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Int. J. Mol. Sci., Volume 25, Issue 20 (October-2 2024) – 465 articles

Cover Story (view full-size image): In the context of a circular economy, this study explores the valorization of blueberry pomace as a source of bioactive compounds through sustainable extraction methods. Microwave-assisted extraction (MAE) and subcritical water extraction (MASWE) were used sequentially to obtain two fractions: MAE 1°, rich in anthocyanins with potential as a natural pigment and anti-diabetic/anti-viral agent, and MASWE 2°, high in phenolics with possible applications in Alzheimer’s, melanogenesis, oxidative stress protection, and anthocyanin preservation. The extract characteristics were compared with a conventional method (MeOH-HCl in reflux), and the protocol’s sustainability was assessed using green metrics, highlighting its environmental impact and efficiency while showcasing an eco-friendly approach to converting agri-food waste into high-value products for multiple sectors. View this paper
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24 pages, 12087 KiB  
Article
The Degradation of Absorbable Surgical Threads in Body Fluids: Insights from Infrared Spectroscopy Studies
by Katarzyna Merkel, Katarzyna Grzybowska, Aleksandra Strach and Marcin Gierek
Int. J. Mol. Sci. 2024, 25(20), 11333; https://doi.org/10.3390/ijms252011333 - 21 Oct 2024
Viewed by 984
Abstract
This study investigates the degradation of six different types of absorbable surgical threads commonly used in clinical practice, focusing on their response to exposure to physiological fluids. The threads were subjected to hydrolytic and enzymatic degradation in physiological saline, bile, and pancreatic juice. [...] Read more.
This study investigates the degradation of six different types of absorbable surgical threads commonly used in clinical practice, focusing on their response to exposure to physiological fluids. The threads were subjected to hydrolytic and enzymatic degradation in physiological saline, bile, and pancreatic juice. Our findings demonstrate that bile and pancreatic juice, particularly when contaminated with bacterial strains such as Escherichia coli, Klebsiella spp., and Enterococcus faecalis, significantly accelerate the degradation process. Using Fourier-transform infrared spectroscopy (FTIR), scanning electron microscopy (SEM), and tensile strength testing, we observed distinct differences in the chemical structure and mechanical integrity of the sutures. Principal component analysis (PCA) of the FTIR spectra revealed that PDS threads exhibited the highest resistance to degradation, maintaining their mechanical properties for a longer duration compared with Monocryl and Vicryl. These results highlight the critical role of thread selection in gastrointestinal surgeries, where prolonged exposure to bile and pancreatic juice can compromise the suture integrity and lead to postoperative complications. The insights gained from this study will contribute to improving the selection and application of absorbable threads in clinical settings. Full article
(This article belongs to the Special Issue Molecular Dynamics, Structures, and Applications of Polymeric Materials)
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17 pages, 2559 KiB  
Article
New Evidence for the Role of the Blood-Brain Barrier and Inflammation in Stress-Associated Depression: A Gene-Environment Analysis Covering 19,296 Genes in 109,360 Humans
by Zsofia Gal, Dora Torok, Xenia Gonda, Nora Eszlari, Ian Muir Anderson, Bill Deakin, Peter Petschner, Gabriella Juhasz and Gyorgy Bagdy
Int. J. Mol. Sci. 2024, 25(20), 11332; https://doi.org/10.3390/ijms252011332 - 21 Oct 2024
Viewed by 805
Abstract
Mounting evidence supports the key role of the disrupted integrity of the blood-brain barrier (BBB) in stress- and inflammation-associated depression. We assumed that variations in genes regulating the expression and coding proteins constructing and maintaining this barrier, along with those involved in inflammation, [...] Read more.
Mounting evidence supports the key role of the disrupted integrity of the blood-brain barrier (BBB) in stress- and inflammation-associated depression. We assumed that variations in genes regulating the expression and coding proteins constructing and maintaining this barrier, along with those involved in inflammation, have a predisposing or protecting role in the development of depressive symptoms after experiencing severe stress. To prove this, genome-by-environment (GxE) interaction analyses were conducted on 6.26 M SNPS covering 19,296 genes on PHQ9 depression in interaction with adult traumatic events scores in the UK Biobank (n = 109,360) in a hypothesis-free setup. Among the 63 genes that were significant in stress-connected depression, 17 were associated with BBB, 23 with inflammatory processes, and 4 with neuroticism. Compared to all genes, the enrichment of significant BBB-associated hits was 3.82, and those of inflammation-associated hits were 1.59. Besides some sex differences, CSMD1 and PTPRD, encoding proteins taking part in BBB integrity, were the most significant hits in both males and females. In conclusion, the identified risk genes and their encoded proteins could provide biomarkers or new drug targets to promote BBB integrity and thus prevent or decrease stress- and inflammation-associated depressive symptoms, and possibly infection, e.g., COVID-19-associated mental and neurological symptoms. Full article
(This article belongs to the Special Issue Activation of the Blood–Brain Barrier and Neurological Dysfunction)
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16 pages, 1187 KiB  
Article
A Novel Biosynthetic Strategy for Ginsenoside Ro: Construction of a Metabolically Engineered Saccharomyces cerevisiae Strain Using a Newly Identified UGAT Gene from Panax ginseng as the Key Enzyme Gene and Optimization of Fermentation Conditions
by Xiaochen Yu, Jinghui Yu, Dinghui Wang, Sizhang Liu, Kangyu Wang, Mingzhu Zhao, Ping Chen, Yanfang Wang, Yi Wang and Meiping Zhang
Int. J. Mol. Sci. 2024, 25(20), 11331; https://doi.org/10.3390/ijms252011331 - 21 Oct 2024
Viewed by 737
Abstract
Ginsenoside Ro, as one of the few oleanane-type ginsenosides, is well known for its unique molecular structure and biological activities. Currently, research on the biosynthesis of ginsenoside Ro is still in its early stages. Therefore, the establishment of a new ginsenoside Ro cell [...] Read more.
Ginsenoside Ro, as one of the few oleanane-type ginsenosides, is well known for its unique molecular structure and biological activities. Currently, research on the biosynthesis of ginsenoside Ro is still in its early stages. Therefore, the establishment of a new ginsenoside Ro cell factory is of great significance for the in-depth development and utilization of genes related to ginsenoside Ro synthesis, as well as for the exploration of pathways to obtain ginsenoside Ro. In this study, we cloned endogenous constitutive promoters, terminators, and other genetic elements from S. cerevisiae BY4741. These elements were then sequentially assembled with the uridine diphosphate glucuronic acid transferase gene identified in our previously study (PgUGAT252645) and several other reported key enzyme genes, to construct DNA fragments used for integration into the genome of S. cerevisiae BY4741. By sequentially transferring these DNA fragments into chemically competent cells of engineering strains and conducting screening and target product detection, we successfully constructed an engineered S. cerevisiae strain (BY-Ro) for ginsenoside Ro biosynthesis using S. cerevisiae BY4741 as the host cell. Strain BY-Ro produced 253.32 μg/L of ginsenoside Ro under optimal fermentation conditions. According to subsequent measurements and calculations, this equates to 0.033 mg/g DCW, corresponding to approximately 31% of the ginsenoside Ro content found in plant samples. This study not only included a deeper investigation into the function of PgUGAT252645 but also provides a novel engineering platform for ginsenoside Ro biosynthesis. Full article
(This article belongs to the Special Issue Molecular Mechanism Discovery of the Bioactive Phytochemicals against Different Diseases Based on Network Pharmacology and Molecular Docking)
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16 pages, 7768 KiB  
Article
Genome-Wide Identification of the Cyclic Nucleotide-Gated Ion Channel Gene Family and Expression Profiles Under Low-Temperature Stress in Luffa cylindrica L.
by Jianting Liu, Yuqian Wang, Lijuan Peng, Mindong Chen, Xinru Ye, Yongping Li, Zuliang Li, Qingfang Wen and Haisheng Zhu
Int. J. Mol. Sci. 2024, 25(20), 11330; https://doi.org/10.3390/ijms252011330 - 21 Oct 2024
Viewed by 764
Abstract
Cyclic nucleotide-gated ion channels (CNGCs) are cell membrane channel proteins for calcium ions. They have been reported to play important roles in survival and in the responses to environmental factors in various plants. However, little is known about the CNGC family and its [...] Read more.
Cyclic nucleotide-gated ion channels (CNGCs) are cell membrane channel proteins for calcium ions. They have been reported to play important roles in survival and in the responses to environmental factors in various plants. However, little is known about the CNGC family and its functions in luffa (Luffa cylindrica L.). In this study, a bioinformatics-based method was used to identify members of the CNGC gene family in L. cylindrica. In total, 20 LcCNGCs were detected, and they were grouped into five subfamilies (I, II, Ⅲ, IV-a, and IV-b) in a phylogenetic analysis with CNGCs from Arabidopsis thaliana (20 AtCNGCs) and Momordica charantia (17 McCNGCs). The 20 LcCNGC genes were unevenly distributed on 11 of the 13 chromosomes in luffa, with none on Chromosomes 1 and 5. The members of each subfamily encoded proteins with highly conserved functional domains. An evolutionary analysis of CNGCs in luffa revealed three gene losses and a motif deletion. An examination of gene replication events during evolution indicated that two tandemly duplicated gene pairs were the primary driving force behind the evolution of the LcCNGC gene family. PlantCARE analyses of the LcCNGC promoter regions revealed various cis-regulatory elements, including those responsive to plant hormones (abscisic acid, methyl jasmonate, and salicylic acid) and abiotic stresses (light, drought, and low temperature). The presence of these cis-acting elements suggested that the encoded CNGC proteins may be involved in stress responses, as well as growth and development. Transcriptome sequencing (RNA-seq) analyses revealed tissue-specific expression patterns of LcCNGCs in various plant parts (roots, stems, leaves, flowers, and fruit) and the upregulation of some LcCNGCs under low-temperature stress. To confirm the accuracy of the RNA-seq data, 10 cold-responsive LcCNGC genes were selected for verification by quantitative real-time polymerase chain reaction (RT-qPCR) analysis. Under cold conditions, LcCNGC4 was highly upregulated (>50-fold increase in its transcript levels), and LcCNGC3, LcCNGC6, and LcCNGC13 were upregulated approximately 10-fold. Our findings provide new information about the evolution of the CNGC family in L. cylindrica and provide insights into the functions of the encoded CNGC proteins. Full article
(This article belongs to the Special Issue Transcription Factors in Plant Gene Expression Regulation)
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14 pages, 976 KiB  
Review
Regenerative Inflammation: The Mechanism Explained from the Perspective of Buffy-Coat Protagonism and Macrophage Polarization
by Rubens Andrade Martins, Fábio Ramos Costa, Luyddy Pires, Márcia Santos, Gabriel Silva Santos, João Vitor Lana, Bruno Ramos Costa, Napoliane Santos, Alex Pontes de Macedo, André Kruel and José Fábio Lana
Int. J. Mol. Sci. 2024, 25(20), 11329; https://doi.org/10.3390/ijms252011329 - 21 Oct 2024
Viewed by 1081
Abstract
The buffy-coat, a layer of leukocytes and platelets obtained from peripheral blood centrifugation, plays a crucial role in tissue regeneration and the modulation of inflammatory responses. This article explores the mechanisms of regenerative inflammation, highlighting the critical role of the buffy-coat in influencing [...] Read more.
The buffy-coat, a layer of leukocytes and platelets obtained from peripheral blood centrifugation, plays a crucial role in tissue regeneration and the modulation of inflammatory responses. This article explores the mechanisms of regenerative inflammation, highlighting the critical role of the buffy-coat in influencing macrophage polarization and its therapeutic potential. Macrophage polarization into M1 and M2 subtypes is pivotal in balancing inflammation and tissue repair, with M1 macrophages driving pro-inflammatory responses and M2 macrophages promoting tissue healing and regeneration. The buffy-coat’s rich composition of progenitor cells, cytokines, and growth factors—such as interleukin-10, transforming growth factor-β, and monocyte colony-stimulating factor—supports the transition from M1 to M2 macrophages, enhancing tissue repair and the resolution of inflammation. This dynamic interaction between buffy-coat components and macrophages opens new avenues for therapeutic strategies aimed at improving tissue regeneration and managing inflammatory conditions, particularly in musculoskeletal diseases such as osteoarthritis. Furthermore, the use of buffy-coat-derived therapies in conjunction with other regenerative modalities, such as platelet-rich plasma, holds promise for more effective clinical outcomes. Full article
(This article belongs to the Special Issue Macrophage Polarization: Learning to Manage It 4.0)
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17 pages, 1754 KiB  
Article
Sexual Dimorphism in Impairment of Acetylcholine-Mediated Vasorelaxation in Zucker Diabetic Fatty (ZDF) Rat Aorta: A Monogenic Model of Obesity-Induced Type 2 Diabetes
by Rifat Ara Islam, Xiaoyuan Han, Sonali Shaligram, Mitra Esfandiarei, John N. Stallone and Roshanak Rahimian
Int. J. Mol. Sci. 2024, 25(20), 11328; https://doi.org/10.3390/ijms252011328 - 21 Oct 2024
Viewed by 723
Abstract
Several reports, including our previous studies, indicate that hyperglycemia and diabetes mellitus exert differential effects on vascular function in males and females. This study examines sex differences in the vascular effects of type 2 diabetes (T2D) in an established monogenic model of obesity-induced [...] Read more.
Several reports, including our previous studies, indicate that hyperglycemia and diabetes mellitus exert differential effects on vascular function in males and females. This study examines sex differences in the vascular effects of type 2 diabetes (T2D) in an established monogenic model of obesity-induced T2D, Zucker Diabetic Fatty (ZDF) rats. Acetylcholine (ACh) responses were assessed in phenylephrine pre-contracted rings before and after apocynin, a NADPH oxidase (NOX) inhibitor. The mRNA expressions of aortic endothelial NOS (eNOS), and key NOX isoforms were also measured. We demonstrated the following: (1) diabetes had contrasting effects on aortic vasorelaxation in ZDF rats, impairing relaxation to ACh in females while enhancing it in male ZDF rats; (2) inhibition of NOX, a major source of superoxide in vasculature, restored aortic vasorelaxation in female ZDF rats; and (3) eNOS and NOX4 mRNA expressions were elevated in female (but not male) ZDF rat aortas compared to their respective leans. This study highlights sexual dimorphism in ACh-mediated vasorelaxation in the aorta of ZDF rats, suggesting that superoxide may play a role in the impaired vasorelaxation observed in female ZDF rats. Full article
(This article belongs to the Special Issue The Impact of Vascular Dysfunction in Obesity and Diabetes)
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12 pages, 1070 KiB  
Article
CYP3A4*1B but Not CYP3A5*3 as Determinant of Long-Term Tacrolimus Dose Requirements in Spanish Solid Organ Transplant Patients
by Julia Concha, Estela Sangüesa, María Pilar Ribate and Cristina B. García
Int. J. Mol. Sci. 2024, 25(20), 11327; https://doi.org/10.3390/ijms252011327 - 21 Oct 2024
Viewed by 627
Abstract
Tacrolimus (TAC) is a commonly used immunosuppressive drug in solid organ transplantation. Pharmacogenetics has been demonstrated before to be decisive in TAC pharmacotherapy. The CYP3A5*3 variant has been reported to be the main determinant of TAC dose requirements; however, other polymorphisms have also [...] Read more.
Tacrolimus (TAC) is a commonly used immunosuppressive drug in solid organ transplantation. Pharmacogenetics has been demonstrated before to be decisive in TAC pharmacotherapy. The CYP3A5*3 variant has been reported to be the main determinant of TAC dose requirements; however, other polymorphisms have also proven to be influential, especially in CYP3A5 non-expressor patients. The aim of this study is to evaluate the influence of genetic polymorphisms in TAC therapy in a cohort of Spanish transplant recipients. Genetic analysis including ten polymorphic variants was performed, and demographic and clinical data and pharmacotherapy of 26 patients were analyzed. No significant differences were found in weight-adjusted dose between CYP3A5 expressors and non-expressors (0.047 mg/kg vs. 0.044 mg/kg), while they were found for carriers of the CYP3A4*1B allele (0.101 mg/kg; p < 0.05). The results showed that patients with at least one CYP3A4*1B allele had a higher TAC dose and lower blood concentration. Dose-adjusted TAC blood levels were also lower in CYP3A4*1B carriers compared to non-carriers (0.72 ng/mL/mg vs. 2.88 ng/mL/mg). These results support the independence of CYP3A5*3 and CYP3A4*1B variants as determinants of dose requirements despite the linkage disequilibrium present between the two. The variability in genotype frequency between ethnicities may be responsible for the discrepancy found between studies. Full article
(This article belongs to the Special Issue Pharmacogenomics, 3rd Edition)
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17 pages, 2996 KiB  
Article
Limosilactobacillus reuteri HY7503 and Its Cellular Proteins Alleviate Endothelial Dysfunction by Increasing Nitric Oxide Production and Regulating Cell Adhesion Molecule Levels
by Hyejin Jeon, Daehyeop Lee, Joo-Yun Kim, Jae-Jung Shim and Jae-Hwan Lee
Int. J. Mol. Sci. 2024, 25(20), 11326; https://doi.org/10.3390/ijms252011326 - 21 Oct 2024
Viewed by 697
Abstract
Endothelial dysfunction, which is marked by a reduction in nitric oxide (NO) production or an imbalance in relaxing and contracting factor levels, exacerbates atherosclerosis by promoting the production of cell adhesion molecules and cytokines. This study aimed to investigate the effects of Limosilactobacillus [...] Read more.
Endothelial dysfunction, which is marked by a reduction in nitric oxide (NO) production or an imbalance in relaxing and contracting factor levels, exacerbates atherosclerosis by promoting the production of cell adhesion molecules and cytokines. This study aimed to investigate the effects of Limosilactobacillus reuteri HY7503, a novel probiotic isolated from raw milk, on endothelial dysfunction. Five lactic acid bacterial strains were screened for their antioxidant, anti-inflammatory, and endothelium-protective properties; L. reuteri HY7503 had the most potent effect. In a mouse model of angiotensin II-induced endothelial dysfunction, L. reuteri HY7503 reduced vascular thickening (19.78%), increased serum NO levels (226.70%), upregulated endothelial NO synthase (eNOS) expression in the aortic tissue, and decreased levels of cell adhesion molecules (intercellular adhesion molecule-1 [ICAM-1] and vascular cell adhesion molecule-1 [VCAM-1]) and serum cytokines (tumor necrosis factor-alpha [TNF-α] and interleukin-6 [IL-6]). In TNF-α-treated human umbilical vein endothelial cells (HUVECs), L. reuteri HY7503 enhanced NO production and reduced cell adhesion molecule levels. In HUVECs, surface-layer proteins (SLPs) were more effective than extracellular vesicles (exosomes) in increasing NO production and decreasing cell adhesion molecule levels. These findings suggested that L. reuteri HY7503 may serve as a functional probiotic that alleviates endothelial dysfunction. Full article
(This article belongs to the Special Issue Endothelial Dysfunction: Molecular Mechanisms and Therapeutic Strategies)
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47 pages, 4071 KiB  
Review
Photodynamic Therapy: Past, Current, and Future
by David Aebisher, Sara Czech, Klaudia Dynarowicz, Maciej Misiołek, Katarzyna Komosińska-Vassev, Aleksandra Kawczyk-Krupka and Dorota Bartusik-Aebisher
Int. J. Mol. Sci. 2024, 25(20), 11325; https://doi.org/10.3390/ijms252011325 - 21 Oct 2024
Viewed by 1020
Abstract
The Greek roots of the word “photodynamic” are as follows: “phos” (φω~ς) means “light” and “dynamis” (δύναμις) means “force” or “power”. Photodynamic therapy (PDT) is an innovative treatment method based on the ability of photosensitizers to produce reactive oxygen species [...] Read more.
The Greek roots of the word “photodynamic” are as follows: “phos” (φω~ς) means “light” and “dynamis” (δύναμις) means “force” or “power”. Photodynamic therapy (PDT) is an innovative treatment method based on the ability of photosensitizers to produce reactive oxygen species after the exposure to light that corresponds to an absorbance wavelength of the photosensitizer, either in the visible or near-infrared range. This process results in damage to pathological cancer cells, while minimizing the impact on healthy tissues. PDT is a promising direction in the treatment of many diseases, with particular emphasis on the fight against cancer and other diseases associated with excessive cell growth. The power of light contributed to the creation of phototherapy, whose history dates back to ancient times. It was then noticed that some substances exposed to the sun have a negative effect on the body, while others have a therapeutic effect. This work provides a detailed review of photodynamic therapy, from its origins to the present day. It is surprising how a seemingly simple beam of light can have such a powerful healing effect, which is used not only in dermatology, but also in oncology, surgery, microbiology, virology, and even dentistry. However, despite promising results, photodynamic therapy still faces many challenges. Moreover, photodynamic therapy requires further research and improvement. Full article
(This article belongs to the Special Issue Advances in Rare Diseases Biomarkers: 2nd Edition)
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14 pages, 900 KiB  
Article
The Influence of Non-Dipping Pattern of Blood Pressure in Gestational Hypertension on Early Onset of Hypertension Later in Life—Single Center Experience in Very-High-Risk Southeast and Central European Country
by Aleksandra Ilić, Anastazija Stojšić-Milosavljević, Tatjana Miljković, Marija Bjelobrk, Snežana Stojšić, Snežana Tadić, Maja Stefanović, Aleksandra Vulin, Andrej Preveden, Nikola Komazec, Milenko Čanković, Milovan Petrović, Djordje Ilić, Lazar Velicki, Mila Kovačević, Dragana Grković and Aleksandra Milovančev
Int. J. Mol. Sci. 2024, 25(20), 11324; https://doi.org/10.3390/ijms252011324 - 21 Oct 2024
Viewed by 648
Abstract
Gestational hypertension (GH) and preeclampsia (PE) are associated with the onset of hypertension. This study aimed to investigate whether the blood pressure (BP) pattern in GH is associated with the prevalence of hypertension later in life. In this prospective cohort study pregnant women [...] Read more.
Gestational hypertension (GH) and preeclampsia (PE) are associated with the onset of hypertension. This study aimed to investigate whether the blood pressure (BP) pattern in GH is associated with the prevalence of hypertension later in life. In this prospective cohort study pregnant women screened for GH underwent medical history, laboratory analysis, ambulatory blood pressure monitoring (AMBP), and transthoracic echocardiography (with left ventricular global longitudinal strain (LVGLS)) assessment. Overall, 138 GH (67 non-dippers and 71 dippers), 55 preeclamptic, and 72 normotensive pregnant controls were included. Women were followed in the postpartum period, first after 6 weeks and later on, for the occurrence of hypertension. The median follow-up was 8.97 years (8.23; 9.03). Non-dippers and PE compared with normotensives and dippers had a higher prevalence of hypertension onset (p < 0.01), as well as significantly reduced absolute values of LVGLS during pregnancy, after delivery, and at the time of onset of hypertension during follow-up (p < 0.01). Night-time diastolic BP, LVGLS, age, and left ventricular ejection fraction were the strongest predictors of postpartum onset of hypertension. The non-dipping BP pattern in GH was significantly associated with the onset of hypertension later in life, as well as with decreased systolic function. Full article
(This article belongs to the Special Issue Pregnancy Complicated by Hypertension—New Horizons in the Pathomechanism, Diagnosis, and Treatment)
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18 pages, 1091 KiB  
Review
A Missing Puzzle in Preclinical Studies—Are CCR2, CCR5, and Their Ligands’ Roles Similar in Obesity-Induced Hypersensitivity and Diabetic Neuropathy?—Evidence from Rodent Models and Clinical Studies
by Aleksandra Bober, Joanna Mika and Anna Piotrowska
Int. J. Mol. Sci. 2024, 25(20), 11323; https://doi.org/10.3390/ijms252011323 - 21 Oct 2024
Viewed by 849
Abstract
Research has shown that obesity is a low-grade inflammatory disease that is often associated with comorbidities, such as diabetes and chronic pain. Recent data have indicated that chemokines may play a role in these conditions due to their pronociceptive and chemotactic properties, which [...] Read more.
Research has shown that obesity is a low-grade inflammatory disease that is often associated with comorbidities, such as diabetes and chronic pain. Recent data have indicated that chemokines may play a role in these conditions due to their pronociceptive and chemotactic properties, which promote hypersensitivity and inflammation. Accumulating evidence suggests that CCR2, CCR5, and their ligands (CCL2, CCL3, CCL4, CCL5, CCL7, CCL8, CCL11 CCL12, and/or CCL13) play a role in rodent models of pain and obesity, as well as in patients with diabetes and obesity. It was proven that the blockade of CCR2 and CCR5, including the simultaneous blockade of both receptors by dual antagonists, effectively reduces hypersensitivity to thermal and mechanical stimuli in chronic pain states, including diabetic neuropathy. The present review discusses these chemokine receptors and the role of their ligands in diabetes and obesity, as well as their involvement in diabetic neuropathy and obesity-induced hypersensitivity. Full article
(This article belongs to the Section Molecular Pathology, Diagnostics, and Therapeutics)
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30 pages, 3714 KiB  
Article
Precision Oncology in Older Cancer Patients: A Single-Center Experience
by Meret Petitat-Berli, Marie Knufinke, Michèle Voegeli, Martina Sonderegger, Bettina Seifert, Elena Diana Chiru, Pirmin Haeuptle, Lisanne van’t Walderveen, Robert Rosenberg, Emanuel Burri, Svetozar Subotic, Fabienne Dominique Schwab, Vérène Dougoud-Chauvin, Heinz Unger, Kirsten Mertz, Loay Tahan and Marcus Vetter
Int. J. Mol. Sci. 2024, 25(20), 11322; https://doi.org/10.3390/ijms252011322 - 21 Oct 2024
Viewed by 607
Abstract
In the last two decades, next-generation sequencing (NGS) has facilitated enormous progress in cancer medicine, in both diagnosis and treatment. However, the usefulness of NGS in older cancer patients is unclear. To determine the role of NGS in older cancer patients, we retrospectively [...] Read more.
In the last two decades, next-generation sequencing (NGS) has facilitated enormous progress in cancer medicine, in both diagnosis and treatment. However, the usefulness of NGS in older cancer patients is unclear. To determine the role of NGS in older cancer patients, we retrospectively assessed demographic, clinicopathologic, and disease-specific data from 100 randomly selected cancer patients (any subtype/stage) who underwent NGS testing in 2020 at our institution and compared the treatment outcomes (progression-free survival [PFS] and overall survival [OS]) in the younger and older patient cohorts (A [n = 34] and B [n = 66]: age < 70 and ≥70 years, respectively). Overall, 27% had targetable mutations, and 8% received NGS-determined targeted therapy (45% and 19% of patients with a targetable mutation in cohorts A and B, respectively; p = 0.2), of whom 38% (3% of the whole cohort) benefited from the therapy (PFS > 6 months). The median OS (from diagnosis) was 192 and 197 weeks in cohorts A and B, respectively (p = 0.08). This pilot study revealed no significant age-stratified difference in the diagnostic approach and treatment strategy. A small, but relevant, proportion of the cohort (3%) benefited from NGS-determined treatment. Nevertheless, older cancer patients with targetable mutations less frequently received targetable therapies. Full article
(This article belongs to the Special Issue Novel Biological Molecules for Cancer Treatments 2.0)
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21 pages, 9460 KiB  
Article
GhASHH1.A and GhASHH2.A Improve Tolerance to High and Low Temperatures and Accelerate the Flowering Response to Temperature in Upland Cotton (Gossypium hirsutum)
by Jisheng Ju, Junning Yang, Jiazhi Wei, Wenmin Yuan, Ying Li, Dandan Li, Pingjie Ling, Qi Ma, Caixiang Wang, Maohua Dai and Junji Su
Int. J. Mol. Sci. 2024, 25(20), 11321; https://doi.org/10.3390/ijms252011321 - 21 Oct 2024
Viewed by 469
Abstract
The trithorax group (TrxG) complex is an important protein in the regulation of plant histone methylation. The ABSENT, SMALL, OR HOMEOTIC DISCS 1 (ASH1) gene family, as important family members of the TrxG complex, has been shown to regulate tolerance to abiotic stress [...] Read more.
The trithorax group (TrxG) complex is an important protein in the regulation of plant histone methylation. The ABSENT, SMALL, OR HOMEOTIC DISCS 1 (ASH1) gene family, as important family members of the TrxG complex, has been shown to regulate tolerance to abiotic stress and growth and development in many plants. In this study, we identified nine GhASH1s in upland cotton. Bioinformatics analysis revealed that GhASH1s contain a variety of cis-acting elements related to stress resistance and growth and development. The transcriptome expression profiles revealed that GhASHH1.A and GhASHH2.A genes expression were upregulated in flower organs and in response to external temperature stress. The results of virus-induced gene silencing (VIGS) indicated that GhASHH1.A and GhASHH2.A genes silencing reduced the ability of cotton to adapt to temperature stress and delayed the development of the flowering phenotype. We also showed that the silencing of these two target genes did not induce early flowering at high temperature (32 °C), suggesting that GhASHH1.A and GhASHH2.A might regulate cotton flowering in response to temperature. These findings provide genetic resources for future breeding of early-maturing and temperature-stress-tolerant cotton varieties. Full article
(This article belongs to the Section Molecular Plant Sciences)
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14 pages, 4168 KiB  
Article
Site-Specific Integration by Circular Donor Improves CRISPR/Cas9-Mediated Homologous Recombination in Human Cell Lines
by Zhimei Liu, Yue Zhao, Sujun Wu, Shiyu Qi, Yefeng Qiu and Zhengxing Lian
Int. J. Mol. Sci. 2024, 25(20), 11320; https://doi.org/10.3390/ijms252011320 - 21 Oct 2024
Viewed by 724
Abstract
The technology for obtaining the high-efficiency expression of target proteins through site-specific recombination has made progress. However, using the CRISPR/Cas9 system for site-specific integration of long fragments and the expression of active proteins remains a challenge. This study optimized the linear DNA circularization [...] Read more.
The technology for obtaining the high-efficiency expression of target proteins through site-specific recombination has made progress. However, using the CRISPR/Cas9 system for site-specific integration of long fragments and the expression of active proteins remains a challenge. This study optimized the linear DNA circularization system, eliminated the prokaryotic plasmid backbone on the traditional foreign gene vector, and generated a homologous arm-free circular donor template with a single guide RNA target site (sgRNA TS). This strategy significantly increased the co-transfection efficiency of the 1.6 kb template and Cas9 plasmid by 1.15-fold, and the average knock-in (KI) efficiency of the 4.7 kb long-fragment template for the two target gene sites increased by 1.3-fold. Subsequently, we used rhBCHE as a reporter gene to efficiently integrate the 5.4 kb fragment containing the gene of interest (GOI) into specific sites in the HEK293T cell line to detect the expression of the circular template at different target sites. Overall, this study further verifies that the length of the circular donor is more conducive to non-homologous integration, and more importantly, we provide a simple and optimized strategy for the construction of long-fragment site integration cell lines. Full article
(This article belongs to the Special Issue CRISPR-Cas Systems and Genome Editing—2nd Edition)
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13 pages, 2332 KiB  
Article
Waste-Derived Caffeine for Green Synthesis of Rhenium Nanoparticles with Enhanced Catalytic Activity in the Hydrogenation of 4-Nitrophenol
by Alicja Kuś, Anna Leśniewicz, Anna Dzimitrowicz, Pawel Pohl and Piotr Cyganowski
Int. J. Mol. Sci. 2024, 25(20), 11319; https://doi.org/10.3390/ijms252011319 - 21 Oct 2024
Viewed by 679
Abstract
Yearly, thousands of tons of wasted coffee grounds are produced according to high coffee consumption. Still, after the coffee brewing, wasted coffee grounds contain some amounts of caffeine (CAF). CAF, in turn, contains multiple O and N chelating atoms in its structure. These [...] Read more.
Yearly, thousands of tons of wasted coffee grounds are produced according to high coffee consumption. Still, after the coffee brewing, wasted coffee grounds contain some amounts of caffeine (CAF). CAF, in turn, contains multiple O and N chelating atoms in its structure. These have a potential to be reductors for complexes of metals. In this context, within the present study, a set of CAF extracts derived from coffee beans and coffee grounds were obtained and then used for the one-step reduction of ReO4− ions with no additional toxic chemicals. Within this approach, CAF was applied as a secondary, green resource for the synthesis of unique rhenium nanoparticles (ReNPs) containing Re species at 0 and +6 oxidation states. The obtained ReNPs were identified and characterized with the use of X-ray powder diffraction (XRD) and high-resolution transmission electron microscopy (HRTEM). Further, the capping and stabilization of ReNPs by CAF were verified with the aid of Fourier transformation infrared spectroscopy (FT-IR). The so-obtained “green” ReNPs were then used as a homogenous catalyst in the catalytic hydrogenation of 4-nitrophenol (4-NP). This new nanomaterial revealed a superior catalytic activity, leading to the complete reduction of 4-NP to 4-aminophenol within 40–60 min with a first-order rate constant of 0.255 min−1. Full article
(This article belongs to the Special Issue Metal Nanoparticles: From Fundamental Studies to New Applications)
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16 pages, 3086 KiB  
Article
Unveiling Novel Mechanism of CIDEB in Fatty Acid Synthesis Through ChIP-Seq and Functional Analysis in Dairy Goat
by Qiuya He, Weiwei Yao, Jiao Wu, Yingying Xia, Yuanmiao Lei and Jun Luo
Int. J. Mol. Sci. 2024, 25(20), 11318; https://doi.org/10.3390/ijms252011318 - 21 Oct 2024
Viewed by 668
Abstract
Goat milk is abundant in nutrients, particularly in milk fats, which confer health benefits to humans. Exploring the regulatory mechanism of fatty acid synthesis is highly important to understand milk composition manipulation. In this study, we used chromatin immunoprecipitation sequencing (ChIP-seq) on goat [...] Read more.
Goat milk is abundant in nutrients, particularly in milk fats, which confer health benefits to humans. Exploring the regulatory mechanism of fatty acid synthesis is highly important to understand milk composition manipulation. In this study, we used chromatin immunoprecipitation sequencing (ChIP-seq) on goat mammary glands at different lactation stages which revealed a novel lactation regulatory factor: cell death-inducing DFFA-like effector B (CIDEB). RT-qPCR results revealed that CIDEB was significantly upregulated during lactation in dairy goats. CIDEB overexpression significantly increased the expression levels of genes involved in fatty acid synthesis (ACACA, SCD1, p < 0.05; ELOVL6, p < 0.01), lipid droplet formation (XDH, p < 0.05), and triacylglycerol (TAG) synthesis (DGAT1, p < 0.05; GPAM, p < 0.01) in goat mammary epithelial cells (GMECs). The contents of lipid droplets, TAG, and cholesterol were increased (p < 0.05) in CIDEB-overexpressing GMECs, and knockdown of CIDEB led to the opposite results. In addition, CIDEB knockdown significantly decreased the proportion of C16:0 and total C18:2. Luciferase reporter assays indicated that X-box binding protein 1 (XBP1) promoted CIDEB transcription via XBP1 binding sites located in the CIDEB promoter. Furthermore, CIDEB knockdown attenuated the stimulatory effect of XBP1 on lipid droplet accumulation. Collectively, these findings elucidate the critical regulatory roles of CIDEB in milk fat synthesis, thus providing new insights into improving the quality of goat milk. Full article
(This article belongs to the Special Issue Sirtuins as Players in Cell Metabolism and Functions)
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15 pages, 22768 KiB  
Article
SAT1/ALOX15 Signaling Pathway Is Involved in Ferroptosis After Skeletal Muscle Contusion
by Huihuang Yang, Yingmin Li, Weihao Zhu, Xiaowei Feng, Hongjian Xin, Hao Chen, Guozhong Zhang, Min Zuo, Bin Cong and Weibo Shi
Int. J. Mol. Sci. 2024, 25(20), 11317; https://doi.org/10.3390/ijms252011317 - 21 Oct 2024
Viewed by 760
Abstract
Skeletal muscle contusion (SMC) is common in daily life and clinical practice, but the molecular mechanisms underlying SMC healing are unclear. Ferroptosis, a regulated cell death type, has gained attention recently. We observed iron overload in skeletal muscle following contusion through HE and [...] Read more.
Skeletal muscle contusion (SMC) is common in daily life and clinical practice, but the molecular mechanisms underlying SMC healing are unclear. Ferroptosis, a regulated cell death type, has gained attention recently. We observed iron overload in skeletal muscle following contusion through HE and Perls staining. Abnormal iron levels are highly likely to induce ferroptosis. Therefore, we aimed to explore whether iron overload after contusion leads to ferroptosis in skeletal muscle and the underlying mechanisms, which will help us understand the effects of iron abnormalities on skeletal muscle repair. Initially, we searched SMC gene expression profiles from the GEO database and used bioinformatics analysis to reveal ferroptosis occurrence. Then, we identified the gene sat1 plays an important role in this process. We further established a rat SMC model and treated rats with ferroptosis inhibitors (Ferrostatin-1, Deferoxamine). Our findings confirmed iron overload from SMC can lead to ferroptosis in rats. We also demonstrated that SAT1 can regulate ferroptosis by affecting ALOX15. Moreover, we constructed a ferroptosis L6 cell model and found that SAT1 knockdown significantly inhibited ALOX15 expression and reduced cellular lipid peroxidation. In conclusion, these results indicated ferroptosis can occur following SMC, and SAT1, as a key regulator, affects skeletal muscle injury healing by mediating high ALOX15 expression, which in turn regulates lipid peroxidation. Full article
(This article belongs to the Section Molecular Endocrinology and Metabolism)
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18 pages, 739 KiB  
Article
Basal State Calibration of a Chemical Reaction Network Model for Autophagy
by Bence Hajdú, Orsolya Kapuy and Tibor Nagy
Int. J. Mol. Sci. 2024, 25(20), 11316; https://doi.org/10.3390/ijms252011316 - 21 Oct 2024
Viewed by 515
Abstract
The modulation of autophagy plays a dual role in tumor cells, with the potential to both promote and suppress tumor proliferation. In order to gain a deeper understanding of the nature of autophagy, we have developed a chemical reaction kinetic model of autophagy [...] Read more.
The modulation of autophagy plays a dual role in tumor cells, with the potential to both promote and suppress tumor proliferation. In order to gain a deeper understanding of the nature of autophagy, we have developed a chemical reaction kinetic model of autophagy and apoptosis based on the mass action kinetic models that have been previously described in the literature. It is regrettable that the authors did not provide all of the information necessary to reconstruct their model, which made their simulation results irreproducible. In this study, based on an extensive literature review, we have identified concentrations for each species in the stress-free, homeostatic state. These ranges were randomly sampled to generate sets of initial concentrations, from which the simulations were run. In every case, abnormal behavior was observed, with apoptosis and autophagy being activated, even in the absence of stress. Consequently, the model failed to reproduce even the basal conditions. Detailed examination of the model revealed erroneous reactions, which were corrected. The influential kinetic parameters of the corrected model were identified and optimized using the Optima++ code. The model is now capable of simulating homeostatic states, and provides a suitable basis for further model development to describe cell response to various stresses. Full article
(This article belongs to the Special Issue Advances in Cell Signaling Pathways and Signal Transduction)
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19 pages, 3353 KiB  
Article
Extremely Low-Frequency Electromagnetic Field (ELF-EMF) Increases Mitochondrial Electron Transport Chain Activities and Ameliorates Depressive Behaviors in Mice
by Masaki Teranishi, Mikako Ito, Zhizhou Huang, Yuki Nishiyama, Akio Masuda, Hiroyuki Mino, Masako Tachibana, Toshiya Inada and Kinji Ohno
Int. J. Mol. Sci. 2024, 25(20), 11315; https://doi.org/10.3390/ijms252011315 - 21 Oct 2024
Viewed by 1127
Abstract
Compromised mitochondrial electron transport chain (ETC) activities are associated with depression in humans and rodents. However, the effects of the enhancement of mitochondrial ETC activities on depression remain elusive. We recently reported that an extremely low-frequency electromagnetic field (ELF-EMF) of as low as [...] Read more.
Compromised mitochondrial electron transport chain (ETC) activities are associated with depression in humans and rodents. However, the effects of the enhancement of mitochondrial ETC activities on depression remain elusive. We recently reported that an extremely low-frequency electromagnetic field (ELF-EMF) of as low as 10 μT induced hormetic activation of mitochondrial ETC complexes in human/mouse cultured cells and mouse livers. Chronic social defeat stress (CSDS) for 10 consecutive days caused behavioral defects mimicking depression in mice, and using an ELF-EMF for two to six weeks ameliorated them. CSDS variably decreased the mitochondrial ETC proteins in the prefrontal cortex (PFC) in 10 days, which were increased by an ELF-EMF in six weeks. CSDS had no effect on the mitochondrial oxygen consumption rate in the PFC in 10 days, but using an ELF-EMF for six weeks enhanced it. CSDS inactivated SOD2 by enhancing its acetylation and increased lipid peroxidation in the PFC. In contrast, the ELF-EMF activated the Sirt3-FoxO3a-SOD2 pathway and suppressed lipid peroxidation. Furthermore, CSDS increased markers for mitophagy, which was suppressed by the ELF-EMF in six weeks. The ELF-EMF exerted beneficial hormetic effects on mitochondrial energy production, mitochondrial antioxidation, and mitochondrial dynamics in a mouse model of depression. We envisage that an ELF-EMF is a promising therapeutic option for depression. Full article
(This article belongs to the Special Issue Advances in the Molecular Biological Effects of Magnetic Fields)
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20 pages, 3666 KiB  
Article
Transition Metals Coordination by Bis-imidazole-calix[4]arene Ligands with and Without Pyrene Units Grafted at the Large Rim
by Ivana Nikšić-Franjić, Dijana Pavlović Saftić, Vilko Smrečki, Benoit Colasson, Olivia Reinaud, Ivo Piantanida and Aleksandar Višnjevac
Int. J. Mol. Sci. 2024, 25(20), 11314; https://doi.org/10.3390/ijms252011314 - 21 Oct 2024
Viewed by 550
Abstract
Herein, the presented results show that previously studied DNA/RNA-interacting bis-imidazole-calix[4]arene systems can, in aqueous solutions, efficiently bind a series of biorelevant transition metal cations by coordination with the two imidazole arms at the small rim of their macrocyclic basket. The SCXRD and NMR [...] Read more.
Herein, the presented results show that previously studied DNA/RNA-interacting bis-imidazole-calix[4]arene systems can, in aqueous solutions, efficiently bind a series of biorelevant transition metal cations by coordination with the two imidazole arms at the small rim of their macrocyclic basket. The SCXRD and NMR results structurally characterised the complexes formed by referent bis-imidazole-calix[4]arene with Cu2+ and Zn2+. In solid-state (crystal), the bis-anilino derivative/Cu2+ complex, only upon exposure to the air, undergoes intramolecular dehydrogenative coupling of two neighbouring aniline units, yielding an azo bridge at the large rim of the calix[4]arene basket. In the biorelevant aqueous solution, the comparison of fluorometric titrations of referent calix[4]arene, with its analogues having one or two pyrene units grafted at the opposite (large) rim, revealed moderate-to-strong affinity towards transition metal cations, and, more importantly, a strong impact of pyrene on the binding affinity towards some cations. The pyrene arm(s) significantly diminished the affinity of the calix[4]arene-imidazole ligand towards Cu+ and strongly increased the affinity towards divalent Co2+ and Cd2+ cations. Moreover, the fluorometric response of some studied derivatives was strappingly sensitive to cation type. Since the counter-anion plays only a marginal role, such a change in selectivity is attributed to the intramolecular interaction of pyrene(s) with the calix[4]arene-imidazole system, sterically controlling the metal cation binding site. Full article
(This article belongs to the Special Issue Supramolecular Receptors for Cations and Anions)
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17 pages, 5532 KiB  
Article
Two Forms of Thick Filament in the Flight Muscle of Drosophila melanogaster
by Hosna Rastegarpouyani, Alimohammad Hojjatian and Kenneth A. Taylor
Int. J. Mol. Sci. 2024, 25(20), 11313; https://doi.org/10.3390/ijms252011313 - 21 Oct 2024
Viewed by 569
Abstract
Invertebrate striated muscle myosin filaments are highly variable in structure. The best characterized myosin filaments are those found in insect indirect flight muscle (IFM) in which the flight-powering muscles are not attached directly to the wings. Four insect orders, Hemiptera, Diptera, Hymenoptera, and [...] Read more.
Invertebrate striated muscle myosin filaments are highly variable in structure. The best characterized myosin filaments are those found in insect indirect flight muscle (IFM) in which the flight-powering muscles are not attached directly to the wings. Four insect orders, Hemiptera, Diptera, Hymenoptera, and Coleoptera, have evolved IFM. IFM thick filaments from the first three orders have highly similar myosin arrangements but differ significantly among their non-myosin proteins. The cryo-electron microscopy of isolated IFM myosin filaments from the Dipteran Drosophila melanogaster described here revealed the coexistence of two distinct filament types, one presenting a tubular backbone like in previous work and the other a solid backbone. Inside an annulus of myosin tails, tubular filaments show no noticeable densities; solid filaments show four paired paramyosin densities. Both myosin heads of the tubular filaments are disordered; solid filaments have one completely and one partially immobilized head. Tubular filaments have the protein stretchin-klp on their surface; solid filaments do not. Two proteins, flightin and myofilin, are identifiable in all the IFM filaments previously determined. In Drosophila, flightin assumes two conformations, being compact in solid filaments and extended in tubular filaments. Nearly identical solid filaments occur in the large water bug Lethocerus indicus, which flies infrequently. The Drosophila tubular filaments occur in younger flies, and the solid filaments appear in older flies, which fly less frequently if at all, suggesting that the solid filament form is correlated with infrequent muscle use. We suggest that the solid form is designed to conserve ATP when the muscle is not in active use. Full article
(This article belongs to the Special Issue Muscle Proteins, Functions and Interactions)
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30 pages, 16711 KiB  
Article
Dinochromosome Heterotermini with Telosomal Anchorages
by Alvin Chun Man Kwok, Kosmo Ting Hin Yan, Shaoping Wen, Shiyong Sun, Chongping Li and Joseph Tin Yum Wong
Int. J. Mol. Sci. 2024, 25(20), 11312; https://doi.org/10.3390/ijms252011312 - 21 Oct 2024
Viewed by 610
Abstract
Dinoflagellate birefringent chromosomes (BfCs) contain some of the largest known genomes, yet they lack typical nucleosomal micrococcal-nuclease protection patterns despite containing variant core histones. One BfC end interacts with extranuclear mitotic microtubules at the nuclear envelope (NE), which remains intact throughout the cell [...] Read more.
Dinoflagellate birefringent chromosomes (BfCs) contain some of the largest known genomes, yet they lack typical nucleosomal micrococcal-nuclease protection patterns despite containing variant core histones. One BfC end interacts with extranuclear mitotic microtubules at the nuclear envelope (NE), which remains intact throughout the cell cycle. Ultrastructural studies, polarized light and fluorescence microscopy, and micrococcal nuclease-resistant profiles (MNRPs) revealed that NE-associated chromosome ends persisted post-mitosis. Histone H3K9me3 inhibition caused S-G2 delay in synchronous cells, without any effects at G1. Differential labeling and nuclear envelope swelling upon decompaction indicate an extension of the inner compartment into telosomal anchorages (TAs). Additionally, limited effects of low-concentration sirtinol on bulk BfCs, coupled with distinct mobility patterns in MNase-digested and psoralen-crosslinked nuclei observed on 2D gels, suggest that telomeric nucleosomes (TNs) are the primary histone structures. The absence of a nucleosomal ladder with cDNA probes, the presence of histone H2A and telomere-enriched H3.3 variants, along with the immuno-localization of H3 variants mainly at the NE further reinforce telomeric regions as the main nucleosomal domains. Cumulative biochemical and molecular analyses suggest that telomeric repeats constitute the major octameric MNRPs that provision chromosomal anchorage at the NE. Full article
(This article belongs to the Section Macromolecules)
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12 pages, 6273 KiB  
Article
Exploring the Blood Biomarkers and Potential Therapeutic Agents for Human Acute Mountain Sickness Based on Transcriptomic Analysis, Inflammatory Infiltrates and Molecular Docking
by Jiayi Yan, Zhuo Zhang, Yunxuan Ge, Junru Chen, Yue Gao and Boli Zhang
Int. J. Mol. Sci. 2024, 25(20), 11311; https://doi.org/10.3390/ijms252011311 - 21 Oct 2024
Viewed by 697
Abstract
A high-altitude, low-pressure hypoxic environment has severe effects on the health and work efficiency of its residents, and inadequate preventive measures and adaptive training may lead to the occurrence of AMS. Acute exposure to hypoxia conditions can have a less-favorable physiological effect on [...] Read more.
A high-altitude, low-pressure hypoxic environment has severe effects on the health and work efficiency of its residents, and inadequate preventive measures and adaptive training may lead to the occurrence of AMS. Acute exposure to hypoxia conditions can have a less-favorable physiological effect on the human immune system. However, the regulation of the immune system in high-altitude environments is extremely complex and remains elusive. This study integrated system bioinformatics methods to screen for changes in immune cell subtypes and their associated targets. It also sought potential therapeutically effective natural compound candidates. The present study observed that monocytes, M1 macrophages and NK cells play a crucial role in the inflammatory response in AMS. IL15RA, CD5, TNFSF13B, IL21R, JAK2 and CXCR3 were identified as hub genes, and JAK2 was positively correlated with monocytes; TNFSF13B was positively correlated with NK cells. The natural compound monomers of jasminoidin and isoliquiritigenin exhibited good binding affinity with JAK2, while dicumarol and artemotil exhibited good binding affinity with TNFSF13B, and all are expected to become a potential therapeutic agents. Full article
(This article belongs to the Collection Feature Papers in Molecular Informatics)
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21 pages, 2289 KiB  
Review
The Gut Microbiota Involvement in the Panorama of Muscular Dystrophy Pathogenesis
by Cristina Russo, Sofia Surdo, Maria Stella Valle and Lucia Malaguarnera
Int. J. Mol. Sci. 2024, 25(20), 11310; https://doi.org/10.3390/ijms252011310 - 21 Oct 2024
Viewed by 1192
Abstract
Muscular dystrophies (MDs) are genetically heterogeneous diseases characterized by primary skeletal muscle atrophy. The collapse of muscle structure and irreversible degeneration of tissues promote the occurrence of comorbidities, including cardiomyopathy and respiratory failure. Mitochondrial dysfunction leads to inflammation, fibrosis, and adipogenic cellular infiltrates [...] Read more.
Muscular dystrophies (MDs) are genetically heterogeneous diseases characterized by primary skeletal muscle atrophy. The collapse of muscle structure and irreversible degeneration of tissues promote the occurrence of comorbidities, including cardiomyopathy and respiratory failure. Mitochondrial dysfunction leads to inflammation, fibrosis, and adipogenic cellular infiltrates that exacerbate the symptomatology of MD patients. Gastrointestinal disorders and metabolic anomalies are common in MD patients and may be determined by the interaction between the intestine and its microbiota. Therefore, the gut–muscle axis is one of the actors involved in the spread of inflammatory signals to all muscles. In this review, we aim to examine in depth how intestinal dysbiosis can modulate the metabolic state, the immune response, and mitochondrial biogenesis in the course and progression of the most investigated MDs such as Duchenne Muscular Dystrophy (DMD) and Myotonic Dystrophy (MD1), to better identify gut microbiota metabolites working as therapeutic adjuvants to improve symptoms of MD. Full article
(This article belongs to the Special Issue Molecular Insights into Muscular Dystrophy)
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18 pages, 5736 KiB  
Article
An Analysis of the Mechanism About CO2 Enrichment Promoting Carbohydrate Metabolism in Cucumber (Cucumis sativus L.) Leaves
by Yanling Li, Hongxia Song, Xuan Li, Leiping Hou and Meilan Li
Int. J. Mol. Sci. 2024, 25(20), 11309; https://doi.org/10.3390/ijms252011309 - 21 Oct 2024
Viewed by 574
Abstract
Elevated CO2 can affect the synthesis and distribution of photosynthetic assimilates. However, the carbohydrate metabolism molecular mechanism of cucumber leaves in response to CO2 enrichment is unclear. Therefore, it is of great significance to investigate the key functional regulatory genes in [...] Read more.
Elevated CO2 can affect the synthesis and distribution of photosynthetic assimilates. However, the carbohydrate metabolism molecular mechanism of cucumber leaves in response to CO2 enrichment is unclear. Therefore, it is of great significance to investigate the key functional regulatory genes in cucumber. In this study, the growth of cucumber leaves under different CO2 conditions was compared. The results showed that under CO2 enrichment, leaf area increased, the number of mesophyll cells increased, stomata enlarged, and more starch grains accumulated in the chloroplasts. Compared with the control, the starch and soluble sugar content of leaves were maximally increased by 194.1% and 55.94%, respectively; the activities of fructose-1,6-bisphosphatase (FBPase), ADPG pyrophosphorylase (AGPase), starch synthase (SSS), sucrose phosphate synthase (SPS), sucrose synthase (SS) and invertase (Inv) were maximally increased by 36.91%, 66.13%, 33.18%, 21.7%, 54.11%, and 46.01%, respectively. Through transcriptome analysis, a total of 1,582 differential expressed genes (DEGs) were identified, in which the starch and sucrose metabolism pathway was significantly enriched, and 23 genes of carbon metabolism were screened. Through metabolome analysis, a total of 22 differential accumulation metabolites (DAMs) were identified. Moreover, D-glucose and D(+)-glucose were significantly accumulated, showing upregulation 2.4-fold and 2.6-fold, respectively. Through combined analysis of transcriptome and metabolome, it was revealed that seven genes were highly related to D-glucose, and Csa6G153460 (AGPase), Csa5G612840 (β-glucosidase), and Csa4G420150 (4-α-glucanotransferase) were significantly correlated to the carbohydrate regulatory network. Furthermore, the mechanism of CO2 enrichment that promotes carbohydrate metabolism in leaves at the molecular level was revealed. This mechanism advances the development of the cell wall and leaf morphology by activating the expression of key genes and improving enzyme activity. Full article
(This article belongs to the Section Molecular Plant Sciences)
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16 pages, 1019 KiB  
Communication
The Role of BAG3 Protein Interactions in Cardiomyopathies
by Hui-Qi Qu, Ju-Fang Wang, Alexandre Rosa-Campos, Hakon Hakonarson and Arthur M. Feldman
Int. J. Mol. Sci. 2024, 25(20), 11308; https://doi.org/10.3390/ijms252011308 - 21 Oct 2024
Viewed by 637
Abstract
Bcl-2-associated athanogene 3 (BAG3) plays an important function in cellular protein quality control (PQC) maintaining proteome stability. Mutations in the BAG3 gene result in cardiomyopathies. Due to its roles in cardiomyopathies and the complexity of BAG3–protein interactions, it is important to understand these [...] Read more.
Bcl-2-associated athanogene 3 (BAG3) plays an important function in cellular protein quality control (PQC) maintaining proteome stability. Mutations in the BAG3 gene result in cardiomyopathies. Due to its roles in cardiomyopathies and the complexity of BAG3–protein interactions, it is important to understand these protein interactions given the importance of the multifunctional cochaperone BAG3 in cardiomyocytes, using an in vitro cardiomyocyte model. The experimental assay was conducted using high pressure liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS) in the human AC16 cardiomyocyte cell line with BioID technology. Proteins with BAG3-interaction were identified in all the 28 hallmark gene sets enriched in idiopathic cardiomyopathies and/or ischemic disease. Among the 24 hallmark gene sets enriched in both idiopathic cardiomyopathies and ischemic disease, 15 gene sets had at least 3 proteins with BAG3-interaction. This study highlights BAG3 protein interactions, unveiling the key gene sets affected in cardiomyopathies, which help to explain the molecular mechanisms of the cardioprotective effects of BAG3. In addition, this study also highlighted the complexity of proteins with BAG3 interactions, implying unwanted effects of BAG3. Full article
(This article belongs to the Special Issue Current Research for Heart Disease Biology and Therapeutics: 2nd Edition)
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15 pages, 2823 KiB  
Article
Proliferative Diabetic Retinopathy Microenvironment Drives Microglial Polarization and Promotes Angiogenesis and Fibrosis via Cyclooxygenase-2/Prostaglandin E2 Signaling
by Shuta Kishishita, Ayumi Usui-Ouchi, Yasuo Ouchi, Yuiko Hata, Nobuyuki Ebihara and Shintaro Nakao
Int. J. Mol. Sci. 2024, 25(20), 11307; https://doi.org/10.3390/ijms252011307 - 21 Oct 2024
Viewed by 739
Abstract
Diabetic retinopathy (DR) is the leading cause of visual impairment, particularly in the proliferative form (proliferative DR [PDR]). The impact of the PDR microenvironment on microglia, which are the resident immune cells in the central nervous system, and the specific pathological changes it [...] Read more.
Diabetic retinopathy (DR) is the leading cause of visual impairment, particularly in the proliferative form (proliferative DR [PDR]). The impact of the PDR microenvironment on microglia, which are the resident immune cells in the central nervous system, and the specific pathological changes it may induce remain unclear. This study aimed to investigate the role of microglia in the progression of PDR under hypoxic and inflammatory conditions. We performed a comprehensive gene expression analysis using human-induced pluripotent stem cell-derived microglia under different stimuli (dimethyloxalylglycine (DMOG), lipopolysaccharide (LPS), and DMOG + LPS) to mimic the hypoxic inflammatory environment characteristic of PDR. Principal component analysis revealed distinct gene expression profiles, with 76 genes synergistically upregulated under combined stimulation. Notably, prostaglandin-endoperoxide synthase 2 (encoding cyclooxygenase (COX)-2) exhibited the most pronounced increase, leading to elevated prostaglandin E2 (PGE2) levels and driving pathological angiogenesis and inflammation via the COX-2/PGE2/PGE receptor 2 signaling axis. Additionally, the upregulation of the fibrogenic genes snail family transcriptional repressor 1 and collagen type I alpha 1 chain suggested a role for microglia in fibrosis. These findings underscore the critical involvement of microglia in PDR and suggest that targeting both the angiogenic and fibrotic pathways may present new therapeutic strategies for managing this condition. Full article
(This article belongs to the Special Issue Molecular Pathogenesis and Therapeutics in Retinopathy)
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20 pages, 1598 KiB  
Review
The Trigeminal Sensory System and Orofacial Pain
by Hyung Kyu Kim, Ki-myung Chung, Juping Xing, Hee Young Kim and Dong-ho Youn
Int. J. Mol. Sci. 2024, 25(20), 11306; https://doi.org/10.3390/ijms252011306 - 21 Oct 2024
Viewed by 977
Abstract
The trigeminal sensory system consists of the trigeminal nerve, the trigeminal ganglion, and the trigeminal sensory nuclei (the mesencephalic nucleus, the principal nucleus, the spinal trigeminal nucleus, and several smaller nuclei). Various sensory signals carried by the trigeminal nerve from the orofacial area [...] Read more.
The trigeminal sensory system consists of the trigeminal nerve, the trigeminal ganglion, and the trigeminal sensory nuclei (the mesencephalic nucleus, the principal nucleus, the spinal trigeminal nucleus, and several smaller nuclei). Various sensory signals carried by the trigeminal nerve from the orofacial area travel into the trigeminal sensory system, where they are processed into integrated sensory information that is relayed to higher sensory brain areas. Thus, knowledge of the trigeminal sensory system is essential for comprehending orofacial pain. This review elucidates the individual nuclei that comprise the trigeminal sensory system and their synaptic transmission. Additionally, it discusses four types of orofacial pain and their relationship to the system. Consequently, this review aims to enhance the understanding of the mechanisms underlying orofacial pain. Full article
(This article belongs to the Special Issue Molecular Mechanisms of Pain and Analgesia)
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13 pages, 1253 KiB  
Article
α4 Nicotinic Acetylcholine Receptors in Lipopolysaccharide-Related Lung Inflammation
by Jeffrey D. Ritzenthaler, Walter H. Watson and Jesse Roman
Int. J. Mol. Sci. 2024, 25(20), 11305; https://doi.org/10.3390/ijms252011305 - 21 Oct 2024
Viewed by 690
Abstract
Sepsis remains an important healthcare challenge. The lungs are often affected in sepsis, resulting in acute lung injury characterized by inflammation. Mechanisms involving lipopolysaccharide (LPS) stimulation of toll-like receptor (TLR) signaling with induction of proinflammatory pathways have been implicated in this process. To [...] Read more.
Sepsis remains an important healthcare challenge. The lungs are often affected in sepsis, resulting in acute lung injury characterized by inflammation. Mechanisms involving lipopolysaccharide (LPS) stimulation of toll-like receptor (TLR) signaling with induction of proinflammatory pathways have been implicated in this process. To date, however, studies targeting these pathways have failed to improve outcomes. We have found that LPS may also promote lung injury through the activation of α4 nicotinic acetylcholine receptors (α4 nAChRs) in immune cells. We observed increased expression of α4 nAChRs in human THP-1 monocytic cells exposed to LPS (100 ng/mL, 24 h). We also observed that LPS stimulated the expression of other relevant genes, including tumor necrosis factor-α, interleukin-1β, plasminogen activator inhibitor-1, the solute carrier family 7 member 11, extracellular superoxide dismutase, and transforming growth factor-β1. Of interest, dihydro-β-erythroidine hydrobromide (DHβE), a specific chemical inhibitor of α4 nAChRs, inhibited the LPS-induced expression of these genes. We generated mice with a global knockout mutation of the α4 nAChR subunit in the C57BL/6 background using CRISPR/Cas9 technology. The lungs of these LPS-treated animals demonstrated a reduction in the expression of the above-mentioned genes when compared with the lungs of wild-type animals. In support of the role of oxidative stress, we observed that LPS induced expression of the cystine transporter Slc7a11 in both THP-1 cells and in wild-type mouse lungs. The effects of LPS on THP-1 cells were blocked by the thiol antioxidant N-acetylcysteine and mimicked by redox stress. Importantly, the induction of IL-1β by redox stress was inhibited by the α4 nAChR inhibitor DHβE. Finally, we showed that LPS stimulated calcium influx in THP-1 cells, which was blocked by the α4 nAChR inhibitor. Our observations suggest that LPS promotes lung injury by stimulating redox stress, which activates α4 nAChR signaling and drives proinflammatory cytokine expression. Full article
(This article belongs to the Special Issue Signaling in Respiratory Diseases)
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Article
Profiling Bioactive Components of Natural Eggshell Membrane (NEM) for Cartilage Protection and Its Protective Effect on Oxidative Stress in Human Chondrocytes
by Jin-Woo Kim, Dong-Ho Lee, Kang-Woo Lee, In-Su Na, Na-Yeon Lee, Jong-Kyu Kim, Yoon-Seok Chun, Nam-Kyu Yoon, Byung-Kwon Kim, Sung-Keun Yang and Soon-Mi Shim
Int. J. Mol. Sci. 2024, 25(20), 11304; https://doi.org/10.3390/ijms252011304 - 21 Oct 2024
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Abstract
The current study aimed to investigate the physicochemical properties of the natural eggshell membrane (NEM) and its protective effects against H2O2-induced oxidative stress in human chondrocytes (SW-1353). Bioactive components from NEM related to cartilage were profiled, consisting of 1.1 [...] Read more.
The current study aimed to investigate the physicochemical properties of the natural eggshell membrane (NEM) and its protective effects against H2O2-induced oxidative stress in human chondrocytes (SW-1353). Bioactive components from NEM related to cartilage were profiled, consisting of 1.1 ± 0.07% hyaluronic acid, 1.2 ± 0.25% total sulfated glycosaminoglycans as chondroitin sulfate, 3.1 ± 0.33% collagen, and 54.4 ± 2.40% total protein. Protein was hydrolyzed up to 43.72 ± 0.76% using in vitro gastro–intestinal digestive enzymes. Peptides eluted at 9.58, 12.46, and 14.58 min using nano-LC-ESI-MS were identified as TEW, SWVE, and VYL peptides with an M/Z value of 435.1874, 520.2402, and 394.2336, respectively. Radical scavenging activity of NEM at 10 mg/mL using the ABTS assay was revealed to be 2.1 times higher than that of the positive control. NEM treatment significantly enhanced cellular SOD expression (p < 0.05). Pre-treatment with NEM (0.1, 1, and 10 mg/mL) dose-dependently reduced H2O2-induced ROS levels in SW-1353. Cell live imaging confirmed that NEM pre-treatment led to a significant reduction in apoptosis expression compared to control. Results from the present study suggest that NEM rich in cartilage protective components including hyaluronic acid, collagen, and chondroitin antioxidative peptides could be a potential therapeutic agent for osteoarthritis (OA) by scavenging oxidative stress. Full article
(This article belongs to the Section Bioactives and Nutraceuticals)
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