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Int. J. Mol. Sci., Volume 25, Issue 4 (February-2 2024) – 505 articles

Cover Story (view full-size image): Traditional nanoparticle delivery faces challenges such as short circulation time and immune recognition. Cell-membrane-coated nanoparticle technology is a recent breakthrough that improves stability and bioavailability and enables controlled drug/gene delivery to specific cells or tissues. The procedure involves the disruption of the membranes of selected cell types by hypotonic lysis and homogenization, followed by several centrifugation steps before the nanoparticles are coated by sonication or extrusion. This review explores current developments in cell-membrane-coated nanoparticles, emphasizing their potential for targeted drug delivery and therapeutic applications. View this paper
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25 pages, 2713 KiB  
Review
The Evolving Role of Dendritic Cells in Atherosclerosis
by Simone Britsch, Harald Langer, Daniel Duerschmied and Tobias Becher
Int. J. Mol. Sci. 2024, 25(4), 2450; https://doi.org/10.3390/ijms25042450 - 19 Feb 2024
Viewed by 730
Abstract
Atherosclerosis, a major contributor to cardiovascular morbidity and mortality, is characterized by chronic inflammation of the arterial wall. This inflammatory process is initiated and maintained by both innate and adaptive immunity. Dendritic cells (DCs), which are antigen-presenting cells, play a crucial role in [...] Read more.
Atherosclerosis, a major contributor to cardiovascular morbidity and mortality, is characterized by chronic inflammation of the arterial wall. This inflammatory process is initiated and maintained by both innate and adaptive immunity. Dendritic cells (DCs), which are antigen-presenting cells, play a crucial role in the development of atherosclerosis and consist of various subtypes with distinct functional abilities. Following the recognition and binding of antigens, DCs become potent activators of cellular responses, bridging the innate and adaptive immune systems. The modulation of specific DC subpopulations can have either pro-atherogenic or atheroprotective effects, highlighting the dual pro-inflammatory or tolerogenic roles of DCs. In this work, we provide a comprehensive overview of the evolving roles of DCs and their subtypes in the promotion or limitation of atherosclerosis development. Additionally, we explore antigen pulsing and pharmacological approaches to modulate the function of DCs in the context of atherosclerosis. Full article
(This article belongs to the Special Issue Molecular Mechanisms and Pathophysiology of Atherosclerosis 2.0)
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23 pages, 10678 KiB  
Article
Microbiota Alterations in Lung, Ileum, and Colon of Guinea Pigs with Cough Variant Asthma
by Chongyang Dou, Lin Hu, Xian Ding, Fangfang Chen, Xi Li, Guihua Wei and Zhiyong Yan
Int. J. Mol. Sci. 2024, 25(4), 2449; https://doi.org/10.3390/ijms25042449 - 19 Feb 2024
Viewed by 713
Abstract
Alterations in the microbiota composition, or ecological dysbiosis, have been implicated in the development of various diseases, including allergic diseases and asthma. Examining the relationship between microbiota alterations in the host and cough variant asthma (CVA) may facilitate the discovery of novel therapeutic [...] Read more.
Alterations in the microbiota composition, or ecological dysbiosis, have been implicated in the development of various diseases, including allergic diseases and asthma. Examining the relationship between microbiota alterations in the host and cough variant asthma (CVA) may facilitate the discovery of novel therapeutic strategies. To elucidate the diversity and difference of microbiota across three ecological niches, we performed 16S rDNA amplicon sequencing on lung, ileum, and colon samples. We assessed the levels of interleukin-12 (IL-12) and interleukin-13 (IL-13) in guinea pig bronchoalveolar lavage fluid using the enzyme-linked immunosorbent assay (ELISA). We applied Spearman’s analytical method to evaluate the correlation between microbiota and cytokines. The results demonstrated that the relative abundance, α-diversity, and β-diversity of the microbial composition of the lung, ileum, and colon varied considerably. The ELISA results indicated a substantial increase in the level of IL-13 and a decreasing trend in the level of IL-12 in the CVA guinea pigs. The Spearman analysis identified a correlation between Mycoplasma, Faecalibaculum, and Ruminococcus and the inflammatory factors in the CVA guinea pigs. Our guinea pig model showed that core microorganisms, such as Mycoplasma in the lung, Faecalibaculum in the ileum, and Ruminococcus in the colon, may play a crucial role in the pathogenesis of CVA. The most conspicuous changes in the ecological niche were observed in the guinea pig ileum, followed by the lung, while relatively minor changes were observed in the colon. Notably, the microbial structure of the ileum niche approximated that of the colon niche. Therefore, the results of this study suggest that CVA development is closely related to the dysregulation of ileal, lung, and colon microbiota and the ensuing inflammatory changes in the lung. Full article
(This article belongs to the Section Molecular Microbiology)
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22 pages, 3385 KiB  
Article
Alcohol Impairs Bioenergetics and Differentiation Capacity of Myoblasts from Simian Immunodeficiency Virus-Infected Female Macaques
by Danielle E. Levitt, Brianna L. Bourgeois, Keishla M. Rodríguez-Graciani, Patricia E. Molina and Liz Simon
Int. J. Mol. Sci. 2024, 25(4), 2448; https://doi.org/10.3390/ijms25042448 - 19 Feb 2024
Viewed by 698
Abstract
Alcohol misuse and HIV independently induce myopathy. We previously showed that chronic binge alcohol (CBA) administration, with or without simian immunodeficiency virus (SIV), decreases differentiation capacity of male rhesus macaque myoblasts. We hypothesized that short-term alcohol and CBA/SIV would synergistically decrease differentiation capacity [...] Read more.
Alcohol misuse and HIV independently induce myopathy. We previously showed that chronic binge alcohol (CBA) administration, with or without simian immunodeficiency virus (SIV), decreases differentiation capacity of male rhesus macaque myoblasts. We hypothesized that short-term alcohol and CBA/SIV would synergistically decrease differentiation capacity and impair bioenergetic parameters in female macaque myoblasts. Myoblasts from naïve (CBA/SIV), vehicle [VEH]/SIV, and CBA/SIV (N = 4–6/group) groups were proliferated (3 days) and differentiated (5 days) with 0 or 50 mM ethanol (short-term). CBA/SIV decreased differentiation and increased non-mitochondrial oxygen consumption rate (OCR) versus naïve and/or VEH/SIV. Short-term alcohol decreased differentiation; increased maximal and non-mitochondrial OCR, mitochondrial reactive oxygen species (ROS) production, and aldolase activity; and decreased glycolytic measures, ATP production, mitochondrial membrane potential (ΔΨm), and pyruvate kinase activity. Mitochondrial ROS production was closely associated with mitochondrial network volume, and differentiation indices were closely associated with key bioenergetic health and function parameters. Results indicate that short-term alcohol and CBA non-synergistically decrease myoblast differentiation capacity. Short-term alcohol impaired myoblast glycolytic function, driving the bioenergetic deficit. Results suggest potentially differing mechanisms underlying decreased differentiation capacity with short-term alcohol and CBA, highlighting the need to elucidate the impact of different alcohol use patterns on myopathy. Full article
(This article belongs to the Special Issue Mitochondrial Metabolism Alterations in Health and Disease)
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13 pages, 2432 KiB  
Article
Interleukin-1β/Interleukin (IL)-1-Receptor-Antagonist (IL1-RA) Axis in Invasive Bladder Cancer—An Exploratory Analysis of Clinical and Tumor Biological Significance
by Marko Vukovic, Jorge M. Chamlati, Jörg Hennenlotter, Tilman Todenhöfer, Thomas Lütfrenk, Sebastian Jersinovic, Igor Tsaur, Arnulf Stenzl and Steffen Rausch
Int. J. Mol. Sci. 2024, 25(4), 2447; https://doi.org/10.3390/ijms25042447 - 19 Feb 2024
Viewed by 782
Abstract
Previous data indicate a role of IL-1 and IL-1RA imbalance in bladder carcinoma (BC); the inhibition of IL-1 signaling might be considered a treatment option. Objective: To assess expression patterns and the prognostic role of IL-1β and IL-1RA in invasive BC and to [...] Read more.
Previous data indicate a role of IL-1 and IL-1RA imbalance in bladder carcinoma (BC); the inhibition of IL-1 signaling might be considered a treatment option. Objective: To assess expression patterns and the prognostic role of IL-1β and IL-1RA in invasive BC and to evaluate their interaction with AKT signaling and proliferation. The study included two independent cohorts of n = 92 and n = 102 patients who underwent a radical cystectomy for BC. Specimen from BC and benign urothelium (n = 22 and n = 39) were processed to a tissue microarray and immunohistochemically stained for IL-1β, IL-1RA, AKT, and Ki-67. Expression scores were correlated to clinical variables and Ki-67 and AKT expression. An association with outcome was assessed using Wilcoxon Kruskal–Wallis tests, Chi-square tests or linear regression, dependent on the variable’s category. Kaplan–Meier and Cox proportional hazard analyses were used to estimate recurrence-free (RFS), cancer-specific (CSS) and overall survival (OS). Both IL-1β and IL-1RA were significantly overexpressed in invasive BC compared to benign urothelium in both cohorts (p < 0.005). IL-1β was associated with vascular invasion (210 vs. 183, p < 0.02), lymphatic invasion (210 vs. 180, <0.05) and G3 cancer (192 vs. 188, <0.04). The survival analysis revealed favorable RFS, CSS, and OS in the case of high IL-1β expression (p < 0.02, <0.03, and <0.006, respectively). Multivariate analyses revealed an independent impact of (low) IL1β expression on RFS, CSS, and OS. The IL-1β and IL-1β/IL-1RA ratios were positively correlated to the AKT expression (p < 0.05 and <0.01, respectively). Additionally, the high expression of Ki-67 (>15%) correlated with higher levels of IL-1β (p = 0.01). The overexpression of IL-1β and IL-1RA is frequently found in BC, with a prognostic significance observed for the IL-1β protein expression. The observed link between the IL-1β/IL-1RA axis and AKT signaling may indicate possible autophagy activation processes besides the known tumor-promoting effects of AKT. Full article
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20 pages, 6586 KiB  
Article
Genetic Ablation of STE20-Type Kinase MST4 Does Not Alleviate Diet-Induced MASLD Susceptibility in Mice
by Mara Caputo, Emma Andersson, Ying Xia, Wei Hou, Emmelie Cansby, Max Erikson, Dan Emil Lind, Bengt Hallberg, Manoj Amrutkar and Margit Mahlapuu
Int. J. Mol. Sci. 2024, 25(4), 2446; https://doi.org/10.3390/ijms25042446 - 19 Feb 2024
Viewed by 1019
Abstract
Metabolic dysfunction-associated steatotic liver disease (MASLD) and its advanced subtype, metabolic dysfunction-associated steatohepatitis (MASH), have emerged as the most common chronic liver disease worldwide, yet there is no targeted pharmacotherapy presently available. This study aimed to investigate the possible in vivo function of [...] Read more.
Metabolic dysfunction-associated steatotic liver disease (MASLD) and its advanced subtype, metabolic dysfunction-associated steatohepatitis (MASH), have emerged as the most common chronic liver disease worldwide, yet there is no targeted pharmacotherapy presently available. This study aimed to investigate the possible in vivo function of STE20-type protein kinase MST4, which was earlier implicated in the regulation of hepatocellular lipotoxic milieu in vitro, in the control of the diet-induced impairment of systemic glucose and insulin homeostasis as well as MASLD susceptibility. Whole-body and liver-specific Mst4 knockout mice were generated by crossbreeding conditional Mst4fl/fl mice with mice expressing Cre recombinase under the Sox2 or Alb promoters, respectively. To replicate the environment in high-risk subjects, Mst4–/– mice and their wild-type littermates were fed a high-fat or a methionine–choline-deficient (MCD) diet. Different in vivo tests were conducted in obese mice to describe the whole-body metabolism. MASLD progression in the liver and lipotoxic damage to adipose tissue, kidney, and skeletal muscle were analyzed by histological and immunofluorescence analysis, biochemical assays, and protein and gene expression profiling. In parallel, intracellular fat storage and oxidative stress were assessed in primary mouse hepatocytes, where MST4 was silenced by small interfering RNA. We found that global MST4 depletion had no effect on body weight or composition, locomotor activity, whole-body glucose tolerance or insulin sensitivity in obese mice. Furthermore, we observed no alterations in lipotoxic injuries to the liver, adipose, kidney, or skeletal muscle tissue in high-fat diet-fed whole-body Mst4–/– vs. wild-type mice. Liver-specific Mst4–/– mice and wild-type littermates displayed a similar severity of MASLD when subjected to an MCD diet, as evidenced by equal levels of steatosis, inflammation, hepatic stellate cell activation, fibrosis, oxidative/ER stress, and apoptosis in the liver. In contrast, the in vitro silencing of MST4 effectively protected primary mouse hepatocytes against ectopic lipid accumulation and oxidative cell injury triggered by exposure to fatty acids. In summary, these results suggest that the genetic ablation of MST4 in mice does not mitigate the initiation or progression of MASLD and has no effect on systemic glucose or insulin homeostasis in the context of nutritional stress. The functional compensation for the genetic loss of MST4 by yet undefined mechanisms may contribute to the apparent discrepancy between in vivo and in vitro phenotypic consequences of MST4 silencing. Full article
(This article belongs to the Section Molecular Endocrinology and Metabolism)
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14 pages, 3937 KiB  
Article
Synthesis and Insecticidal Activity of Novel Anthranilic Diamide Insecticides Containing Indane and Its Analogs
by Zhihui Yang, Ruihan Hu, Jingjing Chen and Xiaohua Du
Int. J. Mol. Sci. 2024, 25(4), 2445; https://doi.org/10.3390/ijms25042445 - 19 Feb 2024
Viewed by 507
Abstract
Diamide insecticides have always been a hot research topic in the field of pesticides. To further discover new compounds with high activity and safety, indane and its analogs were introduced into chlorantraniliprole, and a battery of chlorfenil derivatives, including indane and its analogs, [...] Read more.
Diamide insecticides have always been a hot research topic in the field of pesticides. To further discover new compounds with high activity and safety, indane and its analogs were introduced into chlorantraniliprole, and a battery of chlorfenil derivatives, including indane and its analogs, were designed and prepared for biological testing. Their characterization and verification were carried out through nuclear magnetic resonance (NMR) and high-resolution mass spectrometry (HRMS). Biological detection showed that all the compounds exhibited good insecticidal activity against Mythimna separata. At 0.8 mg/L, the insecticidal activity of compound 8q against Mythimna separata was 80%, which was slightly better than that of chlorantraniliprole. The results of the structure–activity relationship (SAR) analysis indicated that the indane moiety had a significant effect on insecticidal activity, especially in the R-configuration. The results indicated that chlorantraniliprole derivatives containing indane groups could serve as pilot compounds for the further development of new insecticides. Full article
(This article belongs to the Section Molecular Toxicology)
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25 pages, 1595 KiB  
Review
Potential Therapeutic Application and Mechanism of Action of Stem Cell-Derived Extracellular Vesicles (EVs) in Systemic Lupus Erythematosus (SLE)
by Sushmitha Rajeev Kumar, Rajalingham Sakthiswary and Yogeswaran Lokanathan
Int. J. Mol. Sci. 2024, 25(4), 2444; https://doi.org/10.3390/ijms25042444 - 19 Feb 2024
Viewed by 1404
Abstract
Systemic lupus erythematosus (SLE) is a multisystemic autoimmune disease that affects nearly 3.41 million people globally, with 90% of the cases affecting women of childbearing age. SLE is a complex disease due to the interplay of various immunological pathways and mechanisms. This scoping [...] Read more.
Systemic lupus erythematosus (SLE) is a multisystemic autoimmune disease that affects nearly 3.41 million people globally, with 90% of the cases affecting women of childbearing age. SLE is a complex disease due to the interplay of various immunological pathways and mechanisms. This scoping review aims to highlight the latest research findings on the therapeutic mechanisms of action of EVs in SLE. Relevant research articles were identified using the PRISMA framework from databases such as PubMed/MEDLINE (National Library of Medicine), Scopus (Elsevier), and Web of Science: Core Collection (Clarivate Analytics) from July 2023 to October 2023. Eleven studies met the inclusion criteria and thus were included in this scoping review. The findings showed that EVs have therapeutic effects on ameliorating the disease progression of SLE. EVs can reduce the pro-inflammatory cytokines and increase the anti-inflammatory cytokines. Moreover, EVs can increase the levels of regulatory T cells, thus reducing inflammation. EVs also have the potential to regulate B cells to alleviate SLE and reduce its adverse effects. The scoping review has successfully analysed the therapeutic potential in ameliorating the disease progression of SLE. The review also includes prospects to improve the effects of EVs further to increase the therapeutic effects on SLE. Full article
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15 pages, 5579 KiB  
Article
Non-Targeted Metabolomics Investigation of a Sub-Chronic Variable Stress Model Unveils Sex-Dependent Metabolic Differences Induced by Stress
by Seulgi Kang, Woonhee Kim, Jimin Nam, Ke Li, Yua Kang, Boyeon Bae, Kwang-Hoon Chun, ChiHye Chung and Jeongmi Lee
Int. J. Mol. Sci. 2024, 25(4), 2443; https://doi.org/10.3390/ijms25042443 - 19 Feb 2024
Viewed by 670
Abstract
Depression is twice as prevalent in women as in men, however, most preclinical studies of depression have used male rodent models. This study aimed to examine how stress affects metabolic profiles depending on sex using a rodent depression model: sub-chronic variable stress (SCVS). [...] Read more.
Depression is twice as prevalent in women as in men, however, most preclinical studies of depression have used male rodent models. This study aimed to examine how stress affects metabolic profiles depending on sex using a rodent depression model: sub-chronic variable stress (SCVS). The SCVS model of male and female mice was established in discovery and validation sets. The stress-induced behavioral phenotypic changes were similar in both sexes, however, the metabolic profiles of female plasma and brain became substantially different after stress, whereas those of males did not. Four stress-differential plasma metabolites—β-hydroxybutyric acid (BHB), L-serine, glycerol, and myo-inositol—could yield biomarker panels with excellent performance to discern the stressed individuals only for females. Disturbances in BHB, glucose, 1,5-anhydrosorbitol, lactic acid, and several fatty acids in the plasma of stressed females implied a systemic metabolic shift to β-oxidation in females. The plasma levels of BHB and corticosterone only in stressed females were observed not only in SCVS but also in an acute stress model. These results collectively suggest a sex difference in the metabolic responses by stress, possibly involving the energy metabolism shift to β-oxidation and the HPA axis dysregulation in females. Full article
(This article belongs to the Section Molecular Endocrinology and Metabolism)
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29 pages, 5191 KiB  
Article
K2CO3-Modified Smectites as Basic Catalysts for Glycerol Transcarbonation to Glycerol Carbonate
by Yosra Snoussi, David Gonzalez-Miranda, Tomás Pedregal, Néji Besbes, Abderrahim Bouaid and Miguel Ladero
Int. J. Mol. Sci. 2024, 25(4), 2442; https://doi.org/10.3390/ijms25042442 - 19 Feb 2024
Viewed by 463
Abstract
A novel and cost-effective heterogeneous catalyst for glycerol carbonate production through transesterification was developed by impregnating smectite clay with K2CO3. Comprehensive structural and chemical analyses, including X-ray diffraction Analysis (XRD), Scanning Electron Microscopy (SEM)-Electron Dispersion Spectroscopy (EDS), Fourier Transform [...] Read more.
A novel and cost-effective heterogeneous catalyst for glycerol carbonate production through transesterification was developed by impregnating smectite clay with K2CO3. Comprehensive structural and chemical analyses, including X-ray diffraction Analysis (XRD), Scanning Electron Microscopy (SEM)-Electron Dispersion Spectroscopy (EDS), Fourier Transform Infrared Spectroscopy (FTIR), and Brunauer-Emmett-Teller (BET) surface area analysis measurements, were employed to characterize the catalysts. Among the various catalysts prepared, the one impregnated with 40 wt% K2CO3 on smectite and calcined at 550 °C exhibited the highest catalytic activity, primarily due to its superior basicity. To enhance the efficiency of the transesterification process, several reaction parameters were optimized, including the molar ratio between propylene carbonate and glycerol reactor loading of the catalyst and reaction temperature. The highest glycerol carbonate conversion rate, approximately 77.13% ± 1.2%, was achieved using the best catalyst under the following optimal conditions: 2 wt% reactor loading, 110 °C reaction temperature, 2:1 propylene carbonate to glycerol molar ratio, and 6h reaction duration. Furthermore, both the raw clay and the best calcined K2CO3-impregnated catalysts demonstrated remarkable stability, maintaining their high activity for up to four consecutive reaction cycles. Finally, a kinetic analysis was performed using kinetic data from several runs employing raw clay and the most active K2CO3-modified clay at different temperatures, observing that a simple reversible second-order potential kinetic model of the quasi-homogeneous type fits perfectly to such data in diverse temperature ranges. Full article
(This article belongs to the Special Issue Advances in Biofuels and Green Catalysts)
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15 pages, 7097 KiB  
Article
Myconoside and Calceolarioside E Restrain UV-Induced Skin Photoaging by Activating NRF2-Mediated Defense Mechanisms
by Iva D. Stoykova, Ivanka K. Koycheva, Biser K. Binev, Liliya V. Mihaylova, Maria Y. Benina, Kalina I. Alipieva and Milen I. Georgiev
Int. J. Mol. Sci. 2024, 25(4), 2441; https://doi.org/10.3390/ijms25042441 - 19 Feb 2024
Viewed by 1591
Abstract
Chronic and excessive ultraviolet (UVA/UVB) irradiation exposure is known as a major contributor to premature skin aging, which leads to excessive reactive oxygen species generation, disturbed extracellular matrix homeostasis, DNA damage, and chronic inflammation. Sunscreen products are the major preventive option against UVR-induced [...] Read more.
Chronic and excessive ultraviolet (UVA/UVB) irradiation exposure is known as a major contributor to premature skin aging, which leads to excessive reactive oxygen species generation, disturbed extracellular matrix homeostasis, DNA damage, and chronic inflammation. Sunscreen products are the major preventive option against UVR-induced photodamage, mostly counteracting the acute skin effects and only mildly counteracting accelerated aging. Therefore, novel anti-photoaging and photopreventive compounds are a subject of increased scientific interest. Our previous investigations revealed that the endemic plant Haberlea rhodopensis Friv. (HRE) activates the antioxidant defense through an NRF2-mediated mechanism in neutrophiles. In the present study, we aimed to investigate the photoprotective potential of HRE and two of its specialized compounds—the phenylethanoid glycosides myconoside (MYC) and calceolarioside E (CAL)—in UVA/UVB-stimulated human keratinocytes in an in vitro model of photoaging. The obtained data demonstrated that the application of HRE, MYC, and CAL significantly reduced intracellular ROS formation in UVR-exposed HaCaT cells. The NRF2/PGC-1α and TGF-1β/Smad/Wnt signaling pathways were pointed out as having a critical role in the observed CAL- and MYC-induced photoprotective effect. Collectively, CAL is worth further evaluation as a potent natural NRF2 activator and a promising photoprotective agent that leads to the prevention of UVA/UVB-induced premature skin aging. Full article
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25 pages, 6954 KiB  
Review
The Pathophysiology and Treatment of Pyoderma Gangrenosum—Current Options and New Perspectives
by Magdalena Łyko, Anna Ryguła, Michał Kowalski, Julia Karska and Alina Jankowska-Konsur
Int. J. Mol. Sci. 2024, 25(4), 2440; https://doi.org/10.3390/ijms25042440 - 19 Feb 2024
Viewed by 849
Abstract
Pyoderma gangrenosum (PG) is an uncommon inflammatory dermatological disorder characterized by painful ulcers that quickly spread peripherally. The pathophysiology of PG is not fully understood; however, it is most commonly considered a disease in the spectrum of neutrophilic dermatoses. The treatment of PG [...] Read more.
Pyoderma gangrenosum (PG) is an uncommon inflammatory dermatological disorder characterized by painful ulcers that quickly spread peripherally. The pathophysiology of PG is not fully understood; however, it is most commonly considered a disease in the spectrum of neutrophilic dermatoses. The treatment of PG remains challenging due to the lack of generally accepted therapeutic guidelines. Existing therapeutic methods focus on limiting inflammation through the use of immunosuppressive and immunomodulatory therapies. Recently, several reports have indicated the successful use of biologic drugs and small molecules administered for coexisting diseases, resulting in ulcer healing. In this review, we summarize the discoveries regarding the pathophysiology of PG and present treatment options to raise awareness and improve the management of this rare entity. Full article
(This article belongs to the Special Issue Skin, Autoimmunity and Inflammation 2.0)
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15 pages, 704 KiB  
Article
Genetic Mapping and Characterization of Verticillium Wilt Resistance in a Recombinant Inbred Population of Upland Cotton
by Iain W. Wilson, Philippe Moncuquet, Yuman Yuan, Melanie Soliveres, Zitong Li, Warwick Stiller and Qian-Hao Zhu
Int. J. Mol. Sci. 2024, 25(4), 2439; https://doi.org/10.3390/ijms25042439 - 19 Feb 2024
Viewed by 627
Abstract
Verticillium wilt (VW) is an important and widespread disease of cotton and once established is long-lived and difficult to manage. In Australia, the non-defoliating pathotype of Verticillium dahliae is the most common, and extremely virulent. Breeding cotton varieties with increased VW resistance is [...] Read more.
Verticillium wilt (VW) is an important and widespread disease of cotton and once established is long-lived and difficult to manage. In Australia, the non-defoliating pathotype of Verticillium dahliae is the most common, and extremely virulent. Breeding cotton varieties with increased VW resistance is the most economical and effective method of controlling this disease and is greatly aided by understanding the genetics of resistance. This study aimed to investigate VW resistance in 240 F7 recombinant inbred lines (RIL) derived from a cross between MCU-5, which has good resistance, and Siokra 1–4, which is susceptible. Using a controlled environment bioassay, we found that resistance based on plant survival or shoot biomass was complex but with major contributions from chromosomes D03 and D09, with genomic prediction analysis estimating a prediction accuracy of 0.73 based on survival scores compared to 0.36 for shoot biomass. Transcriptome analysis of MCU-5 and Siokra 1–4 roots uninfected or infected with V. dahliae revealed that the two cultivars displayed very different root transcriptomes and responded differently to V. dahliae infection. Ninety-nine differentially expressed genes were located in the two mapped resistance regions and so are potential candidates for further identifying the genes responsible for VW resistance. Full article
(This article belongs to the Section Molecular Genetics and Genomics)
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8 pages, 769 KiB  
Communication
Screening for Rare Mitochondrial Genome Variants Reveals a Potentially Novel Association between MT-CO1 and MT-TL2 Genes and Diabetes Phenotype
by Tomasz Płoszaj, Sebastian Skoczylas, Karolina Gadzalska, Paulina Jakiel, Ewa Juścińska, Monika Gorządek, Agnieszka Robaszkiewicz, Maciej Borowiec and Agnieszka Zmysłowska
Int. J. Mol. Sci. 2024, 25(4), 2438; https://doi.org/10.3390/ijms25042438 - 19 Feb 2024
Viewed by 521
Abstract
Variations in several nuclear genes predisposing humans to the development of MODY diabetes have been very well characterized by modern genetic diagnostics. However, recent reports indicate that variants in the mtDNA genome may also be associated with the diabetic phenotype. As relatively little [...] Read more.
Variations in several nuclear genes predisposing humans to the development of MODY diabetes have been very well characterized by modern genetic diagnostics. However, recent reports indicate that variants in the mtDNA genome may also be associated with the diabetic phenotype. As relatively little research has addressed the entire mitochondrial genome in this regard, the aim of the present study is to evaluate the genetic variations present in mtDNA among individuals susceptible to MODY diabetes. In total, 193 patients with a MODY phenotype were tested with a custom panel with mtDNA enrichment. Heteroplasmic variants were selected for further analysis via further sequencing based on long-range PCR to evaluate the potential contribution of frequent NUMTs (acronym for nuclear mitochondrial DNA) insertions. Twelve extremely rare variants with a potential damaging character were selected, three of which were likely to be the result of NUMTs from the nuclear genome. The variant m.3243A>G in MT-TL1 was responsible for 3.5% of MODY cases in our study group. In addition, a novel, rare, and possibly pathogenic leucine variant m.12278T>C was found in MT-TL2. Our findings also found the MT-CO1 gene to be over-represented in the study group, with a clear phenotype–genotype correlation observed in one family. Our data suggest that heteroplasmic variants in MT-COI and MT-TL2 genes may play a role in the pathophysiology of glucose metabolism in humans. Full article
(This article belongs to the Section Molecular Genetics and Genomics)
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15 pages, 5441 KiB  
Article
Identification of Novel Non-Nucleoside Inhibitors of Zika Virus NS5 Protein Targeting MTase Activity
by Diego Fiorucci, Micaela Meaccini, Giulio Poli, Maria Alfreda Stincarelli, Chiara Vagaggini, Simone Giannecchini, Priscila Sutto-Ortiz, Bruno Canard, Etienne Decroly, Elena Dreassi, Annalaura Brai and Maurizio Botta
Int. J. Mol. Sci. 2024, 25(4), 2437; https://doi.org/10.3390/ijms25042437 - 19 Feb 2024
Viewed by 654
Abstract
Zika virus (ZIKV) is a positive-sense single-stranded virus member of the Flaviviridae family. Among other arboviruses, ZIKV can cause neurological disorders such as Guillain Barré syndrome, and it can have congenital neurological manifestations and affect fertility. ZIKV nonstructural protein 5 (NS5) is essential [...] Read more.
Zika virus (ZIKV) is a positive-sense single-stranded virus member of the Flaviviridae family. Among other arboviruses, ZIKV can cause neurological disorders such as Guillain Barré syndrome, and it can have congenital neurological manifestations and affect fertility. ZIKV nonstructural protein 5 (NS5) is essential for viral replication and limiting host immune detection. Herein, we performed virtual screening to identify novel small-molecule inhibitors of the ZIKV NS5 methyltransferase (MTase) domain. Compounds were tested against the MTases of both ZIKV and DENV, demonstrating good inhibitory activities against ZIKV MTase. Extensive molecular dynamic studies conducted on the series led us to identify other derivatives with improved activity against the MTase and limiting ZIKV infection with an increased selectivity index. Preliminary pharmacokinetic parameters have been determined, revealing excellent stability over time. Preliminary in vivo toxicity studies demonstrated that the hit compound 17 is well tolerated after acute administration. Our results provide the basis for further optimization studies on novel non-nucleoside MTase inhibitors. Full article
(This article belongs to the Special Issue Cutting-Edge Research on Antiviral Therapy)
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16 pages, 2728 KiB  
Article
Transcriptome Analysis Reveals Coexpression Networks and Hub Genes Involved in Papillae Development in Lilium auratum
by Yuntao Zhu, Jie Yang, Xiaolin Liu, Tingting Sun, Yiran Zhao, Fayun Xiang, Feng Chen and Hengbin He
Int. J. Mol. Sci. 2024, 25(4), 2436; https://doi.org/10.3390/ijms25042436 - 19 Feb 2024
Viewed by 542
Abstract
Lilium is a genus of important ornamental plants with many colouring pattern variations. Lilium auratum is the parent of Oriental hybrid lilies. A typical feature of L. auratum is the presence of red-orange special raised spots named papillae on the interior tepals. Unlike [...] Read more.
Lilium is a genus of important ornamental plants with many colouring pattern variations. Lilium auratum is the parent of Oriental hybrid lilies. A typical feature of L. auratum is the presence of red-orange special raised spots named papillae on the interior tepals. Unlike the usual raised spots, the papillae are slightly rounded or connected into sheets and usually have hairy tips. To elucidate the potential genes regulating papillae development in L. auratum, we performed high-throughput sequencing of its tepals at different stages. Genes involved in the flavonoid biosynthesis pathway were significantly enriched during the colouration of the papillae, and CHS, F3H, F3′H, FLS, DFR, ANS, and UFGT were significantly upregulated. To identify the key genes involved in the papillae development of L. auratum, we performed weighted gene coexpression network analysis (WGCNA) and further analysed four modules. In total, 51, 24, 1, and 6 hub genes were identified in four WGCNA modules, MEbrown, MEyellow, MEpurple, and MEred, respectively. Then, the coexpression networks were constructed, and important genes involved in trichome development and coexpressed with anthocyanin biosynthesis genes, such as TT8, TTG1, and GEM, were identified. These results indicated that the papillae are essentially trichomes that accumulate anthocyanins. Finally, we randomly selected 12 hub genes for qRT-PCR analysis to verify the accuracy of our RNA-Seq analysis. Our results provide new insights into the papillae development in L. auratum flowers. Full article
(This article belongs to the Section Molecular Biology)
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22 pages, 5015 KiB  
Article
Antitumor Effects of Intravenous Natural Killer Cell Infusion in an Orthotopic Glioblastoma Xenograft Murine Model and Gene Expression Profile Analysis
by Takayuki Morimoto, Tsutomu Nakazawa, Ryosuke Matsuda, Ryosuke Maeoka, Fumihiko Nishimura, Mitsutoshi Nakamura, Shuichi Yamada, Young-Soo Park, Takahiro Tsujimura and Ichiro Nakagawa
Int. J. Mol. Sci. 2024, 25(4), 2435; https://doi.org/10.3390/ijms25042435 - 19 Feb 2024
Viewed by 770
Abstract
Despite standard multimodality treatment, containing maximum safety resection, temozolomide, radiotherapy, and a tumor-treating field, patients with glioblastoma (GBM) present with a dismal prognosis. Natural killer cell (NKC)-based immunotherapy would play a critical role in GBM treatment. We have previously reported highly activated and [...] Read more.
Despite standard multimodality treatment, containing maximum safety resection, temozolomide, radiotherapy, and a tumor-treating field, patients with glioblastoma (GBM) present with a dismal prognosis. Natural killer cell (NKC)-based immunotherapy would play a critical role in GBM treatment. We have previously reported highly activated and ex vivo expanded NK cells derived from human peripheral blood, which exhibited anti-tumor effect against GBM cells. Here, we performed preclinical evaluation of the NK cells using an in vivo orthotopic xenograft model, the U87MG cell-derived brain tumor in NOD/Shi-scid, IL-2RɤKO (NOG) mouse. In the orthotopic xenograft model, the retro-orbital venous injection of NK cells prolonged overall survival of the NOG mouse, indirectly indicating the growth-inhibition effect of NK cells. In addition, we comprehensively summarized the differentially expressed genes, especially focusing on the expression of the NKC-activating receptors’ ligands, inhibitory receptors’ ligands, chemokines, and chemokine receptors, between murine brain tumor treated with NKCs and with no agents, by using microarray. Furthermore, we also performed differentially expressed gene analysis between an internal and external brain tumor in the orthotopic xenograft model. Our findings could provide pivotal information for the NK-cell-based immunotherapy for patients with GBM. Full article
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19 pages, 12890 KiB  
Article
Selection and Validation of Reference Genes for Gene Expression in Bactericera gobica Loginova under Different Insecticide Stresses
by Hongshuang Wei, Jingyi Zhang, Mengke Yang, Yao Li, Kun Guo, Haili Qiao, Rong Xu, Sai Liu and Changqing Xu
Int. J. Mol. Sci. 2024, 25(4), 2434; https://doi.org/10.3390/ijms25042434 - 19 Feb 2024
Viewed by 475
Abstract
Insecticide resistance has long been a problem in crop pest control. Bactericera gobica is a major pest on the well-known medicinal plants Lycium barbarum L. Investigating insecticide resistance mechanisms of B. gobica will help to identify pesticide reduction strategies to control the pest. [...] Read more.
Insecticide resistance has long been a problem in crop pest control. Bactericera gobica is a major pest on the well-known medicinal plants Lycium barbarum L. Investigating insecticide resistance mechanisms of B. gobica will help to identify pesticide reduction strategies to control the pest. Gene expression normalization by RT-qPCR requires the selection and validation of appropriate reference genes (RGs). Here, 15 candidate RGs were selected from transcriptome data of B. gobica. Their expression stability was evaluated with five algorithms (Delta Ct, GeNorm, Normfinder, BestKeeper and RefFinder) for sample types differing in response to five insecticide stresses and in four other experimental conditions. Our results indicated that the RGs RPL10 + RPS15 for Imidacloprid and Abamectin; RPL10 + AK for Thiamethoxam; RPL32 + RPL10 for λ-cyhalothrin; RPL10 + RPL8 for Matrine; and EF2 + RPL32 under different insecticide stresses were the most suitable RGs for RT-qPCR normalization. EF1α + RPL8, EF1α + β-actin, β-actin + EF2 and β-actin + RPS15 were the optimal combination of RGs under odor stimulation, temperature, developmental stages and both sexes, respectively. Overall, EF2 and RPL8 were the two most stable RGs in all conditions, while α-TUB and RPL32 were the least stable RGs. The corresponding suitable RGs and one unstable RG were used to normalize a target cytochrome P450 CYP6a1 gene between adult and nymph stages and under imidacloprid stress. The results of CYP6a1 expression were consistent with transcriptome data. This study is the first research on the most stable RG selection in B. gobica nymphs exposed to different insecticides, which will contribute to further research on insecticide resistance mechanisms in B. gobica. Full article
(This article belongs to the Collection Feature Papers in Molecular Microbiology)
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13 pages, 4113 KiB  
Article
TIGAR Deficiency Blunts Angiotensin-II-Induced Cardiac Hypertrophy in Mice
by Xiaochen He, Quinesha A. Williams, Aubrey C. Cantrell, Jessie Besanson, Heng Zeng and Jian-Xiong Chen
Int. J. Mol. Sci. 2024, 25(4), 2433; https://doi.org/10.3390/ijms25042433 - 19 Feb 2024
Viewed by 602
Abstract
Hypertension is the key contributor to pathological cardiac hypertrophy. Growing evidence indicates that glucose metabolism plays an essential role in cardiac hypertrophy. TP53-induced glycolysis and apoptosis regulator (TIGAR) has been shown to regulate glucose metabolism in pressure overload-induced cardiac remodeling. In the present [...] Read more.
Hypertension is the key contributor to pathological cardiac hypertrophy. Growing evidence indicates that glucose metabolism plays an essential role in cardiac hypertrophy. TP53-induced glycolysis and apoptosis regulator (TIGAR) has been shown to regulate glucose metabolism in pressure overload-induced cardiac remodeling. In the present study, we investigated the role of TIGAR in cardiac remodeling during Angiotensin II (Ang-II)-induced hypertension. Wild-type (WT) and TIGAR knockout (KO) mice were infused with Angiotensin-II (Ang-II, 1 µg/kg/min) via mini-pump for four weeks. The blood pressure was similar between the WT and TIGAR KO mice. The Ang-II infusion resulted in a similar reduction of systolic function in both groups, as evidenced by the comparable decrease in LV ejection fraction and fractional shortening. The Ang-II infusion also increased the isovolumic relaxation time and myocardial performance index to the same extent in WT and TIGAR KO mice, suggesting the development of similar diastolic dysfunction. However, the knockout of TIGAR significantly attenuated hypertension-induced cardiac hypertrophy. This was associated with higher levels of fructose 2,6-bisphosphate, PFK-1, and Glut-4 in the TIGAR KO mice. Our present study suggests that TIGAR is involved in the control of glucose metabolism and glucose transporters by Ang-II and that knockout of TIGAR attenuates the development of maladaptive cardiac hypertrophy. Full article
(This article belongs to the Special Issue Metabolic Mechanisms of Cardiac Injury)
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34 pages, 6287 KiB  
Article
Immunoinformatic Identification of Multiple Epitopes of gp120 Protein of HIV-1 to Enhance the Immune Response against HIV-1 Infection
by Arslan Habib, Yulai Liang, Xinyi Xu, Naishuo Zhu and Jun Xie
Int. J. Mol. Sci. 2024, 25(4), 2432; https://doi.org/10.3390/ijms25042432 - 19 Feb 2024
Viewed by 866
Abstract
Acquired Immunodeficiency Syndrome is caused by the Human Immunodeficiency Virus (HIV), and a significant number of fatalities occur annually. There is a dire need to develop an effective vaccine against HIV-1. Understanding the structural proteins of viruses helps in designing a vaccine based [...] Read more.
Acquired Immunodeficiency Syndrome is caused by the Human Immunodeficiency Virus (HIV), and a significant number of fatalities occur annually. There is a dire need to develop an effective vaccine against HIV-1. Understanding the structural proteins of viruses helps in designing a vaccine based on immunogenic peptides. In the current experiment, we identified gp120 epitopes using bioinformatic epitope prediction tools, molecular docking, and MD simulations. The Gb-1 peptide was considered an adjuvant. Consecutive sequences of GTG, GSG, GGTGG, and GGGGS linkers were used to bind the B cell, Cytotoxic T Lymphocytes (CTL), and Helper T Lymphocytes (HTL) epitopes. The final vaccine construct consisted of 315 amino acids and is expected to be a recombinant protein of approximately 35.49 kDa. Based on docking experiments, molecular dynamics simulations, and tertiary structure validation, the analysis of the modeled protein indicates that it possesses a stable structure and can interact with Toll-like receptors. The analysis demonstrates that the proposed vaccine can provoke an immunological response by activating T and B cells, as well as stimulating the release of IgA and IgG antibodies. This vaccine shows potential for HIV-1 prophylaxis. The in-silico design suggests that multiple-epitope constructs can be used as potentially effective immunogens for HIV-1 vaccine development. Full article
(This article belongs to the Section Molecular Immunology)
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26 pages, 5084 KiB  
Article
An Integrated Comprehensive Peptidomics and In Silico Analysis of Bioactive Peptide-Rich Milk Fermented by Three Autochthonous Cocci Strains
by Martina Banić, Katarina Butorac, Nina Čuljak, Ana Butorac, Jasna Novak, Andreja Leboš Pavunc, Anamarija Rušanac, Željka Stanečić, Marija Lovrić, Jagoda Šušković and Blaženka Kos
Int. J. Mol. Sci. 2024, 25(4), 2431; https://doi.org/10.3390/ijms25042431 - 19 Feb 2024
Viewed by 853
Abstract
Bioactive peptides (BPs) are molecules of paramount importance with great potential for the development of functional foods, nutraceuticals or therapeutics for the prevention or treatment of various diseases. A functional BP-rich dairy product was produced by lyophilisation of bovine milk fermented by the [...] Read more.
Bioactive peptides (BPs) are molecules of paramount importance with great potential for the development of functional foods, nutraceuticals or therapeutics for the prevention or treatment of various diseases. A functional BP-rich dairy product was produced by lyophilisation of bovine milk fermented by the autochthonous strains Lactococcus lactis subsp. lactis ZGBP5-51, Enterococcus faecium ZGBP5-52 and Enterococcus faecalis ZGBP5-53 isolated from the same artisanal fresh cheese. The efficiency of the proteolytic system of the implemented strains in the production of BPs was confirmed by a combined high-throughput mass spectrometry (MS)-based peptidome profiling and an in silico approach. First, peptides released by microbial fermentation were identified via a non-targeted peptide analysis (NTA) comprising reversed-phase nano-liquid chromatography (RP nano-LC) coupled with matrix-assisted laser desorption/ionisation-time-of-flight/time-of-flight (MALDI-TOF/TOF) MS, and then quantified by targeted peptide analysis (TA) involving RP ultrahigh-performance LC (RP-UHPLC) coupled with triple-quadrupole MS (QQQ-MS). A combined database and literature search revealed that 10 of the 25 peptides identified in this work have bioactive properties described in the literature. Finally, by combining the output of MS-based peptidome profiling with in silico bioactivity prediction tools, three peptides (75QFLPYPYYAKPA86, 40VAPFPEVFGK49, 117ARHPHPHLSF126), whose bioactive properties have not been previously reported in the literature, were identified as potential BP candidates. Full article
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20 pages, 4422 KiB  
Article
Rapid Antibacterial Activity Assessment of Chimeric Lysins
by Jin-Mi Park, Jun-Hyun Kim, Gun Kim, Hun-Ju Sim, Sun-Min Ahn, Kang-Seuk Choi and Hyuk-Joon Kwon
Int. J. Mol. Sci. 2024, 25(4), 2430; https://doi.org/10.3390/ijms25042430 - 19 Feb 2024
Viewed by 504
Abstract
Various chimeric lysins have been developed as efficacious antibiotics against multidrug-resistant bacteria, but direct comparisons of their antibacterial activities have been difficult due to the preparation of multiple recombinant chimeric lysins. Previously, we reported an Escherichia coli cell-free expression method to better screen [...] Read more.
Various chimeric lysins have been developed as efficacious antibiotics against multidrug-resistant bacteria, but direct comparisons of their antibacterial activities have been difficult due to the preparation of multiple recombinant chimeric lysins. Previously, we reported an Escherichia coli cell-free expression method to better screen chimeric lysins against Staphylococcus aureus, but we still needed to increase the amounts of expressed proteins enough to be able to detect them non-isotopically for quantity comparisons. In this study, we improved the previous cell-free expression system by adding a previously reported artificial T7 terminator and reversing the different nucleotides between the T7 promoter and start codon to those of the T7 phage. The new method increased the expressed amount of chimeric lysins enough for us to detect them using Western blotting. Therefore, the qualitative comparison of activity between different chimeric lysins has become possible via the adjustment of the number of variables between samples without protein purification. We applied this method to select more active chimeric lysins derived from our previously reported chimeric lysin (ALS2). Finally, we compared the antibacterial activities of our selected chimeric lysins with reported chimeric lysins (ClyC and ClyO) and lysostaphin and determined the rank orders of antibacterial activities on different Staphylococcus aureus strains in our experimental conditions. Full article
(This article belongs to the Special Issue Recent Research on Antimicrobial Agents)
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11 pages, 3473 KiB  
Communication
Correlation of Experimental and Calculated Inhibition Constants of Protease Inhibitor Complexes
by Peter Goettig, Xingchen Chen and Jonathan M. Harris
Int. J. Mol. Sci. 2024, 25(4), 2429; https://doi.org/10.3390/ijms25042429 - 19 Feb 2024
Viewed by 566
Abstract
Predicting the potency of inhibitors is key to in silico screening of promising synthetic or natural compounds. Here we describe a predictive workflow that provides calculated inhibitory values, which concord well with empirical data. Calculations of the free interaction energy ΔG with the [...] Read more.
Predicting the potency of inhibitors is key to in silico screening of promising synthetic or natural compounds. Here we describe a predictive workflow that provides calculated inhibitory values, which concord well with empirical data. Calculations of the free interaction energy ΔG with the YASARA plugin FoldX were used to derive inhibition constants Ki from PDB coordinates of protease–inhibitor complexes. At the same time, corresponding KD values were obtained from the PRODIGY server. These results correlated well with the experimental values, particularly for serine proteases. In addition, analyses were performed for inhibitory complexes of cysteine and aspartic proteases, as well as of metalloproteases, whereby the PRODIGY data appeared to be more consistent. Based on our analyses, we calculated theoretical Ki values for trypsin with sunflower trypsin inhibitor (SFTI-1) variants, which yielded the more rigid Pro14 variant, with probably higher potency than the wild-type inhibitor. Moreover, a hirudin variant with an Arg1 and Trp3 is a promising basis for novel thrombin inhibitors with high potency. Further examples from antibody interaction and a cancer-related effector-receptor system demonstrate that our approach is applicable to protein interaction studies beyond the protease field. Full article
(This article belongs to the Section Molecular Biophysics)
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21 pages, 2536 KiB  
Article
Multiple Lines of Evidence Support 199 SARS-CoV-2 Positively Selected Amino Acid Sites
by Pedro Ferreira, Ricardo Soares, Hugo López-Fernández, Noé Vazquez, Miguel Reboiro-Jato, Cristina P. Vieira and Jorge Vieira
Int. J. Mol. Sci. 2024, 25(4), 2428; https://doi.org/10.3390/ijms25042428 - 19 Feb 2024
Viewed by 673
Abstract
SARS-CoV-2 amino acid variants that contribute to an increased transmissibility or to host immune system escape are likely to increase in frequency due to positive selection and may be identified using different methods, such as codeML, FEL, FUBAR, and MEME. Nevertheless, when using [...] Read more.
SARS-CoV-2 amino acid variants that contribute to an increased transmissibility or to host immune system escape are likely to increase in frequency due to positive selection and may be identified using different methods, such as codeML, FEL, FUBAR, and MEME. Nevertheless, when using different methods, the results do not always agree. The sampling scheme used in different studies may partially explain the differences that are found, but there is also the possibility that some of the identified positively selected amino acid sites are false positives. This is especially important in the context of very large-scale projects where hundreds of analyses have been performed for the same protein-coding gene. To account for these issues, in this work, we have identified positively selected amino acid sites in SARS-CoV-2 and 15 other coronavirus species, using both codeML and FUBAR, and compared the location of such sites in the different species. Moreover, we also compared our results to those that are available in the COV2Var database and the frequency of the 10 most frequent variants and predicted protein location to identify those sites that are supported by multiple lines of evidence. Amino acid changes observed at these sites should always be of concern. The information reported for SARS-CoV-2 can also be used to identify variants of concern in other coronaviruses. Full article
(This article belongs to the Special Issue Genetic Variability and Molecular Evolution of SARS-CoV-2)
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16 pages, 11538 KiB  
Article
Molecular Mechanism of Different Rooting Capacity between Two Clones of Taxodium hybrid ‘Zhongshanshan’
by Jiaqi Liu, Lei Xuan, Chaoguang Yu, Jianfeng Hua, Ziyang Wang, Yunlong Yin and Zhiquan Wang
Int. J. Mol. Sci. 2024, 25(4), 2427; https://doi.org/10.3390/ijms25042427 - 19 Feb 2024
Viewed by 431
Abstract
The conifer Taxodium hybrid ‘Zhongshanshan’ (T. hybrid ‘Zhongshanshan’) is characterized by rapid growth, strong stress resistance, and high ornamental value and has significant potential for use in afforestation, landscaping, and wood production. The main method of propagating T. hybrid ‘Zhongshanshan’ is tender branch cutting, but [...] Read more.
The conifer Taxodium hybrid ‘Zhongshanshan’ (T. hybrid ‘Zhongshanshan’) is characterized by rapid growth, strong stress resistance, and high ornamental value and has significant potential for use in afforestation, landscaping, and wood production. The main method of propagating T. hybrid ‘Zhongshanshan’ is tender branch cutting, but the cutting rooting abilities of different T. hybrid ‘Zhongshanshan’ clones differ significantly. To explore the causes of rooting ability differences at a molecular level, we analyzed the transcriptome data of cutting base and root tissues of T. hybrid ‘Zhongshanshan 149’ with a rooting rate of less than 5% and T. hybrid ‘Zhongshanshan 118’ with rooting rate greater than 60%, at the developmental time points in this study. The results indicated that differentially expressed genes between the two clones were mainly associated with copper ion binding, peroxidase, and oxidoreductase activity, response to oxidative stress, phenylpropanoid and flavonoid biosynthesis, and plant hormone signal transduction, among others. The expression pattern of ThAP2 was different throughout the development of the adventitive roots of the two clone cuttings. Therefore, this gene was selected for further study. It was shown that ThAP2 was a nuclear-localized transcription factor and demonstrated a positive feedback effect on rooting in transgenic Nicotiana benthamiana cuttings. Thus, the results of this study explain the molecular mechanism of cutting rooting and provide candidate gene resources for developing genetic breeding strategies for optimizing superior clones of T. hybrid ‘Zhongshanshan’. Full article
(This article belongs to the Special Issue Plant Physiology and Molecular Nutrition)
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0 pages, 14539 KiB  
Article
Inhibition of Biofilm Formation in Cutibacterium acnes, Staphylococcus aureus, and Candida albicans by the Phytopigment Shikonin
by Yong-Guy Kim, Jin-Hyung Lee, Sanghun Kim, Sunyoung Park, Yu-Jeong Kim, Choong-Min Ryu, Hwi Won Seo and Jintae Lee
Int. J. Mol. Sci. 2024, 25(4), 2426; https://doi.org/10.3390/ijms25042426 - 19 Feb 2024
Viewed by 805
Abstract
Skin microbiota, such as acne-related Cutibacterium acnes, Staphylococcus aureus, and fungal Candida albicans, can form polymicrobial biofilms with greater antimicrobial tolerance to traditional antimicrobial agents and host immune systems. In this study, the phytopigment shikonin was investigated against single-species and [...] Read more.
Skin microbiota, such as acne-related Cutibacterium acnes, Staphylococcus aureus, and fungal Candida albicans, can form polymicrobial biofilms with greater antimicrobial tolerance to traditional antimicrobial agents and host immune systems. In this study, the phytopigment shikonin was investigated against single-species and multispecies biofilms under aerobic and anaerobic conditions. Minimum inhibitory concentrations of shikonin were 10 µg/mL against C. acnes, S. aureus, and C. albicans, and at 1–5 µg/mL, shikonin efficiently inhibited single biofilm formation and multispecies biofilm development by these three microbes. Shikonin increased porphyrin production in C. acnes, inhibited cell aggregation and hyphal formation by C. albicans, decreased lipase production, and increased hydrophilicity in S. aureus. In addition, shikonin at 5 or 10 µg/mL repressed the transcription of various biofilm-related genes and virulence-related genes in C. acnes and downregulated the gene expression levels of the quorum-sensing agrA and RNAIII, α-hemolysin hla, and nuclease nuc1 in S. aureus, supporting biofilm inhibition. In addition, shikonin prevented multispecies biofilm development on porcine skin, and the antimicrobial efficacy of shikonin was recapitulated in a mouse infection model, in which it promoted skin regeneration. The study shows that shikonin inhibits multispecies biofilm development by acne-related skin microbes and might be useful for controlling bacterial infections. Full article
(This article belongs to the Special Issue New Insights in Bioactive Compounds as Antibiofilm Agents)
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15 pages, 4119 KiB  
Article
Comprehensive Analysis of the GRAS Gene Family in Paulownia fortunei and the Response of DELLA Proteins to Paulownia Witches’ Broom
by Yixiao Li, Yabing Cao, Yujie Fan and Guoqiang Fan
Int. J. Mol. Sci. 2024, 25(4), 2425; https://doi.org/10.3390/ijms25042425 - 19 Feb 2024
Viewed by 524
Abstract
The GRAS (GAI\RGA\SCL) gene family encodes plant-specific transcription factors that play crucial roles in plant growth and development, stress tolerance, and hormone network regulation. Plant dwarfing symptom is mainly regulated by DELLA proteins of the GRAS gene subfamily. In this study, the association [...] Read more.
The GRAS (GAI\RGA\SCL) gene family encodes plant-specific transcription factors that play crucial roles in plant growth and development, stress tolerance, and hormone network regulation. Plant dwarfing symptom is mainly regulated by DELLA proteins of the GRAS gene subfamily. In this study, the association between the GRAS gene family and Paulownia witches’ broom (PaWB) was investigated. A total of 79 PfGRAS genes were identified using bioinformatics methods and categorized into 11 groups based on amino acid sequences. Tandem duplication and fragment duplication were found to be the main modes of amplification of the PfGRAS gene family. Gene structure analysis showed that more than 72.1% of the PfGRASs had no introns. The genes PfGRAS12/18/58 also contained unique DELLA structural domains; only PfGRAS12, which showed significant response to PaWB phytoplasma infection in stems, showed significant tissue specificity and responded to gibberellin (GA3) in PaWB-infected plants. We found that the internodes were significantly elongated under 100 µmol·L−1 GA3 treatment for 30 days. The subcellular localization analysis indicated that PfGRAS12 is located in the nucleus and cell membrane. Yeast two-hybrid (Y2H) and bimolecular fluorescence complementation (BiFC) assays confirmed that PfGRAS12 interacted with PfJAZ3 in the nucleus. Our results will lay a foundation for further research on the functions of the PfGRAS gene family and for genetic improvement and breeding of PaWB-resistant trees. Full article
(This article belongs to the Section Molecular Plant Sciences)
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15 pages, 3857 KiB  
Article
TGF-β1 Signaling Impairs Metformin Action on Glycemic Control
by Quan Pan, Weiqi Ai and Shaodong Guo
Int. J. Mol. Sci. 2024, 25(4), 2424; https://doi.org/10.3390/ijms25042424 - 19 Feb 2024
Viewed by 625
Abstract
Hyperglycemia is a hallmark of type 2 diabetes (T2D). Metformin, the first-line drug used to treat T2D, maintains blood glucose within a normal range by suppressing hepatic glucose production (HGP). However, resistance to metformin treatment is developed in most T2D patients over time. [...] Read more.
Hyperglycemia is a hallmark of type 2 diabetes (T2D). Metformin, the first-line drug used to treat T2D, maintains blood glucose within a normal range by suppressing hepatic glucose production (HGP). However, resistance to metformin treatment is developed in most T2D patients over time. Transforming growth factor beta 1 (TGF-β1) levels are elevated both in the liver and serum of T2D humans and mice. Here, we found that TGF-β1 treatment impairs metformin action on suppressing HGP via inhibiting AMPK phosphorylation at Threonine 172 (T172). Hepatic TGF-β1 deficiency improves metformin action on glycemic control in high fat diet (HFD)-induced obese mice. In our hepatic insulin resistant mouse model (hepatic insulin receptor substrate 1 (IRS1) and IRS2 double knockout (DKO)), metformin action on glycemic control was impaired, which is largely improved by further deletion of hepatic TGF-β1 (TKObeta1) or hepatic Foxo1 (TKOfoxo1). Moreover, blockade of TGF-β1 signaling by chemical inhibitor of TGF-β1 type I receptor LY2157299 improves to metformin sensitivity in mice. Taken together, our current study suggests that hepatic TGF-β1 signaling impairs metformin action on glycemic control, and suppression of TGF-β1 signaling could serve as part of combination therapy with metformin for T2D treatment. Full article
(This article belongs to the Special Issue Drug Therapies for Diabetes)
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13 pages, 10364 KiB  
Review
Autism Spectrum Disorder: Brain Areas Involved, Neurobiological Mechanisms, Diagnoses and Therapies
by Jacopo Lamanna and Jacopo Meldolesi
Int. J. Mol. Sci. 2024, 25(4), 2423; https://doi.org/10.3390/ijms25042423 - 19 Feb 2024
Viewed by 1347
Abstract
Autism spectrum disorder (ASD), affecting over 2% of the pre-school children population, includes an important fraction of the conditions accounting for the heterogeneity of autism. The disease was discovered 75 years ago, and the present review, based on critical evaluations of the recognized [...] Read more.
Autism spectrum disorder (ASD), affecting over 2% of the pre-school children population, includes an important fraction of the conditions accounting for the heterogeneity of autism. The disease was discovered 75 years ago, and the present review, based on critical evaluations of the recognized ASD studies from the beginning of 1990, has been further developed by the comparative analyses of the research and clinical reports, which have grown progressively in recent years up to late 2023. The tools necessary for the identification of the ASD disease and its related clinical pathologies are genetic and epigenetic mutations affected by the specific interaction with transcription factors and chromatin remodeling processes occurring within specific complexes of brain neurons. Most often, the ensuing effects induce the inhibition/excitation of synaptic structures sustained primarily, at dendritic fibers, by alterations of flat and spine response sites. These effects are relevant because synapses, established by specific interactions of neurons with glial cells, operate as early and key targets of ASD. The pathology of children is often suspected by parents and communities and then confirmed by ensuing experiences. The final diagnoses of children and mature patients are then completed by the combination of neuropsychological (cognitive) tests and electro-/magneto-encephalography studies developed in specialized centers. ASD comorbidities, induced by processes such as anxieties, depressions, hyperactivities, and sleep defects, interact with and reinforce other brain diseases, especially schizophrenia. Advanced therapies, prescribed to children and adult patients for the control of ASD symptoms and disease, are based on the combination of well-known brain drugs with classical tools of neurologic and psychiatric practice. Overall, this review reports and discusses the advanced knowledge about the biological and medical properties of ASD. Full article
(This article belongs to the Special Issue Physiology and Pathology of Neurons 2.0)
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16 pages, 330 KiB  
Review
From the Friend to the Foe—Enterococcus faecalis Diverse Impact on the Human Immune System
by Agnieszka Daca and Tomasz Jarzembowski
Int. J. Mol. Sci. 2024, 25(4), 2422; https://doi.org/10.3390/ijms25042422 - 19 Feb 2024
Viewed by 901
Abstract
Enterococcus faecalis is a bacterium which accompanies us from the first days of our life. As a commensal it produces vitamins, metabolizes nutrients, and maintains intestinal pH. All of that happens in exchange for a niche to inhabit. It is not surprising then, [...] Read more.
Enterococcus faecalis is a bacterium which accompanies us from the first days of our life. As a commensal it produces vitamins, metabolizes nutrients, and maintains intestinal pH. All of that happens in exchange for a niche to inhabit. It is not surprising then, that the bacterium was and is used as an element of many probiotics and its positive impact on the human immune system and the body in general is hard to ignore. This bacterium has also a dark side though. The plasticity and relative ease with which one acquires virulence traits, and the ability to hide from or even deceive and use the immune system to spread throughout the body make E. faecalis a more and more dangerous opponent. The statistics clearly show its increasing role, especially in the case of nosocomial infections. Here we present the summarization of current knowledge about E. faecalis, especially in the context of its relations with the human immune system. Full article
(This article belongs to the Special Issue Diverse Responses of Immune Cells to Bacterial Infections)
14 pages, 3517 KiB  
Article
Novel Immortalized Human Multipotent Mesenchymal Stromal Cell Line for Studying Hormonal Signaling
by Alexandra Primak, Natalia Kalinina, Mariya Skryabina, Vladimir Usachev, Vadim Chechekhin, Maksim Vigovskiy, Elizaveta Chechekhina, Nikita Voloshin, Konstantin Kulebyakin, Maria Kulebyakina, Olga Grigorieva, Pyotr Tyurin-Kuzmin, Nataliya Basalova, Anastasia Efimenko, Stalik Dzhauari, Yulia Antropova, Ivan Plyushchii, Zhanna Akopyan, Veronika Sysoeva, Vsevolod Tkachuk and Maxim Karagyauradd Show full author list remove Hide full author list
Int. J. Mol. Sci. 2024, 25(4), 2421; https://doi.org/10.3390/ijms25042421 - 19 Feb 2024
Viewed by 672
Abstract
Multipotent mesenchymal stromal cells (MSCs) integrate hormone and neuromediator signaling to coordinate tissue homeostasis, tissue renewal and regeneration. To facilitate the investigation of MSC biology, stable immortalized cell lines are created (e.g., commercially available ASC52telo). However, the ASC52telo cell line has an impaired [...] Read more.
Multipotent mesenchymal stromal cells (MSCs) integrate hormone and neuromediator signaling to coordinate tissue homeostasis, tissue renewal and regeneration. To facilitate the investigation of MSC biology, stable immortalized cell lines are created (e.g., commercially available ASC52telo). However, the ASC52telo cell line has an impaired adipogenic ability and a depressed response to hormones, including 5-HT, GABA, glutamate, noradrenaline, PTH and insulin compared to primary cells. This markedly reduces the potential of the ASC52telo cell line in studying the mechanisms of hormonal control of MSC’s physiology. Here, we have established a novel immortalized culture of adipose tissue-derived MSCs via forced telomerase expression after lentiviral transduction. These immortalized cell cultures demonstrate high proliferative potential (up to 40 passages), delayed senescence, as well as preserved primary culture-like functional activity (sensitivity to hormones, ability to hormonal sensitization and differentiation) and immunophenotype up to 17–26 passages. Meanwhile, primary adipose tissue-derived MSCs usually irreversibly lose their properties by 8–10 passages. Observed characteristics of reported immortalized human MSC cultures make them a feasible model for studying molecular mechanisms, which regulate the functional activities of these cells, especially when primary cultures or commercially available cell lines are not appropriate. Full article
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