10 pages, 1991 KiB  
Article
KRAS, NRAS, BRAF, HER2 and MSI Status in a Large Consecutive Series of Colorectal Carcinomas
by Aleksandr S. Martianov 1,2, Natalia V. Mitiushkina 1, Anastasia N. Ershova 2, Darya E. Martynenko 1, Mikhail G. Bubnov 1, Priscilla Amankwah 2, Grigory A. Yanus 1,2, Svetlana N. Aleksakhina 1, Vladislav I. Tiurin 1, Aigul R. Venina 1, Aleksandra A. Anuskina 1, Yuliy A. Gorgul 1, Anna D. Shestakova 1, Mikhail A. Maidin 1, Alexey M. Belyaev 1, Liliya S. Baboshkina 1, Aglaya G. Iyevleva 1 and Evgeny N. Imyanitov 1,2,*
1 Department of Tumor Growth Biology, N.N. Petrov Institute of Oncology, 197758 St. Petersburg, Russia
2 Department of Medical Genetics, St.-Petersburg Pediatric Medical University, 194100 St. Petersburg, Russia
Int. J. Mol. Sci. 2023, 24(5), 4868; https://doi.org/10.3390/ijms24054868 - 2 Mar 2023
Cited by 20 | Viewed by 4273
Abstract
This study aimed to analyze clinical and regional factors influencing the distribution of actionable genetic alterations in a large consecutive series of colorectal carcinomas (CRCs). KRAS, NRAS and BRAF mutations, HER2 amplification and overexpression, and microsatellite instability (MSI) were tested in 8355 [...] Read more.
This study aimed to analyze clinical and regional factors influencing the distribution of actionable genetic alterations in a large consecutive series of colorectal carcinomas (CRCs). KRAS, NRAS and BRAF mutations, HER2 amplification and overexpression, and microsatellite instability (MSI) were tested in 8355 CRC samples. KRAS mutations were detected in 4137/8355 (49.5%) CRCs, with 3913 belonging to 10 common substitutions affecting codons 12/13/61/146, 174 being represented by 21 rare hot-spot variants, and 35 located outside the “hot” codons. KRAS Q61K substitution, which leads to the aberrant splicing of the gene, was accompanied by the second function-rescuing mutation in all 19 tumors analyzed. NRAS mutations were detected in 389/8355 (4.7%) CRCs (379 hot-spot and 10 non-hot-spot substitutions). BRAF mutations were identified in 556/8355 (6.7%) CRCs (codon 600: 510; codons 594–596: 38; codons 597–602: 8). The frequency of HER2 activation and MSI was 99/8008 (1.2%) and 432/8355 (5.2%), respectively. Some of the above events demonstrated differences in distribution according to patients’ age and gender. In contrast to other genetic alterations, BRAF mutation frequencies were subject to geographic variation, with a relatively low incidence in areas with an apparently warmer climate (83/1726 (4.8%) in Southern Russia and North Caucasus vs. 473/6629 (7.1%) in other regions of Russia, p = 0.0007). The simultaneous presence of two drug targets, BRAF mutation and MSI, was observed in 117/8355 cases (1.4%). Combined alterations of two driver genes were detected in 28/8355 (0.3%) tumors (KRAS/NRAS: 8; KRAS/BRAF: 4; KRAS/HER2: 12; NRAS/HER2: 4). This study demonstrates that a substantial portion of RAS alterations is represented by atypical mutations, KRAS Q61K substitution is always accompanied by the second gene-rescuing mutation, BRAF mutation frequency is a subject to geographical variations, and a small fraction of CRCs has simultaneous alterations in more than one driver gene. Full article
(This article belongs to the Special Issue Molecular Mechanisms and Therapies of Colorectal Cancer 2.0)
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16 pages, 6226 KiB  
Article
Characterization of a PIP Binding Site in the N-Terminal Domain of V-ATPase a4 and Its Role in Plasma Membrane Association
by Anh Chu 1, Yeqi Yao 1, Golam T. Saffi 2, Ji Hyun Chung 3, Roberto J. Botelho 4, Miroslawa Glibowicka 5, Charles M. Deber 5,6 and Morris F. Manolson 1,6,*
1 Faculty of Dentistry, University of Toronto, Toronto, ON M5G 1G6, Canada
2 Department of Pharmacology and Toxicology, University of Toronto, Toronto, ON M5S 1A8, Canada
3 Faculty of Arts and Science, Queen University, Kingston, ON K7L 3N9, Canada
4 Department of Chemistry and Biology, Toronto Metropolitan University, Toronto, ON M5G 2A7, Canada
5 Division of Molecular Medicine, Research Institute, Hospital for Sick Children, Toronto, ON M5G 1X8, Canada
6 Department of Biochemistry, Faculty of Medicine, University of Toronto, Toronto, ON M1C 1A4, Canada
Int. J. Mol. Sci. 2023, 24(5), 4867; https://doi.org/10.3390/ijms24054867 - 2 Mar 2023
Cited by 2 | Viewed by 2838
Abstract
Vacuolar ATPases (V-ATPases) are multi-subunit ATP-dependent proton pumps necessary for cellular functions, including pH regulation and membrane fusion. The evidence suggests that the V-ATPase a-subunit’s interaction with the membrane signaling lipid phosphatidylinositol (PIPs) regulates the recruitment of V-ATPase complexes to specific membranes. We [...] Read more.
Vacuolar ATPases (V-ATPases) are multi-subunit ATP-dependent proton pumps necessary for cellular functions, including pH regulation and membrane fusion. The evidence suggests that the V-ATPase a-subunit’s interaction with the membrane signaling lipid phosphatidylinositol (PIPs) regulates the recruitment of V-ATPase complexes to specific membranes. We generated a homology model of the N-terminal domain of the human a4 isoform (a4NT) using Phyre2.0 and propose a lipid binding domain within the distal lobe of the a4NT. We identified a basic motif, K234IKK237, critical for interaction with phosphoinositides (PIP), and found similar basic residue motifs in all four mammalian and both yeast a-isoforms. We tested PIP binding of wildtype and mutant a4NT in vitro. In protein lipid overlay assays, the double mutation K234A/K237A and the autosomal recessive distal renal tubular-causing mutation K237del reduced both PIP binding and association with liposomes enriched with PI(4,5)P2, a PIP enriched within plasma membranes. Circular dichroism spectra of the mutant protein were comparable to wildtype, indicating that mutations affected lipid binding, not protein structure. When expressed in HEK293, wildtype a4NT localized to the plasma membrane in fluorescence microscopy and co-purified with the microsomal membrane fraction in cellular fractionation experiments. a4NT mutants showed reduced membrane association and decreased plasma membrane localization. Depletion of PI(4,5)P2 by ionomycin caused reduced membrane association of the WT a4NT protein. Our data suggest that information contained within the soluble a4NT is sufficient for membrane association and that PI(4,5)P2 binding capacity is involved in a4 V-ATPase plasma membrane retention. Full article
(This article belongs to the Special Issue Biochemistry, Molecular Biology and Druggability of Proteins)
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12 pages, 996 KiB  
Article
Diagnostic Performance of Immunohistochemistry Compared to Molecular Techniques for Microsatellite Instability and p53 Mutation Detection in Endometrial Cancer
by Sylvie Streel 1,*,†, Alixe Salmon 1,†, Adriane Dheur 2, Vincent Bours 3, Natacha Leroi 3, Lionel Habran 4, Katty Delbecque 4, Frédéric Goffin 2, Clémence Pleyers 5, Athanasios Kakkos 2, Elodie Gonne 1, Laurence Seidel 6, Frédéric Kridelka 2,‡ and Christine Gennigens 1,*,‡
1 Department of Medical Oncology, CHU Liège, 4000 Liège, Belgium
2 Department of Gynecology and Obstetrics, CHU Liège, 4000 Liège, Belgium
3 Department of Human Genetics, CHU Liège, 4000 Liège, Belgium
4 Department of Pathology, CHU Liège, 4000 Liège, Belgium
5 Department of Radiotherapy Oncology, CHU Liège, 4000 Liège, Belgium
6 Department of Biostatistics, CHU Liège, 4000 Liège, Belgium
These authors contributed equally to this work.
These authors contributed equally to this work.
Int. J. Mol. Sci. 2023, 24(5), 4866; https://doi.org/10.3390/ijms24054866 - 2 Mar 2023
Cited by 19 | Viewed by 3566
Abstract
Molecular algorithms may estimate the risk of recurrence and death for patients with endometrial cancer (EC) and may impact treatment decisions. To detect microsatellite instabilities (MSI) and p53 mutations, immunohistochemistry (IHC) and molecular techniques are used. To select the most appropriate method, and [...] Read more.
Molecular algorithms may estimate the risk of recurrence and death for patients with endometrial cancer (EC) and may impact treatment decisions. To detect microsatellite instabilities (MSI) and p53 mutations, immunohistochemistry (IHC) and molecular techniques are used. To select the most appropriate method, and to have an accurate interpretation of their results, knowledge of the performance characteristics of these respective methods is essential. The objective of this study was to assess the diagnostic performance of IHC versus molecular techniques (gold standard). One hundred and thirty-two unselected EC patients were enrolled in this study. Agreement between the two diagnostic methods was assessed using Cohen’s kappa coefficient. Sensitivity, specificity, positive (PPV) and negative predictive values (NPV) of the IHC were calculated. For MSI status, the sensitivity, specificity, PPV and NPV were 89.3%, 87.3%, 78.1% and 94.1%, respectively. Cohen’s kappa coefficient was 0.74. For p53 status, the sensitivity, specificity, PPV, and NPV were 92.3%, 77.1%, 60.0% and 96.4%, respectively. Cohen’s kappa coefficient was 0.59. For MSI status, IHC presented a substantial agreement with the polymerase chain reaction (PCR) approach. For the p53 status, the moderate agreement observed between IHC and next generation sequencing (NGS) methods implies that they cannot be used interchangeably. Full article
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11 pages, 579 KiB  
Review
Th17/Treg Imbalance: Implications in Lung Inflammatory Diseases
by Rony Thomas, Sai Qiao and Xi Yang *
Department of Immunology, Faculty of Medicine, University of Manitoba, Winnipeg, MB R3E 0T5, Canada
Int. J. Mol. Sci. 2023, 24(5), 4865; https://doi.org/10.3390/ijms24054865 - 2 Mar 2023
Cited by 68 | Viewed by 7649
Abstract
Regulatory T cells (Tregs) and T helper 17 cells (Th17) are two CD4+ T cell subsets with antagonist effects. Th17 cells promote inflammation, whereas Tregs are crucial in maintaining immune homeostasis. Recent studies suggest that Th17 cells and Treg cells are the [...] Read more.
Regulatory T cells (Tregs) and T helper 17 cells (Th17) are two CD4+ T cell subsets with antagonist effects. Th17 cells promote inflammation, whereas Tregs are crucial in maintaining immune homeostasis. Recent studies suggest that Th17 cells and Treg cells are the foremost players in several inflammatory diseases. In this review, we explore the present knowledge on the role of Th17 cells and Treg cells, focusing on lung inflammatory diseases, such as chronic obstructive pulmonary disease (COPD), acute respiratory distress syndrome (ARDS), sarcoidosis, asthma, and pulmonary infectious diseases. Full article
(This article belongs to the Special Issue Molecular Research in Inflammation and Lung Infections)
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22 pages, 2232 KiB  
Review
COVID-19 and Cancer Diseases—The Potential of Coriolus versicolor Mushroom to Combat Global Health Challenges
by Tomasz Jędrzejewski *, Małgorzata Pawlikowska, Justyna Sobocińska and Sylwia Wrotek *
Department of Immunology, Faculty of Biological and Veterinary Sciences, Nicolaus Copernicus University, 1 Lwowska Str., 87-100 Torun, Poland
Int. J. Mol. Sci. 2023, 24(5), 4864; https://doi.org/10.3390/ijms24054864 - 2 Mar 2023
Cited by 19 | Viewed by 12418
Abstract
Coriolus versicolor (CV) is a common species from the Polyporaceae family that has been used in traditional Chinese herbal medicine for over 2000 years. Among well-described and most active compounds identified in CV are polysaccharopeptides, such as polysaccharide peptide (PSP) and Polysaccharide-K (PSK, [...] Read more.
Coriolus versicolor (CV) is a common species from the Polyporaceae family that has been used in traditional Chinese herbal medicine for over 2000 years. Among well-described and most active compounds identified in CV are polysaccharopeptides, such as polysaccharide peptide (PSP) and Polysaccharide-K (PSK, krestin), which, in some countries, are already used as an adjuvant agent in cancer therapy. In this paper, research advances in the field of anti-cancer and anti-viral action of CV are analyzed. The results of data obtained in in vitro and in vivo studies using animal models as well as in clinical research trials have been discussed. The present update provides a brief overview regarding the immunomodulatory effects of CV. A particular focus has been given to the mechanisms of direct effects of CV on cancer cells and angiogenesis. A potential use of CV compounds in anti-viral treatment, including therapy against COVID-19 disease, has also been analyzed based on the most recent literature. Additionally, the significance of fever in viral infection and cancer has been debated, providing evidence that CV affects this phenomenon. Full article
(This article belongs to the Special Issue The Role of Natural Products in Immunopharmacology)
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23 pages, 3960 KiB  
Article
A Diet Containing Rutin Ameliorates Brain Intracellular Redox Homeostasis in a Mouse Model of Alzheimer’s Disease
by Paloma Bermejo-Bescós, Karim L. Jiménez-Aliaga, Juana Benedí and Sagrario Martín-Aragón *
Department of Pharmacology, Pharmacognosy and Botany, Faculty of Pharmacy, Complutense University of Madrid, Plaza Ramón y Cajal s/n, 28040 Madrid, Spain
Int. J. Mol. Sci. 2023, 24(5), 4863; https://doi.org/10.3390/ijms24054863 - 2 Mar 2023
Cited by 19 | Viewed by 3994
Abstract
Quercetin has been studied extensively for its anti-Alzheimer’s disease (AD) and anti-aging effects. Our previous studies have found that quercetin and in its glycoside form, rutin, can modulate the proteasome function in neuroblastoma cells. We aimed to explore the effects of quercetin and [...] Read more.
Quercetin has been studied extensively for its anti-Alzheimer’s disease (AD) and anti-aging effects. Our previous studies have found that quercetin and in its glycoside form, rutin, can modulate the proteasome function in neuroblastoma cells. We aimed to explore the effects of quercetin and rutin on intracellular redox homeostasis of the brain (reduced glutathione/oxidized glutathione, GSH/GSSG), its correlation with β-site APP cleaving enzyme 1 (BACE1) activity, and amyloid precursor protein (APP) expression in transgenic TgAPP mice (bearing human Swedish mutation APP transgene, APPswe). On the basis that BACE1 protein and APP processing are regulated by the ubiquitin–proteasome pathway and that supplementation with GSH protects neurons from proteasome inhibition, we investigated whether a diet containing quercetin or rutin (30 mg/kg/day, 4 weeks) diminishes several early signs of AD. Genotyping analyses of animals were carried out by PCR. In order to determine intracellular redox homeostasis, spectrofluorometric methods were adopted to quantify GSH and GSSG levels using o-phthalaldehyde and the GSH/GSSG ratio was ascertained. Levels of TBARS were determined as a marker of lipid peroxidation. Enzyme activities of SOD, CAT, GR, and GPx were determined in the cortex and hippocampus. ΒACE1 activity was measured by a secretase-specific substrate conjugated to two reporter molecules (EDANS and DABCYL). Gene expression of the main antioxidant enzymes: APP, BACE1, a Disintegrin and metalloproteinase domain-containing protein 10 (ADAM10), caspase-3, caspase-6, and inflammatory cytokines were determined by RT-PCR. First, overexpression of APPswe in TgAPP mice decreased GSH/GSSG ratio, increased malonaldehyde (MDA) levels, and, overall, decreased the main antioxidant enzyme activities in comparison to wild-type (WT) mice. Treatment of TgAPP mice with quercetin or rutin increased GSH/GSSG, diminished MDA levels, and favored the enzyme antioxidant capacity, particularly with rutin. Secondly, both APP expression and BACE1 activity were diminished with quercetin or rutin in TgAPP mice. Regarding ADAM10, it tended to increase in TgAPP mice with rutin treatment. As for caspase-3 expression, TgAPP displayed an increase which was the opposite with rutin. Finally, the increase in expression of the inflammatory markers IL-1β and IFN-γ in TgAPP mice was lowered by both quercetin and rutin. Collectively, these findings suggest that, of the two flavonoids, rutin may be included in a day-to-day diet as a form of adjuvant therapy in AD. Full article
(This article belongs to the Special Issue The Influence of Natural Products in Neurodegenerative Disorders)
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14 pages, 1771 KiB  
Communication
Tryptophan Hydroxylase-2-Mediated Serotonin Biosynthesis Suppresses Cell Reprogramming into Pluripotent State
by Sergey A. Sinenko 1,*, Andrey A. Kuzmin 1, Elena V. Skvortsova 1, Sergey V. Ponomartsev 1, Evgeniya V. Efimova 2, Michael Bader 3, Natalia Alenina 3 and Alexey N. Tomilin 1,2,*
1 Institute of Cytology, Russian Academy of Sciences, Tikhoretsky Ave. 4, 194064 St. Petersburg, Russia
2 Institute of Translational Biomedicine, St-Petersburg State University, 7–9 Universitetskaya Emb, 199034 St. Petersburg, Russia
3 Max-Delbruck Center for Molecular Medicine, 13125 Berlin-Buch, Germany
Int. J. Mol. Sci. 2023, 24(5), 4862; https://doi.org/10.3390/ijms24054862 - 2 Mar 2023
Cited by 9 | Viewed by 4534
Abstract
The monoamine neurotransmitter serotonin (5-hydroxytryptamine, 5-HT) has important functions both in the neural system and during embryonic development in mammals. In this study, we set out to investigate whether and how endogenous serotonin affects reprogramming to pluripotency. As serotonin is synthesized from tryptophan [...] Read more.
The monoamine neurotransmitter serotonin (5-hydroxytryptamine, 5-HT) has important functions both in the neural system and during embryonic development in mammals. In this study, we set out to investigate whether and how endogenous serotonin affects reprogramming to pluripotency. As serotonin is synthesized from tryptophan by the rate limiting enzymes tryptophan hydroxylase-1 and -2 (TPH1 and TPH2), we have assessed the reprogramming of TPH1- and/or TPH2-deficient mouse embryonic fibroblasts (MEFs) to induced pluripotent stem cells (iPSCs). The reprogramming of the double mutant MEFs showed a dramatic increase in the efficiency of iPSC generation. In contrast, ectopic expression of TPH2 alone or in conjunction with TPH1 reverted the rate of reprogramming of the double mutant MEFs to the wild-type level and besides, TPH2 overexpression significantly suppressed reprogramming of wild-type MEFs. Our data thus suggest a negative role of serotonin biosynthesis in the reprogramming of somatic cells to a pluripotent state. Full article
(This article belongs to the Special Issue Tryptophan in Nutrition and Health 2.0)
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26 pages, 1142 KiB  
Review
Hepatic Energy Metabolism under the Local Control of the Thyroid Hormone System
by Joshua Seifert 1,†, Yingfu Chen 2,†, Wenzel Schöning 3, Knut Mai 2,4, Frank Tacke 5, Joachim Spranger 2,4,6, Josef Köhrle 1 and Eva Katrin Wirth 2,6,*
1 Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Institut für Experimentelle Endokrinologie, 10115 Berlin, Germany
2 Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Department of Endocrinology and Metabolism, 10115 Berlin, Germany
3 Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Department of Surgery, 13353 Berlin, Germany
4 NutriAct-Competence Cluster Nutrition Research Berlin-Potsdam, 14558 Nuthetal, Germany
5 Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Department of Hepatology & Gastroenterology, Campus Virchow-Klinikum (CVK) and Campus Charité Mitte (CCM), 13353 Berlin, Germany
6 DZHK (German Centre for Cardiovascular Research), Partner Site Berlin, 10115 Berlin, Germany
These authors contributed equally to this work.
Int. J. Mol. Sci. 2023, 24(5), 4861; https://doi.org/10.3390/ijms24054861 - 2 Mar 2023
Cited by 18 | Viewed by 5657
Abstract
The energy homeostasis of the organism is orchestrated by a complex interplay of energy substrate shuttling, breakdown, storage, and distribution. Many of these processes are interconnected via the liver. Thyroid hormones (TH) are well known to provide signals for the regulation of energy [...] Read more.
The energy homeostasis of the organism is orchestrated by a complex interplay of energy substrate shuttling, breakdown, storage, and distribution. Many of these processes are interconnected via the liver. Thyroid hormones (TH) are well known to provide signals for the regulation of energy homeostasis through direct gene regulation via their nuclear receptors acting as transcription factors. In this comprehensive review, we summarize the effects of nutritional intervention like fasting and diets on the TH system. In parallel, we detail direct effects of TH in liver metabolic pathways with regards to glucose, lipid, and cholesterol metabolism. This overview on hepatic effects of TH provides the basis for understanding the complex regulatory network and its translational potential with regards to currently discussed treatment options of non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) involving TH mimetics. Full article
(This article belongs to the Special Issue Local Control of Thyroid Hormone Action)
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14 pages, 959 KiB  
Review
The Role of NLRP3, a Star of Excellence in Myeloproliferative Neoplasms
by Elisa Parciante 1, Cosimo Cumbo 1, Luisa Anelli 1, Antonella Zagaria 1, Immacolata Redavid 1, Angela Minervini 1, Maria Rosa Conserva 1, Giuseppina Tota 1, Nicoletta Coccaro 1, Francesco Tarantini 1, Crescenzio Francesco Minervini 1, Maria Giovanna Macchia 1, Giorgina Specchia 2, Pellegrino Musto 1 and Francesco Albano 1,*
1 Hematology Section, Department of Precision and Regenerative Medicine and Ionian Area (DiMePRe-J), University of Bari ‘Aldo Moro’, 70124 Bari, Italy
2 School of Medicine, University of Bari ‘Aldo Moro’, 70124 Bari, Italy
Int. J. Mol. Sci. 2023, 24(5), 4860; https://doi.org/10.3390/ijms24054860 - 2 Mar 2023
Cited by 3 | Viewed by 2648
Abstract
Nucleotide-binding domain (NOD)-like receptor protein 3 (NLRP3) is the most widely investigated inflammasome member whose overactivation can be a driver of several carcinomas. It is activated in response to different signals and plays an important role in metabolic disorders and inflammatory and autoimmune [...] Read more.
Nucleotide-binding domain (NOD)-like receptor protein 3 (NLRP3) is the most widely investigated inflammasome member whose overactivation can be a driver of several carcinomas. It is activated in response to different signals and plays an important role in metabolic disorders and inflammatory and autoimmune diseases. NLRP3 belongs to the pattern recognition receptors (PRRs) family, expressed in numerous immune cells, and it plays its primary function in myeloid cells. NLRP3 has a crucial role in myeloproliferative neoplasms (MPNs), considered to be the diseases best studied in the inflammasome context. The investigation of the NLRP3 inflammasome complex is a new horizon to explore, and inhibiting IL-1β or NLRP3 could be a helpful cancer-related therapeutic strategy to improve the existing protocols. Full article
(This article belongs to the Special Issue Latest Review Papers in Molecular Oncology 2023)
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16 pages, 4208 KiB  
Article
Amorphous System of Hesperetin and Piperine—Improvement of Apparent Solubility, Permeability, and Biological Activities
by Kamil Wdowiak 1, Andrzej Miklaszewski 2, Robert Pietrzak 3 and Judyta Cielecka-Piontek 1,*
1 Department of Pharmacognosy, Faculty of Pharmacy, Poznan University of Medical Sciences, Rokietnicka 3, 60-806 Poznan, Poland
2 Institute of Materials Science and Engineering, Poznan University of Technology, Jana Pawla II 24, 61-138 Poznan, Poland
3 Faculty of Chemistry, Adam Mickiewicz University in Poznań, Uniwersytetu Poznańskiego 8, 61-614 Poznan, Poland
Int. J. Mol. Sci. 2023, 24(5), 4859; https://doi.org/10.3390/ijms24054859 - 2 Mar 2023
Cited by 9 | Viewed by 3023
Abstract
The low bioaccessibility of hesperetin and piperine hampers their application as therapeutic agents. Piperine has the ability to improve the bioavailability of many compounds when co-administered. The aim of this paper was to prepare and characterize the amorphous dispersions of hesperetin and piperine, [...] Read more.
The low bioaccessibility of hesperetin and piperine hampers their application as therapeutic agents. Piperine has the ability to improve the bioavailability of many compounds when co-administered. The aim of this paper was to prepare and characterize the amorphous dispersions of hesperetin and piperine, which could help to improve solubility and boost the bioavailability of both plant-origin active compounds. The amorphous systems were successfully obtained by means of ball milling, as confirmed by XRPD and DSC studies. What’s more, the FT-IR-ATR study was used to investigate the presence of intermolecular interactions between the systems’ components. Amorphization enhanced the dissolution rate as a supersaturation state was reached, as well as improving the apparent solubility of both compounds by 245-fold and 183-fold, respectively, for hesperetin and piperine. In the in vitro permeability studies simulating gastrointestinal tract and blood-brain barrier permeabilities, these increased by 775-fold and 257-fold for hesperetin, whereas they were 68-fold and 66-fold for piperine in the GIT and BBB PAMPA models, respectively. Enhanced solubility had an advantageous impact on antioxidant as well as anti-butyrylcholinesterase activities—the best system inhibited 90.62 ± 0.58% of DPPH radicals and 87.57 ± 1.02% butyrylcholinesterase activity. To sum up, amorphization considerably improved the dissolution rate, apparent solubility, permeability, and biological activities of hesperetin and piperine. Full article
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23 pages, 7488 KiB  
Article
Impact of Double-Stranded RNA Internalization on Hematopoietic Progenitors and Krebs-2 Cells and Mechanism
by Genrikh S. Ritter 1,†, Anastasia S. Proskurina 1,†, Maria I. Meschaninova 2, Ekaterina A. Potter 1, Daria D. Petrova 1, Vera S. Ruzanova 1, Evgeniya V. Dolgova 1, Svetlana S. Kirikovich 1, Evgeniy V. Levites 1, Yaroslav R. Efremov 1,3, Valeriy P. Nikolin 1, Nelly A. Popova 1,3, Aliya G. Venyaminova 2, Oleg S. Taranov 4, Alexandr A. Ostanin 5, Elena R. Chernykh 5, Nikolay A. Kolchanov 1 and Sergey S. Bogachev 1,*
1 Institute of Cytology and Genetics of the Siberian Branch of the Russian Academy of Sciences, 630090 Novosibirsk, Russia
2 Institute of Chemical Biology and Fundamental Medicine of the Siberian Branch of the Russian Academy of Sciences, 630090 Novosibirsk, Russia
3 Department of Natural Sciences, Novosibirsk National Research State University, 630090 Novosibirsk, Russia
4 State Research Center of Virology and Biotechnology “Vector”, Novosibirsk Region, 630559 Koltsovo, Russia
5 Research Institute of Fundamental and Clinical Immunology, 630099 Novosibirsk, Russia
These authors contributed equally to this work.
Int. J. Mol. Sci. 2023, 24(5), 4858; https://doi.org/10.3390/ijms24054858 - 2 Mar 2023
Cited by 1 | Viewed by 2286
Abstract
It is well-established that double-stranded RNA (dsRNA) exhibits noticeable radioprotective and radiotherapeutic effects. The experiments conducted in this study directly demonstrated that dsRNA was delivered into the cell in its native form and that it induced hematopoietic progenitor proliferation. The 68 bp synthetic [...] Read more.
It is well-established that double-stranded RNA (dsRNA) exhibits noticeable radioprotective and radiotherapeutic effects. The experiments conducted in this study directly demonstrated that dsRNA was delivered into the cell in its native form and that it induced hematopoietic progenitor proliferation. The 68 bp synthetic dsRNA labeled with 6-carboxyfluorescein (FAM) was internalized into mouse hematopoietic progenitors, c-Kit+ (a marker of long-term hematopoietic stem cells) cells and CD34+ (a marker of short-term hematopoietic stem cells and multipotent progenitors) cells. Treating bone marrow cells with dsRNA stimulated the growth of colonies, mainly cells of the granulocyte–macrophage lineage. A total of 0.8% of Krebs-2 cells internalized FAM-dsRNA and were simultaneously CD34+ cells. dsRNA in its native state was delivered into the cell, where it was present without any signs of processing. dsRNA binding to a cell was independent of cell charge. dsRNA internalization was related to the receptor-mediated process that requires energy from ATP. Synthetic dsRNA did not degrade in the bloodstream for at least 2 h. Hematopoietic precursors that had captured dsRNA reinfused into the bloodstream and populated the bone marrow and spleen. This study, for the first time, directly proved that synthetic dsRNA is internalized into a eukaryotic cell via a natural mechanism. Full article
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17 pages, 608 KiB  
Review
Developmental Toxicity Studies: The Path towards Humanized 3D Stem Cell-Based Models
by Mariana A. Branco 1,2,3, Tiago C. Nunes 2,3, Joaquim M. S. Cabral 2,3 and Maria Margarida Diogo 2,3,*
1 Collaborative Laboratory to Foster Translation and Drug Discovery, Accelbio, 3030-197 Cantanhede, Portugal
2 IBB—Institute for Bioengineering and Biosciences, Department of Bioengineering Instituto Superior Técnico, Universidade de Lisboa, 1049-001 Lisboa, Portugal
3 Associate Laboratory i4HB—Institute for Health and Bioeconomy, Instituto Superior Técnico, Universidade de Lisboa, 1049-001 Lisboa, Portugal
Int. J. Mol. Sci. 2023, 24(5), 4857; https://doi.org/10.3390/ijms24054857 - 2 Mar 2023
Cited by 5 | Viewed by 3496
Abstract
Today, it is recognized that medicines will eventually be needed during pregnancy to help prevent to, ameliorate or treat an illness, either due to gestation-related medical conditions or pre-existing diseases. Adding to that, the rate of drug prescription to pregnant women has increased [...] Read more.
Today, it is recognized that medicines will eventually be needed during pregnancy to help prevent to, ameliorate or treat an illness, either due to gestation-related medical conditions or pre-existing diseases. Adding to that, the rate of drug prescription to pregnant women has increased over the past few years, in accordance with the increasing trend to postpone childbirth to a later age. However, in spite of these trends, information regarding teratogenic risk in humans is often missing for most of the purchased drugs. So far, animal models have been the gold standard to obtain teratogenic data, but inter-species differences have limited the suitability of those models to predict human-specific outcomes, contributing to misidentified human teratogenicity. Therefore, the development of physiologically relevant in vitro humanized models can be the key to surpassing this limitation. In this context, this review describes the pathway towards the introduction of human pluripotent stem cell-derived models in developmental toxicity studies. Moreover, as an illustration of their relevance, a particular emphasis will be placed on those models that recapitulate two very important early developmental stages, namely gastrulation and cardiac specification. Full article
(This article belongs to the Special Issue Organoids: The New 3D-Frontier to Model Different Diseases In Vitro)
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13 pages, 3449 KiB  
Article
Photocatalytic Properties of ZnO:Al/MAPbI3/Fe2O3 Heterostructure: First-Principles Calculations
by Ahmed Al-Shami 1,2, Anass Sibari 3, Zouhir Mansouri 1, Majid El Kassaoui 1, Abdallah El Kenz 1, Abdelilah Benyoussef 4, Mohammed Loulidi 1, Mustapha Jouiad 5, Amine El Moutaouakil 6,* and Omar Mounkachi 1,7,*
1 Laboratory of Condensed Matter and Interdisciplinary Sciences, Physics Department, Faculty of Sciences, Mohammed V University in Rabat, Rabat 10100, Morocco
2 Department of Physics, Faculty of Science, Sana’a University, Sana’a 13060, Yemen
3 Supramolecular Nanomaterials Group, Mohammed VI Polytechnic University, Lot 660, Hay Moulay Rachid, Ben Guerir 43150, Morocco
4 Hassan II Academy of Science and Technology in Rabat, Rabat 10112, Morocco
5 Laboratory of Physics of Condensed Matter, University of Picardie Jules Verne, Scientific Pole, 33 rue Saint-Leu, CEDEX 1, 80039 Amiens, France
6 Department of Electrical and Communication Engineering, College of Engineering, UAE University, Al Ain P.O. Box 15551, United Arab Emirates
7 Modeling, Simulation and Data Analysis, Mohammed VI Polytechnic University, Lot 660, Hay Moulay Rachid, Ben Guerir 43150, Morocco
Int. J. Mol. Sci. 2023, 24(5), 4856; https://doi.org/10.3390/ijms24054856 - 2 Mar 2023
Cited by 10 | Viewed by 3106
Abstract
We report on theoretical investigations of a methylammonium lead halide perovskite system loaded with iron oxide and aluminum zinc oxide (ZnO:Al/MAPbI3/Fe2O3) as a potential photocatalyst. When excited with visible light, this [...] Read more.
We report on theoretical investigations of a methylammonium lead halide perovskite system loaded with iron oxide and aluminum zinc oxide (ZnO:Al/MAPbI3/Fe2O3) as a potential photocatalyst. When excited with visible light, this heterostructure is demonstrated to achieve a high hydrogen production yield via a z-scheme photocatalysis mechanism. The Fe2O3: MAPbI3 heterojunction plays the role of an electron donor, favoring the hydrogen evolution reaction (HER), and the ZnO:Al compound acts as a shield against ions, preventing the surface degradation of MAPbI3 during the reaction, hence improving the charge transfer in the electrolyte. Moreover, our findings indicate that the ZnO:Al/MAPbI3 heterostructure effectively enhances electrons/holes separation and reduces their recombination, which drastically improves the photocatalytic activity. Based on our calculations, our heterostructure yields a high hydrogen production rate, estimated to be 265.05 μmol/g and 362.99 μmol/g, respectively, for a neutral pH and an acidic pH of 5. These theoretical yield values are very promising and provide interesting inputs for the development of stable halide perovskites known for their superlative photocatalytic properties. Full article
(This article belongs to the Special Issue Advancements in Solar Cells and Materials for Photovoltaics)
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14 pages, 1523 KiB  
Review
Fecal Metagenomics and Metabolomics Identifying Microbial Signatures in Non-Alcoholic Fatty Liver Disease
by Satu Pekkala 1,2
1 Faculty of Sport and Health Sciences, University of Jyväskylä, 40014 Jyväskylä, Finland
2 Institute of Biomedicine, Medical Microbiology and Immunology, University of Turku, 20014 Turku, Finland
Int. J. Mol. Sci. 2023, 24(5), 4855; https://doi.org/10.3390/ijms24054855 - 2 Mar 2023
Cited by 10 | Viewed by 4685
Abstract
The frequency of non-alcoholic fatty liver disease (NAFLD) has intensified, creating diagnostic challenges and increasing the need for reliable non-invasive diagnostic tools. Due to the importance of the gut–liver axis in the progression of NAFLD, studies attempt to reveal microbial signatures in NAFLD, [...] Read more.
The frequency of non-alcoholic fatty liver disease (NAFLD) has intensified, creating diagnostic challenges and increasing the need for reliable non-invasive diagnostic tools. Due to the importance of the gut–liver axis in the progression of NAFLD, studies attempt to reveal microbial signatures in NAFLD, evaluate them as diagnostic biomarkers, and to predict disease progression. The gut microbiome affects human physiology by processing the ingested food into bioactive metabolites. These molecules can penetrate the portal vein and the liver to promote or prevent hepatic fat accumulation. Here, the findings of human fecal metagenomic and metabolomic studies relating to NAFLD are reviewed. The studies present mostly distinct, and even contradictory, findings regarding microbial metabolites and functional genes in NAFLD. The most abundantly reproducing microbial biomarkers include increased lipopolysaccharides and peptidoglycan biosynthesis, enhanced degradation of lysine, increased levels of branched chain amino acids, as well as altered lipid and carbohydrate metabolism. Among other causes, the discrepancies between the studies may be related to the obesity status of the patients and the severity of NAFLD. In none of the studies, except for one, was diet considered, although it is an important factor driving gut microbiota metabolism. Future studies should consider diet in these analyses. Full article
(This article belongs to the Special Issue Gut Microbiota in Gastroenterology and Hepatology)
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17 pages, 1176 KiB  
Review
Epigenetic Signatures in Arterial Hypertension: Focus on the Microvasculature
by Alessandro Mengozzi 1,2,3, Sarah Costantino 1,4, Alessia Mongelli 1, Shafeeq A. Mohammed 1, Era Gorica 1, Valentina Delfine 1, Stefano Masi 3,5, Agostino Virdis 3, Frank Ruschitzka 1,4 and Francesco Paneni 1,4,6,*
1 Center for Translational and Experimental Cardiology (CTEC), Zurich University Hospital, University of Zurich, 8952 Schlieren, Switzerland
2 Health Science Interdisciplinary Center, Scuola Superiore Sant’Anna, 56127 Pisa, Italy
3 Department of Clinical and Experimental Medicine, University of Pisa, 56126 Pisa, Italy
4 Department of Cardiology, University Heart Center, University Hospital Zurich, University of Zurich, 8091 Zurich, Switzerland
5 Institute of Cardiovascular Science, University College London, London WC1E 6BT, UK
6 Department of Research and Education, University Hospital Zurich, 8091 Zurich, Switzerland
Int. J. Mol. Sci. 2023, 24(5), 4854; https://doi.org/10.3390/ijms24054854 - 2 Mar 2023
Cited by 5 | Viewed by 3718
Abstract
Systemic arterial hypertension (AH) is a multifaceted disease characterized by accelerated vascular aging and high cardiometabolic morbidity and mortality. Despite extensive work in the field, the pathogenesis of AH is still incompletely understood, and its treatment remains challenging. Recent evidence has shown a [...] Read more.
Systemic arterial hypertension (AH) is a multifaceted disease characterized by accelerated vascular aging and high cardiometabolic morbidity and mortality. Despite extensive work in the field, the pathogenesis of AH is still incompletely understood, and its treatment remains challenging. Recent evidence has shown a deep involvement of epigenetic signals in the regulation of transcriptional programs underpinning maladaptive vascular remodeling, sympathetic activation and cardiometabolic alterations, all factors predisposing to AH. After occurring, these epigenetic changes have a long-lasting effect on gene dysregulation and do not seem to be reversible upon intensive treatment or the control of cardiovascular risk factors. Among the factors involved in arterial hypertension, microvascular dysfunction plays a central role. This review will focus on the emerging role of epigenetic changes in hypertensive-related microvascular disease, including the different cell types and tissues (endothelial cells, vascular smooth muscle cells and perivascular adipose tissue) as well as the involvement of mechanical/hemodynamic factors, namely, shear stress. Full article
(This article belongs to the Special Issue Revolving from Hypertension to Cardiovascular Disease)
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