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Int. J. Mol. Sci., Volume 21, Issue 13 (July-1 2020) – 247 articles

Cover Story (view full-size image): Cell-penetrating peptides (CPPs) can carry cell-impermeable therapeutic entities across the plasma membrane. The cytosolic uptake of the CPP–cargo provides a significant opportunity for targeting the undruggable cytoplasmic domain and, yet, is challenging to evaluate objectively. This article provides a comprehensive review of the current and emerging in vitro assays used to evaluate CPP–cargo cellular uptake and recommends utilization of orthogonal assays to assess the ability of CPPs as delivery vehicles. View this paper
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Article
Differences in the Role of HDACs 4 and 5 in the Modulation of Processes Regulating MAFbx and MuRF1 Expression during Muscle Unloading
Int. J. Mol. Sci. 2020, 21(13), 4815; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21134815 - 07 Jul 2020
Cited by 5 | Viewed by 977
Abstract
Unloading leads to skeletal muscle atrophy via the upregulation of MuRF-1 and MAFbx E3-ligases expression. Reportedly, histone deacetylases (HDACs) 4 and 5 may regulate the expression of MuRF1 and MAFbx. To examine the HDAC-dependent mechanisms involved in the control of E3-ubiquitin ligases expression [...] Read more.
Unloading leads to skeletal muscle atrophy via the upregulation of MuRF-1 and MAFbx E3-ligases expression. Reportedly, histone deacetylases (HDACs) 4 and 5 may regulate the expression of MuRF1 and MAFbx. To examine the HDAC-dependent mechanisms involved in the control of E3-ubiquitin ligases expression at the early stages of muscle unloading we used HDACs 4 and 5 inhibitor LMK-235 and HDAC 4 inhibitor Tasqinimod (Tq). Male Wistar rats were divided into four groups (eight rats per group): nontreated control (C), three days of unloading/hindlimb suspension (HS) and three days HS with HDACs inhibitor LMK-235 (HSLMK) or Tq (HSTq). Treatment with LMK-235 diminished unloading-induced of MAFbx, myogenin (MYOG), ubiquitin and calpain-1 mRNA expression (p < 0.05). Tq administration had no effect on the expression of E3-ligases. The mRNA expression of MuRF1 and MAFbx was significantly increased in both HS and HSTq groups (1.5 and 4.0 folds, respectively; p < 0.05) when compared with the C group. It is concluded that during three days of muscle unloading: (1) the HDACs 4 and 5 participate in the regulation of MAFbx expression as well as the expression of MYOG, ubiquitin and calpain-1; (2) the inhibition of HDAC 4 has no effect on MAFbx expression. Therefore, HDAC 5 is perhaps more important for the regulation of MAFbx expression than HDAC 4. Full article
(This article belongs to the Special Issue Modifications of Molecular Structure and Interactions in Epigenome)
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Article
More P450s Are Involved in Secondary Metabolite Biosynthesis in Streptomyces Compared to Bacillus, Cyanobacteria, and Mycobacterium
Int. J. Mol. Sci. 2020, 21(13), 4814; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21134814 - 07 Jul 2020
Cited by 5 | Viewed by 1221
Abstract
Unraveling the role of cytochrome P450 monooxygenases (CYPs/P450s), heme-thiolate proteins present in living and non-living entities, in secondary metabolite synthesis is gaining momentum. In this direction, in this study, we analyzed the genomes of 203 Streptomyces species for P450s and unraveled their association [...] Read more.
Unraveling the role of cytochrome P450 monooxygenases (CYPs/P450s), heme-thiolate proteins present in living and non-living entities, in secondary metabolite synthesis is gaining momentum. In this direction, in this study, we analyzed the genomes of 203 Streptomyces species for P450s and unraveled their association with secondary metabolism. Our analyses revealed the presence of 5460 P450s, grouped into 253 families and 698 subfamilies. The CYP107 family was found to be conserved and highly populated in Streptomyces and Bacillus species, indicating its key role in the synthesis of secondary metabolites. Streptomyces species had a higher number of P450s than Bacillus and cyanobacterial species. The average number of secondary metabolite biosynthetic gene clusters (BGCs) and the number of P450s located in BGCs were higher in Streptomyces species than in Bacillus, mycobacterial, and cyanobacterial species, corroborating the superior capacity of Streptomyces species for generating diverse secondary metabolites. Functional analysis via data mining confirmed that many Streptomyces P450s are involved in the biosynthesis of secondary metabolites. This study was the first of its kind to conduct a comparative analysis of P450s in such a large number (203) of Streptomyces species, revealing the P450s’ association with secondary metabolite synthesis in Streptomyces species. Future studies should include the selection of Streptomyces species with a higher number of P450s and BGCs and explore the biotechnological value of secondary metabolites they produce. Full article
(This article belongs to the Special Issue Cytochromes P450: Drug Metabolism, Bioactivation and Biodiversity 2.0)
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Article
A Pilot Study of the Predictive Potential of Chemosensitivity and Gene Expression Assays Using Circulating Tumour Cells from Patients with Recurrent Ovarian Cancer
Int. J. Mol. Sci. 2020, 21(13), 4813; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21134813 - 07 Jul 2020
Cited by 7 | Viewed by 1376
Abstract
Circulating tumour cells (CTCs) from liquid biopsies are under current investigation in several cancers, including epithelial ovarian cancer (EOC) but face significant drawbacks in terms of non-standardised methodology, low viable cell numbers and accuracy of CTC identification. In this pilot study, we report [...] Read more.
Circulating tumour cells (CTCs) from liquid biopsies are under current investigation in several cancers, including epithelial ovarian cancer (EOC) but face significant drawbacks in terms of non-standardised methodology, low viable cell numbers and accuracy of CTC identification. In this pilot study, we report that chemosensitivity assays using liquid biopsy-derived metastatic EOC CTCs, from 10 patients, nine with stage IIIC and one with stage IV disease, in progression after systemic chemotherapy, submitted for hypoxic isolated abdominal perfusion (HAP), are both feasible and useful in predicting response to therapy. Viable metastatic EOC CTCs (>5 cells/mL for all 10 blood samples), enriched by transient culture and identified by reverse transcription polymerase chain reaction (RT-PCR) and indirect immunofluorescence (IF), were subjected to flow cytometry-based Annexin V-PE assays for chemosensitivity to several chemotherapeutic agents and by RT-PCR for tumour gene expression profiling. Using a cut-off value of >80% cell death, CTC chemosensitivity tests were predictive of patient RECIST 1.1 responses to HAP therapy associated with 100% sensitivity, 50% specificity, 33% positive predictive, 100% negative predictive and 60% accuracy values. We propose that the methodology employed in this study is feasible and has the potential to predict response to therapy, setting the stage for a larger study. Full article
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Review
Steroids and Alzheimer’s Disease: Changes Associated with Pathology and Therapeutic Potential
Int. J. Mol. Sci. 2020, 21(13), 4812; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21134812 - 07 Jul 2020
Cited by 6 | Viewed by 1624
Abstract
Alzheimer’s disease (AD) is a multifactorial age-related neurodegenerative disease that today has no effective treatment to prevent or slow its progression. Neuroactive steroids, including neurosteroids and sex steroids, have attracted attention as potential suitable candidates to alleviate AD pathology. Accumulating evidence shows that [...] Read more.
Alzheimer’s disease (AD) is a multifactorial age-related neurodegenerative disease that today has no effective treatment to prevent or slow its progression. Neuroactive steroids, including neurosteroids and sex steroids, have attracted attention as potential suitable candidates to alleviate AD pathology. Accumulating evidence shows that they exhibit pleiotropic neuroprotective properties that are relevant for AD. This review focuses on the relationship between selected neuroactive steroids and the main aspects of AD disease, pointing out contributions and gaps with reference to sex differences. We take into account the regulation of brain steroid concentrations associated with human AD pathology. Consideration is given to preclinical studies in AD models providing current knowledge on the neuroprotection offered by neuroactive (neuro)steroids on major AD pathogenic factors, such as amyloid-β (Aβ) and tau pathology, mitochondrial impairment, neuroinflammation, neurogenesis and memory loss. Stimulating endogenous steroid production opens a new steroid-based strategy to potentially overcome AD pathology. This article is part of a Special Issue entitled Steroids and the Nervous System. Full article
(This article belongs to the Special Issue Steroids and the Nervous System)
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Article
A Dipeptidyl Peptidase-4 Inhibitor Inhibits Foam Cell Formation of Macrophages in Type 1 Diabetes via Suppression of CD36 and ACAT-1 Expression
Int. J. Mol. Sci. 2020, 21(13), 4811; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21134811 - 07 Jul 2020
Cited by 9 | Viewed by 1130
Abstract
Dipeptidyl peptidase-4 (DPP-4) inhibitors have been reported to play a protective role against atherosclerosis in both animal models and patients with type 2 diabetes (T2D). However, since T2D is associated with dyslipidemia, hypertension and insulin resistance, part of which are ameliorated by DPP-4 [...] Read more.
Dipeptidyl peptidase-4 (DPP-4) inhibitors have been reported to play a protective role against atherosclerosis in both animal models and patients with type 2 diabetes (T2D). However, since T2D is associated with dyslipidemia, hypertension and insulin resistance, part of which are ameliorated by DPP-4 inhibitors, it remains unclear whether DPP-4 inhibitors could have anti-atherosclerotic properties directly by attenuating the harmful effects of hyperglycemia. Therefore, we examined whether a DPP-4 inhibitor, teneligliptin, could suppress oxidized low-density lipoprotein (ox-LDL) uptake, foam cell formation, CD36 and acyl-coenzyme A: cholesterol acyltransferase-1 (ACAT-1) gene expression of macrophages isolated from streptozotocin-induced type 1 diabetes (T1D) mice and T1D patients as well as advanced glycation end product (AGE)-exposed mouse peritoneal macrophages and THP-1 cells. Foam cell formation, CD36 and ACAT-1 gene expression of macrophages derived from T1D mice or patients increased compared with those from non-diabetic controls, all of which were inhibited by 10 nmol/L teneligliptin. AGEs mimicked the effects of T1D; teneligliptin attenuated all the deleterious effects of AGEs in mouse macrophages and THP-1 cells. Our present findings suggest that teneligliptin may inhibit foam cell formation of macrophages in T1D via suppression of CD36 and ACAT-1 gene expression partly by attenuating the harmful effects of AGEs. Full article
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Article
Regulation of Human Platelet Activation and Prevention of Arterial Thrombosis in Mice by Auraptene through Inhibition of NF-κB Pathway
Int. J. Mol. Sci. 2020, 21(13), 4810; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21134810 - 07 Jul 2020
Cited by 5 | Viewed by 966
Abstract
Platelets are major players in the occurrence of cardiovascular diseases. Auraptene is the most abundant coumarin derivative from plants, and it has been demonstrated to possess a potent capacity to inhibit platelet activation. Although platelets are anucleated cells, they also express the transcription [...] Read more.
Platelets are major players in the occurrence of cardiovascular diseases. Auraptene is the most abundant coumarin derivative from plants, and it has been demonstrated to possess a potent capacity to inhibit platelet activation. Although platelets are anucleated cells, they also express the transcription factor, nuclear factor-κB (NF-κB), that may exert non-genomic functions in platelet activation. In the current study, we further investigated the inhibitory roles of auraptene in NF-κB-mediated signal events in platelets. MG-132 (an inhibitor of proteasome) and BAY11-7082 (an inhibitor of IκB kinase; IKK), obviously inhibited platelet aggregation; however, BAY11-7082 exhibited more potent activity than MG-132 in this reaction. The existence of NF-κB (p65) in platelets was observed by confocal microscopy, and auraptene attenuated NF-κB activation such as IκBα and p65 phosphorylation and reversed IκBα degradation in collagen-activated platelets. To investigate cellular signaling events between PLCγ2-PKC and NF-κB, we found that BAY11-7082 abolished PLCγ2-PKC activation; nevertheless, neither U73122 nor Ro31-8220 had effect on NF-κB activation. Furthermore, both auraptene and BAY11-7082 significantly diminished HO• formation in activated platelets. For in vivo study, auraptene prolonged the occlusion time of platelet plug in mice. In conclusion, we propose a novel inhibitory pathway of NF-κB-mediated PLCγ2-PKC activation by auraptene in human platelets, and further supported that auraptene possesses potent activity for thromboembolic diseases. Full article
(This article belongs to the Special Issue Molecular Research on Platelet Activity in Health and Disease 2.0)
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Article
Silencing of TaCKX1 Mediates Expression of Other TaCKX Genes to Increase Yield Parameters in Wheat
Int. J. Mol. Sci. 2020, 21(13), 4809; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21134809 - 07 Jul 2020
Cited by 10 | Viewed by 1045
Abstract
TaCKX, Triticum aestivum (cytokinin oxidase/dehydrogenase) family genes influence the development of wheat plants by the specific regulation of cytokinin content in different organs. However, their detailed role is not known. The TaCKX1, highly and specifically expressed in developing spikes and in [...] Read more.
TaCKX, Triticum aestivum (cytokinin oxidase/dehydrogenase) family genes influence the development of wheat plants by the specific regulation of cytokinin content in different organs. However, their detailed role is not known. The TaCKX1, highly and specifically expressed in developing spikes and in seedling roots, was silenced by RNAi-mediated gene silencing via Agrobacterium tumefaciens and the effect of silencing was investigated in 7 DAP (days after pollination) spikes of T1 and T2 generations. Various levels of TaCKX1 silencing in both generations influence different models of co-expression with other TaCKX genes and parameters of yield-related traits. Only a high level of silencing in T2 resulted in strong down-regulation of TaCKX11 (3), up-regulation of TaCKX2.1, 2.2, 5, and 9 (10), and a high yielding phenotype. This phenotype is characterized by a higher spike number, grain number, and grain yield, but lower thousand grain weight (TGW). The content of most of cytokinin forms in 7 DAP spikes of silenced T2 lines increased from 23% to 76% compared to the non-silenced control. The CKs cross talk with other phytohormones. Each of the tested yield-related traits is regulated by various up- or down-regulated TaCKX genes and phytohormones. The coordinated effect of TaCKX1 silencing on the expression of other TaCKX genes, phytohormone levels in 7 DAP spikes, and yield-related traits in silenced T2 lines is presented. Full article
(This article belongs to the Special Issue Plant Genomics 2019)
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Article
Large-Scale Production of Human iPSC-Derived Macrophages for Drug Screening
Int. J. Mol. Sci. 2020, 21(13), 4808; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21134808 - 07 Jul 2020
Cited by 10 | Viewed by 3754
Abstract
Tissue-resident macrophages are key players in inflammatory processes, and their activation and functionality are crucial in health and disease. Numerous diseases are associated with alterations in homeostasis or dysregulation of the innate immune system, including allergic reactions, autoimmune diseases, and cancer. Macrophages are [...] Read more.
Tissue-resident macrophages are key players in inflammatory processes, and their activation and functionality are crucial in health and disease. Numerous diseases are associated with alterations in homeostasis or dysregulation of the innate immune system, including allergic reactions, autoimmune diseases, and cancer. Macrophages are a prime target for drug discovery due to their major regulatory role in health and disease. Currently, the main sources of macrophages used for therapeutic compound screening are primary cells isolated from blood or tissue or immortalized or neoplastic cell lines (e.g., THP-1). Here, we describe an improved method to employ induced pluripotent stem cells (iPSCs) for the high-yield, large-scale production of cells resembling tissue-resident macrophages. For this, iPSC-derived macrophage-like cells are thoroughly characterized to confirm their cell identity and thus their suitability for drug screening purposes. These iPSC-derived macrophages show strong cellular identity with primary macrophages and recapitulate key functional characteristics, including cytokine release, phagocytosis, and chemotaxis. Furthermore, we demonstrate that genetic modifications can be readily introduced at the macrophage-like progenitor stage in order to interrogate drug target-relevant pathways. In summary, this novel method overcomes previous shortcomings with primary and leukemic cells and facilitates large-scale production of genetically modified iPSC-derived macrophages for drug screening applications. Full article
(This article belongs to the Special Issue Disease Modeling Using Human Induced Pluripotent Stem Cells 2.0)
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Article
Implications of SARS-CoV-2 Mutations for Genomic RNA Structure and Host microRNA Targeting
Int. J. Mol. Sci. 2020, 21(13), 4807; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21134807 - 07 Jul 2020
Cited by 26 | Viewed by 2667
Abstract
The SARS-CoV-2 virus is a recently-emerged zoonotic pathogen already well adapted to transmission and replication in humans. Although the mutation rate is limited, recently introduced mutations in SARS-CoV-2 have the potential to alter viral fitness. In addition to amino acid changes, mutations could [...] Read more.
The SARS-CoV-2 virus is a recently-emerged zoonotic pathogen already well adapted to transmission and replication in humans. Although the mutation rate is limited, recently introduced mutations in SARS-CoV-2 have the potential to alter viral fitness. In addition to amino acid changes, mutations could affect RNA secondary structure critical to viral life cycle, or interfere with sequences targeted by host miRNAs. We have analysed subsets of genomes from SARS-CoV-2 isolates from around the globe and show that several mutations introduce changes in Watson–Crick pairing, with resultant changes in predicted secondary structure. Filtering to targets matching miRNAs expressed in SARS-CoV-2-permissive host cells, we identified ten separate target sequences in the SARS-CoV-2 genome; three of these targets have been lost through conserved mutations. A genomic site targeted by the highly abundant miR-197-5p, overexpressed in patients with cardiovascular disease, is lost by a conserved mutation. Our results are compatible with a model that SARS-CoV-2 replication within the human host is constrained by host miRNA defences. The impact of these and further mutations on secondary structures, miRNA targets or potential splice sites offers a new context in which to view future SARS-CoV-2 evolution, and a potential platform for engineering conditional attenuation to vaccine development, as well as providing a better understanding of viral tropism and pathogenesis. Full article
(This article belongs to the Section Molecular Biology)
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Review
Modelling Epithelial Ovarian Cancer in Mice: Classical and Emerging Approaches
Int. J. Mol. Sci. 2020, 21(13), 4806; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21134806 - 07 Jul 2020
Cited by 2 | Viewed by 979
Abstract
High-grade serous epithelial ovarian cancer (HGSC) is the most aggressive subtype of epithelial ovarian cancer. The identification of germline and somatic mutations along with genomic information unveiled by The Cancer Genome Atlas (TCGA) and other studies has laid the foundation for establishing preclinical [...] Read more.
High-grade serous epithelial ovarian cancer (HGSC) is the most aggressive subtype of epithelial ovarian cancer. The identification of germline and somatic mutations along with genomic information unveiled by The Cancer Genome Atlas (TCGA) and other studies has laid the foundation for establishing preclinical models with high fidelity to the molecular features of HGSC. Notwithstanding such progress, the field of HGSC research still lacks a model that is both robust and widely accessible. In this review, we discuss the recent advancements and utility of HGSC genetically engineered mouse models (GEMMs) to date. Further analysis and critique on alternative approaches to modelling HGSC considers technological advancements in somatic gene editing and modelling prototypic organs, capable of tumorigenesis, on a chip. Full article
(This article belongs to the Special Issue Genetically Engineered Mice to Study Cancer)
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Article
Single Nucleotide Polymorphisms as Practical Molecular Tools to Support European Chestnut Agrobiodiversity Management
Int. J. Mol. Sci. 2020, 21(13), 4805; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21134805 - 07 Jul 2020
Cited by 3 | Viewed by 1242
Abstract
European chestnut orchards are multifunctional agroforestry systems with a key role in environmental management. Their biodiversity is at risk of erosion and farmers do not have enough tools to protect and valorize traditional ecotypes. In particular, cost effective and reliable molecular markers for [...] Read more.
European chestnut orchards are multifunctional agroforestry systems with a key role in environmental management. Their biodiversity is at risk of erosion and farmers do not have enough tools to protect and valorize traditional ecotypes. In particular, cost effective and reliable molecular markers for cultivar identification are lacking. The aim of this research was to develop a new molecular tool for varietal identification in European chestnuts. A set of cultivars was preliminarily characterized to evaluate the range of genetic diversity using random amplified polymorphic DNA (RAPD) markers. The genetic distances indicated a sufficiently wide variability range among tested genotypes and confirmed they were suitable for our goal. A single nucleotide polymorphism (SNP) mining within 64 expressed sequence tags (EST), covering all the linkage groups, was performed by high-resolution melting (HRM) and validated by target resequencing. Fifty-six SNPs were retrieved by monitoring the variability present on the whole set of considered cultivars in loci uniformly distributed on the genome. A subset of 37 SNPs was finally transformed into kompetitive allele-specific PCR (KASP) markers that were successfully evaluated for varietal discrimination. Three assays (C1083, G0115 and A5096) were identified as necessary and sufficient for distinguishing among the tested cultivars. The developed tools can be effectively exploited by stakeholders for improving the management of the European chestnut genetic resources. Full article
(This article belongs to the Collection Genetics and Molecular Breeding in Plants)
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Article
Robust and Scalable Angiogenesis Assay of Perfused 3D Human iPSC-Derived Endothelium for Anti-Angiogenic Drug Screening
Int. J. Mol. Sci. 2020, 21(13), 4804; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21134804 - 07 Jul 2020
Cited by 5 | Viewed by 2383
Abstract
To advance pre-clinical vascular drug research, in vitro assays are needed that closely mimic the process of angiogenesis in vivo. Such assays should combine physiological relevant culture conditions with robustness and scalability to enable drug screening. We developed a perfused 3D angiogenesis [...] Read more.
To advance pre-clinical vascular drug research, in vitro assays are needed that closely mimic the process of angiogenesis in vivo. Such assays should combine physiological relevant culture conditions with robustness and scalability to enable drug screening. We developed a perfused 3D angiogenesis assay that includes endothelial cells (ECs) from induced pluripotent stem cells (iPSC) and assessed its performance and suitability for anti-angiogenic drug screening. Angiogenic sprouting was compared with primary ECs and showed that the microvessels from iPSC-EC exhibit similar sprouting behavior, including tip cell formation, directional sprouting and lumen formation. Inhibition with sunitinib, a clinically used vascular endothelial growth factor (VEGF) receptor type 2 inhibitor, and 3-(3-pyridinyl)-1-(4-pyridinyl)-2-propen-1-one (3PO), a transient glycolysis inhibitor, both significantly reduced the sprouting of both iPSC-ECs and primary ECs, supporting that both cell types show VEGF gradient-driven angiogenic sprouting. The assay performance was quantified for sunitinib, yielding a minimal signal window of 11 and Z-factor of at least 0.75, both meeting the criteria to be used as screening assay. In conclusion, we have developed a robust and scalable assay that includes physiological relevant culture conditions and is amenable to screening of anti-angiogenic compounds. Full article
(This article belongs to the Special Issue hiPSC-Derived Cells as Models for Drug Discovery)
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Article
Acute Hyperglycemia Aggravates Lung Injury via Activation of the SGK1–NKCC1 Pathway
Int. J. Mol. Sci. 2020, 21(13), 4803; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21134803 - 07 Jul 2020
Cited by 3 | Viewed by 932
Abstract
Acute lung injury (ALI) is characterized by severe hypoxemia and has significantly high mortality rates. Acute hyperglycemia occurs in patients with conditions such as sepsis or trauma, among others, and it results in aggravated inflammation and induces damage in patients with ALI. Regulation [...] Read more.
Acute lung injury (ALI) is characterized by severe hypoxemia and has significantly high mortality rates. Acute hyperglycemia occurs in patients with conditions such as sepsis or trauma, among others, and it results in aggravated inflammation and induces damage in patients with ALI. Regulation of alveolar fluid is essential for the development and resolution of pulmonary edema in lung injury. Pulmonary sodium-potassium-chloride co-transporter 1 (NKCC1) regulates the net influx of ions and water into alveolar cells. The activation of with-no-lysine kinase 4 (WNK4), STE20/SPS1-related proline/alanine rich kinase (SPAK) and the NKCC1 pathway lead to an increase in the expression of NKCC1 and aggravation of ALI. Moreover, hyperglycemia is known to induce NKCC1 expression via the activation of the serum-glucocorticoid kinase 1 (SGK1)–NKCC1 pathway. We aim to evaluate the influence of acute hyperglycemia on the SGK1–NKCC1 pathway in ALI. ALI was induced using a high tidal volume for four hours in a rat model. Acute hyperglycemia was induced by injection with 0.5 mL of 40% glucose solution followed by continuous infusion at 2 mL/h. The animals were divided into sham, sham+ hyperglycemia, ALI, ALI + hyperglycemia, ALI + inhaled bumetanide (NKCC1 inhibitor) pretreatment, ALI + hyperglycemia + inhalational bumetanide pretreatment, and ALI + hyperglycemia + post-ALI inhalational bumetanide groups. Severe lung injury along with pulmonary edema, alveolar protein leakage, and lung inflammation was observed in ALI with hyperglycemia than in ALI without hyperglycemia. This was concurrent with the higher expression of pro-inflammatory cytokines, infiltration of neutrophils and alveolar macrophages (AM) 1, and NKCC1 expression. Inhalational NKCC1 inhibitor significantly inhibited the SGK1–NKCC1, and WNK4–SPAK–NKCC1 pathways. Additionally, it reduced pulmonary edema, inflammation, levels of pro-inflammatory cytokines, neutrophils and AM1 and increased AM2. Therefore, acute hyperglycemia aggravates lung injury via the further activation of the SGK1–NKCC1 pathway. The NKCC1 inhibitor can effectively attenuate lung injury aggravated by acute hyperglycemia. Full article
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Article
Proteomics-Based Machine Learning Approach as an Alternative to Conventional Biomarkers for Differential Diagnosis of Chronic Kidney Diseases
Int. J. Mol. Sci. 2020, 21(13), 4802; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21134802 - 07 Jul 2020
Cited by 5 | Viewed by 1289
Abstract
Diabetic nephropathy, hypertension, and glomerulonephritis are the most common causes of chronic kidney diseases (CKD). Since CKD of various origins may not become apparent until kidney function is significantly impaired, a differential diagnosis and an appropriate treatment are needed at the very early [...] Read more.
Diabetic nephropathy, hypertension, and glomerulonephritis are the most common causes of chronic kidney diseases (CKD). Since CKD of various origins may not become apparent until kidney function is significantly impaired, a differential diagnosis and an appropriate treatment are needed at the very early stages. Conventional biomarkers may not have sufficient separation capabilities, while a full-proteomic approach may be used for these purposes. In the current study, several machine learning algorithms were examined for the differential diagnosis of CKD of three origins. The tested dataset was based on whole proteomic data obtained after the mass spectrometric analysis of plasma and urine samples of 34 CKD patients and the use of label-free quantification approach. The k-nearest-neighbors algorithm showed the possibility of separation of a healthy group from renal patients in general by proteomics data of plasma with high confidence (97.8%). This algorithm has also be proven to be the best of the three tested for distinguishing the groups of patients with diabetic nephropathy and glomerulonephritis according to proteomics data of plasma (96.3% of correct decisions). The group of hypertensive nephropathy could not be reliably separated according to plasma data, whereas analysis of entire proteomics data of urine did not allow differentiating the three diseases. Nevertheless, the group of hypertensive nephropathy was reliably separated from all other renal patients using the k-nearest-neighbors classifier “one against all” with 100% of accuracy by urine proteome data. The tested algorithms show good abilities to differentiate the various groups across proteomic data sets, which may help to avoid invasive intervention for the verification of the glomerulonephritis subtypes, as well as to differentiate hypertensive and diabetic nephropathy in the early stages based not on individual biomarkers, but on the whole proteomic composition of urine and blood. Full article
(This article belongs to the Special Issue Biomarkers of Renal Diseases)
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Editorial
Special Issue “Molecular and Cellular Mechanisms of Preeclampsia”
Int. J. Mol. Sci. 2020, 21(13), 4801; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21134801 - 07 Jul 2020
Cited by 1 | Viewed by 807
Abstract
Over the last few decades, massive research efforts have been put into deciphering the etiology of the pregnancy pathology preeclampsia [...] Full article
(This article belongs to the Special Issue Molecular and Cellular Mechanisms of Preeclampsia)
Article
CPPF, A Novel Microtubule Targeting Anticancer Agent, Inhibits the Growth of a Wide Variety of Cancers
Int. J. Mol. Sci. 2020, 21(13), 4800; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21134800 - 07 Jul 2020
Cited by 1 | Viewed by 1054
Abstract
In the past, several microtubule targeting agents (MTAs) have been developed into successful anticancer drugs. However, the usage of these drugs has been limited by the acquisition of drug resistance in many cancers. Therefore, there is a constant demand for the development of [...] Read more.
In the past, several microtubule targeting agents (MTAs) have been developed into successful anticancer drugs. However, the usage of these drugs has been limited by the acquisition of drug resistance in many cancers. Therefore, there is a constant demand for the development of new therapeutic drugs. Here we report the discovery of 5-5 (3-cchlorophenyl)-N-(3-pyridinyl)-2-furamide (CPPF), a novel microtubule targeting anticancer agent. Using both 2D and 3D culture systems, we showed that CPPF was able to suppress the proliferation of diverse cancer cell lines. In addition, CPPF was able to inhibit the growth of multidrug-resistant cell lines that are resistant to other MTAs, such as paclitaxel and colchicine. Our results showed that CPPF inhibited growth by depolymerizing microtubules leading to mitotic arrest and apoptosis. We also confirmed CPPF anticancer effects in vivo using both a mouse xenograft and a two-step skin cancer mouse model. Using established zebrafish models, we showed that CPPF has low toxicity in vivo. Overall, our study proves that CPPF has the potential to become a successful anticancer chemotherapeutic drug. Full article
(This article belongs to the Section Molecular Pharmacology)
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Article
Oxidation of Erythrocytes Enhance the Production of Reactive Species in the Presence of Artemisinins
Int. J. Mol. Sci. 2020, 21(13), 4799; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21134799 - 07 Jul 2020
Cited by 4 | Viewed by 824
Abstract
In red blood cells, hemoglobin iron represents the most plausible candidate to catalyze artemisinin activation but the limited reactivity of iron bound to hemoglobin does not play in favor for its direct involvement. Denatured hemoglobin appears a more likely candidate for artemisinin redox [...] Read more.
In red blood cells, hemoglobin iron represents the most plausible candidate to catalyze artemisinin activation but the limited reactivity of iron bound to hemoglobin does not play in favor for its direct involvement. Denatured hemoglobin appears a more likely candidate for artemisinin redox activation because it is expected to contain reactive iron and it has been described to release free heme and/or iron in erythrocyte. The aim of our study is to investigate, using three different methods: fluorescence, electron paramagnetic resonance and liquid chromatography coupled to mass spectrometry, how increasing the level of accessible iron into the red blood cells can enhance the reactive oxygen species (ROS) production derived from artemisinin. The over-increase of iron was achieved using phenylhydrazine, a strong oxidant that causes oxidative stress within erythrocytes, resulting in oxidation of oxyhemoglobin and leading to the formation of methemoglobin, which is subsequently converted into irreversible hemichromes (iron (III) compounds). Our findings confirmed, using the iron III chelator, desferrioxamine, the indirect participation of iron (III) compounds in the activation process of artemisinins. Furthermore, in strong reducing conditions, the activation of artemisinin and the consequent production of ROS was enhanced. In conclusion, we demonstrate, through the measurement of intra-erythrocytic superoxide and hydrogen peroxide production using various methods, that artemisinin activation can be drastically enhanced by pre-oxidation of erythrocytes. Full article
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Article
Inhalations with Brine Solution from the ‘Wieliczka’ Salt Mine Diminish Airway Hyperreactivity and Inflammation in a Murine Model of Non-Atopic Asthma
Int. J. Mol. Sci. 2020, 21(13), 4798; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21134798 - 07 Jul 2020
Cited by 1 | Viewed by 715
Abstract
Inhalations with brine solutions are old but underestimated add-ons to pharmacological treatments of inflammatory lung diseases. Although widely used, not all features underlying their action on the respiratory system have been explored. The aim of the present study was to elucidate the mechanism [...] Read more.
Inhalations with brine solutions are old but underestimated add-ons to pharmacological treatments of inflammatory lung diseases. Although widely used, not all features underlying their action on the respiratory system have been explored. The aim of the present study was to elucidate the mechanism of the beneficial action of inhalations of brine solution from the ‘Wieliczka’ Salt Mine, a Polish health resort, in a murine model of non-atopic asthma. Asthma was induced in BALB/c mice by skin sensitization with dinitrofluorobenzene followed by an intratracheal challenge of cognate hapten. All animals underwent 12 inhalation sessions with brine solution, pure water or physiological saline. Control mice were not inhaled. We found that brine inhalations reduced, as compared to non-inhaled mice, the typical asthma-related symptoms, like airway hyperreactivity (AHR), the infiltration of pro-inflammatory cells into the bronchial tree, and the inflammation of the airways at the level of pro-inflammatory cytokines IL-1α, IL-1β and IL-6. The level of the anti-inflammatory IL-10 was elevated in brine-inhaled mice. Inhalations with pure water increased AHR, whereas saline had no influence, either on AHR or cytokine concentrations. These observations indicate that inhalations with a brine solution from the ‘Wieliczka’ Salt Mine diminish the asthma-related symptoms, mostly by reducing the inflammatory status and by decreasing AHR. Full article
(This article belongs to the Special Issue Molecular Mechanisms of Asthma)
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Article
Integrative Analyses of Widely Targeted Metabolic Profiling and Transcriptome Data Reveals Molecular Insight into Metabolomic Variations during Apple (Malus domestica) Fruit Development and Ripening
Int. J. Mol. Sci. 2020, 21(13), 4797; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21134797 - 07 Jul 2020
Cited by 11 | Viewed by 1323
Abstract
The apple is a favorite fruit for human diet and is one of the most important commercial fruit crops around the world. Investigating metabolic variations during fruit development can provide a better understanding on the formation of fruit quality. The present study applied [...] Read more.
The apple is a favorite fruit for human diet and is one of the most important commercial fruit crops around the world. Investigating metabolic variations during fruit development can provide a better understanding on the formation of fruit quality. The present study applied a widely targeted LC-MS-based metabolomics approach with large-scale detection, identification and quantification to investigate the widespread metabolic changes during “Pinova” apple development and ripening. A total of 462 primary and secondary metabolites were simultaneously detected, and their changes along with the four fruit-development stages were further investigated. The results indicated that most of the sugars presented increasing accumulation levels while organic acid, including Tricarboxylic acid cycle (TCA) intermediates, showed a distinct decreasing trend across the four fruit-development stages. A total of 207 secondary metabolites consisted of 104 flavonoids and 103 other secondary metabolites. Many flavonoids maintained relatively high levels in the early fruit stage and then rapidly decreased their levels at the following developmental stages. Further correlation analyses of each metabolite–metabolite pair highlighted the cross talk between the primary and secondary metabolisms across fruit development and ripening, indicating the significant negative correlations between sugars and secondary metabolites. Moreover, transcriptome analysis provided the molecular basis for metabolic variations during fruit development. The results showed that most differentially expressed genes (DEGs) involved in the TCA cycle were upregulated from the early fruit stage to the preripening stage. The extensive downregulation of controlling genes involved in the flavonoid pathway is probably responsible for the rapid decrease of flavonoid content at the early fruit stage. These data provide a global view of the apple metabolome and a comprehensive analysis on metabolomic variations during fruit development, providing a broader and better understanding on the molecular and metabolic basis of important fruit quality traits in commercial apples. Full article
(This article belongs to the Special Issue Plant Cell and Organism Development)
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Review
MicroRNAs as Guardians of the Prostate: Those Who Stand before Cancer. What Do We Really Know about the Role of microRNAs in Prostate Biology?
Int. J. Mol. Sci. 2020, 21(13), 4796; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21134796 - 07 Jul 2020
Cited by 1 | Viewed by 997
Abstract
Prostate cancer is the second leading cause of cancer-related deaths of men in the Western world. Despite recent advancement in genomics, transcriptomics and proteomics to understand prostate cancer biology and disease progression, castration resistant metastatic prostate cancer remains a major clinical challenge and [...] Read more.
Prostate cancer is the second leading cause of cancer-related deaths of men in the Western world. Despite recent advancement in genomics, transcriptomics and proteomics to understand prostate cancer biology and disease progression, castration resistant metastatic prostate cancer remains a major clinical challenge and often becomes incurable. MicroRNAs (miRNAs), about 22-nucleotide-long non-coding RNAs, are a group of regulatory molecules that mainly work through post-transcriptional gene silencing via translational repression. Expression analysis studies have revealed that miRNAs are aberrantly expressed in cancers and have been recognized as regulators of prostate cancer progression. In this critical review, we provide an analysis of reported miRNA functions and conflicting studies as they relate to expression levels of specific miRNAs and prostate cancer progression; oncogenic and/or tumor suppressor roles; androgen receptor signaling; epithelial plasticity; and the current status of diagnostic and therapeutic applications. This review focuses on select miRNAs, highly expressed in normal and cancer tissue, to emphasize the current obstacles faced in utilizing miRNA data for significant impacts on prostate cancer therapeutics. Full article
(This article belongs to the Special Issue MicroRNA as Biomarkers in Cancer Diagnostics and Therapeutics (II))
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Article
Gonadal Hormones E2 and P Mitigate Cerebral Ischemia-Induced Upregulation of the AIM2 and NLRC4 Inflammasomes in Rats
Int. J. Mol. Sci. 2020, 21(13), 4795; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21134795 - 07 Jul 2020
Cited by 5 | Viewed by 1165
Abstract
Acute ischemic stroke (AIS) is a devastating neurological condition with a lack of neuroprotective therapeutic options, despite the reperfusion modalities thrombolysis and thrombectomy. Post-ischemic brain damage is aggravated by an excessive inflammatory cascade involving the activation and regulation of the pro-inflammatory cytokines IL-1β [...] Read more.
Acute ischemic stroke (AIS) is a devastating neurological condition with a lack of neuroprotective therapeutic options, despite the reperfusion modalities thrombolysis and thrombectomy. Post-ischemic brain damage is aggravated by an excessive inflammatory cascade involving the activation and regulation of the pro-inflammatory cytokines IL-1β and IL-18 by inflammasomes. However, the role of AIM2 and NLRC4 inflammasomes and the influence of the neuroprotective steroids 17β-estradiol (E2) and progesterone (P) on their regulation after ischemic stroke have not yet been conclusively elucidated. To address the latter, we subjected a total of 65 rats to 1 h of transient Middle Cerebral Artery occlusion (tMCAO) followed by a reperfusion period of 72 h. Moreover, we evaluated the expression and regulation of AIM2 and NLRC4 in glial single-cell cultures (astroglia and microglia) after oxygen–glucose deprivation (OGD). The administration of E2 and P decreased both infarct sizes and neurological impairments after cerebral ischemia in rats. We detected a time-dependent elevation of gene and protein levels (Western Blot/immunohistochemistry) of the AIM2 and NLRC4 inflammasomes in the post-ischemic brains. E2 or P selectively mitigated the stroke-induced increase of AIM2 and NLRC4. While both inflammasomes seemed to be exclusively abundant in neurons under physiological and ischemic conditions in vivo, single-cell cultures of cortical astrocytes and microglia equally expressed both inflammasomes. In line with the in vivo data, E and P selectively reduced AIM2 and NLRC4 in primary cortical astrocytes and microglial cells after OGD. In conclusion, the post-ischemic elevation of AIM2 and NLRC4 and their down-regulation by E2 and P may shed more light on the anti-inflammatory effects of both gonadal hormones after stroke. Full article
(This article belongs to the Special Issue Inflammasome)
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Article
Transcriptomic Profile of Primary Culture of Skeletal Muscle Cells Isolated from Semitendinosus Muscle of Beef and Dairy Bulls
Int. J. Mol. Sci. 2020, 21(13), 4794; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21134794 - 07 Jul 2020
Cited by 2 | Viewed by 1122
Abstract
The aim of the study was to identify differences in the transcriptomic profiles of primary muscle cell cultures derived from the semitendinosus muscle of bulls of beef breeds (Limousin (LIM) and Hereford (HER)) and a dairy breed (Holstein-Friesian (HF)) (n = 4 [...] Read more.
The aim of the study was to identify differences in the transcriptomic profiles of primary muscle cell cultures derived from the semitendinosus muscle of bulls of beef breeds (Limousin (LIM) and Hereford (HER)) and a dairy breed (Holstein-Friesian (HF)) (n = 4 for each breed). Finding a common expression pattern for proliferating cells may point to such an early orientation of the cattle beef phenotype at the transcriptome level of unfused myogenic cells. To check this hypothesis, microarray analyses were performed. The analysis revealed 825 upregulated and 1300 downregulated transcripts similar in both beef breeds (LIM and HER) and significantly different when compared with the dairy breed (HF) used as a reference. Ontological analyses showed that the largest group of genes were involved in muscle organ development. Muscle cells of beef breeds showed higher expression of genes involved in myogenesis (including erbb-3, myf5, myog, des, igf-1, tgfb2) and those encoding proteins comprising the contractile apparatus (acta1, actc1, myh3, myh11, myl1, myl2, myl4, tpm1, tnnt2, tnnc1). The obtained results confirmed our hypothesis that the expression profile of several groups of genes is common in beef breeds at the level of proliferating satellite cells but differs from that observed in typical dairy breeds. Full article
(This article belongs to the Section Molecular Genetics and Genomics)
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Article
Theoretical Investigations on Interactions of Arylsulphonyl Indazole Derivatives as Potential Ligands of VEGFR2 Kinase
Int. J. Mol. Sci. 2020, 21(13), 4793; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21134793 - 07 Jul 2020
Cited by 3 | Viewed by 816
Abstract
Vascular endothelial growth factor receptor 2 (VEGFR2) is a key receptor in the angiogenesis process. The VEGFR2 expression is upregulated in many cancers so this receptor is an important target for anticancer agents. In the present paper, we analyse interactions of several dimeric [...] Read more.
Vascular endothelial growth factor receptor 2 (VEGFR2) is a key receptor in the angiogenesis process. The VEGFR2 expression is upregulated in many cancers so this receptor is an important target for anticancer agents. In the present paper, we analyse interactions of several dimeric indazoles, previously investigated for anticancer activity, with the amino acids present in the VEGFR2 binding pocket. Using the docking method and MD simulations as well as theoretical computations (SAPT0, PIEDA, semi-empirical PM7), we confirmed that these azoles can efficiently bind into the kinase pocket and their poses can be stabilised by the formation of hydrogen bonds, π–π stacking, π–cation, and hybrid interactions with some amino acids of the kinase cavity like Ala866, Lys868, Glu885, Thr916, Glu917, and Phe918. Full article
(This article belongs to the Section Molecular Pharmacology)
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Review
Functional Markers for Precision Plant Breeding
Int. J. Mol. Sci. 2020, 21(13), 4792; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21134792 - 06 Jul 2020
Cited by 7 | Viewed by 1688
Abstract
Advances in molecular biology including genomics, high-throughput sequencing, and genome editing enable increasingly faster and more precise cultivar development. Identifying genes and functional markers (FMs) that are highly associated with plant phenotypic variation is a grand challenge. Functional genomics approaches such as transcriptomics, [...] Read more.
Advances in molecular biology including genomics, high-throughput sequencing, and genome editing enable increasingly faster and more precise cultivar development. Identifying genes and functional markers (FMs) that are highly associated with plant phenotypic variation is a grand challenge. Functional genomics approaches such as transcriptomics, targeting induced local lesions in genomes (TILLING), homologous recombinant (HR), association mapping, and allele mining are all strategies to identify FMs for breeding goals, such as agronomic traits and biotic and abiotic stress resistance. The advantage of FMs over other markers used in plant breeding is the close genomic association of an FM with a phenotype. Thereby, FMs may facilitate the direct selection of genes associated with phenotypic traits, which serves to increase selection efficiencies to develop varieties. Herein, we review the latest methods in FM development and how FMs are being used in precision breeding for agronomic and quality traits as well as in breeding for biotic and abiotic stress resistance using marker assisted selection (MAS) methods. In summary, this article describes the use of FMs in breeding for development of elite crop cultivars to enhance global food security goals. Full article
(This article belongs to the Special Issue Functional Genomics for Plant Breeding)
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Article
Ketamine and Ro 25-6981 Reverse Behavioral Abnormalities in Rats Subjected to Dietary Zinc Restriction
Int. J. Mol. Sci. 2020, 21(13), 4791; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21134791 - 06 Jul 2020
Cited by 1 | Viewed by 2106
Abstract
Clinical and preclinical studies indicate that zinc (Zn) is an essential factor in the development and treatment of major depressive disorder (MDD). Conventional monoamine-based antidepressants mobilize zinc in the blood and brain of depressed patients as well as rodents. N-methyl-D-aspartate acid receptor (NMDAR) [...] Read more.
Clinical and preclinical studies indicate that zinc (Zn) is an essential factor in the development and treatment of major depressive disorder (MDD). Conventional monoamine-based antidepressants mobilize zinc in the blood and brain of depressed patients as well as rodents. N-methyl-D-aspartate acid receptor (NMDAR) antagonists exhibit antidepressant-like activity. However, not much is known about the antidepressant efficacy of NMDAR antagonists in zinc-deficient (ZnD) animals. We evaluated the antidepressant-like activity of two NMDAR antagonists (ketamine; global NMDAR antagonist and Ro 25-6981 (Ro); selective antagonist of the GluN2B NMDAR subunit) in ZnD rats using the forced swim test (FST) and sucrose intake test (SIT). A single dose of either Ro 25-6981 or ketamine normalized depressive-like behaviors in ZnD rats; however, Ro was effective in both tests, while ketamine was only effective in the FST. Additionally, we investigated the mechanism of antidepressant action of Ro at the molecular (analysis of protein expression by Western blotting) and anatomical (density of dendritic spines by Golgi Cox-staining) levels. ZnD rats exhibited decreased phosphorylation of the p70S6K protein, and enhanced density of dendritic spines in the prefrontal cortex (PFC) compared to control rats. The antidepressant-like activity of Ro was associated with the increased phosphorylation of p70S6K and ERK in the PFC. In summary, single doses of the NMDAR antagonists ketamine and Ro exhibited antidepressant-like activity in the ZnD animal model of depression. Animals were only deprived of Zn for 4 weeks and the biochemical effects of Zn deprivation and Ro were investigated in the PFC and hippocampus. The shorter duration of dietary Zn restriction may be a limitation of the study. However, future studies with longer durations of dietary Zn restriction, as well as the investigation of multiple brain structures, are encouraged as a supplement to this study. Full article
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Review
Cell Fate Determination of Lymphatic Endothelial Cells
Int. J. Mol. Sci. 2020, 21(13), 4790; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21134790 - 06 Jul 2020
Cited by 2 | Viewed by 1162
Abstract
The lymphatic vasculature, along with the blood vasculature, is a vascular system in our body that plays important functions in fluid homeostasis, dietary fat uptake, and immune responses. Defects in the lymphatic system are associated with various diseases such as lymphedema, atherosclerosis, fibrosis, [...] Read more.
The lymphatic vasculature, along with the blood vasculature, is a vascular system in our body that plays important functions in fluid homeostasis, dietary fat uptake, and immune responses. Defects in the lymphatic system are associated with various diseases such as lymphedema, atherosclerosis, fibrosis, obesity, and inflammation. The first step in lymphangiogenesis is determining the cell fate of lymphatic endothelial cells. Several genes involved in this commitment step have been identified using animal models, including genetically modified mice. This review provides an overview of these genes in the mammalian system and related human diseases. Full article
(This article belongs to the Special Issue Transgenic Mice in Human Diseases: Insights from Molecular Research)
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Article
Indocyanine Green Loaded Modified Mesoporous Silica Nanoparticles as an Effective Photothermal Nanoplatform
Int. J. Mol. Sci. 2020, 21(13), 4789; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21134789 - 06 Jul 2020
Viewed by 928
Abstract
Photothermal therapy possesses great advantages for the treatment of drug-resistant tumors. Herein, Near Infrared (NIR)-triggered photothermal nanoparticles were developed through loading indocyanine green (ICG), a kind of NIR dye, into amino group-modified silica nanoparticles (SiO2-NH2 NPs). SiO2-NH2 [...] Read more.
Photothermal therapy possesses great advantages for the treatment of drug-resistant tumors. Herein, Near Infrared (NIR)-triggered photothermal nanoparticles were developed through loading indocyanine green (ICG), a kind of NIR dye, into amino group-modified silica nanoparticles (SiO2-NH2 NPs). SiO2-NH2 NPs were prepared with immobilization of the amino groups into the framework of silica nanoparticles (SiO2 NPs) by employing (3-aminopropyl)-triethoxysilane (APTES). Before and after the modification of the amino group, the particle sizes of SiO2 NPs showed similar value, around 100 nm. ICG was further adsorbed into SiO2-NH2 NPs by electrostatic attraction to enable SiO2-NH2@ICG NPs as a kind of photothermal agent. The loading rate of ICG to SiO2-NH2 was greatly increased compared to unmodified SiO2, and the stability of ICG was also improved. Moreover, the SiO2-NH2@ICG NPs exhibited efficient photothermal effects due to ICG transforming laser power into local heat through the connected ICG, when NIR laser irradiation turned on for a couple of minutes. Finally, the in vitro antitumor efficacy of SiO2-NH2@ICG NPs was investigated by recording cell proliferation rate and further chronicled the apoptotic morphology evidence by a Calcein-AM/PI fluorescent staining assay, indicating the efficient photothermal targeted therapy for the HepG2 tumor cells. Full article
(This article belongs to the Collection Bioactive Nanoparticles)
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Review
The NLRP1 Inflammasome in Human Skin and Beyond
Int. J. Mol. Sci. 2020, 21(13), 4788; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21134788 - 06 Jul 2020
Cited by 9 | Viewed by 2059
Abstract
Inflammasomes represent a group of protein complexes that contribute to host defense against pathogens and repair processes upon the induction of inflammation. However, aberrant and chronic inflammasome activation underlies the pathology of numerous common inflammatory diseases. Inflammasome assembly causes activation of the protease [...] Read more.
Inflammasomes represent a group of protein complexes that contribute to host defense against pathogens and repair processes upon the induction of inflammation. However, aberrant and chronic inflammasome activation underlies the pathology of numerous common inflammatory diseases. Inflammasome assembly causes activation of the protease caspase-1 which in turn activates proinflammatory cytokines and induces a lytic type of cell death termed pyroptosis. Although NLRP1 (NACHT, leucine-rich repeat and pyrin domain containing 1) was the first inflammasome sensor, described almost 20 years ago, the molecular mechanisms underlying its activation and the resulting downstream events are incompletely understood. This is partially a consequence of the poor conservation of the NLRP1 pathway between human and mice. Moreover, recent evidence demonstrates a complex and multi-stage mechanism of NLRP1 inflammasome activation. In contrast to other inflammasome sensors, NLRP1 possesses protease activity required for proteolytic self-cleavage and activation mediated by the function-to-find domain (FIIND). CARD8 is a second FIIND protein and is expressed in humans but not in mice. In immune cells and AML (acute myeloid leukemia) cells, the anti-cancer drug talabostat induces CARD8 activation and causes caspase-1-dependent pyroptosis. In contrast, in human keratinocytes talabostat induces NLRP1 activation and massive proinflammatory cytokine activation. NLRP1 is regarded as the principal inflammasome sensor in human keratinocytes and UVB radiation induces its activation, which is believed to underlie the induction of sunburn. Moreover, gain-of-function mutations of NLRP1 cause inflammatory skin syndromes and a predisposition for the development of skin cancer. SNPs (single nucleotide polymorphisms) of NLRP1 are associated with several (auto)inflammatory diseases with a major skin phenotype, such as psoriasis or vitiligo. Here, we summarize knowledge about NLRP1 with emphasis on its role in human keratinocytes and skin. Due to its accessibility, pharmacological targeting of NLRP1 activation in epidermal keratinocytes represents a promising strategy for the treatment of the numerous patients suffering from NLRP1-dependent inflammatory skin conditions and cancer. Full article
(This article belongs to the Special Issue Inflammasome)
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Article
Protein–Protein Interactions Efficiently Modeled by Residue Cluster Classes
Int. J. Mol. Sci. 2020, 21(13), 4787; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21134787 - 06 Jul 2020
Cited by 1 | Viewed by 1037
Abstract
Predicting protein–protein interactions (PPI) represents an important challenge in structural bioinformatics. Current computational methods display different degrees of accuracy when predicting these interactions. Different factors were proposed to help improve these predictions, including choosing the proper descriptors of proteins to represent these interactions, [...] Read more.
Predicting protein–protein interactions (PPI) represents an important challenge in structural bioinformatics. Current computational methods display different degrees of accuracy when predicting these interactions. Different factors were proposed to help improve these predictions, including choosing the proper descriptors of proteins to represent these interactions, among others. In the current work, we provide a representative protein structure that is amenable to PPI classification using machine learning approaches, referred to as residue cluster classes. Through sampling and optimization, we identified the best algorithm–parameter pair to classify PPI from more than 360 different training sets. We tested these classifiers against PPI datasets that were not included in the training set but shared sequence similarity with proteins in the training set to reproduce the situation of most proteins sharing sequence similarity with others. We identified a model with almost no PPI error (96–99% of correctly classified instances) and showed that residue cluster classes of protein pairs displayed a distinct pattern between positive and negative protein interactions. Our results indicated that residue cluster classes are structural features relevant to model PPI and provide a novel tool to mathematically model the protein structure/function relationship. Full article
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Communication
Hypoxia Promotes Prostate Cancer Aggressiveness by Upregulating EMT-Activator Zeb1 and SK3 Channel Expression
Int. J. Mol. Sci. 2020, 21(13), 4786; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21134786 - 06 Jul 2020
Cited by 5 | Viewed by 1019
Abstract
Hypoxia is a well-established feature of prostate cancer (PCa) and is associated with disease aggressiveness. The hypoxic microenvironment initiates multiple adaptive responses including epithelial-to-mesenchymal transition (EMT) and a remodeling of calcium homeostasis involved in cancer progression. In the present study, we identified a [...] Read more.
Hypoxia is a well-established feature of prostate cancer (PCa) and is associated with disease aggressiveness. The hypoxic microenvironment initiates multiple adaptive responses including epithelial-to-mesenchymal transition (EMT) and a remodeling of calcium homeostasis involved in cancer progression. In the present study, we identified a new hypoxia signaling pathway with a positive feedback loop between the EMT transcription factor Zeb1 and SK3, a Ca2+-activated K+ channel, which leads to amplifying store-operated Ca2+ entry. Zeb1 and SK3 channel were strongly upregulated by hypoxia both in vitro and ex vivo in organotypic cultures of human PCa. Taking into account the sensitivity of the SK3 channel to the membrane lipid composition, we identified lipids such as Ohmline (an alkyl ether lipid and SK3 inhibitor), linoleic acid (LA) and eicosapentaenoic acid (EPA) (fatty acids associated with indolent PCa), which were able to completely abrogate the hypoxia-induced changes in Zeb1 expression. Ultimately, better understanding of this new hypoxia-induced EMT pathway may allow to develop adjuvant therapeutic strategies, in order to control PCa aggressiveness and improve treatment outcomes. Full article
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