Translational research : the journal of laboratory and clinical medicine
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Transforming growth factor-beta 1 (TGF-β1)-mediated tissue fibrosis is an important regulator of lymphatic dysfunction in secondary lymphedema. However, TGF-β1 targeting can cause toxicity and autoimmune complications, limiting clinical utility. Angiotensin II (Ang II) modulates intracellular TGF-β1 signaling, and inhibition of Ang II production using angiotensin-converting enzyme (ACE) inhibitors, such as captopril, has antifibrotic efficacy in some pathological settings. ⋯ Furthermore, topical captopril decreases fibrosis, activation of intracellular TGF-β1 signaling pathways, inflammation, and swelling in mouse models of lymphedema. Captopril treatment also improves lymphatic function and immune cell trafficking by increasing collecting lymphatic pumping. Our results show that the renin-angiotensin system in the skin plays an important role in the regulation of fibrosis in lymphedema, and inhibition of this signaling pathway may hold merit for treating lymphedema.
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Phosphoglucomutase 1 (PGM1) deficiency is recognized as the third most common N-linked congenital disorders of glycosylation (CDG) in humans. Affected individuals present with liver, musculoskeletal, endocrine, and coagulation symptoms; however, the most life-threatening complication is the early onset of dilated cardiomyopathy (DCM). Recently, we discovered that oral D-galactose supplementation improved liver disease, endocrine, and coagulation abnormalities, but does not alleviate the fatal cardiomyopathy and the associated myopathy. ⋯ Transcriptomic analysis of hearts from mutant mice demonstrated a gene signature of DCM. Although proteomics revealed only mild changes in global protein expression in left ventricular tissue of mutant mice, a glycoproteomic analysis unveiled broad glycosylation changes with significant alterations in sarcolemmal proteins including different subunits of laminin-211, which was confirmed by immunoblot analyses. Finally, augmentation of PGM1 in KO mice via AAV9-PGM1 gene replacement therapy prevented and halted the progression of the DCM phenotype.
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According to previous studies, circular RNAs (circRNAs) are involved in multiple pathological processes of acute ischemic stroke (AIS). However, the relationship between circFOXP1 and IS has not yet been reported. Here, we found that circFOXP1 expression was significantly decreased in the peripheral blood of AIS patients compared to controls and was associated with the severity and prognosis of AIS. ⋯ Mechanistically, decreased QKI expression inhibited circFOXP1 biogenesis under hypoxic conditions. Decreased circFOXP1 expression accelerated signal transducer and activator of transcription 3 (STAT3) protein degradation by binding to and increasing STAT3 protein ubiquitination, ultimately aggravating brain injury after cerebral ischemia by activating apoptotic signaling. In summary, our study is the first to reveal that circFOXP1 alleviates brain injury after cerebral ischemia by regulating STAT3/apoptotic signaling, which provides a potentially novel therapeutic target for AIS.
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Cardiac fibrosis is a common pathological change in the development of heart disease. Circular RNA (circRNA) has been shown to be related to the occurrence and development of various cardiovascular diseases. This study aimed to evaluate the effects and potential mechanisms of circHelz in cardiac fibrosis. ⋯ Moreover, silencing YAP1 reversed the detrimental effects caused by circHelz in vitro, as indicated by the observed decreases in cell viability, fibrotic marker expression levels, proliferation and migration. Collectively, the protective effect of circHelz knockdown against cardiac fibrosis injury is accomplished by inhibiting the nuclear translocation of YAP1. Thus, circHelz may be a novel target for the prevention and treatment of cardiovascular disease.
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Traumatic Brain Injury (TBI) is a major cause of death and disability in the US and a recognized risk factor for the development of Alzheimer's disease (AD). The relationship between these conditions is not completely understood, but the conditions may share additive or synergistic pathological hallmarks that may serve as novel therapeutic targets. Heightened inflammasome signaling plays a critical role in the pathogenesis of central nervous system injury (CNS) and the release of apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC) speck from neurons and activated microglia contribute significantly to TBI and AD pathology. ⋯ Moreover, treatment of injured AD mice with IC100, an anti-ASC monoclonal antibody, inhibited the inflammasome, as evidenced by IL-1β reduction in the injured cortex at 1-week post injury. These findings show that the inflammasome response is heightened in mice genetically predisposed to AD and suggests that AD may exacerbate TBI pathology. Thus, dampening inflammasome signaling may offer a novel approach for the treatment of AD and TBI.