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Int. J. Mol. Sci., Volume 23, Issue 2 (January-2 2022) – 431 articles

Cover Story (view full-size image): In detail, cancer cells (in shades of grey) produce active paracrine factors (blue points) and exosomes (blue circles), stimulating the activity of associated fibroblasts in their vicinity (from light to dark blue). Reciprocally, these CAFs activate cancer cells via released paracrine factors (red points) and exosomes (red circles). Moreover, paracrine factors and exosomes are readily intravasated. This contributes to the formation of distant premetastatic niches necessary for the docking of circulating cancer cells during metastasis formation. View this paper
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Article
Maternal Fructose Intake Causes Developmental Reprogramming of Hepatic Mitochondrial Catalytic Activity and Lipid Metabolism in Weanling and Young Adult Offspring
Int. J. Mol. Sci. 2022, 23(2), 999; https://doi.org/10.3390/ijms23020999 - 17 Jan 2022
Viewed by 895
Abstract
Excess dietary fructose is a major public health concern, yet little is known about its influence on offspring development and later-life disease when consumed in excess during pregnancy. To determine whether increased maternal fructose intake could have long-term consequences on offspring health, we [...] Read more.
Excess dietary fructose is a major public health concern, yet little is known about its influence on offspring development and later-life disease when consumed in excess during pregnancy. To determine whether increased maternal fructose intake could have long-term consequences on offspring health, we investigated the effects of 10% w/v fructose water intake during preconception and pregnancy in guinea pigs. Female Dunkin Hartley guinea pigs were fed a control diet (CD) or fructose diet (FD; providing 16% of total daily caloric intake) ad libitum 60 days prior to mating and throughout gestation. Dietary interventions ceased at day of delivery. Offspring were culled at day 21 (D21) (weaning) and at 4 months (4 M) (young adult). Fetal exposure to excess maternal fructose intake significantly increased male and female triglycerides at D21 and 4 M and circulating palmitoleic acid and total omega-7 through day 0 (D0) to 4 M. Proteomic and functional analysis of significantly differentially expressed proteins revealed that FD offspring (D21 and 4 M) had significantly increased mitochondrial metabolic activities of β-oxidation, electron transport chain (ETC) and oxidative phosphorylation and reactive oxygen species production compared to the CD offspring. Western blotting analysis of both FD offspring validated the increased protein abundances of mitochondrial ETC complex II and IV, SREBP-1c and FAS, whereas VDAC1 expression was higher at D21 but lower at 4 M. We provide evidence demonstrating offspring programmed hepatic mitochondrial metabolism and de novo lipogenesis following excess maternal fructose exposure. These underlying asymptomatic programmed pathways may lead to a predisposition to metabolic dysfunction later in life. Full article
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Article
Anti-Inflammatory Effect of IKK-Activated GSK-3β Inhibitory Peptide Prevented Nigrostriatal Neurodegeneration in the Rodent Model of Parkinson’s Disease
Int. J. Mol. Sci. 2022, 23(2), 998; https://doi.org/10.3390/ijms23020998 - 17 Jan 2022
Viewed by 624
Abstract
Parkinson’s disease (PD) is a progressive movement disorder caused by nigrostriatal neurodegeneration. Since chronically activated neuroinflammation accelerates neurodegeneration in PD, we considered that modulating chronic neuroinflammatory response might provide a novel therapeutic approach. Glycogen synthase kinase 3 (GSK-3) is a multifunctional serine/threonine protein [...] Read more.
Parkinson’s disease (PD) is a progressive movement disorder caused by nigrostriatal neurodegeneration. Since chronically activated neuroinflammation accelerates neurodegeneration in PD, we considered that modulating chronic neuroinflammatory response might provide a novel therapeutic approach. Glycogen synthase kinase 3 (GSK-3) is a multifunctional serine/threonine protein kinase with two isoforms, GSK-3α and GSK-3β, and GSK-3β plays crucial roles in inflammatory response, which include microglial migration and peripheral immune cell activation. GSK-3β inhibitory peptide (IAGIP) is specifically activated by activated inhibitory kappa B kinase (IKK), and its therapeutic effects have been demonstrated in a mouse model of colitis. Here, we investigated whether the anti-inflammatory effects of IAGIP prevent neurodegeneration in the rodent model of PD. IAGIP significantly reduced MPP+-induced astrocyte activation and inflammatory response in primary astrocytes without affecting the phosphorylations of ERK or JNK. In addition, IAGIP inhibited LPS-induced cell migration and p65 activation in BV-2 microglial cells. In vivo study using an MPTP-induced mouse model of PD revealed that intravenous IAGIP effectively prevented motor dysfunction and nigrostriatal neurodegeneration. Our findings suggest that IAGIP has a curative potential in PD models and could offer new therapeutic possibilities for targeting PD. Full article
(This article belongs to the Special Issue Pharmacological Strategies for Neuroinflammation in Brain Injury)
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Commentary
Hemopexin and Cancer
Int. J. Mol. Sci. 2022, 23(2), 997; https://doi.org/10.3390/ijms23020997 - 17 Jan 2022
Viewed by 395
Abstract
Hemopexin is the plasma protein with the highest affinity for heme. Seminal studies have highlighted its role in different kinds of heme-associated disorders, but its implication in cancer has been neglected for a long time. Considering the emerging importance of heme in tumors, [...] Read more.
Hemopexin is the plasma protein with the highest affinity for heme. Seminal studies have highlighted its role in different kinds of heme-associated disorders, but its implication in cancer has been neglected for a long time. Considering the emerging importance of heme in tumors, the present review proposes an update of the works investigating hemopexin involvement in cancer, with the attempt to stimulate further future studies on this topic. Full article
(This article belongs to the Special Issue Heme and Hemopexin: Multitasking Molecules)
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Review
Deranged Myocardial Fatty Acid Metabolism in Heart Failure
Int. J. Mol. Sci. 2022, 23(2), 996; https://doi.org/10.3390/ijms23020996 - 17 Jan 2022
Cited by 1 | Viewed by 648
Abstract
The heart requires fatty acids to maintain its activity. Various mechanisms regulate myocardial fatty acid metabolism, such as energy production using fatty acids as fuel, for which it is known that coordinated control of fatty acid uptake, β-oxidation, and mitochondrial oxidative phosphorylation steps [...] Read more.
The heart requires fatty acids to maintain its activity. Various mechanisms regulate myocardial fatty acid metabolism, such as energy production using fatty acids as fuel, for which it is known that coordinated control of fatty acid uptake, β-oxidation, and mitochondrial oxidative phosphorylation steps are important for efficient adenosine triphosphate (ATP) production without unwanted side effects. The fatty acids taken up by cardiomyocytes are not only used as substrates for energy production but also for the synthesis of triglycerides and the replacement reaction of fatty acid chains in cell membrane phospholipids. Alterations in fatty acid metabolism affect the structure and function of the heart. Recently, breakthrough studies have focused on the key transcription factors that regulate fatty acid metabolism in cardiomyocytes and the signaling systems that modify their functions. In this article, we reviewed the latest research on the role of fatty acid metabolism in the pathogenesis of heart failure and provide an outlook on future challenges. Full article
(This article belongs to the Special Issue Nutrients (Amino Acid, Glucose and Lipid)-Mediated Signaling)
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Article
Clinical and Genetic Re-Evaluation of Inherited Retinal Degeneration Pedigrees following Initial Negative Findings on Panel-Based Next Generation Sequencing
Int. J. Mol. Sci. 2022, 23(2), 995; https://doi.org/10.3390/ijms23020995 - 17 Jan 2022
Cited by 1 | Viewed by 586
Abstract
Although rare, inherited retinal degenerations (IRDs) are the most common reason for blind registration in the working age population. They are highly genetically heterogeneous (>300 known genetic loci), and confirmation of a molecular diagnosis is a prerequisite for many therapeutic clinical trials and [...] Read more.
Although rare, inherited retinal degenerations (IRDs) are the most common reason for blind registration in the working age population. They are highly genetically heterogeneous (>300 known genetic loci), and confirmation of a molecular diagnosis is a prerequisite for many therapeutic clinical trials and approved treatments. First-tier genetic testing of IRDs with panel-based next-generation sequencing (pNGS) has a diagnostic yield of ≈70–80%, leaving the remaining more challenging cases to be resolved by second-tier testing methods. This study describes the phenotypic reassessment of patients with a negative result from first-tier pNGS and the rationale, outcomes, and cost of second-tier genetic testing approaches. Removing non-IRD cases from consideration and utilizing case-appropriate second-tier genetic testing techniques, we genetically resolved 56% of previously unresolved pedigrees, bringing the overall resolve rate to 92% (388/423). At present, pNGS remains the most cost-effective first-tier approach for the molecular assessment of diverse IRD populations Second-tier genetic testing should be guided by clinical (i.e., reassessment, multimodal imaging, electrophysiology), and genetic (i.e., single alleles in autosomal recessive disease) indications to achieve a genetic diagnosis in the most cost-effective manner. Full article
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Review
Shigella Outer Membrane Vesicles as Promising Targets for Vaccination
Int. J. Mol. Sci. 2022, 23(2), 994; https://doi.org/10.3390/ijms23020994 - 17 Jan 2022
Viewed by 562
Abstract
The clinical symptoms of shigellosis, a gastrointestinal infection caused by Shigella spp. range from watery diarrhea to fulminant dysentery. Endemic infections, particularly among children in developing countries, represent the majority of clinical cases. The situation is aggravated due to the high mortality rate [...] Read more.
The clinical symptoms of shigellosis, a gastrointestinal infection caused by Shigella spp. range from watery diarrhea to fulminant dysentery. Endemic infections, particularly among children in developing countries, represent the majority of clinical cases. The situation is aggravated due to the high mortality rate of shigellosis, the rapid dissemination of multi-resistant Shigella strains and the induction of only serotype-specific immunity. Thus, infection prevention due to vaccination, encompassing as many of the circulating serotypes as possible, has become a topic of interest. However, vaccines have turned out to be ineffective so far. Outer membrane vesicles (OMVs) are promising novel targets for vaccination. OMVs are constitutively secreted by Gram-negative bacteria including Shigella during growth. They are composed of soluble luminal portions and an insoluble membrane and can contain toxins, bioactive periplasmic and cytoplasmic (lipo-) proteins, (phospho-) lipids, nucleic acids and/or lipopolysaccharides. Thus, OMVs play an important role in bacterial cell–cell communication, growth, survival and pathogenesis. Furthermore, they modulate the secretion and transport of biomolecules, the stress response, antibiotic resistance and immune responses of the host. Thus, OMVs serve as novel secretion machinery. Here, we discuss the current literature and highlight the properties of OMVs as potent vaccine candidates because of their immunomodulatory, antigenic and adjuvant properties. Full article
(This article belongs to the Special Issue Inflammatory Bowel Disease: From Pre-clinial Models into Translation)
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Review
Development of the Ontogenetic Self-Regulation Clock
Int. J. Mol. Sci. 2022, 23(2), 993; https://doi.org/10.3390/ijms23020993 - 17 Jan 2022
Viewed by 501
Abstract
To date, there is no overarching proposition for the ontogenetic-neurobiological basis of self-regulation. This paper suggests that the balanced self-regulatory reaction of the fetus, newborn and infant is based on a complex mechanism starting from early brainstem development and continuing to progressive control [...] Read more.
To date, there is no overarching proposition for the ontogenetic-neurobiological basis of self-regulation. This paper suggests that the balanced self-regulatory reaction of the fetus, newborn and infant is based on a complex mechanism starting from early brainstem development and continuing to progressive control of the cortex over the brainstem. It is suggested that this balance occurs through the synchronous reactivity between the sympathetic and parasympathetic systems, both which originate from the brainstem. The paper presents an evidence-based approach in which molecular excitation-inhibition balance, interchanges between excitatory and inhibitory roles of neurotransmitters as well as cardiovascular and white matter development across gestational ages, are shown to create sympathetic-parasympathetic synchrony, including the postnatal development of electroencephalogram waves and vagal tone. These occur in developmental milestones detectable in the same time windows (sensitive periods of development) within a convergent systematic progress. This ontogenetic stepwise process is termed “the self-regulation clock” and suggest that this clock is located in the largest connection between the brainstem and the cortex, the corticospinal tract. This novel evidence-based new theory paves the way towards more accurate hypotheses and complex studies of self-regulation and its biological basis, as well as pointing to time windows for interventions in preterm infants. The paper also describes the developing indirect signaling between the suprachiasmatic nucleus and the corticospinal tract. Finally, the paper proposes novel hypotheses for molecular, structural and functional investigation of the “clock” circuitry, including its associations with other biological clocks. This complex circuitry is suggested to be responsible for the developing self-regulatory functions and their neurobehavioral correlates. Full article
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Review
CRLF1 and CLCF1 in Development, Health and Disease
Int. J. Mol. Sci. 2022, 23(2), 992; https://doi.org/10.3390/ijms23020992 - 17 Jan 2022
Cited by 2 | Viewed by 477
Abstract
Cytokines and their receptors have a vital function in regulating various processes such as immune function, inflammation, haematopoiesis, cell growth and differentiation. The interaction between a cytokine and its specific receptor triggers intracellular signalling cascades that lead to altered gene expression in the [...] Read more.
Cytokines and their receptors have a vital function in regulating various processes such as immune function, inflammation, haematopoiesis, cell growth and differentiation. The interaction between a cytokine and its specific receptor triggers intracellular signalling cascades that lead to altered gene expression in the target cell and consequent changes in its proliferation, differentiation, or activation. In this review, we highlight the role of the soluble type I cytokine receptor CRLF1 (cytokine receptor-like factor-1) and the Interleukin (IL)-6 cytokine CLCF1 (cardiotrophin-like cytokine factor 1) during development in physiological and pathological conditions with particular emphasis on Crisponi/cold-induced sweating syndrome (CS/CISS) and discuss new insights, challenges and possibilities arising from recent studies. Full article
(This article belongs to the Special Issue Cytokine Receptors In Development, Homeostasis & Disease)
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Article
Inulin Improves Diet-Induced Hepatic Steatosis and Increases Intestinal Akkermansia Genus Level
Int. J. Mol. Sci. 2022, 23(2), 991; https://doi.org/10.3390/ijms23020991 - 17 Jan 2022
Viewed by 586
Abstract
Hepatic steatosis is characterized by triglyceride accumulation within hepatocytes in response to a high calorie intake, and it may be related to intestinal microbiota disturbances. The prebiotic inulin is a naturally occurring polysaccharide with a high dietary fiber content. Here, we evaluate the [...] Read more.
Hepatic steatosis is characterized by triglyceride accumulation within hepatocytes in response to a high calorie intake, and it may be related to intestinal microbiota disturbances. The prebiotic inulin is a naturally occurring polysaccharide with a high dietary fiber content. Here, we evaluate the effect of inulin on the intestinal microbiota in a non-alcoholic fatty liver disease model. Mice exposed to a standard rodent diet or a fat-enriched diet, were supplemented or not, with inulin. Liver histology was evaluated with oil red O and H&E staining and the intestinal microbiota was determined in mice fecal samples by 16S rRNA sequencing. Inulin treatment effectively prevents liver steatosis in the fat-enriched diet group. We also observed that inulin re-shaped the intestinal microbiota at the phylum level, were Verrucomicrobia genus significantly increased in the fat-diet group; specifically, we observed that Akkermansia muciniphila increased by 5-fold with inulin supplementation. The family Prevotellaceae was also significantly increased in the fat-diet group. Overall, we propose that inulin supplementation in liver steatosis-affected animals, promotes a remodeling in the intestinal microbiota composition, which might regulate lipid metabolism, thus contributing to tackling liver steatosis. Full article
(This article belongs to the Special Issue Nutrition, Obesity and Associated Morbidities)
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Article
Individual and Binary Mixture Toxicity of Five Nanoparticles in Marine Microalga Heterosigma akashiwo
Int. J. Mol. Sci. 2022, 23(2), 990; https://doi.org/10.3390/ijms23020990 - 17 Jan 2022
Viewed by 469
Abstract
The investigation of the combined toxic action of different types of nanoparticles (NPs) and their interaction between each other and with aquatic organisms is an important problem of modern ecotoxicology. In this study, we assessed the individual and mixture toxicities of cadmium and [...] Read more.
The investigation of the combined toxic action of different types of nanoparticles (NPs) and their interaction between each other and with aquatic organisms is an important problem of modern ecotoxicology. In this study, we assessed the individual and mixture toxicities of cadmium and zinc sulfides (CdS and ZnS), titanium dioxide (TiO2), and two types of mesoporous silicon dioxide (with no inclusions (SMB3) and with metal inclusions (SMB24)) by a microalga growth inhibition bioassay. The counting and size measurement of microalga cells and NPs were performed by flow cytometry. The biochemical endpoints were measured by a UV-VIS microplate spectrophotometer. The highest toxicity was observed for SMB24 (EC50, 3.6 mg/L) and CdS (EC50, 21.3 mg/L). A combined toxicity bioassay demonstrated that TiO2 and the SMB3 NPs had a synergistic toxic effect in combinations with all the tested samples except SMB24, probably caused by a “Trojan horse effect”. Sample SMB24 had antagonistic toxic action with CdS and ZnS, which was probably caused by metal ion scavenging. Full article
(This article belongs to the Special Issue Toxicology, Nanotoxicology and Occupational Diseases)
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Article
Rewired Cellular Metabolic Profiles in Response to Metformin under Different Oxygen and Nutrient Conditions
Int. J. Mol. Sci. 2022, 23(2), 989; https://doi.org/10.3390/ijms23020989 - 17 Jan 2022
Cited by 1 | Viewed by 441
Abstract
Metformin is a metabolic disruptor, and its efficacy and effects on metabolic profiles under different oxygen and nutrient conditions remain unclear. Therefore, the present study examined the effects of metformin on cell growth, the metabolic activities and consumption of glucose, glutamine, and pyruvate, [...] Read more.
Metformin is a metabolic disruptor, and its efficacy and effects on metabolic profiles under different oxygen and nutrient conditions remain unclear. Therefore, the present study examined the effects of metformin on cell growth, the metabolic activities and consumption of glucose, glutamine, and pyruvate, and the intracellular ratio of nicotinamide adenine dinucleotide (NAD+) and reduced nicotinamide adenine dinucleotide (NADH) under normoxic (21% O2) and hypoxic (1% O2) conditions. The efficacy of metformin with nutrient removal from culture media was also investigated. The results obtained show that the efficacy of metformin was closely associated with cell types and environmental factors. Acute exposure to metformin had no effect on lactate production from glucose, glutamine, or pyruvate, whereas long-term exposure to metformin increased the consumption of glucose and pyruvate and the production of lactate in the culture media of HeLa and HaCaT cells as well as the metabolic activity of glucose. The NAD+/NADH ratio decreased during growth with metformin regardless of its efficacy. Furthermore, the inhibitory effects of metformin were enhanced in all cell lines following the removal of glucose or pyruvate from culture media. Collectively, the present results reveal that metformin efficacy may be regulated by oxygen conditions and nutrient availability, and indicate the potential of the metabolic switch induced by metformin as combinational therapy. Full article
(This article belongs to the Section Biochemistry)
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Article
Electrospun PEO/rGO Scaffolds: The Influence of the Concentration of rGO on Overall Properties and Cytotoxicity
Int. J. Mol. Sci. 2022, 23(2), 988; https://doi.org/10.3390/ijms23020988 - 17 Jan 2022
Viewed by 1077
Abstract
Reduced graphene oxide (rGO) is one of the graphene derivatives that can be employed to engineer bioactive and/or electroactive scaffolds. However, the influence of its low and especially high concentrations on scaffolds’ overall properties and cytotoxicity has yet to be explored. In this [...] Read more.
Reduced graphene oxide (rGO) is one of the graphene derivatives that can be employed to engineer bioactive and/or electroactive scaffolds. However, the influence of its low and especially high concentrations on scaffolds’ overall properties and cytotoxicity has yet to be explored. In this study, polyethylene oxide (PEO)-based scaffolds containing from 0.1 to 20 wt% rGO were obtained by electrospinning. Morphological, thermal and electrical properties of the scaffolds were characterized by SEM, Raman spectroscopy, XRD, DSC and electrical measurements. The diameter of the fibers decreased from 0.52 to 0.19 µm as the concentration of rGO increased from 0.1 wt% to 20 wt%. The presence of rGO above the percolation threshold (5.7 wt%) resulted in a significantly reduced electrical resistivity of the scaffolds. XRD and Raman analysis revealed delamination of the graphene layers (interlayer spacing increased from 0.36 nm to 0.40–0.41 nm), and exfoliation of rGO was detected for the samples with an rGO concentration lower than 1 wt%. In addition, an evident trend of increasing cell viability as a function of the rGO concentration was evidenced. The obtained results can serve as further guidance for the judicious selection of the rGO content incorporated into the PEO matrix for constructing electroactive scaffolds. Full article
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Article
Tissue Proteome of 2-Hydroxyacyl-CoA Lyase Deficient Mice Reveals Peroxisome Proliferation and Activation of ω-Oxidation
Int. J. Mol. Sci. 2022, 23(2), 987; https://doi.org/10.3390/ijms23020987 - 17 Jan 2022
Viewed by 680
Abstract
Peroxisomal fatty acid α-oxidation is an essential pathway for the degradation of β-carbon methylated fatty acids such as phytanic acid. One enzyme in this pathway is 2-hydroxyacyl CoA lyase (HACL1), which is responsible for the cleavage of 2-hydroxyphytanoyl-CoA into pristanal and formyl-CoA. Hacl1 [...] Read more.
Peroxisomal fatty acid α-oxidation is an essential pathway for the degradation of β-carbon methylated fatty acids such as phytanic acid. One enzyme in this pathway is 2-hydroxyacyl CoA lyase (HACL1), which is responsible for the cleavage of 2-hydroxyphytanoyl-CoA into pristanal and formyl-CoA. Hacl1 deficient mice do not present with a severe phenotype, unlike mice deficient in other α-oxidation enzymes such as phytanoyl-CoA hydroxylase deficiency (Refsum disease) in which neuropathy and ataxia are present. Tissues from wild-type and Hacl1−/− mice fed a high phytol diet were obtained for proteomic and lipidomic analysis. There was no phenotype observed in these mice. Liver, brain, and kidney tissues underwent trypsin digestion for untargeted proteomic liquid chromatography-mass spectrometry analysis, while liver tissues also underwent fatty acid hydrolysis, extraction, and derivatisation for fatty acid gas chromatography-mass spectrometry analysis. The liver fatty acid profile demonstrated an accumulation of phytanic and 2-hydroxyphytanic acid in the Hacl1−/− liver and significant decrease in heptadecanoic acid. The liver proteome showed a significant decrease in the abundance of Hacl1 and a significant increase in the abundance of proteins involved in PPAR signalling, peroxisome proliferation, and omega oxidation, particularly Cyp4a10 and Cyp4a14. In addition, the pathway associated with arachidonic acid metabolism was affected; Cyp2c55 was upregulated and Cyp4f14 and Cyp2b9 were downregulated. The kidney proteome revealed fewer significantly upregulated peroxisomal proteins and the brain proteome was not significantly different in Hacl1−/− mice. This study demonstrates the powerful insight brought by proteomic and metabolomic profiling of Hacl1−/− mice in better understanding disease mechanism in fatty acid α-oxidation disorders. Full article
(This article belongs to the Section Biochemistry)
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Case Report
Biallelic Variants in PYROXD2 Cause a Severe Infantile Metabolic Disorder Affecting Mitochondrial Function
Int. J. Mol. Sci. 2022, 23(2), 986; https://doi.org/10.3390/ijms23020986 - 17 Jan 2022
Viewed by 528
Abstract
Pyridine Nucleotide-Disulfide Oxidoreductase Domain 2 (PYROXD2; previously called YueF) is a mitochondrial inner membrane/matrix-residing protein and is reported to regulate mitochondrial function. The clinical importance of PYROXD2 has been unclear, and little is known of the protein’s precise biological function. [...] Read more.
Pyridine Nucleotide-Disulfide Oxidoreductase Domain 2 (PYROXD2; previously called YueF) is a mitochondrial inner membrane/matrix-residing protein and is reported to regulate mitochondrial function. The clinical importance of PYROXD2 has been unclear, and little is known of the protein’s precise biological function. In the present paper, we report biallelic variants in PYROXD2 identified by genome sequencing in a patient with suspected mitochondrial disease. The child presented with acute neurological deterioration, unresponsive episodes, and extreme metabolic acidosis, and received rapid genomic testing. He died shortly after. Magnetic resonance imaging (MRI) brain imaging showed changes resembling Leigh syndrome, one of the more common childhood mitochondrial neurological diseases. Functional studies in patient fibroblasts showed a heightened sensitivity to mitochondrial metabolic stress and increased mitochondrial superoxide levels. Quantitative proteomic analysis demonstrated decreased levels of subunits of the mitochondrial respiratory chain complex I, and both the small and large subunits of the mitochondrial ribosome, suggesting a mitoribosomal defect. Our findings support the critical role of PYROXD2 in human cells, and suggest that the biallelic PYROXD2 variants are associated with mitochondrial dysfunction, and can plausibly explain the child’s clinical presentation. Full article
(This article belongs to the Special Issue Mitochondria and Energy Metabolism in Rare Diseases)
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Review
Involvement of the Innate Immune System in the Pathogenesis of Chronic Obstructive Pulmonary Disease
Int. J. Mol. Sci. 2022, 23(2), 985; https://doi.org/10.3390/ijms23020985 - 17 Jan 2022
Viewed by 728
Abstract
Chronic obstructive pulmonary disease (COPD) is a common, socially significant disease characterized by progressive airflow limitation due to chronic inflammation in the bronchi. Although the causes of COPD are considered to be known, the pathogenesis of the disease continues to be a relevant [...] Read more.
Chronic obstructive pulmonary disease (COPD) is a common, socially significant disease characterized by progressive airflow limitation due to chronic inflammation in the bronchi. Although the causes of COPD are considered to be known, the pathogenesis of the disease continues to be a relevant topic of study. Mechanisms of the innate immune system are involved in various links in the pathogenesis of COPD, leading to persistence of chronic inflammation in the bronchi, their bacterial colonization and disruption of lung structure and function. Bronchial epithelial cells, neutrophils, macrophages and other cells are involved in the development and progression of the disease, demonstrating multiple compromised immune mechanisms. Full article
(This article belongs to the Special Issue Molecular Mechanisms of Host-Pathogen Interaction)
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Article
Intrinsic Expression of Coagulation Factors and Protease Activated Receptor 1 (PAR1) in Photoreceptors and Inner Retinal Layers
Int. J. Mol. Sci. 2022, 23(2), 984; https://doi.org/10.3390/ijms23020984 - 17 Jan 2022
Viewed by 293
Abstract
The aim of this study was to characterize the distribution of the thrombin receptor, protease activated receptor 1 (PAR1), in the neuroretina. Neuroretina samples of wild-type C57BL/6J and PAR1−/− mice were processed for indirect immunofluorescence and Western blot analysis. Reverse transcription quantitative [...] Read more.
The aim of this study was to characterize the distribution of the thrombin receptor, protease activated receptor 1 (PAR1), in the neuroretina. Neuroretina samples of wild-type C57BL/6J and PAR1−/− mice were processed for indirect immunofluorescence and Western blot analysis. Reverse transcription quantitative real-time PCR (RT-qPCR) was used to determine mRNA expression of coagulation Factor X (FX), prothrombin (PT), and PAR1 in the isolated neuroretina. Thrombin activity following KCl depolarization was assessed in mouse neuroretinas ex vivo. PAR1 staining was observed in the retinal ganglion cells, inner nuclear layer cells, and photoreceptors in mouse retinal cross sections by indirect immunofluorescence. PAR1 co-localized with rhodopsin in rod outer segments but was not expressed in cone outer segments. Western blot analysis confirmed PAR1 expression in the neuroretina. Factor X, prothrombin, and PAR1 mRNA expression was detected in isolated neuroretinas. Thrombin activity was elevated by nearly four-fold in mouse neuroretinas following KCl depolarization (0.012 vs. 0.044 mu/mL, p = 0.0497). The intrinsic expression of coagulation factors in the isolated neuroretina together with a functional increase in thrombin activity following KCl depolarization may suggest a role for the PAR1/thrombin pathway in retinal function. Full article
(This article belongs to the Section Molecular Neurobiology)
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Article
Host- and Age-Dependent Transcriptional Changes in Mycobacterium tuberculosis Cell Envelope Biosynthesis Genes after Exposure to Human Alveolar Lining Fluid
Int. J. Mol. Sci. 2022, 23(2), 983; https://doi.org/10.3390/ijms23020983 - 17 Jan 2022
Viewed by 364
Abstract
Tuberculosis (TB) infection, caused by the airborne pathogen Mycobacterium tuberculosis (M.tb), resulted in almost 1.4 million deaths in 2019, and the number of deaths is predicted to increase by 20% over the next 5 years due to the COVID-19 pandemic. Upon [...] Read more.
Tuberculosis (TB) infection, caused by the airborne pathogen Mycobacterium tuberculosis (M.tb), resulted in almost 1.4 million deaths in 2019, and the number of deaths is predicted to increase by 20% over the next 5 years due to the COVID-19 pandemic. Upon reaching the alveolar space, M.tb comes into close contact with the lung mucosa before and after its encounter with host alveolar compartment cells. Our previous studies show that homeostatic, innate soluble components of the alveolar lining fluid (ALF) can quickly alter the cell envelope surface of M.tb upon contact, defining subsequent M.tb–host cell interactions and infection outcomes in vitro and in vivo. We also demonstrated that ALF from 60+ year old elders (E-ALF) vs. healthy 18- to 45-year-old adults (A-ALF) is dysfunctional, with loss of homeostatic capacity and impaired innate soluble responses linked to high local oxidative stress. In this study, a targeted transcriptional assay shows that M.tb exposure to human ALF alters the expression of its cell envelope genes. Specifically, our results indicate that A-ALF-exposed M.tb upregulates cell envelope genes associated with lipid, carbohydrate, and amino acid metabolism, as well as genes associated with redox homeostasis and transcriptional regulators. Conversely, M.tb exposure to E-ALF shows a lesser transcriptional response, with most of the M.tb genes unchanged or downregulated. Overall, this study indicates that M.tb responds and adapts to the lung alveolar environment upon contact, and that the host ALF status, determined by factors such as age, might play an important role in determining infection outcome. Full article
(This article belongs to the Section Molecular Microbiology)
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Article
Regulation of the Receptor Tyrosine Kinase AXL in Response to Therapy and Its Role in Therapy Resistance in Glioblastoma
Int. J. Mol. Sci. 2022, 23(2), 982; https://doi.org/10.3390/ijms23020982 - 17 Jan 2022
Cited by 1 | Viewed by 464
Abstract
The receptor tyrosine kinase AXL (RTK-AXL) is implicated in therapy resistance and tumor progression in glioblastoma multiforme (GBM). Here, we investigated therapy-induced receptor modifications and how endogenous RTK-AXL expression and RTK-AXL inhibition contribute to therapy resistance in GBM. GBM cell lines U118MG and [...] Read more.
The receptor tyrosine kinase AXL (RTK-AXL) is implicated in therapy resistance and tumor progression in glioblastoma multiforme (GBM). Here, we investigated therapy-induced receptor modifications and how endogenous RTK-AXL expression and RTK-AXL inhibition contribute to therapy resistance in GBM. GBM cell lines U118MG and SF126 were exposed to temozolomide (TMZ) and radiation (RTX). Receptor modifications in response to therapy were investigated on protein and mRNA levels. TMZ-resistant and RTK-AXL overexpressing cell lines were exposed to increasing doses of TMZ and RTX, with and without RTK-AXL tyrosine kinase inhibitor (TKI). Colorimetric microtiter (MTT) assay and colony formation assay (CFA) were used to assess cell viability. Results showed that the RTK-AXL shedding product, C-terminal AXL (CT-AXL), rises in response to repeated TMZ doses and under hypoxia, acts as a surrogate marker for radio-resistance. Endogenous RTX-AXL overexpression leads to therapy resistance, whereas combination therapy of TZM and RTX with TKI R428 significantly increases therapeutic effects. This data proves the role of RTK-AXL in acquired and intrinsic therapy resistance. By demonstrating that therapy resistance may be overcome by combining AXL TKI with standard treatments, we have provided a rationale for future study designs investigating AXL TKIs in GBM. Full article
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Article
Cold Response Transcriptome Analysis of the Alternative Splicing Events Induced by the Cold Stress in D. catenatum
Int. J. Mol. Sci. 2022, 23(2), 981; https://doi.org/10.3390/ijms23020981 - 17 Jan 2022
Viewed by 452
Abstract
Dendrobium catenatum Lindl is a valuable medicinal herb and gardening plant due to its ornamental value and special medical value. Low temperature is a major bottleneck restricting D. catenatum expansion towards the north, which influences the quality and yield of D. catenatum. [...] Read more.
Dendrobium catenatum Lindl is a valuable medicinal herb and gardening plant due to its ornamental value and special medical value. Low temperature is a major bottleneck restricting D. catenatum expansion towards the north, which influences the quality and yield of D. catenatum. In this study, we analysed the cold response of D. catenatum by RNA-Seq. A total of 4302 differentially expressed genes were detected under cold stress, which were mainly linked to protein kinase activity, membrane transport and the glycan biosynthesis and metabolism pathway. We also identified 4005 differential alternative events in 2319 genes significantly regulated by cold stress. Exon skipping and intron retention were the most common alternative splicing isoforms. Numerous genes were identified that differentially modulated under cold stress, including cold-induced transcription factors and splicing factors mediated by AS (alternative splicing). GO enrichment analysis found that differentially alternatively spliced genes without differential expression levels were related to RNA/mRNA processing and spliceosomes. DAS (differentially alternative splicing) genes with different expression levels were mainly enriched in protein kinase activity, plasma membrane and cellular response to stimulus. We further identified and cloned DcCBP20 in D. catenatum; we found that DcCBP20 promotes the generation of alternative splicing variants in cold-induced genes under cold stress via genetic experiments and RT–PCR. Taken together, our results identify the main cold-response pathways and alternative splicing events in D. catenatum responding to cold treatment and that DcCBP20 of D. catenatum get involved in regulating the AS and gene expression of cold-induced genes during this process. Our study will contribute to understanding the role of AS genes in regulating the cold stress response in D. catenatum. Full article
(This article belongs to the Special Issue Plant Genomics and Genome Editing)
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Article
Reactions of Recombinant Neuronal Nitric Oxide Synthase with Redox Cycling Xenobiotics: A Mechanistic Study
Int. J. Mol. Sci. 2022, 23(2), 980; https://doi.org/10.3390/ijms23020980 - 17 Jan 2022
Viewed by 259
Abstract
Neuronal nitric oxide synthase (nNOS) catalyzes single-electron reduction of quinones (Q), nitroaromatic compounds (ArNO2) and aromatic N-oxides (ArN → O), and is partly responsible for their oxidative stress-type cytotoxicity. In order to expand a limited knowledge on the enzymatic mechanisms [...] Read more.
Neuronal nitric oxide synthase (nNOS) catalyzes single-electron reduction of quinones (Q), nitroaromatic compounds (ArNO2) and aromatic N-oxides (ArN → O), and is partly responsible for their oxidative stress-type cytotoxicity. In order to expand a limited knowledge on the enzymatic mechanisms of these processes, we aimed to disclose the specific features of nNOS in the reduction of such xenobiotics. In the absence or presence of calmodulin (CAM), the reactivity of Q and ArN → O increases with their single-electron reduction midpoint potential (E17). ArNO2 form a series with lower reactivity. The calculations according to an “outer-sphere” electron transfer model show that the binding of CAM decreases the electron transfer distance from FMNH2 to quinone by 1–2 Å. The effects of ionic strength point to the interaction of oxidants with a negatively charged protein domain close to FMN, and to an increase in accessibility of the active center induced by high ionic strength. The multiple turnover experiments of nNOS show that, in parallel with reduced FAD-FMN, duroquinone reoxidizes the reduced heme, in particular its Fe2+-NO form. This finding may help to design the heme-targeted bioreductively activated agents and contribute to the understanding of the role of P-450-type heme proteins in the bioreduction of quinones and other prooxidant xenobiotics. Full article
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Review
Complex Interplay of Heme-Copper Oxidases with Nitrite and Nitric Oxide
Int. J. Mol. Sci. 2022, 23(2), 979; https://doi.org/10.3390/ijms23020979 - 17 Jan 2022
Cited by 1 | Viewed by 395
Abstract
Nitrite and nitric oxide (NO), two active and critical nitrogen oxides linking nitrate to dinitrogen gas in the broad nitrogen biogeochemical cycle, are capable of interacting with redox-sensitive proteins. The interactions of both with heme-copper oxidases (HCOs) serve as the foundation not only [...] Read more.
Nitrite and nitric oxide (NO), two active and critical nitrogen oxides linking nitrate to dinitrogen gas in the broad nitrogen biogeochemical cycle, are capable of interacting with redox-sensitive proteins. The interactions of both with heme-copper oxidases (HCOs) serve as the foundation not only for the enzymatic interconversion of nitrogen oxides but also for the inhibitory activity. From extensive studies, we now know that NO interacts with HCOs in a rapid and reversible manner, either competing with oxygen or not. During interconversion, a partially reduced heme/copper center reduces the nitrite ion, producing NO with the heme serving as the reductant and the cupric ion providing a Lewis acid interaction with nitrite. The interaction may lead to the formation of either a relatively stable nitrosyl-derivative of the enzyme reduced or a more labile nitrite-derivative of the enzyme oxidized through two different pathways, resulting in enzyme inhibition. Although nitrite and NO show similar biochemical properties, a growing body of evidence suggests that they are largely treated as distinct molecules by bacterial cells. NO seemingly interacts with all hemoproteins indiscriminately, whereas nitrite shows high specificity to HCOs. Moreover, as biologically active molecules and signal molecules, nitrite and NO directly affect the activity of different enzymes and are perceived by completely different sensing systems, respectively, through which they are linked to different biological processes. Further attempts to reconcile this apparent contradiction could open up possible avenues for the application of these nitrogen oxides in a variety of fields, the pharmaceutical industry in particular. Full article
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Article
R-Ras1 and R-Ras2 Expression in Anatomical Regions and Cell Types of the Central Nervous System
Int. J. Mol. Sci. 2022, 23(2), 978; https://doi.org/10.3390/ijms23020978 - 17 Jan 2022
Viewed by 597
Abstract
Since the optic nerve is one of the most myelinated tracts in the central nervous system (CNS), many myelin diseases affect the visual system. In this sense, our laboratory has recently reported that the GTPases R-Ras1 and R-Ras2 are essential for oligodendrocyte survival [...] Read more.
Since the optic nerve is one of the most myelinated tracts in the central nervous system (CNS), many myelin diseases affect the visual system. In this sense, our laboratory has recently reported that the GTPases R-Ras1 and R-Ras2 are essential for oligodendrocyte survival and maturation. Hypomyelination produced by the absence of one or both proteins triggers axonal degeneration and loss of visual and motor function. However, little is known about R-Ras specificity and other possible roles that they could play in the CNS. In this work, we describe how a lack of R-Ras1 and/or R-Ras2 could not be compensated by increased expression of the closely related R-Ras3 or classical Ras. We further studied R-Ras1 and R-Ras2 expression within different CNS anatomical regions, finding that both were more abundant in less-myelinated regions, suggesting their expression in non-oligodendroglial cells. Finally, using confocal immunostaining colocalization, we report for the first time that R-Ras2 is specifically expressed in neurons. Neither microglia nor astrocytes expressed R-Ras1 or R-Ras2. These results open a new avenue for the study of neuronal R-Ras2’s contribution to the process of myelination. Full article
(This article belongs to the Special Issue Molecular Research on Neurological Visual Diseases)
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Review
Lung Microbiome in Idiopathic Pulmonary Fibrosis and Other Interstitial Lung Diseases
Int. J. Mol. Sci. 2022, 23(2), 977; https://doi.org/10.3390/ijms23020977 - 17 Jan 2022
Viewed by 678
Abstract
Interstitial lung diseases represent a heterogeneous and wide group of diseases in which factors leading to disease initiation and progression are not fully understood. Recent evidence suggests that the lung microbiome might influence the pathogenesis and progression of interstitial lung diseases. In recent [...] Read more.
Interstitial lung diseases represent a heterogeneous and wide group of diseases in which factors leading to disease initiation and progression are not fully understood. Recent evidence suggests that the lung microbiome might influence the pathogenesis and progression of interstitial lung diseases. In recent years, the utilization of culture-independent methodologies has allowed the identification of complex and dynamic communities of microbes, in patients with interstitial lung diseases. However, the potential mechanisms by which these changes may drive disease pathogenesis and progression are largely unknown. The aim of this review is to discuss the role of the altered lung microbiome in several interstitial lung diseases. Untangling the host–microbiome interaction in the lung and airway of interstitial lung disease patients is a research priority. Thus, lung dysbiosis is a potentially treatable trait across several interstitial lung diseases, and its proper characterization and treatment might be crucial to change the natural history of these diseases and improve outcomes. Full article
(This article belongs to the Special Issue Molecular Research in Inflammation and Lung Infections)
Article
Transcriptome Analysis Reveals Multiple Genes and Complex Hormonal-Mediated Interactions with PEG during Adventitious Root Formation in Apple
Int. J. Mol. Sci. 2022, 23(2), 976; https://doi.org/10.3390/ijms23020976 - 17 Jan 2022
Cited by 3 | Viewed by 435
Abstract
Adventitious root (AR) formation is a bottleneck for the mass propagation of apple rootstocks, and water stress severely restricts it. Different hormones and sugar signaling pathways in apple clones determine AR formation under water stress, but these are not entirely understood. To identify [...] Read more.
Adventitious root (AR) formation is a bottleneck for the mass propagation of apple rootstocks, and water stress severely restricts it. Different hormones and sugar signaling pathways in apple clones determine AR formation under water stress, but these are not entirely understood. To identify them, GL-3 stem cuttings were cultured on polyethylene glycol (PEG) treatment. The AR formation was dramatically decreased compared with the PEG-free control (CK) cuttings by increasing the endogenous contents of abscisic acid (ABA), zeatin riboside (ZR), and methyl jasmonate (JA-me) and reducing the indole-3-acetic acid (IAA) and gibberellic acid 3 (GA3) contents. We performed a transcriptomic analysis to identify the responses behind the phenotype. A total of 3204 differentially expressed genes (DEGs) were identified between CK and PEG, with 1702 upregulated and 1502 downregulated genes. Investigation revealed that approximately 312 DEGs were strongly enriched in hormone signaling, sugar metabolism, root development, and cell cycle-related pathways. Thus, they were selected for their possible involvement in adventitious rooting. However, the higher accumulation of ABA, ZR, and JA-me contents and the upregulation of their related genes, as well as the downregulation of sugar metabolism-related genes, lead to the inhibition of ARs. These results indicate that AR formation is a complicated biological process chiefly influenced by multiple hormonal signaling pathways and sugar metabolism. This is the first study to demonstrate how PEG inhibits AR formation in apple plants. Full article
(This article belongs to the Special Issue Drought-Stress Induced Physiological and Molecular Changes in Plants)
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Review
New Insights and Potential Therapeutic Targeting of CB2 Cannabinoid Receptors in CNS Disorders
Int. J. Mol. Sci. 2022, 23(2), 975; https://doi.org/10.3390/ijms23020975 - 17 Jan 2022
Cited by 1 | Viewed by 795
Abstract
The endocannabinoid system (ECS) is ubiquitous in most human tissues, and involved in the regulation of mental health. Consequently, its dysregulation is associated with neuropsychiatric and neurodegenerative disorders. Together, the ECS and the expanded endocannabinoidome (eCBome) are composed of genes coding for CB1 [...] Read more.
The endocannabinoid system (ECS) is ubiquitous in most human tissues, and involved in the regulation of mental health. Consequently, its dysregulation is associated with neuropsychiatric and neurodegenerative disorders. Together, the ECS and the expanded endocannabinoidome (eCBome) are composed of genes coding for CB1 and CB2 cannabinoid receptors (CB1R, CB2R), endocannabinoids (eCBs), and the metabolic enzyme machinery for their synthesis and catabolism. The activation of CB1R is associated with adverse effects on the central nervous system (CNS), which has limited the therapeutic use of drugs that bind this receptor. The discovery of the functional neuronal CB2R raised new possibilities for the potential and safe targeting of the ECS for the treatment of CNS disorders. Previous studies were not able to detect CB2R mRNA transcripts in brain tissue and suggested that CB2Rs were absent in the brain and were considered peripheral receptors. Studies done on the role of CB2Rs as a potential therapeutic target for treating different disorders revealed the important putative role of CB2Rs in certain CNS disorders, which requires further clinical validation. This review addresses recent advances on the role of CB2Rs in neuropsychiatric and neurodegenerative disorders, including, but not limited to, anxiety, depression, schizophrenia, Parkinson’s disease (PD), Alzheimer’s disease (AD), Huntington’s disease (HD) and addiction. Full article
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Article
Soluble CD146 as a Potential Target for Preventing Triple Negative Breast Cancer MDA-MB-231 Cell Growth and Dissemination
Int. J. Mol. Sci. 2022, 23(2), 974; https://doi.org/10.3390/ijms23020974 - 17 Jan 2022
Viewed by 427
Abstract
Background: Triple Negative Breast Cancers (TNBC) are the most aggressive breast cancers and lead to poor prognoses. This is due to a high resistance to therapies, mainly because of the presence of Cancer Stem Cells (CSCs). Plasticity, a feature of CSCs, is acquired [...] Read more.
Background: Triple Negative Breast Cancers (TNBC) are the most aggressive breast cancers and lead to poor prognoses. This is due to a high resistance to therapies, mainly because of the presence of Cancer Stem Cells (CSCs). Plasticity, a feature of CSCs, is acquired through the Epithelial to Mesenchymal Transition (EMT), a process that has been recently shown to be regulated by a key molecule, CD146. Of interest, CD146 is over-expressed in TNBC. Methods: The MDA-MB-231 TNBC cell line was used as a model to study the role of CD146 and its secreted soluble form (sCD146) in the development and dissemination of TNBC using in vitro and in vivo studies. Results: High expression of CD146 in a majority of MDA-MB-231 cells leads to an increased secretion of sCD146 that up-regulates the expression of EMT and CSC markers on the cells. These effects can be blocked with a specific anti-sCD146 antibody, M2J-1 mAb. M2J-1 mAb was able to reduce tumour development and dissemination in a model of cells xenografted in nude mice and an experimental model of metastasis, respectively, in part through its effects on CSC. Conclusion: We propose that M2J-1 mAb could be used as an additional therapeutic approach to fight TNBC. Full article
(This article belongs to the Special Issue Breast Cancer Mechanistic Insights and Targeted Therapies)
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Article
Identifying Candidate Protein Markers of Acute Kidney Injury in Acute Decompensated Heart Failure
Int. J. Mol. Sci. 2022, 23(2), 1009; https://doi.org/10.3390/ijms23021009 - 17 Jan 2022
Viewed by 571
Abstract
One-quarter of patients with acute decompensated heart failure (ADHF) experience acute kidney injury (AKI)—an abrupt reduction or loss of kidney function associated with increased long-term mortality. There is a critical need to identify early and real-time markers of AKI in ADHF; however, to [...] Read more.
One-quarter of patients with acute decompensated heart failure (ADHF) experience acute kidney injury (AKI)—an abrupt reduction or loss of kidney function associated with increased long-term mortality. There is a critical need to identify early and real-time markers of AKI in ADHF; however, to date, no protein biomarkers have exhibited sufficient diagnostic or prognostic performance for widespread clinical uptake. We aimed to identify novel protein biomarkers of AKI associated with ADHF by quantifying changes in protein abundance in the kidneys that occur during ADHF development and recovery in an ovine model. Relative quantitative protein profiling was performed using sequential window acquisition of all theoretical fragment ion spectra–mass spectrometry (SWATH–MS) in kidney cortices from control sheep (n = 5), sheep with established rapid-pacing-induced ADHF (n = 8), and sheep after ~4 weeks recovery from ADHF (n = 7). Of the 790 proteins quantified, we identified 17 candidate kidney injury markers in ADHF, 1 potential kidney marker of ADHF recovery, and 2 potential markers of long-term renal impairment (differential abundance between groups of 1.2–2.6-fold, adjusted p < 0.05). Among these 20 candidate protein markers of kidney injury were 6 candidates supported by existing evidence and 14 novel candidates not previously implicated in AKI. Proteins of differential abundance were enriched in pro-inflammatory signalling pathways: glycoprotein VI (activated during ADHF development; adjusted p < 0.01) and acute phase response (repressed during recovery from ADHF; adjusted p < 0.01). New biomarkers for the early detection of AKI in ADHF may help us to evaluate effective treatment strategies to prevent mortality and improve outcomes for patients. Full article
(This article belongs to the Special Issue Recent Advances in Molecular Mechanisms of Kidney Injury and Repair)
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Article
Biochemical and Expression Analyses Revealed the Involvement of Proanthocyanidins and/or Their Derivatives in Fiber Pigmentation of Gossypium stocksii
Int. J. Mol. Sci. 2022, 23(2), 1008; https://doi.org/10.3390/ijms23021008 - 17 Jan 2022
Cited by 1 | Viewed by 399
Abstract
The wild cotton species Gossypium stocksii produces a brown fiber that provides a valuable resource for the color improvement of naturally colored cotton (NCC) fiber. However, the biochemical basis and molecular mechanism of its fiber pigmentation remain unclear. Herein, we analyzed the dynamics [...] Read more.
The wild cotton species Gossypium stocksii produces a brown fiber that provides a valuable resource for the color improvement of naturally colored cotton (NCC) fiber. However, the biochemical basis and molecular mechanism of its fiber pigmentation remain unclear. Herein, we analyzed the dynamics of proanthocyanidins (PAs) accumulation in developing the fiber of G. stocksii, which suggested a similar role of PAs and/or their derivatives in the fiber coloration of G. stocksii. In addition, comparative transcriptomics analyses revealed that the PA biosynthetic genes were expressed at higher levels and for a longer period in developing fibers of G. stocksii than G. arboreum (white fiber), and the transcription factors, such as TT8, possibly played crucial regulatory roles in regulating the PA branch genes. Moreover, we found that the anthocyanidin reductase (ANR) was expressed at a higher level than the leucoanthocyanidin reductases (LARs) and significantly upregulated during fiber elongation, suggesting a major role of ANR in PA synthesis in G. stocksii fiber. In summary, this work revealed the accumulation of PAs and the expression enhancement of PA biosynthetic genes in developing fibers of G. stocksii. We believe this work will help our understanding of the molecular mechanisms of cotton fiber coloration and further promote the future breeding of novel NCCs. Full article
(This article belongs to the Topic Plant Functional Genomics and Crop Genetic Improvement)
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Article
Transcriptome-Guided Drug Repurposing for Aggressive SCCs
Int. J. Mol. Sci. 2022, 23(2), 1007; https://doi.org/10.3390/ijms23021007 - 17 Jan 2022
Cited by 1 | Viewed by 536
Abstract
Despite a significant rise in the incidence of cutaneous squamous cell carcinoma (SCC) in recent years, most SCCs are well treatable. However, against the background of pre-existing risk factors such as immunosuppression upon organ transplantation, or conditions such as recessive dystrophic epidermolysis bullosa [...] Read more.
Despite a significant rise in the incidence of cutaneous squamous cell carcinoma (SCC) in recent years, most SCCs are well treatable. However, against the background of pre-existing risk factors such as immunosuppression upon organ transplantation, or conditions such as recessive dystrophic epidermolysis bullosa (RDEB), SCCs arise more frequently and follow a particularly aggressive course. Notably, such SCC types display molecular similarities, despite their differing etiologies. We leveraged the similarities in transcriptomes between tumors from organ transplant recipients and RDEB-patients, augmented with data from more common head and neck (HN)-SCCs, to identify drugs that can be repurposed to treat these SCCs. The in silico approach used is based on the assumption that SCC-derived transcriptome profiles reflect critical tumor pathways that, if reversed towards healthy tissue, will attenuate the malignant phenotype. We determined tumor-specific signatures based on differentially expressed genes, which were then used to mine drug-perturbation data. By leveraging recent efforts in the systematic profiling and cataloguing of thousands of small molecule compounds, we identified drugs including selumetinib that specifically target key molecules within the MEK signaling cascade, representing candidates with the potential to be effective in the treatment of these rare and aggressive SCCs. Full article
(This article belongs to the Special Issue Molecular Research and Treatment of Skin Diseases)
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Article
Comparative Phosphoproteomics of Neuro-2a Cells under Insulin Resistance Reveals New Molecular Signatures of Alzheimer’s Disease
Int. J. Mol. Sci. 2022, 23(2), 1006; https://doi.org/10.3390/ijms23021006 - 17 Jan 2022
Viewed by 599
Abstract
Insulin in the brain is a well-known critical factor in neuro-development and regulation of adult neurogenesis in the hippocampus. The abnormality of brain insulin signaling is associated with the aging process and altered brain plasticity, and could promote neurodegeneration in the late stage [...] Read more.
Insulin in the brain is a well-known critical factor in neuro-development and regulation of adult neurogenesis in the hippocampus. The abnormality of brain insulin signaling is associated with the aging process and altered brain plasticity, and could promote neurodegeneration in the late stage of Alzheimer’s disease (AD). The precise molecular mechanism of the relationship between insulin resistance and AD remains unclear. The development of phosphoproteomics has advanced our knowledge of phosphorylation-mediated signaling networks and could elucidate the molecular mechanisms of certain pathological conditions. Here, we applied a reliable phosphoproteomic approach to Neuro2a (N2a) cells to identify their molecular features under two different insulin-resistant conditions with clinical relevance: inflammation and dyslipidemia. Despite significant difference in overall phosphoproteome profiles, we found molecular signatures and biological pathways in common between two insulin-resistant conditions. These include the integrin and adenosine monophosphate-activated protein kinase pathways, and we further verified these molecular targets by subsequent biochemical analysis. Among them, the phosphorylation levels of acetyl-CoA carboxylase and Src were reduced in the brain from rodent AD model 5xFAD mice. This study provides new molecular signatures for insulin resistance in N2a cells and possible links between the molecular features of insulin resistance and AD. Full article
(This article belongs to the Section Molecular Neurobiology)
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