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Topic Review
Milk Exosomes as Drug Delivery Agents
Milk is a unique natural source of exosomes available in semi-preparative and preparative quantities. Milk exosomes are highly resistant to the harsh conditions of the gastrointestinal tract. In vitro studies have demonstrated that milk exosomes have an affinity to epithelial cells, are digested by cells by endocytosis mechanism, and can be used for oral delivery. With milk exosome membranes containing hydrophilic and hydrophobic components, exosomes can be loaded with hydrophilic and lipophilic drugs.
  • 1.1K
  • 21 Jun 2023
Topic Review
ORP5 and ORP8
Oxysterol binding related proteins 5 and 8 (ORP5 and ORP8) are two close homologs of the larger oxysterol binding protein (OSBP) family of sterol sensors and lipid transfer proteins (LTP). Early studies indicated these transmembrane proteins, anchored to the endoplasmic reticulum (ER), bound and sensed cholesterol and oxysterols. They were identified as important for diverse cellular functions including sterol homeostasis, vesicular trafficking, proliferation and migration. In addition, they were implicated in lipid-related diseases such as atherosclerosis and diabetes, but also cancer, although their mechanisms of action remained poorly understood. Then, alongside the increasing recognition that membrane contact sites (MCS) serve as hubs for non-vesicular lipid transfer, added to their structural similarity to other LTPs, came discoveries showing that ORP5 and 8 were in fact phospholipid transfer proteins that rather sense and exchange phosphatidylserine (PS) for phosphoinositides, including phosphatidylinositol-4-phosphate (PI(4)P) and potentially phosphatidylinositol-(4,5)-bisphosphate (PI(4,5)P2). Evidence now points to their action at MCS between the ER and various organelles including the plasma membrane, lysosomes, mitochondria, and lipid droplets. Dissecting exactly how this unexpected phospholipid transfer function connects with sterol regulation in health or disease remains a challenge for future studies.
  • 1.1K
  • 15 Jul 2021
Topic Review
Metabolic Regulation of Mitochondrial Protein Biogenesis in neurons
Neurons critically depend on mitochondria for ATP production and Ca2+ buffering. They are highly compartmentalized cells and therefore a finely tuned mitochondrial network constantly adapting to the local requirements is necessary. For neuronal maintenance, old or damaged mitochondria need to be degraded, while the functional mitochondrial pool needs to be replenished with freshly synthesized components. Mitochondrial biogenesis is known to be primarily regulated via the PGC-1α-NRF1/2-TFAM pathway at the transcriptional level. However, while transcriptional regulation of mitochondrial genes can change the global mitochondrial content in neurons, it does not explain how a morphologically complex cell like a neuron adapts to local differences in mitochondrial demand. 
  • 1.1K
  • 07 Nov 2022
Topic Review
P2X7 Variants
The human P2X7 gene is highly polymorphic, and several splice variants of the receptor have been identified in time. P2X7 single-nucleotide polymorphisms (SNPs) have been broadly analyzed by studies relating them to pathologies as different as infectious, inflammatory, nervous, and bone diseases, among which cancer is included. Moreover, in the last years, an increasing number of reports concentrated on P2X7 splice variants’ different roles and their implications in pathological conditions, including oncogenesis. Our article on P2X7 variants in oncogenesis recently published in Cells gives an overview of established and recent literature demonstrating a role for human P2X7 gene products in oncological conditions. Here you find the main structural information on P2X7 variants.
  • 1.1K
  • 02 Feb 2021
Topic Review
Breakdown of Filamentous Myofibrils
Protein degradation maintains cellular integrity by regulating virtually all biological pro- cesses, whereas impaired proteolysis perturbs protein quality control, and often leads to human disease. Two major proteolytic systems are responsible for protein breakdown in all cells: autophagy, which facilitates the loss of organelles, protein aggregates, and cell surface proteins; and the ubiquitin-proteasome system (UPS), which promotes degradation of mainly soluble proteins. Recent findings indicate that more complex protein structures, such as filamentous assemblies, which are not acces- sible to the catalytic core of the proteasome in vitro, can be efficiently degraded by this proteolytic machinery in systemic catabolic states in vivo. Mechanisms that loosen the filamentous structure seem to be activated first, hence increasing the accessibility of protein constituents to the UPS. In this review, we will discuss the mechanisms underlying the disassembly and loss of the intricate insoluble filamentous myofibrils, which are responsible for muscle contraction, and whose degradation by the UPS causes weakness and disability in aging and disease. Several lines of evidence indicate that myofibril breakdown occurs in a strictly ordered and controlled manner, and the function of AAA-ATPases is crucial for their disassembly and loss.
  • 1.1K
  • 30 Apr 2021
Topic Review
Sarcoma Metabolomics
Sarcoma metabolomics is a broadly unexplored field that can offer diverse opportunities. Deeper characterization and a sharper picture of sarcoma metabolic and microenvironment landscape may pave the way for diagnostic and staging refinement and identification of new potential therapeutic targets, resulting in benefits for patients.
  • 1.1K
  • 02 Jul 2021
Topic Review
Stem Cells Radiation-Induced Regenerative Response
Radiotherapy is involved in the treatment of many cancers, but damage induced to the surrounding normal tissue is often inevitable. Evidence suggests that the maintenance of homeostasis and regeneration of normal tissues is driven by specific adult tissue stem/progenitor cells. These tasks involve the input from several signaling pathways. Irradiation also targets these stem/progenitor cells, triggering a cellular response aimed at achieving tissue regeneration.  
  • 1.1K
  • 03 Mar 2021
Topic Review
Botulinum Toxin Type A
Botulinum neurotoxin A (BoNT-A) which is generally known as anti-contraction of muscles has been reported as a successful treatment in various types of chronic ulcers.
  • 1.1K
  • 22 Jun 2022
Topic Review
ER Lipid Raft-Associated Protein
ER lipid raft-associated protein 1 (ERLIN1) and 2 (ERLIN2) are 40 kDa transmembrane glycoproteins belonging to the family of prohibitins, containing a PHB domain. They are generally localized in the endoplasmic reticulum (ER), where ERLIN1 forms a heteroligomeric complex with its closely related ERLIN2. Well-defined functions of ERLINS are promotion of ER-associated protein degradation, mediation of inositol 1,4,5-trisphosphate (IP3) receptors, processing and regulation of lipid metabolism.
  • 1.1K
  • 18 Oct 2021
Topic Review
WWOX Controls Cell Survival, Immune Response, Disease Progression
Tumor suppressor WWOX inhibits cancer growth and retards Alzheimer’s disease (AD) progression. Supporting evidence shows that the more strongly WWOX binds intracellular protein partners, the weaker is cancer cell growth in vivo. Whether this correlates with retardation of AD progression is unknown. Two functional forms of WWOX exhibit opposite functions. pY33-WWOX is proapoptotic and anticancer, and is essential for maintaining normal physiology. 
  • 1.1K
  • 14 Jul 2022
Topic Review
Cyclin-Dependent Inhibitors in Diet-Induced Obesity and Cancer
Overweight and obesity constitute the most impactful lifestyle-dependent risk factors for cancer and have been tightly linked to a higher number of tumor-related deaths nowadays. The excessive accumulation of energy can lead to an imbalance in the level of essential cellular biomolecules that may result in inflammation and cell-cycle dysregulation. Nutritional strategies and phytochemicals are gaining interest in the management of obesity-related cancers, with several ongoing and completed clinical studies that support their effectiveness. At the same time, cyclin-dependent kinases (CDKs) are becoming an important target in breast and ovarian cancer treatment, with various FDA-approved CDK4/6 inhibitors that have recently received more attention for their potential role in diet-induced obesity (DIO).
  • 1.1K
  • 10 Jun 2022
Topic Review
SUMOylation
SUMOylation is a dynamic and essential Post-Translation Modification (PTM) consisting on the conjugation of Small Ubiquitin-like Modifiers (SUMOs) to an acceptor lysine of a substrate protein. SUMOylation predominantly regulates nuclear processes and its dysregulation is associated to diseases including cancer. SUMOs share a similar three-dimensional structure with other Ubiquitin-Like Modifiers (UBLs). However, SUMOs differ due to their flexible N-terminus, which also contains the site for SUMO chain formation. All eukaryotes express at least one SUMO paralogue. Five SUMO family members have been identified in humans (SUMO1, SUMO2, SUMO3, SUMO4, and SUMO5. However, SUMO1, SUMO2, and SUMO3 are the main family members where they are commonly classified as SUMO1 and SUMO2/3 because of the high similarity between mature SUMO2 and SUMO3. All SUMO paralogues are similar in structure but differ in expression levels. SUMO2 is the most abundant family member in mammalian cells. Studies in mice show that the knockout of SUMO2 is embryonic lethal, while SUMO1 and SUMO3 knockout mice were associated to mild phenotypes, possibly because SUMO2 might compensate the loss of either SUMO1 or SUMO3. Similarly to ubiquitination, SUMO is conjugated in a in a 3-step enzymatic cascade that involves a dimeric E1 activating enzyme (SAE1 and SAE2), an E2 conjugating enzyme (Ubc9), and several SUMO E3 enzymes.
  • 1.1K
  • 28 Mar 2022
Topic Review
TRPV4 Ion Channel
The transient receptor potential vanilloid 4 channel (TRPV4) belongs to the mammalian TRP superfamily of cation channels. TRPV4 is ubiquitously expressed, activated by a disparate array of stimuli, interacts with a multitude of proteins, and is modulated by a range of post-translational modifications, the majority of which we are only just beginning to understand. Not surprisingly, a great number of physiological roles have emerged for TRPV4, as have various disease states that are attributable to the absence, or abnormal functioning, of this ion channel. This review will highlight structural features of TRPV4, endogenous and exogenous activators of the channel, and discuss the reported roles of TRPV4 in health and disease.
  • 1.1K
  • 01 Feb 2021
Topic Review
HFpEF
Heart failure (HF) with preserved left ventricular ejection fraction (HFpEF) is becoming the predominant form of HF. However, medical therapy that improves cardiovascular outcome in HF patients with almost normal and normal systolic left ventricular function, but diastolic dysfunction is missing. The cause of this unmet need is incomplete understanding of HFpEF pathophysiology, the heterogeneity of the patient population, and poor matching of therapeutic mechanisms and primary pathophysiological processes.
  • 1.1K
  • 11 Mar 2022
Topic Review
Pericytes
Pericytes are increasingly recognized as being important in the control of blood–brain barrier permeability and vascular flow. Research on this important cell type has been hindered by widespread confusion regarding the phenotypic identity and nomenclature of pericytes and other perivascular cell types. In addition, pericyte heterogeneity and mouse–human species differences have contributed to confusion.
  • 1.1K
  • 17 Jun 2021
Topic Review
Lipid-Based mRNA Nanoparticles
Messenger RNA (mRNA) is being extensively used in gene therapy and vaccination due to its safety over DNA, in the following ways: its lack of integration risk, cytoplasmic expression, and transient expression compatible with fine regulations. However, clinical applications of mRNA are limited by its fast degradation by nucleases, and the activation of detrimental immune responses. Advances in mRNA applications, with the recent approval of COVID-19 vaccines, were fueled by optimization of the mRNA sequence and the development of mRNA delivery systems. Although delivery systems and mRNA sequence optimization have been abundantly reviewed, understanding of the intracellular processing of mRNA is mandatory to improve its applications. 
  • 1.1K
  • 12 Jul 2021
Topic Review
NF-κB and Human Cancer
Transcription factor NF-κB has been extensively studied for its varied roles in cancer since its initial characterization as a potent retroviral oncogene several decades ago. It is now clear that NF-κB plays a major role in a large variety of human cancers, including especially ones of immune cell origin. NF-κB is generally constitutively or aberrantly activated in human cancers where it is involved.
  • 1.1K
  • 25 Dec 2021
Topic Review
Natural Killer Cell-Derived Extracellular Vesicles for Cancer
Cancer is the second leading contributor to global deaths caused by non-communicable diseases. The cancer cells are known to interact with the surrounding non-cancerous cells, including the immune cells and stromal cells, within the tumor microenvironment (TME) to modulate the tumor progression, metastasis and resistance. Chemotherapy and radiotherapy are the standard treatments for cancers. A new generation of immunotherapy using natural killer (NK) cells, cytotoxic CD8+ T-lymphocytes or macrophages was developed to achieve tumor-specific targeting and circumvent the adverse effects.
  • 1.1K
  • 21 Feb 2023
Topic Review
PDE2A for Mouse Liver Development
cAMP and cGMP are intracellular signaling molecules produced in response to a plethora of extracellular signals in order to coordinate cellular metabolism, proliferation, differentiation and apoptosis. Phosphodiesterases (PDEs) are the enzymes that hydrolyze cAMP and cGMP in order to end or to limit the responses to these signals. To date 11 PDE families (named PDE1 to PDE11) have been identified across each cell type expressed in a peculiar pattern. They enclose 21 genes that codify approximately 100 enzymes that form a redundant network ensuring the compensation of activity in case of alteration of activity or lack of expression of one of the members. PDE2A, a cAMP-hydrolyzing enzyme, represents the exception to this picture, as PDE2A knockout is embryonic lethal. Knockout embryos show that the lack of the enzyme has the greatest impact on the development of the heart and of the liver, which is no longer able to assume its hematopoietic role. The increase of the intracellular cAMP level and the downregulation of the anti-apoptotic gene Bcl2 might explain the loss of integrity in the PDE2A knockout liver niche that compromises the hematopoietic function and maturation.
  • 1.1K
  • 29 Oct 2020
Topic Review
Cell–Cell Fusion and Cancer
In addition to physiological processes, such as fertilization, placentation, myogenesis, osteoclastogenesis and wound healing/tissue regeneration the biological phenomenon of cell-cell fusion also plays a role in cancer, which was already postulated by the German physician Otto Aichel in 1911. Indeed, cancer cells could either fuse with other cancer cells or could hybridize with macrophages, fibroblasts and stem cells, thereby giving rise to tumor hybrid cells that could exhibit novel properties, such as an increased drug resistance and/or an enhanced metastasis formation capacity. 
  • 1.1K
  • 28 Jun 2021
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