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Topic Review
GPCRs In Intracellular Compartments: Implications For Drug Discovery
The architecture of eukaryotic cells is defined by extensive membrane-delimited compartments, which entails separate metabolic processes that would otherwise interfere with each other, leading to functional differences between cells. G protein-coupled receptors (GPCRs) are the largest class of cell surface receptors, and their signal transduction is traditionally viewed as a chain of events initiated from the plasma membrane. Furthermore, their intracellular trafficking, internalization, and recycling were considered only to regulate receptor desensitization and cell surface expression. On the contrary, accumulating data strongly suggest that GPCRs also signal from intracellular compartments. GPCRs localize in the membranes of endosomes, nucleus, Golgi and endoplasmic reticulum apparatuses, mitochondria, and cell division compartments. Importantly, from these sites they have shown to orchestrate multiple signals that regulate different cell pathways. 
  • 887
  • 08 Oct 2022
Topic Review
Fibrin Glue and MSCs to Regenerate Nerve Injuries
Cell-based therapy is a promising treatment to favor tissue healing through less invasive strategies. Mesenchymal stem cells (MSCs) highlighted as potential candidates due to their angiogenic, anti-apoptotic and immunomodulatory properties, in addition to their ability to differentiate into several specialized cell lines. Cells can be carried through a biological delivery system, such as fibrin glue, which acts as a temporary matrix that favors cell-matrix interactions and allows local and paracrine functions of MSCs. MSCs favored axonal regeneration, remyelination of nerve fibers, as well as promoted an increase in the number of myelinated fibers, myelin sheath thickness, number of axons and expression of growth factors, with significant improvement in motor function recovery. Fibrin glue combined with MSCs has the potential to regenerate nervous system lesions.
  • 885
  • 24 Jan 2022
Topic Review
EVs–PEG–cECMH Product
The combination of cardiosphere-derived extracellular vesciles (EVs), polyethylene glycol (PEG), and cardiac extracellular matrix hydrogel (cECMH), EVs–PEG–cECMH, is a potential multipronged product with improved gelation time and mechanical properties, increased on-site retention, and maintained bioactivity that, all together, may translate into boosted therapeutic efficacy.
  • 884
  • 14 Sep 2021
Topic Review
Membrane Lipids in Light-Activation of Drosophila TRP Channels
Transient Receptor Potential (TRP) channels constitute a large superfamily of polymodal channel proteins with diverse roles in many physiological and sensory systems that function both as ionotropic and metabotropic receptors. From the early days of TRP channel discovery, membrane lipids were suggested to play a fundamental role in channel activation and regulation. A prominent example is the Drosophila TRP and TRP-like (TRPL) channels, which are predominantly expressed in the visual system of Drosophila. Light activation of the TRP and TRPL channels, the founding members of the TRP channel superfamily, requires activation of phospholipase Cβ (PLC), which hydrolyzes phosphatidylinositol 4,5-bisphosphate (PIP2) into Diacylglycerol (DAG) and Inositol 1, 4,5-trisphosphate (IP3).
  • 884
  • 19 Apr 2022
Topic Review
Aging of Human Hematopoietic Stem and Progenitor Cells
In human blood and immune system, aging is characterized by a decline of innate immunity and regenerative potential of hematopoietic stem cells. This decline is defined at a molecular level in the  hematopoietic stem and progenitor cells (HSPC) compartment. A series of studies have demonstrated that aging of HSPC is induced by an accumulation of senescent cells in the HSPC compartment of the aging human bone marrow. Multi-omics studies have provided evidence that senescent cells are characterized by elevated central carbon metabolism. This property has rendered an enrichment of senescent HSPC for in depth mechanistic studies possible, and in addition has provided novel targets for senolysis therapy strategies. 
  • 884
  • 02 Apr 2022
Topic Review Video
Photodynamic Therapy for Prostate Cancer
Prostate cancer is a major health concern worldwide, and current treatments, such as surgery, radiation therapy, and chemotherapy, are associated with significant side effects and limitations. Photodynamic therapy (PDT) is a promising alternative that has the potential to provide a minimally invasive and highly targeted approach to treating prostate cancer. PDT involves the use of photosensitizers (PSs) that are activated by light to produce reactive oxygen species (ROS), which can induce tumor cell death. 
  • 884
  • 03 Sep 2023
Topic Review
Torsin AAA+ Proteins
Torsin ATPases are members of the AAA+ (ATPases associated with various cellular activities) superfamily of proteins, which participate in essential cellular processes. While AAA+ proteins are ubiquitously expressed and demonstrate distinct subcellular localizations, Torsins are the only AAA+ to reside within the nuclear envelope (NE) and endoplasmic reticulum (ER) network. Moreover, due to the absence of integral catalytic features, Torsins require the NE- and ER-specific regulatory cofactors, lamina-associated polypeptide 1 (LAP1) and luminal domain like LAP1 (LULL1), to efficiently trigger their atypical mode of ATP hydrolysis. Despite their implication in an ever-growing list of diverse processes, the specific contributions of Torsin/cofactor assemblies in maintaining normal cellular physiology remain largely enigmatic. Resolving gaps in the functional and mechanistic principles of Torsins and their cofactors are of considerable medical importance, as aberrant Torsin behavior is the principal cause of the movement disorder DYT1 early-onset dystonia.
  • 883
  • 30 Jun 2021
Topic Review
Transient Nuclear Envelope Rupture during Metastasis
Metastasis is the process that allows the seeding of tumor cells in a new organ. The migration and invasion of cancer cells involves the pulling, pushing, and squeezing of cells through narrow spaces and pores. Tumor cells need to cross several physical barriers, such as layers of basement membranes as well as the endothelium wall during the way in and out of the blood stream, to reach the new organ.
  • 883
  • 10 Feb 2022
Topic Review
Chemokine uptake in Endothelial Cells
The chemokines CCL5 and CXCL4 are deposited by platelets onto endothelial cells, inducing monocyte arrest. Here, the fate of CCL5 and CXCL4 after endothelial deposition was investigated. Human umbilical vein endothelial cells (HUVECs) and EA.hy926 cells were incubated with CCL5 or CXCL4 for up to 120 min, and chemokine uptake was analyzed by microscopy and by ELISA. Intracellular calcium signaling was visualized upon chemokine treatment, and monocyte arrest was evaluated under laminar flow. Whereas CXCL4 remained partly on the cell surface, all of the CCL5 was internalized into endothelial cells. Endocytosis of CCL5 and CXCL4 was shown as a rapid and active process that primarily depended on dynamin, clathrin, and G protein-coupled receptors (GPCRs), but not on surface proteoglycans. Intracellular calcium signals were increased after chemokine treatment. Confocal microscopy and ELISA measurements in cell organelle fractions indicated that both chemokines accumulated in the nucleus. Internalization did not affect leukocyte arrest, as pretreatment of chemokines and subsequent washing did not alter monocyte adhesion to endothelial cells. Endothelial cells rapidly and actively internalize CCL5 and CXCL4 by clathrin and dynamin-dependent endocytosis, where the chemokines appear to be directed to the nucleus. These findings expand our knowledge of how chemokines attract leukocytes to sites of inflammation.
  • 882
  • 22 Sep 2021
Topic Review
Golgi Proteostasis
The Golgi apparatus is a central hub for cellular protein trafficking and signaling. Golgi structure and function is tightly coupled and undergoes dynamic changes in health and disease. A crucial requirement for maintaining Golgi homeostasis is the ability of the Golgi to target aberrant, misfolded, or otherwise unwanted proteins to degradation. Recent studies have revealed that the Golgi apparatus may degrade such proteins through autophagy, retrograde trafficking to the ER for ER-associated degradation (ERAD), and locally, through Golgi apparatus-related degradation (GARD).
  • 881
  • 02 Mar 2022
Topic Review
Purinergic Signaling in Colorectal Cancer
Colorectal cancer is a leading cause of cancer-related death. Activated immune cells have the potential to eliminate tumor cells, but cancers gain the ability to suppress immune cell functions and escape immune attack. The researchers explored one mechanism that cancers use to evade immune cells in colorectal cancer. This mechanism alters levels of molecules known as purines. Purines are key players in cellular energetics and many cellular processes and can also lead to immune suppression in cancer.
  • 881
  • 21 Nov 2022
Topic Review
Pseudophosphatases in Disease
Pseudophosphatases are important regulators, and their proper regulation is important for maintaining homeostasis and preventing diseases.
  • 880
  • 14 Jul 2021
Topic Review
Cytoplasmic Actins in Endothelial Cell
The primary function of the endothelial cells (EC) lining the inner surface of all vessels is to regulate permeability of vascular walls and to control exchange between circulating blood and tissue fluids of organs. The EC actin cytoskeleton plays a crucial role in maintaining endothelial barrier function. Actin cytoskeleton reorganization result in EC contraction and provides a structural basis for the increase in vascular permeability, which is typical for many diseases. Actin cytoskeleton in non-muscle cells presented two actin isoforms: non-muscle β-cytoplasmic and γ-cytoplasmic actins (β-actins and γ-actins), which are encoded by ACTB and ACTG1 genes, respectively. They are ubiquitously expressed in the different cells in vivo and in vitro and the β/γ-actin ratio depends on the cell type. Both cytoplasmic actins are essential for cell survival, but they perform various functions in the interphase and cell division and play different roles in neoplastic transformation. 
  • 880
  • 09 Aug 2021
Topic Review
Radiotracers Available for Cancer and Disease
Various factors have been linked to abnormal metabolic reprogramming, including gene mutations, epigenetic modifications, altered protein epitopes, and their involvement in the development of disease, including cancer. The presence of multiple distinct hallmarks and the resulting cellular reprogramming process have gradually revealed that these metabolism-related molecules may be able to be used to track or prevent the progression of cancer. Consequently, translational medicines have been developed using metabolic substrates, precursors, and other products depending on their biochemical mechanism of action. It is important to note that these metabolic analogs can also be used for imaging and therapeutic purposes in addition to competing for metabolic functions. In particular, due to their isotopic labeling, these compounds may also be used to localize and visualize tumor cells after uptake.
  • 880
  • 10 Feb 2023
Topic Review
ATRX/DAXX and ALT
ATRX is named for its causal role in ATR-X syndrome (α-thalassemia with mental impairment, X-linked), an X-linked disorder characterized by developmental delays, urogenital abnormalities, distinctive craniofacial features, and α-thalassemia caused by insufficient α-globin expression. Because of the central role of decreased α-globin mRNA expression in the ATR-X phenotype, research on ATRX initially focused on its potential as a transcriptional regulator. In fact, ATRX in concert with DAXX play wide-ranging roles in maintaining chromatin and reckoning with problematic DNA repeat sequences, with downstream effects on gene expression that have critical impacts in development. Proliferating cells must enact a telomere maintenance mechanism to ensure genomic stability. In a subset of tumors, telomeres are maintained not by telomerase, but through a homologous recombination-based mechanism termed Alternative Lengthening of Telomeres or ALT. The ALT process is linked to mutations in the ATRX/DAXX/H3.3 histone chaperone complex. This complex is responsible for depositing non-replicative histone variant H3.3 at pericentric and telomeric heterochromatin but has also been found to have roles in ameliorating replication in repeat sequences and in promoting DNA repair.
  • 879
  • 17 Apr 2023
Topic Review
Targeting Tie2 in the Tumor Microenvironment
The dissemination of cancer cells from their original location to distant organs where they grow, a process called metastasis, causes more than 90% of cancer deaths. The identification of the molecular mechanisms of metastasis and the development of anti-metastatic therapies are essential to increase patient survival. In recent years, targeting the tumor microenvironment has become a promising avenue to prevent both tumor growth and metastasis. As the tumor microenvironment contains not only cancer cells but also blood vessels, immune cells, and other non-cancerous cells, it is naïve to think that therapy only affects a single cell type in this complex environment. Here to stress the importance, and ways to inhibit the function, of one therapeutic target: the receptor Tie2. Tie2 is a receptor present on the cell surface of several cell types within the tumor microenvironment and regulates tumor angiogenesis, growth, and metastasis to distant organs.
  • 878
  • 06 Dec 2021
Topic Review
Pivotal Role of Inflammation in Celiac Disease
Celiac disease (CD) is an immune mediate disease characterised by gluten dependent T-cell mediated activation, autoimmunity and derangement of the intestinal mucosa in a specific genetic background. Although the activation of the T-cells has been studied in dept, the central question remains still unanswered, namely, why a pro-inflammatory T cell response to gluten is generated instead of a regulatory response, which normally promotes oral tolerance to dietary protein antigens. There is an inflamed environment in CD intestine, enriched in cytokines, such as IL-15, or type I interferons, in which T cells tend to acquire a pro- inflammatory phenotype. The factors that create a pro-inflammatory environment in the CD intestine, leading to an expansion of gliadin-specific T cells in genetically susceptible individuals and further shifting them towards a pro-inflammatory phenotype, remain to be identified. Gluten exacerbates these constitutive alterations, by increasing the same markers already altered before the gluten introduction, both in vitro and in vivo. All these new observations add this disease “tout court” to the big family of increasing chronic inflammatory diseases where nutrients can have pro-inflammatory or anti-inflammatory effects, directly or indirectly mediated by the intestinal microbiota, where the intestine functions as a cross road for the control of the inflammation both local and at distance.
  • 878
  • 20 Jul 2022
Topic Review
Cellular and Interaction Diversity of Tumor Microenvironment
The tumor microenvironment is a complex network of various interactions between immune cells and non-cellular components such as the extracellular matrix, exosomes and interleukins. Moreover, tumor heterogeneity and its constant modification may alter the immunophenotype and become responsible for its resistance regarding the therapies applied However, it should be remembered that in a strongly immunosuppressive neoplastic microenvironment, the immune system cells undergo reprogramming and most often cease to fulfill their original function. Therefore, understanding what happens within the tumor microenvironment, and which mechanisms are responsible for tumor development and progression should let us know how cancer could protect itself against the immune system.
  • 876
  • 12 Jul 2022
Topic Review
Disruption of Claudin-Made Tight Junction Barriers by CpE
Claudins are a family of integral membrane proteins that enable epithelial cell/cell interactions by localizing to and driving the formation of tight junctions. Via claudin self-assembly within the membranes of adjoining cells, their extracellular domains interact, forming barriers to the paracellular transport of small molecules and ions. The bacterium Clostridium perfringens causes prevalent gastrointestinal disorders in mammals by employing an enterotoxin (CpE) that targets claudins. CpE binds to claudins at or near tight junctions in the gut and disrupts their barrier function, potentially by disabling their assembly or via cell signaling means—the mechanism(s) remain unclear.
  • 874
  • 10 Mar 2022
Topic Review
ROS and Enzymatic Antioxidants in Small Domestic Ruminants
Oxygen is a fundamental element in aerobic life and oxidative metabolism representing the principal energy source for aerobic cells. Reactive oxygen species (ROS) are generated by a variety of cellular metabolic activities and as a by-product of ATP generation mediated by mitochondrial respiration. ROS are engaged in many redox-governing cell activities for the preservation of cellular homeostasis.
  • 873
  • 25 Jul 2023
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