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Int. J. Mol. Sci., Volume 23, Issue 20 (October-2 2022) – 652 articles

Cover Story (view full-size image): Macrophages are critical immune maintainers by resisting pathogen invasion and the secretion of inflammation mediators. Ambient air pollution is more austere in the global environment and increases the risks to human health. After exposure to different pollutants, macrophages could polarize into two subgroups, M1 or M2, to regulate inflammation responses in the lung. Functions such as phagocytosis, chemotaxis, and the adhesion of macrophages were also altered by exposure to pollutants and influenced tissue homeostasis. View this paper
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8 pages, 1394 KiB  
Article
The Mutation Hotspots at UGT1A Locus May Be Associated with Gilbert’s Syndrome Affecting the Taiwanese Population
by Paul Wei-Che Hsu, Po-Cheng Liao, Yu-Hsiang Kao, Xin-Yu Lin, Rong-Nan Chien, Chau-Ting Yeh, Chi-Chun Lai, Yu-Chiau Shyu and Chih-Lang Lin
Int. J. Mol. Sci. 2022, 23(20), 12709; https://doi.org/10.3390/ijms232012709 - 21 Oct 2022
Cited by 2 | Viewed by 2492
Abstract
Gilbert’s syndrome is mainly diagnosed through genetic analysis and is primarily detected through a mutation in the promoter region of the UGT1A1 gene. However, most of the research has been conducted on Caucasian populations. In this study, we studied the Han population in [...] Read more.
Gilbert’s syndrome is mainly diagnosed through genetic analysis and is primarily detected through a mutation in the promoter region of the UGT1A1 gene. However, most of the research has been conducted on Caucasian populations. In this study, we studied the Han population in Taiwan to investigate the possibility of other mutations that could cause Gilbert’s syndrome. This study comprised a test group of 45 Taiwanese individuals with Gilbert’s syndrome and 180 healthy Taiwanese individuals as a control group. We extracted DNA from the blood samples and then used Axiom Genome-Wide TWB 2.0 array plates for genotyping. Out of 302,771 single nucleotide polymorphisms (SNPs) from 225 subjects, we detected 57 SNPs with the most significant shift in allele frequency; 27 SNPs among them were located in the UGT1A region. Most of the detected SNPs highly correlated with each other and are located near the first exon of UGT1A1, UGT1A3, UGT1A6, and UGT1A7. We used these SNPs as an input for the machine learning algorithms and developed prediction models. Our study reveals a good association between the 27 SNPs detected and Gilbert’s syndrome. Hence, this study provides a reference for diagnosing Gilbert’s syndrome in the Taiwanese population in the future. Full article
(This article belongs to the Section Molecular Pathology, Diagnostics, and Therapeutics)
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19 pages, 1185 KiB  
Review
Clinical Efficacies of FLT3 Inhibitors in Patients with Acute Myeloid Leukemia
by Moo-Kon Song, Byeong-Bae Park and Ji-Eun Uhm
Int. J. Mol. Sci. 2022, 23(20), 12708; https://doi.org/10.3390/ijms232012708 - 21 Oct 2022
Cited by 6 | Viewed by 3680
Abstract
FLT3 mutations are the most common genomic alteration detected in acute myeloid leukemia (AML) with a worse clinical prognosis. The highly frequent FLT3 mutations, together with the side effects associated with clinical prognosis, make FLT3 promising treatment targets and have provoked the advancement [...] Read more.
FLT3 mutations are the most common genomic alteration detected in acute myeloid leukemia (AML) with a worse clinical prognosis. The highly frequent FLT3 mutations, together with the side effects associated with clinical prognosis, make FLT3 promising treatment targets and have provoked the advancement of FLT3 inhibitors. Recently, numerous FLT3 inhibitors were actively developed, and thus the outcomes of this aggressive subtype of AML were significantly improved. Recently, midostaurin and gilteritinib were approved as frontline treatment of AML and as therapeutic agents in the recurred disease by the United States Food and Drug Administration. Recently, numerous promising clinical trials attempted to seek appropriate management in frontline settings, in relapsed/refractory disease, or after stem cell transplantation in AML. This review follows numerous clinical trials about the usefulness of FLT3 inhibitors as frontline therapy, as relapsed/refractory conditioning, and as maintenance therapy of stem cell transplantation. The cumulative data of FLT3 inhibitors would be important clinical evidence for further management with FLT3 inhibitors in AML patients with FLT3 mutations. Full article
(This article belongs to the Special Issue Immune, Inflammatory and Metabolic Mechanisms in Cancer)
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16 pages, 2136 KiB  
Article
Correlation of Immunological and Histopathological Features with Gene Expression-Based Classifiers in Colon Cancer Patients
by Simone van de Weerd, Marloes A. Smit, Jessica Roelands, Wilma E. Mesker, Davide Bedognetti, Peter J. K. Kuppen, Hein Putter, Rob A. E. M. Tollenaar, Jeanine M. L. Roodhart, Wouter Hendrickx, Jan Paul Medema and J. Han J. M. van Krieken
Int. J. Mol. Sci. 2022, 23(20), 12707; https://doi.org/10.3390/ijms232012707 - 21 Oct 2022
Cited by 1 | Viewed by 1992
Abstract
The purpose of this study was to evaluate the association between four distinct histopathological features: (1) tumor infiltrating lymphocytes, (2) mucinous differentiation, (3) tumor-stroma ratio, plus (4) tumor budding and two gene expression-based classifiers—(1) consensus molecular subtypes (CMS) plus (2) colorectal cancer intrinsic [...] Read more.
The purpose of this study was to evaluate the association between four distinct histopathological features: (1) tumor infiltrating lymphocytes, (2) mucinous differentiation, (3) tumor-stroma ratio, plus (4) tumor budding and two gene expression-based classifiers—(1) consensus molecular subtypes (CMS) plus (2) colorectal cancer intrinsic subtypes (CRIS). All four histopathological features were retrospectively scored on hematoxylin and eosin sections of the most invasive part of the primary tumor in 218 stage II and III colon cancer patients from two independent cohorts (AMC-AJCC-90 and AC-ICAM). RNA-based CMS and CRIS assignments were independently obtained for all patients. Contingency tables were constructed and a χ2 test was used to test for statistical significance. Odds ratios with 95% confidence intervals were calculated. The presence of tumor infiltrating lymphocytes and a mucinous phenotype (>50% mucinous surface area) were strongly correlated with CMS1 (p < 0.001 and p = 0.008) and CRIS-A (p = 0.006 and p < 0.001). The presence of mucus (≥ 10%) was associated with CMS3: mucus was present in 64.1% of all CMS3 tumors (p < 0.001). Although a clear association between tumor-stroma ratio and CMS4 was established in this study (p = 0.006), still 32 out of 61 (52.5%) CMS4 tumors were scored as stroma-low, indicating that CMS4 tumors cannot be identified solely based on stromal content. Higher budding counts were seen in CMS4 and CRIS-B tumors (p = 0.045 and p = 0.046). No other associations of the measured parameters were seen for any of the other CRIS subtypes. Our analysis revealed clear associations between histopathologic features and CMS or CRIS subtypes. However, identification of distinct molecular subtypes solely based on histopathology proved to be infeasible. Combining both molecular and morphologic features could potentially improve patient stratification. Full article
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28 pages, 2001 KiB  
Review
Phase Behavior of Ionic Liquid-Based Aqueous Two-Phase Systems
by Lirong Nie, Ziwei Zheng, Mingxia Lu, Shun Yao and Dong Guo
Int. J. Mol. Sci. 2022, 23(20), 12706; https://doi.org/10.3390/ijms232012706 - 21 Oct 2022
Cited by 4 | Viewed by 2748
Abstract
As an environmentally friendly separation medium, the ionic liquid (IL)-based aqueous two-phase system (ATPS) is attracting long-term attention from a growing number of scientists and engineers. Phase equilibrium data of IL-based ATPSs are an important basis for the design and optimization of chemical [...] Read more.
As an environmentally friendly separation medium, the ionic liquid (IL)-based aqueous two-phase system (ATPS) is attracting long-term attention from a growing number of scientists and engineers. Phase equilibrium data of IL-based ATPSs are an important basis for the design and optimization of chemical reactions and separation processes involving ILs. This article provides the recent significant progress that has been made in the field and highlights the possible directions of future developments. The effects of each component (such as salting-out agents and ILs) on the phase behavior of IL-based ATPSs are summarized and discussed in detail. We mainly focus on the phase behavior of ATPSs by using ILs, expecting to provide meaningful and valuable information that may promote further research and application. Full article
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19 pages, 1422 KiB  
Article
Effects of Sub-Minimum Inhibitory Concentrations of Imipenem and Colistin on Expression of Biofilm-Specific Antibiotic Resistance and Virulence Genes in Acinetobacter baumannii Sequence Type 1894
by Abebe Mekuria Shenkutie, Jiaying Zhang, Mianzhi Yao, Daniel Asrat, Franklin W. N. Chow and Polly H. M. Leung
Int. J. Mol. Sci. 2022, 23(20), 12705; https://doi.org/10.3390/ijms232012705 - 21 Oct 2022
Cited by 11 | Viewed by 2738
Abstract
Antibiotics at suboptimal doses promote biofilm formation and the development of antibiotic resistance. The underlying molecular mechanisms, however, were not investigated. Here, we report the effects of sub-minimum inhibitory concentrations (sub-MICs) of imipenem and colistin on genes associated with biofilm formation and biofilm-specific [...] Read more.
Antibiotics at suboptimal doses promote biofilm formation and the development of antibiotic resistance. The underlying molecular mechanisms, however, were not investigated. Here, we report the effects of sub-minimum inhibitory concentrations (sub-MICs) of imipenem and colistin on genes associated with biofilm formation and biofilm-specific antibiotic resistance in a multidrug-tolerant clinical strain of Acinetobacter baumannii Sequence Type (ST) 1894. Comparative transcriptome analysis was performed in untreated biofilm and biofilm treated with sub-MIC doses of imipenem and colistin. RNA sequencing data showed that 78 and 285 genes were differentially expressed in imipenem and colistin-treated biofilm cells, respectively. Among the differentially expressed genes (DEGs), 48 and 197 genes were upregulated exclusively in imipenem and colistin-treated biofilm cells, respectively. The upregulated genes included those encoding matrix synthesis (pgaB), multidrug efflux pump (novel00738), fimbrial proteins, and homoserine lactone synthase (AbaI). Upregulation of biofilm-associated genes might enhance biofilm formation when treated with sub-MICs of antibiotics. The downregulated genes include those encoding DNA gyrase (novel00171), 30S ribosomal protein S20 (novel00584), and ribosome releasing factor (RRF) were downregulated when the biofilm cells were treated with imipenem and colistin. Downregulation of these genes affects protein synthesis, which in turn slows down cell metabolism and makes biofilm cells more tolerant to antibiotics. In this investigation, we also found that 5 of 138 small RNAs (sRNAs) were differentially expressed in biofilm regardless of antibiotic treatment or not. Of these, sRNA00203 showed the highest expression levels in biofilm. sRNAs regulate gene expression and are associated with biofilm formation, which may in turn affect the expression of biofilm-specific antibiotic resistance. In summary, when biofilm cells were exposed to sub-MIC doses of colistin and imipenem, coordinated gene responses result in increased biofilm production, multidrug efflux pump expression, and the slowdown of metabolism, which leads to drug tolerance in biofilm. Targeting antibiotic-induced or repressed biofilm-specific genes represents a new strategy for the development of innovative and effective treatments for biofilm-associated infections caused by A. baumannii. Full article
(This article belongs to the Special Issue Genomics: Infectious Disease and Host-Pathogen Interaction)
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26 pages, 3833 KiB  
Review
Molecular Mechanisms of RSV and Air Pollution Interaction: A Scoping Review
by August Wrotek and Teresa Jackowska
Int. J. Mol. Sci. 2022, 23(20), 12704; https://doi.org/10.3390/ijms232012704 - 21 Oct 2022
Cited by 4 | Viewed by 3040
Abstract
RSV is one of the major infectious agents in paediatrics, and its relationship with air pollution is frequently observed. However, the molecular basis of this interaction is sparsely reported. We sought to systematically review the existing body of literature and identify the knowledge [...] Read more.
RSV is one of the major infectious agents in paediatrics, and its relationship with air pollution is frequently observed. However, the molecular basis of this interaction is sparsely reported. We sought to systematically review the existing body of literature and identify the knowledge gaps to answer the question: which molecular mechanisms are implied in the air pollutants–RSV interaction? Online databases were searched for original studies published before August 2022 focusing on molecular mechanisms of the interaction. The studies were charted and a narrative synthesis was based upon three expected directions of influence: a facilitated viral entry, an altered viral replication, and an inappropriate host reaction. We identified 25 studies published between 1993 and 2020 (without a noticeable increase in the number of studies) that were performed in human (n = 12), animal (n = 10) or mixed (n = 3) models, and analysed mainly cigarette smoke (n = 11), particulate matter (n = 4), nanoparticles (n = 3), and carbon black (n = 2). The data on a damage to the epithelial barrier supports the hypothesis of facilitated viral entry; one study also reported accelerated viral entry upon an RSV conjugation to particulate matter. Air pollution may result in the predominance of necrosis over apoptosis, and, as an effect, an increased viral load was reported. Similarly, air pollution mitigates epithelium function with decreased IFN-γ and Clara cell secretory protein levels and decreased immune response. Immune response might also be diminished due to a decreased viral uptake by alveolar macrophages and a suppressed function of dendritic cells. On the other hand, an exuberant inflammatory response might be triggered by air pollution and provoke airway hyperresponsiveness (AHR), prolonged lung infiltration, and tissue remodeling, including a formation of emphysema. AHR is mediated mostly by increased IFN-γ and RANTES concentrations, while the risk of emphysema was related to the activation of the IL-17 → MCP-1 → MMP-9 → MMP-12 axis. There is a significant lack of evidence on the molecular basics of the RSV–air pollution interaction, which may present a serious problem with regards to future actions against air pollution effects. The major knowledge gaps concern air pollutants (mostly the influence of cigarette smoke was investigated), the mechanisms facilitating an acute infection or a worse disease course (since it might help plan short-term, especially non-pharmacological, interventions), and the mechanisms of an inadequate response to the infection (which may lead to a prolonged course of an acute infection and long-term sequelae). Thus far, the evidence is insufficient regarding the broadness and complexity of the interaction, and future studies should focus on common mechanisms stimulated by various air pollutants and a comparison of influence of the different contaminants at various concentrations. Full article
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14 pages, 3347 KiB  
Article
Exploring the Concept of In Vivo Guided Tissue Engineering by a Single-Stage Surgical Procedure in a Rodent Model
by Clara Ibel Chamorro, Said Zeiai, Nikolai Juul, Oliver Willacy, Jinxing Huo, Jöns Hilborn and Magdalena Fossum
Int. J. Mol. Sci. 2022, 23(20), 12703; https://doi.org/10.3390/ijms232012703 - 21 Oct 2022
Cited by 2 | Viewed by 1576
Abstract
In severe malformations with a lack of native tissues, treatment options are limited. We aimed at expanding tissue in vivo using the body as a bioreactor and developing a sustainable single-staged procedure for autologous tissue reconstruction in malformation surgery. Autologous micro-epithelium from skin [...] Read more.
In severe malformations with a lack of native tissues, treatment options are limited. We aimed at expanding tissue in vivo using the body as a bioreactor and developing a sustainable single-staged procedure for autologous tissue reconstruction in malformation surgery. Autologous micro-epithelium from skin was integrated with plastically compressed collagen and a degradable knitted fabric mesh. Sixty-three scaffolds were implanted in nine rats for histological and mechanical analyses, up to 4 weeks after transplantation. Tissue integration, cell expansion, proliferation, inflammation, strength, and elasticity were evaluated over time in vivo and validated in vitro in a bladder wound healing model. After 5 days in vivo, we observed keratinocyte proliferation on top of the transplant, remodeling of the collagen, and neovascularization within the transplant. At 4 weeks, all transplants were fully integrated with the surrounding tissue. Tensile strength and elasticity were retained during the whole study period. In the in vitro models, a multilayered epithelium covered the defect after 4 weeks. Autologous micro-epithelial transplants allowed for cell expansion and reorganization in vivo without conventional pre-operative in vitro cell propagation. The method was easy to perform and did not require handling outside the operating theater. Full article
(This article belongs to the Special Issue Tissue Engineering and Cell Therapy)
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13 pages, 2923 KiB  
Article
A Xanthohumol-Rich Hop Extract Diminishes Endotoxin-Induced Activation of TLR4 Signaling in Human Peripheral Blood Mononuclear Cells: A Study in Healthy Women
by Finn Jung, Raphaela Staltner, Anja Baumann, Katharina Burger, Emina Halilbasic, Claus Hellerbrand and Ina Bergheim
Int. J. Mol. Sci. 2022, 23(20), 12702; https://doi.org/10.3390/ijms232012702 - 21 Oct 2022
Cited by 6 | Viewed by 1762
Abstract
Infections with Gram-negative bacteria are still among the leading causes of infection-related deaths. Several studies suggest that the chalcone xanthohumol (XN) found in hop (Humulus lupulus) possesses anti-inflammatory effects. In a single-blinded, placebo controlled randomized cross-over design study we assessed if the oral [...] Read more.
Infections with Gram-negative bacteria are still among the leading causes of infection-related deaths. Several studies suggest that the chalcone xanthohumol (XN) found in hop (Humulus lupulus) possesses anti-inflammatory effects. In a single-blinded, placebo controlled randomized cross-over design study we assessed if the oral intake of a single low dose of 0.125 mg of a XN derived through a XN-rich hop extract (75% XN) affects lipopolysaccharide (LPS)-induced immune responses in peripheral blood mononuclear cells (PBMCs) ex vivo in normal weight healthy women (n = 9) (clinicaltrials.gov: NCT04847193) and determined associated molecular mechanisms. LPS-stimulation of PBMCs isolated from participants 1 h after the intake of the placebo for 2 h resulted in a significant induction of pro-inflammatory cytokine release which was significantly attenuated when participants had consumed XN. The XN-dependent attenuation of proinflammatory cytokine release was less pronounced 6 h after the LPS stimulation while the release of sCD14 was significantly reduced at this timepoint. The LPS-dependent activation of hTLR4 transfected HEK293 cells was significantly and dose-dependently suppressed by the XN-rich hop extract which was attenuated when cells were co-challenged with sCD14. Taken together, our results suggest even a one-time intake of low doses of XN consumed in a XN-rich hop extract can suppress LPS-dependent stimulation of PBMCs and that this is related to the interaction of the hop compound with the CD14/TLR4 signaling cascade. Full article
(This article belongs to the Special Issue The Role of Toll-Like Receptors (TLR) in Infection and Inflammation)
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15 pages, 4295 KiB  
Article
Identification and Expression Analysis of Dsx and Its Positive Transcriptional Regulation of IAG in Black Tiger Shrimp (Penaeus monodon)
by Wen-Ya Wei, Jian-Hua Huang, Fa-Lin Zhou, Qi-Bin Yang, Yun-Dong Li, Song Jiang, Shi-Gui Jiang and Li-Shi Yang
Int. J. Mol. Sci. 2022, 23(20), 12701; https://doi.org/10.3390/ijms232012701 - 21 Oct 2022
Cited by 6 | Viewed by 1645
Abstract
Doublesex (Dsx) is a polymorphic transcription factor of the DMRTs family, which is involved in male sex trait development and controls sexual dimorphism at different developmental stages in arthropods. However, the transcriptional regulation of the Dsx gene is largely unknown in [...] Read more.
Doublesex (Dsx) is a polymorphic transcription factor of the DMRTs family, which is involved in male sex trait development and controls sexual dimorphism at different developmental stages in arthropods. However, the transcriptional regulation of the Dsx gene is largely unknown in decapods. In this study, we reported the cDNA sequence of PmDsx in Penaeus monodon, which encodes a 257 amino acid polypeptide. It shared many similarities with Dsx homologs and has a close relationship in the phylogeny of different species. We demonstrated that the expression of the male sex differentiation gene Dsx was predominantly expressed in the P. monodon testis, and that PmDsx dsRNA injection significantly decreased the expression of the insulin-like androgenic gland hormone (IAG) and male sex-determining gene while increasing the expression of the female sex-determining gene. We also identified a 5′-flanking region of PmIAG that had two potential cis-regulatory elements (CREs) for the PmDsx transcription. Further, the dual-luciferase reporter analysis and truncated mutagenesis revealed that PmDsx overexpression significantly promoted the transcriptional activity of the PmIAG promoter via a specific CRE. These results suggest that PmDsx is engaged in male reproductive development and positively regulates the transcription of the PmIAG by specifically binding upstream of the promoter of the PmIAG. It provides a theoretical basis for exploring the sexual regulation pathway and evolutionary dynamics of Dmrt family genes in P. monodon. Full article
(This article belongs to the Section Molecular Genetics and Genomics)
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18 pages, 1926 KiB  
Article
Synthesis, Biological Activity and Molecular Docking of Chimeric Peptides Targeting Opioid and NOP Receptors
by Karol Wtorek, Alessia Ghidini, Luca Gentilucci, Anna Adamska-Bartłomiejczyk, Justyna Piekielna-Ciesielska, Chiara Ruzza, Chiara Sturaro, Girolamo Calò, Stefano Pieretti, Alicja Kluczyk, John McDonald, David G. Lambert and Anna Janecka
Int. J. Mol. Sci. 2022, 23(20), 12700; https://doi.org/10.3390/ijms232012700 - 21 Oct 2022
Cited by 3 | Viewed by 2096
Abstract
Recently, mixed opioid/NOP agonists came to the spotlight for their favorable functional profiles and promising outcomes in clinical trials as novel analgesics. This study reports on two novel chimeric peptides incorporating the fragment Tyr-c[D-Lys-Phe-Phe]Asp-NH2 (RP-170), a cyclic peptide with high [...] Read more.
Recently, mixed opioid/NOP agonists came to the spotlight for their favorable functional profiles and promising outcomes in clinical trials as novel analgesics. This study reports on two novel chimeric peptides incorporating the fragment Tyr-c[D-Lys-Phe-Phe]Asp-NH2 (RP-170), a cyclic peptide with high affinity for µ and κ opioid receptors (or MOP and KOP, respectively), conjugated with the peptide Ac-RYYRIK-NH2, a known ligand of the nociceptin/orphanin FQ receptor (NOP), yielding RP-170-RYYRIK-NH2 (KW-495) and RP-170-Gly3-RYYRIK-NH2 (KW-496). In vitro, the chimeric KW-496 gained affinity for KOP, hence becoming a dual KOP/MOP agonist, while KW-495 behaved as a mixed MOP/NOP agonist with low nM affinity. Hence, KW-495 was selected for further in vivo experiments. Intrathecal administration of this peptide in mice elicited antinociceptive effects in the hot-plate test; this action was sensitive to both the universal opioid receptor antagonist naloxone and the selective NOP antagonist SB-612111. The rotarod test revealed that KW-495 administration did not alter the mice motor coordination performance. Computational studies have been conducted on the two chimeras to investigate the structural determinants at the basis of the experimental activities, including any role of the Gly3 spacer. Full article
(This article belongs to the Special Issue Protein Structure–Function Relationships 2.0)
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21 pages, 3004 KiB  
Article
Brain Effects of SC-Nanophytosomes on a Rotenone-Induced Rat Model of Parkinson’s Disease—A Proof of Concept for a Mitochondria-Targeted Therapy
by Daniela Mendes, Francisco Peixoto, Maria Manuel Oliveira, Paula Branquinho Andrade and Romeu António Videira
Int. J. Mol. Sci. 2022, 23(20), 12699; https://doi.org/10.3390/ijms232012699 - 21 Oct 2022
Cited by 1 | Viewed by 2388
Abstract
Mitochondria are an attractive target to fight neurodegenerative diseases due to their important functions for cells and the particularly close relationship between the functional connectivity among brain regions and mitochondrial performance. This work presents a mitochondria-targeted therapy designed to modulate the functionality of [...] Read more.
Mitochondria are an attractive target to fight neurodegenerative diseases due to their important functions for cells and the particularly close relationship between the functional connectivity among brain regions and mitochondrial performance. This work presents a mitochondria-targeted therapy designed to modulate the functionality of the mitochondrial respiratory chain and lipidome, parameters that are affected in neurodegeneration, including in Parkinson’s disease (PD). This therapy is supported by SC-Nanophytosomes constructed with membrane polar lipids, from Codium tomentosum, and elderberry anthocyanin-enriched extract, from Sambucus nigra L. SC-Nanophytosomes are nanosized vesicles with a high negative surface charge that preserve their properties, including anthocyanins in the flavylium cation form, under conditions that mimic the gastrointestinal tract pH changes. SC-Nanophytosomes, 3 µM in phospholipid, and 2.5 mg/L of EAE-extract, delivered by drinking water to a rotenone-induced PD rat model, showed significant positive outcomes on disabling motor symptoms associated with the disease. Ex vivo assays were performed with two brain portions, one comprising the basal ganglia and cerebellum (BG-Cereb) and the other with the cerebral cortex (C-Cortex) regions. Results showed that rotenone-induced neurodegeneration increases the α-synuclein levels in the BG-Cereb portion and compromises mitochondrial respiratory chain functionality in both brain portions, well-evidenced by a 50% decrease in the respiratory control rate and up to 40% in complex I activity. Rotenone-induced PD phenotype is also associated with changes in superoxide dismutase and catalase activities that are dependent on the brain portion. Treatment with SC-Nanophytosomes reverted the α-synuclein levels and antioxidant enzymes activity to the values detected in control animals. Moreover, it mitigated mitochondrial dysfunction, with positive outcomes on the respiratory control rate, the activity of individual respiratory complexes, and the fatty acid profile of the membrane phospholipids. Therefore, SC-Nanophytosomes are a promising tool to support mitochondria-targeted therapy for neurodegenerative diseases. Full article
(This article belongs to the Special Issue Mitochondrial Function in Human Health and Disease)
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25 pages, 2542 KiB  
Review
Epigenetics and Pregnancy: Conditional Snapshot or Rolling Event
by Mariana Andrawus, Lital Sharvit and Gil Atzmon
Int. J. Mol. Sci. 2022, 23(20), 12698; https://doi.org/10.3390/ijms232012698 - 21 Oct 2022
Cited by 10 | Viewed by 5793
Abstract
Epigenetics modification such as DNA methylation can affect maternal health during the gestation period. Furthermore, pregnancy can drive a range of physiological and molecular changes that have the potential to contribute to pathological conditions. Pregnancy-related risk factors include multiple environmental, behavioral, and hereditary [...] Read more.
Epigenetics modification such as DNA methylation can affect maternal health during the gestation period. Furthermore, pregnancy can drive a range of physiological and molecular changes that have the potential to contribute to pathological conditions. Pregnancy-related risk factors include multiple environmental, behavioral, and hereditary factors that can impact maternal DNA methylation with long-lasting consequences. Identification of the epigenetic patterns linked to poor pregnancy outcomes is crucial since changes in DNA methylation patterns can have long-term effects. In this review, we provide an overview of the epigenetic changes that influence pregnancy-related molecular programming such as gestational diabetes, immune response, and pre-eclampsia, in an effort to close the gap in current understanding regarding interactions between the environment, the genetics of the fetus, and the pregnant woman. Full article
(This article belongs to the Special Issue Advance in the Study of DNA Methylation)
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16 pages, 2817 KiB  
Article
Tissue Sheet Engineered Using Human Umbilical Cord-Derived Mesenchymal Stem Cells Improves Diabetic Wound Healing
by Jingbo Zhang, Xiang Qu, Junjun Li, Akima Harada, Ying Hua, Noriko Yoshida, Masako Ishida, Yoshiki Sawa, Li Liu and Shigeru Miyagawa
Int. J. Mol. Sci. 2022, 23(20), 12697; https://doi.org/10.3390/ijms232012697 - 21 Oct 2022
Cited by 5 | Viewed by 2924
Abstract
Diabetic foot ulceration is a common chronic diabetic complication. Human umbilical cord-derived mesenchymal stem cells (hUC-MSCs) have been widely used in regenerative medicine owing to their multipotency and easy availability. We developed poly(lactic-co-glycolic acid) (PLGA)-based scaffold to create hUC-MSC tissue sheets. In vitro [...] Read more.
Diabetic foot ulceration is a common chronic diabetic complication. Human umbilical cord-derived mesenchymal stem cells (hUC-MSCs) have been widely used in regenerative medicine owing to their multipotency and easy availability. We developed poly(lactic-co-glycolic acid) (PLGA)-based scaffold to create hUC-MSC tissue sheets. In vitro immunostaining showed that hUC-MSC tissue sheets formed thick and solid tissue sheets with an abundance of extracellular matrix (ECM). Diabetic wounds in mice treated with or without either the hUC-MSC tissue sheet, hUC-MSC injection, or fiber only revealed that hUC-MSC tissue sheet transplantation promoted diabetic wound healing with improved re-epithelialization, collagen deposition, blood vessel formation and maturation, and alleviated inflammation compared to that observed in other groups. Taken collectively, our findings suggest that hUC-MSCs cultured on PLGA scaffolds improve diabetic wound healing, collagen deposition, and angiogenesis, and provide a novel and effective method for cell transplantation, and a promising alternative for diabetic skin wound treatment. Full article
(This article belongs to the Section Macromolecules)
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20 pages, 3297 KiB  
Article
The Transcriptomic Landscape of Pediatric Astrocytoma
by Abrahan Hernández-Hernández, Tayde López-Santaella, Aranxa Torres-Caballero, Amarantha Serrato, Ulises Torres-Flores, Diego Montesinos-Valencia, Fernando Chico-Ponce de León, Vicente González-Carranza, Samuel Torres-García, Rosa Rebollar-Vega, Inti Alberto De la Rosa-Velázquez, Rosario Ortiz, Monserrat Pérez-Ramírez, Normand García-Hernández, Antonio García-Méndez and Francisco Arenas-Huertero
Int. J. Mol. Sci. 2022, 23(20), 12696; https://doi.org/10.3390/ijms232012696 - 21 Oct 2022
Cited by 3 | Viewed by 2096
Abstract
Central nervous system tumors are the most common solid neoplasia during childhood and represent one of the leading causes of cancer-related mortality. Tumors arising from astrocytic cells (astrocytomas) are the most frequently diagnosed, and according to their histological and pathological characteristics, they are [...] Read more.
Central nervous system tumors are the most common solid neoplasia during childhood and represent one of the leading causes of cancer-related mortality. Tumors arising from astrocytic cells (astrocytomas) are the most frequently diagnosed, and according to their histological and pathological characteristics, they are classified into four categories. However, an additional layer of molecular classification considering the DNA sequence of the tumorigenesis-associated genes IDH1/2 and H3F3A has recently been incorporated into the classification guidelines. Although mutations in H3F3A are found exclusively in a subtype of grade IV pediatric astrocytoma, mutations in IDH1/2 genes are very rare in children under 14 years of age. The transcriptomic profiles of astrocytoma in adults and children have been extensively studied. However, there is scarce information on these profiles in pediatric populations considering the status of tumorigenesis-associated genes. Therefore, here we report the transcriptomic landscape of the four grades of pediatric astrocytoma by RNA sequencing. We found several well-documented biological functions associated with the misregulated genes in the four grades of astrocytoma, as well as additional biological pathways. Among the four grades of astrocytoma, we found shared misregulated genes that could have implications in tumorigenesis. Finally, we identified a transcriptional signature for almost all grades of astrocytoma that could be used as a transcription-based identification method. Full article
(This article belongs to the Special Issue State-of-the-Art Molecular Oncology in Mexico)
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22 pages, 3165 KiB  
Article
Role of Glycolysis and Fatty Acid Synthesis in the Activation and T Cell-Modulating Potential of Dendritic Cells Stimulated with a TLR5-Ligand Allergen Fusion Protein
by Alexandra Goretzki, Yen-Ju Lin, Jennifer Zimmermann, Hannah Rainer, Ann-Christine Junker, Sonja Wolfheimer, Stefan Vieths, Stephan Scheurer and Stefan Schülke
Int. J. Mol. Sci. 2022, 23(20), 12695; https://doi.org/10.3390/ijms232012695 - 21 Oct 2022
Cited by 5 | Viewed by 2009
Abstract
Trained immune responses, based on metabolic and epigenetic changes in innate immune cells, are de facto innate immune memory and, therefore, are of great interest in vaccine development. In previous studies, the recombinant fusion protein rFlaA:Betv1, combining the adjuvant and toll-like receptor (TLR)5-ligand [...] Read more.
Trained immune responses, based on metabolic and epigenetic changes in innate immune cells, are de facto innate immune memory and, therefore, are of great interest in vaccine development. In previous studies, the recombinant fusion protein rFlaA:Betv1, combining the adjuvant and toll-like receptor (TLR)5-ligand flagellin (FlaA) and the major birch pollen allergen Bet v 1 into a single molecule, significantly suppressed allergic sensitization in vivo while also changing the metabolism of myeloid dendritic cells (mDCs). Within this study, the immune–metabolic effects of rFlaA:Betv1 during mDC activation were elucidated. In line with results for other well-characterized TLR-ligands, rFlaA:Betv1 increased glycolysis while suppressing oxidative phosphorylation to different extents, making rFlaA:Betv1 a suitable model to study the immune–metabolic effects of TLR-adjuvanted vaccines. In vitro pretreatment of mDCs with cerulenin (inhibitor of fatty acid biosynthesis) led to a decrease in both rFlaA:Betv1-induced anti-inflammatory cytokine Interleukin (IL) 10 and T helper cell type (TH) 1-related cytokine IL-12p70, while the pro-inflammatory cytokine IL 1β was unaffected. Interestingly, pretreatment with the glutaminase inhibitor BPTES resulted in an increase in IL-1β, but decreased IL-12p70 secretion while leaving IL-10 unchanged. Inhibition of the glycolytic enzyme hexokinase-2 by 2-deoxyglucose led to a decrease in all investigated cytokines (IL-10, IL-12p70, and IL-1β). Inhibitors of mitochondrial respiration had no effect on rFlaA:Betv1-induced IL-10 level, but either enhanced the secretion of IL-1β (oligomycin) or decreased IL-12p70 (antimycin A). In extracellular flux measurements, mDCs showed a strongly enhanced glycolysis after rFlaA:Betv1 stimulation, which was slightly increased after respiratory shutdown using antimycin A. rFlaA:Betv1-stimulated mDCs secreted directly antimicrobial substances in a mTOR- and fatty acid metabolism-dependent manner. In co-cultures of rFlaA:Betv1-stimulated mDCs with CD4+ T cells, the suppression of Bet v 1-specific TH2 responses was shown to depend on fatty acid synthesis. The effector function of rFlaA:Betv1-activated mDCs mainly relies on glycolysis, with fatty acid synthesis also significantly contributing to rFlaA:Betv1-mediated cytokine secretion, the production of antimicrobial molecules, and the modulation of T cell responses. Full article
(This article belongs to the Special Issue Molecular Mechanisms of Allergy and Asthma 2.0)
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20 pages, 3815 KiB  
Article
Network Pharmacology Analysis and Experimental Validation of Kaempferol in the Treatment of Ischemic Stroke by Inhibiting Apoptosis and Regulating Neuroinflammation Involving Neutrophils
by Shan-Shan Zhang, Man Liu, Dong-Ni Liu, Yu-Fu Shang, Guan-Hua Du and Yue-Hua Wang
Int. J. Mol. Sci. 2022, 23(20), 12694; https://doi.org/10.3390/ijms232012694 - 21 Oct 2022
Cited by 16 | Viewed by 2436
Abstract
Kaempferol, a natural plant flavonoid compound, has a neuroprotective effect on ischemic stroke, while the specific mechanism remains unclear. In the current study, we applied the comprehensive strategy that combines network pharmacology and experimental evaluation to explore the potential mechanism of kaempferol in [...] Read more.
Kaempferol, a natural plant flavonoid compound, has a neuroprotective effect on ischemic stroke, while the specific mechanism remains unclear. In the current study, we applied the comprehensive strategy that combines network pharmacology and experimental evaluation to explore the potential mechanism of kaempferol in the treatment of cerebral ischemia. First, network pharmacology analysis identified the biological process of kaempferol, suggesting that kaempferol may partly help in treating ischemic stroke by regulating apoptosis and inflammatory response. Then, we evaluated the efficacy of kaempferol in the acute stage of ischemic stroke and elucidated its effects and possible mechanisms on cell apoptosis and neuroinflammation involved by neutrophils. The results showed that kaempferol could significantly reduce the modified neurological severity score (mNSS), and reduce the volume of cerebral infarction and the degree of cerebral edema. In terms of anti-apoptosis, kaempferol could significantly reduce the number of TUNEL-positive cells, inhibit the expression of pro-apoptotic proteins and promote the expression of anti-apoptotic proteins. Kaempferol may play an anti-apoptotic role by up-regulating the expression level of the BDNF-TrkB-PI3K/AKT signaling pathway. In addition, we found that kaempferol inhibited neuron loss and the activation of glial cells, as well as the expression level of the inflammatory protein COX-2 and the classic pro-inflammatory signaling pathway TLR4/MyD88/NF-κB in the ischemic brain, reduced MPO activity and neutrophil counts in peripheral blood, and down-regulated neutrophil aggregation and infiltration in the ischemic brain. Western blot revealed that kaempferol down-regulated the activation of the JAK1/STAT3 signaling pathway in neutrophils and ischemic brains. Our study showed that kaempferol inhibited the activation and number of neutrophils in the rat peripheral blood and brain, which may be related to the down-regulation of the JAK1/STAT3 pathway. Full article
(This article belongs to the Special Issue Development of New Drugs against Stroke)
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19 pages, 4851 KiB  
Article
Sex Difference Leads to Differential Gene Expression Patterns and Therapeutic Efficacy in Mucopolysaccharidosis IVA Murine Model Receiving AAV8 Gene Therapy
by Matthew Piechnik, Paige C. Amendum, Kazuki Sawamoto, Molly Stapleton, Shaukat Khan, Nidhi Fnu, Victor Álvarez, Angelica Maria Herreño Pachon, Olivier Danos, Joseph T. Bruder, Subha Karumuthil-Melethil and Shunji Tomatsu
Int. J. Mol. Sci. 2022, 23(20), 12693; https://doi.org/10.3390/ijms232012693 - 21 Oct 2022
Cited by 3 | Viewed by 2156
Abstract
Adeno-associated virus (AAV) vector-based therapies can effectively correct some disease pathology in murine models with mucopolysaccharidoses. However, immunogenicity can limit therapeutic effect as immune responses target capsid proteins, transduced cells, and gene therapy products, ultimately resulting in loss of enzyme activity. Inherent differences [...] Read more.
Adeno-associated virus (AAV) vector-based therapies can effectively correct some disease pathology in murine models with mucopolysaccharidoses. However, immunogenicity can limit therapeutic effect as immune responses target capsid proteins, transduced cells, and gene therapy products, ultimately resulting in loss of enzyme activity. Inherent differences in male versus female immune response can significantly impact AAV gene transfer. We aim to investigate sex differences in the immune response to AAV gene therapies in mice with mucopolysaccharidosis IVA (MPS IVA). MPS IVA mice, treated with different AAV vectors expressing human N-acetylgalactosamine 6-sulfate sulfatase (GALNS), demonstrated a more robust antibody response in female mice resulting in subsequent decreased GALNS enzyme activity and less therapeutic efficacy in tissue pathology relative to male mice. Under thyroxine-binding globulin promoter, neutralizing antibody titers in female mice were approximately 4.6-fold higher than in male mice, with GALNS enzyme activity levels approximately 6.8-fold lower. Overall, male mice treated with AAV-based gene therapy showed pathological improvement in the femur and tibial growth plates, ligaments, and articular cartilage as determined by contrasting differences in pathology scores compared to females. Cardiac histology revealed a failure to normalize vacuolation in females, in contrast, to complete correction in male mice. These findings promote the need for further determination of sex-based differences in response to AAV-mediated gene therapy related to developing treatments for MPS IVA. Full article
(This article belongs to the Special Issue Mucopolysaccharidoses: Diagnosis, Treatment, and Management 3.0)
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16 pages, 3178 KiB  
Article
High-Molecular-Weight Dextran-Type Exopolysaccharide Produced by the Novel Apilactobacillus waqarii Improves Metabolic Syndrome: In Vitro and In Vivo Analyses
by Waqar Ahmad, Jacqueline L. Boyajian, Ahmed Abosalha, Anam Nasir, Iram Ashfaq, Paromita Islam, Sabrina Schaly, Rahul Thareja, Azam Hayat, Mujaddad ur Rehman, Munir Ahmad Anwar and Satya Prakash
Int. J. Mol. Sci. 2022, 23(20), 12692; https://doi.org/10.3390/ijms232012692 - 21 Oct 2022
Cited by 3 | Viewed by 2033
Abstract
Metabolic syndrome is a leading medical concern that affects one billion people worldwide. Metabolic syndrome is defined by a clustering of risk factors that predispose an individual to cardiovascular disease, diabetes and stroke. In recent years, the apparent role of the gut microbiota [...] Read more.
Metabolic syndrome is a leading medical concern that affects one billion people worldwide. Metabolic syndrome is defined by a clustering of risk factors that predispose an individual to cardiovascular disease, diabetes and stroke. In recent years, the apparent role of the gut microbiota in metabolic syndrome has drawn attention to microbiome-engineered therapeutics. Specifically, lactic acid bacteria (LAB) harbors beneficial metabolic characteristics, including the production of exopolysaccharides and other microbial byproducts. We recently isolated a novel fructophilic lactic acid bacterium (FLAB), Apilactobacillus waqarii strain HBW1, from honeybee gut and found it produces a dextran-type exopolysaccharide (EPS). The objective of this study was to explore the therapeutic potential of the new dextran in relation to metabolic syndrome. Findings revealed the dextran’s ability to improve the viability of damaged HT-29 intestinal epithelial cells and exhibit antioxidant properties. In vivo analyses demonstrated reductions in body weight gain and serum cholesterol levels in mice supplemented with the dextran, compared to control (5% and 17.2%, respectively). Additionally, blood glucose levels decreased by 16.26% following dextran supplementation, while increasing by 15.2% in non-treated mice. Overall, this study displays biotherapeutic potential of a novel EPS to improve metabolic syndrome and its individual components, warranting further investigation. Full article
(This article belongs to the Special Issue Bioactive Compounds in Metabolic Syndrome)
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19 pages, 3708 KiB  
Article
Heparanase Increases Podocyte Survival and Autophagic Flux after Adriamycin-Induced Injury
by Hanan Abu-Tayeh Suleiman, Shereen Said, Haya Ali Saleh, Aviva Gamliel-Lazarovich, Eyas Haddad, Irina Minkov, Yaniv Zohar, Neta Ilan, Israel Vlodavsky, Zaid Abassi and Suheir Assady
Int. J. Mol. Sci. 2022, 23(20), 12691; https://doi.org/10.3390/ijms232012691 - 21 Oct 2022
Cited by 2 | Viewed by 1965
Abstract
The kidney glomerular filtration barrier (GFB) is enriched with heparan sulfate (HS) proteoglycans, which contribute to its permselectivity. The endoglycosidase heparanase cleaves HS and hence appears to be involved in the pathogenesis of kidney injury and glomerulonephritis. We have recently reported, nonetheless, that [...] Read more.
The kidney glomerular filtration barrier (GFB) is enriched with heparan sulfate (HS) proteoglycans, which contribute to its permselectivity. The endoglycosidase heparanase cleaves HS and hence appears to be involved in the pathogenesis of kidney injury and glomerulonephritis. We have recently reported, nonetheless, that heparanase overexpression preserved glomerular structure and kidney function in an experimental model of Adriamycin-induced nephropathy. To elucidate mechanisms underlying heparanase function in podocytes—key GFB cells, we utilized a human podocyte cell line and transgenic mice overexpressing heparanase. Notably, podocytes overexpressing heparanase (H) demonstrated significantly higher survival rates and viability after exposure to Adriamycin or hydrogen peroxide, compared with mock-infected (V) podocytes. Immunofluorescence staining of kidney cryo-sections and cultured H and V podocytes as well as immunoblotting of proteins extracted from cultured cells, revealed that exposure to toxic injury resulted in a significant increase in autophagic flux in H podocytes, which was reversed by the heparanase inhibitor, Roneparstat (SST0001). Heparanase overexpression was also associated with substantial transcriptional upregulation of autophagy genes BCN1, ATG5, and ATG12, following Adriamycin treatment. Moreover, cleaved caspase-3 was attenuated in H podocytes exposed to Adriamycin, indicating lower apoptotic cell death in H vs. V podocytes. Collectively, these findings suggest that in podocytes, elevated levels of heparanase promote cytoprotection. Full article
(This article belongs to the Special Issue Cellular and Molecular Mechanisms in Glomerulonephritis 2.0)
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20 pages, 4090 KiB  
Article
Fatty Acid Amide Hydrolase Deficiency Is Associated with Deleterious Cardiac Effects after Myocardial Ischemia and Reperfusion in Mice
by Sanela Rajlic, Luise Surmann, Pia Zimmermann, Christina Katharina Weisheit, Laura Bindila, Hendrik Treede, Markus Velten, Andreas Daiber and Georg Daniel Duerr
Int. J. Mol. Sci. 2022, 23(20), 12690; https://doi.org/10.3390/ijms232012690 - 21 Oct 2022
Cited by 3 | Viewed by 1820
Abstract
Ischemic cardiomyopathy leads to inflammation and left ventricular (LV) dysfunction. Animal studies provided evidence for cardioprotective effects of the endocannabinoid system, including cardiomyocyte adaptation, inflammation, and remodeling. Cannabinoid type-2 receptor (CB2) deficiency led to increased apoptosis and infarctions with worsened LV function in [...] Read more.
Ischemic cardiomyopathy leads to inflammation and left ventricular (LV) dysfunction. Animal studies provided evidence for cardioprotective effects of the endocannabinoid system, including cardiomyocyte adaptation, inflammation, and remodeling. Cannabinoid type-2 receptor (CB2) deficiency led to increased apoptosis and infarctions with worsened LV function in ischemic cardiomyopathy. The aim of our study was to investigate a possible cardioprotective effect of endocannabinoid anandamide (AEA) after ischemia and reperfusion (I/R). Therefore, fatty acid amide hydrolase deficient (FAAH)−/− mice were subjected to repetitive, daily, 15 min, left anterior descending artery (LAD) occlusion over 3 and 7 consecutive days. Interestingly, FAAH−/− mice showed stigmata such as enhanced inflammation, cardiomyocyte loss, stronger remodeling, and persistent scar with deteriorated LV function compared to wild-type (WT) littermates. As endocannabinoids also activate PPAR-α (peroxisome proliferator-activated receptor), PPAR-α mediated effects of AEA were eliminated with PPAR-α antagonist GW6471 i.v. in FAAH−/− mice. LV function was assessed using M-mode echocardiography. Immunohistochemical analysis revealed apoptosis, macrophage accumulation, collagen deposition, and remodeling. Hypertrophy was determined by cardiomyocyte area and heart weight/tibia length. Molecular analyses involved Taqman® RT-qPCR and immune cells were analyzed with fluorescence-activated cell sorting (FACS). Most importantly, collagen deposition was reduced to WT levels when FAAH−/− mice were treated with GW6471. Chemokine ligand-2 (CCL2) expression was significantly higher in FAAH−/− mice compared to WT, followed by higher macrophage infiltration in infarcted areas, both being reversed by GW6471 treatment. Besides restoring antioxidative properties and contractile elements, PPAR-α antagonism also reversed hypertrophy and remodeling in FAAH−/− mice. Finally, FAAH−/−-mice showed more substantial downregulation of PPAR-α compared to WT, suggesting a compensatory mechanism as endocannabinoids are also ligands for PPAR-α, and its activation causes lipotoxicity leading to cardiomyocyte apoptosis. Our study gives novel insights into the role of endocannabinoids acting via PPAR-α. We hypothesize that the increase in endocannabinoids may have partially detrimental effects on cardiomyocyte survival due to PPAR-α activation. Full article
(This article belongs to the Special Issue Lipids Metabolism and Cardiometabolic Diseases)
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28 pages, 3656 KiB  
Article
Aberrant Transferrin and Ferritin Upregulation Elicits Iron Accumulation and Oxidative Inflammaging Causing Ferroptosis and Undermines Estradiol Biosynthesis in Aging Rat Ovaries by Upregulating NF-Κb-Activated Inducible Nitric Oxide Synthase: First Demonstration of an Intricate Mechanism
by Stephen Cho Wing Sze, Liang Zhang, Shiqing Zhang, Kaili Lin, Tzi Bun Ng, Man Ling Ng, Kai-Fai Lee, Jenny Ka Wing Lam, Zhang Zhang and Ken Kin Lam Yung
Int. J. Mol. Sci. 2022, 23(20), 12689; https://doi.org/10.3390/ijms232012689 - 21 Oct 2022
Cited by 17 | Viewed by 3427
Abstract
We report herein a novel mechanism, unraveled by proteomics and validated by in vitro and in vivo studies, of the aberrant aging-associated upregulation of ovarian transferrin and ferritin in rat ovaries. The ovarian mass and serum estradiol titer plummeted while the ovarian labile [...] Read more.
We report herein a novel mechanism, unraveled by proteomics and validated by in vitro and in vivo studies, of the aberrant aging-associated upregulation of ovarian transferrin and ferritin in rat ovaries. The ovarian mass and serum estradiol titer plummeted while the ovarian labile ferrous iron and total iron levels escalated with age in rats. Oxidative stress markers, such as nitrite/nitrate, 3-nitrotyrosine, and 4-hydroxy-2-nonenal, accumulated in the aging ovaries due to an aberrant upregulation of the ovarian transferrin, ferritin light/heavy chains, and iron regulatory protein 2(IRP2)-mediated transferrin receptor 1 (TfR1). Ferritin inhibited estradiol biosynthesis in ovarian granulosa cells in vitro via the upregulation of a nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and p65/p50-induced oxidative and inflammatory factor inducible nitric oxide synthase (iNOS). An in vivo study demonstrated how the age-associated activation of NF-κB induced the upregulation of iNOS and the tumor necrosis factor α (TNFα). The downregulation of the keap1-mediated nuclear factor erythroid 2-related factor 2 (Nrf2), that induced a decrease in glutathione peroxidase 4 (GPX4), was observed. The aberrant transferrin and ferritin upregulation triggered an iron accumulation via the upregulation of an IRP2-induced TfR1. This culminates in NF-κB-iNOS-mediated ovarian oxi-inflamm-aging and serum estradiol decrement in naturally aging rats. The iron accumulation and the effect on ferroptosis-related proteins including the GPX4, TfR1, Nrf2, Keap1, and ferritin heavy chain, as in testicular ferroptosis, indicated the triggering of ferroptosis. In young rats, an intraovarian injection of an adenovirus, which expressed iron regulatory proteins, upregulated the ovarian NF-κB/iNOS and downregulated the GPX4. These novel findings have contributed to a prompt translational research on the ovarian aging-associated iron metabolism and aging-associated ovarian diseases. Full article
(This article belongs to the Special Issue Nitric Oxide Synthases: Function and Regulation)
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15 pages, 5175 KiB  
Article
Computational Docking Reveals Co-Evolution of C4 Carbon Delivery Enzymes in Diverse Plants
by Chao Wu and Dianjing Guo
Int. J. Mol. Sci. 2022, 23(20), 12688; https://doi.org/10.3390/ijms232012688 - 21 Oct 2022
Cited by 3 | Viewed by 1593
Abstract
Proteins are modular functionalities regulating multiple cellular activities in prokaryotes and eukaryotes. As a consequence of higher plants adapting to arid and thermal conditions, C4 photosynthesis is the carbon fixation process involving multi-enzymes working in a coordinated fashion. However, how these enzymes interact [...] Read more.
Proteins are modular functionalities regulating multiple cellular activities in prokaryotes and eukaryotes. As a consequence of higher plants adapting to arid and thermal conditions, C4 photosynthesis is the carbon fixation process involving multi-enzymes working in a coordinated fashion. However, how these enzymes interact with each other and whether they co-evolve in parallel to maintain interactions in different plants remain elusive to date. Here, we report our findings on the global protein co-evolution relationship and local dynamics of co-varying site shifts in key C4 photosynthetic enzymes. We found that in most of the selected key C4 photosynthetic enzymes, global pairwise co-evolution events exist to form functional couplings. Besides, protein–protein interactions between these enzymes may suggest their unknown functionalities in the carbon delivery process. For PEPC and PPCK regulation pairs, pocket formation at the interactive interface are not necessary for their function. This feature is distinct from another well-known regulation pair in C4 photosynthesis, namely, PPDK and PPDK-RP, where the pockets are necessary. Our findings facilitate the discovery of novel protein regulation types and contribute to expanding our knowledge about C4 photosynthesis. Full article
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0 pages, 2962 KiB  
Article
DR5-Selective TRAIL Variant DR5-B Functionalized with Tumor-Penetrating iRGD Peptide for Enhanced Antitumor Activity against Glioblastoma
by Anne V. Yagolovich, Alina A. Isakova, Artem A. Artykov, Yekaterina V. Vorontsova, Diana V. Mazur, Nadezhda V. Antipova, Marat S. Pavlyukov, Mikhail I. Shakhparonov, Anastasia M. Gileva, Elena A. Markvicheva, Ekaterina A. Plotnikova, Andrey A. Pankratov, Mikhail P. Kirpichnikov, Marine E. Gasparian and Dmitry A. Dolgikh
Int. J. Mol. Sci. 2022, 23(20), 12687; https://doi.org/10.3390/ijms232012687 - 21 Oct 2022
Cited by 3 | Viewed by 2034 | Correction
Abstract
TRAIL (TNF-related apoptosis-inducing ligand) and its derivatives are potentials for anticancer therapy due to the selective induction of apoptosis in tumor cells upon binding to death receptors DR4 or DR5. Previously, we generated a DR5-selective TRAIL mutant variant DR5-B overcoming receptor-dependent resistance of [...] Read more.
TRAIL (TNF-related apoptosis-inducing ligand) and its derivatives are potentials for anticancer therapy due to the selective induction of apoptosis in tumor cells upon binding to death receptors DR4 or DR5. Previously, we generated a DR5-selective TRAIL mutant variant DR5-B overcoming receptor-dependent resistance of tumor cells to TRAIL. In the current study, we improved the antitumor activity of DR5-B by fusion with a tumor-homing iRGD peptide, which is known to enhance the drug penetration into tumor tissues. The obtained bispecific fusion protein DR5-B-iRGD exhibited dual affinity for DR5 and integrin αvβ3 receptors. DR5-B-iRGD penetrated into U-87 tumor spheroids faster than DR5-B and demonstrated an enhanced antitumor effect in human glioblastoma cell lines T98G and U-87, as well as in primary patient-derived glioblastoma neurospheres in vitro. Additionally, DR5-B-iRGD was highly effective in a xenograft mouse model of the U-87 human glioblastoma cell line in vivo. We suggest that DR5-B-iRGD may become a promising candidate for targeted therapy for glioblastoma. Full article
(This article belongs to the Special Issue Advances in Protein-Protein Interactions)
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19 pages, 2802 KiB  
Article
Genome ARTIST_v2—An Autonomous Bioinformatics Tool for Annotation of Natural Transposons in Sequenced Genomes
by Alexandru Al. Ecovoiu, Alexandru Marian Bologa, David Ioan Mihail Chifiriuc, Andrei Mihai Ciuca, Nicoleta Denisa Constantin, Iulian Constantin Ghionoiu, Iulian Cristian Ghita and Attila Cristian Ratiu
Int. J. Mol. Sci. 2022, 23(20), 12686; https://doi.org/10.3390/ijms232012686 - 21 Oct 2022
Cited by 2 | Viewed by 2442
Abstract
The annotation of transposable elements (transposons) is a very dynamic field of genomics and various tools assigned to support this bioinformatics endeavor have been developed and described. Genome ARTIST v1.19 (GA_v1.19) software was conceived for mapping artificial transposons mobilized during insertional mutagenesis projects, [...] Read more.
The annotation of transposable elements (transposons) is a very dynamic field of genomics and various tools assigned to support this bioinformatics endeavor have been developed and described. Genome ARTIST v1.19 (GA_v1.19) software was conceived for mapping artificial transposons mobilized during insertional mutagenesis projects, but the new functions of GA_v2 qualify it as a tool for the mapping and annotation of natural transposons (NTs) in long reads, contigs and assembled genomes. The tabular export of mapping and annotation data for high-throughput data analysis, the generation of a list of flanking sequences around the coordinates of insertion or around the target site duplications and the computing of a consensus sequence for the flanking sequences are all key assets of GA_v2. Additionally, we developed a set of scripts that enable the user to annotate NTs, to harness annotations offered by FlyBase for Drosophila melanogaster genome, to convert sequence files from .fasta to .raw, and to extract junction query sequences essential for NTs mapping. Herein, we present the applicability of GA_v2 for a preliminary annotation of P-element and hobo class II NTs and copia retrotransposon in the genome of D. melanogaster strain Horezu_LaPeri (Horezu), Romania, which was sequenced with Nanopore technology in our laboratory. We used contigs assembled with Flye tool and a Q10 quality filter of the reads. Our results suggest that GA_v2 is a reliable autonomous tool able to perform mapping and annotation of NTs in genomes sequenced by long sequencing technology. GA_v2 is open-source software compatible with Linux, Mac OS and Windows and is available at GitHub repository and dedicated website. Full article
(This article belongs to the Section Molecular Informatics)
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25 pages, 15926 KiB  
Article
Cheminformatics Study on Structural and Bactericidal Activity of Latest Generation β-Lactams on Widespread Pathogens
by Ana Maria Raluca Gherman, Nicoleta Elena Dina and Vasile Chiș
Int. J. Mol. Sci. 2022, 23(20), 12685; https://doi.org/10.3390/ijms232012685 - 21 Oct 2022
Viewed by 1441
Abstract
Raman spectra of oxacillin (OXN), carbenicillin (CBC), and azlocillin (AZL) are reported for the first time together with their full assignment of the normal modes, as calculated using Density Functional Theory (DFT) methods with the B3LYP exchange-correlation functional coupled to the 6-31G(d) and [...] Read more.
Raman spectra of oxacillin (OXN), carbenicillin (CBC), and azlocillin (AZL) are reported for the first time together with their full assignment of the normal modes, as calculated using Density Functional Theory (DFT) methods with the B3LYP exchange-correlation functional coupled to the 6-31G(d) and 6-311+G(2d,p) basis sets. Molecular docking studies were performed on five penicillins, including OXN, CBC, and AZL. Subsequently, their chemical reactivity and correlated efficiency towards specific pathogenic strains were revealed by combining frontier molecular orbital (FMO) data with molecular electrostatic potential (MEP) surfaces. Their bactericidal activity was tested and confirmed on a couple of species, both Gram-positive and Gram-negative, by using the disk diffusion method. Additionally, a surface-enhanced Raman spectroscopy (SERS)—principal component analysis (PCA)-based resistogram of A. hydrophila is proposed as a clinically relevant insight resulting from the synergistic cheminformatics and vibrational study on CBC and AZL. Full article
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12 pages, 3815 KiB  
Article
Promoter of Vegetable Soybean GmTIP1;6 Responds to Diverse Abiotic Stresses and Hormone Signals in Transgenic Arabidopsis
by Zhijuan Feng, Na Liu, Guwen Zhang, Yuanpeng Bu, Bin Wang and Yaming Gong
Int. J. Mol. Sci. 2022, 23(20), 12684; https://doi.org/10.3390/ijms232012684 - 21 Oct 2022
Cited by 2 | Viewed by 1816
Abstract
Tonoplast intrinsic proteins (TIPs), a sub-family of aquaporins (AQPs), are known to play important roles in plant abiotic stress responses. However, evidence for the promoters of TIPs involvement in abiotic stress processes remains scarce. In this study, the promoter of the vegetable soybean [...] Read more.
Tonoplast intrinsic proteins (TIPs), a sub-family of aquaporins (AQPs), are known to play important roles in plant abiotic stress responses. However, evidence for the promoters of TIPs involvement in abiotic stress processes remains scarce. In this study, the promoter of the vegetable soybean GmTIP1;6 gene, which had the highest similarity to TIP1-type AQPs from other plants, was cloned. Expression pattern analyses indicated that the GmTIP1;6 gene was dramatically induced by drought, salt, abscisic acid (ABA), and methyl jasmonate (MeJA) stimuli. Promoter analyses revealed that the GmTIP1;6 promoter contained drought, ABA, and MeJA cis-acting elements. Histochemical staining of the GmTIP1;6 promoter in transgenic Arabidopsis corroborated that it was strongly expressed in the vascular bundles of leaves, stems, and roots. Beta-glucuronidase (GUS) activity assays showed that the activities of the GmTIP1;6 promoter were enhanced by different concentrations of polyethylene glycol 6000 (PEG 6000), NaCl, ABA, and MEJA treatments. Integrating these results revealed that the GmTIP1;6 promoter could be applied for improving the tolerance to abiotic stresses of the transgenic plants by promoting the expression of vegetable soybean AQPs. Full article
(This article belongs to the Special Issue Advanced Research in Plant Responses to Environmental Stresses 2.0)
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20 pages, 976 KiB  
Review
Physiological and Pathological Remodeling of Cerebral Microvessels
by Pavel P. Tregub, Anton S. Averchuk, Tatyana I. Baranich, Maria V. Ryazanova and Alla B. Salmina
Int. J. Mol. Sci. 2022, 23(20), 12683; https://doi.org/10.3390/ijms232012683 - 21 Oct 2022
Cited by 7 | Viewed by 1972
Abstract
There is growing evidence that the remodeling of cerebral microvessels plays an important role in plastic changes in the brain associated with development, experience, learning, and memory consolidation. At the same time, abnormal neoangiogenesis, and deregulated regulation of microvascular regression, or pruning, could [...] Read more.
There is growing evidence that the remodeling of cerebral microvessels plays an important role in plastic changes in the brain associated with development, experience, learning, and memory consolidation. At the same time, abnormal neoangiogenesis, and deregulated regulation of microvascular regression, or pruning, could contribute to the pathogenesis of neurodevelopmental diseases, stroke, and neurodegeneration. Aberrant remodeling of microvesselsis associated with blood–brain barrier breakdown, development of neuroinflammation, inadequate microcirculation in active brain regions, and leads to the dysfunction of the neurovascular unit and progressive neurological deficits. In this review, we summarize current data on the mechanisms of blood vessel regression and pruning in brain plasticity and in Alzheimer’s-type neurodegeneration. We discuss some novel approaches to modulating cerebral remodeling and preventing degeneration-coupled aberrant microvascular activity in chronic neurodegeneration. Full article
(This article belongs to the Special Issue Molecular Advances in Alzheimer's Disease)
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15 pages, 1434 KiB  
Article
Isomelezitose Overproduction by Alginate-Entrapped Recombinant E. coli Cells and In Vitro Evaluation of Its Potential Prebiotic Effect
by Martin Garcia-Gonzalez, Fadia V. Cervantes, Ricardo P. Ipiales, Angeles de la Rubia, Francisco J. Plou and María Fernández-Lobato
Int. J. Mol. Sci. 2022, 23(20), 12682; https://doi.org/10.3390/ijms232012682 - 21 Oct 2022
Cited by 2 | Viewed by 1610
Abstract
In this work, the trisaccharide isomelezitose was overproduced from sucrose using a biocatalyst based on immobilized Escherichia coli cells harbouring the α-glucosidase from the yeast Metschnikowia reukaufii, the best native producer of this sugar described to date. The overall process for isomelezitose [...] Read more.
In this work, the trisaccharide isomelezitose was overproduced from sucrose using a biocatalyst based on immobilized Escherichia coli cells harbouring the α-glucosidase from the yeast Metschnikowia reukaufii, the best native producer of this sugar described to date. The overall process for isomelezitose production and purification was performed in three simple steps: (i) oligosaccharides synthesis by alginate-entrapped E. coli; (ii) elimination of monosaccharides (glucose and fructose) using alginate-entrapped Komagataella phaffii cells; and (iii) semi-preparative high performance liquid chromatography under isocratic conditions. As result, approximately 2.15 g of isomelezitose (purity exceeding 95%) was obtained from 15 g of sucrose. The potential prebiotic effect of this sugar on probiotic bacteria (Lactobacillus casei, Lactobacillus rhamnosus and Enterococcus faecium) was analysed using in vitro assays for the first time. The growth of all probiotic bacteria cultures supplemented with isomelezitose was significantly improved and was similar to that of cultures supplemented with a commercial mixture of fructo-oligosaccharides. In addition, when isomelezitose was added to the bacteria cultures, the production of organic acids (mainly butyrate) was significantly promoted. Therefore, these results confirm that isomelezitose is a potential novel prebiotic that could be included in healthier foodstuffs designed for human gastrointestinal balance maintenance. Full article
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21 pages, 1319 KiB  
Review
Magnetic-Based Human Tissue 3D Cell Culture: A Systematic Review
by Inês Alexandra Marques, Carolina Fernandes, Nuno Tiago Tavares, Ana Salomé Pires, Ana Margarida Abrantes and Maria Filomena Botelho
Int. J. Mol. Sci. 2022, 23(20), 12681; https://doi.org/10.3390/ijms232012681 - 21 Oct 2022
Cited by 6 | Viewed by 4039
Abstract
Cell-based assays, conducted on monolayer (2D) cultured cells, are an unquestionably valuable tool for biomedical research. However, three-dimensional (3D) cell culture models have gained relevance over the last few years due to the advantages of better mimicking the microenvironment and tissue microarchitecture in [...] Read more.
Cell-based assays, conducted on monolayer (2D) cultured cells, are an unquestionably valuable tool for biomedical research. However, three-dimensional (3D) cell culture models have gained relevance over the last few years due to the advantages of better mimicking the microenvironment and tissue microarchitecture in vivo. Recent magnetic-based 3D (m3D) cell culture systems can be used for this purpose. These systems are based on exposing magnetized cells to magnetic fields by levitation, bioprinting, or ring formation to promote cell aggregation into 3D structures. However, the successful development of these structures is dependent on several methodological characteristics and can be applied to mimic different human tissues. Thus, a systematic review was performed using Medline (via Pubmed), Scopus, and Web of Science (until February 2022) databases to aggregate studies using m3D culture in which human tissues were mimicked. The search generated 3784 records, of which 25 met the inclusion criteria. The usability of these m3D systems for the development of homotypic or heterotypic spheroids with or without scaffolds was explored in these studies. We also explore methodological differences specifically related to the magnetic method. Generally, the development of m3D cultures has been increasing, with bioprinting and levitation systems being the most used to generate homotypic or heterotypic cultures, mainly to mimic the physiology of human tissues, but also to perform therapeutic screening. This systematic review showed that there are areas of research where the application of this method remains barely explored, such as cancer research. Full article
(This article belongs to the Special Issue Challenges of Radiation Biology for Cancer Management)
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18 pages, 2172 KiB  
Article
Macrophage Phenotypes and Gene Expression Patterns Are Unique in Naturally Occurring Metabolically Healthy Obesity
by Alistaire D. Ruggiero, Ravichandra Vemuri, Masha Block, Darla DeStephanis, Matthew Davis, Jeff Chou, Abigail Williams, Ashlynn Brock, Swapan Kumar Das and Kylie Kavanagh
Int. J. Mol. Sci. 2022, 23(20), 12680; https://doi.org/10.3390/ijms232012680 - 21 Oct 2022
Cited by 5 | Viewed by 2168
Abstract
Obesity impacts 650 million individuals globally, often co-occurring with metabolic syndrome. Though many obese individuals experience metabolic abnormalities (metabolically unhealthy obese [MUO]), ~30% do not (metabolically healthy obese [MHO]). Conversely, >10% of lean individuals are metabolically unhealthy (MUL). To evaluate the physiologic drivers [...] Read more.
Obesity impacts 650 million individuals globally, often co-occurring with metabolic syndrome. Though many obese individuals experience metabolic abnormalities (metabolically unhealthy obese [MUO]), ~30% do not (metabolically healthy obese [MHO]). Conversely, >10% of lean individuals are metabolically unhealthy (MUL). To evaluate the physiologic drivers of these phenotypes, a 44-animal African green monkey cohort was selected using metabolic syndrome risk criteria to represent these four clinically defined health groups. Body composition imaging and subcutaneous adipose tissue (SQ AT) biopsies were collected. Differences in adipocyte size, macrophage subtype distribution, gene expression, vascularity and fibrosis were analyzed using digital immunohistopathology, unbiased RNA-seq, endothelial CD31, and Masson’s trichrome staining, respectively. MHO AT demonstrated significant increases in M2 macrophages (p = 0.02) and upregulation of fatty acid oxidation-related terms and transcripts, including FABP7 (p = 0.01). MUO AT demonstrated downregulation of these factors and co-occurring upregulation of immune responses. These changes occurred without differences in AT distributions, adipocyte size, AT endothelial cells, collagen I deposition, or circulating cytokine levels. Without unhealthy diet consumption, healthy obesity is defined by an increased SQ AT M2/M1 macrophage ratio and lipid handling gene expression. We highlight M2 macrophages and fatty acid oxidation as targets for improving metabolic health with obesity. Full article
(This article belongs to the Special Issue New Insights into Adipose Tissue Metabolic Function and Dysfunction)
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