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Nature Communications Oct 2023palmitoylation, a reversible post-translational modification, is initiated by the DHHC family of palmitoyltransferases and reversed by several acyl protein...
palmitoylation, a reversible post-translational modification, is initiated by the DHHC family of palmitoyltransferases and reversed by several acyl protein thioesterases. However, the role and mechanisms for protein palmitoylation in renal fibrosis have not been elucidated. Here we show protein palmitoylation and DHHC9 were downregulated in the fibrotic kidneys of mouse models and chronic kidney disease (CKD) patients. Ablating DHHC9 in tubular cells aggravated, while inducing DHHC9 overexpression with adeno-DHHC9 transfection or iproniazid treatment protected against kidney fibrosis in male mouse models. Mechanistically, DHHC9 palmitoylated β-catenin, thereby promoted its ubiquitination and degradation. Additionally, acyl protein thioesterase 1 (APT1) was induced in the fibrotic kidneys, which depalmitoylated β-catenin, increased its abundance and nuclear translocation. Ablating tubular APT1 or inhibiting APT1 with ML348 markedly protected against unilateral ureter obstruction (UUO) or ischemia/reperfusion injury (IRI)-induced kidney fibrosis in male mice. This study reveals the regulatory mechanism of protein palmitoylation in kidney fibrosis.
Topics: Humans; Male; Mice; Animals; beta Catenin; Lipoylation; Renal Insufficiency, Chronic; Ureteral Obstruction; Fibrosis; Kidney
PubMed: 37865665
DOI: 10.1038/s41467-023-42476-z -
Journal of Cachexia, Sarcopenia and... Oct 2023DJ-1 is a causative gene for Parkinson's disease. DJ-1-deficient mice develop gait-associated progressive behavioural abnormalities and hypoactive forearm grip strength....
BACKGROUND
DJ-1 is a causative gene for Parkinson's disease. DJ-1-deficient mice develop gait-associated progressive behavioural abnormalities and hypoactive forearm grip strength. However, underlying activity mechanisms are not fully explored.
METHODS
Western blotting and quantitative real-time polymerase chain reaction approaches were adopted to analyse DJ-1 expression in skeletal muscle from aged humans or mice and compared with young subjects. Skeletal muscle-specific-DJ-1 knockout (MDKO) mice were generated, followed by an assessment of the physical activity phenotypes (grip strength, maximal load capacity, and hanging, rotarod, and exercise capacity tests) of the MDKO and control mice on the chow diet. Muscular atrophy phenotypes (cross-sectional area and fibre types) were determined by imaging and quantitative real-time polymerase chain reaction. Mitochondrial function and skeletal muscle morphology were evaluated by oxygen consumption rate and electron microscopy, respectively. Tail suspension was applied to address disuse atrophy. RNA-seq analysis was performed to indicate molecular changes in muscles with DJ-1 ablation. Dual-luciferase reporter assays were employed to identify the promoter region of Trim63 and Fbxo32 genes, which were indirectly regulated by DJ-1 via the FoxO1 pathway. Cytoplasmic and nuclear fractions of DJ-1-deleted muscle cells were analysed by western blotting. Compound 23 was administered into the gastrocnemius muscle to mimic the of DJ-1 deletion effects.
RESULTS
DJ-1 expression decreased in atrophied muscles of aged human (young men, n = 2; old with aged men, n = 2; young women, n = 2; old with aged women, n = 2) and immobilization mice (n = 6, P < 0.01). MDKO mice exhibited no body weight difference compared with control mice on the chow diet (Flox, n = 8; MDKO, n = 9). DJ-1-deficient muscles were slightly dystrophic (Flox, n = 7; MDKO, n = 8; P < 0.05), with impaired physical activities and oxidative capacity (n = 8, P < 0.01). In disuse-atrophic conditions, MDKO mice showed smaller cross-sectional area (n = 5, P < 0.01) and more central nuclei than control mice (Flox, n = 7; MDKO, n = 6; P < 0.05), without alteration in muscle fibre types (Flox, n = 6; MDKO, n = 7). Biochemical analysis indicated that reduced mitochondrial function and upregulated of atrogenes induced these changes. Furthermore, RNA-seq analysis revealed enhanced activity of the FoxO1 signalling pathway in DJ-1-ablated muscles, which was responsible for the induction of atrogenes. Finally, compound 23 (an inhibitor of DJ-1) could mimic the effects of DJ-1 ablation in vivo.
CONCLUSIONS
Our results illuminate the crucial of skeletal muscle DJ-1 in the regulation of catabolic signals from mechanical stimulation, providing a therapeutic target for muscle wasting diseases.
Topics: Male; Humans; Animals; Female; Mice; Aged; Muscle, Skeletal; Muscular Atrophy; Muscle Fibers, Skeletal; Muscular Disorders, Atrophic; Mitochondria
PubMed: 37469245
DOI: 10.1002/jcsm.13290 -
Frontiers in Cardiovascular Medicine 2023For many years, guidelines have suggested thermal ablation for the treatment of atrial fibrillation. Thermal ablation involves the destruction of tissue, leading to... (Review)
Review
For many years, guidelines have suggested thermal ablation for the treatment of atrial fibrillation. Thermal ablation involves the destruction of tissue, leading to multiple complications. This ablation technique has been tried and tested, however, newer techniques are being investigated in order to avoid these complications. Pulsed field ablation, a nonthermal method of tissue ablation, is being explored as a more safe and efficient way to treat atrial fibrillation. This mini review aims to highlight the mechanisms of pulsed field ablation, its history and evolution, previous studies showing its efficacy, its major challenges and pitfalls, and future advancements to overcome these challenges. This method of ablation could potentially revolutionize the treatment of atrial fibrillation and prevent recurrences, thereby making it easier for the physicians and patients involved.
PubMed: 37937293
DOI: 10.3389/fcvm.2023.1235317 -
Journal of Arrhythmia Oct 2023A 72-year-old man was treated for recurrent atrial tachycardia (AT) and underwent ablation. The AT was diagnosed as bi-AT based on the activation map and the postpacing...
A 72-year-old man was treated for recurrent atrial tachycardia (AT) and underwent ablation. The AT was diagnosed as bi-AT based on the activation map and the postpacing interval. Another AT appeared and was diagnosed as bi-AT by the same method. Surprisingly, the circuits of both ATs were perfectly matched and rotated in opposite directions. The left atrial anteroseptal wall was ablated during the AT. The AT was immediately stopped and was no longer induced.
PubMed: 37799785
DOI: 10.1002/joa3.12919 -
Journal of Experimental & Clinical... Dec 2023Myeloid cells (granulocytes and monocytes/macrophages) play an important role in neuroblastoma. By inducing a complex immunosuppressive network, myeloid cells pose a... (Review)
Review
Myeloid cells (granulocytes and monocytes/macrophages) play an important role in neuroblastoma. By inducing a complex immunosuppressive network, myeloid cells pose a challenge for the adaptive immune system to eliminate tumor cells, especially in high-risk neuroblastoma. This review first summarizes the pro- and anti-tumorigenic functions of myeloid cells, including granulocytes, monocytes, macrophages, and myeloid-derived suppressor cells (MDSC) during the development and progression of neuroblastoma. Secondly, we discuss how myeloid cells are engaged in the current treatment regimen and explore novel strategies to target these cells in neuroblastoma. These strategies include: (1) engaging myeloid cells as effector cells, (2) ablating myeloid cells or blocking the recruitment of myeloid cells to the tumor microenvironment and (3) reprogramming myeloid cells. Here we describe that despite their immunosuppressive traits, tumor-associated myeloid cells can still be engaged as effector cells, which is clear in anti-GD2 immunotherapy. However, their full potential is not yet reached, and myeloid cell engagement can be enhanced, for example by targeting the CD47/SIRPα axis. Though depletion of myeloid cells or blocking myeloid cell infiltration has been proven effective, this strategy also depletes possible effector cells for immunotherapy from the tumor microenvironment. Therefore, reprogramming of suppressive myeloid cells might be the optimal strategy, which reverses immunosuppressive traits, preserves myeloid cells as effectors of immunotherapy, and subsequently reactivates tumor-infiltrating T cells.
Topics: Humans; Neuroblastoma; Neoplasms; Myeloid Cells; Immunotherapy; Myeloid-Derived Suppressor Cells; Macrophages; Tumor Microenvironment
PubMed: 38087370
DOI: 10.1186/s13046-023-02913-9 -
BioRxiv : the Preprint Server For... Sep 2023Mesenchymal plasticity has been extensively described in advanced and metastatic epithelial cancers; however, its functional role in malignant progression, metastatic...
Mesenchymal plasticity has been extensively described in advanced and metastatic epithelial cancers; however, its functional role in malignant progression, metastatic dissemination and therapy response is controversial. More importantly, the role of epithelial mesenchymal transition (EMT) and cell plasticity in tumor heterogeneity, clonal selection and clonal evolution is poorly understood. Functionally, our work clarifies the contribution of EMT to malignant progression and metastasis in pancreatic cancer. We leveraged somatic mosaic genome engineering, lineage tracing and ablation technologies and dynamic genetic reporters to trace and ablate tumor-specific lineages along the phenotypic spectrum of epithelial to mesenchymal plasticity. The experimental evidences clarify the essential contribution of mesenchymal lineages to pancreatic cancer evolution and metastatic dissemination. Spatial genomic analysis combined with single cell transcriptomic and epigenomic profiling of epithelial and mesenchymal lineages reveals that EMT promotes with the emergence of chromosomal instability (CIN). Specifically tumor lineages with mesenchymal features display highly conserved patterns of genomic evolution including complex structural genomic rearrangements and chromotriptic events. Genetic ablation of mesenchymal lineages robustly abolished these mutational processes and evolutionary patterns, as confirmed by cross species analysis of pancreatic and other human epithelial cancers. Mechanistically, we discovered that malignant cells with mesenchymal features display increased chromatin accessibility, particularly in the pericentromeric and centromeric regions, which in turn results in delayed mitosis and catastrophic cell division. Therefore, EMT favors the emergence of high-fitness tumor cells, strongly supporting the concept of a cell-state, lineage-restricted patterns of evolution, where cancer cell sub-clonal speciation is propagated to progenies only through restricted functional compartments. Restraining those evolutionary routes through genetic ablation of clones capable of mesenchymal plasticity and extinction of the derived lineages completely abrogates the malignant potential of one of the most aggressive form of human cancer.
PubMed: 37786705
DOI: 10.1101/2023.09.18.558231 -
World Journal of Urology Jan 2024To review available and emerging evidence of radiotherapy for symptom management and disease control in metastatic bladder cancer. (Review)
Review
PURPOSE
To review available and emerging evidence of radiotherapy for symptom management and disease control in metastatic bladder cancer.
METHODS
A literature search and subsequent cross-referencing were carried out for articles in the PubMed and Scopus databases using terms 'radiotherapy' OR 'palliative radiation therapy' with 'metastatic bladder cancer' OR 'advanced bladder cancer' between 1990 and 2023, excluding articles with no English translation.
RESULTS
Palliative radiotherapy is an effective and accessible treatment for the alleviation of haematuria and pain due to the primary and metastatic disease. With growing recognition of oligometastatic disease state at diagnosis, response, or progression, radiotherapy can consolidate response by ablating residual or resistant lesions. Experience with other primary cancers supports positive impact of radiotherapy on disease control, quality of life, and survival in oligometastatic stage, without significant adverse effects. Alongside immune checkpoint inhibitors, fibroblast growth receptor inhibitors, and antibody-drug conjugates, the immunomodulatory potential of radiotherapy is being explored in combination with these systemic therapies for metastatic bladder cancer.
CONCLUSION
Radiotherapy is an effective, safe, and accessible treatment modality for palliation as well as disease control in various clinical settings of metastatic bladder cancer. Its role in oligometastatic stage in combination with systemic therapy is expected to expand with emerging evidence.
Topics: Humans; Quality of Life; Urinary Bladder Neoplasms
PubMed: 38244091
DOI: 10.1007/s00345-023-04744-x