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Int. J. Mol. Sci., Volume 25, Issue 13 (July-1 2024) – 494 articles

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14 pages, 1449 KiB  
Review
Mitochondrial Quality Control Processes at the Crossroads of Cell Death and Survival: Mechanisms and Signaling Pathways
by Emanuele Marzetti, Riccardo Calvani, Francesco Landi, Helio José Coelho-Júnior and Anna Picca
Int. J. Mol. Sci. 2024, 25(13), 7305; https://doi.org/10.3390/ijms25137305 (registering DOI) - 3 Jul 2024
Abstract
Biological aging results from an accumulation of damage in the face of reduced resilience. One major driver of aging is cell senescence, a state in which cells remain viable but lose their proliferative capacity, undergo metabolic alterations, and become resistant to apoptosis. This [...] Read more.
Biological aging results from an accumulation of damage in the face of reduced resilience. One major driver of aging is cell senescence, a state in which cells remain viable but lose their proliferative capacity, undergo metabolic alterations, and become resistant to apoptosis. This is accompanied by complex cellular changes that enable the development of a senescence-associated secretory phenotype (SASP). Mitochondria, organelles involved in energy provision and activities essential for regulating cell survival and death, are negatively impacted by aging. The age-associated decline in mitochondrial function is also accompanied by the development of chronic low-grade sterile inflammation. The latter shares some features and mediators with the SASP. Indeed, the unloading of damage-associated molecular patterns (DAMPs) at the extracellular level can trigger sterile inflammatory responses and mitochondria can contribute to the generation of DAMPs with pro-inflammatory properties. The extrusion of mitochondrial DNA (mtDNA) via mitochondrial outer membrane permeabilization under an apoptotic stress triggers senescence programs. Additional pathways can contribute to sterile inflammation. For instance, pyroptosis is a caspase-dependent inducer of systemic inflammation, which is also elicited by mtDNA release and contributes to aging. Herein, we overview the molecular mechanisms that may link mitochondrial dyshomeostasis, pyroptosis, sterile inflammation, and senescence and discuss how these contribute to aging and could be exploited as molecular targets for alleviating the cell damage burden and achieving healthy longevity. Full article
(This article belongs to the Section Molecular Biology)
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27 pages, 750 KiB  
Review
The Effect of Neuropsychiatric Drugs on the Oxidation-Reduction Balance in Therapy
by Karina Sommerfeld-Klatta, Wiktoria Jiers, Szymon Rzepczyk, Filip Nowicki, Magdalena Łukasik-Głębocka, Paweł Świderski, Barbara Zielińska-Psuja, Zbigniew Żaba and Czesław Żaba
Int. J. Mol. Sci. 2024, 25(13), 7304; https://doi.org/10.3390/ijms25137304 (registering DOI) - 3 Jul 2024
Abstract
The effectiveness of available neuropsychiatric drugs in the era of an increasing number of patients is not sufficient, and the complexity of neuropsychiatric disease entities that are difficult to diagnose and therapeutically is increasing. Also, discoveries about the pathophysiology of neuropsychiatric diseases are [...] Read more.
The effectiveness of available neuropsychiatric drugs in the era of an increasing number of patients is not sufficient, and the complexity of neuropsychiatric disease entities that are difficult to diagnose and therapeutically is increasing. Also, discoveries about the pathophysiology of neuropsychiatric diseases are promising, including those initiating a new round of innovations in the role of oxidative stress in the etiology of neuropsychiatric diseases. Oxidative stress is highly related to mental disorders, in the treatment of which the most frequently used are first- and second-generation antipsychotics, mood stabilizers, and antidepressants. Literature reports on the effect of neuropsychiatric drugs on oxidative stress are divergent. They are starting with those proving their protective effect and ending with those confirming disturbances in the oxidation–reduction balance. The presented publication reviews the state of knowledge on the role of oxidative stress in the most frequently used therapies for neuropsychiatric diseases using first- and second-generation antipsychotic drugs, i.e., haloperidol, clozapine, risperidone, olanzapine, quetiapine, or aripiprazole, mood stabilizers: lithium, carbamazepine, valproic acid, oxcarbazepine, and antidepressants: citalopram, sertraline, and venlafaxine, along with a brief pharmacological characteristic, preclinical and clinical studies effects. Full article
(This article belongs to the Special Issue Targeting Oxidative Stress for Disease)
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14 pages, 2008 KiB  
Article
Ceanothanes Derivatives as Peripheric Anionic Site and Catalytic Active Site Inhibitors of Acetylcholinesterase: Insights for Future Drug Design
by Sofía Pastene-Burgos, Evelyn Muñoz-Nuñez, Soledad Quiroz-Carreño, Edgar Pastene-Navarrete, Luis Espinoza Catalan, Luis Bustamante and Julio Alarcón-Enos
Int. J. Mol. Sci. 2024, 25(13), 7303; https://doi.org/10.3390/ijms25137303 (registering DOI) - 3 Jul 2024
Abstract
Alzheimer’s disease (AD) is a multifactorial and fatal neurodegenerative disorder. Acetylcholinesterase (AChE) plays a key role in the regulation of the cholinergic system and particularly in the formation of amyloid plaques; therefore, the inhibition of AChE has become one of the most promising [...] Read more.
Alzheimer’s disease (AD) is a multifactorial and fatal neurodegenerative disorder. Acetylcholinesterase (AChE) plays a key role in the regulation of the cholinergic system and particularly in the formation of amyloid plaques; therefore, the inhibition of AChE has become one of the most promising strategies for the treatment of AD, particularly concerning AChE inhibitors that interact with the peripheral anionic site (PAS). Ceanothic acid isolated from the Chilean Rhamnaceae plants is an inhibitor of AChE through its interaction with PAS. In this study, six ceanothic acid derivatives were prepared, and all showed inhibitory activity against AChE. The structural modifications were performed starting from ceanothic acid by application of simple synthetic routes: esterification, reduction, and oxidation. AChE activity was determined by the Ellmann method for all compounds. Kinetic studies indicated that its inhibition was competitive and reversible. According to the molecular coupling and displacement studies of the propidium iodide test, the inhibitory effect of compounds would be produced by interaction with the PAS of AChE. In silico predictions of physicochemical properties, pharmacokinetics, drug-likeness, and medicinal chemistry friendliness of the ceanothane derivatives were performed using the Swiss ADME tool. Full article
(This article belongs to the Special Issue Novel Therapeutic Strategies for Neurodegenerative Disease)
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22 pages, 6365 KiB  
Article
Pirfenidone Prevents Heart Fibrosis during Chronic Chagas Disease Cardiomyopathy
by Tatiana Araújo Silva, Diane Thomas, Jair L. Siqueira-Neto and Claudia Magalhaes Calvet
Int. J. Mol. Sci. 2024, 25(13), 7302; https://doi.org/10.3390/ijms25137302 (registering DOI) - 3 Jul 2024
Abstract
Cardiac fibrosis is a severe outcome of Chagas disease (CD), caused by the protozoan Trypanosoma cruzi. Clinical evidence revealed a correlation between fibrosis levels with impaired cardiac performance in CD patients. Therefore, we sought to analyze the effect of inhibitors of TGF-β [...] Read more.
Cardiac fibrosis is a severe outcome of Chagas disease (CD), caused by the protozoan Trypanosoma cruzi. Clinical evidence revealed a correlation between fibrosis levels with impaired cardiac performance in CD patients. Therefore, we sought to analyze the effect of inhibitors of TGF-β (pirfenidone), p38-MAPK (losmapimod) and c-Jun (SP600125) on the modulation of collagen deposition in cardiac fibroblasts (CF) and in vivo models of T. cruzi chronic infection. Sirius Red/Fast Green dye was used to quantify both collagen expression and total protein amount, assessing cytotoxicity. The compounds were also used to treat C57/Bl6 mice chronically infected with T. cruzi, Brazil strain. We identified an anti-fibrotic effect in vitro for pirfenidone (TGF-β inhibitor, IC50 114.3 μM), losmapimod (p38 inhibitor, IC50 17.6 μM) and SP600125 (c-Jun inhibitor, IC50 3.9 μM). This effect was independent of CF proliferation since these compounds do not affect T. cruzi-induced host cell multiplication as measured by BrdU incorporation. Assays of chronic infection of mice with T. cruzi have shown a reduction in heart collagen by pirfenidone. These results propose a novel approach to fibrosis therapy in CD, with the prospect of repurposing pirfenidone to prevent the onset of ECM accumulation in the hearts of the patients. Full article
(This article belongs to the Special Issue Molecular Mechanisms and Pathophysiology of Myocardial Disease)
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21 pages, 5789 KiB  
Article
Activation and Autoinhibition Mechanisms of NLR Immune Receptor Pi36 in Rice
by Yang Yang, Liu Tan, **ngzhe Xu, Qiaoyi Tang, Ji Wang, Shiyue **ng, Rui Wang, Ting Zou, Shiquan Wang, Jun Zhu, Shuangcheng Li, Yueyang Liang, Qiming Deng and ** Li
Int. J. Mol. Sci. 2024, 25(13), 7301; https://doi.org/10.3390/ijms25137301 (registering DOI) - 2 Jul 2024
Abstract
Nucleotide-binding and leucine-rich repeat receptors (NLRs) are the most important and largest class of immune receptors in plants. The Pi36 gene encodes a canonical CC-NBS-LRR protein that confers resistance to rice blast fungal infections. Here, we show that the CC domain of Pi36 [...] Read more.
Nucleotide-binding and leucine-rich repeat receptors (NLRs) are the most important and largest class of immune receptors in plants. The Pi36 gene encodes a canonical CC-NBS-LRR protein that confers resistance to rice blast fungal infections. Here, we show that the CC domain of Pi36 plays a role in cell death induction. Furthermore, self-association is required for the CC domain-mediated cell death, and the self-association ability is correlated with the cell death level. In addition, the NB-ARC domain may suppress the activity of the CC domain through intramolecular interaction. The mutations D440G next to the RNBS-D motif and D503V in the MHD motif autoactivated Pi36, but the mutation K212 in the P-loop motif inhibited this autoactivation, indicating that nucleotide binding of the NB-ARC domain is essential for Pi36 activation. We also found that the LRR domain is required for D503V- and D440G-mediated Pi36 autoactivation. Interestingly, several mutations in the CC domain compromised the CC domain-mediated cell death without affecting the D440G- or D503V-mediated Pi36 autoactivation. The autoactivate Pi36 variants exhibited stronger self-associations than the inactive variants. Taken together, we speculated that the CC domain of Pi36 executes cell death activities, whereas the NB-ARC domain suppressed CC-mediated cell death via intermolecular interaction. The NB-ARC domain releases its suppression of the CC domain and strengthens the self-association of Pi36 to support the CC domain, possibly through nucleotide exchange. Full article
(This article belongs to the Section Molecular Plant Sciences)
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18 pages, 2830 KiB  
Article
Bio-Based Polyurethane Networks Containing Sunflower Oil Based Polyols
by Katalin Czifrák, Csilla Lakatos, Csaba Cserháti, Gergő Vecsei, Miklós Zsuga and Sándor Kéki
Int. J. Mol. Sci. 2024, 25(13), 7300; https://doi.org/10.3390/ijms25137300 (registering DOI) - 2 Jul 2024
Abstract
This work focused on the preparation and investigation of polyurethane (SO-PU)-containing sunflower oil glycerides. By transesterification of sunflower oil with glycerol, we synthesized a glyceride mixture with an equilibrium composition, which was used as a new diol component in polyurethanes in addition to [...] Read more.
This work focused on the preparation and investigation of polyurethane (SO-PU)-containing sunflower oil glycerides. By transesterification of sunflower oil with glycerol, we synthesized a glyceride mixture with an equilibrium composition, which was used as a new diol component in polyurethanes in addition to poly(ε-caprolactone)diol (PCLD2000). The structure of the glyceride mixture was characterized by physicochemical methods, matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS), nuclear magnetic resonance spectroscopy (NMR), and size exclusion chromatography (SEC) measurements. The synthesis of polyurethanes was performed in two steps: first the prepolymer with the isocyanate end was synthesized, followed by crosslinking with an additional amount of diisocyanate. For the synthesis of the prepolymer, 4,4’-methylene diphenyl diisocyanate (MDI) or 1,6-hexamethylene diisocyanate (HDI) were used as isocyanate components, while the crosslinking was carried out using an additional amount of MDI or HDI. The obtained SO-PU flexible polymer films were characterized by attenuated total reflectance Fourier transform infrared spectroscopy (ATR-FTIR), differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), and scanning electron microscopy (SEM). The so-obtained flexible SO-PU films were proved to be suitable for the preparation of potentially biocompatible and/or biodegradable scaffolds. In addition, the stress versus strain curves for the SO-PU polymers were interpreted in terms of a mechanical model, taking into account the yield and the strain hardening. Full article
(This article belongs to the Section Materials Science)
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Graphical abstract

25 pages, 603 KiB  
Review
Investigating the Interplay: Periodontal Disease and Type 1 Diabetes Mellitus—A Comprehensive Review of Clinical Studies
by Stefania Vlachou, Alexandre Loumé, Catherine Giannopoulou, Evangelos Papathanasiou and Alkisti Zekeridou
Int. J. Mol. Sci. 2024, 25(13), 7299; https://doi.org/10.3390/ijms25137299 (registering DOI) - 2 Jul 2024
Abstract
Diabetes mellitus (DM) poses a significant challenge to global health, with its prevalence projected to rise dramatically by 2045. This narrative review explores the bidirectional relationship between periodontitis (PD) and type 1 diabetes mellitus (T1DM), focusing on cellular and molecular mechanisms derived from [...] Read more.
Diabetes mellitus (DM) poses a significant challenge to global health, with its prevalence projected to rise dramatically by 2045. This narrative review explores the bidirectional relationship between periodontitis (PD) and type 1 diabetes mellitus (T1DM), focusing on cellular and molecular mechanisms derived from the interplay between oral microbiota and the host immune response. A comprehensive search of studies published between 2008 and 2023 was conducted to elucidate the association between these two diseases. Preclinical and clinical evidence suggests a bidirectional relationship, with individuals with T1DM exhibiting heightened susceptibility to periodontitis, and vice versa. The review includes recent findings from human clinical studies, revealing variations in oral microbiota composition in T1DM patients, including increases in certain pathogenic species such as Porphyromonas gingivalis, Prevotella intermedia, and Aggregatibacter actinomycetemcomitans, along with shifts in microbial diversity and abundance. Molecular mechanisms underlying this association involve oxidative stress and dysregulated host immune responses, mediated by inflammatory cytokines such as IL-6, IL-8, and MMPs. Furthermore, disruptions in bone turnover markers, such as RANKL and OPG, contribute to periodontal complications in T1DM patients. While preventive measures to manage periodontal complications in T1DM patients may improve overall health outcomes, further research is needed to understand the intricate interactions between oral microbiota, host response, periodontal disease, and systemic health in this population. Full article
(This article belongs to the Special Issue Periodontal Disease, Association with Systemic Conditions and Periodontal Pathogens)
25 pages, 5580 KiB  
Article
Insight into Mantle Cell Lymphoma Pathobiology, Diagnosis, and Treatment Using Network-Based and Drug-Repurposing Approaches
by Georgia Orfanoudaki, Konstantina Psatha and Michalis Aivaliotis
Int. J. Mol. Sci. 2024, 25(13), 7298; https://doi.org/10.3390/ijms25137298 - 2 Jul 2024
Viewed by 49
Abstract
Mantle cell lymphoma (MCL) is a rare, incurable, and aggressive B-cell non-Hodgkin lymphoma (NHL). Early MCL diagnosis and treatment is critical and puzzling due to inter/intra-tumoral heterogeneity and limited understanding of the underlying molecular mechanisms. We developed and applied a multifaceted analysis of [...] Read more.
Mantle cell lymphoma (MCL) is a rare, incurable, and aggressive B-cell non-Hodgkin lymphoma (NHL). Early MCL diagnosis and treatment is critical and puzzling due to inter/intra-tumoral heterogeneity and limited understanding of the underlying molecular mechanisms. We developed and applied a multifaceted analysis of selected publicly available transcriptomic data of well-defined MCL stages, integrating network-based methods for pathway enrichment analysis, co-expression module alignment, drug repurposing, and prediction of effective drug combinations. We demonstrate the “butterfly effect” emerging from a small set of initially differentially expressed genes, rapidly expanding into numerous deregulated cellular processes, signaling pathways, and core machineries as MCL becomes aggressive. We explore pathogenicity-related signaling circuits by detecting common co-expression modules in MCL stages, pointing out, among others, the role of VEGFA and SPARC proteins in MCL progression and recommend further study of precise drug combinations. Our findings highlight the benefit that can be leveraged by such an approach for better understanding pathobiology and identifying high-priority novel diagnostic and prognostic biomarkers, drug targets, and efficacious combination therapies against MCL that should be further validated for their clinical impact. Full article
(This article belongs to the Special Issue Molecular Pathology and Immunotherapy of Lymphoma)
16 pages, 3872 KiB  
Article
The Effecting Mechanisms of 100 nm Sized Polystyrene Nanoplastics on the Typical Coastal Alexandrium tamarense
by Luying Li, Qian Liu, Bo Li and Yan Zhao
Int. J. Mol. Sci. 2024, 25(13), 7297; https://doi.org/10.3390/ijms25137297 - 2 Jul 2024
Viewed by 72
Abstract
Due to the increase in nanoplastics (NPs) abundance in aquatic environments, their effects on phytoplankton have aroused large research attention. In this study, 100 nm sized polystyrene NPs were chosen to investigate their effecting performance and mechanisms on a typical dinoflagellates Alexandrium tamarense [...] Read more.
Due to the increase in nanoplastics (NPs) abundance in aquatic environments, their effects on phytoplankton have aroused large research attention. In this study, 100 nm sized polystyrene NPs were chosen to investigate their effecting performance and mechanisms on a typical dinoflagellates Alexandrium tamarense. The results indicated the population growth and photosynthetic efficiencies of A. tamarense were significantly inhibited by NPs exposure, as well as the increase in cellular total carotenoids and paralytic shellfish toxins (PSTs). Meanwhile, the cellar ROS levels increased, corresponding to the increased activities or contents of multiple antioxidant components, including SOD, CAT, GPX, GR, GSH and GSSG. The transcriptional results support the physiological–biochemical results and further revealed the down-regulation of genes encoding the light reaction centers (PSI and PSII) and up-regulation of genes encoding the antioxidant components. Up-regulation of genes encoding key enzymes of the Calvin cycle and glycolytic pathway together with the TCA cycle could accelerate organic carbon and ATP production for A. tamarense cells resistant to NPs stress. Finally, more Glu and acetyl-CoA produced by the enhanced GSH cycle and the glycolytic pathway, respectively, accompanied by the up-regulation of Glu and Arg biosynthesis genes supported the increase in the PST contents under NPs exposure. This study established a data set involving physiological–biochemical changes and gene information about marine dinoflagellates responding to NPs, providing a data basis for further evaluating the ecological risk of NPs in marine environments. Full article
(This article belongs to the Section Molecular Toxicology)
11 pages, 1707 KiB  
Article
Cryptic Extensibility in von Willebrand Factor Revealed by Molecular Nanodissection
by Mária Csilla Csányi, Dominik Sziklai, Tímea Feller, Jolán Hársfalvi and Miklós Kellermayer
Int. J. Mol. Sci. 2024, 25(13), 7296; https://doi.org/10.3390/ijms25137296 - 2 Jul 2024
Viewed by 106
Abstract
Von Willebrand factor (VWF) is a multimer with a variable number of protomers, each of which is a head-to-head dimer of two multi-domain monomers. VWF responds to shear through the unfolding and extension of distinct domains, thereby mediating platelet adhesion and aggregation to [...] Read more.
Von Willebrand factor (VWF) is a multimer with a variable number of protomers, each of which is a head-to-head dimer of two multi-domain monomers. VWF responds to shear through the unfolding and extension of distinct domains, thereby mediating platelet adhesion and aggregation to the injured blood vessel wall. VWF's C1-6 segment uncoils and then the A2 domain unfolds and extends in a hierarchical and sequential manner. However, it is unclear whether there is any reservoir of further extensibility. Here, we explored the presence of cryptic extensibility in VWF by nanodissecting individual, pre-stretched multimers with atomic force microscopy (AFM). The AFM cantilever tip was pressed into the surface and moved in a direction perpendicular to the VWF axis. It was possible to pull out protein loops from VWF, which resulted in a mean contour length gain of 217 nm. In some cases, the loop became cleaved, and a gap was present along the contour. Frequently, small nodules appeared in the loops, indicating that parts of the nanodissected VWF segment remained folded. After analyzing the nodal structure, we conclude that the cryptic extensibility lies within the C1-6 and A1-3 regions. Cryptic extensibility may play a role in maintaining VWF’s functionality in extreme shear conditions. Full article
(This article belongs to the Special Issue Advances in Molecular and Cellular Imaging, Microscopy, and Biomedical Spectroscopy)
27 pages, 2482 KiB  
Review
From Atherosclerotic Plaque to Myocardial Infarction—The Leading Cause of Coronary Artery Occlusion
by Ewelina Młynarska, Witold Czarnik, Piotr Fularski, Joanna Hajdys, Gabriela Majchrowicz, Magdalena Stabrawa, Jacek Rysz and Beata Franczyk
Int. J. Mol. Sci. 2024, 25(13), 7295; https://doi.org/10.3390/ijms25137295 - 2 Jul 2024
Viewed by 101
Abstract
Cardiovascular disease (CVD) constitutes the most common cause of death worldwide. In Europe alone, approximately 4 million people die annually due to CVD. The leading component of CVD leading to mortality is myocardial infarction (MI). MI is classified into several types. Type 1 [...] Read more.
Cardiovascular disease (CVD) constitutes the most common cause of death worldwide. In Europe alone, approximately 4 million people die annually due to CVD. The leading component of CVD leading to mortality is myocardial infarction (MI). MI is classified into several types. Type 1 is associated with atherosclerosis, type 2 results from inadequate oxygen supply to cardiomyocytes, type 3 is defined as sudden cardiac death, while types 4 and 5 are associated with procedures such as percutaneous coronary intervention and coronary artery bypass grafting, respectively. Of particular note is type 1, which is also the most frequently occurring form of MI. Factors predisposing to its occurrence include, among others, high levels of low-density lipoprotein cholesterol (LDL-C) in the blood, cigarette smoking, chronic kidney disease (CKD), diabetes mellitus (DM), hypertension, and familial hypercholesterolaemia (FH). The primary objective of this review is to elucidate the issues with regard to type 1 MI. Our paper delves into, amidst other aspects, its pathogenesis, risk assessment, diagnosis, pharmacotherapy, and interventional treatment options in both acute and long-term conditions. Full article
(This article belongs to the Special Issue Lipids and Cardiovascular Disease 2.0)
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16 pages, 3336 KiB  
Article
3′-UTR Sequence of Exosomal NANOGP8 DNA as an Extracellular Vesicle-Localization Signal
by Manjusha Vaidya, Ayaka Kimura, Arjun Bajaj and Kiminobu Sugaya
Int. J. Mol. Sci. 2024, 25(13), 7294; https://doi.org/10.3390/ijms25137294 (registering DOI) - 2 Jul 2024
Viewed by 54
Abstract
Extracellular vesicles (EVs) are garnering attention as a safe and efficient biomolecule delivery system. EVs intrinsically play a crucial role in intercellular communication and pathophysiology by transporting functionally active DNA molecules. The internalized DNA pleiotropically affects the recipient cells. Considering these salient features, [...] Read more.
Extracellular vesicles (EVs) are garnering attention as a safe and efficient biomolecule delivery system. EVs intrinsically play a crucial role in intercellular communication and pathophysiology by transporting functionally active DNA molecules. The internalized DNA pleiotropically affects the recipient cells. Considering these salient features, an intentional incorporation of specific DNA gene cassettes into EVs and their subsequent delivery to the target cells has potential applications in genetic engineering. Moreover, efficient ways to insert the DNA into EVs during their biogenesis is valuable. Our current research is a step in the development of this technology. As such, cancer cells are known to secrete exosomes containing increased amounts of double-stranded DNA than normal cells. The clonal analysis in our previously published data revealed that exosomes released from various cancer cells contained a significantly larger population of NANOGP8 DNA with a 22-base pair insertion in the 3′-untranslated region (UTR) compared to those secreted by normal cells. This finding led us to hypothesize that the 22-base pair insertion may act as a signal to facilitate the incorporation of NANOGP8 DNA into the exosomes. To test this hypothesis, we compared the EV localization of an Enhanced Green Fluorescent Protein (EGFP) gene fused with the NANOGP8 3′-UTR, with and without the 22-base pair insertion. The quantitative PCR analysis showed a significantly higher EGFP DNA accumulation in exosomes released from cells transfected with the gene cassette containing the 3′-UTR with the 22-base pair insertion. The discovery of a DNA localization signal in exosomal DNA’s 3’-UTR could pave the way for the development of an EV-based DNA delivery system. This technology will open new possibilities in genetic engineering and innovative therapies using nucleic acid medicine. Full article
(This article belongs to the Special Issue Regeneration Therapy for Neurological Diseases)
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8 pages, 4694 KiB  
Case Report
Long-Term Remission with Novel Combined Immune-Targeted Treatment for Histiocytic Sarcoma Accompanied by Follicular Lymphoma: Case Report and Literature Review
by Minyue Zhang, Fei **ao, Jianchen Fang, Zebing Liu, Yanying Shen, Di Zhu, Yiwei Zhang, Jian Hou and Honghui Huang
Int. J. Mol. Sci. 2024, 25(13), 7293; https://doi.org/10.3390/ijms25137293 - 2 Jul 2024
Viewed by 127
Abstract
Histiocytic sarcoma (HS) is an extremely rare but aggressive hematopoietic malignancy, and the prognosis has been reported to be rather unfavorable with a median overall survival of merely 6 months. We presented a 58-year-old female patient complaining of abdominal pain and fever, who [...] Read more.
Histiocytic sarcoma (HS) is an extremely rare but aggressive hematopoietic malignancy, and the prognosis has been reported to be rather unfavorable with a median overall survival of merely 6 months. We presented a 58-year-old female patient complaining of abdominal pain and fever, who was admitted to our institution in September 2021. Fluorine-18-fluorodeoxyglucose (FDG) positron emission tomography–computed tomography (PET/CT) scan showed enlargement of generalized multiple lymph nodes. Subsequently, laparoscopic retroperitoneal lesion biopsy and bone marrow aspiration were performed. The pathological findings indicated the diagnosis of HS concurrent with follicular lymphoma. The immunohistochemistry (IHC) staining of the tumor lesion revealed a high expression of CD38 and PD-L1 proteins. Furthermore, KRAS gene mutation was identified by means of next-generation sequencing. The patient exhibited poor treatment response to both first- and second-line cytotoxic chemotherapies. Therefore, she underwent six cycles of Daratumumab (anti-CD38 monoclonal antibody), Pazopanib (multi-target receptor tyrosine kinases inhibitor) combined with third-line chemotherapy, followed by involved-site radiotherapy and maintenance therapy with the PD-1 inhibitor Tislelizumab. Long-term partial remission was finally achieved after multi-modality treatment. Duration of remission and overall survival reached 22 and 32 months, respectively. Our case indicated that immuno-targeted treatment coupled with chemotherapy and radiotherapy might constitute a potential therapeutic option for HS. Full article
(This article belongs to the Special Issue New Advances in B-cell Lymphoma Biology)
13 pages, 1181 KiB  
Review
Modifications of Nanobubble Therapy for Cancer Treatment
by Katarzyna M. Terlikowska, Bozena Dobrzycka and Slawomir J. Terlikowski
Int. J. Mol. Sci. 2024, 25(13), 7292; https://doi.org/10.3390/ijms25137292 - 2 Jul 2024
Viewed by 109
Abstract
Cancer development is related to genetic mutations in primary cells, where 5–10% of all cancers are derived from acquired genetic defects, most of which are a consequence of the environment and lifestyle. As it turns out, over half of cancer deaths are due [...] Read more.
Cancer development is related to genetic mutations in primary cells, where 5–10% of all cancers are derived from acquired genetic defects, most of which are a consequence of the environment and lifestyle. As it turns out, over half of cancer deaths are due to the generation of drug resistance. The local delivery of chemotherapeutic drugs may reduce their toxicity by increasing their therapeutic dose at targeted sites and by decreasing the plasma levels of circulating drugs. Nanobubbles have attracted much attention as an effective drug distribution system due to their non-invasiveness and targetability. This review aims to present the characteristics of nanobubble systems and their efficacy within the biomedical field with special emphasis on cancer treatment. In vivo and in vitro studies on cancer confirm nanobubbles’ ability and good blood capillary perfusion; however, there is a need to define their safety and side effects in clinical trials. Full article
(This article belongs to the Special Issue Molecular Targeted Therapies and Precision Medicine for Malignant Diseases)
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17 pages, 4994 KiB  
Article
First Immunohistochemical Demonstration of the Expression of a Type-2 Vomeronasal Receptor, V2R2, in Wild Canids
by Irene Ortiz-Leal, Mateo V. Torres, Ana López-Beceiro, Luis Fidalgo, Taekyun Shin and Pablo Sanchez-Quinteiro
Int. J. Mol. Sci. 2024, 25(13), 7291; https://doi.org/10.3390/ijms25137291 - 2 Jul 2024
Viewed by 82
Abstract
The mammalian vomeronasal system enables the perception of chemical signals crucial for social communication via the receptor families V1R and V2R. These receptors are linked with the G-protein subunits, Gαi2 and Gαo, respectively. Exploring the evolutionary pathways of V1Rs and V2Rs across mammalian [...] Read more.
The mammalian vomeronasal system enables the perception of chemical signals crucial for social communication via the receptor families V1R and V2R. These receptors are linked with the G-protein subunits, Gαi2 and Gαo, respectively. Exploring the evolutionary pathways of V1Rs and V2Rs across mammalian species remains a significant challenge, particularly when comparing genomic data with emerging immunohistochemical evidence. Recent studies have revealed the expression of Gαo in the vomeronasal neuroepithelium of wild canids, including wolves and foxes, contradicting predictions based on current genomic annotations. Our study provides detailed immunohistochemical evidence, map** the expression of V2R receptors in the vomeronasal sensory epithelium, focusing particularly on wild canids, specifically wolves and foxes. An additional objective involves contrasting these findings with those from domestic species like dogs to highlight the evolutionary impacts of domestication on sensory systems. The employment of a specific antibody raised against the mouse V2R2, a member of the C-family of vomeronasal receptors, V2Rs, has confirmed the presence of V2R2-immunoreactivity (V2R2-ir) in the fox and wolf, but it has revealed the lack of expression in the dog. This may reflect the impact of domestication on the regression of the VNS in this species, in contrast to their wild counterparts, and it underscores the effects of artificial selection on sensory functions. Thus, these findings suggest a more refined chemical detection capability in wild species. Full article
(This article belongs to the Special Issue Molecular Research on Olfactory and Gustatory Receptors)
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19 pages, 3816 KiB  
Article
The Prognostic and Therapeutic Potential of Fragile X Mental Retardation 1 (FMR1) Gene Expression in Prostate Adenocarcinoma: Insights into Survival Outcomes and Oncogenic Pathway Modulation
by Salem Baldi, Bushra Amer, Fawze Alnadari, Maged AL-Mogahed, Yaqin Gao and Yaser Gamallat
Int. J. Mol. Sci. 2024, 25(13), 7290; https://doi.org/10.3390/ijms25137290 - 2 Jul 2024
Viewed by 88
Abstract
Prostate adenocarcinoma (PRAD) is the second most common tumor associated with death. The role and mechanisms of the fragile X mental retardation 1 (FMR1) gene in PRAD remain unknown. We conducted an analysis of FMR1 expression in PRAD to determine its prognostic importance [...] Read more.
Prostate adenocarcinoma (PRAD) is the second most common tumor associated with death. The role and mechanisms of the fragile X mental retardation 1 (FMR1) gene in PRAD remain unknown. We conducted an analysis of FMR1 expression in PRAD to determine its prognostic importance and connection to carcinogenic pathways such as PI3K_AKT_mTOR. Survival analyses were utilized to establish a correlation between FMR1 expression and patient outcomes. We used the integration of genomic data with bioinformatic predictions to predict the regulatory factors of the FMR1 gene in PRAD. Our data revealed that individuals with higher levels of FMR1 expression experience worse survival outcomes compared to those with lower expression (hazard ratio [HR] = 5.08, 95% confidence interval [CI] = 1.07 – 24, p = 0.0412). FMR1 expression was significantly higher in patients with advanced pathological tumor stages, particularly in the pT3 and pT4 combined stages and the pN1 nodal stage. Furthermore, patients with high Gleason scores (GSs) (combined GSs 8 and 9) exhibited increased levels of FMR1 expression. Our results further identify a possible regulatory link between FMR1 and key oncogenic pathways, including PI3K_AKT_mTOR, and predict the possible mechanism by which FMR1 is regulated in PRAD. Our data suggest that the FMR1 gene could serve as a biomarker for PRAD progression. However, in-depth investigations, including those with large patient samples and in vitro studies, are needed to validate this finding and understand the mechanisms involved. Full article
(This article belongs to the Special Issue Molecular Research on Prostate Cancer)
12 pages, 4712 KiB  
Article
Latrophilins as Downstream Effectors of Androgen Receptors including a Splice Variant, AR-V7, Induce Prostate Cancer Progression
by Yuki Teramoto, Mohammad Amin Elahi Najafi, Takuo Matsukawa, Adhya Sharma, Takuro Goto and Hiroshi Miyamoto
Int. J. Mol. Sci. 2024, 25(13), 7289; https://doi.org/10.3390/ijms25137289 - 2 Jul 2024
Viewed by 97
Abstract
Latrophilins (LPHNs), a group of the G-protein–coupled receptor to which a spider venom latrotoxin (LTX) is known to bind, remain largely uncharacterized in neoplastic diseases. In the present study, we aimed to determine the role of LPHNs in the progression of prostate cancer. [...] Read more.
Latrophilins (LPHNs), a group of the G-protein–coupled receptor to which a spider venom latrotoxin (LTX) is known to bind, remain largely uncharacterized in neoplastic diseases. In the present study, we aimed to determine the role of LPHNs in the progression of prostate cancer. We assessed the actions of LPHNs, including LPHN1, LPHN2, and LPHN3, in human prostate cancer lines via their ligand (e.g., α-LTX, FLRT3) treatment or shRNA infection, as well as in surgical specimens. In androgen receptor (AR)-positive LNCaP/C4-2/22Rv1 cells, dihydrotestosterone considerably increased the expression levels of LPHNs, while chromatin immunoprecipitation assay revealed the binding of endogenous ARs, including AR-V7, to the promoter region of each LPHN. Treatment with α-LTX or FLRT3 resulted in induction in the cell viability and migration of both AR-positive and AR-negative lines. α-LTX and FLRT3 also enhanced the expression of Bcl-2 and phosphorylated forms of JAK2 and STAT3. Meanwhile, the knockdown of each LPHN showed opposite effects on all of those mediated by ligand treatment. Immunohistochemistry in radical prostatectomy specimens further showed the significantly elevated expression of each LPHN in prostate cancer, compared with adjacent normal-appearing prostate, which was associated with a significantly higher risk of postoperative biochemical recurrence in both univariate and multivariable settings. These findings indicate that LPHNs function as downstream effectors of ARs and promote the growth of androgen-sensitive, castration-resistant, or even AR-negative prostate cancer. Full article
(This article belongs to the Special Issue Male Genitourinary Tumors: Molecular Mechanisms and Potential Therapeutic Targets)
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15 pages, 7307 KiB  
Article
Carex meyeriana Kunth Extract Is a Novel Natural Drug against Candida albicans
by Panpan Du, Bingyan Liu, Xueting Wang, Zhong Zheng, Shu Liu, Songlei Guan and Zong Hou
Int. J. Mol. Sci. 2024, 25(13), 7288; https://doi.org/10.3390/ijms25137288 - 2 Jul 2024
Viewed by 133
Abstract
As a widely distributed plant in Northeast China, Carex meyeriana Kunth (CMK) is generally considered to have antibacterial properties; however, there is a lack of scientific evidence for this. Therefore, we investigated the chemical composition of CMK extract and its effect against C. [...] Read more.
As a widely distributed plant in Northeast China, Carex meyeriana Kunth (CMK) is generally considered to have antibacterial properties; however, there is a lack of scientific evidence for this. Therefore, we investigated the chemical composition of CMK extract and its effect against C. albicans. A total of 105 compounds were identified in the alcohol extracts of CMK by UPLC-Q-TOF-MS. Most were flavonoids, with Luteolin being the most represented. Among them, 19 compounds are found in the C. albicans lysates. After treatment with CMK ethanol extract, a significant reduction in the number of C. albicans colonies was observed in a vaginal douche solution from day 5 (p < 0.05). Furthermore, the CMK extract can reduce the number of C. albicans spores. The levels of IL-4, IL-6, IL-10, IL-1β, and TNF-α in vaginal tissues all exhibited a significant decrease (p < 0.05) compared to those in the model group as determined by ELISA. The results of HE staining showed that CMK extract can eliminate vaginal mucosa inflammation. CMK adjusts the vaginal mucosa cells by targeting twenty-six different metabolites and five specific metabolic pathways in order to effectively eliminate inflammation. Simultaneously, the CMK regulates twenty-three types of metabolites and six metabolic pathways against C. albicans infection. So, CMK strongly inhibits the growth of C. albicans and significantly reduces vaginal inflammation, making it a promising candidate for treating C. albicans infection. Full article
(This article belongs to the Section Bioactives and Nutraceuticals)
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15 pages, 7712 KiB  
Article
Alpha 1,3 N-Acetylgalactosaminyl Transferase (GTA) Impairs Invasion Potential of Trophoblast Cells in Preeclampsia
by Yaqi Li, Hongpan Wu, **aosong Pei, Shuai Liu and Qiu Yan
Int. J. Mol. Sci. 2024, 25(13), 7287; https://doi.org/10.3390/ijms25137287 - 2 Jul 2024
Viewed by 136
Abstract
Preeclampsia (PE) is a pregnancy-specific disorder associated with shallow invasion of the trophoblast cells and insufficient remodeling of the uterine spiral artery. Protein glycosylation plays an important role in trophoblast cell invasion. However, the glycobiological mechanism of PE has not been fully elucidated. [...] Read more.
Preeclampsia (PE) is a pregnancy-specific disorder associated with shallow invasion of the trophoblast cells and insufficient remodeling of the uterine spiral artery. Protein glycosylation plays an important role in trophoblast cell invasion. However, the glycobiological mechanism of PE has not been fully elucidated. In the current study, employing the Lectin array, we found that soybean agglutinin (SBA), which recognizes the terminal N-acetylgalactosamine α1,3-galactose (GalNAc α1,3 Gal) glycotype, was significantly increased in placental trophoblast cells from PE patients compared with third-trimester pregnant controls. Upregulating the expression of the key enzyme α1,3 N-acetylgalactosaminyl transferase (GTA) promoted the biosynthesis of terminal GalNAc α1,3 Gal and inhibited the migration/invasion of HTR8/SVneo trophoblast cells. Moreover, the methylation status of GTA promoter in placental tissues from PE patients was lower than that in the third trimester by methylation-specific PCR (MSP) and bisulfite sequencing PCR (BSP) analysis. Elevated GTA expression in combination with the DNA methylation inhibitor 5-azacytidine (5-AzaC) treatment increased the glycotype biosynthesis and impaired the invasion potential of trophoblast cells, leading to preeclampsia. This study suggests that elevated terminal GalNAc α1,3 Gal biosynthesis and GTA expression may be applied as the new markers for evaluating placental function and the auxiliary diagnosis of preeclampsia. Full article
(This article belongs to the Section Biochemistry)
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45 pages, 2100 KiB  
Article
Long-Term Proton Pump Inhibitor–Acid Suppressive Treatment Can Cause Vitamin B12 Deficiency in Zollinger–Ellison Syndrome (ZES) Patients
by Tetsuhide Ito, Irene Ramos-Alvarez and Robert T. Jensen
Int. J. Mol. Sci. 2024, 25(13), 7286; https://doi.org/10.3390/ijms25137286 - 2 Jul 2024
Viewed by 158
Abstract
Whether the long-term treatment of patients with proton pump inhibitors (PPIs) with different diseases [GERD, Zollinger–Ellison syndrome (ZES), etc.] can result in vitamin B12 (VB12) deficiency is controversial. In this study, in 175 patients undergoing long-term ZES treatment with anti-acid [...] Read more.
Whether the long-term treatment of patients with proton pump inhibitors (PPIs) with different diseases [GERD, Zollinger–Ellison syndrome (ZES), etc.] can result in vitamin B12 (VB12) deficiency is controversial. In this study, in 175 patients undergoing long-term ZES treatment with anti-acid therapies, drug-induced control acid secretory rates were correlated with the presence/absence of VB12 deficiency, determined by assessing serum VB12 levels, measurements of VB12 body stores (blood methylmalonic acid (MMA) and total homocysteine[tHYC]), and other features of ZES. After a mean of 10.2 yrs. of any acid treatment (5.6 yrs. with PPIs), 21% had VB12 deficiency with significantly lower serum and body VB12 levels (p < 0.0001). The presence of VB12 deficiency did not correlate with any feature of ZES but was associated with a 12-fold lower acid control rate, a 2-fold higher acid control pH (6.4 vs. 3.7), and acid control secretory rates below those required for the activation of pepsin (pH > 3.5). Over a 5-yr period, the patients with VB12 deficiency had a higher rate of achlorhydria (73% vs. 24%) and a lower rate of normal acid secretion (0% vs. 49%). In conclusion, in ZES patients, chronic long-term PPI treatment results in marked acid hyposecretion, resulting in decreased serum VB12 levels and decreased VB12-body stores, which can result in VB12 deficiency. Full article
(This article belongs to the Special Issue Short and Long-Term Profound Acid Inhibition: Indications and Concerns)
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14 pages, 2908 KiB  
Article
Verification of Outer Hair Cell Motor Protein, Prestin, as a Serological Biomarker for Mouse Cochlear Damage
by **g Zheng, Yingjie Zhou, Robert J. Fuentes and **aodong Tan
Int. J. Mol. Sci. 2024, 25(13), 7285; https://doi.org/10.3390/ijms25137285 - 2 Jul 2024
Viewed by 209
Abstract
The motor protein prestin, found in the inner ear’s outer hair cells (OHCs), is responsible for high sensitivity and sharp frequency selectivity in mammalian hearing. Some studies have suggested that prestin could be a serological biomarker for cochlear damage, as OHCs are highly [...] Read more.
The motor protein prestin, found in the inner ear’s outer hair cells (OHCs), is responsible for high sensitivity and sharp frequency selectivity in mammalian hearing. Some studies have suggested that prestin could be a serological biomarker for cochlear damage, as OHCs are highly vulnerable to damage from various sources. However, the reported data are inconsistent and lack appropriate negative controls. To investigate whether prestin can be used as a serological biomarker for cochlear damage or stress, we measured prestin quantities in the bloodstreams of mice using ELISA kits from different companies. Wildtype (WT) mice were exposed to different ototoxic treatments, including noise exposure and ototoxic reagents that rapidly kill OHCs. Prestin-knockout (KO) mice were used as a negative control. Our data show that some ELISA kits were not able to detect prestin specifically. The ELISA kit that could detect the prestin protein from cochlear homogenates failed to detect prestin in the bloodstream, despite there being significant damage to OHCs in the cochleae. Furthermore, the optical densities of the serum samples, which correlate to prestin quantities, were significantly influenced by hemolysis in the samples. In conclusion, Prestin from OHCs is not a sensitive and reliable serological biomarker for detecting cochlear damage in mice using ELISA. Full article
(This article belongs to the Special Issue Exploring the Molecular, Cellular, and Physiological Basis of Hearing Disorders)
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27 pages, 1130 KiB  
Review
Vitamin C Supplementation in the Treatment of Autoimmune and Onco-Hematological Diseases: From Prophylaxis to Adjuvant Therapy
by Stefania Isola, Luca Gammeri, Fabiana Furci, Sebastiano Gangemi, Giovanni Pioggia and Alessandro Allegra
Int. J. Mol. Sci. 2024, 25(13), 7284; https://doi.org/10.3390/ijms25137284 - 2 Jul 2024
Viewed by 239
Abstract
Vitamin C is a water-soluble vitamin introduced through the diet with anti-inflammatory, immunoregulatory, and antioxidant activities. Today, this vitamin is integrated into the treatment of many inflammatory pathologies. However, there is increasing evidence of possible use in treating autoimmune and neoplastic diseases. We [...] Read more.
Vitamin C is a water-soluble vitamin introduced through the diet with anti-inflammatory, immunoregulatory, and antioxidant activities. Today, this vitamin is integrated into the treatment of many inflammatory pathologies. However, there is increasing evidence of possible use in treating autoimmune and neoplastic diseases. We reviewed the literature to delve deeper into the rationale for using vitamin C in treating this type of pathology. There is much evidence in the literature regarding the beneficial effects of vitamin C supplementation for treating autoimmune diseases such as Systemic Lupus Erythematosus (SLE) and Rheumatoid Arthritis (RA) and neoplasms, particularly hematological neoplastic diseases. Vitamin C integration regulates the cytokines microenvironment, modulates immune response to autoantigens and cancer cells, and regulates oxidative stress. Moreover, integration therapy has an enhanced effect on chemotherapies, ionizing radiation, and target therapy used in treating hematological neoplasm. In the future, integrative therapy will have an increasingly important role in preventing pathologies and as an adjuvant to standard treatments. Full article
(This article belongs to the Section Molecular Pathology, Diagnostics, and Therapeutics)
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26 pages, 7828 KiB  
Article
De Novo Hybrid Assembly Unveils Multi-Chromosomal Mitochondrial Genomes in Ludwigia Species, Highlighting Genomic Recombination, Gene Transfer, and RNA Editing Events
by Guillaume Doré, Dominique Barloy and Frédérique Barloy-Hubler
Int. J. Mol. Sci. 2024, 25(13), 7283; https://doi.org/10.3390/ijms25137283 - 2 Jul 2024
Viewed by 151
Abstract
Biological invasions have been identified as the fifth cause of biodiversity loss, and their subsequent dispersal represents a major ecological challenge. The aquatic invasive species Ludwigia grandiflora subsp. hexapetala (Lgh) and Ludwigia peploides subsp. montevidensis (Lpm) are largely distributed [...] Read more.
Biological invasions have been identified as the fifth cause of biodiversity loss, and their subsequent dispersal represents a major ecological challenge. The aquatic invasive species Ludwigia grandiflora subsp. hexapetala (Lgh) and Ludwigia peploides subsp. montevidensis (Lpm) are largely distributed in aquatic environments in North America and in Europe. However, they also present worrying terrestrial forms that are able to colonize wet meadows. To comprehend the mechanisms of the terrestrial adaptation of Lgh and Lpm, it is necessary to develop their genomic resources, which are currently poorly documented. We performed de novo assembly of the mitogenomes of Lgh and Lpm through hybrid assemblies, combining short reads (SR) and/or long reads (LR) before annotating both mitogenomes. We successfully assembled the mitogenomes of Lgh and Lpm into two circular molecules each, resulting in a combined total length of 711,578 bp and 722,518 bp, respectively. Notably, both the Lgh and Lpm molecules contained plastome-origin sequences, comprising 7.8% of the mitochondrial genome length. Additionally, we identified recombinations that were mediated by large repeats, suggesting the presence of multiple alternative conformations. In conclusion, our study presents the first high-quality mitogenomes of Lpm and Lgh, which are the only ones in the Myrtales order found as two circular molecules. Full article
(This article belongs to the Section Molecular Plant Sciences)
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18 pages, 2735 KiB  
Article
Stable Production of a Recombinant Single-Chain Eel Follicle-Stimulating Hormone Analog in CHO DG44 Cells
by Munkhzaya Byambaragchaa, Sei Hyen Park, Sang-Gwon Kim, Min Gyu Shin, Shin-Kwon Kim, Myung-Hum Park, Myung-Hwa Kang and Kwan-Sik Min
Int. J. Mol. Sci. 2024, 25(13), 7282; https://doi.org/10.3390/ijms25137282 - 2 Jul 2024
Viewed by 143
Abstract
This study aimed to produce single-chain recombinant Anguillid eel follicle-stimulating hormone (rec-eel FSH) analogs with high activity in Cricetulus griseus ovary DG44 (CHO DG44) cells. We recently reported that an O-linked glycosylated carboxyl-terminal peptide (CTP) of the equine chorionic gonadotropin (eCG) β-subunit contributes [...] Read more.
This study aimed to produce single-chain recombinant Anguillid eel follicle-stimulating hormone (rec-eel FSH) analogs with high activity in Cricetulus griseus ovary DG44 (CHO DG44) cells. We recently reported that an O-linked glycosylated carboxyl-terminal peptide (CTP) of the equine chorionic gonadotropin (eCG) β-subunit contributes to high activity and time-dependent secretion in mammalian cells. We constructed a mutant (FSH-M), in which a linker including the eCG β-subunit CTP region (amino acids 115–149) was inserted between the β-subunit and α-subunit of wild-type single-chain eel FSH (FSH-wt). Plasmids containing eel FSH-wt and eel FSH-M were transfected into CHO DG44 cells, and single cells expressing each protein were isolated from 10 and 7 clones. Secretion increased gradually during the cultivation period and peaked at 4000–5000 ng/mL on day 9. The molecular weight of eel FSH-wt was 34–40 kDa, whereas that of eel FSH-M increased substantially, with two bands at 39–46 kDa. Treatment with PNGase F to remove the N glycosylation sites decreased the molecular weight remarkably to approximately 8 kDa. The EC50 value and maximal responsiveness of eel FSH-M were approximately 1.23- and 1.06-fold higher than those of eel FSH-wt, indicating that the mutant showed slightly higher biological activity. Phosphorylated extracellular-regulated kinase (pERK1/2) activation exhibited a sharp peak at 5 min, followed by a rapid decline. These findings indicate that the new rec-eel FSH molecule with the eCG β-subunit CTP linker shows potent activity and could be produced in massive quantities using the stable CHO DG44 cell system. Full article
(This article belongs to the Special Issue New Sights into Bioinformatics of Gene Regulations and Structure)
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22 pages, 3850 KiB  
Article
Synthesis, Anticancer Activity, and Docking Studies of Novel Hydroquinone-Chalcone-Pyrazoline Hybrid Derivatives
by Javier Maldonado, Alfonso Oliva, Leda Guzmán, Aurora Molinari and Waldo Acevedo
Int. J. Mol. Sci. 2024, 25(13), 7281; https://doi.org/10.3390/ijms25137281 - 2 Jul 2024
Viewed by 127
Abstract
A novel series of antitumor hybrids was synthesized using 1,4-benzohydroquinone and chalcone, furane, or pyrazoline scaffolds. This were achieved through isosteric substitution of the aryl group of the chalcone β-carbon with the furanyl moiety and structural modification of the α,β-unsaturated carbonyl system. The [...] Read more.
A novel series of antitumor hybrids was synthesized using 1,4-benzohydroquinone and chalcone, furane, or pyrazoline scaffolds. This were achieved through isosteric substitution of the aryl group of the chalcone β-carbon with the furanyl moiety and structural modification of the α,β-unsaturated carbonyl system. The potential antitumor activity of these hybrids was evaluated in vivo on MCF-7 breast adenocarcinoma and HT-29 colorectal carcinoma cells, demonstrating cytotoxic activity with IC50 values ranging from 28.8 to 124.6 µM. The incorporation of furan and pyrazoline groups significantly enhanced antiproliferative properties compared to their analogues and precursors (VII–X), which were inactive against both neoplastic cell lines. Compounds 4, 5, and 6 exhibited enhanced cytotoxicity against both cell lines, whereas compound 8 showed higher cytotoxic activity against HT-29 cells. Molecular docking studies revealed superior free-energy values (ΔGbin) for carcinogenic pathway-involved kinase proteins, with our in silico data suggesting that these derivatives could be promising chemotherapeutic agents targeting kinase pathways. Among all the synthesized PIBHQ compounds, derivatives 7 and 8 exhibited the best drug-likeness properties, with values of 0.53 and 0.83, respectively. ADME results collectively suggest that most of these compounds hold promise as potential candidates for preclinical assays. Full article
(This article belongs to the Special Issue Bioactive Compounds in Cancers)
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24 pages, 5440 KiB  
Article
Comprehensive Expression Analysis of the WRKY Gene Family in Phoebe bournei under Drought and Waterlogging Stresses
by Zhongxuan Wang, Limei You, Na Gong, Can Li, Zhuoqun Li, Jun Shen, Lulu Wan, Kai** Luo, **aoqing Su, Lizhen Feng, Shipin Chen and Wenjun Lin
Int. J. Mol. Sci. 2024, 25(13), 7280; https://doi.org/10.3390/ijms25137280 - 2 Jul 2024
Viewed by 160
Abstract
In response to biotic and abiotic stresses, the WRKY gene family plays a crucial role in plant growth and development. This study focused on Phoebe bournei and involved genome-wide identification of WRKY gene family members, clarification of their molecular evolutionary characteristics, and comprehensive [...] Read more.
In response to biotic and abiotic stresses, the WRKY gene family plays a crucial role in plant growth and development. This study focused on Phoebe bournei and involved genome-wide identification of WRKY gene family members, clarification of their molecular evolutionary characteristics, and comprehensive map** of their expression profiles under diverse abiotic stress conditions. A total of 60 WRKY gene family members were identified, and their phylogenetic classification revealed three distinct groups. A conserved motif analysis underscored the significant conservation of motif 1 and motif 2 among the majority of PbWRKY proteins, with proteins within the same class sharing analogous gene structures. Furthermore, an examination of cis-acting elements and protein interaction networks revealed several genes implicated in abiotic stress responses in P. bournei. Transcriptomic data were utilized to analyze the expression patterns of WRKY family members under drought and waterlogged conditions, with subsequent validation by quantitative real-time PCR (RT-qPCR) experiments. Notably, PbWRKY55 exhibited significant expression modulation under drought stress; PbWRKY36 responded prominently to waterlogging stress; and PbWRKY18, PbWRKY38, and PbWRKY57 demonstrated altered expression under both drought and waterlogging stresses. This study revealed the PbWRKY candidate genes that potentially play a pivotal role in enhancing abiotic stress resilience in P. bournei. The findings have provided valuable insights and knowledge that can guide further research aimed at understanding and addressing the impacts of abiotic stress within this species. Full article
(This article belongs to the Special Issue New Trends in Genomics and Metabolomics of Horticultural Plants at Fujian Agriculture and Forestry University 2.0)
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18 pages, 18651 KiB  
Article
GAL3ST1 Deficiency Reduces Epithelial–Mesenchymal Transition and Tumorigenic Capacity in a Cholangiocarcinoma Cell Line
by Lin Chen, Montserrat Elizalde, Ludwig J. Dubois, Anjali A. Roeth, Ulf P. Neumann, Steven W. M. Olde Damink, Frank G. Schaap and Gloria Alvarez-Sola
Int. J. Mol. Sci. 2024, 25(13), 7279; https://doi.org/10.3390/ijms25137279 - 2 Jul 2024
Viewed by 176
Abstract
Cholangiocarcinoma (CCA), or bile duct cancer, is the second most common liver malignancy, with an increasing incidence in Western countries. The lack of effective treatments associated with the absence of early symptoms highlights the need to search for new therapeutic targets for CCA. [...] Read more.
Cholangiocarcinoma (CCA), or bile duct cancer, is the second most common liver malignancy, with an increasing incidence in Western countries. The lack of effective treatments associated with the absence of early symptoms highlights the need to search for new therapeutic targets for CCA. Sulfatides (STs), a type of sulfoglycosphingolipids, have been found in the biliary tract, with increased levels in CCA and other types of cancer. STs are involved in protein trafficking and cell adhesion as part of the lipid rafts of the plasma membrane. We aimed to study the role of STs in CCA by the genetic targeting of GAL3ST1, an enzyme involved in ST synthesis. We used the CRISPR-Cas9 system to generate GAL3ST1-deficient TFK1 cells. GAL3ST1 KO cells showed lower proliferation and clonogenic activity and reduced glycolytic activity compared to TFK1 cells. Polarized TFK1 GAL3ST1 KO cells displayed increased transepithelial resistance and reduced permeability compared to TFK1 wt cells. The loss of GAL3ST1 showed a negative effect on growth in 30 out of 34 biliary tract cancer cell lines from the DepMap database. GAL3ST1 deficiency partially restored epithelial identity and barrier function and reduced proliferative activity in CCA cells. Sulfatide synthesis may provide a novel therapeutic target for CCA. Full article
(This article belongs to the Special Issue Gene Editing for Disease Modeling and Therapeutics)
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40 pages, 2588 KiB  
Review
Targeting Macrophage Polarization for Reinstating Homeostasis following Tissue Damage
by Qiran Du, Anna Dickinson, Pruthvi Nakuleswaran, Susan Maghami, Savindu Alagoda, Andrew L. Hook and Amir M. Ghaemmaghami
Int. J. Mol. Sci. 2024, 25(13), 7278; https://doi.org/10.3390/ijms25137278 - 2 Jul 2024
Viewed by 149
Abstract
Tissue regeneration and remodeling involve many complex stages. Macrophages are critical in maintaining micro-environmental homeostasis by regulating inflammation and orchestrating wound healing. They display high plasticity in response to various stimuli, showing a spectrum of functional phenotypes that vary from M1 (pro-inflammatory) to [...] Read more.
Tissue regeneration and remodeling involve many complex stages. Macrophages are critical in maintaining micro-environmental homeostasis by regulating inflammation and orchestrating wound healing. They display high plasticity in response to various stimuli, showing a spectrum of functional phenotypes that vary from M1 (pro-inflammatory) to M2 (anti-inflammatory) macrophages. While transient inflammation is an essential trigger for tissue healing following an injury, sustained inflammation (e.g., in foreign body response to implants, diabetes or inflammatory diseases) can hinder tissue healing and cause tissue damage. Modulating macrophage polarization has emerged as an effective strategy for enhancing immune-mediated tissue regeneration and promoting better integration of implantable materials in the host. This article provides an overview of macrophages’ functional properties followed by discussing different strategies for modulating macrophage polarization. Advances in the use of synthetic and natural biomaterials to fabricate immune-modulatory materials are highlighted. This reveals that the development and clinical application of more effective immunomodulatory systems targeting macrophage polarization under pathological conditions will be driven by a detailed understanding of the factors that regulate macrophage polarization and biological function in order to optimize existing methods and generate novel strategies to control cell phenotype. Full article
(This article belongs to the Special Issue Macrophages in Human Diseases and Their Treatment)
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15 pages, 5974 KiB  
Article
A PNPLA3-Deficient iPSC-Derived Hepatocyte Screen Identifies Pathways to Potentially Reduce Steatosis in Metabolic Dysfunction-Associated Fatty Liver Disease
by Caren Doueiry, Christiana S. Kappler, Carla Martinez-Morant and Stephen A. Duncan
Int. J. Mol. Sci. 2024, 25(13), 7277; https://doi.org/10.3390/ijms25137277 - 2 Jul 2024
Viewed by 156
Abstract
The incidence of nonalcoholic fatty liver disease (NAFLD), or metabolic dysfunction-associated fatty liver disease (MAFLD), is increasing in adults and children. Unfortunately, effective pharmacological treatments remain unavailable. Single nucleotide polymorphisms (SNPs) in the patatin-like phospholipase domain-containing protein (PNPLA3 I148M) have the most significant [...] Read more.
The incidence of nonalcoholic fatty liver disease (NAFLD), or metabolic dysfunction-associated fatty liver disease (MAFLD), is increasing in adults and children. Unfortunately, effective pharmacological treatments remain unavailable. Single nucleotide polymorphisms (SNPs) in the patatin-like phospholipase domain-containing protein (PNPLA3 I148M) have the most significant genetic association with the disease at all stages of its progression. A roadblock to identifying potential treatments for PNPLA3-induced NAFLD is the lack of a human cell platform that recapitulates the PNPLA3 I148M-mediated onset of lipid accumulation. Hepatocyte-like cells were generated from PNPLA3−/− and PNPLA3I148M/M-induced pluripotent stem cells (iPSCs). Lipid levels were measured by staining with BODIPY 493/503 and were found to increase in PNPLA3 variant iPSC-derived hepatocytes. A small-molecule screen identified multiple compounds that target Src/PI3K/Akt signaling and could eradicate lipid accumulation in these cells. We found that drugs currently in clinical trials for cancer treatment that target the same pathways also reduced lipid accumulation in PNPLA3 variant cells. Full article
(This article belongs to the Special Issue Recent Research in Stem Cells to Organoids)
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35 pages, 1218 KiB  
Review
Exploring the Link between Oxidative Stress, Selenium Levels, and Obesity in Youth
by Teofana Otilia Bizerea-Moga, Laura Pitulice, Otilia Bizerea-Spiridon and Tudor Voicu Moga
Int. J. Mol. Sci. 2024, 25(13), 7276; https://doi.org/10.3390/ijms25137276 - 2 Jul 2024
Viewed by 169
Abstract
Obesity is a worldwide increasing concern. Although in adults this is easily estimated with the body mass index, in children, who are constantly growing and whose bodies are changing, the reference points to assess weight status are age and gender, and need corroboration [...] Read more.
Obesity is a worldwide increasing concern. Although in adults this is easily estimated with the body mass index, in children, who are constantly growing and whose bodies are changing, the reference points to assess weight status are age and gender, and need corroboration with complementary data, making their quantification highly difficult. The present review explores the interaction spectrum of oxidative stress, selenium status, and obesity in children and adolescents. Any factor related to oxidative stress that triggers obesity and, conversely, obesity that induces oxidative stress are part of a vicious circle, a complex chain of mechanisms that derive from each other and reinforce each other with serious health consequences. Selenium and its compounds exhibit key antioxidant activity and also have a significant role in the nutritional evaluation of obese children. The balance of selenium intake, retention, and metabolism emerges as a vital aspect of health, reflecting the complex interactions between diet, oxidative stress, and obesity. Understanding whether selenium status is a contributor to or a consequence of obesity could inform nutritional interventions and public health strategies aimed at preventing and managing obesity from an early age. Full article
(This article belongs to the Special Issue Oxidative Stress in Metabolic and Endocrine Diseases: Basic and Translational Aspects 3.0)
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