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Int. J. Mol. Sci., Volume 24, Issue 12 (June-2 2023) – 632 articles

Cover Story (view full-size image): Diabetes is a global health issue causing morbidity and mortality. Diabetic retinopathy (DR) leads to preventable blindness in developed nations. The ocular surface of diabetic eyes is often overlooked, despite being prone to injury. Inflammatory changes in the corneas of diabetic patients indicate that inflammation plays a significant role in diabetic complications, much like in DR. The eye's immune privilege normally maintains immune balance, but chronic inflammation from diabetes disrupts immune regulation. This review summarizes the impact of diabetes on the ocular immune system, including immune cells and inflammatory mediators. View this paper
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22 pages, 2130 KiB  
Review
Molecular Mechanisms of Craniofacial and Dental Abnormalities in Osteopetrosis
by Yu Ma, Yali Xu, Yanli Zhang and Xiaohong Duan
Int. J. Mol. Sci. 2023, 24(12), 10412; https://doi.org/10.3390/ijms241210412 - 20 Jun 2023
Cited by 4 | Viewed by 1877
Abstract
Osteopetrosis is a group of genetic bone disorders characterized by increased bone density and defective bone resorption. Osteopetrosis presents a series of clinical manifestations, including craniofacial deformities and dental problems. However, few previous reports have focused on the features of craniofacial and dental [...] Read more.
Osteopetrosis is a group of genetic bone disorders characterized by increased bone density and defective bone resorption. Osteopetrosis presents a series of clinical manifestations, including craniofacial deformities and dental problems. However, few previous reports have focused on the features of craniofacial and dental problems in osteopetrosis. In this review, we go through the clinical features, types, and related pathogenic genes of osteopetrosis. Then we summarize and describe the characteristics of craniofacial and dental abnormalities in osteopetrosis that have been published in PubMed from 1965 to the present. We found that all 13 types of osteopetrosis have craniomaxillofacial and dental phenotypes. The main pathogenic genes, such as chloride channel 7 gene (CLCN7), T cell immune regulator 1 (TCIRG1), osteopetrosis-associated transmembrane protein 1 (OSTM1), pleckstrin homology domain-containing protein family member 1 (PLEKHM1), and carbonic anhydrase II (CA2), and their molecular mechanisms involved in craniofacial and dental phenotypes, are discussed. We conclude that the telltale craniofacial and dental abnormalities are important for dentists and other clinicians in the diagnosis of osteopetrosis and other genetic bone diseases. Full article
(This article belongs to the Special Issue Molecular Mechanisms of Craniofacial Birth Defects)
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15 pages, 5403 KiB  
Article
Identification and Functional Characterization of ZmSCYL2 Involved in Phytosterol Accumulation in Plants
by Chenchen Zhang, Wanlu Ma, Minyan Xu, Tao Li, Guomin Han, Longjiang Gu, Meng Chen, Mengting Zhang, Beijiu Cheng and Xin Zhang
Int. J. Mol. Sci. 2023, 24(12), 10411; https://doi.org/10.3390/ijms241210411 - 20 Jun 2023
Cited by 3 | Viewed by 1170
Abstract
Phytosterols are natural active substances widely found in plants and play an important role in hypolipidemia, antioxidants, antitumor, immunomodulation, plant growth, and development. In this study, phytosterols were extracted and identified from the seed embryos of 244 maize inbred lines. Based on this, [...] Read more.
Phytosterols are natural active substances widely found in plants and play an important role in hypolipidemia, antioxidants, antitumor, immunomodulation, plant growth, and development. In this study, phytosterols were extracted and identified from the seed embryos of 244 maize inbred lines. Based on this, a genome-wide association study (GWAS) was used to predict the possible candidate genes responsible for phytosterol content; 9 SNPs and 32 candidate genes were detected, and ZmSCYL2 was identified to be associated with phytosterol accumulation. We initially confirmed its functions in transgenic Arabidopsis and found that mutation of ZmSCYL2 resulted in slow plant growth and a significant reduction in sterol content, while overexpression of ZmSCYL2 accelerated plant growth and significantly increased sterol content. These results were further confirmed in transgenic tobacco and suggest that ZmSCYL2 was closely related to plant growth; overexpression of ZmSCYL2 not only facilitated plant growth and development but also promoted the accumulation of phytosterols. Full article
(This article belongs to the Section Molecular Plant Sciences)
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21 pages, 6113 KiB  
Article
Integrated Transcriptome and Metabolome Analysis Revealed the Causal Agent of Primary Bud Necrosis in ‘Summer Black’ Grape
by Shaogang Fan, Yanshuai Xu, Miao Bai, Feixiong Luo, Jun Yu and Guoshun Yang
Int. J. Mol. Sci. 2023, 24(12), 10410; https://doi.org/10.3390/ijms241210410 - 20 Jun 2023
Viewed by 1139
Abstract
Primary bud necrosis of grape buds is a physiological disorder that leads to decreased berry yield and has a catastrophic impact on the double cropping system in sub-tropical areas. The pathogenic mechanisms and potential solutions remain unknown. In this study, the progression and [...] Read more.
Primary bud necrosis of grape buds is a physiological disorder that leads to decreased berry yield and has a catastrophic impact on the double cropping system in sub-tropical areas. The pathogenic mechanisms and potential solutions remain unknown. In this study, the progression and irreversibility patterns of primary bud necrosis in ‘Summer Black’ were examined via staining and transmission electron microscopy observation. Primary bud necrosis was initiated at 60 days after bud break and was characterized by plasmolysis, mitochondrial swelling, and severe damage to other organelles. To reveal the underlying regulatory networks, winter buds were collected during primary bud necrosis progression for integrated transcriptome and metabolome analysis. The accumulation of reactive oxygen species and subsequent signaling cascades disrupted the regulation systems for cellular protein quality. ROS cascade reactions were related to mitochondrial stress that can lead to mitochondrial dysfunction, lipid peroxidation causing damage to membrane structure, and endoplasmic reticulum stress leading to misfolded protein aggregates. All these factors ultimately resulted in primary bud necrosis. Visible tissue browning was associated with the oxidation and decreased levels of flavonoids during primary bud necrosis, while the products of polyunsaturated fatty acids and stilbenes exhibited an increasing trend, leading to a shift in carbon flow from flavonoids to stilbene. Increased ethylene may be closely related to primary bud necrosis, while auxin accelerated cell growth and alleviated necrosis by co-chaperone VvP23-regulated redistribution of auxin in meristem cells. Altogether, this study provides important clues for further study on primary bud necrosis. Full article
(This article belongs to the Section Molecular Plant Sciences)
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16 pages, 1080 KiB  
Review
Microbiota and Glucidic Metabolism: A Link with Multiple Aspects and Perspectives
by Tiziana Ciarambino, Pietro Crispino, Gaetano Leto, Giovanni Minervini, Ombretta Para and Mauro Giordano
Int. J. Mol. Sci. 2023, 24(12), 10409; https://doi.org/10.3390/ijms241210409 - 20 Jun 2023
Cited by 1 | Viewed by 1155
Abstract
The global prevalence of overweight and obesity has dramatically increased in the last few decades, with a significant socioeconomic burden. In this narrative review, we include clinical studies aiming to provide the necessary knowledge on the role of the gut microbiota in the [...] Read more.
The global prevalence of overweight and obesity has dramatically increased in the last few decades, with a significant socioeconomic burden. In this narrative review, we include clinical studies aiming to provide the necessary knowledge on the role of the gut microbiota in the development of diabetic pathology and glucose-metabolism-related disorders. In particular, the role of a certain microbial composition of the fermentative type seems to emerge without a specific link to the development in certain subjects of obesity and the chronic inflammation of the adipose tissues, which underlies the pathological development of all the diseases related to glucose metabolism and metabolic syndrome. The gut microbiota plays an important role in glucose tolerance. Conclusion. New knowledge and new information is presented on the development of individualized therapies for patients affected by all the conditions related to reduced glucose tolerance and insulin resistance. Full article
(This article belongs to the Special Issue Study on Lipid Metabolism and Lipoprotein Application)
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18 pages, 4361 KiB  
Article
Identification of Somatic Mutations in Plasma Cell-Free DNA from Patients with Metastatic Oral Squamous Cell Carcinoma
by Li-Han Lin, Kuo-Wei Chang, Hui-Wen Cheng and Chung-Ji Liu
Int. J. Mol. Sci. 2023, 24(12), 10408; https://doi.org/10.3390/ijms241210408 - 20 Jun 2023
Viewed by 1688
Abstract
The accurate diagnosis and treatment of oral squamous cell carcinoma (OSCC) requires an understanding of its genomic alterations. Liquid biopsies, especially cell-free DNA (cfDNA) analysis, are a minimally invasive technique used for genomic profiling. We conducted comprehensive whole-exome sequencing (WES) of 50 paired [...] Read more.
The accurate diagnosis and treatment of oral squamous cell carcinoma (OSCC) requires an understanding of its genomic alterations. Liquid biopsies, especially cell-free DNA (cfDNA) analysis, are a minimally invasive technique used for genomic profiling. We conducted comprehensive whole-exome sequencing (WES) of 50 paired OSCC cell-free plasma with whole blood samples using multiple mutation calling pipelines and filtering criteria. Integrative Genomics Viewer (IGV) was used to validate somatic mutations. Mutation burden and mutant genes were correlated to clinico-pathological parameters. The plasma mutation burden of cfDNA was significantly associated with clinical staging and distant metastasis status. The genes TTN, PLEC, SYNE1, and USH2A were most frequently mutated in OSCC, and known driver genes, including KMT2D, LRP1B, TRRAP, and FLNA, were also significantly and frequently mutated. Additionally, the novel mutated genes CCDC168, HMCN2, STARD9, and CRAMP1 were significantly and frequently present in patients with OSCC. The mutated genes most frequently found in patients with metastatic OSCC were RORC, SLC49A3, and NUMBL. Further analysis revealed that branched-chain amino acid (BCAA) catabolism, extracellular matrix–receptor interaction, and the hypoxia-related pathway were associated with OSCC prognosis. Choline metabolism in cancer, O-glycan biosynthesis, and protein processing in the endoplasmic reticulum pathway were associated with distant metastatic status. About 20% of tumors carried at least one aberrant event in BCAA catabolism signaling that could possibly be targeted by an approved therapeutic agent. We identified molecular-level OSCC that were correlated with etiology and prognosis while defining the landscape of major altered events of the OSCC plasma genome. These findings will be useful in the design of clinical trials for targeted therapies and the stratification of patients with OSCC according to therapeutic efficacy. Full article
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18 pages, 1685 KiB  
Article
Mild Cognitive Impairment Is Associated with Enhanced Activation of Th17 Lymphocytes in Non-Alcoholic Fatty Liver Disease
by Alessandra Fiorillo, Juan-José Gallego, Franc Casanova-Ferrer, Carla Giménez-Garzó, Amparo Urios, Maria-Pilar Ballester, Lucia Durbán, Maria-Pilar Rios, Javier Megías, Teresa San Miguel, Elena Kosenko, Desamparados Escudero-García, Salvador Benlloch, Vicente Felipo and Carmina Montoliu
Int. J. Mol. Sci. 2023, 24(12), 10407; https://doi.org/10.3390/ijms241210407 - 20 Jun 2023
Cited by 1 | Viewed by 1251
Abstract
Patients with nonalcoholic fatty liver disease (NAFLD) may show mild cognitive impairment (MCI). The mechanisms involved remain unclear. The plasma concentrations of several cytokines and chemokines were measured in 71 NAFLD patients (20 with and 51 without MCI) and 61 controls. Characterization and [...] Read more.
Patients with nonalcoholic fatty liver disease (NAFLD) may show mild cognitive impairment (MCI). The mechanisms involved remain unclear. The plasma concentrations of several cytokines and chemokines were measured in 71 NAFLD patients (20 with and 51 without MCI) and 61 controls. Characterization and activation of leukocyte populations and CD4+ sub-populations were carried out and analyzed by flow cytometry. We analyzed the cytokines released from CD4+ cell cultures and the mRNA expression of transcription factors and receptors in peripheral blood mononuclear cells. The appearance of MCI in NAFLD patients was associated with increased activation of CD4+ T lymphocytes, mainly of the Th17 subtype, increased plasma levels of pro-inflammatory and anti-inflammatory cytokines such as IL-17A, IL-23, IL-21, IL-22, IL-6, INF-γ, and IL-13, and higher expression of the CCR2 receptor. Constitutive expression of IL-17 was found in cultures of CD4+ cells from MCI patients, reflecting Th17 activation. High IL-13 plasma levels were predictive of MCI and could reflect a compensatory anti-inflammatory response to the increased expression of pro-inflammatory cytokines. This study identified some specific alterations of the immune system associated with the appearance of neurological alterations in MCI patients with NAFLD that could be the basis to improve and restore cognitive functions and quality of life in these patients. Full article
(This article belongs to the Section Molecular Pathology, Diagnostics, and Therapeutics)
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21 pages, 8046 KiB  
Article
Novel Molecular Vehicle-Based Approach for Cardiac Cell Transplantation Leads to Rapid Electromechanical Graft–Host Coupling
by Aleria Aitova, Serafima Scherbina, Andrey Berezhnoy, Mikhail Slotvitsky, Valeriya Tsvelaya, Tatyana Sergeeva, Elena Turchaninova, Elizaveta Rybkina, Sergey Bakumenko, Ilya Sidorov, Mikhail A. Popov, Vladislav Dontsov, Evgeniy G. Agafonov, Anton E. Efimov, Igor Agapov, Dmitriy Zybin, Dmitriy Shumakov and Konstantin Agladze
Int. J. Mol. Sci. 2023, 24(12), 10406; https://doi.org/10.3390/ijms241210406 - 20 Jun 2023
Cited by 1 | Viewed by 2103
Abstract
Myocardial remodeling is an inevitable risk factor for cardiac arrhythmias and can potentially be corrected with cell therapy. Although the generation of cardiac cells ex vivo is possible, specific approaches to cell replacement therapy remain unclear. On the one hand, adhesive myocyte cells [...] Read more.
Myocardial remodeling is an inevitable risk factor for cardiac arrhythmias and can potentially be corrected with cell therapy. Although the generation of cardiac cells ex vivo is possible, specific approaches to cell replacement therapy remain unclear. On the one hand, adhesive myocyte cells must be viable and conjugated with the electromechanical syncytium of the recipient tissue, which is unattainable without an external scaffold substrate. On the other hand, the outer scaffold may hinder cell delivery, for example, making intramyocardial injection difficult. To resolve this contradiction, we developed molecular vehicles that combine a wrapped (rather than outer) polymer scaffold that is enveloped by the cell and provides excitability restoration (lost when cells were harvested) before engraftment. It also provides a coating with human fibronectin, which initiates the process of graft adhesion into the recipient tissue and can carry fluorescent markers for the external control of the non-invasive cell position. In this work, we used a type of scaffold that allowed us to use the advantages of a scaffold-free cell suspension for cell delivery. Fragmented nanofibers (0.85 µm ± 0.18 µm in diameter) with fluorescent labels were used, with solitary cells seeded on them. Cell implantation experiments were performed in vivo. The proposed molecular vehicles made it possible to establish rapid (30 min) electromechanical contact between excitable grafts and the recipient heart. Excitable grafts were visualized with optical mapping on a rat heart with Langendorff perfusion at a 0.72 ± 0.32 Hz heart rate. Thus, the pre-restored grafts’ excitability (with the help of a wrapped polymer scaffold) allowed rapid electromechanical coupling with the recipient tissue. This information could provide a basis for the reduction of engraftment arrhythmias in the first days after cell therapy. Full article
(This article belongs to the Special Issue Advanced Therapies and Functional Materials for Wound Healing)
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12 pages, 572 KiB  
Review
Arrhythmias after COVID-19 Vaccination: Have We Left All Stones Unturned?
by Nino Cocco, Gregor Leibundgut, Francesco Pelliccia, Valeria Cammalleri, Annunziata Nusca, Fabio Mangiacapra, Giulio Cocco, Valerio Fanale, Gian Paolo Ussia and Francesco Grigioni
Int. J. Mol. Sci. 2023, 24(12), 10405; https://doi.org/10.3390/ijms241210405 - 20 Jun 2023
Cited by 4 | Viewed by 13015
Abstract
SARS-CoV-2 vaccination offered the opportunity to emerge from the pandemic and, thereby, worldwide health, social, and economic disasters. However, in addition to efficacy, safety is an important issue for any vaccine. The mRNA-based vaccine platform is considered to be safe, but side effects [...] Read more.
SARS-CoV-2 vaccination offered the opportunity to emerge from the pandemic and, thereby, worldwide health, social, and economic disasters. However, in addition to efficacy, safety is an important issue for any vaccine. The mRNA-based vaccine platform is considered to be safe, but side effects are being reported more frequently as more and more people around the world become treated. Myopericarditis is the major, but not the only cardiovascular complication of this vaccine; hence it is important not to underestimate other side effects. We report a case series of patients affected by cardiac arrhythmias post-mRNA vaccine from our clinical practice and the literature. Reviewing the official vigilance database, we found that heart rhythm disorders after COVID vaccination are not uncommon and deserve more clinical and scientific attention. Since the COVID vaccine is the only vaccination related to this side effect, questions arose about whether these vaccines could affect heart conduction. Although the risk–benefit ratio is clearly in favor of vaccination, heart rhythm disorders are not a negligible issue, and there are red flags in the literature about the risk of post-vaccination malignant arrhythmias in some predisposed patients. In light of these findings, we reviewed the potential molecular pathways for the COVID vaccine to impact cardiac electrophysiology and cause heart rhythm disorders. Full article
(This article belongs to the Special Issue COVID-19 Pandemic: Therapeutic Strategies and Vaccines)
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17 pages, 2986 KiB  
Article
Genome-Wide Association Study of Lint Percentage in Gossypium hirsutum L. Races
by Yuanyuan Wang, Xinlei Guo, Xiaoyan Cai, Yanchao Xu, Runrun Sun, Muhammad Jawad Umer, Kunbo Wang, Tengfei Qin, Yuqing Hou, Yuhong Wang, Pan Zhang, Zihan Wang, Fang Liu, Qinglian Wang and Zhongli Zhou
Int. J. Mol. Sci. 2023, 24(12), 10404; https://doi.org/10.3390/ijms241210404 - 20 Jun 2023
Cited by 1 | Viewed by 1183
Abstract
Lint percentage is one of the most essential yield components and an important economic index for cotton planting. Improving lint percentage is an effective way to achieve high-yield in cotton breeding worldwide, especially upland cotton (Gossypium hirsutum L.). However, the genetic basis [...] Read more.
Lint percentage is one of the most essential yield components and an important economic index for cotton planting. Improving lint percentage is an effective way to achieve high-yield in cotton breeding worldwide, especially upland cotton (Gossypium hirsutum L.). However, the genetic basis controlling lint percentage has not yet been systematically understood. Here, we performed a genome-wide association mapping for lint percentage using a natural population consisting of 189 G. hirsutum accessions (188 accessions of G. hirsutum races and one cultivar TM-1). The results showed that 274 single-nucleotide polymorphisms (SNPs) significantly associated with lint percentage were detected, and they were distributed on 24 chromosomes. Forty-five SNPs were detected at least by two models or at least in two environments, and their 5 Mb up- and downstream regions included 584 makers related to lint percentage identified in previous studies. In total, 11 out of 45 SNPs were detected at least in two environments, and their 550 Kb up- and downstream region contained 335 genes. Through RNA sequencing, gene annotation, qRT-PCR, protein–protein interaction analysis, the cis-elements of the promotor region, and related miRNA prediction, Gh_D12G0934 and Gh_A08G0526 were selected as key candidate genes for fiber initiation and elongation, respectively. These excavated SNPs and candidate genes could supplement marker and gene information for deciphering the genetic basis of lint percentage and facilitate high-yield breeding programs of G. hirsutum ultimately. Full article
(This article belongs to the Special Issue Cotton Molecular Genomics and Genetics 2.0)
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21 pages, 6150 KiB  
Review
Genetic and Epigenetic Mechanisms of Longevity in Forest Trees
by Anastasia Y. Batalova and Konstantin V. Krutovsky
Int. J. Mol. Sci. 2023, 24(12), 10403; https://doi.org/10.3390/ijms241210403 - 20 Jun 2023
Cited by 4 | Viewed by 1894
Abstract
Trees are unique in terms of development, sustainability and longevity. Some species have a record lifespan in the living world, reaching several millennia. The aim of this review is to summarize the available data on the genetic and epigenetic mechanisms of longevity in [...] Read more.
Trees are unique in terms of development, sustainability and longevity. Some species have a record lifespan in the living world, reaching several millennia. The aim of this review is to summarize the available data on the genetic and epigenetic mechanisms of longevity in forest trees. In this review, we have focused on the genetic aspects of longevity of a few well-studied forest tree species, such as Quercus robur, Ginkgo biloba, Ficus benghalensis and F. religiosa, Populus, Welwitschia and Dracaena, as well as on interspecific genetic traits associated with plant longevity. A key trait associated with plant longevity is the enhanced immune defense, with the increase in gene families such as RLK, RLP and NLR in Quercus robur, the expansion of the CC-NBS-LRR disease resistance families in Ficus species and the steady expression of R-genes in Ginkgo biloba. A high copy number ratio of the PARP1 family genes involved in DNA repair and defense response was found in Pseudotsuga menziesii, Pinus sylvestris and Malus domestica. An increase in the number of copies of the epigenetic regulators BRU1/TSK/MGO3 (maintenance of meristems and genome integrity) and SDE3 (antiviral protection) was also found in long-lived trees. CHG methylation gradually declines in the DAL 1 gene in Pinus tabuliformis, a conservative age biomarker in conifers, as the age increases. It was shown in Larix kaempferi that grafting, cutting and pruning change the expression of age-related genes and rejuvenate plants. Thus, the main genetic and epigenetic mechanisms of longevity in forest trees were considered, among which there are both general and individual processes. Full article
(This article belongs to the Special Issue Comparative Genomics and Functional Genomics Analysis in Plants 2.0)
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21 pages, 2044 KiB  
Review
Regulatory Roles of Flavonoids in Caspase-11 Non-Canonical Inflammasome-Mediated Inflammatory Responses and Diseases
by Young-Su Yi
Int. J. Mol. Sci. 2023, 24(12), 10402; https://doi.org/10.3390/ijms241210402 - 20 Jun 2023
Cited by 5 | Viewed by 1304
Abstract
Inflammasomes are multiprotein complexes that activate inflammatory responses by inducing pyroptosis and secretion of pro-inflammatory cytokines. Along with many previous studies on inflammatory responses and diseases induced by canonical inflammasomes, an increasing number of studies have demonstrated that non-canonical inflammasomes, such as mouse [...] Read more.
Inflammasomes are multiprotein complexes that activate inflammatory responses by inducing pyroptosis and secretion of pro-inflammatory cytokines. Along with many previous studies on inflammatory responses and diseases induced by canonical inflammasomes, an increasing number of studies have demonstrated that non-canonical inflammasomes, such as mouse caspase-11 and human caspase-4 inflammasomes, are emerging key players in inflammatory responses and various diseases. Flavonoids are natural bioactive compounds found in plants, fruits, vegetables, and teas and have pharmacological properties in a wide range of human diseases. Many studies have successfully demonstrated that flavonoids play an anti-inflammatory role and ameliorate many inflammatory diseases by inhibiting canonical inflammasomes. Others have demonstrated the anti-inflammatory roles of flavonoids in inflammatory responses and various diseases, with a new mechanism by which flavonoids inhibit non-canonical inflammasomes. This review discusses recent studies that have investigated the anti-inflammatory roles and pharmacological properties of flavonoids in inflammatory responses and diseases induced by non-canonical inflammasomes and further provides insight into developing flavonoid-based therapeutics as potential nutraceuticals against human inflammatory diseases. Full article
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13 pages, 1049 KiB  
Review
Molecular Pathways of Altered Brain Development in Fetuses Exposed to Hypoxia
by Anna Orzeł, Katarzyna Unrug-Bielawska, Dagmara Filipecka-Tyczka, Krzysztof Berbeka, Natalia Zeber-Lubecka, Małgorzata Zielińska and Anna Kajdy
Int. J. Mol. Sci. 2023, 24(12), 10401; https://doi.org/10.3390/ijms241210401 - 20 Jun 2023
Cited by 1 | Viewed by 2422
Abstract
Perinatal hypoxia is a major cause of neurodevelopmental impairment and subsequent motor and cognitive dysfunctions; it is associated with fetal growth restriction and uteroplacental dysfunction during pregnancy. This review aims to present the current knowledge on brain development resulting from perinatal asphyxia, including [...] Read more.
Perinatal hypoxia is a major cause of neurodevelopmental impairment and subsequent motor and cognitive dysfunctions; it is associated with fetal growth restriction and uteroplacental dysfunction during pregnancy. This review aims to present the current knowledge on brain development resulting from perinatal asphyxia, including the causes, symptoms, and means of predicting the degree of brain damage. Furthermore, this review discusses the specificity of brain development in the growth-restricted fetus and how it is replicated and studied in animal models. Finally, this review aims at identifying the least understood and missing molecular pathways of abnormal brain development, especially with respect to potential treatment intervention. Full article
(This article belongs to the Section Molecular Neurobiology)
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18 pages, 4624 KiB  
Article
COX5A Alleviates Doxorubicin-Induced Cardiotoxicity by Suppressing Oxidative Stress, Mitochondrial Dysfunction and Cardiomyocyte Apoptosis
by Peipei Zhang, Hao Lu, Yuan Wu, Danbo Lu, Chenguang Li, Xiangdong Yang, Zhangwei Chen, Juying Qian and Junbo Ge
Int. J. Mol. Sci. 2023, 24(12), 10400; https://doi.org/10.3390/ijms241210400 - 20 Jun 2023
Cited by 2 | Viewed by 1670
Abstract
Doxorubicin (DOX) as a chemotherapeutic agent can cause mitochondrial dysfunction and heart failure. COX5A has been described as an important regulator of mitochondrial energy metabolism. We investigate the roles of COX5A in DOX-induced cardiomyopathy and explore the underlying mechanisms. C57BL/6J mice and H9c2 [...] Read more.
Doxorubicin (DOX) as a chemotherapeutic agent can cause mitochondrial dysfunction and heart failure. COX5A has been described as an important regulator of mitochondrial energy metabolism. We investigate the roles of COX5A in DOX-induced cardiomyopathy and explore the underlying mechanisms. C57BL/6J mice and H9c2 cardiomyoblasts were treated with DOX, and the COX5A expression was assessed. An adeno-associated virus serum type 9 (AAV9) and lenti-virus system were used to upregulate COX5A expression. Echocardiographic parameters, morphological and histological analyses, transmission electron microscope and immunofluorescence assays were used to assess cardiac and mitochondrial function. In a human study, we found that cardiac COX5A expression was dramatically decreased in patients with end-stage dilated cardiomyopathy (DCM) compared to the control group. COX5A was significantly downregulated following DOX stimulation in the heart of mice and H9c2 cells. Reduced cardiac function, decreased myocardium glucose uptake, mitochondrial morphology disturbance, reduced activity of mitochondrial cytochrome c oxidase (COX) and lowered ATP content were detected after DOX stimulation in mice, which could be significantly improved by overexpression of COX5A. Overexpression of COX5A effectively protected against DOX-induced oxidative stress, mitochondrial dysfunction and cardiomyocyte apoptosis in vivo and in vitro. Mechanistically, the phosphorylation of Akt (Thr308) and Akt (Ser473) were also decreased following DOX treatment, which could be reserved by the upregulation of COX5A. Furthermore, PI3K inhibitors abrogated the protection effects of COX5A against DOX-induced cardiotoxicity in H9c2 cells. Thus, we identified that PI3K/Akt signaling was responsible for the COX5A-mediated protective role in DOX-induced cardiomyopathy. These results demonstrated the protective effect of COX5A in mitochondrial dysfunction, oxidative stress, and cardiomyocyte apoptosis, providing a potential therapeutic target in DOX-induced cardiomyopathy. Full article
(This article belongs to the Section Molecular Pathology, Diagnostics, and Therapeutics)
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16 pages, 3882 KiB  
Article
Fluorinated Benzofuran and Dihydrobenzofuran as Anti-Inflammatory and Potential Anticancer Agents
by Abeer J. Ayoub, Ghewa A. El-Achkar, Sandra E. Ghayad, Layal Hariss, Razan H. Haidar, Leen M. Antar, Zahraa I. Mallah, Bassam Badran, René Grée, Ali Hachem, Eva Hamade and Aida Habib
Int. J. Mol. Sci. 2023, 24(12), 10399; https://doi.org/10.3390/ijms241210399 - 20 Jun 2023
Viewed by 1552
Abstract
Benzofuran and 2,3-dihydrobenzofuran scaffolds are heterocycles of high value in medicinal chemistry and drug synthesis. Targeting inflammation in cancer associated with chronic inflammation is a promising therapy. In the present study, we investigated the anti-inflammatory effects of fluorinated benzofuran and dihydrobenzofuran derivatives in [...] Read more.
Benzofuran and 2,3-dihydrobenzofuran scaffolds are heterocycles of high value in medicinal chemistry and drug synthesis. Targeting inflammation in cancer associated with chronic inflammation is a promising therapy. In the present study, we investigated the anti-inflammatory effects of fluorinated benzofuran and dihydrobenzofuran derivatives in macrophages and in the air pouch model of inflammation, as well as their anticancer effects in the human colorectal adenocarcinoma cell line HCT116. Six of the nine compounds suppressed lipopolysaccharide-stimulated inflammation by inhibiting the expression of cyclooxygenase-2 and nitric oxide synthase 2 and decreased the secretion of the tested inflammatory mediators. Their IC50 values ranged from 1.2 to 9.04 µM for interleukin-6; from 1.5 to 19.3 µM for Chemokine (C-C) Ligand 2; from 2.4 to 5.2 µM for nitric oxide; and from 1.1 to 20.5 µM for prostaglandin E2. Three novel synthesized benzofuran compounds significantly inhibited cyclooxygenase activity. Most of these compounds showed anti-inflammatory effects in the zymosan-induced air pouch model. Because inflammation may lead to tumorigenesis, we tested the effects of these compounds on the proliferation and apoptosis of HCT116. Two compounds with difluorine, bromine, and ester or carboxylic acid groups inhibited the proliferation by approximately 70%. Inhibition of the expression of the antiapoptotic protein Bcl-2 and concentration-dependent cleavage of PARP-1, as well as DNA fragmentation by approximately 80%, were described. Analysis of the structure–activity relationship suggested that the biological effects of benzofuran derivatives are enhanced in the presence of fluorine, bromine, hydroxyl, and/or carboxyl groups. In conclusion, the designed fluorinated benzofuran and dihydrobenzofuran derivatives are efficient anti-inflammatory agents, with a promising anticancer effect and a combinatory treatment in inflammation and tumorigenesis in cancer microenvironments. Full article
(This article belongs to the Special Issue Advances in Pharmacology of Prostaglandins)
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11 pages, 1126 KiB  
Brief Report
Doubtful Clinical Value of Subtyping Anti-U1-RNP Antibodies Regarding the RNP-70 kDa Antigen in Sera of Patients with Systemic Lupus Erythematosus
by Awais Ahmad, André Brylid, Charlotte Dahle, Muna Saleh, Örjan Dahlström, Helena Enocsson and Christopher Sjöwall
Int. J. Mol. Sci. 2023, 24(12), 10398; https://doi.org/10.3390/ijms241210398 - 20 Jun 2023
Cited by 1 | Viewed by 2253
Abstract
The detection of antinuclear antibodies is central to the diagnosis and prognosis of systemic lupus erythematosus (SLE), primary Sjögren’s syndrome (pSS) and mixed connective tissue disease (MCTD). Anti-U1-RNP and anti-RNP70 antibodies were assayed in the sera of patients with SLE (n = [...] Read more.
The detection of antinuclear antibodies is central to the diagnosis and prognosis of systemic lupus erythematosus (SLE), primary Sjögren’s syndrome (pSS) and mixed connective tissue disease (MCTD). Anti-U1-RNP and anti-RNP70 antibodies were assayed in the sera of patients with SLE (n = 114), pSS (n = 54) and MCTD (n = 12). In the SLE group, 34/114 (30%) were anti-U1-RNP positive, and 21/114 (18%) were both anti-RNP70 positive and anti-U1-RNP positive. In the MCTD group, 10/12 (83%) were anti-U1-RNP positive, and 9/12 (75%) were anti-RNP70 positive. Only one individual with pSS was antibody positive (for both anti-U1-RNP and anti-RNP70). All anti-RNP70-positive samples were also anti-U1-RNP positive. Anti-U1-RNP-positive subjects with SLE were younger (p < 0.0001); showed lower concentrations of complement protein 3 (p = 0.03); had lower eosinophil (p = 0.0005), lymphocyte (p = 0.006) and monocyte (p = 0.03) counts; and had accrued less organ damage (p = 0.006) than the anti-U1-RNP-negative SLE patients. However, we observed no significant clinical or laboratory parameter differences between the anti-U1-RNP-positive individuals with/without anti-RNP70 in the SLE group. In conclusion, anti-RNP70 antibodies are not exclusive to MCTD but are rarely detected in pSS and healthy individuals. In SLE, anti-U1-RNP antibodies are associated with a clinical phenotype that resembles MCTD, with hematologic involvement and less damage accrual. Based on our results, the clinical value of subtyping anti-RNP70 in anti-U1-RNP-positive sera appears to be of limited value. Full article
(This article belongs to the Special Issue Technological and Molecular Advances in Systemic Lupus Erythematosus)
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18 pages, 2616 KiB  
Article
Effects of Modified Glucosamine on the Chondrogenic Potential of Circulating Stem Cells under Experimental Inflammation
by Marco Gasparella, Carola Cenzi, Monica Piccione, Valentina Noemi Madia, Roberto Di Santo, Valeria Tudino, Marco Artico, Samanta Taurone, Chiara De Ponte, Roberta Costi and Rosa Di Liddo
Int. J. Mol. Sci. 2023, 24(12), 10397; https://doi.org/10.3390/ijms241210397 - 20 Jun 2023
Viewed by 1060
Abstract
Glucosamine (GlcN) is a glycosaminoglycan (GAGs) constituent in connective tissues. It is naturally produced by our body or consumed from diets. In the last decade, in vitro and in vivo trials have demonstrated that the administration of GlcN or its derivates has a [...] Read more.
Glucosamine (GlcN) is a glycosaminoglycan (GAGs) constituent in connective tissues. It is naturally produced by our body or consumed from diets. In the last decade, in vitro and in vivo trials have demonstrated that the administration of GlcN or its derivates has a protective effect on cartilage when the balance between catabolic and anabolic processes is disrupted and cells are no longer able to fully compensate for the loss of collagen and proteoglycans. To date, these benefits are still controversial because the mechanism of action of GlcN is not yet well clarified. In this study, we have characterized the biological activities of an amino acid (AA) derivate of GlcN, called DCF001, in the growth and chondrogenic induction of circulating multipotent stem cells (CMCs) after priming with tumor necrosis factor-alpha (TNFα), a pleiotropic cytokine commonly expressed in chronic inflammatory joint diseases. In the present work, stem cells were isolated from the human peripheral blood of healthy donors. After priming with TNFα (10 ng/mL) for 3 h, cultures were treated for 24 h with DCF001 (1 μg/mL) dissolved in a proliferative (PM) or chondrogenic (CM) medium. Cell proliferation was analyzed using a Corning® Cell Counter and trypan blue exclusion technique. To evaluate the potentialities of DCF001 in counteracting the inflammatory response to TNFα, we measured the amount of extracellular ATP (eATP) and the expression of adenosine-generating enzymes CD39/CD73, TNFα receptors, and NF-κB inhibitor IκBα using flow cytometry. Finally, total RNA was extracted to perform a gene expression study of some chondrogenic differentiation markers (COL2A1, RUNX2, and MMP13). Our analysis has shed light on the ability of DCF001 to (a) regulate the expression of CD39, CD73, and TNF receptors; (b) modulate eATP under differentiative induction; (c) enhance the inhibitory activity of IκBα, reducing its phosphorylation after TNFα stimulation; and (d) preserve the chondrogenic potentialities of stem cells. Although preliminary, these results suggest that DCF001 could be a valuable supplement for ameliorating the outcome of cartilage repair interventions, enhancing the efficacy of endogenous stem cells under inflammatory stimuli. Full article
(This article belongs to the Special Issue Regulation of Inflammatory Reactions in Health and Disease 2.0)
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15 pages, 2293 KiB  
Article
Cholesterol, Amyloid Beta, Fructose, and LPS Influence ROS and ATP Concentrations and the Phagocytic Capacity of HMC3 Human Microglia Cell Line
by Oscar M. Muñoz Herrera, Brian V. Hong, Ulises Ruiz Mendiola, Izumi Maezawa, Lee-Way Jin, Carlito B. Lebrilla, Danielle J. Harvey and Angela M. Zivkovic
Int. J. Mol. Sci. 2023, 24(12), 10396; https://doi.org/10.3390/ijms241210396 - 20 Jun 2023
Cited by 1 | Viewed by 1907
Abstract
Research has found that genes specific to microglia are among the strongest risk factors for Alzheimer’s disease (AD) and that microglia are critically involved in the etiology of AD. Thus, microglia are an important therapeutic target for novel approaches to the treatment of [...] Read more.
Research has found that genes specific to microglia are among the strongest risk factors for Alzheimer’s disease (AD) and that microglia are critically involved in the etiology of AD. Thus, microglia are an important therapeutic target for novel approaches to the treatment of AD. High-throughput in vitro models to screen molecules for their effectiveness in reversing the pathogenic, pro-inflammatory microglia phenotype are needed. In this study, we used a multi-stimulant approach to test the usefulness of the human microglia cell 3 (HMC3) cell line, immortalized from a human fetal brain-derived primary microglia culture, in duplicating critical aspects of the dysfunctional microglia phenotype. HMC3 microglia were treated with cholesterol (Chol), amyloid beta oligomers (AβO), lipopolysaccharide (LPS), and fructose individually and in combination. HMC3 microglia demonstrated changes in morphology consistent with activation when treated with the combination of Chol + AβO + fructose + LPS. Multiple treatments increased the cellular content of Chol and cholesteryl esters (CE), but only the combination treatment of Chol + AβO + fructose + LPS increased mitochondrial Chol content. Microglia treated with combinations containing Chol + AβO had lower apolipoprotein E (ApoE) secretion, with the combination of Chol + AβO + fructose + LPS having the strongest effect. Combination treatment with Chol + AβO + fructose + LPS also induced APOE and TNF-α expression, reduced ATP production, increased reactive oxygen species (ROS) concentration, and reduced phagocytosis events. These findings suggest that HMC3 microglia treated with the combination of Chol + AβO + fructose + LPS may be a useful high-throughput screening model amenable to testing on 96-well plates to test potential therapeutics to improve microglial function in the context of AD. Full article
(This article belongs to the Special Issue The Role of Microglia in Neurological Disorders)
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19 pages, 2417 KiB  
Article
BSR1, a Rice Receptor-like Cytoplasmic Kinase, Positively Regulates Defense Responses to Herbivory
by Yasukazu Kanda, Tomonori Shinya, Satoru Maeda, Kadis Mujiono, Yuko Hojo, Keisuke Tomita, Kazunori Okada, Takashi Kamakura, Ivan Galis and Masaki Mori
Int. J. Mol. Sci. 2023, 24(12), 10395; https://doi.org/10.3390/ijms241210395 - 20 Jun 2023
Cited by 2 | Viewed by 1669
Abstract
Crops experience herbivory by arthropods and microbial infections. In the interaction between plants and chewing herbivores, lepidopteran larval oral secretions (OS) and plant-derived damage-associated molecular patterns (DAMPs) trigger plant defense responses. However, the mechanisms underlying anti-herbivore defense, especially in monocots, have not been [...] Read more.
Crops experience herbivory by arthropods and microbial infections. In the interaction between plants and chewing herbivores, lepidopteran larval oral secretions (OS) and plant-derived damage-associated molecular patterns (DAMPs) trigger plant defense responses. However, the mechanisms underlying anti-herbivore defense, especially in monocots, have not been elucidated. The receptor-like cytoplasmic kinase Broad-Spectrum Resistance 1 (BSR1) of Oryza sativa L. (rice) mediates cytoplasmic defense signaling in response to microbial pathogens and enhances disease resistance when overexpressed. Here, we investigated whether BSR1 contributes to anti-herbivore defense responses. BSR1 knockout suppressed rice responses triggered by OS from the chewing herbivore Mythimna loreyi Duponchel (Lepidoptera: Noctuidae) and peptidic DAMPs OsPeps, including the activation of genes required for biosynthesis of diterpenoid phytoalexins (DPs). BSR1-overexpressing rice plants exhibited hyperactivation of DP accumulation and ethylene signaling after treatment with simulated herbivory and acquired enhanced resistance to larval feeding. As the biological significance of herbivory-induced accumulation of rice DPs remains unexplained, their physiological activities in M. loreyi were analyzed. The addition of momilactone B, a rice DP, to the artificial diet suppressed the growth of M. loreyi larvae. Altogether, this study revealed that BSR1 and herbivory-induced rice DPs are involved in the defense against chewing insects, in addition to pathogens. Full article
(This article belongs to the Special Issue Signal Transduction Mechanism in Plant Disease and Immunity)
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4 pages, 192 KiB  
Editorial
Editorial for the IJMS Special Issue on “Molecular Genetics of Autism and Intellectual Disability”
by Hyung-Goo Kim
Int. J. Mol. Sci. 2023, 24(12), 10394; https://doi.org/10.3390/ijms241210394 - 20 Jun 2023
Viewed by 849
Abstract
Autism spectrum disorder (ASD), a neurodevelopmental illness that affects children at an early age with a global prevalence of 1%, is diagnosed based on clinical features such as social impairment, repetitive behaviors, and restricted interests [...] Full article
(This article belongs to the Special Issue Molecular Genetics of Autism and Intellectual Disability)
22 pages, 6556 KiB  
Article
The Effects of 2-Hydroxy-3,6-Dimethoxychalcone on Melanogenesis and Inflammation
by Sungmin Bae and Chang-Gu Hyun
Int. J. Mol. Sci. 2023, 24(12), 10393; https://doi.org/10.3390/ijms241210393 - 20 Jun 2023
Viewed by 1118
Abstract
In this study, we demonstrated that 2-hydroxy-3,6-dimethoxychalcone (3,6-DMC) alleviated α-MSH-induced melanogenesis and lipopolysaccharides (LPS)-induced inflammation in mouse B16F10 and RAW 264.7 cells. In vitro analysis results showed that the melanin content and intracellular tyrosinase activity were [...] Read more.
In this study, we demonstrated that 2-hydroxy-3,6-dimethoxychalcone (3,6-DMC) alleviated α-MSH-induced melanogenesis and lipopolysaccharides (LPS)-induced inflammation in mouse B16F10 and RAW 264.7 cells. In vitro analysis results showed that the melanin content and intracellular tyrosinase activity were significantly decreased by 3,6-DMC, without cytotoxicity, via decreases in tyrosinase and the tyrosinase-related protein 1 (TRP-1) and TRP-2 melanogenic proteins, as well as the downregulation of microphthalmia-associated transcription factor (MITF) expression through the upregulation of the phosphorylation of extracellular-signal-regulated kinase (ERK), phosphoinositide 3-kinase (PI3K)/Akt, and glycogen synthase kinase-3β (GSK-3β)/catenin, and downregulation of the phosphorylation of p38, c-Jun N-terminal kinase (JNK), and protein kinase A (PKA). Furthermore, we investigated the effect of 3,6-DMC on macrophage RAW264.7 cells with LPS stimulation. 3,6-DMC significantly inhibited LPS-stimulated nitric oxide production. 3,6-DMC also suppressed the expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase (COX)-2 on the protein level. In addition, 3,6-DMC decreased the production of the tumor necrosis factor-α and interleukin-6. Successively, our mechanistic studies revealed that 3,6-DMC also suppressed the LPS-induced phosphorylation of the inhibitor of IκBα, p38MAPK, ERK, and JNK. The Western blot assay results showed that 3,6-DMC suppresses LPS-induced p65 translocation from cytosol to the nucleus. Finally, the topical applicability of 3,6-DMC was tested through primary skin irritation, and it was found that 3,6-DMC, at 5 and 10 μM concentrations, did not cause any adverse effects. Therefore, 3,6-DMC may provide a potential candidate for preventing and treating melanogenic and inflammatory skin diseases. Full article
(This article belongs to the Special Issue Chalcones: Biosynthesis, Functions, and Biological Implications)
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18 pages, 2568 KiB  
Article
Impact of Manganese and Chromate on Specific DNA Double-Strand Break Repair Pathways
by Vivien M. M. Haberland, Simon Magin, George Iliakis and Andrea Hartwig
Int. J. Mol. Sci. 2023, 24(12), 10392; https://doi.org/10.3390/ijms241210392 - 20 Jun 2023
Cited by 5 | Viewed by 1180
Abstract
Manganese is an essential trace element; nevertheless, on conditions of overload, it becomes toxic, with neurotoxicity being the main concern. Chromate is a well-known human carcinogen. The underlying mechanisms seem to be oxidative stress as well as direct DNA damage in the case [...] Read more.
Manganese is an essential trace element; nevertheless, on conditions of overload, it becomes toxic, with neurotoxicity being the main concern. Chromate is a well-known human carcinogen. The underlying mechanisms seem to be oxidative stress as well as direct DNA damage in the case of chromate, but also interactions with DNA repair systems in both cases. However, the impact of manganese and chromate on DNA double-strand break (DSB) repair pathways is largely unknown. In the present study, we examined the induction of DSB as well as the effect on specific DNA DSB repair mechanisms, namely homologous recombination (HR), non-homologous end joining (NHEJ), single strand annealing (SSA), and microhomology-mediated end joining (MMEJ). We applied DSB repair pathway-specific reporter cell lines, pulsed field gel electrophoresis as well as gene expression analysis, and investigated the binding of specific DNA repair proteins via immunoflourescence. While manganese did not seem to induce DNA DSB and had no impact on NHEJ and MMEJ, HR and SSA were inhibited. In the case of chromate, the induction of DSB was further supported. Regarding DSB repair, no inhibition was seen in the case of NHEJ and SSA, but HR was diminished and MMEJ was activated in a pronounced manner. The results indicate a specific inhibition of error-free HR by manganese and chromate, with a shift towards error-prone DSB repair mechanisms in both cases. These observations suggest the induction of genomic instability and may explain the microsatellite instability involved in chromate-induced carcinogenicity. Full article
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11 pages, 2273 KiB  
Article
Role of the Hox Genes, Sex combs reduced, Fushi tarazu and Antennapedia, in Leg Development of the Spider Mite Tetranychus urticae
by Xiang Luo, Yu-Qi Xu, Dao-Chao Jin, Jian-Jun Guo and Tian-Ci Yi
Int. J. Mol. Sci. 2023, 24(12), 10391; https://doi.org/10.3390/ijms241210391 - 20 Jun 2023
Cited by 2 | Viewed by 1004
Abstract
Mites, the second largest arthropod group, exhibit rich phenotypic diversity in the development of appendages (legs). For example, the fourth pair of legs (L4) does not form until the second postembryonic developmental stage, namely the protonymph stage. These leg developmental diversities drive body [...] Read more.
Mites, the second largest arthropod group, exhibit rich phenotypic diversity in the development of appendages (legs). For example, the fourth pair of legs (L4) does not form until the second postembryonic developmental stage, namely the protonymph stage. These leg developmental diversities drive body plan diversity in mites. However, little is known about the mechanisms of leg development in mites. Hox genes, homeotic genes, can regulate the development of appendages in arthropods. Three Hox genes, Sex combs reduced (Scr), Fushi tarazu (Ftz) and Antennapedia (Antp), have previously been shown to be expressed in the leg segments of mites. Here, the quantitative real-time reverse transcription PCR shows that three Hox genes are significantly increased in the first molt stage. RNA interference results in a set of abnormalities, including L3 curl and L4 loss. These results suggest that these Hox genes are required for normal leg development. Furthermore, the loss of single Hox genes results in downregulating the expression of the appendage marker Distal-less (Dll), suggesting that the three Hox genes can work together with Dll to maintain leg development in Tetranychus urticae. This study will be essential to understanding the diversity of leg development in mites and changes in Hox gene function. Full article
(This article belongs to the Section Molecular Biology)
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15 pages, 2502 KiB  
Article
Weak, Broken, but Working—Intramolecular Hydrogen Bond in 2,2′-bipyridine
by Ilya G. Shenderovich
Int. J. Mol. Sci. 2023, 24(12), 10390; https://doi.org/10.3390/ijms241210390 - 20 Jun 2023
Cited by 1 | Viewed by 2006
Abstract
From an academic and practical point of view, it is desirable to be able to assess the possibility of the proton exchange of a given molecular system just by knowing the positions of the proton acceptor and the proton donor. This study addresses [...] Read more.
From an academic and practical point of view, it is desirable to be able to assess the possibility of the proton exchange of a given molecular system just by knowing the positions of the proton acceptor and the proton donor. This study addresses the difference between intramolecular hydrogen bonds in 2,2′-bipyridinium and 1,10-phenanthrolinium. Solid-state 15N NMR and model calculations show that these hydrogen bonds are weak; their energies are 25 kJ/mol and 15 kJ/mol, respectively. Neither these hydrogen bonds nor N-H stretches can be responsible for the fast reversible proton transfer observed for 2,2′-bipyridinium in a polar solvent down to 115 K. This process must have been caused by an external force, which was a fluctuating electric field present in the solution. However, these hydrogen bonds are the grain that tips the scales precisely because they are an integral part of a large system of interactions, including both intramolecular interactions and environmental influence. Full article
(This article belongs to the Special Issue Advances in NMR Spectroscopy for Bioactive Small Molecules)
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15 pages, 3637 KiB  
Article
Effect of Hesperidin on Barrier Function and Reactive Oxygen Species Production in an Oral Epithelial Cell Model, and on Secretion of Macrophage-Derived Inflammatory Mediators during Porphyromonas gingivalis Infection
by Patricia Milagros Maquera-Huacho, Denise Palomari Spolidorio, John Manthey and Daniel Grenier
Int. J. Mol. Sci. 2023, 24(12), 10389; https://doi.org/10.3390/ijms241210389 - 20 Jun 2023
Cited by 1 | Viewed by 1273
Abstract
Porphyromonas gingivalis is a periodontopathogenic bacterium that can adhere to and colonize periodontal tissues, leading to an inflammatory process, and, consequently, tissue destruction. New therapies using flavonoids, such as hesperidin, are being studied, and their promising properties have been highlighted. The aim of [...] Read more.
Porphyromonas gingivalis is a periodontopathogenic bacterium that can adhere to and colonize periodontal tissues, leading to an inflammatory process, and, consequently, tissue destruction. New therapies using flavonoids, such as hesperidin, are being studied, and their promising properties have been highlighted. The aim of this study was to evaluate the effect of hesperidin on the epithelial barrier function, reactive oxygen species (ROS) production, and on the inflammatory response caused by P. gingivalis in in vitro models. The integrity of the epithelial tight junctions challenged by P. gingivalis was determined by monitoring the transepithelial electrical resistance (TER). P. gingivalis adherence to a gingival keratinocyte monolayer and a basement membrane model were evaluated by a fluorescence assay. A fluorometric assay was used to determine the ROS production in gingival keratinocytes. The level of pro-inflammatory cytokines and matrix metalloproteinases (MMPs) secretion was evaluated by ELISA; to assess NF-κB activation, the U937-3xjB-LUC monocyte cell line transfected with a luciferase reporter gene was used. Hesperidin protected against gingival epithelial barrier dysfunction caused by P. gingivalis and reduced the adherence of P. gingivalis to the basement membrane model. Hesperidin dose-dependently inhibited P. gingivalis-mediated ROS production by oral epithelial cells as well as the secretion of IL-1β, TNF-α, IL-8, MMP-2, and MMP-9 by macrophages challenged with P. gingivalis. Additionally, it was able to attenuate NF-κB activation in macrophages stimulated with P. gingivalis. These findings suggest that hesperidin has a protective effect on the epithelial barrier function, in addition to reducing ROS production and attenuating the inflammatory response associated with periodontal disease. Full article
(This article belongs to the Special Issue Bioactive Compounds: Potential New Anti-inflammatory Drugs 2.0)
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13 pages, 4304 KiB  
Article
Quantitative Loop-Mediated Isothermal Amplification Detection of Ustilaginoidea virens Causing Rice False Smut
by Yu Zhang, Xinyue Li, Shuya Zhang, Tianling Ma, Chengxin Mao and Chuanqing Zhang
Int. J. Mol. Sci. 2023, 24(12), 10388; https://doi.org/10.3390/ijms241210388 - 20 Jun 2023
Viewed by 939
Abstract
Rice false smut caused by Ustilaginoidea virens is one of the most devastating diseases in rice worldwide, which results in serious reductions in rice quality and yield. As an airborne fungal disease, early diagnosis of rice false smut and monitoring its epidemics and [...] Read more.
Rice false smut caused by Ustilaginoidea virens is one of the most devastating diseases in rice worldwide, which results in serious reductions in rice quality and yield. As an airborne fungal disease, early diagnosis of rice false smut and monitoring its epidemics and distribution of its pathogens is particularly important to manage the infection. In this study, a quantitative loop-mediated isothermal amplification (q-LAMP) method for U. virens detection and quantification was developed. This method has higher sensitivity and efficiency compared to the quantitative real-time PCR (q-PCR) method. The species-specific primer that the UV-2 set used was designed based on the unique sequence of the U. virens ustiloxins biosynthetic gene (NCBI accession number: BR001221.1). The q-LAMP assay was able to detect a concentration of 6.4 spores/mL at an optimal reaction temperature of 63.4 °C within 60 min. Moreover, the q-LAMP assay could even achieve accurate quantitative detection when there were only nine spores on the tape. A linearized equation for the standard curve, y = −0.2866x + 13.829 (x is the amplification time, the spore number = 100.65y), was established for the detection and quantification of U. virens. In field detection applications, this q-LAMP method is more accurate and sensitive than traditional observation methods. Collectively, this study has established a powerful and simple monitoring tool for U. virens, which provides valuable technical support for the forecast and management of rice false smut, and a theoretical basis for precise fungicide application. Full article
(This article belongs to the Section Molecular Microbiology)
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11 pages, 3254 KiB  
Article
Single-Droplet Microsensor for Ultra-Short Circulating EFGR Mutation Detection in Lung Cancer Based on Multiplex EFIRM Liquid Biopsy
by Fang Wei, Peter Yu, Jordan Cheng, Feng Li, David Chia and David T. W. Wong
Int. J. Mol. Sci. 2023, 24(12), 10387; https://doi.org/10.3390/ijms241210387 - 20 Jun 2023
Viewed by 1344
Abstract
Liquid biopsy is a rapidly emerging field that involves the minimal/non-invasive assessment of signature somatic mutations through the analysis of circulating tumor DNA (ctDNA) shed by tumor cells in bodily fluids. Broadly speaking, the unmet need in liquid biopsy lung cancer detection is [...] Read more.
Liquid biopsy is a rapidly emerging field that involves the minimal/non-invasive assessment of signature somatic mutations through the analysis of circulating tumor DNA (ctDNA) shed by tumor cells in bodily fluids. Broadly speaking, the unmet need in liquid biopsy lung cancer detection is the lack of a multiplex platform that can detect a mutation panel of lung cancer genes using a minimum amount of sample, especially for ultra-short ctDNA (usctDNA). Here, we developed a non-PCR and non-NGS-based single-droplet-based multiplexing microsensor technology, “Electric-Field-Induced Released and Measurement (EFIRM) Liquid Biopsy” (m-eLB), for lung cancer-associated usctDNA. The m-eLB provides a multiplexable assessment of usctDNA within a single droplet of biofluid in only one well of micro-electrodes, as each electrode is coated with different probes for the ctDNA. This m-eLB prototype demonstrates accuracy for three tyrosine-kinase-inhibitor-related EGFR target sequences in synthetic nucleotides. The accuracy of the multiplexing assay has an area under the curve (AUC) of 0.98 for L858R, 0.94 for Ex19 deletion, and 0.93 for T790M. In combination, the 3 EGFR assay has an AUC of 0.97 for the multiplexing assay. Full article
(This article belongs to the Special Issue Biosensors for the Early Diagnosis of High-Impact Human Diseases)
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11 pages, 573 KiB  
Review
Reasons for the Sex Bias in Osteoarthritis Research: A Review of Preclinical Studies
by Madeline Franke, Chiara Mancino and Francesca Taraballi
Int. J. Mol. Sci. 2023, 24(12), 10386; https://doi.org/10.3390/ijms241210386 - 20 Jun 2023
Cited by 4 | Viewed by 1732
Abstract
Osteoarthritis (OA) is one of the most common degenerative diseases of articular cartilage. During OA, all the elements that contribute to the joint undergo physiological and structural changes that impair the joint function and cause joint pain and stiffness. OA can arise naturally, [...] Read more.
Osteoarthritis (OA) is one of the most common degenerative diseases of articular cartilage. During OA, all the elements that contribute to the joint undergo physiological and structural changes that impair the joint function and cause joint pain and stiffness. OA can arise naturally, with the aging population witnessing an increase in diagnoses of this pathology, but the root causes of OA have yet to be identified, and increasing interest is arising towards investigating biological sex as a risk factor. Clinical studies show increased prevalence and worse clinical outcomes for female patients, yet most clinical and preclinical studies have disproportionately focused on male subjects. This review provides a critical overview of preclinical practices in the context of OA, highlighting the underlying need for taking biological sex as both a risk factor and an important component affecting treatment outcome. A unique insight into the possible reasons for female underrepresentation in preclinical studies is offered, including factors such as lack of specific guidelines requiring the analysis of sex as a biological variable (SABV), research-associated costs and animal handling, and wrongful application of the reduction principle. Additionally, a thorough investigation of sex-related variables is provided, stressing how each of them could add valuable information for the understanding of OA pathophysiology, as well as sex-dependent treatment strategies. Full article
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19 pages, 2845 KiB  
Communication
Radiosensitizing Effects of Irinotecan versus Oxaliplatin Alone and in Combination with 5-Fluorouracil on Human Colorectal Cancer Cells
by Bernd Frerker, Felix Bock, Marie-Louise Cappel, Stephan Kriesen, Gunther Klautke, Guido Hildebrandt and Katrin Manda
Int. J. Mol. Sci. 2023, 24(12), 10385; https://doi.org/10.3390/ijms241210385 - 20 Jun 2023
Viewed by 1347
Abstract
To date, oxaliplatin and irinotecan are used in combination with 5-flourouracil (5-FU) for metastatic colorectal cancer. In this study it was tested whether oxaliplatin and irinotecan and their combinations with 5-FU have an enhanced effect when treated simultaneously with ionizing radiation. In addition, [...] Read more.
To date, oxaliplatin and irinotecan are used in combination with 5-flourouracil (5-FU) for metastatic colorectal cancer. In this study it was tested whether oxaliplatin and irinotecan and their combinations with 5-FU have an enhanced effect when treated simultaneously with ionizing radiation. In addition, it should be compared whether one combination therapy is more effective than the other. Colorectal cancer cells (HT-29) were treated with irinotecan or oxaliplatin, both alone and in combination with 5-FU, and subsequently irradiated. The cell growth, metabolic activity and proliferation of cells were investigated, and the clonogenic survival was determined. Furthermore, the assessment of radiation-induced DNA damage and the influence of the drugs and their combinations on DNA damage repair was investigated. Treatment with irinotecan or oxaliplatin in combination with 5-FU inhibited proliferation and metabolic activity as well as clonogenic survival and the DNA damage repair capacity of the tumor cells. The comparison of oxaliplatin and irinotecan with simultaneous irradiation showed the same effect of both drugs. When oxaliplatin or irinotecan was combined with 5-FU, tumor cell survival was significantly lower than with monotherapy; however, there was no superiority of either combination regimen. Our results have shown that the combination of 5-FU and irinotecan is as effective as the combination of 5-FU with oxaliplatin. Therefore, our data support the use of FOLFIRI as a radiosensitizer. Full article
(This article belongs to the Special Issue Molecular Advances in Cancer Radiotherapy)
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23 pages, 9468 KiB  
Article
Partner, Neighbor, Housekeeper and Dimension: 3D versus 2D Glomerular Co-Cultures Reveal Drawbacks of Currently Used Cell Culture Models
by Anna Rederer, Victoria Rose, René Krüger, Linda Schmittutz, Izabela Swierzy, Lena Fischer, Ingo Thievessen, Julian Bauer, Oliver Friedrich, Mario Schiffer and Janina Müller-Deile
Int. J. Mol. Sci. 2023, 24(12), 10384; https://doi.org/10.3390/ijms241210384 - 20 Jun 2023
Cited by 2 | Viewed by 1844
Abstract
Signaling-pathway analyses and the investigation of gene responses to different stimuli are usually performed in 2D monocultures. However, within the glomerulus, cells grow in 3D and are involved in direct and paracrine interactions with different glomerular cell types. Thus, the results from 2D [...] Read more.
Signaling-pathway analyses and the investigation of gene responses to different stimuli are usually performed in 2D monocultures. However, within the glomerulus, cells grow in 3D and are involved in direct and paracrine interactions with different glomerular cell types. Thus, the results from 2D monoculture experiments must be taken with caution. We cultured glomerular endothelial cells, podocytes and mesangial cells in 2D/3D monocultures and 2D/3D co-cultures and analyzed cell survival, self-assembly, gene expression, cell–cell interaction, and gene pathways using live/dead assay, time-lapse analysis, bulk-RNA sequencing, qPCR, and immunofluorescence staining. Without any need for scaffolds, 3D glomerular co-cultures self-organized into spheroids. Podocyte- and glomerular endothelial cell-specific markers and the extracellular matrix were increased in 3D co-cultures compared to 2D co-cultures. Housekeeping genes must be chosen wisely, as many genes used for the normalization of gene expression were themselves affected in 3D culture conditions. The transport of podocyte-derived VEGFA to glomerular endothelial cells confirmed intercellular crosstalk in the 3D co-culture models. The enhanced expression of genes important for glomerular function in 3D, compared to 2D, questions the reliability of currently used 2D monocultures. Hence, glomerular 3D co-cultures might be more suitable in the study of intercellular communication, disease modelling and drug screening ex vivo. Full article
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29 pages, 4354 KiB  
Article
Albumin Is a Component of the Esterase Status of Human Blood Plasma
by Daria A. Belinskaia, Polina A. Voronina, Polina I. Popova, Natalia G. Voitenko, Vladimir I. Shmurak, Mikhail A. Vovk, Tatiana I. Baranova, Anastasia A. Batalova, Ekaterina A. Korf, Pavel V. Avdonin, Richard O. Jenkins and Nikolay V. Goncharov
Int. J. Mol. Sci. 2023, 24(12), 10383; https://doi.org/10.3390/ijms241210383 - 20 Jun 2023
Cited by 6 | Viewed by 1104
Abstract
The esterase status of blood plasma can claim to be one of the universal markers of various diseases; therefore, it deserves attention when searching for markers of the severity of COVID-19 and other infectious and non-infectious pathologies. When analyzing the esterase status of [...] Read more.
The esterase status of blood plasma can claim to be one of the universal markers of various diseases; therefore, it deserves attention when searching for markers of the severity of COVID-19 and other infectious and non-infectious pathologies. When analyzing the esterase status of blood plasma, the esterase activity of serum albumin, which is the major protein in the blood of mammals, should not be ignored. The purpose of this study is to expand understanding of the esterase status of blood plasma and to evaluate the relationship of the esterase status, which includes information on the amount and enzymatic activity of human serum albumin (HSA), with other biochemical parameters of human blood, using the example of surviving and deceased patients with confirmed COVID-19. In experiments in vitro and in silico, the activity of human plasma and pure HSA towards various substrates was studied, and the effect of various inhibitors on this activity was tested. Then, a comparative analysis of the esterase status and a number of basic biochemical parameters of the blood plasma of healthy subjects and patients with confirmed COVID-19 was performed. Statistically significant differences have been found in esterase status and biochemical indices (including albumin levels) between healthy subjects and patients with COVID-19, as well as between surviving and deceased patients. Additional evidence has been obtained for the importance of albumin as a diagnostic marker. Of particular interest is a new index, [Urea] × [MDA] × 1000/(BChEb × [ALB]), which in the group of deceased patients was 10 times higher than in the group of survivors and 26 times higher than the value in the group of apparently healthy elderly subjects. Full article
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