scholarly journals New Therapeutic Targets for Hepatic Fibrosis in the Integrin Family, α8β1 and α11β1, Induced Specifically on Activated Stellate Cells

2021 ◽  
Vol 22 (23) ◽  
pp. 12794
Author(s):  
Yasuyuki Yokosaki ◽  
Norihisa Nishimichi
Keyword(s):  
Clinical Trial ◽  
Stellate Cells ◽  
Ligand Specificity ◽  
Central Target ◽  
The Road ◽  
Rgd Sequence ◽  
Cell Matrix ◽  
A Cell ◽  
Cell Type Specific ◽  
Integrin Family

A huge effort has been devoted to developing drugs targeting integrins over 30 years, because of the primary roles of integrins in the cell-matrix milieu. Five αv-containing integrins, in the 24 family members, have been a central target of fibrosis. Currently, a small molecule against αvβ1 is undergoing a clinical trial for NASH-associated fibrosis as a rare agent aiming at fibrogenesis. Latent TGFβ activation, a distinct talent of αv-integrins, has been intriguing as a therapeutic target. None of the αv-integrin inhibitors, however, has been in the clinical market. αv-integrins commonly recognize an Arg-Gly-Asp (RGD) sequence, and thus the pharmacophore of inhibitors for the 5-integrins is based on the same RGD structure. The RGD preference of the integrins, at the same time, dilutes ligand specificity, as the 5-integrins share ligands containing RGD sequence such as fibronectin. With the inherent little specificity in both drugs and targets, “disease specificity” has become less important for the inhibitors than blocking as many αv-integrins. In fact, an almighty inhibitor for αv-integrins, pan-αv, was in a clinical trial. On the contrary, approved integrin inhibitors are all specific to target integrins, which are expressed in a cell-type specific manner: αIIbβ3 on platelets, α4β1, α4β7 and αLβ2 on leukocytes. Herein, “disease specific” integrins would serve as attractive targets. α8β1 and α11β1 are selectively expressed in hepatic stellate cells (HSCs) and distinctively induced upon culture activation. The exceptional specificity to activated HSCs reflects a rather “pathology specific” nature of these new integrins. The monoclonal antibodies against α8β1 and α11β1 in preclinical examinations may illuminate the road to the first medical agents.

scholarly journals New Therapeutic Targets for Hepatic Fibrosis in the Integrin Family, α8β1 and α11β1, Induced Specifically on Activated Stellate Cells

2021 ◽  
Author(s):  
Yasuyuki Yokosaki ◽  
Norohisa Nishimichi
Keyword(s):  
Clinical Trial ◽  
Stellate Cells ◽  
Ligand Specificity ◽  
Central Target ◽  
The Road ◽  
Rgd Sequence ◽  
Cell Matrix ◽  
Cell Type Specific ◽  
Disease Specificity ◽  
Integrin Family

Huge effort has been devoted to developing drugs targeting integrins over 30 years, because of the primary roles of integrins in the cell-matrix milieu. Five αv-containing integrins, in the 24 family members, have been a central target of fibrosis. Currently, a small molecule against αvβ1 is undergoing a clinical trial for NASH-associated fibrosis as a rare reagent aiming at fibrogenesis. Latent TGFβ activation, a distinct talent of αv-integrins, has been intriguing as therapeutic target. None of the αv-integrin inhibitors, however, has been in the clinical market. αv-integrins commonly recognize an Arg-Gly-Asp (RGD) sequence, and thus the pharmacophore of inhibitors for the 5-integrins is based on the same RGD structure. The RGD preference of the integrins, at the same time, dilutes ligand specificity, as the 5-integrins share ligands containing RGD sequence such as fibronectin. With the inherent little specificity in both drugs and targets, “disease specificity” has become less important for the inhibitors than blocking as many αv-integrins. In fact, an almighty inhibitor for αv-integrins, pan-αv, was in a clinical trial. On the contrary, approved integrin inhibitors are all specific to target integrins, which are expressed in cell-type specific manner: αIIbβ3 on platelets, α4β1, α4β7 and αLβ2 on leukocytes. Herein, “disease specific” integrins would serve as attractive targets. α8β1 and α11β1 are selectively expressed in hepatic stellate cells (HSCs) and distinctively induced upon culture activation. The exceptional specificity to activated HSCs reflects rather “pathology specific” nature of these new integrins. The monoclonal antibodies against α8β1 and α11β1 in preclinical examinations may illuminate the road to the first medical reagents.

IFIH1-deficiency results in a cell-type specific alteration of autophagic activity in response to S. typhimurium

2017 ◽  
Vol 55 (05) ◽  
pp. e28-e56
Author(s):  
S Macheiner ◽  
R Gerner ◽  
A Pfister ◽  
A Moschen ◽  
H Tilg
Keyword(s):  
Cell Type ◽  
A Cell ◽  
Cell Type Specific ◽  
Autophagic Activity ◽  
Specific Alteration

Digital Technologies – Innovative Solutions for Agriculture

2020 ◽  
Vol 67 (1) ◽  
pp. 127-132
Author(s):  
Marina A. Nikitina ◽  
Dmitriy N. Osyanin ◽  
Irina V. Petrunina
Keyword(s):  
Farm Animals ◽  
High Tech ◽  
Mathematical Apparatus ◽  
Online Mode ◽  
Cell Matrix ◽  
Algorithmic Support ◽  
Quality Product ◽  
A Cell ◽  
Parametric Description ◽  
Animal Feeding

High-tech decision support systems based on the knowledge of experts in the field of animal feeding and a rigorous mathematical apparatus make it possible to increase the productivity of the animals and provide a high-quality product with the ability to trace the trophological chain from the field to the counter. (Research purpose) To identify methodological approaches for the development of algorithmic support and software for assessment and optimizing the animals diet. (Materials and Methods) The authors complied a structural-parametric model of a productive animal feeding in a cell matrix form. They represented the whole variety of existing known and unknown relationships between the factors of the farm animal state and the feeding ration characteristics. It was found that when forming a feeding ration, it was necessary to assess the degree of influence on productivity of not individual indicators, but its combination. (Results and discussion) The authors considered parametric descriptions of farm animals; diet with selected groups of indicators, characteristics and properties. It was stated that the parametric description of feeding contained a set of parameters taking into account at least 25 nutritional indicators. They presented a mathematical apparatus for evaluating and optimizing the feeding ration. It was determined that the automation of the process of calculating the daily ration of an animal allowed to change the diets depending on the availability of feed in the farm and their chemical composition in real time. The authors found out that an increase in the productivity of animals and poultry by 30-50 percent was possible due to balanced full-fledged feeding. (Conclusions) The authors showed a systematic approach to the development of software for evaluating and optimizing the animal feeding diet. It was revealed that a computer system in the online mode would help to find the best option for a feeding ration, taking into account multifactor and limitations.

scholarly journals A cell type‐specific expression map of NCoR1 and SMRT transcriptional co‐repressors in the mouse brain

2020 ◽  
Vol 528 (13) ◽  
pp. 2218-2238 ◽  
Author(s):  
Attilio Iemolo ◽  
Patricia Montilla‐Perez ◽  
I‐Chi Lai ◽  
Yinuo Meng ◽  
Syreeta Nolan ◽  
...  
Keyword(s):  
Mouse Brain ◽  
Cell Type ◽  
Specific Expression ◽  
Cell Type Specific Expression ◽  
A Cell ◽  
Cell Type Specific

scholarly journals Nanonet force microscopy for measuring forces in single smooth muscle cells of the human aorta

2017 ◽  
Vol 28 (14) ◽  
pp. 1894-1900 ◽  
Author(s):  
Alexander Hall ◽  
Patrick Chan ◽  
Kevin Sheets ◽  
Matthew Apperson ◽  
Christopher Delaughter ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
External Perturbation ◽  
Human Aorta ◽  
Cycle Times ◽  
Force Microscopy ◽  
Cell Matrix ◽  
Innovative Methods ◽  
A Cell ◽  
Inside Out

A number of innovative methods exist to measure cell–matrix adhesive forces, but they have yet to accurately describe and quantify the intricate interplay of a cell and its fibrous extracellular matrix (ECM). In cardiovascular pathologies, such as aortic aneurysm, new knowledge on the involvement of cell–matrix forces could lead to elucidation of disease mechanisms. To better understand this dynamics, we measured primary human aortic single smooth muscle cell (SMC) forces using nanonet force microscopy in both inside-out (I-O intrinsic contractility) and outside-in (O-I external perturbation) modes. For SMC populations, we measured the I-O and O-I forces to be 12.9 ± 1.0 and 57.9 ± 2.5 nN, respectively. Exposure of cells to oxidative stress conditions caused a force decrease of 57 and 48% in I-O and O-I modes, respectively, and an increase in migration rate by 2.5-fold. Finally, in O-I mode, we cyclically perturbed cells at constant strain of varying duration to simulate in vivo conditions of the cardiac cycle and found that I-O forces decrease with increasing duration and O-I forces decreased by half at shorter cycle times. Thus our findings highlight the need to study forces exerted and felt by cells simultaneously to comprehensively understand force modulation in cardiovascular disease.

scholarly journals Oversight and management of a cell therapy clinical trial network: Experience and lessons learned

2011 ◽  
Vol 32 (5) ◽  
pp. 614-619 ◽  
Author(s):  
Lemuel A. Moyé ◽  
Shelly L. Sayre ◽  
Lynette Westbrook ◽  
Beth C. Jorgenson ◽  
Eileen Handberg ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Cell Therapy ◽  
Lessons Learned ◽  
Trial Network ◽  
Clinical Trial Network ◽  
A Cell ◽  
Therapy Clinical Trial

scholarly journals Adhesive multiplicity in the interaction of embryonic fibroblasts and myoblasts with extracellular matrices.

1984 ◽  
Vol 99 (4) ◽  
pp. 1398-1404 ◽  
Author(s):  
C Decker ◽  
R Greggs ◽  
K Duggan ◽  
J Stubbs ◽  
A Horwitz
Keyword(s):  
Skeletal Muscle ◽  
Cardiac Muscle ◽  
Cardiac Fibroblasts ◽  
Cell Types ◽  
Extracellular Matrices ◽  
Common Denominator ◽  
Cell Matrix ◽  
Skeletal Myoblasts ◽  
A Cell ◽  
Cell Matrix Adhesion

Neff et al. (1982, J. Cell Biol., 95:654-666) have described a monoclonal antibody, CSAT, directed against a cell surface antigen that participates in the adhesion of skeletal muscle to extracellular matrices. We used the same antibody to compare and parse the determinants of adhesion and morphology on myogenic and fibrogenic cells. We report here that the antigen is present on skeletal and cardiac muscle and on tendon, skeletal, dermal, and cardiac fibroblasts; however, its contribution to their morphology and adhesion is different. The antibody produces large alterations in the morphology and adhesion of skeletal myoblasts and tendon fibroblasts; in contrast, its effects on the cardiac fibroblasts are not readily detected. The effects of CSAT on the other cell types, i.e., dermal and skeletal fibroblasts, cardiac muscle, 5-bromodeoxyuridine-treated skeletal muscle, lie between these extremes. The effects of CSAT on the skeletal myoblasts depends on the calcium concentration in the growth medium and on the culture age. We interpret these differential responses to CSAT as revealing differences in the adhesion of the various cells to extracellular matrices. This interpretation is supported by parallel studies using quantitative assays of cell-matrix adhesion. The likely origin of these adhesive differences is the progressive display of different kinds of adhesion-related molecules and their organizational complexes on increasingly adhesive cells. The antigen to which CSAT is directed is present on all of the above cells and thus appears to be a lowest common denominator of their adhesion to extracellular matrices.

Gene therapy can target mutations such as BRAF, which have been shown to make tumors more susceptible to autophagy suppression

2021 ◽  
Author(s):  
Moataz Dowaidar
Keyword(s):  
Signaling Pathways ◽  
Chemotherapy Resistance ◽  
Effective Strategy ◽  
Cell Type ◽  
Normal Cells ◽  
A Cell ◽  
Cell Type Specific ◽  
Catabolic Process ◽  
Specific Impact

Autophagy is a double-edged sword in cancer, and numerous aspects should be taken into account before deciding on the most effective strategy to target the process. The fact that several clinical studies are now ongoing does not mean that the patient group that may benefit from autophagy-targeting medicines has been identified. Autophagy inhibitors that are more potent and specialized, as well as autophagy indicators, are also desperately required. The fact that these inhibitors only work against tumors that rely on autophagy for survival (RAS mutants) makes it difficult to distinguish them from tumors that continue to develop even when autophagy is absent. Furthermore, mutations such as BRAF have been shown to make tumors more susceptible to autophagy suppression, suggesting that targeting such tumours may be a viable strategy for overcoming their chemotherapy resistance. In the meantime, we are unable to identify if autophagy regulation works in vivo or whether it selectively targets a disease while inflicting injury to other healthy organs and tissues. A cell-type-specific impact appears to be observed with such therapy. As a result, it is just as important to consider the differences between tumors that originate in different organs as it is to consider the signaling pathways that are similar across them. For a therapy or cure to be effective, the proposed intervention must be tailored to the specific needs of each patient.Over the last several years, a growing amount of data has implicated autophagy in a variety of disorders, including cancer. In normal cells, this catabolic process is also required for cell survival and homeostasis. Despite the fact that medications targeting intermediates in the autophagy signaling pathway are being created and evaluated at both the preclinical and clinical levels, given the complicated function of autophagy in cancer, we still have a long way to go in terms of establishing an effective therapeutic approach. This article discusses current tactics for exploiting cancer cells' autophagy dependency, as well as obstacles in the area. We believe that the unanswered concerns raised in this work will stimulate researchers to investigate previously unknown connections between autophagy and other signaling pathways, which might lead to the development of novel, highly specialized autophagy therapies.

Elements regulating an alternatively spliced exon of the rat fibronectin gene

1993 ◽  
Vol 13 (9) ◽  
pp. 5301-5314 ◽  
Author(s):  
G S Huh ◽  
R O Hynes
Keyword(s):  
Splice Sites ◽  
Cell Type ◽  
Long Distance ◽  
Sequence Elements ◽  
Alternatively Spliced ◽  
A Cell ◽  
Cell Type Specific ◽  
Alternatively Spliced Exons

We have investigated the regulation of splicing of one of the alternatively spliced exons in the rat fibronectin gene, the EIIIB exon. This 273-nucleotide exon is excluded by some cells and included to various degrees by others. We find that EIIIB is intrinsically poorly spliced and that both its exon sequences and its splice sites contribute to its poor recognition. Therefore, cells which recognize the EIIIB exon must have mechanisms for improving its splicing. Furthermore, in order for EIIB to be regulated, a balance must exist between the EIIIB splice sites and those of its flanking exons. Although the intron upstream of EIIIB does not appear to play a role in the recognition of EIIIB for splicing, the intron downstream contains sequence elements which can promote EIIIB recognition in a cell-type-specific fashion. These elements are located an unusually long distance from the exon that they regulate, more than 518 nucleotides downstream from EIIIB, and may represent a novel mode of exon regulation.

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