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Biomolecules, Volume 12, Issue 8 (August 2022) – 152 articles

Cover Story (view full-size image): More than two years after the appearance of SARS-CoV-2, COVID-19 is still a public health emergency. Thus, the need to develop new active therapies based on nanomaterials but also derived from natural matrices is evident. Herein, we have reviewed the most innovative nanomaterials that show potential for use as therapeutic agents as well as measures to control virus spread. Furthermore, the review shows how computer-aided technologies can identify, in a rapid and constantly updated way, plant drugs potentially able to inhibit SARS-CoV-2 cell penetration. View this paper
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Article
N-Palmitoyl-D-Glucosamine Inhibits TLR-4/NLRP3 and Improves DNBS-Induced Colon Inflammation through a PPAR-α-Dependent Mechanism
Biomolecules 2022, 12(8), 1163; https://doi.org/10.3390/biom12081163 - 22 Aug 2022
Viewed by 653
Abstract
Similar to canine inflammatory enteropathy, inflammatory bowel disease (IBD) is a chronic idiopathic condition characterized by remission periods and recurrent flares in which diarrhea, visceral pain, rectal bleeding/bloody stools, and weight loss are the main clinical symptoms. Intestinal barrier function alterations often persist [...] Read more.
Similar to canine inflammatory enteropathy, inflammatory bowel disease (IBD) is a chronic idiopathic condition characterized by remission periods and recurrent flares in which diarrhea, visceral pain, rectal bleeding/bloody stools, and weight loss are the main clinical symptoms. Intestinal barrier function alterations often persist in the remission phase of the disease without ongoing inflammatory processes. However, current therapies include mainly anti-inflammatory compounds that fail to promote functional symptoms-free disease remission, urging new drug discoveries to handle patients during this step of the disease. ALIAmides (ALIA, autacoid local injury antagonism) are bioactive fatty acid amides that recently gained attention because of their involvement in the control of inflammatory response, prompting the use of these molecules as plausible therapeutic strategies in the treatment of several chronic inflammatory conditions. N-palmitoyl-D-glucosamine (PGA), an under-researched ALIAmide, resulted in being safe and effective in preclinical models of inflammation and pain, suggesting its potential engagement in the treatment of IBD. In our study, we demonstrated that micronized PGA significantly and dose-dependently reduces colitis severity, improves intestinal mucosa integrity by increasing the tight junction proteins expression, and downregulates the TLR-4/NLRP3/iNOS pathway via PPAR-α receptors signaling in DNBS-treated mice. The possibility of clinically exploiting micronized PGA as support for the treatment and prevention of inflammation-related changes in IBD patients would represent an innovative, effective, and safe strategy. Full article
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Article
Palmitic Acid Impedes Extravillous Trophoblast Activity by Increasing MRP1 Expression and Function
Biomolecules 2022, 12(8), 1162; https://doi.org/10.3390/biom12081162 - 22 Aug 2022
Viewed by 497
Abstract
Normal function of placental extravillous trophoblasts (EVTs), which are responsible for uteroplacental vascular remodeling, is critical for adequate delivery of oxygen and nutrients to the developing fetus and normal fetal programming. Proliferation and invasion of spiral arteries by EVTs depends upon adequate levels [...] Read more.
Normal function of placental extravillous trophoblasts (EVTs), which are responsible for uteroplacental vascular remodeling, is critical for adequate delivery of oxygen and nutrients to the developing fetus and normal fetal programming. Proliferation and invasion of spiral arteries by EVTs depends upon adequate levels of folate. Multidrug resistance-associated protein 1 (MRP1), which is an efflux transporter, is known to remove folate from these cells. We hypothesized that palmitic acid increases MRP1-mediated folate removal from EVTs, thereby interfering with EVTs’ role in early placental vascular remodeling. HTR-8/SVneo and Swan-71 cells, first trimester human EVTs, were grown in the absence or presence of 0.5 mM and 0.7 mM palmitic acid, respectively, for 72 h. Palmitic acid increased ABCC1 gene expression and MRP1 protein expression in both cell lines. The rate of folate efflux from the cells into the media increased with a decrease in migration and invasion functions in the cultured cells. Treatment with N-acetylcysteine (NAC) prevented the palmitic acid-mediated upregulation of MRP1 and restored invasion and migration in the EVTs. Finally, in an ABCC1 knockout subline of Swan-71 cells, there was a significant increase in invasion and migration functions. The novel finding in this study that palmitic acid increases MRP1-mediated folate efflux provides a missing link that helps to explain how maternal consumption of saturated fatty acids compromises the in utero environment. Full article
(This article belongs to the Collection Feature Papers in Molecular Reproduction)
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Review
Synaptic Effects of Palmitoylethanolamide in Neurodegenerative Disorders
Biomolecules 2022, 12(8), 1161; https://doi.org/10.3390/biom12081161 - 22 Aug 2022
Viewed by 583
Abstract
Increasing evidence strongly supports the key role of neuroinflammation in the pathophysiology of neurodegenerative diseases, such as Alzheimer’s disease, frontotemporal dementia, and amyotrophic lateral sclerosis. Neuroinflammation may alter synaptic transmission contributing to the progression of neurodegeneration, as largely documented in animal models and [...] Read more.
Increasing evidence strongly supports the key role of neuroinflammation in the pathophysiology of neurodegenerative diseases, such as Alzheimer’s disease, frontotemporal dementia, and amyotrophic lateral sclerosis. Neuroinflammation may alter synaptic transmission contributing to the progression of neurodegeneration, as largely documented in animal models and in patients’ studies. In the last few years, palmitoylethanolamide (PEA), an endogenous lipid mediator, and its new composite, which is a formulation constituted of PEA and the well-recognized antioxidant flavonoid luteolin (Lut) subjected to an ultra-micronization process (co-ultraPEALut), has been identified as a potential therapeutic agent in different disorders by exerting potential beneficial effects on neurodegeneration and neuroinflammation by modulating synaptic transmission. In this review, we will show the potential therapeutic effects of PEA in animal models and in patients affected by neurodegenerative disorders. Full article
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Article
The Resistome of ESKAPEE Pathogens in Untreated and Treated Wastewater: A Polish Case Study
Biomolecules 2022, 12(8), 1160; https://doi.org/10.3390/biom12081160 - 21 Aug 2022
Viewed by 510
Abstract
The aim of this study was to quantify ESKAPEE bacteria, genes encoding resistance to antibiotics targeting this group of pathogens, as well as integrase genes in municipal wastewater and river water. Environmental DNA was extracted from the collected samples and used in deep [...] Read more.
The aim of this study was to quantify ESKAPEE bacteria, genes encoding resistance to antibiotics targeting this group of pathogens, as well as integrase genes in municipal wastewater and river water. Environmental DNA was extracted from the collected samples and used in deep sequencing with the Illumina TruSeq kit. The abundance of bacterial genera and species belonging to the ESKAPEE group, 400 ARGs associated with this microbial group, and three classes of integrase genes were determined. A taxonomic analysis revealed that Acinetobacter was the dominant bacterial genus, whereas Acinetobacter baumannii and Escherichia coli were the dominant bacterial species. The analyzed samples were characterized by the highest concentrations of the following ARGs: blaGES, blaOXA-58, blaTEM, qnrB, and qnrS. Acinetobacter baumannii, E. coli, and genes encoding resistance to β-lactams (blaVEB-1, blaIMP-1, blaGES, blaOXA-58, blaCTX-M, and blaTEM) and fluoroquinolones (qnrS) were detected in samples of river water collected downstream from the wastewater discharge point. The correlation analysis revealed a strong relationship between A. baumannii (bacterial species regarded as an emerging human pathogen) and genes encoding resistance to all tested groups of antimicrobials. The transmission of the studied bacteria (in particular A. baumannii) and ARGs to the aquatic environment poses a public health risk. Full article
(This article belongs to the Special Issue State-of-the-Art in Antibiotics Resistance)
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Article
Testosterone Enanthate: An In Vitro Study of the Effects Triggered in MG-63 Cells
Biomolecules 2022, 12(8), 1159; https://doi.org/10.3390/biom12081159 - 21 Aug 2022
Viewed by 439
Abstract
The aim of this study was to investigate the effects of the androgenic hormone testosterone enanthate (TE) on human MG-63 cells. MG-63 were cultured for 24 h in the presence of TE at increasing concentrations to assess its lethal dose. Therefore, the suitable [...] Read more.
The aim of this study was to investigate the effects of the androgenic hormone testosterone enanthate (TE) on human MG-63 cells. MG-63 were cultured for 24 h in the presence of TE at increasing concentrations to assess its lethal dose. Therefore, the suitable concentration for a prolonged use of TE in vitro was assessed by viability assay over 9 days. Finally, MG-63 were exposed to TE for 14 days and assayed for differentiation by qPCR and Alizarin Red S staining. TE in the amount of 100 µM resulted as the maximum dose tolerated by MG-63 cells after 24 h. However, a prolonged exposure in culture TE in the amount of 100 µM showed a cytostatic effect on cell proliferation. On the contrary, TE 10 µM was tolerated by the cells and did not boost cell proliferation, but did enhance new bone formation, as revealed by COL1A1, ALPL, BGLAP, and IBSP gene expression after 3, 7, and 14 days, and calcium deposition by Alizarin Red S staining after 14 days. Based on the current study, 10 µM is the critical dose of TE that should be used in vitro to support bone differentiation of MG-63 cells. Full article
(This article belongs to the Section Synthetic Biology and Bioengineering)
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Review
Research Progress on the Role of RNA m6A Modification in Glial Cells in the Regulation of Neurological Diseases
Biomolecules 2022, 12(8), 1158; https://doi.org/10.3390/biom12081158 - 21 Aug 2022
Viewed by 753
Abstract
Glial cells are the most abundant and widely distributed cells that maintain cerebral homeostasis in the central nervous system. They mainly include microglia, astrocytes, and the oligodendrocyte lineage cells. Moreover, glial cells may induce pathological changes, such as inflammatory responses, demyelination, and disruption [...] Read more.
Glial cells are the most abundant and widely distributed cells that maintain cerebral homeostasis in the central nervous system. They mainly include microglia, astrocytes, and the oligodendrocyte lineage cells. Moreover, glial cells may induce pathological changes, such as inflammatory responses, demyelination, and disruption of the blood–brain barrier, to regulate the occurrence and development of neurological diseases through various molecular mechanisms. Furthermore, RNA m6A modifications are involved in various pathological processes associated with glial cells. In this review, the roles of glial cells in physiological and pathological states, as well as advances in understanding the mechanisms by which glial cells regulate neurological diseases under RNA m6A modification, are summarized, hoping to provide new perspectives on the deeper mechanisms and potential therapeutic targets for neurological diseases. Full article
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Article
Periostin Augments Vascular Smooth Muscle Cell Calcification via β-Catenin Signaling
Biomolecules 2022, 12(8), 1157; https://doi.org/10.3390/biom12081157 - 21 Aug 2022
Viewed by 486
Abstract
Medial vascular calcification is common in chronic kidney disease (CKD) and is closely linked to hyperphosphatemia. Vascular smooth muscle cells (VSMCs) can take up pro-calcific properties and actively augment vascular calcification. Various pro-inflammatory mediators are able to promote VSMC calcification. In this study, [...] Read more.
Medial vascular calcification is common in chronic kidney disease (CKD) and is closely linked to hyperphosphatemia. Vascular smooth muscle cells (VSMCs) can take up pro-calcific properties and actively augment vascular calcification. Various pro-inflammatory mediators are able to promote VSMC calcification. In this study, we investigated the effects and mechanisms of periostin, a matricellular signaling protein, in calcifying human VSMCs and human serum samples. As a result, periostin induced the mRNA expression of pro-calcific markers in VSMCs. Furthermore, periostin augmented the effects of β-glycerophosphate on the expression of pro-calcific markers and aggravated the calcification of VSMCs. A periostin treatment was associated with an increased β-catenin abundance as well as the expression of target genes. The pro-calcific effects of periostin were ameliorated by WNT/β-catenin pathway inhibitors. Moreover, a co-treatment with an integrin αvβ3-blocking antibody blunted the pro-calcific effects of periostin. The silencing of periostin reduced the effects of β-glycerophosphate on the expression of pro-calcific markers and the calcification of VSMCs. Elevated serum periostin levels were observed in hemodialysis patients compared with healthy controls. These observations identified periostin as an augmentative factor in VSMC calcification. The pro-calcific effects of periostin involve integrin αvβ3 and the activation of the WNT/β-catenin pathway. Thus, the inhibition of periostin may be beneficial to reduce the burden of vascular calcification in CKD patients. Full article
(This article belongs to the Special Issue Calcification in Cardiovascular Disease)
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Article
Prediction of Potential Commercially Available Inhibitors against SARS-CoV-2 by Multi-Task Deep Learning Model
Biomolecules 2022, 12(8), 1156; https://doi.org/10.3390/biom12081156 - 21 Aug 2022
Cited by 2 | Viewed by 538
Abstract
The outbreak of COVID-19 caused millions of deaths worldwide, and the number of total infections is still rising. It is necessary to identify some potentially effective drugs that can be used to prevent the development of severe symptoms, or even death for those [...] Read more.
The outbreak of COVID-19 caused millions of deaths worldwide, and the number of total infections is still rising. It is necessary to identify some potentially effective drugs that can be used to prevent the development of severe symptoms, or even death for those infected. Fortunately, many efforts have been made and several effective drugs have been identified. The rapidly increasing amount of data is of great help for training an effective and specific deep learning model. In this study, we propose a multi-task deep learning model for the purpose of screening commercially available and effective inhibitors against SARS-CoV-2. First, we pretrained a model on several heterogenous protein–ligand interaction datasets. The model achieved competitive results on some benchmark datasets. Next, a coronavirus-specific dataset was collected and used to fine-tune the model. Then, the fine-tuned model was used to select commercially available drugs against SARS-CoV-2 protein targets. Overall, twenty compounds were listed as potential inhibitors. We further explored the model interpretability and exhibited the predicted important binding sites. Based on this prediction, molecular docking was also performed to visualize the binding modes of the selected inhibitors. Full article
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Article
The Beneficial Effects of Ultramicronized Palmitoylethanolamide in the Management of Neuropathic Pain and Associated Mood Disorders Induced by Paclitaxel in Mice
Biomolecules 2022, 12(8), 1155; https://doi.org/10.3390/biom12081155 - 20 Aug 2022
Viewed by 518
Abstract
Chemotherapy-induced peripheral neuropathy (CIPN) is a common complication of antineoplastic drugs, particularly paclitaxel (PTX). It can affect the quality of patients’ lives and increase the risk of developing mood disorders. Although several drugs are recommended, they yielded inconclusive results in clinical trials. The [...] Read more.
Chemotherapy-induced peripheral neuropathy (CIPN) is a common complication of antineoplastic drugs, particularly paclitaxel (PTX). It can affect the quality of patients’ lives and increase the risk of developing mood disorders. Although several drugs are recommended, they yielded inconclusive results in clinical trials. The aim of the present work is to investigate whether the palmitoylethanolamide (PEA) would reduce PTX-induced CIPN and associated mood disorders. Moreover, the role PPAR-α and the endocannabinoid system will also be investigated. CIPN was induced by intraperitoneally injection of PTX (8 mg/kg) every other day for a week. PEA, 30 mg/kg, was orally administrated in a bioavailable form (i.e., ultramicronized PEA, um-PEA) one hour after the last PTX injection, for 7 days. In the antagonism experiments, AM281 (1 mg/kg) and GW6471 (2 mg/kg) were administrated 30 min before um-PEA. Our results demonstrated that um-PEA reduced the development of hypersensitivity with the effect being associated with the reduction in spinal and hippocampal pro-inflammatory cytokines, as well as antidepressive and anxiolytic effects. Moreover, the PPAR-α and CB1 receptor antagonists blocked the behavioral and antinociceptive effects of um-PEA. Our findings suggest that um-PEA is a promising adjunct in CIPN and associated mood disorders through the activation of PPAR-α, which influences the endocannabinoid system. Full article
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Article
Isolation, Purification, and Characterisation of a Phage Tail-Like Bacteriocin from the Insect Pathogenic Bacterium Brevibacillus laterosporus
Biomolecules 2022, 12(8), 1154; https://doi.org/10.3390/biom12081154 - 20 Aug 2022
Viewed by 593
Abstract
The Gram-positive and spore-forming bacterium Brevibacillus laterosporus (Bl) belongs to the Brevibacillus brevis phylogenetic cluster. Isolates of the species have demonstrated pesticidal potency against a wide range of invertebrate pests and plant diseases. Two New Zealand isolates, Bl 1821L and Bl [...] Read more.
The Gram-positive and spore-forming bacterium Brevibacillus laterosporus (Bl) belongs to the Brevibacillus brevis phylogenetic cluster. Isolates of the species have demonstrated pesticidal potency against a wide range of invertebrate pests and plant diseases. Two New Zealand isolates, Bl 1821L and Bl 1951, are under development as biopesticides for control of diamondback moth and other pests. However, due to the often-restricted growth of these endemic isolates, production can be an issue. Based on the previous work, it was hypothesised that the putative phages might be involved. During investigations of the cause of the disrupted growth, electron micrographs of crude lysate of Bl 1821L showed the presence of phages’ tail-like structures. A soft agar overlay method with PEG 8000 precipitation was used to differentiate between the antagonistic activity of the putative phage and phage tail-like structures (bacteriocins). Assay tests authenticated the absence of putative phage activity. Using the same method, broad-spectrum antibacterial activity of Bl 1821L lysate against several Gram-positive bacteria was found. SDS-PAGE of sucrose density gradient purified and 10 kD MWCO concentrated lysate showed a prominent protein band of ~48 kD, and transmission electron microscopy revealed the presence of polysheath-like structures. N-terminal sequencing of the ~48 kD protein mapped to a gene with weak predicted amino acid homology to a Bacillus PBSX phage-like element xkdK, the translated product of which shared >90% amino acid similarity to the phage tail-sheath protein of another Bl published genome, LMG15441. Bioinformatic analysis also identified an xkdK homolog in the Bl 1951 genome. However, genome comparison of the region around the xkdK gene between Bl 1821L and Bl 1951 found differences including two glycine rich protein encoding genes which contain imperfect repeats (1700 bp) in Bl 1951, while a putative phage region resides in the analogous Bl 1821L region. Although comparative analysis of the genomic organisation of Bl 1821L and Bl 1951 PBSX-like region with the defective phages PBSX, PBSZ, and PBP 180 of Bacillus subtilis isolates 168 and W23, and Bacillus phage PBP180 revealed low amino acids similarity, the genes encode similar functional proteins in similar arrangements, including phage tail-sheath (XkdK), tail (XkdO), holin (XhlB), and N-acetylmuramoyl-l-alanine (XlyA). AMPA analysis identified a bactericidal stretch of 13 amino acids in the ~48 kD sequenced protein of Bl 1821L. Antagonistic activity of the purified ~48 kD phage tail-like protein in the assays differed remarkably from the crude lysate by causing a decrease of 34.2% in the number of viable cells of Bl 1951, 18 h after treatment as compared to the control. Overall, the identified inducible phage tail-like particle is likely to have implications for the in vitro growth of the insect pathogenic isolate Bl 1821L. Full article
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Review
Heat Shock Protein 90 (Hsp90) and Hsp70 as Potential Therapeutic Targets in Autoimmune Skin Diseases
Biomolecules 2022, 12(8), 1153; https://doi.org/10.3390/biom12081153 - 20 Aug 2022
Cited by 1 | Viewed by 541
Abstract
Over a hundred different autoimmune diseases have been described to date, which can affect every organ in the body, including the largest one, the skin. In fact, up to one-fifth of the world’s population suffers from chronic, noninfectious inflammatory skin diseases, the development [...] Read more.
Over a hundred different autoimmune diseases have been described to date, which can affect every organ in the body, including the largest one, the skin. In fact, up to one-fifth of the world’s population suffers from chronic, noninfectious inflammatory skin diseases, the development of which is significantly influenced by an autoimmune response. One of the hallmarks of autoimmune diseases is the loss of immune tolerance, which leads to the formation of autoreactive lymphocytes or autoantibodies and, consequently, to chronic inflammation and tissue damage. The treatment of autoimmune skin diseases mainly focuses on immunosuppression (using, e.g., corticosteroids) but almost never leads to the development of permanent mechanisms of immune tolerance. In addition, current therapies and their long-term administration may cause serious adverse effects. Hence, safer and more effective therapies that bring sustained balance between pro- and anti-inflammatory responses are still desired. Both intra- and extracellular heat shock proteins (Hsps), specifically well-characterized inducible Hsp90 and Hsp70 chaperones, have been highlighted as therapeutic targets for autoimmune diseases. This review presents preclinical data on the involvement of Hsp90 and Hsp70 in modulating the immune response, specifically in the context of the treatment of selected autoimmune skin diseases with emphasis on autoimmune bullous skin diseases and psoriasis. Full article
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Review
STIM Proteins and Regulation of SOCE in ER-PM Junctions
Biomolecules 2022, 12(8), 1152; https://doi.org/10.3390/biom12081152 - 20 Aug 2022
Viewed by 416
Abstract
ER-PM junctions are membrane contact sites formed by the endoplasmic reticulum (ER) and plasma membrane (PM) in close apposition together. The formation and stability of these junctions are dependent on constitutive and dynamic enrichment of proteins, which either contribute to junctional stability or [...] Read more.
ER-PM junctions are membrane contact sites formed by the endoplasmic reticulum (ER) and plasma membrane (PM) in close apposition together. The formation and stability of these junctions are dependent on constitutive and dynamic enrichment of proteins, which either contribute to junctional stability or modulate the lipid levels of both ER and plasma membranes. The ER-PM junctions have come under much scrutiny recently as they serve as hubs for assembling the Ca2+ signaling complexes. This review summarizes: (1) key findings that underlie the abilities of STIM proteins to accumulate in ER-PM junctions; (2) the modulation of Orai/STIM complexes by other components found within the same junction; and (3) how Orai1 channel activation is coordinated and coupled with downstream signaling pathways. Full article
(This article belongs to the Special Issue Lipid-Gating and Lipid-Protein Interactions in Ion Channels)
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Article
Klotho Levels and Their Relationship with Inflammation and Survival among Alcoholic Patients
Biomolecules 2022, 12(8), 1151; https://doi.org/10.3390/biom12081151 - 20 Aug 2022
Viewed by 407
Abstract
α-Klotho (Klotho) is an antiaging hormone with anti-inflammatory and antioxidative properties. Some studies suggest that Klotho increases in response to enhanced oxidative damage and inflammation. Alcoholism is a proinflammatory condition. The aim of this study was to analyze the relationship between Klotho and [...] Read more.
α-Klotho (Klotho) is an antiaging hormone with anti-inflammatory and antioxidative properties. Some studies suggest that Klotho increases in response to enhanced oxidative damage and inflammation. Alcoholism is a proinflammatory condition. The aim of this study was to analyze the relationship between Klotho and the serum levels of the inflammatory markers in alcoholic liver disease and to assess its prognostic value. We included 184 alcoholics and 35 age- and sex-matched controls. We determined the serum levels of Klotho, the tumor necrosis factor (TNF)-α, interleukin (IL)-6, IL-8, and malondialdehyde (MDA), and routine laboratory variables. Patients were followed-up with during 16 ± 18 months; 67 patients died. Klotho levels were higher among cirrhotics (with KW = 37.00 and p < 0.001) and were related to the Child–Pugh score (with KW = 15.96 and p < 0.001) and to the TNF-α (ρ = 0.28; p < 0.001) and MDA (ρ = 0.21; p = 0.006). The child’s groups were associated with mortality, both in the univariate (with the log-rank = 13.56, p = 0.001, Breslow = 12.33, and p = 0.002) and multivariate (with β = 0.43, p = 0.02, and OR = 1.53 (1.07–2.15)) analyses, also introducing Klotho and the TNF-α as dichotomic variables. However, the independent prognostic value of the Child’s groups was displaced by Klotho when only cirrhotics were considered; Klotho, over the median (574.4 pg/mL), was associated with higher mortality (with p = 0.04 and OR = 2.68 (1.06–6.84)). We conclude that Klotho is increased in liver cirrhosis. It is directly related to TNF-α, MDA, and to mortality in cirrhotics. Full article
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Review
The Proteasome Activator PA200/PSME4: An Emerging New Player in Health and Disease
Biomolecules 2022, 12(8), 1150; https://doi.org/10.3390/biom12081150 - 20 Aug 2022
Viewed by 502
Abstract
Proteasomes comprise a family of proteasomal complexes essential for maintaining protein homeostasis. Accordingly, proteasomes represent promising therapeutic targets in multiple human diseases. Several proteasome inhibitors are approved for treating hematological cancers. However, their side effects impede their efficacy and broader therapeutic applications. Therefore, [...] Read more.
Proteasomes comprise a family of proteasomal complexes essential for maintaining protein homeostasis. Accordingly, proteasomes represent promising therapeutic targets in multiple human diseases. Several proteasome inhibitors are approved for treating hematological cancers. However, their side effects impede their efficacy and broader therapeutic applications. Therefore, understanding the biology of the different proteasome complexes present in the cell is crucial for developing tailor-made inhibitors against specific proteasome complexes. Here, we will discuss the structure, biology, and function of the alternative Proteasome Activator 200 (PA200), also known as PSME4, and summarize the current evidence for its dysregulation in different human diseases. We hereby aim to stimulate research on this enigmatic proteasome regulator that has the potential to serve as a therapeutic target in cancer. Full article
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Article
Comparative Transcriptome Analysis Reveals Hormone Signal Transduction and Sucrose Metabolism Related Genes Involved in the Regulation of Anther Dehiscence in Photo-Thermo-Sensitive Genic Male Sterile Wheat
Biomolecules 2022, 12(8), 1149; https://doi.org/10.3390/biom12081149 - 20 Aug 2022
Cited by 1 | Viewed by 392
Abstract
Anther dehiscence is an important process to release pollen and then is a critical event in pollination. In the wheat photo-thermo-sensitive genic male sterility (PTGMS) line, pollen cannot release from anther since the anther cannot dehisce during anther dehiscence stage in a sterile [...] Read more.
Anther dehiscence is an important process to release pollen and then is a critical event in pollination. In the wheat photo-thermo-sensitive genic male sterility (PTGMS) line, pollen cannot release from anther since the anther cannot dehisce during anther dehiscence stage in a sterile condition. In this study, we carried out RNA-sequencing to analyze the transcriptome of one wheat PTGMS line BS366 during anther dehiscence under fertile and sterile conditions to explore the mechanism. We identified 6306 differentially expressed genes (DEGs). Weighted gene co-expression network analysis (WGCNA) and KEGG analysis showed that DEGs were mainly related to “hormone signal transduction pathway” and “starch and sucrose metabolism”. We identified 35 and 23 DEGs related hormone signal transduction and sucrose metabolism, respectively. Compared with conventional wheat Jing411, there were some changes in the contents of hormones, including JA, IAA, BR, ABA and GA3, and sucrose, during three anther dehiscence stages in the sterile condition in BS366. We performed qRT-PCR to verify the expression levels of some critical DEGs of the hormone signaling pathway and the starch and sucrose metabolism pathway. The results showed disparate expression patterns of the critical DEGs of the hormone signaling pathway and the starch and sucrose metabolism pathway in different conditions, suggesting these genes may be involved in the regulation of the anther dehiscence in BS366. Finally, we conducted a hypothesis model to reveal the regulation pathway of hormones and sucrose on anther dehiscence. The information provided new clues to the molecular mechanisms of anther dehiscence in wheat and improved wheat hybrid breeding. Full article
(This article belongs to the Special Issue Molecular-Genetic Bases of Plant Breeding)
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Review
Human Pulmonary Tuberculosis: Understanding the Immune Response in the Bronchoalveolar System
Biomolecules 2022, 12(8), 1148; https://doi.org/10.3390/biom12081148 - 20 Aug 2022
Viewed by 789
Abstract
Mycobacterium tuberculosis, the causal agent of one of the most devastating infectious diseases worldwide, can evade or modulate the host immune response and remain dormant for many years. In this review, we focus on identifying the local immune response induced in vivo [...] Read more.
Mycobacterium tuberculosis, the causal agent of one of the most devastating infectious diseases worldwide, can evade or modulate the host immune response and remain dormant for many years. In this review, we focus on identifying the local immune response induced in vivo by M. tuberculosis in the lungs of patients with active tuberculosis by analyzing data from untouched cells from bronchoalveolar lavage fluid (BALF) or exhaled breath condensate (EBC) samples. The most abundant resident cells in patients with active tuberculosis are macrophages and lymphocytes, which facilitate the recruitment of neutrophils. The cellular response is characterized by an inflammatory state and oxidative stress produced mainly by macrophages and T lymphocytes. In the alveolar microenvironment, the levels of cytokines such as interleukins (IL), chemokines, and matrix metalloproteinases (MMP) are increased compared with healthy patients. The production of cytokines such as interferon (IFN)-γ and IL-17 and specific immunoglobulin (Ig) A and G against M. tuberculosis indicate that the adaptive immune response is induced despite the presence of a chronic infection. The role of epithelial cells, the processing and presentation of antigens by macrophages and dendritic cells, as well as the role of tissue-resident memory T cells (Trm) for in situ vaccination remains to be understood. Full article
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Article
Adenine-Induced Nephropathy Reduces Atherosclerosis in ApoE Knockout Mice
Biomolecules 2022, 12(8), 1147; https://doi.org/10.3390/biom12081147 - 19 Aug 2022
Viewed by 454
Abstract
Background: Cardiovascular events are the main cause of death in patients with chronic kidney disease. We hypothesize that the protective effects of renal cholesterol and vitamin D3 metabolism are lost under this condition. Nephropathy was induced by adenine in Apolipoprotein E knockout [...] Read more.
Background: Cardiovascular events are the main cause of death in patients with chronic kidney disease. We hypothesize that the protective effects of renal cholesterol and vitamin D3 metabolism are lost under this condition. Nephropathy was induced by adenine in Apolipoprotein E knockout mice. The atherosclerotic phenotype was compared to mice with normal renal function. Methods: Mice were fed a western diet ±0.15% adenine. Urine and feces were collected to assess renal function and fecal output. Atherosclerosis, serum lipoprotein composition and functionality, hepatic lipids, and expression of genes involved in lipid metabolism, vitamin D3 and Na+ homeostasis, were assessed. Bones were analyzed by microCT. Results: Mice fed with adenine showed enhanced urinary Na+, Ca2+, and Pi excretion, reduced urinary pH, UreaUrine/UreaSerum, and CreatinineUrine/CreatinineSerum ratios. They developed less atherosclerosis. Lipoproteins in serum and hepatic lipids remained unchanged. Cholesterol efflux increased. Fecal output of cholesteryl ester and triglycerides increased. In the liver, mRNA levels of Cyp27a1, Cyp7a1, and Scarb1 increased; in the kidneys, Slc9a3, Slc12a3, Vdr, and Cyp24a1 decreased. Adenine increased cholesterol efflux in vitro. Tibias were shorter. Conclusion: Adenine induced tubular damage and was athero-protective because of enhanced cholesterol efflux and lipids elimination in feces. Bone growth was also affected. Full article
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Review
Race for the Cure: From the Oldest to the Newest Monoclonal Antibodies for Multiple Myeloma Treatment
Biomolecules 2022, 12(8), 1146; https://doi.org/10.3390/biom12081146 - 19 Aug 2022
Viewed by 623
Abstract
Multiple myeloma is characterized by a wide clinical heterogeneity due to an intricate network of interactions between bone marrow-resident clonal plasma cells and the microenvironment. Over the last years, dramatic improvement in the understanding of these pathways led to the introduction of novel [...] Read more.
Multiple myeloma is characterized by a wide clinical heterogeneity due to an intricate network of interactions between bone marrow-resident clonal plasma cells and the microenvironment. Over the last years, dramatic improvement in the understanding of these pathways led to the introduction of novel drugs with immune-mediated mechanisms of action. Some of these compounds, such as the anti-cd38 daratumumab and isatuximab, the anti-slamf-7 elotuzumab, and the antibody-drug conjugate belantamab-mafodotin, have been tested in large clinical trials and have now fully entered the real-life management. The bispecific T-cell engagers are under investigation with promising results, and other satisfactory data is expected from the application of nanotechnologies. The perfect timing to introduce these drugs in the sequence of treatment and their adverse events represent new challenges to be addressed, and further experience is required to improve their use. Full article
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Article
The Catalytic Domain Mediates Homomultimerization of MT1-MMP and the Prodomain Interferes with MT1-MMP Oligomeric Complex Assembly
Biomolecules 2022, 12(8), 1145; https://doi.org/10.3390/biom12081145 - 19 Aug 2022
Cited by 1 | Viewed by 440
Abstract
Homomultimerization of MT1-MMP (membrane type 1 matrix metalloproteinase) through the hemopexin, transmembrane, and cytoplasmic domains plays a very important role in the activation of proMMP-2 and the degradation of pericellular collagen. MT1-MMP is overexpressed in many types of cancers, and it is considered [...] Read more.
Homomultimerization of MT1-MMP (membrane type 1 matrix metalloproteinase) through the hemopexin, transmembrane, and cytoplasmic domains plays a very important role in the activation of proMMP-2 and the degradation of pericellular collagen. MT1-MMP is overexpressed in many types of cancers, and it is considered to be a key enzyme in facilitating cancer cell migration. Since the oligomerization of MT1-MMP is important for its proteolytic activity in promoting cancer invasion, we have further investigated the multimerization by using heterologously expressed MT1-MMP ectodomains in insect cells to gain additional mechanistic insight into this process. We show that the whole ectodomain of MT1-MMP can form dimers and higher-order oligomeric complexes. The enzyme is secreted in its active form and the multimeric complex assembly is mediated by the catalytic domain. Blocking the prodomain removal determines the enzyme to adopt the monomeric structure, suggesting that the prodomain prevents the MT1-MMP oligomerization process. The binding affinity of MT1-MMP to type I collagen is dependent on the oligomeric state. Thus, the monomers have the weakest affinity, while the binding strength increases proportionally with the complexity of the multimers. Collectively, our experimental results indicate that the catalytic domain of MT1-MMP is necessary and sufficient to mediate the formation of multimeric structures. Full article
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Article
Hsa-mir-135a Shows Potential as A Putative Diagnostic Biomarker in Saliva and Plasma for Endometriosis
Biomolecules 2022, 12(8), 1144; https://doi.org/10.3390/biom12081144 - 19 Aug 2022
Viewed by 366
Abstract
Endometriosis is a chronic disease characterized by the implantation and proliferation of endometrial tissue outside of the uterine cavity. The nonspecific nature of the symptoms and the lack of sensitive, noninvasive diagnostic methods often lead to a significant delay in diagnosis, highlighting the [...] Read more.
Endometriosis is a chronic disease characterized by the implantation and proliferation of endometrial tissue outside of the uterine cavity. The nonspecific nature of the symptoms and the lack of sensitive, noninvasive diagnostic methods often lead to a significant delay in diagnosis, highlighting the need for diagnostic biomarkers. The correlation of circulating miRNAs with altered inflammatory signals seen in patients with endometriosis has raised the possibility that miRNAs can serve as biomarkers for the disease. In our study, we analyzed miRNA expression in saliva of women with and without endometriosis using a FireFly custom multiplex circulating miRNA assay. This focused panel included 28 human miRNAs, 25 of which have been previously found to be differentially expressed either in plasma, serum, and/or blood of women with endometriosis, compared to controls. We found that hsa-mir-135a was expressed significantly higher in the saliva of women with endometriosis, independent of disease stage and menstrual cycle phase. We confirmed that hsa-mir-135a also showed significantly elevated expression in the plasma of endometriosis patients. This indicates that hsa-mir-135a is a putative noninvasive biomarker of endometriosis in both saliva and plasma, but further validation studies are required to assess its clinical value as a biomarker. Full article
(This article belongs to the Special Issue Molecular and Cell Biology in Endometriosis and Endometrial Cancer)
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Article
Maternal Chronic Ethanol Exposure Decreases Stress Responses in Zebrafish Offspring
Biomolecules 2022, 12(8), 1143; https://doi.org/10.3390/biom12081143 - 19 Aug 2022
Viewed by 386
Abstract
In humans, prenatal alcohol exposure can cause serious health issues in children, known collectively as Foetal Alcohol Spectrum Disorders (FASD). Despite the high prevalence of FASD and a lack of effective treatments, the underlying mechanisms causing the teratogenic action of ethanol are still [...] Read more.
In humans, prenatal alcohol exposure can cause serious health issues in children, known collectively as Foetal Alcohol Spectrum Disorders (FASD). Despite the high prevalence of FASD and a lack of effective treatments, the underlying mechanisms causing the teratogenic action of ethanol are still obscure. The limitations of human studies necessitate the use of animal models for identifying the underlying processes, but few studies have investigated the effects of alcohol in the female germline. Here, we used the zebrafish Danio rerio to investigate the effects of chronic (repeated for seven days) exposure to alcohol. Specifically, we tested whether the offspring of females chronically exposed to ethanol during oogenesis exhibited hormonal abnormalities when subjected to a stressor (alarm cue) as larvae, and if they exhibited anxiety-like behaviours as adults. Exposure to alarm cue increased whole-body cortisol in control larvae but not in those of ethanol-treated females. Furthermore, adult offspring of ethanol-treated females showed some reduced anxiety-like behaviours. These findings suggest that the offspring of ethanol-treated females had reduced stress responses. This study is the first to investigate how maternal chronic ethanol exposure prior to fertilisation influences hormonal and behavioural effects in a non-rodent model. Full article
(This article belongs to the Special Issue Biomolecules in Parental–Embryo Communication and Implantation)
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Article
ADAR2 Protein Is Associated with Overall Survival in GBM Patients and Its Decrease Triggers the Anchorage-Independent Cell Growth Signature
Biomolecules 2022, 12(8), 1142; https://doi.org/10.3390/biom12081142 - 19 Aug 2022
Viewed by 450
Abstract
Background: Epitranscriptomic mechanisms, such as A-to-I RNA editing mediated by ADAR deaminases, contribute to cancer heterogeneity and patients’ stratification. ADAR enzymes can change the sequence, structure, and expression of several RNAs, affecting cancer cell behavior. In glioblastoma, an overall decrease in ADAR2 RNA [...] Read more.
Background: Epitranscriptomic mechanisms, such as A-to-I RNA editing mediated by ADAR deaminases, contribute to cancer heterogeneity and patients’ stratification. ADAR enzymes can change the sequence, structure, and expression of several RNAs, affecting cancer cell behavior. In glioblastoma, an overall decrease in ADAR2 RNA level/activity has been reported. However, no data on ADAR2 protein levels in GBM patient tissues are available; and most data are based on ADARs overexpression experiments. Methods: We performed IHC analysis on GBM tissues and correlated ADAR2 levels and patients’ overall survival. We silenced ADAR2 in GBM cells, studied cell behavior, and performed a gene expression/editing analysis. Results: GBM tissues do not all show a low/no ADAR2 level, as expected by previous studies. Although, different amounts of ADAR2 protein were observed in different patients, with a low level correlating with a poor patient outcome. Indeed, reducing the endogenous ADAR2 protein in GBM cells promotes cell proliferation and migration and changes the cell’s program to an anchorage-independent growth mode. In addition, deep-seq data and bioinformatics analysis indicated multiple RNAs are differently expressed/edited upon siADAR2. Conclusion: ADAR2 protein is an important deaminase in GBM and its amount correlates with patient prognosis. Full article
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Article
Altered Conformational Landscape upon Sensing Guanine Nucleotides in a Disease Mutant of Elongation Factor-like 1 (EFL1) GTPase
Biomolecules 2022, 12(8), 1141; https://doi.org/10.3390/biom12081141 - 19 Aug 2022
Viewed by 438
Abstract
The final maturation step of the 60S ribosomal subunit requires the release of eukaryotic translation initiation factor 6 (human eIF6, yeast Tif6) to enter the pool of mature ribosomes capable of engaging in translation. This process is mediated by the concerted action of [...] Read more.
The final maturation step of the 60S ribosomal subunit requires the release of eukaryotic translation initiation factor 6 (human eIF6, yeast Tif6) to enter the pool of mature ribosomes capable of engaging in translation. This process is mediated by the concerted action of the Elongation Factor-like 1 (human EFL1, yeast Efl1) GTPase and its effector, the Shwachman-Bodian-Diamond syndrome protein (human SBDS, yeast Sdo1). Mutations in these proteins prevent the release of eIF6 and cause a disease known as Shwachman–Diamond Syndrome (SDS). While some mutations in EFL1 or SBDS result in insufficient proteins to meet the cell production of mature large ribosomal subunits, others do not affect the expression levels with unclear molecular defects. We studied the functional consequences of one such mutation using Saccharomyces cerevisiae Efl1 R1086Q, equivalent to human EFL1 R1095Q described in SDS patients. We characterised the enzyme kinetics and energetic basis outlining the recognition of this mutant to guanine nucleotides and Sdo1, and their interplay in solution. From our data, we propose a model where the conformational change in Efl1 depends on a long-distance network of interactions that are disrupted in mutant R1086Q, whereby Sdo1 and the guanine nucleotides no longer elicit the conformational changes previously described in the wild-type protein. These findings point to the molecular malfunction of an EFL1 mutant and its possible impact on SDS pathology. Full article
(This article belongs to the Section Biomacromolecules: Proteins)
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Article
Prediction of Aggregation of Biologically-Active Peptides with the UNRES Coarse-Grained Model
Biomolecules 2022, 12(8), 1140; https://doi.org/10.3390/biom12081140 - 18 Aug 2022
Viewed by 496
Abstract
The UNited RESidue (UNRES) model of polypeptide chains was applied to study the association of 20 peptides with sizes ranging from 6 to 32 amino-acid residues. Twelve of those were potentially aggregating hexa- or heptapeptides excised from larger proteins, while the remaining eight [...] Read more.
The UNited RESidue (UNRES) model of polypeptide chains was applied to study the association of 20 peptides with sizes ranging from 6 to 32 amino-acid residues. Twelve of those were potentially aggregating hexa- or heptapeptides excised from larger proteins, while the remaining eight contained potentially aggregating sequences, functionalized by attaching larger ends rich in charged residues. For 13 peptides, the experimental data of aggregation were used. The remaining seven were synthesized, and their properties were measured in this work. Multiplexed replica-exchange simulations of eight-chain systems were conducted at 12 temperatures from 260 to 370 K at concentrations from 0.421 to 5.78 mM, corresponding to the experimental conditions. The temperature profiles of the fractions of monomers and octamers showed a clear transition corresponding to aggregate dissociation. Low simulated transition temperatures were obtained for the peptides, which did not precipitate after incubation, as well as for the H-GNNQQNY-NH2 prion–protein fragment, which forms small fibrils. A substantial amount of inter-strand β-sheets was found in most of the systems. The results suggest that UNRES simulations can be used to assess peptide aggregation except for glutamine- and asparagine-rich peptides, for which a revision of the UNRES sidechain–sidechain interaction potentials appears necessary. Full article
(This article belongs to the Collection Feature Papers in Bioinformatics and Systems Biology Section)
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Article
In Silico Pleiotropy Analysis in KEGG Signaling Networks Using a Boolean Network Model
Biomolecules 2022, 12(8), 1139; https://doi.org/10.3390/biom12081139 - 18 Aug 2022
Viewed by 468
Abstract
Pleiotropy, which refers to the ability of different mutations on the same gene to cause different pathological effects in human genetic diseases, is important in understanding system-level biological diseases. Although some biological experiments have been proposed, still little is known about pleiotropy on [...] Read more.
Pleiotropy, which refers to the ability of different mutations on the same gene to cause different pathological effects in human genetic diseases, is important in understanding system-level biological diseases. Although some biological experiments have been proposed, still little is known about pleiotropy on gene–gene dynamics, since most previous studies have been based on correlation analysis. Therefore, a new perspective is needed to investigate pleiotropy in terms of gene–gene dynamical characteristics. To quantify pleiotropy in terms of network dynamics, we propose a measure called in silico Pleiotropic Scores (sPS), which represents how much a gene is affected against a pair of different types of mutations on a Boolean network model. We found that our model can identify more candidate pleiotropic genes that are not known to be pleiotropic than the experimental database. In addition, we found that many types of functionally important genes tend to have higher sPS values than other genes; in other words, they are more pleiotropic. We investigated the relations of sPS with the structural properties in the signaling network and found that there are highly positive relations to degree, feedback loops, and centrality measures. This implies that the structural characteristics are principles to identify new pleiotropic genes. Finally, we found some biological evidence showing that sPS analysis is relevant to the real pleiotropic data and can be considered a novel candidate for pleiotropic gene research. Taken together, our results can be used to understand the dynamics pleiotropic characteristics in complex biological systems in terms of gene–phenotype relations. Full article
(This article belongs to the Section Bioinformatics and Systems Biology)
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Article
Development of Artificial System to Induce Chromatin Loosening in Saccharomyces cerevisiae
Biomolecules 2022, 12(8), 1138; https://doi.org/10.3390/biom12081138 - 18 Aug 2022
Viewed by 449
Abstract
In eukaryotic cells, loosening of chromatin causes changes in transcription and DNA replication. The artificial conversion of tightly packed chromatin (heterochromatin) to loosely packed chromatin (euchromatin) enables gene expression and regulates cell differentiation. Although some chemicals convert chromatin structures through histone modifications, they [...] Read more.
In eukaryotic cells, loosening of chromatin causes changes in transcription and DNA replication. The artificial conversion of tightly packed chromatin (heterochromatin) to loosely packed chromatin (euchromatin) enables gene expression and regulates cell differentiation. Although some chemicals convert chromatin structures through histone modifications, they lack sequence specificity. This study attempted to establish a novel technology for inducing chromatin loosening in target regions of Saccharomyces cerevisiae. We focused on histone acetylation, which is one of the mechanisms of euchromatin induction. The sequence-recognizing ability of the dead Cas9 (dCas9) and guide RNA (gRNA) complex was used to promote histone acetylation at a targeted genomic locus. We constructed a plasmid to produce a fusion protein consisting of dCas9 and histone acetyltransferase Gcn5 and a plasmid to express gRNA recognizing the upstream region of heterochromatic URA3. Confocal microscopy revealed that the fusion proteins were localized in the nucleus. The yeast strain producing the fusion protein and gRNA grew well in the uracil-deficient medium, while the strain harboring empty plasmids or the strain containing the mutations that cause loss of nucleosomal histone acetylation activity of Gcn5 did not. This suggests that the heterochromatin was loosened as much as euchromatin through nucleosomal histone acetylation. The amount of euchromatic DNA at the target locus increased, indicating that chromatin loosening was induced by our system. Nucleosomal histone acetylation in heterochromatic loci by our developed system is a promising method for inducing euchromatic state in a target locus. Full article
(This article belongs to the Collection Feature Papers in Synthetic Biology and Bioengineering)
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Article
Limb Remote Ischemic Conditioning Promotes Neurogenesis after Cerebral Ischemia by Modulating miR-449b/Notch1 Pathway in Mice
Biomolecules 2022, 12(8), 1137; https://doi.org/10.3390/biom12081137 - 18 Aug 2022
Cited by 1 | Viewed by 480
Abstract
Neurogenesis plays an important role in the prognosis of stroke patients and is known to be promoted by the activation of the Notch1 signaling pathway. Studies on the airway epithelium have shown that miR-449b represses the Notch pathway. The study aimed to investigate [...] Read more.
Neurogenesis plays an important role in the prognosis of stroke patients and is known to be promoted by the activation of the Notch1 signaling pathway. Studies on the airway epithelium have shown that miR-449b represses the Notch pathway. The study aimed to investigate whether limb remote ischemic conditioning (LRIC) was able to promote neurogenesis in cerebral ischemic mice, and to investigate the role of the miR-449b/Notch1 pathway in LRIC-induced neuroprotection. Male C57BL/6 mice (22–25 g) were subjected to transient middle cerebral artery occlusion (MCAO), and LRIC was performed in the bilateral lower limbs immediately after MCA occlusion. Immunofluorescence staining was performed to assess neurogenesis. The cell line NE-4C was used to elucidate the proliferation of neuronal stem cells in 8% O2. After LRIC treatment on day 28, mice recovered neurological function. Neuronal precursor proliferation was enhanced in the SVZ, and neuronal precursor migration was enhanced in the basal ganglia on day 7. LRIC promoted the improvement of neurological function in mice on day 28, promoted neuronal precursor proliferation in the SVZ, and enhanced neuronal precursor migration in the basal ganglia on day 7. The neurological function score was negatively correlated with the number of BrdU-positive/DCX-positive cells in the SVZ and striatum. LRIC promoted activated Notch1 protein expression in the SVZ and substantially downregulated miR-449b levels in the SVZ and plasma. In vitro, miR-449b was found to target Notch1. Lentivirus-mediated miR-449b knockdown increased Notch1 levels in NE-4C cells and increased proliferation in the cells. The effects of miR-449b inhibition on neurogenesis were ablated by the application of Notch1 shRNA. Our study showed that LRIC promoted the proliferation and migration of neural stem cells after MCAO, and these effects were modulated by the miR-449b/Notch1 pathway. Full article
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Review
In Vitro Modeling of the Blood–Brain Barrier for the Study of Physiological Conditions and Alzheimer’s Disease
Biomolecules 2022, 12(8), 1136; https://doi.org/10.3390/biom12081136 - 18 Aug 2022
Viewed by 561
Abstract
The blood–brain barrier (BBB) is an essential structure for the maintenance of brain homeostasis. Alterations to the BBB are linked with a myriad of pathological conditions and play a significant role in the onset and evolution of neurodegenerative diseases, including Alzheimer’s disease. Thus, [...] Read more.
The blood–brain barrier (BBB) is an essential structure for the maintenance of brain homeostasis. Alterations to the BBB are linked with a myriad of pathological conditions and play a significant role in the onset and evolution of neurodegenerative diseases, including Alzheimer’s disease. Thus, a deeper understanding of the BBB’s structure and function is mandatory for a better knowledge of neurodegenerative disorders and the development of effective therapies. Because studying the BBB in vivo imposes overwhelming difficulties, the in vitro approach remains the main possible way of research. With many in vitro BBB models having been developed over the last years, the main aim of this review is to systematically present the most relevant designs used in neurological research. In the first part of the article, the physiological and structural–functional parameters of the human BBB are detailed. Subsequently, available BBB models are presented in a comparative approach, highlighting their advantages and limitations. Finally, the new perspectives related to the study of Alzheimer’s disease with the help of novel devices that mimic the in vivo human BBB milieu gives the paper significant originality. Full article
(This article belongs to the Special Issue Blood-Brain Barrier Modeling, Biology, and Brain Drug Delivery)
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Review
A Review of Biomarkers of Cardiac Allograft Rejection: Toward an Integrated Diagnosis of Rejection
Biomolecules 2022, 12(8), 1135; https://doi.org/10.3390/biom12081135 - 18 Aug 2022
Viewed by 404
Abstract
Despite major advances in immunosuppression, allograft rejection remains an important complication after heart transplantation, and it is associated with increased morbidity and mortality. The gold standard invasive strategy to monitor and diagnose cardiac allograft rejection, based on the pathologic evaluation of endomyocardial biopsies, [...] Read more.
Despite major advances in immunosuppression, allograft rejection remains an important complication after heart transplantation, and it is associated with increased morbidity and mortality. The gold standard invasive strategy to monitor and diagnose cardiac allograft rejection, based on the pathologic evaluation of endomyocardial biopsies, suffers from many limitations including the low prevalence of rejection, sample bias, high inter-observer variability, and international working formulations based on arbitrary cut-offs that simplify the landscape of rejection. The development of innovative diagnostic and prognostic strategies—integrating conventional histology, molecular profiling of allograft biopsy, and the discovery of new tissue or circulating biomarkers—is one of the major challenges of translational medicine in solid organ transplantation, and particularly in heart transplantation. Major advances in the field of biomarkers of rejection have paved the way for a paradigm shift in the monitoring and diagnosis of cardiac allograft rejection. We review the recent developments in the field, including non-invasive biomarkers to minimize the number of protocol endomyocardial biopsies and tissue biomarkers as companion tools of pathology to refine the diagnosis of cardiac rejection. Finally, we discuss the potential role of these biomarkers to provide an integrated bio-histomolecular diagnosis of cardiac allograft rejection. Full article
(This article belongs to the Special Issue New Biomarkers in Solid Organ Transplantation)
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Article
(3α,5α)3-Hydroxypregnan-20-one (3α,5α-THP) Regulation of the HPA Axis in the Context of Different Stressors and Sex
Biomolecules 2022, 12(8), 1134; https://doi.org/10.3390/biom12081134 - 18 Aug 2022
Cited by 1 | Viewed by 373
Abstract
Corticotropin-releasing factor (CRF) regulates the stress response in the hypothalamus and modulates neurotransmission across the brain through CRF receptors. Acute stress increases hypothalamic CRF and the GABAergic neurosteroid (3α,5α)3-hydroxypregnan-20-one (3α,5α-THP). We previously showed that 3α,5α-THP regulation of CRF is sex and brain region [...] Read more.
Corticotropin-releasing factor (CRF) regulates the stress response in the hypothalamus and modulates neurotransmission across the brain through CRF receptors. Acute stress increases hypothalamic CRF and the GABAergic neurosteroid (3α,5α)3-hydroxypregnan-20-one (3α,5α-THP). We previously showed that 3α,5α-THP regulation of CRF is sex and brain region dependent. In this study, we investigated 3α,5α-THP regulation of stress-induced hypothalamic CRF, CRF receptor type 1 (CRFR1), CRF binding protein (CRFBP), pro-opiomelanocortin (POMC), and glucocorticoid receptor (GR) by western blot and circulating corticosterone (CORT) by enzyme-linked immunosorbent assay (ELISA) in male and female Sprague Dawley rats. Tissue was collected after rats were injected with 3α,5α-THP (15 mg/kg, IP) or vehicle 15 min prior to 30 min of restraint stress (RS), or 10 min of forced swim stress (FSS) and 20 min recovery. The initial exposure to a stress stimulus increased circulating CORT levels in both males and females, but 3α,5α-THP attenuated the CORT response only in females after RS. 3α,5α-THP reduced GR levels in male and females, but differently between stressors. 3α,5α-THP decreased the CRF stress response after FSS in males and females, but after RS, only in female rats. 3α,5α-THP reduced the CRFR1, CRFBP, and POMC increases after RS and FSS in males, but in females only after FSS. Our results showed different stress responses following different types of stressors: 3α,5α-THP regulated the HPA axis at different levels, depending on sex. Full article
(This article belongs to the Special Issue Recent Advances in Steroid Research and Nervous System Function)
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