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Journal of Pediatric Urology Jun 2024Many pediatric urology conditions affect putatively normal tissues or appear too commonly to be based solely on specific DNA mutations. Understanding epigenetic...
INTRODUCTION
Many pediatric urology conditions affect putatively normal tissues or appear too commonly to be based solely on specific DNA mutations. Understanding epigenetic mechanisms in pediatric urology, therefore, has many implications that can impact cell and tissue responses to settings, such as environmental and hormonal influences on urethral development, uropathogenic infections, obstructive stimuli, all of which originate externally or extracellularly. Indeed, the cell's response to external stimuli is often mediated epigenetically. In this commentary, we highlight work on the critical role that epigenetic machinery, such as DNA methyltransferases (DNMTs), Enhancer of Zeste Polycomb Repressive Complex 2 Subunit (EZH2), and others play in regulating gene expression and cellular functions in three urological contexts.
DESIGN
Animal and cellular constructs were used to model clinical pediatric uropathology. The hypertrophy, trabeculation, and fibrosis of the chronically obstructed bladder was explored using smooth muscle cell models employing disorganised vs. normal extracellular matrix (ECM), as well as a new animal model of chronic obstructive bladder disease (COBD) which retains its pathologic features even after bladder de-obstruction. Cell models from human and murine hypospadias or genital tubercles (GT) were used to illustrate developmental responses and epigenetic dependency of key developmental genes. Finally, using bladder urothelial and organoid culture systems, we examined activity of epigenetic machinery in response to non uropathogenic vs. uropathogenic E.coli (UPEC). DNMT and EZH2 expression and function were interrogated in these model systems.
RESULTS
Disordered ECM exerted a principal mitogenic and epigenetic role for on bladder smooth muscle both in vitro and in CODB in vivo. Key genes, e.g., BDNF and KCNB2 were under epigenetic regulation in actively evolving obstruction and COBD, though each condition showed distinct epigenetic responses. In models of hypospadias, estrogen strongly dysregulated WNT and Hox expression, which was normalized by epigenetic inhibition. Finally, DNA methylation machinery in the urothelium showed specific activation when challenged by uropathogenic E.coli. Similarly, UPEC induces hypermethylation and downregulation of the growth suppressor p16INK4A. Moreover, host cells exposed to UPEC produced secreted factors inducing epigenetic responses transmissible from one affected cell to another without ongoing bacterial presence.
DISCUSSION
Microenvironmental influences altered epigenetic activity in the three described urologic contexts. Considering that many obstructed bladders continue to display abnormal architecture and dysfunction despite relief of obstruction similar to after resection of posterior valves or BPH, the epigenetic mechanisms described highlight novel approaches for understanding the underlying smooth muscle myopathy of this crucial clinical problem. Similarly, there is evidence for an epigenetic basis of xenoestrogen on development of hypospadias, and UTI-induced pan-urothelial alteration of epigenetic marks and propensity for subsequent (recurrent) UTI. The impact of mechanical, hormonal, infectious triggers on genitourinary epigenetic machinery activity invite novel avenues for targeting epigenetic modifications associated with these non-cancer diseases in urology. This includes the use of deactivated CRISPR-based technologies for precise epigenome targeting and editing. Overall, we underscore the importance of understanding epigenetic regulation in pediatric urology for the development of innovative therapeutic and management strategies.
PubMed: 38944627
DOI: 10.1016/j.jpurol.2024.06.008 -
Seminars in Nuclear Medicine Jun 2024Recent advancements in PET technology have culminated in the development of total-body PET (TB-PET) systems, which overcome many limitations of traditional scanners.... (Review)
Review
Recent advancements in PET technology have culminated in the development of total-body PET (TB-PET) systems, which overcome many limitations of traditional scanners. These TB-PET scanners, while still becoming widely available, represent the forefront of clinical imaging across numerous medical institutions worldwide. Early clinical applications have demonstrated their enhanced image quality, precise lesion quantification, and overall superior performance relative to conventional scanners. The capabilities of TB-PET technology, including extended scan range, ultrahigh sensitivity, exceptional temporal resolution, and dynamic imaging, offer significant potential to tackle unresolved clinical challenges in medical imaging. In this discussion, we aim to explore the emerging applications, opportunities, and future perspectives of TB-PET/CT in musculoskeletal disorders (MSDs). Clinical applications for both oncologic and non-oncologic musculoskeletal diseases are discussed, including inflammatory arthritis, infections, osteoarthritis, osteoporosis, and skeletal muscle disorders. From the ability to visualize small musculoskeletal structures and the entire axial and appendicular skeleton, TB-PET shows significant potential in the diagnosis and management of MSD conditions as it becomes more widely available.
PubMed: 38944556
DOI: 10.1053/j.semnuclmed.2024.05.009 -
Journal of Fish Diseases Jun 2024Melanized focal changes (MFCs) in the fillet of farmed Atlantic salmon is a major quality concern. The changes are thought to initially appear as acute red focal changes...
Melanized focal changes (MFCs) in the fillet of farmed Atlantic salmon is a major quality concern. The changes are thought to initially appear as acute red focal changes (RFCs) that progress into chronic MFCs. Recent findings have indicated that hypoxia may be important in their development, possibly leading to necrosis affecting not only myocytes but also adipocytes. Thus, the aim of this study was to investigate possible hypoxic conditions in RFCs and the subsequent inflammatory responses and lesions in the adipose tissue in RFCs and MFCs. A collection of RFCs, MFCs and control muscle samples from several groups of farmed salmon was studied. Using immunohistochemistry, we found induction of the hypoxia-inducible factor 1 pathway in RFCs. Histological investigations of RFCs and MFCs revealed different stages of fat necrosis, including necrotic adipocytes, a myospherulosis-like reaction and the formation of pseudocystic spaces. Accumulations of foamy macrophages were detected in MFCs, indicating degradation and phagocytosis of lipids. Using in situ hybridization, we showed the presence of tyrosinase- and tyrosinase-related protein-1-expressing amelanotic cells in RFCs, which in turn became melanized in MFCs. In conclusion, we propose a sequence of events leading to the formation of MFCs, highlighting the pivotal role of adiposity, hypoxia and fat necrosis.
PubMed: 38943363
DOI: 10.1111/jfd.13988 -
Nutrition & Metabolism Jun 2024Conflicting findings regarding the impact of High protein intake during the early phase in critically ill patients have been reported. Therefore, we aimed to assess the...
BACKGROUND
Conflicting findings regarding the impact of High protein intake during the early phase in critically ill patients have been reported. Therefore, we aimed to assess the influence of higher early protein intake on the prognosis of critically ill patients.
METHODS
This randomized controlled trial involved 173 critically ill patients who stayed in the Intensive Care Unit/Emergency ICU (ICU/EICU) for at least 7 days. The Low group (n = 87) and High group (n = 86) received protein supplementation of 0.8 g/kg.d and 1.5 g/kg.d, respectively, within 1-3 days of enteral nutrition (EN) initiation, with both groups transitioning to 1.5 g/kg.d on the 4th day. The serum prealbumin (PA), blood urea nitrogen/creatinine, and rectus femoris muscle thickness and cross-sectional area of all patients was measured on the 1th, 3rd, 5th, 7th day, and the day of ICU/EICU discharge.
RESULTS
Patients in both Low and High groups showed no significant differences in age, APACHE II scores, or other demographic and baseline characteristics. There were also no significant differences in the primary outcome (28-day mortality rate) and secondary outcomes (incidence rate of refeeding syndrome and EN tolerance score) between the two groups. However, the Low group exhibited a significantly higher 28-day mortality rate (HR = 2.462, 95% CI: 1.021-5.936, P = 0.045) compared to High group, as determined by Cox proportional hazards models incorporating the time factor. The High group exhibited significantly shorter durations of mechanical ventilation and ICU stay compared to the Low group. Serum PA levels were higher, and rectus femoris muscle atrophy rates were lower in the High group. Furthermore, for septic patients, high protein intake significantly reduced the 28-day mortality rate despite a small sample size (n = 34).
CONCLUSIONS
Our study indicates that increasing early protein intake to 1.5 g/kg.d may be safe and help improve the nutritional status and prognosis of critically ill patients.
TRIAL REGISTRATION
This study was registered with the Chinese Clinical Trial Registry (ChiCTR2000039997, https://www.chictr.org.cn/ ).
PubMed: 38943189
DOI: 10.1186/s12986-024-00818-8 -
Scientific Reports Jun 2024Telocytes are closely associated with the regulation of tissue smooth muscle dynamics in digestive system disorders. They are widely distributed in the biliary system...
Telocytes are closely associated with the regulation of tissue smooth muscle dynamics in digestive system disorders. They are widely distributed in the biliary system and exert their influence on biliary motility through mechanisms such as the regulation of CCK and their electrophysiological effects on smooth muscle cells. To investigate the relationship between telocytes and benign biliary diseases,such as gallbladder stone disease and biliary dilation syndrome, we conducted histopathological analysis on tissues affected by these conditions. Additionally, we performed immunohistochemistry and immunofluorescence double staining experiments for telocytes. The results indicate that the quantity of telocytes in the gallbladder and bile duct is significantly lower in pathological conditions compared to the control group. This reveals a close association between the decrease in telocyte quantity and impaired gallbladder motility and biliary fibrosis. Furthermore, further investigations have shown a correlation between telocytes in cholesterol gallstones and cholecystokinin-A receptor (CCK-AR), suggesting that elevated cholesterol levels may impair telocytes, leading to a reduction in the quantity of CCK-AR and ultimately resulting in impaired gallbladder motility.Therefore, we hypothesize that telocytes may play a crucial role in maintaining biliary homeostasis, and their deficiency may be associated with the development of benign biliary diseases, including gallstone disease and biliary dilation.
Topics: Telocytes; Cholelithiasis; Humans; Gallbladder; Female; Male; Bile Ducts; Middle Aged; Aged; Dilatation, Pathologic
PubMed: 38942924
DOI: 10.1038/s41598-024-65776-w -
Physiological Reports Jul 2024Supplemental O (hyperoxia) is a critical intervention for premature infants (<34 weeks) but consequently is associated with development of bronchial airway...
Supplemental O (hyperoxia) is a critical intervention for premature infants (<34 weeks) but consequently is associated with development of bronchial airway hyperreactivity (AHR) and asthma. Clinical practice shifted toward the use of moderate hyperoxia (<60% O), but risk for subsequent airway disease remains. In mouse models of moderate hyperoxia, neonatal mice have increased AHR with effects on airway smooth muscle (ASM), a cell type involved in airway tone, bronchodilation, and remodeling. Understanding mechanisms by which moderate O during the perinatal period initiates sustained airway changes is critical to drive therapeutic advancements toward treating airway diseases. We propose that cellular clock factor BMAL1 is functionally important in developing mouse airways. In adult mice, cellular clocks target pathways highly relevant to asthma pathophysiology and Bmal1 deletion increases inflammatory response, worsens lung function, and impacts survival outcomes. Our understanding of BMAL1 in the developing lung is limited, but our previous findings show functional relevance of clocks in human fetal ASM exposed to O. Here, we characterize Bmal1 in our established mouse neonatal hyperoxia model. Our data show that Bmal1 KO deleteriously impacts the developing lung in the context of O and these data highlight the importance of neonatal sex in understanding airway disease.
Topics: Animals; Hyperoxia; ARNTL Transcription Factors; Mice; Female; Animals, Newborn; Male; Lung; Mice, Inbred C57BL; Mice, Knockout; Sex Characteristics
PubMed: 38942729
DOI: 10.14814/phy2.16122 -
Journal of Oral Biosciences Jun 2024This study aimed to investigate the regulatory mechanisms governing dental mesenchymal cell commitment during tooth development, focusing on odontoblast differentiation...
Exploring the Role of DNMT1 in Dental Papilla Cell Fate Specification during Mouse Tooth Germ Development through Integrated Single-Cell Transcriptomics and Bulk RNA Sequencing.
OBJECTIVES
This study aimed to investigate the regulatory mechanisms governing dental mesenchymal cell commitment during tooth development, focusing on odontoblast differentiation and the role of epigenetic regulation in this process.
METHODS
We performed single-cell RNA sequencing (scRNA-seq) of dental cells from embryonic day 14.5 (E14.5) mice to understand the heterogeneity of developing tooth germ cells. Computational analyses including gene regulatory network (GRN) assessment were conducted. We validated our findings using immunohistochemistry (IHC) and in vitro loss-of-function analyses using the DNA methyltransferase 1 (DNMT1) inhibitor Gsk-3484862 in primary dental mesenchymal cells (DMCs) isolated from E14.5 mouse tooth germs. Bulk RNA-seq of Gsk-3484862-treated DMCs was performed to identify potential downstream targets of DNMT1.
RESULTS
scRNA-seq analysis revealed diverse cell populations within the tooth germs, including epithelial, mesenchymal, immune, and muscle cells. Using single-cell regulatory network inference and clustering (SCENIC), we identified Dnmt1 as a key regulator of early odontoblast development. IHC analysis showed the ubiquitous expression of DNMT1 in the dental papilla and epithelium. Bulk RNA-seq of cultured DMCs showed that Gsk-3484862 treatment upregulated odontoblast-related genes, whereas genes associated with cell division and the cell cycle were downregulated. Integrated analysis of bulk RNA-seq data with scRNA-seq SCENIC profiles was used to identify the potential Dnmt1 target genes.
CONCLUSIONS
Dnmt1 may negatively affect odontoblast commitment and differentiation during tooth development. These findings contribute to a better understanding of the molecular mechanisms underlying tooth development and future development of hard-tissue regenerative therapies.
PubMed: 38942194
DOI: 10.1016/j.job.2024.06.010 -
Medicine Jun 2024Dyskinesia is one of the most common complications of stroke. Acupuncture therapy (AT) and mirror therapy (MT) are promising rehabilitation measures for the treatment of... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Dyskinesia is one of the most common complications of stroke. Acupuncture therapy (AT) and mirror therapy (MT) are promising rehabilitation measures for the treatment of post-stroke dyskinesia. Although some studies suggested that AT and MT are effective and safe for dyskinesia, the effects, and safety remain uncertain due to lacking strong evidence. The purpose of this study is to investigate the efficacy and safety of AT combined with MT in the treatment of post-stroke dyskinesia.
METHODS
We searched the following databases: PubMed, Web of Science, Cochrane Library, EMBASE, Medline, China Knowledge Network, WANFANG, and China Biomedical Literature Database, from inception to 1 January 2023 to identify eligible studies. Total effective rate, the Fugl-Meyer assessment scale (FMA) upper and lower limb scores, modified Barthel index scores, Berg balance scale, modified Ashworth scale, and adverse reactions were adopted as outcome indicators. The Grading of Recommendations Assessment Development and Evaluation system was used by 2 independent reviewers to assess the quality of evidence for the outcome indicators included in the study. The statistical analysis was conducted by RevMan V.5.4 software.
RESULTS
A total of 24 randomized controlled studies included 2133 patients with post-stroke dyskinesia were included. The total effective rate of AT combined with MT was more advantageous in the treatment of post-stroke dyskinesia (relative risk = 1.31, 95% confidence interval [CI] [1.22-1.42], Z = 6.96, P < .0001). AT combined with MT was more advantageous for FMA upper limb score (mean difference [MD] = 6.67, 95% CI [5.21-8.13], Z = 8.97, P < .00001) and FMA lower limb score (MD = 3.72, 95% CI [2.81-4.63], Z = 7.98, P < .00001). Meta-analysis showed that AT combined with MT for post-stroke dyskinesia had a more advantageous modified Barthel index score (MD = 9.51, 95% CI [7.44-11.58], Z = 9.01, P < .00001).
CONCLUSION
AT combined with MT is effective in improving motor function and daily living ability of patients, especially in improving muscle spasms. However, these results should be regarded with caution given the low quality of evidence for the evaluation results.
Topics: Humans; Acupuncture Therapy; Stroke; Dyskinesias; Stroke Rehabilitation; Randomized Controlled Trials as Topic; Combined Modality Therapy; Treatment Outcome
PubMed: 38941386
DOI: 10.1097/MD.0000000000038733 -
Diabetes Care Jun 2024The aim of this study was to investigate the impact of the sodium-glucose cotransporter 2 (SGLT2) inhibitor dapagliflozin on tissue fatty acid (FA) uptake in the...
SGLT2 Inhibitor Dapagliflozin Increases Skeletal Muscle and Brain Fatty Acid Uptake in Individuals With Type 2 Diabetes: A Randomized Double-Blind Placebo-Controlled Positron Emission Tomography Study.
OBJECTIVE
The aim of this study was to investigate the impact of the sodium-glucose cotransporter 2 (SGLT2) inhibitor dapagliflozin on tissue fatty acid (FA) uptake in the skeletal muscle, brain, small intestine, and subcutaneous and visceral adipose tissue of individuals with type 2 diabetes by using positron emission tomography (PET).
RESEARCH DESIGN AND METHODS
In a 6-week randomized double-blind placebo-controlled trial, 53 patients with type 2 diabetes treated with metformin received either 10 mg dapagliflozin or placebo daily. Tissue FA uptake was quantified at baseline and end of treatment with PET and the long-chain FA analog radiotracer 14(R,S)-[18F]fluoro-6-thia-heptadecanoic acid. Treatment effects were assessed using ANCOVA, and the results are reported as least square means and 95% CIs for the difference between groups.
RESULTS
A total of 38 patients (dapagliflozin n = 21; placebo n = 17) completed the study. After 6 weeks, skeletal muscle FA uptake was increased by dapagliflozin compared with placebo (1.0 [0.07, 2.0] μmol ⋅ 100 g-1 ⋅ min-1; P = 0.032), whereas uptake was not significantly changed in the small intestine or visceral or subcutaneous adipose tissue. Dapagliflozin treatment significantly increased whole-brain FA uptake (0.10 [0.02, 0.17] μmol ⋅ 100 g-1 ⋅ min-1; P = 0.01), an effect observed in both gray and white matter regions.
CONCLUSIONS
Six weeks of treatment with dapagliflozin increases skeletal muscle and brain FA uptake, partly driven by a rise in free FA availability. This finding is in accordance with previous indirect measurements showing enhanced FA metabolism in response to SGLT2 inhibition and extends the notion of a shift toward increased FA use to muscle and brain.
PubMed: 38941156
DOI: 10.2337/dc24-0470 -
Cardiovascular Drugs and Therapy Jun 2024Heme oxygenase-1 (HO-1) is a crucial enzyme in heme metabolism, facilitating the breakdown of heme into biliverdin, carbon monoxide, and free iron. Renowned for its... (Review)
Review
PURPOSE
Heme oxygenase-1 (HO-1) is a crucial enzyme in heme metabolism, facilitating the breakdown of heme into biliverdin, carbon monoxide, and free iron. Renowned for its potent cytoprotective properties, HO-1 showcases notable antioxidant, anti-inflammatory, and anti-apoptotic effects. In this review, the authors aim to explore the profound impact of HO-1 on cardiac senescence and its potential implications in myocardial infarction (MI).
RESULTS
Recent research has unveiled the intricate role of HO-1 in cellular senescence, characterized by irreversible growth arrest and functional decline. Notably, cardiac senescence has emerged as a pivotal factor in the development of various cardiovascular conditions, including MI. Notably, cardiac senescence has emerged as an important factor in the development of various cardiovascular conditions, including myocardial infarction (MI). The accumulation of senescent cells, spanning vascular endothelial cells, vascular smooth muscle cells, cardiomyocytes, and progenitor cells, poses a significant risk for cardiovascular diseases such as vascular aging, atherosclerosis, myocardial infarction, and ventricular remodeling. Inhibition of cardiomyocyte senescence not only reduces senescence-associated inflammation but also impacts other myocardial lineages, hinting at a broader mechanism of propagation in pathological remodeling. HO-1 has been shown to improve heart function and mitigate cardiomyocyte senescence induced by ischemic injury and aging. Furthermore, HO-1 induction has been found to alleviate HO-induced cardiomyocyte senescence. As we grow in our understanding of antiproliferative, antiangiogenic, anti-aging, and vascular effects of HO-1, we see the potential to exploit potential links between individual susceptibility to cardiac senescence and myocardial infarction.
CONCLUSIONS
This review investigates strategies for upregulating HO-1, including gene targeting and pharmacological agents, as potential therapeutic approaches. By synthesizing compelling evidence from diverse experimental models and clinical investigations, this study elucidates the therapeutic potential of targeting HO-1 as an innovative strategy to mitigate cardiac senescence and improve outcomes in myocardial infarction, emphasizing the need for further research in this field.
PubMed: 38940935
DOI: 10.1007/s10557-024-07590-0