scholarly journals Dickkopf-1 Inhibition Reactivates Wnt/β-Catenin Signaling in Rhabdomyosarcoma, Induces Myogenic Markers In Vitro and Impairs Tumor Cell Survival In Vivo

2021 ◽  
Vol 22 (23) ◽  
pp. 12921
Author(s):  
Irina Giralt ◽  
Gabriel Gallo-Oller ◽  
Natalia Navarro ◽  
Patricia Zarzosa ◽  
Guillem Pons ◽  
...  
Keyword(s):  
Therapeutic Potential ◽  
Positive Effects ◽  
Novel Therapeutic Strategies ◽  
And Function ◽  
Myogenic Markers ◽  
First Time ◽  
Dickkopf 1 ◽  
Proliferation And Invasion

The Wnt/β-catenin signaling pathway plays a pivotal role during embryogenesis and its deregulation is a key mechanism in the origin and progression of several tumors. Wnt antagonists have been described as key modulators of Wnt/β-catenin signaling in cancer, with Dickkopf-1 (DKK-1) being the most studied member of the DKK family. Although the therapeutic potential of DKK-1 inhibition has been evaluated in several diseases and malignancies, little is known in pediatric tumors. Only a few works have studied the genetic inhibition and function of DKK-1 in rhabdomyosarcoma. Here, for the first time, we report the analysis of the therapeutic potential of DKK-1 pharmaceutical inhibition in rhabdomyosarcoma, the most common soft tissue sarcoma in children. We performed DKK-1 inhibition via shRNA technology and via the chemical inhibitor WAY-2626211. Its inhibition led to β-catenin activation and the modulation of focal adhesion kinase (FAK), with positive effects on in vitro expression of myogenic markers and a reduction in proliferation and invasion. In addition, WAY-262611 was able to impair survival of tumor cells in vivo. Therefore, DKK-1 could constitute a molecular target, which could lead to novel therapeutic strategies in RMS, especially in those patients with high DKK-1 expression.

scholarly journals Targeting necroptosis as therapeutic potential in chronic myocardial infarction

2021 ◽  
Vol 28 (1) ◽  
Author(s):  
Chanon Piamsiri ◽  
Chayodom Maneechote ◽  
Natthaphat Siri-Angkul ◽  
Siriporn C. Chattipakorn ◽  
Nipon Chattipakorn
Keyword(s):  
Myocardial Infarction ◽  
Therapeutic Potential ◽  
Coronary Perfusion ◽  
Beneficial Effects ◽  
Cell Death Pathways ◽  
Threatening Condition ◽  
Underlying Mechanisms ◽  
Novel Therapeutic Strategies

AbstractCardiovascular diseases (CVDs) are considered the predominant cause of morbidity and mortality globally. Of these, myocardial infarction (MI) is the most common cause of CVD mortality. MI is a life-threatening condition which occurs when coronary perfusion is interrupted leading to cardiomyocyte death. Subsequent to MI, consequences include adverse cardiac remodeling and cardiac dysfunction mainly contribute to the development of heart failure (HF). It has been shown that loss of functional cardiomyocytes in MI-induced HF are associated with several cell death pathways, in particular necroptosis. Although the entire mechanism underlying necroptosis in MI progression is still not widely recognized, some recent studies have reported beneficial effects of necroptosis inhibitors on cell viability and cardiac function in chronic MI models. Therefore, extensive investigation into the necroptosis signaling pathway is indicated for further study. This article comprehensively reviews the context of the underlying mechanisms of necroptosis in chronic MI-induced HF in in vitro, in vivo and clinical studies. These findings could inform ways of developing novel therapeutic strategies to improve the clinical outcomes in MI patients from this point forward.

scholarly journals Multiplexed RNAi therapy against brain tumor-initiating cells via lipopolymeric nanoparticle infusion delays glioblastoma progression

2017 ◽  
Vol 114 (30) ◽  
pp. E6147-E6156 ◽  
Author(s):  
Dou Yu ◽  
Omar F. Khan ◽  
Mario L. Suvà ◽  
Biqin Dong ◽  
Wojciech K. Panek ◽  
...  
Keyword(s):  
Brain Tumor ◽  
Therapeutic Potential ◽  
Therapy Resistance ◽  
Tumor Initiating Cells ◽  
Convection Enhanced Delivery ◽  
Individual Gene ◽  
Brain Tumor Initiating Cells ◽  
Novel Therapeutic Strategies

Brain tumor-initiating cells (BTICs) have been identified as key contributors to therapy resistance, recurrence, and progression of diffuse gliomas, particularly glioblastoma (GBM). BTICs are elusive therapeutic targets that reside across the blood–brain barrier, underscoring the urgent need to develop novel therapeutic strategies. Additionally, intratumoral heterogeneity and adaptations to therapeutic pressure by BTICs impede the discovery of effective anti-BTIC therapies and limit the efficacy of individual gene targeting. Recent discoveries in the genetic and epigenetic determinants of BTIC tumorigenesis offer novel opportunities for RNAi-mediated targeting of BTICs. Here we show that BTIC growth arrest in vitro and in vivo is accomplished via concurrent siRNA knockdown of four transcription factors (SOX2, OLIG2, SALL2, and POU3F2) that drive the proneural BTIC phenotype delivered by multiplexed siRNA encapsulation in the lipopolymeric nanoparticle 7C1. Importantly, we demonstrate that 7C1 nano-encapsulation of multiplexed RNAi is a viable BTIC-targeting strategy when delivered directly in vivo in an established mouse brain tumor. Therapeutic potential was most evident via a convection-enhanced delivery method, which shows significant extension of median survival in two patient-derived BTIC xenograft mouse models of GBM. Our study suggests that there is potential advantage in multiplexed targeting strategies for BTICs and establishes a flexible nonviral gene therapy platform with the capacity to channel multiplexed RNAi schemes to address the challenges posed by tumor heterogeneity.

scholarly journals The Challenging Melanoma Landscape: From Early Drug Discovery to Clinical Approval

Cells ◽  
2021 ◽  
Vol 10 (11) ◽  
pp. 3088
Author(s):  
Mariana Matias ◽  
Jacinta O. Pinho ◽  
Maria João Penetra ◽  
Gonçalo Campos ◽  
Catarina Pinto Reis ◽  
...  
Keyword(s):  
Therapeutic Potential ◽  
Drug Evaluation ◽  
Three Dimensional ◽  
Experimental Models ◽  
In Vivo Studies ◽  
Murine Models ◽  
In Vivo Experiments ◽  
Novel Therapeutic Strategies

Melanoma is recognized as the most dangerous type of skin cancer, with high mortality and resistance to currently used treatments. To overcome the limitations of the available therapeutic options, the discovery and development of new, more effective, and safer therapies is required. In this review, the different research steps involved in the process of antimelanoma drug evaluation and selection are explored, including information regarding in silico, in vitro, and in vivo experiments, as well as clinical trial phases. Details are given about the most used cell lines and assays to perform both two- and three-dimensional in vitro screening of drug candidates towards melanoma. For in vivo studies, murine models are, undoubtedly, the most widely used for assessing the therapeutic potential of new compounds and to study the underlying mechanisms of action. Here, the main melanoma murine models are described as well as other animal species. A section is dedicated to ongoing clinical studies, demonstrating the wide interest and successful efforts devoted to melanoma therapy, in particular at advanced stages of the disease, and a final section includes some considerations regarding approval for marketing by regulatory agencies. Overall, considerable commitment is being directed to the continuous development of optimized experimental models, important for the understanding of melanoma biology and for the evaluation and validation of novel therapeutic strategies.

scholarly journals Intrinsic Abnormalities of Cystic Fibrosis Airway Connective Tissue Revealed by an In Vitro 3D Stromal Model

Cells ◽  
2020 ◽  
Vol 9 (6) ◽  
pp. 1371
Author(s):  
Claudia Mazio ◽  
Laura S. Scognamiglio ◽  
Rossella De Cegli ◽  
Luis J. V. Galietta ◽  
Diego Di Bernardo ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Inflammatory Response ◽  
Bacterial Infections ◽  
Inflammatory Cells ◽  
Lung Model ◽  
Lung Dysfunction ◽  
Novel Therapeutic Strategies ◽  
And Function

Cystic fibrosis is characterized by lung dysfunction involving mucus hypersecretion, bacterial infections, and inflammatory response. Inflammation triggers pro-fibrotic signals that compromise lung structure and function. At present, several in vitro cystic fibrosis models have been developed to study epithelial dysfunction but none of these focuses on stromal alterations. Here we show a new cystic fibrosis 3D stromal lung model made up of primary fibroblasts embedded in their own extracellular matrix and investigate its morphological and transcriptomic features. Cystic fibrosis fibroblasts showed a high proliferation rate and produced an abundant and chaotic matrix with increased protein content and elastic modulus. More interesting, they had enhanced pro-fibrotic markers and genes involved in epithelial function and inflammatory response. In conclusion, our study reveals that cystic fibrosis fibroblasts maintain in vitro an activated pro-fibrotic state. This abnormality may play in vivo a role in the modulation of epithelial and inflammatory cell behavior and lung remodeling. We argue that the proposed bioengineered model may provide new insights on epithelial/stromal/inflammatory cells crosstalk in cystic fibrosis, paving the way for novel therapeutic strategies.

scholarly journals Knockdown of SPOCK1 Inhibits the Proliferation and Invasion in Colorectal Cancer Cells by Suppressing the PI3K/Akt Pathway

2016 ◽  
Vol 24 (6) ◽  
pp. 437-445 ◽  
Author(s):  
Ping Zhao ◽  
Hai-Tao Guan ◽  
Zhi-Jun Dai ◽  
Yu-Guang Ma ◽  
Xiao-Xu Liu ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Potential Therapeutic Target ◽  
Colorectal Cancer Cells ◽  
First Time ◽  
Proliferation In Vitro ◽  
Proliferation And Invasion ◽  
Hct116 Cells

Sparc/osteonectin, cwcv, and kazal-like domains proteoglycan (testican) 1 (SPOCK1), known as testican-1, were found to be involved in the development and progression of tumors. However, in colorectal cancer (CRC), the expression pattern of SPOCK1 and its functional role remain poorly investigated. In the present study, we explored the role of SPOCK1 in CRC. Our results demonstrated that SPOCK1 is overexpressed in CRC cell lines. SPOCK1 silencing significantly inhibited the proliferation in vitro and the tumor growth in vivo. Furthermore, SPOCK1 silencing significantly attenuated the migration/invasion by reversing the EMT process in CRC cells. Finally, knockdown of SPOCK1 obviously decreased the protein expression levels of p-PI3K and p-Akt in HCT116 cells. In total, our study demonstrated for the first time that knockdown of SPOCK1 inhibits the proliferation and invasion in CRC cells, possibly through the PI3K/Akt signaling pathway. Therefore, SPOCK1 may be a potential therapeutic target for the treatment of CRC.

Abstract P183: Chemokine-like Receptor 1 Mediates the Vasoconstrictor Actions of Chemerin in vitro and in vivo

Hypertension ◽  
2016 ◽  
Vol 68 (suppl_1) ◽  
Author(s):  
Amanda Kennedy ◽  
Peiran Yang ◽  
Cai Read ◽  
Rhoda Kuc ◽  
Janet Maguire ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Smooth Muscle ◽  
Therapeutic Potential ◽  
Plasma Concentrations ◽  
Resistance Arteries ◽  
Resistance Vessels ◽  
Increased Risk ◽  
First Time

Hypertensive patients have significantly higher plasma concentrations of the adipokine chemerin compared with healthy controls, and levels of chemerin positively correlate with systolic and diastolic blood pressure. Chemerin activates chemokine-like receptor 1 (CMKLR1 or ChemR23) but it also activates the ‘orphan’ G protein-coupled receptor 1 (GPR1) which has been linked with hypertension. It is therefore crucial to determine whether one or both of these receptors mediate the constrictor actions of chemerin in the vasculature in order to identify a potential new therapeutic target for the treatment of hypertension. Using immunohistochemistry and molecular biology, we localized chemerin to the endothelium, smooth muscle and adventitia, and CMKLR1 and GPR1 to the smooth muscle in human conduit and resistance vessels. Chemerin activated β-arrestin via heterologously expressed receptors GPR1 (pD 2 =9.30±0.05) and CMKLR1 (pD 2 =9.23±0.03) with comparable potency. CCX832, a small molecule antagonist, was fully characterized as highly selective for CMKLR1, with no effect on GPR1 in binding or cell-based functional assays. The C-terminal fragment of chemerin, C9 (chemerin149-157) contracted human saphenous vein (pD 2 =7.30±0.31) and resistance arteries (pD 2 =6.23±0.16), and caused a significant increase in blood pressure in rats in vivo (0.2 μmol, 9.1±1.0 mmHg). These actions were blocked by CCX832, confirming for the first time that a single chemerin receptor, CMKLR1, mediates the constrictor response in humans and in vivo. Our data suggest that chemerin activation of CMKLR1 may contribute to elevated blood pressure; this in combination with the known roles of chemerin in metabolic syndrome and diabetes, could lead to increased risk of cardiovascular disease. This study provides proof of principle that the therapeutic potential of selective CMKLR1 antagonists should be explored.

Rapid recovery from T lymphopenia by CD28 superagonist therapy

Blood ◽  
2003 ◽  
Vol 102 (5) ◽  
pp. 1764-1770 ◽  
Author(s):  
Karin Elflein ◽  
Marta Rodriguez-Palmero ◽  
Thomas Kerkau ◽  
Thomas Hünig
Keyword(s):  
T Cells ◽  
T Cell ◽  
Opportunistic Infections ◽  
Therapeutic Potential ◽  
Cell Receptor ◽  
Cancer Therapies ◽  
Repertoire Diversity ◽  
And Function

AbstractSlow recovery of T-cell numbers and function contributes to the high incidence of life-threatening infections after cytotoxic cancer therapies. We have tested the therapeutic potential of a novel class of superagonistic CD28–specific antibodies that induce polyclonal T-cell proliferation without T-cell receptor engagement in an experimental rat model of T lymphopenia. We show that in lethally irradiated, bone marrow–reconstituted hosts, CD28 superagonist is able to dramatically accelerate repopulation by a small inoculum of mature, allotype-marked T cells. CD28-driven recovery of CD4 cells was superior to that of CD8 T cells. CD28 superagonist– expanded CD4 T cells had maintained repertoire diversity and were functional both in vitro and in vivo, suggesting that treatment with a human CD28–specific superagonist will protect T-lymphopenic patients from opportunistic infections.

scholarly journals The lysophosphatidylserine receptor GPR174 constrains regulatory T cell development and function

2015 ◽  
Vol 212 (7) ◽  
pp. 1011-1020 ◽  
Author(s):  
Michael J. Barnes ◽  
Chien-Ming Li ◽  
Ying Xu ◽  
Jinping An ◽  
Yong Huang ◽  
...  
Keyword(s):  
T Cell ◽  
Regulatory T Cell ◽  
Therapeutic Potential ◽  
Lymphoid Organ ◽  
Cell Generation ◽  
Autoimmune Encephalomyelitis ◽  
Cell Accumulation ◽  
And Function

Regulatory T cell (T reg cell) numbers and activities are tightly calibrated to maintain immune homeostasis, but the mechanisms involved are incompletely defined. Here, we report that the lysophosphatidylserine (LysoPS) receptor GPR174 is abundantly expressed in developing and mature T reg cells. In mice that lacked this X-linked gene, T reg cell generation in the thymus was intrinsically favored, and a higher fraction of peripheral T reg cells expressed CD103. LysoPS could act in vitro via GPR174 to suppress T cell proliferation and T reg cell generation. In vivo, LysoPS was detected in lymphoid organ and spinal cord tissues and was abundant in the colon. Gpr174−/Y mice were less susceptible to experimental autoimmune encephalomyelitis than wild-type mice, and GPR174 deficiency in T reg cells contributed to this phenotype. This study provides evidence that a bioactive lipid, LysoPS, negatively influences T reg cell accumulation and activity through GPR174. As such, GPR174 antagonists might have therapeutic potential for promoting immune regulation in the context of autoimmune disease.

scholarly journals Autophagy is activated to protect against podocyte injury in adriamycin-induced nephropathy

2017 ◽  
Vol 313 (1) ◽  
pp. F74-F84 ◽  
Author(s):  
Mixuan Yi ◽  
Lei Zhang ◽  
Yu Liu ◽  
Man J. Livingston ◽  
Jian-Kang Chen ◽  
...  
Keyword(s):  
Therapeutic Potential ◽  
Glomerular Disease ◽  
Podocyte Injury ◽  
Knockout Mouse Model ◽  
Filtration Barrier ◽  
Induced Apoptosis ◽  
And Function

Podocytes are highly differentiated epithelial cells wrapping glomerular capillaries to form the filtration barrier in kidneys. As such, podocyte injury or dysfunction is a critical pathogenic event in glomerular disease. Autophagy plays an important role in the maintenance of the homeostasis and function of podocytes. However, it is less clear whether and how autophagy contributes to podocyte injury in glomerular disease. Here, we have examined the role of autophagy in adriamycin-induced nephropathy, a classic model of glomerular disease. We show that autophagy was induced by adriamycin in cultured podocytes in vitro and in podocytes in mice. In cultured podocytes, activation of autophagy with rapamycin led to the suppression of adriamycin-induced apoptosis, whereas inhibition of autophagy with chloroquine enhanced podocyte apoptosis during adriamycin treatment. To determine the role of autophagy in vivo, we established an inducible podocyte-specific autophagy-related gene 7 knockout mouse model (Podo-Atg7-KO). Compared with wild-type littermates, Podo-Atg7-KO mice showed higher levels of podocyte injury, glomerulopathy, and proteinuria during adriamycin treatment. Together, these observations support an important role of autophagy in protecting podocytes under the pathological conditions of glomerular disease, suggesting the therapeutic potential of autophagy induction.

scholarly journals Furcellaran-Coated Microcapsules as Carriers of Cyprinus carpio Skin-Derived Antioxidant Hydrolysate: An In Vitro and In Vivo Study

Nutrients ◽  
2019 ◽  
Vol 11 (10) ◽  
pp. 2502 ◽  
Author(s):  
Joanna Tkaczewska ◽  
Ewelina Jamróz ◽  
Ewa Piątkowska ◽  
Barbara Borczak ◽  
Joanna Kapusta-Duch ◽  
...  
Keyword(s):  
Antioxidant Status ◽  
Wistar Rats ◽  
Therapeutic Potential ◽  
Antioxidant Properties ◽  
Significant Rise ◽  
Bioactive Peptide ◽  
Laboratory Animals ◽  
Positive Effects

Carp skin gelatine hydrolysate (CSGH) may be a possible bioactive peptide source, as promising antioxidant properties have been noted during in vivo testing. Hence, the present study focused on improving the bioavailability of the antioxidant peptides from CSGH and on the use of furcellaran (FUR), which can protect the biopeptides during digestion in the gastrointestinal tract. Therefore, in this study, microcapsules coated with furcellaran and containing CSGH cores were prepared. The structural properties of the sample were determined using FT-IR and SEM analysis. The antioxidant properties of hydrolysate, uncoated, and encapsulated samples were investigated. In vivo analysis included determination of its safety in an animal organism and evaluation of the lipid profile, antioxidant blood status, and mRNA expression of some genes involved in antioxidant status in Wistar rats. The results showed no adverse effects of microencapsulated protein hydrolysates in laboratory animals. Nonetheless, there was a statistically significant rise in the level of total antioxidant status blood serum among animals consuming CSGH and not inducing oxidative stress. This can be viewed as a promising indication of the positive effects of antioxidant properties tested in vivo. The process of CSGH microencapsulation in FUR cause a decrease in antioxidant hydrolysate activity, both in vitro, as well as in healthy Wistar rats. When considering the results of the presented diverse therapeutic potential, further research on CSGH being a potential bioactive peptide source used as a functional food or nutraceutical, but with a different microencapsulation coating, is encouraged.

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