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Topic Review
Venom Constituents of Rattlesnake Venoms
Venom components are invaluable in biomedical research owing to their specificity and potency. Many of these components exist in two genera of rattlesnakes, Crotalus and Sistrurus, with high toxicity and proteolytic activity variation. 
  • 1.3K
  • 18 Apr 2024
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?
  • 1.3K
  • 17 Jul 2020
Topic Review
Calcium Dyshomeostasis in Alzheimer’s Disease
Alzheimer’s disease (AD) is the most common age-related neurodegenerative disorder that is characterized by amyloid β-protein deposition in senile plaques, neurofibrillary tangles consisting of abnormally phosphorylated tau protein, and neuronal loss leading to cognitive decline and dementia. Despite extensive research, the exact mechanisms underlying AD remain unknown and effective treatment is not available. Many hypotheses have been proposed to explain AD pathophysiology; however, there is general consensus that the abnormal aggregation of the amyloid β peptide (Aβ) is the initial event triggering a pathogenic cascade of degenerating events in cholinergic neurons. The dysregulation of calcium homeostasis has been studied considerably to clarify the mechanisms of neurodegeneration induced by Aβ. Intracellular calcium acts as a second messenger and plays a key role in the regulation of neuronal functions, such as neural growth and differentiation, action potential, and synaptic plasticity. The calcium hypothesis of AD posits that activation of the amyloidogenic pathway affects neuronal Ca2+ homeostasis and the mechanisms responsible for learning and memory. Aβ can disrupt Ca2+ signaling through several mechanisms, by increasing the influx of Ca2+ from the extracellular space and by activating its release from intracellular stores. Here, we review the different molecular mechanisms and receptors involved in calcium dysregulation in AD and possible therapeutic strategies for improving the treatment.
  • 1.3K
  • 11 Oct 2021
Topic Review
FTO Dioxygenase
The FTO (FaT mass and Obesity-associated) protein is an alpha-ketoglutarate and iron dependent dioxygenase, a member of ALKBH family proteins. FTO removes the methyl groups from modified nucleotides on single stranded DNA or RNA with N6-methyladenozine in the mRNA removed most efficiently. It is engaged in wide range of key physiological processes such as adipogenesis, cell cycle progression, heart remodelling, neural development and osteogenesis. Impairments of FTO activity is lethal or leads to serious developmental disorders. It is also one of the factors responsible for development and maintenance of many type of cancers. FTO acts in cooperation with other proteins e.g. CaMKII, MRS, SFPQ or XPO2. Similarly to other dioxygenases, it shows ability to form homodimer. Recently, it was shown that FTO interacts with the calmodulin (CaM) in Ca2+ dependent manner.
  • 1.3K
  • 26 Oct 2021
Topic Review
Marine Algae Polysaccharide in Gut Microbiota
Cardiovascular disease (CVD) is the number one cause of death worldwide. Evidence has demonstrated an association between the gut microbiota and CVD, including heart failure, cerebrovascular illness, hypertension, and stroke. Marine algal polysaccharides (MAPs) are valuable natural sources of diverse bioactive compounds. MAPs have many pharmaceutical activities, including antioxidant, anti-inflammatory, immunomodulatory, and antidiabetic effects. 
  • 1.3K
  • 28 Nov 2022
Topic Review
Phytochemicals in Redox Homeostasis
Redox homeostasis, a dynamic process ensuring a balance between cellular oxidizing and reducing reactions, is crucial for maintaining healthy cellular physiology and regulating many biological processes, requiring continuous monitoring and fine-tuning. Reactive species play a critical role in intra/intercellular signaling, and each cell has a specific system guarding cellular redox homeostasis. Reactive oxygen species (ROS) signaling and oxidative stress are involved in cancer initiation and progression.
  • 1.3K
  • 24 Apr 2023
Topic Review
Antioxidant Potential of Psychotropic Drugs
Due to high oxygen consumption, the brain is particularly vulnerable to oxidative stress, which is considered an important element in the etiopathogenesis of several mental disorders, including schizophrenia, depression and dependencies. Despite the fact that it is not established yet whether oxidative stress is a cause or a consequence of clinic manifestations, the intake of antioxidant supplements in combination with the psychotropic therapy constitutes a valuable solution in patients’ treatment. When the psychoactive compounds possess themselves antioxidant capacity, this is an added-value for the therapy.
  • 1.3K
  • 12 Oct 2020
Topic Review
Tau protein Interaction Partners
Tau protein belongs to the family of microtubule-associated proteins (MAPs) and can influence axonal transport and growth, neuronal polarization, and thus the normal function of neurons and the brain.
  • 1.3K
  • 15 Dec 2021
Topic Review
Polymer- and Lipid-Based siRNA Nanoparticles
The mechanism of RNA interference (RNAi) could represent a breakthrough in the therapy of all diseases that arise from a gene defect or require the inhibition of a specific gene expression. In particular, small interfering RNA (siRNA) offers an attractive opportunity to achieve a new milestone in the therapy of human diseases.
  • 1.3K
  • 17 Nov 2022
Topic Review
Nutriepigenomics in Environmental-Associated Oxidative Stress
Complex molecular mechanisms define our responses to environmental stimuli. Beyond the DNA sequence itself, epigenetic machinery orchestrates changes in gene expression induced by diet, physical activity, stress and pollution, among others. Importantly, nutrition has a strong impact on epigenetic players and, consequently, sustains a promising role in the regulation of cellular responses such as oxidative stress. As oxidative stress is a natural physiological process where the presence of reactive oxygen-derived species and nitrogen-derived species overcomes the uptake strategy of antioxidant defenses, it plays an essential role in epigenetic changes induced by environmental pollutants and culminates in signaling the disruption of redox control. 
  • 1.3K
  • 18 Apr 2023
Topic Review
Irisin and Autophagy: First Update
Aging and sedentary life style are considered independent risk factors for many disorders. Under these conditions, accumulation of dysfunctional and damaged cellular proteins and organelles occurs, resulting in a cellular degeneration and cell death. Autophagy is a conserved recycling pathway responsible for the degradation, then turnover of cellular proteins and organelles. This process is a part of the molecular underpinnings by which exercise promotes healthy aging and mitigate age-related pathologies. Irisin is a myokine released during physical activity and acts as a link between muscles and other tissues and organs. Its main beneficial function is the change of subcutaneous and visceral adipose tissue into brown adipose tissue, with a consequential increase in thermogenesis. Irisin modulates metabolic processes, acting on glucose homeostasis, reduces systemic inflammation, maintains the balance between resorption and bone formation, and regulates the functioning of the nervous system. Recently, some of its pleiotropic and favorable properties have been attributed to autophagy induction, posing irisin as an important regulator of autophagy by exercise.
  • 1.3K
  • 29 Oct 2020
Topic Review
PARP Inhibitors
 Poly (adenosine diphosphate-ribose) polymerase inhibitors (PARPis) belong to a class of targeted drugs developed for the treatment of homologous recombination repair (HRR)-defective tumors. Preclinical and limited clinical data suggest that PARP inhibition is effective against prostate cancer (PC) in patients with HRR-deficient tumors and that PARPis can improve the mortality rate of PC in patients with BRCA1/2 mutations through a synthetic lethality. 
  • 1.3K
  • 24 May 2021
Topic Review
Engineering and Expression Strategies for Optimization of L-Asparaginase
L-asparaginase, an enzyme widely used in the clinic for the treatment of leukemia and in bakeries for the reduction of acrylamide. Newly developed recombinant L-asparaginase (L-ASNase) may have a low affinity for asparagine, reduced catalytic activity, low stability, and increased glutaminase activity or immunogenicity. Some successful commercial preparations of L-ASNase are now available. Therefore, obtaining novel L-ASNases with improved properties suitable for food or clinical applications remains a challenge. 
  • 1.3K
  • 23 Nov 2023
Topic Review
Mechanisms of Alcohol-Mediated Toxicity
Alcohol is one of the commonly used drugs. Ethanol, together with its derivatives and metabolites, exhibits diverse direct and indirect toxic effects, which are responsible for damage to many organs. This toxicity depends on many factors, such as dose, gender, associated comorbidities, or genetic predisposition.
  • 1.3K
  • 26 Nov 2021
Topic Review
The Origin of Translation
Extant biology uses RNA to record genetic information and proteins to execute biochemical functions. Nucleotides are translated into amino acids via transfer RNA in the central dogma. tRNA is essential in translation as it connects the codon and the cognate amino acid. Among the three steps in the central dogma, translation is the most important as it bridges the world of nucleic acids and the world of amino acids. In the “RNA world” hypothesis, RNA came first from the primordial environment, recorded the genetic information, and catalyzed fundamental biochemical reactions. Later, RNA alienated the catalytic function of peptides and proteins and released the information storage function to DNA. DNA self-copy, i.e., replication, and DNA-templated RNA polymerization, i.e., transcription, are more intuitive and practicable in prebiotic settings compared to RNA-coded peptide formation. Translation takes place in the endoplasmic reticulum membrane in the cytoplasm with messenger RNA as the template, transfer RNA as the adaptor, and ribosome RNA as the catalytic core. 
  • 1.3K
  • 31 Jan 2023
Topic Review
SRC-3
Steroid receptor coactivator-3 (SRC-3), also known as amplified in breast cancer 1 (AIB1), is a member of the SRC family. SRC-3 regulates not only the transcriptional activity of nuclear receptors but also many other transcription factors. Besides the essential role of SRC-3 in physiological functions, it also acts as an oncogene to promote multiple aspects of cancer.
  • 1.3K
  • 25 May 2021
Topic Review
Chronic Inflammation and Radiation-Induced Cystitis
Radiation cystitis is a potential complication following the therapeutic irradiation of pelvic cancers.
  • 1.3K
  • 19 Jan 2021
Topic Review
FHL2
Four and a half LIM domains 2 (FHL2) was originally described as ‘Down-regulated in Rhabdomyosarcoma LIM protein’ (DRAL) and is composed of LIM domains that are named after their initial discovery in the proteins Lin11, Isl-1 and Mec-3. FHL2 consists of four and a half LIM domains, each composed of two zinc fingers, except the first ‘half’ LIM-domain which has only one. While the structure of the four and a half LIM domains had been uncovered previously using Nuclear Magnetic Resonance (NMR) spectroscopy, the complete FHL2 protein structure is unknown; however, it has recently been predicted using the protein structure neural network AlphaFold.
  • 1.3K
  • 19 Oct 2021
Topic Review
Alternative Splicing and Isoforms
Alternative splicing of pre-mRNA is a key mechanism for increasing the complexity of proteins in humans, causing a diversity of expression of transcriptomes and proteomes in a tissue-specific manner. Alternative splicing is an essential process in post-transcriptional mRNA processing, and produces various mature mRNAs with different structures and functions.
  • 1.3K
  • 10 Mar 2022
Topic Review
Impact of TRAP1 on Cancer Metabolism
The Hsp90 chaperone TNF-receptor-associated protein-1 (TRAP1) is primarily localized to the mitochondria and controls both cellular metabolic reprogramming and mitochondrial apoptosis. TRAP1 upregulation facilitates the growth and progression of many cancers by promoting glycolytic metabolism and antagonizing the mitochondrial permeability transition that precedes multiple cell death pathways. TRAP1 attenuation induces apoptosis in cellular models of cancer, identifying TRAP1 as a potential therapeutic target in cancer. Similar to cytosolic Hsp90 proteins, TRAP1 is also subject to post-translational modifications (PTM) that regulate its function and mediate its impact on downstream effectors, or ‘clients’.
  • 1.3K
  • 08 Jun 2022
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