Therapeutic Targets
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2021 ◽  
Vol 8 ◽  
Lei Liu ◽  
Changjun Yang ◽  
Eduardo Candelario-Jalil

Bromodomain and extra-terminal domain (BET) proteins consist of four mammalian members (BRD2, BRD3, BRD4, and BRDT), which play a pivotal role in the transcriptional regulation of the inflammatory response. Dysregulated inflammation is a key pathological process in various CNS disorders through multiple mechanisms, including NF-κB and Nrf2 pathways, two well-known master regulators of inflammation. A better mechanistic understanding of the BET proteins’ role in regulating the inflammatory process is of great significance since it could reveal novel therapeutic targets to reduce neuroinflammation associated with many CNS diseases. In this minireview, we first outline the structural features of BET proteins and summarize genetic and pharmacological approaches for BET inhibition, including novel strategies using proteolysis-targeting chimeras (PROTACs). We emphasize in vitro and in vivo evidence of the interplay between BET proteins and NF-κB and Nrf2 signaling pathways. Finally, we summarize recent studies showing that BET proteins are essential regulators of inflammation and neuropathology in various CNS diseases.

2021 ◽  
Vol 12 ◽  
Hengzhen Wang ◽  
Wenjing Jiang ◽  
Haijun Wang ◽  
Zheng Wei ◽  
Hali Li ◽  

Liver hepatocellular carcinoma (LIHC) is a primary malignancy, and there is a lack of effective treatment for advanced patients. Although numerous studies exist to reveal the carcinogenic mechanism of LIHC, few studies have integrated multi-omics data to systematically analyze pathogenesis and reveal potential therapeutic targets. Here, we integrated genomic variation data and RNA-seq profiles obtained by high-throughput sequencing to define high- and low-genomic instability samples. The mutational landscape was reported, and the advanced patients of LIHC were characterized by high-genomic instability. We found that the tumor microenvironment underwent metabolic reprograming driven by mutations accumulate to satisfy tumor proliferation and invasion. Further, the co-expression network identifies three mutant long non-coding RNAs as potential therapeutic targets, which can promote tumor progression by participating in specific carcinogenic mechanisms. Then, five potential prognostic markers (RP11-502I4.3, SPINK5, CHRM3, SLC5A12, and RP11-467L13.7) were identified by examining the association of genes and patient survival. By characterizing the immune landscape of LIHC, loss of immunogenicity was revealed as a key factor of immune checkpoint suppression. Macrophages were found to be significantly associated with patient risk scores, and high levels of macrophages accelerated patient mortality. In summary, the mutation-driven mechanism and immune landscape of LIHC revealed by this study will serve precision medicine.

Benjamin Steinhorn ◽  
Emrah Eroglu ◽  
Thomas Michel

Chemogenetics refers to experimental systems that dynamically regulate the activity of a recombinant protein by providing or withholding the protein's specific biochemical stimulus. Chemogenetic tools permit precise dynamic control of specific signaling molecules to delineate the roles of those molecules in physiology and disease. Yeast d-amino acid oxidase (DAAO) enables chemogenetic manipulation of intracellular redox balance by generating hydrogen peroxide only in the presence of d-amino acids. Advances in biosensors have allowed the precise quantitation of these signaling molecules. The combination of chemogenetic approaches with biosensor methodologies has opened up new lines of investigation, allowing the analysis of intracellular redox pathways that modulate physiological and pathological cell responses. We anticipate that newly developed transgenic chemogenetic models will permit dynamic modulation of cellular redox balance in diverse cells and tissues and will facilitate the identification and validation of novel therapeutic targets involved in both physiological redox pathways and pathological oxidative stress. Expected final online publication date for the Annual Review of Pharmacology and Toxicology, Volume 62 is January 2022. Please see for revised estimates.

2021 ◽  
Vol 8 ◽  
Jianwen Yu ◽  
Danli Xie ◽  
Naya Huang ◽  
Qin Zhou

Circular RNAs (circRNAs) are a novel type of non-coding RNAs that have aroused growing attention in this decade. They are widely expressed in eukaryotes and generally have high stability owing to their special closed-loop structure. Many circRNAs are abundant, evolutionarily conserved, and exhibit cell-type-specific and tissue-specific expression patterns. Mounting evidence suggests that circRNAs have regulatory potency for gene expression by acting as microRNA sponges, interacting with proteins, regulating transcription, or directly undergoing translation. Dysregulated expression of circRNAs were found in many pathological conditions and contribute to the pathogenesis and progression of various disorders, including renal diseases. Recent studies have revealed that circRNAs may serve as novel reliable biomarkers for the diagnosis and prognosis prediction of multiple kidney diseases, such as renal cell carcinoma (RCC), acute kidney injury (AKI), diabetic kidney disease (DKD), and other glomerular diseases. Furthermore, circRNAs expressed by intrinsic kidney cells are shown to play a substantial role in kidney injury, mostly reported in DKD and RCC. Herein, we review the biogenesis and biological functions of circRNAs, and summarize their roles as promising biomarkers and therapeutic targets in common kidney diseases.

2021 ◽  
Vol 8 ◽  
Penglong Wu ◽  
Mingqi Cai ◽  
Jinbao Liu ◽  
Xuejun Wang

Background: Catecholamine surges and resultant excessive β-adrenergic stimulation occur in a broad spectrum of diseases. Excessive β-adrenergic stimulation causes cardiomyocyte necrosis, but the underlying mechanism remains obscure. Necroptosis, a major form of regulated necrosis mediated by RIPK3-centered pathways, is implicated in heart failure; however, it remains unknown whether excessive β-adrenergic stimulation-induced cardiac injury involves necroptosis. Hence, we conducted the present study to address these critical gaps.Methods and Results: Two consecutive daily injections of isoproterenol (ISO; 85 mg/kg, s.c.) or saline were administered to adult mixed-sex mice. At 24 h after the second ISO injection, cardiac area with Evans blue dye (EBD) uptake and myocardial protein levels of CD45, RIPK1, Ser166-phosphorylated RIPK1, RIPK3, and Ser345-phosphorylated MLKL (p-MLKL) were significantly greater, while Ser321-phosphorylated RIPK1 was significantly lower, in the ISO-treated than in saline-treated wild-type (WT) mice. The ISO-induced increase of EBD uptake was markedly less in RIPK3−/− mice compared with WT mice (p = 0.016). Pretreatment with the RIPK1-selective inhibitor necrostatin-1 diminished ISO-induced increases in RIPK3 and p-MLKL in WT mice and significantly attenuated ISO-induced increases of EBD uptake in WT but not RIPK3−/− mice.Conclusions: A large proportion of cardiomyocyte necrosis induced by excessive β-adrenergic stimulation belongs to necroptosis and is mediated by a RIPK1–RIPK3-dependent pathway, identifying RIPK1 and RIPK3 as potential therapeutic targets for catecholamine surges.

2021 ◽  
Yiheng Du ◽  
Jin Cao ◽  
Xiang Jiang ◽  
Xiaowei Cai ◽  
Bo Wang ◽  

Abstract Background Bladder cancer (BLCA) is the most common genitourinary tumor but lacks specific diagnostic biomarkers. Recent years have seen significant advances in the use and approval of immune checkpoint blockade (ICB) therapy to manage bladder cancer at advanced stages when platinum-based therapy has failed. The tumor microenvironment (TME) in bladder cancer is an essential player in patient's responsiveness to ICB therapy. Therefore, this manuscript explored the TME and identified CXCL12, a specific marker for inflammatory cancer associated fibroblasts(iCAFs), as potential molecular markers and therapeutic targets for bladder cancer. Methods We examined the gene expression profiles in the TCGA and GEO datasets to reveal the potential association of CXCL12 with the carcinogenesis and prognosis of bladder cancer. Methylation analysis of CXCL12 was performed using the UALCAN and MethSurv databases. The MCP-COUNTER, ESTIMATE, and TIDE algorithms were applied to estimate the TME components and predict immunotherapy responsiveness. An iCAFs signature was constructed using the ssGSEA algorithm. Bioinformatics analysis results were validated through immunohistochemistry of clinical samples. IMvigor210 cohort was used to validate bioinformatic predictions of therapeutic responsiveness to immune checkpoint inhibitors Results Our analysis revealed the potential association between aberrant promoter methylation of CXCL12 and bladder cancer carcinogenesis. CpG sites methylation of the CXCL12 gene body was associated with bladder cancer prognosis. Moreover, the expression level of CXCL12 exhibited a significant correlation with patients' pathological features and prognosis. Through gene enrichment analysis, CXCL12 was demonstrated to be associated with immune modulation and tumor microenvironment remodeling. The MCP-COUNTER and ESTIMATE algorithms verified significant correlations between CXCL12 and TME components, particularly CAFs, macrophages, and T cells. The TIDE algorithm provided evidence that T-cell clearance and dysfunction were more pronounced in bladder cancers characterized by high CXCL12 expression and high iCAFs scores, contributing to inferior responsiveness to ICB therapy. Patients who expressed high CXCL12 levels and had high iCAFs scores were likely to have less frequent FGFR3 mutation and a stromal-rich molecular subtype. Immunohistochemistry revealed that the close association of CXCL12 with iCAFs in bladder cancer potentially influenced the intratumoral infiltration of CD8 + T cells. CXCL12 expression in MIBC was increased significantly in NMIBC, which supports the bioinformatics analysis results. The IMvigor210 cohort confirmed the iCAFs score to be significantly associated with the responsiveness to immune checkpoint blockade therapy. Conclusions This work explores carcinogenesis and cancer-promoting roles of CXCL12 in bladder cancer. As a specific marker gene of iCAFs, CXCL12 potentially promotes bladder cancer progression by regulating the tumor microenvironment. Further exploration of the association between CXCL12 and iCAFs may unravel potential therapeutic targets for bladder precision medicine and improve the responsiveness of immune checkpoint blockade therapy.

Luhan Xie ◽  
Qingqing Zhang ◽  
Jun Mao ◽  
Jun Zhang ◽  
Lianhong Li

In recent years, long non-coding RNAs (lncRNAs) have been demonstrated to be associated with many physiological and pathological processes in cardiac. Recent studies have shown that lncRNAs are expressed dynamically in cardiovascular diseases and participate in regulation through a variety of molecular mechanisms, which have become a critical part of the epigenetic and transcriptional regulatory pathways in heart development, as well as the initiation and progress of myocardial infarction. In this review, we summarized some current research about the roles of lncRNAs in heart development and myocardial infarction, with the emphasis on molecular mechanisms of pathological responses, and highlighted their functions in the secondary changes of myocardial infarction. We also discussed the possibility of lncRNAs as novel diagnostic biomarkers and potential therapeutic targets for myocardial infarction.

2021 ◽  
Vol 9 (1) ◽  
Paula Marazuela ◽  
Montse Solé ◽  
Anna Bonaterra-Pastra ◽  
Jesús Pizarro ◽  
Jessica Camacho ◽  

AbstractBrain accumulation of amyloid-beta (Aβ) is a crucial feature in Alzheimer´s disease (AD) and cerebral amyloid angiopathy (CAA), although the pathophysiological relationship between these diseases remains unclear. Numerous proteins are associated with Aβ deposited in parenchymal plaques and/or cerebral vessels. We hypothesized that the study of these proteins would increase our understanding of the overlap and biological differences between these two pathologies and may yield new diagnostic tools and specific therapeutic targets. We used a laser capture microdissection approach combined with mass spectrometry in the APP23 transgenic mouse model of cerebral-β-amyloidosis to specifically identify vascular Aβ-associated proteins. We focused on one of the main proteins detected in the Aβ-affected cerebrovasculature: MFG-E8 (milk fat globule-EGF factor 8), also known as lactadherin. We first validated the presence of MFG-E8 in mouse and human brains. Immunofluorescence and immunoblotting studies revealed that MFG-E8 brain levels were higher in APP23 mice than in WT mice. Furthermore, MFG-E8 was strongly detected in Aβ-positive vessels in human postmortem CAA brains, whereas MFG-E8 was not present in parenchymal Aβ deposits. Levels of MFG-E8 were additionally analysed in serum and cerebrospinal fluid (CSF) from patients diagnosed with CAA, patients with AD and control subjects. Whereas no differences were found in MFG-E8 serum levels between groups, MFG-E8 concentration was significantly lower in the CSF of CAA patients compared to controls and AD patients. Finally, in human vascular smooth muscle cells MFG-E8 was protective against the toxic effects of the treatment with the Aβ40 peptide containing the Dutch mutation. In summary, our study shows that MFG-E8 is highly associated with CAA pathology and highlights MFG-E8 as a new CSF biomarker that could potentially be used to differentiate cerebrovascular Aβ pathology from parenchymal Aβ deposition.

2021 ◽  
Vol 13 ◽  
Md. Mahiuddin Ahmed ◽  
Noah R. Johnson ◽  
Timothy D. Boyd ◽  
Christina Coughlan ◽  
Heidi J. Chial ◽  

Innate immune system activation and inflammation are associated with and may contribute to clinical outcomes in people with Down syndrome (DS), neurodegenerative diseases such as Alzheimer’s disease (AD), and normal aging. In addition to serving as potential diagnostic biomarkers, innate immune system activation and inflammation may play a contributing or causal role in these conditions, leading to the hypothesis that effective therapies should seek to dampen their effects. However, recent intervention studies with the innate immune system activator granulocyte-macrophage colony-stimulating factor (GM-CSF) in animal models of DS, AD, and normal aging, and in an AD clinical trial suggest that activating the innate immune system and inflammation may instead be therapeutic. We consider evidence that DS, AD, and normal aging are accompanied by innate immune system activation and inflammation and discuss whether and when during the disease process it may be therapeutically beneficial to suppress or promote such activation.

2021 ◽  
pp. candisc.1851.2020
Shan Lin ◽  
Clement Larrue ◽  
Nastassja K Scheidegger ◽  
Bo Kyung A. Seong ◽  
Neekesh V Dharia ◽  

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