH
• Thermometry methods   MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Review MeSH

PURPOSE: The International Study of Movement Behaviors in the Early Years (SUNRISE) was conducted in Tunisia to assess the proportion of preschoolers who met the World Health Organization guidelines for physical activity, sedentary behavior, and sleep. The study also evaluated the feasibility of the methods for the SUNRISE study. METHODS: Five kindergartens were recruited from urban and rural areas in Tunisia. Physical activity and sleep duration were assessed using a waist-worn ActiGraph. Screen time and sleep quality were assessed via an interview-administered parent questionnaire. The NIH Toolbox was used. RESULTS: A total of 112 preschoolers were assessed (50 boys, age = 4.1 [0.58]). Only 18% of children met all recommendations of the World Health Organization guidelines, while 53% met the sedentary screen time (in minutes per day), and 41% met physical activity recommendation (in minutes per day). Eighty-one percent of children met the sleep duration recommendation (in minutes per day). There was good compliance with the ActiGraph protocol. CONCLUSIONS: This pilot study provided important insights into the feasibility of the study and the movement behaviors of Tunisian preschool children. The results suggest there is a need to promote healthy levels of physical activity and sedentary screen time in children, which should be a priority in public health initiatives, including preschool curricula, in Tunisia.

• MeSH
• Actigraphy MeSH
• Screen Time MeSH
• Exercise * MeSH
• Humans MeSH
• Pilot Projects MeSH
• Child, Preschool MeSH
• Surveys and Questionnaires MeSH
• Sedentary Behavior * MeSH
• Sleep * MeSH
• Feasibility Studies MeSH
• Check Tag
• Humans MeSH
• Male MeSH
• Child, Preschool MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Geographicals
• Tunisia MeSH

OBJECTIVES: This study quantified blood bicarbonate (HCO3-) kinetics and gastrointestinal upset to determine the gender-related ergogenic potential of sodium bicarbonate (0.15-, 0.25- and 0.35 gSB·kgFat-free mass (FFM)-1) in high intensity functional training. DESIGN: Double-blind randomized placebo-controlled crossover. METHODS: Thirty female and male athletes performed two bouts of the Wingate Anaerobic Test (WAnTPRE-HIFT and WAnTPOST-HIFT) interspaced with two 3-min bouts of Wall Balls and Burpees 120 min after ingestion of three sodium bicarbonate doses. Blood HCO3- was determined pre-ingestion, after supplementation and before/post exercise. Gastrointestinal upset was evaluated 120 min post-ingestion. Control (CTRL) measurements were performed. RESULTS: There were significant gender × treatment interactions for: changes in blood HCO3- at 60 min post-ingestion (p = 0.014; η2p = 0.104; at 0.15 gSB·kgFFM-1 males experienced higher increase than females); peak power (p = 0.015; η2p = 0.103) and average power (p = 0.005; η2p = 0.124) during WAnTPOST-HIFT, and changes in peak power between the Wingate Anaerobic Test bouts (p = 0.049; η2p = 0.081). Sodium bicarbonate compared to PLA had no significant impact on Wall Balls and Burpees performance. The dose of 0.35 gSB·kgFFM-1 resulted in higher less severe gastrointestinal symptoms compared to CTRL and 0.15 gSB·kgFFM-1 (p = 0.001; W = 0.178); and higher total gastrointestinal upset compared to CTRL, PLA and 0.15 gSB·kgFFM-1 (p < 0.001; W = 0.323). CONCLUSIONS: There were dose- and gender-related differences in extracellular buffering capacity and ergogenic potential of sodium bicarbonate. The study suggested a detrimental impact of gastrointestinal upset on performance.

• MeSH
• Adult MeSH
• Double-Blind Method MeSH
• Sodium Bicarbonate * administration & dosage   pharmacology   blood   MeSH
• Cross-Over Studies * MeSH
• Performance-Enhancing Substances administration & dosage   pharmacology   MeSH
• Humans MeSH
• Young Adult MeSH
• Sex Factors MeSH
• Exercise Test MeSH
• Check Tag
• Adult MeSH
• Humans MeSH
• Young Adult MeSH
• Male MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Randomized Controlled Trial MeSH

Rational prescribing in geriatrics represents an important ethical as well as socio-economic issue. The aim of this project was to analyze the drug-related problems (DRPs) among the Czech nursing home residents and increase public awareness of further possible employment of clinical pharmacists in social care. The project was designed as a multicenter observational study. A total of 16 nursing homes and 800 participants with an average age of 84.6 ± 7.3 years were included in the study. Of them, a DRP was noted in 93.3% of people. The total amount of DRPs identified was 2215, which means an average of 2.8 ± 1.6 DRPs per patient. The most common DRPs identified were 'overtreatment' (19.5%), 'undertreatment' (12.8%), inappropriate dose (10.6%), recommendations for laboratory monitoring (10.4%) and adverse effects (10.3%). Of different drug classes, BZDs (OR 16.6, 95% CI 1.0-270.2), PPIs (OR 2.5, 95% CI 1.1-5.6) and NSAIDs (OR 4.4, 95% CI 1.1-18.3) were identified to be most commonly associated with DRPs. The risk of DRP identification clearly increased with the number of drugs used, with seven drugs demonstrated as the best cut-off for predicting DRP identification (AUC 0.842, sensitivity 0.602; specificity 0.796). 'SENIOR' project has confirmed a high rate of excessive polypharmacy among nursing home residents in the Czech republic resulting in high risk of potential and manifested DRPs. The project emphasized the role of clinical pharmacists in optimizing safety and effectiveness of treatment among older nursing home residents.

• MeSH
• Homes for the Aged * statistics & numerical data   MeSH
• Pharmacists MeSH
• Pharmaceutical Services * organization & administration   MeSH
• Humans MeSH
• Inappropriate Prescribing * statistics & numerical data   prevention & control   MeSH
• Drug-Related Side Effects and Adverse Reactions * epidemiology   diagnosis   prevention & control   MeSH
• Nursing Homes * statistics & numerical data   MeSH
• Polypharmacy MeSH
• Aged, 80 and over MeSH
• Aged MeSH
• Check Tag
• Humans MeSH
• Male MeSH
• Aged, 80 and over MeSH
• Aged MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Multicenter Study MeSH
• Observational Study MeSH
• Geographicals
• Czech Republic MeSH