intracellular pathways
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2022 ◽  
Vol 12 ◽  
Author(s):  
Etelka Pöstyéni ◽  
Alma Ganczer ◽  
Andrea Kovács-Valasek ◽  
Robert Gabriel

The mammalian retina contains approximately 30 neuropeptides that are synthetized by different neuronal cell populations, glia, and the pigmented epithelium. The presence of these neuropeptides leaves a mark on normal retinal molecular processes and physiology, and they are also crucial in fighting various pathologies (e.g., diabetic retinopathy, ischemia, age-related pathologies, glaucoma) because of their protective abilities. Retinal pathologies of different origin (metabolic, genetic) are extensively investigated by genetically manipulated in vivo mouse models that help us gain a better understanding of the molecular background of these pathomechanisms. These models offer opportunities to manipulate gene expression in different cell types to help reveal their roles in the preservation of retinal health or identify malfunction during diseases. In order to assess the current status of transgenic technologies available, we have conducted a literature survey focused on retinal disorders of metabolic origin, zooming in on the role of retinal neuropeptides in diabetic retinopathy and ischemia. First, we identified those neuropeptides that are most relevant to retinal pathologies in humans and the two clinically most relevant models, mice and rats. Then we continued our analysis with metabolic disorders, examining neuropeptide-related pathways leading to systemic or cellular damage and rescue. Last but not least, we reviewed the available literature on genetically modified mouse strains to understand how the manipulation of a single element of any given pathway (e.g., signal molecules, receptors, intracellular signaling pathways) could lead either to the worsening of disease conditions or, more frequently, to substantial improvements in retinal health. Most attention was given to studies which reported successful intervention against specific disorders. For these experiments, a detailed evaluation will be given and the possible role of converging intracellular pathways will be discussed. Using these converging intracellular pathways, curative effects of peptides could potentially be utilized in fighting metabolic retinal disorders.


Author(s):  
Sandhya Rani Mandadi ◽  
Lankalapalli Srinivas ◽  
V. V. S. Rajendra Prasad

Nanotherapeutics for the cure of breast cancer remains unswervingly succeeding and being practiced to eradicate innumerable restrictions of conventional practice obtainable for the supervision of breast cancer. Nanoparticles offer an interdisciplinary extent for exploration in imaging, diagnosis and targeting of breast cancer. Through a progressive physicochemical features and improved bioavailability, they spectacle persistent blood circulation through effective tumor targeting. Nanoparticles remain capable to diminish cytotoxic consequence of the active anticancer medications through amassed cancer cell targeting in contrast to conventional preparations. Several nanoparticles-based preparations remain in the preclinical and clinical phases of progress; amongst them, polymeric drug micelles, liposomes, and dendrimer, remain the utmost common. In this review, we have conferred the role of nanoparticles through detail to oncology, by predominantly aiming on the breast cancer and several nanodelivery systems practiced for targeting action and signaling forces through further intracellular pathways in breast cancer.


2021 ◽  
Author(s):  
Nicolò Ilacqua ◽  
Irene Anastasia ◽  
Andrea Raimondi ◽  
Philippe Lemieux ◽  
Thomas Q. de Aguiar Vallim ◽  
...  

Hepatic lipid homeostasis depends on intracellular pathways that respire fatty acid (FA) in peroxisomes and mitochondria and on systemic pathways that secrete FA into the bloodstream, either free or condensed in very-low-density lipoprotein (VLDL) triglycerides. These systemic and intracellular pathways are interdependent, but it is unclear whether and how they integrate into a single cellular circuit. Here, we report that mouse liver wrappER, a distinct ER compartment with apparent FA- and VLDL-secretion functions, connects peroxisomes and mitochondria. Correlative light electron microscopy, quantitative serial section electron tomography, and 3D organelle reconstruction analysis show that the number of peroxisome-wrappER-mitochondria complexes changes throughout fasting-to-feeding transitions and doubles when VLDL synthesis stops following acute genetic ablation of Mttp in the liver. Quantitative proteomic analysis of peroxisome-wrappER-mitochondria complex-enriched fractions indicates that the loss of Mttp upregulates global FA β-oxidation, thereby integrating the dynamics of this three-organelle association into hepatic FA flux responses. Therefore, liver lipid homeostasis occurs through the convergence of systemic and intracellular FA-elimination pathways in the peroxisome-wrappER-mitochondria complex.


2021 ◽  
Vol 9 ◽  
Author(s):  
Alexia Gomart ◽  
Alexandre Vallée ◽  
Yves Lecarpentier

Necrotizing enterocolitis (NEC) represents one of the major causes of morbidity and mortality in premature infants. Several recent studies, however, have contributed to a better understanding of the pathophysiology of this dreadful disease. Numerous intracellular pathways play a key role in NEC, namely: bacterial lipopolysaccharide (LPS), LPS toll-like receptor 4 (TLR4), canonical Wnt/β-catenin signaling and PPARγ. In a large number of pathologies, canonical Wnt/β-catenin signaling and PPARγ operate in opposition to one another, so that when one of the two pathways is overexpressed the other is downregulated and vice-versa. In NEC, activation of TLR4 by LPS leads to downregulation of the canonical Wnt/β-catenin signaling and upregulation of PPARγ. This review aims to shed light on the complex intracellular mechanisms involved in this pathophysiological profile by examining additional pathways such as the GSK-3β, NF-κB, TGF-β/Smads, and PI3K-Akt pathways.


2021 ◽  
Vol 12 ◽  
Author(s):  
Mariam S. Khelifa ◽  
Louise J. Skov ◽  
Birgitte Holst

Anorexia Nervosa (AN) is a complex disease that impairs the metabolic, mental and physiological health of affected individuals in a severe and sometimes lethal way. Many of the common symptoms in AN patients, such as reduced food intake, anxiety, impaired gut motility or overexercising are connected to both the orexigenic gut hormone ghrelin and the dopaminergic system. Targeting the ghrelin receptor (GhrR) to treat AN seems a promising possibility in current research. However, GhrR signaling is highly complex. First, the GhrR can activate four known intracellular pathways Gαq, Gαi/o, Gα12/13 and the recruitment of β-arrestin. Biased signaling provides the possibility to activate or inhibit only one or a subset of the intracellular pathways of a pleiotropic receptor. This allows specific targeting of physiological functions without adverse effects. Currently little is known on how biased signaling could specifically modulate GhrR effects. Second, GhrR signaling has been shown to be interconnected with the dopaminergic system, particularly in the context of AN symptoms. This review highlights that a biased agonist for the GhrR may be a promising target for the treatment of AN, however extensive and systematic translational studies are still needed and the connection to the dopaminergic system has to be taken into account.


2021 ◽  
Author(s):  
An-An Liu ◽  
En-Ze Sun ◽  
Zhi-Gang Wang ◽  
Shu-Lin Liu ◽  
Dai-Wen Pang

ABSTRACT Live cells, as reservoirs of biochemical reactions, can serve as amazing integrated chemical plants where precursor formation, nucleation and growth of nanocrystals, and functional assembly can be carried out accurately following an artificial program. It is crucial but challenging to deliberately direct intracellular pathways to synthesize desired nanocrystals that cannot be produced naturally in cells, because the relevant reactions exist in different spatiotemporal dimensions and will never encounter spontaneously. This article summarizes progress in the introduction of inorganic functional nanocrystals into live cells via the ‘artificial-regulated space–time-coupled live-cell synthesis’ strategy. We also describe ingenious bio-applications of the nanocrystal–cell systems, and quasi-biosynthesis strategies expanded from live-cell synthesis. Artificial-regulated live-cell synthesis—which involves the interdisciplinary application of biology, chemistry, nanoscience and medicine—will enable researchers to better exploit the unanticipated potentialities of live cells and open up new directions in synthetic biology.


2021 ◽  
Author(s):  
Bavleen Kaur ◽  
Jenna Kerbrat ◽  
Jia Kho ◽  
Manreet Kaler ◽  
Stefanos Kanatsios ◽  
...  

2021 ◽  
Vol 22 (16) ◽  
pp. 8871
Author(s):  
Paola Pontrelli ◽  
Margherita Gigante ◽  
Federica Spadaccino ◽  
Giuseppe Stefano Netti ◽  
Marilisa Saldarelli ◽  
...  

CD40 crosslinking plays an important role in regulating cell migration, adhesion and proliferation in renal cell carcinoma (RCC). CD40/CD40L interaction on RCC cells activates different intracellular pathways but the molecular mechanisms leading to cell scattering are not yet clearly defined. Aim of our study was to investigate the main intracellular pathways activated by CD40 ligation and their specific involvement in RCC cell migration. CD40 ligation increased the phosphorylation of extracellular signal-regulated kinase (ERK), c-Jun NH (2)-terminal kinase (JNK) and p38 MAPK. Furthermore, CD40 crosslinking activated different transcriptional factors on RCC cell lines: AP-1, NFkB and some members of the Nuclear Factor of Activated T cells (NFAT) family. Interestingly, the specific inhibition of NFAT factors by cyclosporine A, completely blocked RCC cell motility induced by CD40 ligation. In tumor tissue, we observed a higher expression of NFAT factors and in particular an increased activation and nuclear migration of NFATc4 on RCC tumor tissues belonging to patients that developed metastases when compared to those who did not. Moreover, CD40-CD40L interaction induced a cytoskeleton reorganization and increased the expression of integrin β1 on RCC cell lines, and this effect was reversed by cyclosporine A and NFAT inhibition. These data suggest that CD40 ligation induces the activation of different intracellular signaling pathways, in particular the NFATs factors, that could represent a potential therapeutic target in the setting of patients with metastatic RCC.


Author(s):  
Antonio Espinosa de los Monteros-Zúñiga ◽  
Guadalupe Martínez-Lorenzana ◽  
Miguel Condés-Lara ◽  
Abimael González-Hernández

Antioxidants ◽  
2021 ◽  
Vol 10 (8) ◽  
pp. 1201
Author(s):  
Jérôme Delroisse ◽  
Aline Léonet ◽  
Henri Alexandre ◽  
Igor Eeckhaut

In holothuroids, oocyte maturation is stopped in ovaries at the prophase I stage of meiosis. In natural conditions, the blockage is removed during the spawning by an unknown mechanism. When oocytes are isolated by dissection, the meiotic release can be successfully induced by a natural inducer, the REES (i.e., Rough Extract of Echinoid Spawn) that is used in aquaculture to obtain viable larvae in mass. A thioredoxin has recently been identified in the REES as the molecule responsible for holothuroid oocyte maturation. As a redox-active protein, thioredoxin is thought to reduce target proteins within the oocyte membrane and initiate an intracellular reaction cascade that leads to the unblocking of the oocyte meiosis. Our results allow us to understand additional steps in the intracellular reaction cascade induced by the action of thioredoxin on oocytes. Pharmacological agents known to have activating or inhibiting actions on oocyte maturation have been used (Forskolin, Isobutylmethylxanthine, Hypoxanthine, 6-dimethyaminopurine, Lavendustin, Genistein, Roscovitine, Cycloheximide). The effects of these agents were analysed on oocytes of the holothuroid Holothuria tubulosa incubated with or without REES and were compared to those obtained with another reducing agent, the dithiothreitol. Our results demonstrated that, at the opposite of dithiothreitol-induced oocyte maturation, thioredoxin-induced oocyte maturation is cAMP independent, but dependent of the presence of calcium in the seawater. Both pathways of induction require the activation of protein serine/threonine kinases.


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