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Topic Review
Hydrogen Sulfide as a Regulator of Autophagy
The term “autophagy”, (from the Greek words auto, meaning “self” and phagein, meaning “to eat”)—literally, eating one’s self—was first created by Christian de Duve over 40 years ago, who discovered lysosomes and provided clear proof of their participation in this process. It is an evolutionarily conserved process of degradation and recycling in eukaryotic organisms. H2S is already considered a physiological mediator involved in many physiological and pathological processes in animals and plants, including autophagy.
  • 815
  • 11 Apr 2022
Topic Review
Metabolism and Bone Diseases
Bone, a highly mineralized organ that serves as a skeleton of the body, is continuously depositing and resorbing bone matrix to maintain homeostasis. This highly coordinated event is regulated throughout life by bone cells such as osteoblasts, osteoclasts, and osteocytes, and requires synchronized activities from different metabolic pathways. The dysregulation of these metabolic pathways leads to bone disorders.
  • 814
  • 30 Dec 2020
Topic Review
The V-ATPase a3 Subunit
This entry focuses on one of the 16 proteins composing the V-ATPase complex responsible for resorbing bone: the a3 subunit. The rationale for focusing on this biomolecule is that mutations in this one protein account for over 50% of osteopetrosis cases, highlighting its critical role in bone physiology. Despite its essential role in bone remodeling and its involvement in bone diseases, little is known about the way in which this subunit is targeted and regulated within osteoclasts. To this end, this review is broadened to include the three other mammalian paralogues (a1, a2 and a4) and the two yeast orthologs (Vph1p and Stv1p). By examining the literature on all of the paralogues/orthologs of the V-ATPase a subunit, we hope to provide insight into the molecular mechanisms and future research directions specific to a3. This review starts with an overview on bone, highlighting the role of V-ATPases in osteoclastic bone resorption. We then cover V-ATPases in other location/functions, highlighting the roles which the four mammalian a subunit paralogues might play in differential targeting and/or regulation. Author review the ways in which the energy of ATP hydrolysis is converted into proton translocation, and go in depth into the diverse role of the a subunit, not only in proton translocation but also in lipid binding, cell signaling and human diseases. Finally, the therapeutic implication of targeting a3 specifically for bone diseases and cancer is discussed, with concluding remarks on future directions.
  • 814
  • 21 Jul 2021
Topic Review
Let-7 as a Target in Aging-Related Diseases
Lethal-7 (let-7) was discovered in Caenorhabditis elegans (C. elegans) and plays an important role in development by regulating cell fate regulators. Accumulating evidence has shown that let-7 is elevated in aging tissues and participates in multiple pathways that regulate the aging process, including affecting tissue stem cell function, body metabolism, and various aging-related diseases (ARDs). Moreover, recent studies have found that let-7 plays an important role in the senescence of B cells, suggesting that let-7 may also participate in the aging process by regulating immune function. Therefore, these studies show the diversity and complexity of let-7 expression and regulatory functions during aging.
  • 814
  • 31 Aug 2022
Topic Review
Telomerase in Leishmania spp.
Leishmaniases are a  group of neglected tropical diseases caused by more than twenty different species of parasites of the genus Leishmania, presenting a variety of symptoms and degrees of severeness. These protozoans parasites are at the mainstream of biology/medical studies since understanding their biological particularities is crucial for the future development of antiparasitic therapies. Moreover, the comprehension of their cell cycle and its molecular mechanisms is of great value for the search of new possible treatments. In that sense,  telomeres emerge as a relevant subject in Leishmania spp. molecular biology research. They are the physical ends of eukaryotic chromosomes, granting stability to the genome and continued cell proliferation. Telomere elongation/maintenance is accomplished by a ribonucleoproteic complex called telomerase. The enzyme synthesis and adds repetitive telomeric sequences to the chromosome end termini using the 3’overhangs as substrates. In mammals, their gradual loss after many cell duplications can determine the cell fate by inducing replicative senescence or apoptosis. Here, we cover the main aspects of telomerase activity in Leishmania spp.
  • 813
  • 02 Mar 2022
Topic Review
Auxin's Role in Nitrate-Regulated Plant Growth and Development
As a major component of vital macromolecules such as nucleic acids, amino acids, and chlorophyll, nitrogen is an essential macronutrient for plants. Although nitrogen is one of the most abundant elements in nature, accounting for about 70% of atmospheric gasses, its availability for plant uptake in the soil varies temporally and spatially. Therefore, modern agriculture relies heavily on nitrogen fertilization to maximize crop quality and yield. Auxins are a group of naturally occurring molecules derived from tryptophan, with indole-3-acetic acid (IAA) being the major form of auxin. The biosynthesis of IAA is defined by a two-step metabolic pathway, in which the TAA family of aminotransferases converts tryptophan (Trp) to indole-3-pyruvate (IPA), followed by a YUC flavin monooxygenases-mediated conversion of IPA to IAA. Auxin has extensive regulatory functions in plant development. 
  • 813
  • 10 Jul 2023
Topic Review
Tetraoctylammonium
Alkylammonium salts have been used extensively to study the structure and function of potassium channels. Here, we use the long-chain, hydrophobic tetraoctylammonium (TOA+) to shed light on the structure of the inactivated state of KcsA, a tetrameric prokaryotic potassium channel. By the combined use of a thermal denaturation assay and the analysis of homo-Förster resonance energy transfer in a mutant channel containing a single tryptophan (W67) per subunit, we found that TOA+ binds the channel cavity with high affinity, either with the inner gate open or closed. Moreover, bound TOA+ induces a decrease in the affinity for K+ in the two characteristic K+ binding events to the channel selectivity filter at pH 7.0, when the channel inner gate is in the closed conformation. This is similar to that observed in the absence of TOA+ upon acidic-pH-induced channel inactivation. Therefore, this suggests that TOA+ binding by itself causes inactivation at pH 7.0 when the inner gate is closed. Furthermore, in apparent agreement with such conclusion, the presence of bound TOA+ in the pH 4.0 samples has only modest effects on the affinity of the two binding events for K+, likely because the channel is already inactivated. Finally, we also observed that TOA+ bound at the cavity, allosterically modifies the conformation of the pore helices, leading to longer W67-W67 intersubunit distances at any K+ concentration and both at pH 7.0 and pH 4.0. The changes in the pore helix conformation, along with the decreased affinity for K+ at pH 7.0 caused by TOA+, seen in both homo-FRET and thermal denaturation experiments, are very similar to those effects caused by inactivation at pH 4.0.
  • 812
  • 30 Apr 2021
Topic Review
STAMP2 in Diabetes, Inflammatory Diseases and Cancers
STAMP2 plays a pivotal role in the pathogenesis of  type II diabetes, inflammation and cancers. The six transmembrane protein of prostate 2 (STAMP2), a metalloreductase involved in iron and copper homeostasis, is well known for its critical role in the coordination of glucose/lipid metabolism and inflammation in metabolic tissues. STAMP2 is a critical modulator for coordinating metabolism and inflammation. Although STAMP2 has been widely studied focusing on the inhibitory role in inflammation and metabolism, the underlying mechanism is not fully understood. In addition to its role in metabolism and inflammation, STAMP2 is also associated with tumorigenesis. For example, STAMP2 overexpression may increase ROS, which may contribute to increased mutational rates and further progression of prostate cancer.
  • 812
  • 02 Sep 2022
Topic Review
E3 Ubiquitin Ligase TRIP12
The Thyroid hormone Receptor Interacting Protein 12 (TRIP12) protein belongs to the 28-member Homologous to the E6-AP C-Terminus (HECT) E3 ubiquitin ligase family. First described as an interactor of the thyroid hormone receptor, TRIP12’s biological importance was revealed by the embryonic lethality of a murine model bearing an inactivating mutation in the TRIP12 gene. Further studies showed the participation of TRIP12 in the regulation of major biological processes such as cell cycle progression, DNA damage repair, chromatin remodeling, and cell differentiation by an ubiquitination-mediated degradation of key protein substrates. Moreover, alterations of TRIP12 expression have been reported in cancers that can serve as predictive markers of therapeutic response. The TRIP12 gene is also referenced as a causative gene associated to intellectual disorders such as Clark–Baraitser syndrome and is clearly implicated in Autism Spectrum Disorder. The aim of the review is to provide an exhaustive and integrated overview of the different aspects of TRIP12 ranging from its regulation, molecular functions and physio-pathological implications.
  • 811
  • 23 Nov 2020
Topic Review
Non-Alcoholic Steatohepatitis and Organokines
Non-alcoholic steatohepatitis (NASH) is characterized by steatosis, lobular inflammation, and enlargement of the diameter of hepatocytes (ballooning hepatocytes), with or without fibrosis. It affects 20% of patients with non-alcoholic fatty liver disease (NAFLD). Due to liver dysfunction and the numerous metabolic changes that commonly accompany the condition (obesity, insulin resistance, type 2 diabetes, and metabolic syndrome), the secretion of organokines is modified, which may contribute to the pathogenesis or progression of the disease. 
  • 811
  • 23 Jul 2023
Topic Review
Cu2+ and Osteoclast
Copper-containing biomaterials are increasingly applied for bone regeneration due to their pro-angiogenetic, pro-osteogenetic and antimicrobial properties. Therefore, the effect of Cu2+ on osteoclasts, which play a major role in bone remodeling was studied in detail. Methods: Human primary osteoclasts, differentiated from human monocytes were differentiated or cultivated in the presence of Cu2+. Osteoclast formation and activity were analyzed by measurement of osteoclast-specific enzyme activities, gene expression analysis and resorption assays. Furthermore, the glutathione levels of the cells were checked to evaluate oxidative stress induced by Cu2+. Results: Up to 8 µM Cu2+ did not induce cytotoxic effects. Activity of tartrate-resistant acid phosphatase (TRAP) was significantly increased, while other osteoclast specific enzyme activities were not affected. However, gene expression of TRAP was not upregulated. Resorptive activity of osteoclasts towards dentin was not changed in the presence of 8 µM Cu2+ but decreased in the presence of extracellular bone matrix. When Cu2+ was added to mature osteoclasts TRAP activity was not increased and resorption decreased only moderately. The glutathione level of both differentiating and mature osteoclasts was significantly decreased in the presence of Cu2+. Conclusions: Differentiating and mature osteoclasts react differently to Cu2+. High TRAP activities are not necessarily related to high resorption.
  • 810
  • 16 Mar 2021
Topic Review
Multifunctionality in Microbial Adhesins
Microbial adhesins have multiple functions, and these activities are all evolved and selected. Adhesins can act as enzymes, as assembly scaffolds and components of complex nano-machines. Sometimes, these activities are called secondary because they were discovered secondarily. For instance, microbial type IV pili were first called adhesive. In contrast, phosphoglycerate kinase has its well-known enzymatic activity, but in fungi it also moonlights as an extracellular adhesin.
  • 810
  • 16 Jun 2023
Topic Review
Novel Therapies for T1D
It is well established that genetic and environmental factors contribute to the initiation and progression of type 1 diabetes, but recent studies show that epigenetic modifications are also important.  Key epigenetic modifications associated with type 1 diabetes pathogenesis and the ways to harness epigenetic mechanisms to prevent, reverse, or manage T1D have been discussed in details. 
  • 809
  • 20 Nov 2020
Topic Review
Brain Tissue Respiration in Trauma
The passage of oxygen (O2) from vessels into the cells comprises multiple steps in different volumes (e.g., intracellular erythrocytes, plasma, interstitial tissue, intracellular brain cells) and is influenced by multiple physiological factors (e.g., cerebral blood flow, capillary density, concentration of hemoglobin (Hb), O2 affinity for Hb). The pathogenesis of brain trauma may alter the mechanisms that regulate these steps.
  • 809
  • 10 May 2021
Topic Review
Plasma Proteomics in Morquio-A Disease
Mucopolysaccharidosis type IVA (MPS IVA) is a lysosomal disease caused by mutations in the gene encoding the enzymeN-acetylgalactosamine-6-sulfate sulfatase (GALNS), and is characterized by systemic skeletal dysplasia due to excessive storage of keratan sulfate (KS) and chondroitin-6-sulfate in chondrocytes. Although improvements in the activity of daily living and endurance tests have been achieved with enzyme replacement therapy (ERT) with recombinant human GALNS, recovery of bone lesions and bone growth in MPS IVA has not been demonstrated to date. Moreover, no correlation has been described between therapeutic efficacy and urine levels of KS, which accumulates in MPS IVA patients. 
  • 809
  • 26 Jul 2021
Topic Review
AR and PI3K/AKT in Prostate Cancer
The androgen receptor (AR) has a pivotal role in the pathogenesis and progression of PCa. Many therapies targeting AR signaling have been developed over the years. AR signaling inhibitors (ARSIs), including androgen synthesis inhibitors and AR antagonists, have proven to be effective in castration-sensitive PCa (CSPC) and improve survival, but men with castration-resistant PCa (CRPC) continue to have a poor prognosis. Despite a good initial response, drug resistance develops in almost all patients with metastatic CRPC, and ARSIs are no longer effective. Several mechanisms confer resistance to ARSI and include AR mutations but also hyperactivation of other pathways, such as PI3K/AKT/mTOR. This pathway controls key cellular processes, including proliferation and tumor progression, and it is the most frequently deregulated pathway in human cancers.
  • 808
  • 02 Feb 2023
Topic Review
Epigenetic Alterations in Pancreatic Cancer
Pancreatic ductal adenocarcinoma (PDA) has long been thought of as a disease arising and progressing from genetic mutations. More recently, it has become clear that epigenetic alterations are also important contributors to PDA progression and metastasis. While no single epigenetic regulator is commonly mutated in PDA, a growing body of evidence indicated that metastatic tissues exhibit distinct epigenetic status compared to primary tumor tissues, which might be exploited for cancer therapeutics and diagnostics.
  • 807
  • 10 Aug 2021
Topic Review
Consequences of COVID-19 for Pancreas
Coronaviruses are enveloped, single- and positive-stranded RNA viruses that infect birds and mammals. In humans, coronaviruses cause respiratory tract infection, usually the common cold, but they can also cause severe respiratory illness including severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS), caused by severe acute respiratory syndrome-related coronavirus (SARS-CoV) and Middle East respiratory syndrome-related coronavirus (MERS-CoV), respectively. Although coronavirus disease 2019 (COVID-19)-related major health consequences involve the lungs, a growing body of evidence indicates that COVID-19 is not inert to the pancreas either. 
  • 807
  • 26 Jan 2022
Topic Review
Cancer Stem Cells in Tumor Microenvironment
Cancer is a multi-step process during which cells acquire an untamed ability to grow, proliferate, and (most times) differentiate, ultimately leading to either improper organ growth or the establishment of inadequate cells in locations where they contribute negatively to the body homeostasis, causing (amongst other things) high levels of inflammation. Colorectal and gastric cancers are the most prevalent cancer in the digestive track. They represent the third and fifth leading causes of cancer-related deaths. With over 500,000–990,000 new cases worldwide, they typically have a five-year survival rate (mainly due to late diagnosis).
  • 807
  • 31 Aug 2022
Topic Review
m6A Modification and Glucose Metabolism
The highly conserved and dynamically reversible N6-methyladenine (m6A) modification has emerged as a critical gene expression regulator by affecting RNA splicing, translation efficiency, and stability at the post-transcriptional level, which has been established to be involved in various physiological and pathological processes, including glycolipid metabolism and the development of glycolipid metabolic disease (GLMD). Hence, accumulating studies have focused on the effects and regulatory mechanisms of m6A modification on glucose metabolism, lipid metabolism, and GLMD. Glucose metabolism involves a very complex regulatory network, including anaerobic glycolysis, aerobic oxidation, pentose phosphate pathway, glycogen synthesis, and gluconeogenesis. An increasing number of studies have reported that m6A modification is an important regulatory mechanism of glucose homeostasis and downstream effects.
  • 807
  • 14 Feb 2023
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