Translational research : the journal of laboratory and clinical medicine
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Cardiovascular disease is a leading cause of mortality in the world and is exacerbated by the presence of cardiac fibrosis, defined by the accumulation of noncontractile extracellular matrix proteins. Cardiac fibrosis is directly linked to cardiac dysfunction and increased risk of arrhythmia. Despite its prevalence, there is a lack of efficacious therapies for inhibiting or reversing cardiac fibrosis, largely due to the complexity of the cell types and signaling pathways involved. ⋯ Significant advances in cell transplantation therapy and biomaterials engineering have also demonstrated potential in regenerating the myocardium. Novel techniques, such as cellular direct reprogramming, and molecular targets, such as noncoding RNAs and epigenetic modifiers, are uncovering novel therapeutic options targeting fibrosis. This review provides an overview of current approaches and discuss future directions for treating cardiac fibrosis.
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Radiation-induced pulmonary fibrosis (RIPF) is a serious treatment complication that affects about 9%-30% cancer patients receiving radiotherapy for thoracic tumors. RIPF is characterized by progressive and irreversible destruction of lung tissues and deterioration of lung function, which can compromise quality of life and eventually lead to respiratory failure and death. ⋯ Recently, an increasing body of evidence suggests that induction of senescence by radiation may play an important role in RIPF and clearance of senescent cells (SnCs) with a senolytic agent, small molecule that can selectively kill SnCs, has the potential to be developed as a novel therapeutic strategy for RIPF. This review discusses some of these new findings to promote further study on the role of cellular senescence in RIPF and the development of senolytic therapeutics for RIPF.
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Prader-Willi syndrome (PWS) is a complex and multisystem neurobehavioral disorder. The molecular mechanism of PWS is deficiency of paternally expressed gene gene or genes from the chromosome 15q11-q13. Due to imprinted gene regulation, the same genes in the maternal chromosome 15q11-q13 are structurally intact but transcriptionally repressed by an epigenetic mechanism. ⋯ High content screening of small molecule libraries using cells derived from transgenic mice carrying the SNRPN-EGFP fusion protein has discovered that inhibitors of EHMT2/G9a, a histone 3 lysine 9 methyltransferase, are capable of reactivating expression of paternally expressed SNRPN and SNORD116 from the maternal chromosome, both in cultured PWS patient-derived fibroblasts and in a PWS mouse model. Treatment with an EMHT2/G9a inhibitor also rescues perinatal lethality and failure to thrive phenotypes in a PWS mouse model. These findings present the first evidence to support a proof-of-principle for epigenetic-based therapy for the PWS in humans.
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The literature describing the prognosis of patients with gastrointestinal (GI) cancers and brain metastases (BM) is sparse. Our group previously published a prognostic index, the Graded Prognostic Assessment (GPA) for GI cancer patients with BM, based on 209 patients diagnosed from 1985-2005. The purpose of this analysis is to identify prognostic factors for GI cancer patients with newly diagnosed BM in a larger contemporary cohort. ⋯ Notably, 37% (267/716) presented with poor prognosis (GPA 0-1.0). Although little improvement in overall survival in this cohort has been achieved in recent decades, survival varies widely and multiple new prognostic factors were identified. Future work will translate these factors into a prognostic index to facilitate clinical decision-making and stratification of future clinical trials.
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Mast cells (MCs) have been implicated in the pathogenesis of cardiometabolic diseases by releasing pro-inflammatory mediators. Patients and animals with diabetic cardiomyopathy (DCM) also show inflammatory cell accumulation in the heart. Here, we detected MCs in mouse heart after streptozotocin (STZ)-induced DCM. ⋯ Yet, adoptive transfer of BMMCs from Il6-/- and Tnf-/- mice failed to make these corrections or at much less extent than the WT BMMCs. Mechanistic studies demonstrated a role of MC and MC-derived IL6 and TNF-α in promoting cardiomyocyte death and cardiac fibroblast TGF-β signaling, and collagen synthesis and deposition. Therefore, MC inhibition may have therapeutic potential in attenuating DCM progression.