Project description:Annexin A1, a well-known endogenous anti-inflammatory mediator, plays a critical role in a variety of pathological processes. Fibrosis is described by a failure of tissue regeneration and contributes to the development of many diseases. Accumulating evidence supports that Annexin A1 participates in the progression of tissue fibrosis. However, the fundamental mechanisms by which Annexin A1 regulates fibrosis remain elusive, and even the functions of Annexin A1 in fibrotic diseases are still paradoxical. This review focuses on the roles of Annexin A1 in the development of fibrosis of lung, liver, heart, and other tissues, with emphasis on the therapy potential of Annexin A1 in fibrosis, and presents future research interests and directions in fibrotic diseases.
Project description:Introduction: T-cell lymphomas represent a broad group of malignant T-cell neoplasms with marked molecular, clinical, and biologic heterogeneity. Survival rates after conventional chemotherapy regimens are poor for most subtypes and new therapies are needed. Rapidly expanding knowledge in the field of epigenomics and the development of an increasing number of epigenetic-modifying agents have created new opportunities for epigenetic therapies for patients with this complex group of diseases.Areas covered: The present review summarizes current knowledge on epigenetic alterations in T-cell lymphomas, availability, and mechanisms of action of epigenetic-modifying agents, results of clinical trials of epigenetic therapies in T-cell lymphomas, status of FDA approval, and biomarker approaches to guide therapy. Promising future directions are discussed.Expert opinion: Mutations in epigenetic-modifying genes are among the most common genetic alterations in T-cell lymphomas, highlighting the potential for epigenetic therapies to improve management of this group of diseases. Single-agent efficacy is well documented, leading to FDA approval for several indications, but overall response rates and durability of responses remain modest. Critical next steps for the field include optimizing combination therapies that incorporate epigenetic-modifying agents and developing predictive biomarkers that help guide patient and drug selection.
Project description:Peyronie and Dupuytren are pathologies characterized by the appearance of localized fibrotic lesions in an organ. These disorders originate from an excessive production of collagen in the tissue provoking dysfunction and functional limitations to the patients. Local administration of collagenase is the most used treatment for these fibrotic-type diseases, but a high lability of the enzyme limits its therapeutic efficacy. Herein, we present a novel methodology for the preparation of collagenase nanocapsules without affecting its enzymatic activity and capable of releasing the enzyme in response to an ultraviolet A (UVA) light stimulus. Polymeric coating around collagenase was formed by free-radical polymerization of acrylamide-type monomers. Their degradation capacity under UVA irradiation was provided by incorporating a novel photocleavable acrylamide-type crosslinker within the polymeric framework. This property allowed collagenase release to be triggered in a controlled manner by employing an easily focused stimulus. Additionally, UVA irradiation presents considerable benefits by itself due to its capacity to induce collagenase production in situ. An expected synergistic effect of collagenase nanocapsules in conjunction with UVA effect may present a promising treatment for these fibrotic diseases.
Project description:Approximately 15,000 new cases of pediatric cancer are diagnosed yearly in Europe, with 8-10% corresponding to neuroblastoma, a rare disease with an incidence of 8-9 cases per million children <15 years of age. Although the survival rate for low-risk and intermediate-risk patients is excellent, half of children with high-risk, refractory, or relapsed tumors will be cured, and two-thirds of the other half will suffer major side effects and life-long disabilities. Epigenetic therapies aimed at reversing the oncogenic alterations in chromatin structure and function are an emerging alternative against aggressive tumors that are or will become resistant to conventional treatments. This approach proposes targeting epigenetic regulators, which are proteins that are involved in the creation, detection, and interpretation of epigenetic signals, such as methylation or histone post-translational modifications. In this review, we focused on the most promising epigenetic regulators for targeting and current drugs that have already reached clinical trials.
Project description:Endometrial cancer is one of the most frequently diagnosed gynecological malignancies worldwide. However, its prognosis in advanced stages is poor, and there are only few available treatment options when it recurs. Epigenetic changes in gene function, such as DNA methylation, histone modification, and non-coding RNA, have been studied for the last two decades. Epigenetic dysregulation is often reported in the development and progression of various cancers. Recently, epigenetic changes in endometrial cancer have also been discussed. In this review, we give the main points of the role of DNA methylation and histone modification in endometrial cancer, the diagnostic tools to determine these modifications, and inhibitors targeting epigenetic regulators that are currently in preclinical studies and clinical trials.
Project description:Protein neddylation is a post-translational modification, and its best recognized substrates are cullin family proteins, which are the core component of Cullin-RING ligases (CRLs). Given that most neddylation pathway proteins are overactivated in different cancers and fibrotic diseases, targeting neddylation becomes an emerging approach for the treatment of these diseases. To date, numerous neddylation inhibitors have been developed, of which MLN4924 has entered phase I/II/III clinical trials for cancer treatment, such as acute myeloid leukemia, melanoma, lymphoma and solid tumors. Here, we systematically describe the structures and biological functions of the critical enzymes in neddylation, highlight the medicinal chemistry advances in the development of neddylation inhibitors and propose the perspectives concerning targeting neddylation for cancer and fibrotic diseases.
Project description:Nintedanib, a Food and Drug Administration-approved drug for the treatment of patients with idiopathic pulmonary fibrosis (IPK), inhibits both tyrosine kinase receptors and non-receptor kinases, and block activation of platelet-derived growth factor receptors, fibroblast growth factor receptor, vascular endothelial growth factor receptors, and Src family kinases. Preclinical and clinical studies have revealed the potent anti-fibrotic effect of nintedanib in IPK in human and animal models. Recent preclinical studies have also demonstrated the inhibitory effect of nintedanib on the development and progression of tissue fibrosis in other organs, including liver, kidney, and skin. The anti-fibrotic actions of nintedanib occur through a number of mechanisms, including blocking differentiation of fibroblasts to myofibroblasts, inhibition of epithelial-mesenchymal transition, and suppression of inflammation and angiogenesis. In this article, we summarize the mechanisms and efficacy of nintedanib in the treatment of fibrotic diseases in animal models and clinical trials, provide an update on recent advances in the development of other novel antifibrotic agents in preclinical and clinical study, and offer our perspective about the possible clinical application of these agents in fibrotic diseases.
Project description:Post-translational modifications can affect gene expression in a long-term manner without changes in the primary nucleotide sequence of the DNA. These epigenetic alterations involve dynamic processes that occur in histones, chromatin-associated proteins and DNA. In response to environmental stimuli, abnormal epigenetic alterations cause disorders in the cell cycle, apoptosis and other cellular processes and thus contribute to the incidence of diverse diseases, including cancers. In this review, we will summarize recent studies focusing on certain epigenetic readers, writers, and erasers associated with cancer development and how newly discovered natural compounds and their derivatives could interact with these targets. These advances provide insights into epigenetic alterations in cancers and the potential utility of these alterations as therapeutic targets for the future development of chemopreventive and chemotherapeutic drugs.
Project description:Follistatin-like 1 (FSTL1) is a matricellular protein that is upregulated during development and disease, including idiopathic pulmonary fibrosis (IPF), keloid, and arthritis. The profibrotic and pro-inflammatory roles of FSTL1 have been intensively studied during the last several years, as well as in this report. We screened and identified epitope-specific monoclonal neutralizing antibodies (nAbs) to functionally block FSTL1. FSTL1 nAbs attenuated bleomycin-induced pulmonary and dermal fibrosis in vivo and transforming growth factor (TGF)-β1-induced dermal fibrosis ex vivo in human skin. In addition, FSTL1 nAbs significantly reduced existing lung fibrosis and skin fibrosis in experimental models. FSTL1 nAbs exerted their potent antifibrotic effects via reduced TGF-β1 responsiveness and subsequent myofibroblast activation and extracellular matrix production. We also observed that FSTL1 nAbs attenuated the severity of collagen-induced arthritis in mice, which was accompanied by reduced inflammatory responses in vitro. Our findings suggest that FSTL1 nAbs are a promising new therapeutic strategy for the treatment of multiple organ fibrosis and systemic autoimmune diseases.
Project description:The growing and rapid development of high-throughput sequencing technologies have allowed a greater understanding of the mechanisms underlying gene expression regulation. Editing the epigenome and epitranscriptome directs the fate of the transcript influencing the functional outcome of each mRNA. In this context, non-coding RNAs play a decisive role in addressing the expression regulation at the gene and chromosomal levels. Long-noncoding RNAs, consisting of more than 200 nucleotides, have been shown to act as epigenetic regulators in several key molecular processes involving neurodegenerative disorders, such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis and Huntington's disease. Long-noncoding RNAs are abundantly expressed in the central nervous system, suggesting that their deregulation could trigger neuronal degeneration through RNA modifications. The evaluation of their diagnostic significance and therapeutic potential could lead to new treatments for these diseases for which there is no cure.