Therapeutic Approaches
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2021 ◽  
Michael Martin Orlich ◽  
Rodrigo Diéguez-Hurtado ◽  
Regine Muehlfriedel ◽  
Vithiyanjali Sothilingam ◽  
Hartwig Wolburg ◽  

Rationale: Pericytes (PCs) and vascular smooth muscle cells (vSMCs), collectively known as mural cells(MCs), are recruited through PDGFB-PDGFRB signaling. MCs are essential for vascular integrity, and their loss has been associated with numerous diseases. Most of this knowledge is based on studies in which MCs are insufficiently recruited or fully absent upon inducible ablation. In contrast, little is known about the physiological consequences that result from impairment of specific MC functions. Objective: Here, we characterize the role of the transcription factor serum response factor (SRF) in MCs and study its function in developmental and pathological contexts. Methods and Results: We generated a mouse model of MC-specific inducible Srf gene deletion and studied its consequences during retinal angiogenesis. By postnatal day (P)6, PCs lacking SRF were morphologically abnormal and failed to properly co-migrate with angiogenic sprouts. As a consequence, PC-deficient vessels at the retinal sprouting front became dilated and leaky. By P12, also the vSMCs had lost SRF, which coincided with the formation of pathological arteriovenous (AV) shunts. Mechanistically, we show that PDGFB-dependent SRF activation is mediated via MRTF co-factors. We further show that MRTF-SRF signaling promotes pathological PC activation during ischemic retinopathy. RNA-sequencing, immunohistology, in vivo live imaging and in vitro experiments demonstrated that SRF regulates expression of contractile SMC proteins essential to maintain the vascular tone. Conclusions: SRF is crucial for distinct functions in PCs and vSMCs. SRF directs PC migration downstream of PDGFRB signaling and mediates pathological PC activation during ischemic retinopathy. In vSMCs, SRF is essential for expression of the contractile machinery, and its deletion triggers formation of AV shunts. These essential roles in physiological and pathological contexts provide a rational for novel therapeutic approaches through targeting SRF activity in MCs.

2021 ◽  
Vol 12 (1) ◽  
Limei Wu ◽  
Srinivas Chatla ◽  
Qiqi Lin ◽  
Fabliha Ahmed Chowdhury ◽  
Werner Geldenhuys ◽  

AbstractChemoresistance posts a major hurdle for treatment of acute leukemia. There is increasing evidence that prolonged and intensive chemotherapy often fails to eradicate leukemic stem cells, which are protected by the bone marrow niche and can induce relapse. Thus, new therapeutic approaches to overcome chemoresistance are urgently needed. By conducting an ex vivo small molecule screen, here we have identified Quinacrine (QC) as a sensitizer for Cytarabine (AraC) in treating acute lymphoblastic leukemia (ALL). We show that QC enhances AraC-mediated killing of ALL cells, and subsequently abrogates AraC resistance both in vitro and in an ALL-xenograft model. However, while combo AraC+QC treatment prolongs the survival of primary transplanted recipients, the combination exhibits limited efficacy in secondary transplanted recipients, consistent with the survival of niche-protected leukemia stem cells. Introduction of Cdc42 Activity Specific Inhibitor, CASIN, enhances the eradication of ALL leukemia stem cells by AraC+QC and prolongs the survival of both primary and secondary transplanted recipients without affecting normal long-term human hematopoiesis. Together, our findings identify a small-molecule regimen that sensitizes AraC-mediated leukemia eradication and provide a potential therapeutic approach for better ALL treatment.

2021 ◽  
Vol 12 (1) ◽  
Anita Rogic ◽  
Ila Pant ◽  
Luca Grumolato ◽  
Ruben Fernandez-Rodriguez ◽  
Andrew Edwards ◽  

AbstractInflammatory Breast Cancer (IBC) is a highly aggressive malignancy with distinct clinical and histopathological features whose molecular basis is unresolved. Here we describe a human IBC cell line, A3250, that recapitulates key IBC features in a mouse xenograft model, including skin erythema, diffuse tumor growth, dermal lymphatic invasion, and extensive metastases. A3250 cells express very high levels of the CCL2 chemokine and induce tumors enriched in macrophages. CCL2 knockdown leads to a striking reduction in macrophage densities, tumor proliferation, skin erythema, and metastasis. These results establish IBC-derived CCL2 as a key factor driving macrophage expansion, and indirectly tumor growth, with transcriptomic analysis demonstrating the activation of multiple inflammatory pathways. Finally, primary human IBCs exhibit macrophage infiltration and an enriched macrophage RNA signature. Thus, this human IBC model provides insight into the distinctive biology of IBC, and highlights potential therapeutic approaches to this deadly disease.

Maria Borrello ◽  
Derek Mann

Chronic liver diseases comprises a broad spectrum of burdensome diseases that still lack effective pharmacological therapies. Our research group focuses on Fibrosis which is a major precursor of liver cirrhosis. Fibrosis consists in a progressive disturbance of liver sinusoidal architecture characterised by connective tissue deposition as a reparative response to tissue injury. Multifactorial events and several types of cells, participate in fibrosis initiation and progression and the process still needs to be completely understood. The development of experimental models of liver fibrosis alongside the identification of critical factors progressing fibrosis to cirrhosis will facilitate the development of more effective therapeutic approaches for such condition. This review provides an overlook of the main process leading to hepatic fibrosis and therapeutic approaches that have emerged from a deep knowledge of the molecular regulation of fibrogenesis in the liver.

2021 ◽  
Vol 6 (1) ◽  
Yun-yu Zhang ◽  
Bo-tao Ning

AbstractSepsis is defined as life-threatening organ dysfunction caused by dysregulated host systemic inflammatory and immune response to infection. Over decades, advanced understanding of host–microorganism interaction has gradually unmasked the genuine nature of sepsis, guiding toward new definition and novel therapeutic approaches. Diverse clinical manifestations and outcomes among infectious patients have suggested the heterogeneity of immunopathology, while systemic inflammatory responses and deteriorating organ function observed in critically ill patients imply the extensively hyperactivated cascades by the host defense system. From focusing on microorganism pathogenicity, research interests have turned toward the molecular basis of host responses. Though progress has been made regarding recognition and management of clinical sepsis, incidence and mortality rate remain high. Furthermore, clinical trials of therapeutics have failed to obtain promising results. As far as we know, there was no systematic review addressing sepsis-related molecular signaling pathways and intervention therapy in literature. Increasing studies have succeeded to confirm novel functions of involved signaling pathways and comment on efficacy of intervention therapies amid sepsis. However, few of these studies attempt to elucidate the underlining mechanism in progression of sepsis, while other failed to integrate preliminary findings and describe in a broader view. This review focuses on the important signaling pathways, potential molecular mechanism, and pathway-associated therapy in sepsis. Host-derived molecules interacting with activated cells possess pivotal role for sepsis pathogenesis by dynamic regulation of signaling pathways. Cross-talk and functions of these molecules are also discussed in detail. Lastly, potential novel therapeutic strategies precisely targeting on signaling pathways and molecules are mentioned.

2021 ◽  
Atsushi Fujimoto ◽  
Catherine Elorette ◽  
J Megan Fredericks ◽  
Satoka H Fujimoto ◽  
Lazar Fleysher ◽  

Background: Virally-mediated chemogenetic techniques hold the promise of circuit-specific neuromodulation for human brain disorders. Their protracted development in primates and issues related to the specificity of the actuator drugs has significantly slowed their implementation. Here we took a multi-disciplinary approach to assessing the translational appropriateness of a newly identified actuator drug, deschloroclozapine (DCZ). Methods: Resting-state functional MRI (rs-fMRI) data was acquired from seven rhesus macaques (6 males and 1 female) after administration of either vehicle, 0.1 or 0.3 mg/kg DCZ, the latter of which produce 80% and near 100% chemogenetic receptor occupancy, respectively. Seed-based comparative-connectome analysis and independent component analysis assessed dose dependent neural impact. Two subsets of subjects were tested on socio-emotional tasks (N = 4), and a probabilistic learning task (N = 3), assessing DCZ's impact on unconditioned and conditioned affective responses, respectively. Results: Neither vehicle nor 0.1 mg/kg DCZ changed overall functional connectivity, affective responses, or reaction times in the learning task. 0.3 mg/kg DCZ increased functional connectivity, particularly in frontal regions, and increased reaction times in the learning task. Notably, there was a positive correlation between changes in overall functional connectivity and reaction time. Conclusions: These experiments show the utility of rs-fMRI for in-vivo drug screening and benchmarking. We found that low dose DCZ does not alter brain function or affective behavior. However, higher doses of DCZ impacts frontal connectivity and is associated with deficits in task execution. Implementation of these methods will accelerate the development of chemogenetic in primates for research and therapeutic approaches.

Marta Moya ◽  
Leticia López-Valencia ◽  
Borja García-Bueno ◽  
Laura Orio

Wernicke-Korsakoff syndrome (WKS) is induced by thiamine deficiency (TD) and mainly related to alcohol consumption. Frontal cortex dysfunction has been associated to impulsivity and disinhibition in WKS patients. The pathophysiology involves oxidative stress, excitotoxicity and inflammatory responses leading to neuronal death, but the relative contributions of each factor (alcohol and TD, isolate or in interaction) to these phenomena are still poorly understood. A rat model was used by forced consumption of 20% (w/v) alcohol for 9 months (CA), TD hit (TD diet + pyrithiamine 0.25 mg/kg, i.p. daily injections the last 12 days of experimentation; TDD), and both combined treatments (CA+TDD). Motor and cognitive performance and cortical damage were examined. CA caused hyperlocomotion as a possible sensitization of ethanol-induced excitatory effects and recognition memory deficits. In addition, CA+TDD animals showed a disinhibited-like behavior, which appears to be dependent on TDD. Also, combined treatment led to more pronounced alterations in nitrosative stress, lipid peroxidation, apoptosis and cell damage markers. Correlations between injury signals and disinhibition suggest that CA+TDD disrupts behaviors dependent on the frontal cortex. Our study sheds light on the potential disease-specific mechanisms, reinforcing the need for neuroprotective therapeutic approaches along with preventive treatments for the nutritional deficiency in WKS.

Biomedicines ◽  
2021 ◽  
Vol 9 (12) ◽  
pp. 1754
Joana Sofia Correia ◽  
Andreia Neves-Carvalho ◽  
Bárbara Mendes-Pinheiro ◽  
Joel Pires ◽  
Fábio Gabriel Teixeira ◽  

The low regeneration potential of the central nervous system (CNS) represents a challenge for the development of new therapeutic strategies for neurodegenerative diseases, including spinocerebellar ataxias. Spinocerebellar ataxia type 3 (SCA3)—or Machado–Joseph disease (MJD)—is the most common dominant ataxia, being mainly characterized by motor deficits; however, SCA3/MJD has a complex and heterogeneous pathophysiology, involving many CNS brain regions, contributing to the lack of effective therapies. Mesenchymal stem cells (MSCs) have been proposed as a potential therapeutic tool for CNS disorders. Beyond their differentiation potential, MSCs secrete a broad range of neuroregulatory factors that can promote relevant neuroprotective and immunomodulatory actions in different pathophysiological contexts. The objective of this work was to study the effects of (1) human MSC transplantation and (2) human MSC secretome (CM) administration on disease progression in vivo, using the CMVMJD135 mouse model of SCA3/MJD. Our results showed that a single CM administration was more beneficial than MSC transplantation—particularly in the cerebellum and basal ganglia—while no motor improvement was observed when these cell-based therapeutic approaches were applied in the spinal cord. However, the effects observed were mild and transient, suggesting that continuous or repeated administration would be needed, which should be further tested.

Kim M. Pabst ◽  
Thomas Decker ◽  
David Kersting ◽  
Timo Bartel ◽  
Miriam Sraieb ◽  

Background: A variety of therapeutic approaches are employed to treat patients suffering from breast cancer. Likewise, a broad spectrum of imaging ligands has been introduced for non-invasive PET/CT imaging to enable comprehensive tumor characterization and more accurate response evaluation. Summary: In recent years, novel radioactively labelled ligands have been developed for PET/CT imaging in metastatic breast cancer. One promising tracer is [18F]fluoroestradiol, which was recently approved by the Food and Drug Administration. It can be used for a whole-body assessment of estrogen receptor status. Another radionuclide currently under development is [68Ga]Ga-FAPI. In addition to new radionuclides, the field of application for existing tracers like [18F]fluorodeoxyglucose (FDG) were broadened. It has been shown that an early therapeutic response to various therapies can be detected by [18F]FDG PET/CT, which leads to early treatment optimization. Key Message: In this review, we highlighted new tracers and applications of PET/CT imaging as well as therapeutic approaches in patients with advanced breast cancer. Furthermore, we give an outlook on the application of artificial intelligence, immunoPET and liquid biopsy.

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