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Topic Review
Ring-Opening of Cyclodextrins
The chemical synthesis of linear high DP oligomaltoses (OMs) is much more efficient by the opening of cyclodextrins (CDs). The α, β, and γ-CDs are cyclic oligosaccharides composed of 6, 7, or 8 glucose units respectively linked by a α-1,4 glycosidic bond. They are industrially prepared using CD glucanotransferase on starch.
  • 852
  • 03 Sep 2021
Topic Review
Differentiation of Genes Encoding Peroxisome Proliferator-Activated Receptors
The heritability of the tendency to obesity is estimated to vary widely (from 5% to 90%), depending on the research method and the hypotheses being tested. Genetic components may play an important role, both in regulating metabolism and influencing behavioral aspects-in the presence of certain critical genetic variants, the dysregulation of energy metabolism can undoubtedly lead to an increased risk of obesity. Genes code for protein products that are directly involved in the processes of digestion, assimilation, and physiological utilization of nutrients supplied to the body. There are also genes whose products are important factors that influence the activation and regulation of various metabolic pathways and also determine the maintenance of the balance of metabolic changes and the shift of this balance in a specific direction. Finally, there are the genes that code for factors that influence human behavior, eating habits, dietary preferences and so on. Systemic regulation of metabolism takes place in human cells at many levels. At the deepest molecular level, metabolic flexibility depends on the configuration of many different metabolic pathways regulated by key transcription factors, many of which interact closely with each other. From this point of view, transcription factors are considered very important elements of metabolic regulatory networks. In this group, genes encoding peroxisome proliferator-activated receptors (PPARs) are among the best studied. PPARs provide balance in nutrient and energy metabolism and maintain metabolic flexibility important for lipid metabolism, glucose homeostasis, cholesterol metabolism, and other important metabolic networks. Differentiation of PPAR genes may affect the efficacy of reduction diets and post-exercise weight loss.
  • 852
  • 06 Jan 2023
Topic Review
Phytochemical Information and Pharmacology of European Orchids
The Orchidaceae family has thousands of members, and most of them are mentioned in the folk medicine of nations around the world. The use of terrestrial orchids in European and Mediterranean regions has been reported since ancient times. Plant collection for human use is still listed as one of the main threats for terrestrial orchids (i.e. harvesting for Salep), alongside other menacing factors such as wrong habitat management and disturbance to symbionts, such as pollinators and mycorrhizal fungi. Here, phytochemical data are discussed to evaluate the presence of bioactive compounds of pharmacological relevance. Furthermore, it is debated whether the presence of these compounds could support the therapeutic employment of the different orchid organs.
  • 852
  • 09 Feb 2023
Topic Review
Neuroinflammation Receptors in Alzheimer’s Disease
Fibrillar aggregates and soluble oligomers of both Amyloid-β peptides (Aβs) and hyperphosphorylated Tau proteins (p-Tau-es), as well as a chronic neuroinflammation are the main drivers causing progressive neuronal losses and dementia in Alzheimer's disease (AD). However, the underlying pathogenetic mechanisms are still much disputed. Several endogenous neurotoxic ligands, including Aβs, and/or p-Tau-es activate innate immunity-related danger-sensing/pattern recognition receptors (PPRs) thereby advancing AD's neuroinflammation and progression. The major PRR families involved include scavenger, Toll-like, NOD-like, AIM2-like, RIG-like, and CLEC-2 receptors, plus the calcium-sensing receptor (CaSR). This quite intricate picture stresses the need to identify the pathogenetically topmost Aβ-activated PRR, whose signaling would trigger AD's three main drivers and their intra-brain spread. In theory, the candidate might belong to any PRR family. However, results of preclinical studies using in vitro nontumorigenic human cortical neurons and astrocytes and in vivo AD-model animals have started converging on the CaSR as the pathogenetically upmost PRR candidate. In fact, the CaSR binds both Ca2+ and Aβs and promotes the spread of both  Ca2+ dyshomeostasis and AD's three main drivers, causing a progressive neurons' death. Since CaSR's negative allosteric modulators block all these effects, CaSR's candidacy for topmost pathogenetic PRR has assumed a growing therapeutic potential worth clinical testing.
  • 850
  • 10 Jan 2021
Topic Review Peer Reviewed
Ecdysteroids
Ecdysteroid: member of a class of polyhydroxylated steroids found in invertebrate animals (zooecdysteroids; moulting hormones), plants (phytoecdysteroids) and fungi (mycoecdysteroids). Over 500 structural analogues are currently known. Biosynthetically, they derive from C27-, C28- or C29-sterols. The most frequently encountered analogue (in arthropods and plants) is 20-hydroxyecdysone (2β,3β,14α,20R,22R,25-hexahydroxycholest-7-en-6-one). In arthropods, ecdysteroids occur universally and regulate development by inducing moulting and reproduction, where their action is mediated by high-affinity binding to an intracellular member of the class of nuclear receptor (NR) proteins (ecdysteroid receptor; EcR) dimerised with a second NR (USP/RxR). This receptor complex binds to specific DNA promoter sites and regulates gene expression. In plants, ecdysteroids are a class of secondary compounds, occurring in varying amounts in certain species, but not all in others. Phytoecdysteroids are believed to contribute to the reduction of invertebrate predation by acting as feeding deterrents or endocrine disruptors. Ecdysteroids also possess a wide range of positive pharmacological effects in mammals, where the mode of action involves moderate-affinity binding to plasma-membrane-bound receptors and not interaction with the classical NRs for vertebrate steroid hormones.
  • 849
  • 13 Apr 2022
Topic Review
Extracellular Hemoglobin
Hemoglobin is essential for maintaining cellular bioenergetic homeostasis through its ability to bind and transport oxygen to the tissues. Besides its ability to transport oxygen, hemoglobin within erythrocytes plays an important role in cellular signaling and modulation of the inflammatory response either directly by binding gas molecules (NO, CO, and CO2) or indirectly by acting as their source. Once hemoglobin reaches the extracellular environment, it acquires several secondary functions affecting surrounding cells and tissues. By modulating the cell functions, this macromolecule becomes involved in the etiology and pathophysiology of various diseases. The up-to-date results disclose the impact of extracellular hemoglobin on (i) redox status, (ii) inflammatory state of cells, (iii) proliferation and chemotaxis, (iv) mitochondrial dynamic, (v) chemoresistance and (vi) differentiation.
  • 849
  • 06 Dec 2022
Topic Review
Amniotic epithelial cell immunomodulation
Amniotic epithelial cells (AEC) have been proposed as promising candidates for regenerative medicine thanks to their multipotency, non-tumorigenicity, low-immunogenic profile as well as for their anti-inflammatory and immunomodulatory properties.
  • 848
  • 30 Oct 2020
Topic Review
Vitamin C Anticancer Action
Vitamin C is an indispensable micronutrient in the human diet due to the multiple functions it carries out in the body. Reports of clinical studies have indicated that, when administered at high dosage by the intravenous route, vitamin C may exert beneficial antitumor effects in patients with advanced stage cancers, including those refractory to previous treatment with chemotherapy. 
  • 848
  • 19 May 2021
Topic Review
Melatonin and Plant Cadmium Tolerance
Cadmium (Cd) is one of the most injurious heavy metals, affecting plant growth and development. Melatonin (N-acetyl-5-methoxytryptamine) was discovered in plants in 1995, and it is since known to act as a multifunctional molecule to alleviate abiotic and biotic stresses, especially Cd stress. Endogenously triggered or exogenously applied melatonin re-establishes the redox homeostasis by the improvement of the antioxidant defense system. It can also affect the Cd transportation and sequestration by regulating the transcripts of genes related to the major metal transport system, as well as the increase in glutathione (GSH) and phytochelatins (PCs). 
  • 846
  • 10 Nov 2021
Topic Review
Strategies to Increase HDR-Dependent CRISPR-Cas9 Mediated Genome Editing
CRISPR (Clustered regularly interspaced short palindromic repeats) technology affords a simple and robust way to edit the genomes of cells, providing powerful tools for basic research and medicine. While using Cas9 to cleave a genomic site is very efficient, making a specific mutation at that site is much less so, as it depends on the endogenous DNA repair machinery. Various strategies have been developed to increase the efficiency of knock-in mutagenesis, mostly focusing on improving homology-directed repair (HDR) while reducing non-homologous end joining (NHEJ). Some approaches affect these repair mechanisms globally, while others target their modulations to the site of the Cas9-induced double-strand break (DSB). Other innovations serve to increase the specificity and the efficiency of the editing mechanisms. In addition, methods such as base editing and prime editing produce knock-in mutations without a DSB.
  • 845
  • 19 Oct 2022
Topic Review
Förster Resonance Energy Transfer (FRET)-Based Biosensor
Förster resonance energy transfer (FRET)-based biosensors are being fabricated for specific detection of biomolecules or changes in the microenvironment. FRET is a non-radiative transfer of energy from an excited donor fluorophore molecule to a nearby acceptor fluorophore molecule. In a FRET-based biosensor, the donor and acceptor molecules are typically fluorescent proteins or fluorescent nanomaterials such as quantum dots (QDs) or small molecules that are engineered to be in close proximity to each other. When the biomolecule of interest is present, it can cause a change in the distance between the donor and acceptor, leading to a change in the efficiency of FRET and a corresponding change in the fluorescence intensity of the acceptor. This change in fluorescence can be used to detect and quantify the biomolecule of interest.
  • 843
  • 18 Apr 2023
Topic Review
Therapeutic Potential of Intrabodies for Cancer Immunotherapy
Tumor cells are characterized by overexpressed tumor-associated antigens or mutated neoantigens, which are expressed on the cell surface or intracellularly. One strategy of cancer immunotherapy is to target cell-surface-expressed tumor-associated antigens (TAAs) with therapeutic antibodies. Intrabodies are suitable to knockdown TAAs and neoantigens without off-target effects. Intrabodies can now be selected against virtually any protein inside the cell. RNA sequencing and proteome analysis of single tumor cells combined with computational methods is bringing forward the identification of new neoantigens for the selection of anti-cancer intrabodies, which can be easily performed using phage display antibody repertoires. Anti-cancer intrabodies demonstrated tumor growth inhibition in appropriate xenograft tumor mouse models. At the moment, the biggest challenge in translating TAA/neoantigen-directed intrabodies into the clinic is the specific targeting of the intrabodies to the tumor cells. The promising development of tumor-specific lipid nanoparticles which could be embedded with an mRNA transgene or new capsid-modified and tumor-specific recombinant AAVs should enable tumor-cell-specific intrabody transfection/transduction in cancer patients and may finally bring intrabodies into the clinic.
  • 843
  • 02 Sep 2022
Topic Review
COP9 Signalosome
The COP9 signalosome (CSN) is a regulator of the ubiquitin proteasome system (UPS). In mammalian cells it occurs as an eight-subunit protein complex, six Proteasome-COP9 signalosome-Initiation factor eIF3 (PCI)-domain subunits including CSN1-4, CSN7 and CSN8 and two MOV34-Pad1-N-terminal (MPN)-domain subunits called CSN5 and CSN6. The CSN regulates cullin-RING-ubiquitin ligases (CRLs) by specifically removing NEDD8 from cullins. In cooperation with CAND1 it controls the adaptation of the CRL network to fluctuations in substrate availability. The CSN complex belongs to the JAMM family of deubiquitylating enzymes (DUBs). In addition, it interacts with other deubiquitylating enzymes including USP15 and USP48 coordinating ubiquitylation and deubiquitylation activities.
  • 842
  • 26 Oct 2020
Topic Review
Aptamers as Theragnostic Tools in Prostate Cancer
Aptamers are DNA and RNA oligonucleotides that can adopt tridimensional structures that enable them to join specifically to any desired target. Aptamers are capable of binding to specific molecules including drugs, proteins, carbohydrates, cells, and viruses. Aptamers were first described in 1990, and since then several groups have used their binding properties to isolate a diversity of specific aptamers. Aptamers have been studied for treatment and detection of many diseases including cancer. In Prostate Cancer, numerous works have reported their use in the development of new approaches in diagnostics and treatment strategies. Aptamers have been joined with drugs or other specific molecules such as silencing RNAs (aptamer–siRNA chimeras) to specifically reduce the expression of oncogenes in prostate cancer (PCa) cells. These studies have shown good results in the early stages, more research is still needed to demonstrate the clinical value of aptamers in PCa. 
  • 842
  • 19 Aug 2022
Topic Review
Gap Junction Channel
In most tissues, cells in contact with each other exchange cytosolic molecules of low molecular weight via channels aggregated at gap junctions. Gap junction mediated cell-to-cell communication allows neighboring cells to coordinate and regulate many functional activities in mature and developing organs. A gap junction channel is made of the interaction of two hemichannels (connexons/innexons) that form a hydrophilic pathway across the two apposed plasma membranes and the extracellular space (gap). Each connexon/innexon is an oligomer of six proteins (connexins/innexins) that span the plasma membrane and create a hydrophilic pore insulated from lipid bilayer and extracellular medium (Rev. in: Peracchia, C., Gap junction stucture and chemical regulation. Direct calmodulin role in cell-to-cell channel gating. Academic Press. An imprint of Elsevier: London, UK, 2019). Gap junction channels have been thought to possess as many as four types of gates: fast transjunctional voltage (Vj) gate, slow Vj-gate, chemical gate and gate sensitive to membrane potential (Vm). However, since the behavior of the slow Vj-gate and the Vm-sensitive is the same as that of the chemical gate, most likely these gates are the same. We have named this gate “chemical/slow gate” (Peracchia, C. Calmodulin-mediated regulation of gap junction channels. Int. J. Mol. Sci. 2020, 21, 485). In 2000, we proposed a calmodulin (CaM)-mediated “cork-type” gating model. The model proposes two mechanisms. One, “Ca-CaM-Cork”, envisions physical blockage of the channel’s mouth by a CaM lobe (N-lobe?), likely to be combined with conformational connexin changes induced by Ca2+-CaM binding to connexin sites. The other, “CaM-Cork”, also proposes a physical blockage of the channel’s mouth by a CaM lobe, but without calcium-ctivation. The first is only reversed by the return of intracellular Ca2+ concentration ([Ca2+]i) to resting values. The latter is reversed by Vj positive at the gated side (Peracchia, C. Calmodulin-Cork model of gap junction channel gating. - One molecule, two mechanisms. Int. J. Mol. Sci. 2020, 21, 4938). Evidence that gap junction mediated cell communication is finely regulated by nanomolar [Ca2+]i via the direct action of Ca2+-CaM indicates that gap junction channel gating is not just a safety mechanism for protecting cells from damaged/dead neighbors (healing-over). Rather, it is also a mechanism designed to finely modulate cell–cell exchange of small molecules. In summary: At resting [Ca2+]i, (<50nM) some channels are spontaneously closed by the CaM-Cork gating mechanism. With moderate [Ca2+]i rise (50–100 nM, the CaMKII cascade may be activated causing channels closed by the CaM-Cork mechanism to open. With greater [Ca2+]i rise (>100 nM), the channels start closing by the Ca-CaM-Cork mechanism. CaM lobe channel mouth plugging is likely to include connexin conformational changes. CaM-Cork gated channels could be reopened by Vj positive at gated side, but since they would close at the negative side no Gj change would occur. This is not the case with heterotypic channels between wild-type connexins paired with more gating-sensitive mutants. Most Ca-CaM-Cork gated channels reopen with a drop in [Ca2+]i to resting values (<50 nM). However, with prolonged exposure to high [Ca2+]i, channel gating may not be reversible. Many questions still need to be answered in terms of molecular details, such as: Is CaM anchored to the NT or the CL2 domain? Is CaM anchored to connexins by the C-lobe or the N-lobe? Is the gating lobe the N-lobe or the C-lobe? Does the gating lobe bind to the CL2 or the NT CaM binding site? Are all of the CaMs anchored to a connexon Ca2+-activated? If so, how many lobes gate the channel? Does CaM activation cause connexin conformational changes?
  • 841
  • 17 Jul 2020
Topic Review
Type 2 Transglutaminase in Coeliac Disease
Coeliac disease (CD) is a multifactiorial enteropathy that affects the small intestine of genetically predisposed individuals. A condition of partial to total atrophy, together with crypt hyperplasia and consistent lymphocytic infiltration, characterises the intestinal mucosa of affected patients. The main environmental trigger is a heterogenic proteic component of some dietary cereals, commonly known as gluten. A strong immune response against gluten, both cellular and humoral, is mounted in CD, accompanied by a humoral autoimmune response against self-proteins, in particular type 2 transglutaminase (TG2).
  • 841
  • 22 Jul 2022
Topic Review
MDM2-Based Proteolysis-Targeting Chimeras (PROTACs)
Proteolysis-targeting chimeras (PROTACs) are molecules that selectively degrade a protein of interest (POI). The incorporation of ligands that recruit mouse double minute 2 (MDM2) into PROTACs, forming the so-called MDM2-based PROTACs, has shown promise in cancer treatment due to its dual mechanism of action: a PROTAC that recruits MDM2 prevents its binding to p53, resulting not only in the degradation of POI but also in the increase of intracellular levels of the p53 suppressor, with the activation of a whole set of biological processes, such as cell cycle arrest or apoptosis. In addition, these PROTACs, in certain cases, allow for the degradation of the target, with nanomolar potency, in a rapid and sustained manner over time, with less susceptibility to the development of resistance and tolerance, without causing changes in protein expression, and with selectivity to the target, including the respective isoforms or mutations, and to the cell type, overcoming some limitations associated with the use of inhibitors for the same therapeutic target.
  • 841
  • 15 Oct 2022
Topic Review
LGR4
Leucine-rich repeats containing G protein-coupled receptor 4 (LGR4) is a receptor that belongs to the superfamily of G protein-coupled receptors that can be activated by R-spondins (RSPOs), Norrin, circLGR4, and the ligand of the receptor activator of nuclear factor kappa-B (RANKL) ligands to regulate signaling pathways in normal and pathological processes.
  • 840
  • 21 May 2021
Topic Review
Macrophage Polarization States
The M1/M2 macrophage paradigm plays a key role in tumor progression. M1 macrophages are historically regarded as anti-tumor, while M2-polarized macrophages, commonly deemed tumor-associated macrophages (TAMs), are contributors to many pro-tumorigenic outcomes in cancer through angiogenic and lymphangiogenic regulation, immune suppression, hypoxia induction, tumor cell proliferation, and metastasis.
  • 839
  • 21 Jul 2021
Topic Review
Metabolic Enzymes in Saccharomyces cerevisiae
Condensate formation by a group of metabolic enzymes in the cell is an efficient way of regulating cell metabolism through the formation of “membrane-less organelles.” Because of the use of green fluorescent protein (GFP) for investigating protein localization, various enzymes were found to form condensates or filaments in living Saccharomyces cerevisiae, mammalian cells, and in other organisms, thereby regulating cell metabolism in the certain status of the cells. 
  • 839
  • 26 Jan 2022
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