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Int. J. Mol. Sci., Volume 24, Issue 13 (July-1 2023) – 820 articles

Cover Story (view full-size image): Hepatocellular carcinoma (HCC) is often diagnosed at an unresectable advanced stage. Advanced HCC is treated with systemic chemotherapy as well as transarterial chemoembolization and hepatic transarterial infusion chemotherapy with cisplatin, which have long been the standard of care for patients with unresectable HCC, but have been limited to the treatment of intrahepatic disease. Recently, systemic chemotherapy with molecularly targeted agents and immune checkpoint inhibitors has been reported to be effective in treating unresectable HCC, and the treatment of unresectable HCC has undergone a major paradigm shift. This review summarizes the action and resistance mechanisms of cisplatin and describes the treatment of major hepatobiliary cancers with cisplatin. View this paper
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16 pages, 5545 KiB  
Article
Mosaic Genome of a British Cider Yeast
by Beatrice Bernardi, Florian Michling, Jürgen Fröhlich and Jürgen Wendland
Int. J. Mol. Sci. 2023, 24(13), 11232; https://doi.org/10.3390/ijms241311232 - 07 Jul 2023
Viewed by 1248
Abstract
Hybrid formation and introgressions had a profound impact on fermentative yeasts domesticated for beer, wine and cider fermentations. Here we provide a comparative genomic analysis of a British cider yeast isolate (E1) and characterize its fermentation properties. E1 has a Saccharomyces uvarum genome [...] Read more.
Hybrid formation and introgressions had a profound impact on fermentative yeasts domesticated for beer, wine and cider fermentations. Here we provide a comparative genomic analysis of a British cider yeast isolate (E1) and characterize its fermentation properties. E1 has a Saccharomyces uvarum genome into which ~102 kb of S. eubayanus DNA were introgressed that replaced the endogenous homologous 55 genes of chromosome XIV between YNL182C and YNL239W. Sequence analyses indicated that the DNA donor was either a lager yeast or a yet unidentified S. eubayanus ancestor. Interestingly, a second introgression event added ~66 kb of DNA from Torulaspora microellipsoides to the left telomere of SuCHRX. This region bears high similarity with the previously described region C introgression in the wine yeast EC1118. Within this region FOT1 and FOT2 encode two oligopeptide transporters that promote improved nitrogen uptake from grape must in E1, as was reported for EC1118. Comparative laboratory scale grape must fermentations between the E1 and EC1118 indicated beneficial traits of faster consumption of total sugars and higher glycerol production but low acetic acid and reduced ethanol content. Importantly, the cider yeast strain produced high levels of fruity ester, including phenylethyl and isoamyl acetate. Full article
(This article belongs to the Section Molecular Genetics and Genomics)
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12 pages, 2514 KiB  
Article
Effect of Trace Metal Ions on the Conformational Stability of the Visual Photoreceptor Rhodopsin
by Feifei Wang, Pol Fernandez-Gonzalez, Eva Ramon, Patricia Gomez-Gutierrez, Margarita Morillo and Pere Garriga
Int. J. Mol. Sci. 2023, 24(13), 11231; https://doi.org/10.3390/ijms241311231 - 07 Jul 2023
Viewed by 948
Abstract
Trace metals are essential elements that play key roles in a number of biochemical processes governing human visual physiology in health and disease. Several trace metals, such as zinc, have been shown to play important roles in the visual phototransduction process. In spite [...] Read more.
Trace metals are essential elements that play key roles in a number of biochemical processes governing human visual physiology in health and disease. Several trace metals, such as zinc, have been shown to play important roles in the visual phototransduction process. In spite of this, there has been little research conducted on the direct effect of trace metal elements on the visual photoreceptor rhodopsin. In the current study, we have determined the effect of several metal ions, such as iron, copper, chromium, manganese, and nickel, on the conformational stability of rhodopsin. To this aim, we analyzed, by means of UV-visible and fluorescence spectroscopic methods, the effects of these trace elements on the thermal stability of dark rhodopsin, the stability of its active Metarhodopsin II conformation, and its chromophore regeneration. Our results show that copper prevented rhodopsin regeneration and slowed down the retinal release process after illumination. In turn, Fe3+, but not Fe2+, increased the thermal stability of the dark inactive conformation of rhodopsin, whereas copper ions markedly decreased it. These findings stress the important role of trace metals in retinal physiology at the photoreceptor level and may be useful for the development of novel therapeutic strategies to treat retinal disease. Full article
(This article belongs to the Special Issue Molecular Basis of Sensory Transduction in Health and Disease 2.0)
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19 pages, 7389 KiB  
Article
EPs® 7630 Stimulates Tissue Repair Mechanisms and Modifies Tight Junction Protein Expression in Human Airway Epithelial Cells
by Lei Fang, Liang Zhou, Žarko Kulić, Martin D. Lehner, Michael Tamm and Michael Roth
Int. J. Mol. Sci. 2023, 24(13), 11230; https://doi.org/10.3390/ijms241311230 - 07 Jul 2023
Cited by 2 | Viewed by 1648
Abstract
Airway epithelium repair after infection consists of wound repair, re-synthesis of the extracellular matrix (ECM), and tight junction proteins. In humans, EPs® 7630 obtained from Pelargonium sidoides roots reduces the severity and duration of acute respiratory tract infections. The effect of EPs [...] Read more.
Airway epithelium repair after infection consists of wound repair, re-synthesis of the extracellular matrix (ECM), and tight junction proteins. In humans, EPs® 7630 obtained from Pelargonium sidoides roots reduces the severity and duration of acute respiratory tract infections. The effect of EPs® 7630 on tissue repair of rhinovirus-16 (RV-16) infected and control human airway epithelial cells was assessed for: (i) epithelial cell proliferation by manual cell counts, (ii) epithelial wound repair by “scratch assay”, (iii) ECM composition by Western-blotting and cell-based ELISA, and (iv) epithelial tight junction proteins by Western-blotting. EPs® 7630 stimulated cell proliferation through cAMP, CREB, and p38 MAPK. EPs® 7630 significantly improved wound repair. Pro-inflammatory collagen type-I expression was reduced by EPs® 7630, while fibronectin was increased. Virus-binding tight junction proteins desmoglein2, desmocollin2, ZO-1, claudin1, and claudin4 were downregulated by EPs® 7630. The RV16-induced shift of the ECM towards the pro-inflammatory type was prevented by EPs® 7630. Most of the effects of EPs® 7630 on tissue repair and regeneration were sensitive to inhibition of cAMP-induced signaling. The data suggest that EPs® 7630-dependent modification of epithelial cell metabolism and function might underlie the faster recovery time from viral infections, as reported by others in clinical studies. Full article
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20 pages, 973 KiB  
Review
Stem/Progenitor Cells and Related Therapy in Bronchopulmonary Dysplasia
by Manuela Marega, Natalia El-Merhie, Mira Y. Gökyildirim, Valerie Orth, Saverio Bellusci and Cho-Ming Chao
Int. J. Mol. Sci. 2023, 24(13), 11229; https://doi.org/10.3390/ijms241311229 - 07 Jul 2023
Cited by 2 | Viewed by 1662
Abstract
Bronchopulmonary dysplasia (BPD) is a chronic lung disease commonly seen in preterm infants, and is triggered by infection, mechanical ventilation, and oxygen toxicity. Among other problems, lifelong limitations in lung function and impaired psychomotor development may result. Despite major advances in understanding the [...] Read more.
Bronchopulmonary dysplasia (BPD) is a chronic lung disease commonly seen in preterm infants, and is triggered by infection, mechanical ventilation, and oxygen toxicity. Among other problems, lifelong limitations in lung function and impaired psychomotor development may result. Despite major advances in understanding the disease pathologies, successful interventions are still limited to only a few drug therapies with a restricted therapeutic benefit, and which sometimes have significant side effects. As a more promising therapeutic option, mesenchymal stem cells (MSCs) have been in focus for several years due to their anti-inflammatory effects and their secretion of growth and development promoting factors. Preclinical studies provide evidence in that MSCs have the potential to contribute to the repair of lung injuries. This review provides an overview of MSCs, and other stem/progenitor cells present in the lung, their identifying characteristics, and their differentiation potential, including cytokine/growth factor involvement. Furthermore, animal studies and clinical trials using stem cells or their secretome are reviewed. To bring MSC-based therapeutic options further to clinical use, standardized protocols are needed, and upcoming side effects must be critically evaluated. To fill these gaps of knowledge, the MSCs’ behavior and the effects of their secretome have to be examined in more (pre-) clinical studies, from which only few have been designed to date. Full article
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13 pages, 3066 KiB  
Article
Elevation of Arginase-II in Podocytes Contributes to Age-Associated Albuminuria in Male Mice
by Guillaume Ajalbert, Andrea Brenna, Xiu-Fen Ming, Zhihong Yang and Duilio M. Potenza
Int. J. Mol. Sci. 2023, 24(13), 11228; https://doi.org/10.3390/ijms241311228 - 07 Jul 2023
Viewed by 872
Abstract
One of the manifestations of renal aging is podocyte dysfunction and loss, which are associated with proteinuria and glomerulosclerosis. Studies show a male bias in glomerular dysfunction and chronic kidney diseases, and the underlying mechanisms remain obscure. Recent studies demonstrate the role of [...] Read more.
One of the manifestations of renal aging is podocyte dysfunction and loss, which are associated with proteinuria and glomerulosclerosis. Studies show a male bias in glomerular dysfunction and chronic kidney diseases, and the underlying mechanisms remain obscure. Recent studies demonstrate the role of an age-associated increase in arginase-II (Arg-II) in proximal tubules of both male and female mice. However, it is unclear whether Arg-II is also involved in aging glomeruli. The current study investigates the role of the sex-specific elevation of Arg-II in podocytes in age-associated increased albuminuria. Young (3–4 months) and old (20–22 months) male and female mice of wt and arginase-II knockout (arg-ii−/−) were used. Albuminuria was employed as a readout of glomerular function. Cellular localization and expression of Arg-II in glomeruli were analyzed using an immunofluorescence confocal microscope. A more pronounced age-associated increase in albuminuria was found in male than in female mice. An age-associated induction of Arg-II in glomeruli and podocytes (as demonstrated by co-localization of Arg-II with the podocyte marker synaptopodin) was also observed in males but not in females. Ablation of the arg-ii gene in mice significantly reduces age-associated albuminuria in males. Also, age-associated decreases in podocyte density and glomerulus hypertrophy are significantly prevented in male arg-ii−/− but not in female mice. However, age-associated glomerulosclerosis is not affected by arg-ii ablation in both sexes. These results demonstrate a role of Arg-II in sex-specific podocyte injury in aging. They may explain the sex-specific differences in the development of renal disease in humans during aging. Full article
(This article belongs to the Special Issue Molecular Mechanisms of Kidney Injury 2.0)
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33 pages, 4978 KiB  
Review
AB Toxins as High-Affinity Ligands for Cell Targeting in Cancer Therapy
by Ana Márquez-López and Mónica L. Fanarraga
Int. J. Mol. Sci. 2023, 24(13), 11227; https://doi.org/10.3390/ijms241311227 - 07 Jul 2023
Cited by 1 | Viewed by 1885
Abstract
Conventional targeted therapies for the treatment of cancer have limitations, including the development of acquired resistance. However, novel alternatives have emerged in the form of targeted therapies based on AB toxins. These biotoxins are a diverse group of highly poisonous molecules that show [...] Read more.
Conventional targeted therapies for the treatment of cancer have limitations, including the development of acquired resistance. However, novel alternatives have emerged in the form of targeted therapies based on AB toxins. These biotoxins are a diverse group of highly poisonous molecules that show a nanomolar affinity for their target cell receptors, making them an invaluable source of ligands for biomedical applications. Bacterial AB toxins, in particular, are modular proteins that can be genetically engineered to develop high-affinity therapeutic compounds. These toxins consist of two distinct domains: a catalytically active domain and an innocuous domain that acts as a ligand, directing the catalytic domain to the target cells. Interestingly, many tumor cells show receptors on the surface that are recognized by AB toxins, making these high-affinity proteins promising tools for developing new methods for targeting anticancer therapies. Here we describe the structure and mechanisms of action of Diphtheria (Dtx), Anthrax (Atx), Shiga (Stx), and Cholera (Ctx) toxins, and review the potential uses of AB toxins in cancer therapy. We also discuss the main advances in this field, some successful results, and, finally, the possible development of innovative and precise applications in oncology based on engineered recombinant AB toxins. Full article
(This article belongs to the Special Issue Bacterial Toxins and Cancer)
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27 pages, 1733 KiB  
Review
Eukaryotic Cell Membranes: Structure, Composition, Research Methods and Computational Modelling
by Anatoly Zhukov and Valery Popov
Int. J. Mol. Sci. 2023, 24(13), 11226; https://doi.org/10.3390/ijms241311226 - 07 Jul 2023
Cited by 3 | Viewed by 4127
Abstract
This paper deals with the problems encountered in the study of eukaryotic cell membranes. A discussion on the structure and composition of membranes, lateral heterogeneity of membranes, lipid raft formation, and involvement of actin and cytoskeleton networks in the maintenance of membrane structure [...] Read more.
This paper deals with the problems encountered in the study of eukaryotic cell membranes. A discussion on the structure and composition of membranes, lateral heterogeneity of membranes, lipid raft formation, and involvement of actin and cytoskeleton networks in the maintenance of membrane structure is included. Modern methods for the study of membranes and their constituent domains are discussed. Various simplified models of biomembranes and lipid rafts are presented. Computer modelling is considered as one of the most important methods. This is stated that from the study of the plasma membrane structure, it is desirable to proceed to the diverse membranes of all organelles of the cell. The qualitative composition and molar content of individual classes of polar lipids, free sterols and proteins in each of these membranes must be considered. A program to create an open access electronic database including results obtained from the membrane modelling of individual cell organelles and the key sites of the membranes, as well as models of individual molecules composing the membranes, has been proposed. Full article
(This article belongs to the Section Biochemistry)
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17 pages, 1542 KiB  
Article
Transforming Psoriasis Care: Probiotics and Prebiotics as Novel Therapeutic Approaches
by Mihaela Cristina Buhaș, Rareș Candrea, Laura Ioana Gavrilaș, Doina Miere, Alexandru Tătaru, Andreea Boca and Adrian Cătinean
Int. J. Mol. Sci. 2023, 24(13), 11225; https://doi.org/10.3390/ijms241311225 - 07 Jul 2023
Cited by 5 | Viewed by 4834
Abstract
Psoriasis is a chronic inflammatory skin disease with autoimmune pathological characteristics. Recent research has found a link between psoriasis, inflammation, and gut microbiota dysbiosis, and that probiotics and prebiotics provide benefits to patients. This 12-week open-label, single-center clinical trial evaluated the efficacy of [...] Read more.
Psoriasis is a chronic inflammatory skin disease with autoimmune pathological characteristics. Recent research has found a link between psoriasis, inflammation, and gut microbiota dysbiosis, and that probiotics and prebiotics provide benefits to patients. This 12-week open-label, single-center clinical trial evaluated the efficacy of probiotics (Bacillus indicus (HU36), Bacillus subtilis (HU58), Bacillus coagulans (SC208), Bacillus licheniformis (SL307), and Bacillus clausii (SC109)) and precision prebiotics (fructooligosaccharides, xylooligosaccharides, and galactooligosaccharides) in patients with psoriasis receiving topical therapy, with an emphasis on potential metabolic, immunological, and gut microbiota changes. In total, 63 patients were evaluated, with the first 42 enrolled patients assigned to the intervention group and the next 21 assigned to the control group (2:1 ratio; non-randomized). There were between-group differences in several patient characteristics at baseline, including age, psoriasis severity (the incidence of severe psoriasis was greater in the intervention group than in the control group), the presence of nail psoriasis, and psoriatic arthritis, though it is not clear whether or how these differences may have affected the study findings. Patients with psoriasis receiving anti-psoriatic local therapy and probiotic and prebiotic supplementation performed better in measures of disease activity, including Psoriasis Area and Severity Index, Dermatology Life Quality Index, inflammatory markers, and skin thickness compared with those not receiving supplementation. Furthermore, in the 15/42 patients in the intervention group who received gut microbiota analysis, the gut microbiota changed favorably following 12 weeks of probiotic and prebiotic supplementation, with a shift towards an anti-inflammatory profile. Full article
(This article belongs to the Special Issue Psoriatic Arthritis and Skin Diseases: Pathogenesis and Therapies)
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14 pages, 2114 KiB  
Review
The Zebrafish Embryo as a Model Organism for Testing mRNA-Based Therapeutics
by Tjessa Bondue, Sante Princiero Berlingerio, Lambertus van den Heuvel and Elena Levtchenko
Int. J. Mol. Sci. 2023, 24(13), 11224; https://doi.org/10.3390/ijms241311224 - 07 Jul 2023
Cited by 5 | Viewed by 2972
Abstract
mRNA-based therapeutics have revolutionized the world of molecular therapy and have proven their potential in the vaccination campaigns for SARS-CoV2 and clinical trials for hereditary disorders. Preclinical studies have mainly focused on in vitro and rodent studies. However, research in rodents is costly [...] Read more.
mRNA-based therapeutics have revolutionized the world of molecular therapy and have proven their potential in the vaccination campaigns for SARS-CoV2 and clinical trials for hereditary disorders. Preclinical studies have mainly focused on in vitro and rodent studies. However, research in rodents is costly and labour intensive, and requires ethical approval for all interventions. Zebrafish embryonic disease models are not always classified as laboratory animals and have been shown to be extremely valuable for high-throughput drug testing. Zebrafish larvae are characterized by their small size, optical transparency and high number of embryos, and are therefore also suited for the study of mRNA-based therapeutics. First, the one-cell stage injection of naked mRNA can be used to assess the effectivity of gene addition in vivo. Second, the intravascular injection in older larvae can be used to assess tissue targeting efficiency of (packaged) mRNA. In this review, we describe how zebrafish can be used as a steppingstone prior to testing mRNA in rodent models. We define the procedures that can be employed for both the one-cell stage and later-stage injections, as well as the appropriate procedures for post-injection follow-up. Full article
(This article belongs to the Special Issue Zebrafish as a Model for Biomedical Studies)
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23 pages, 4275 KiB  
Review
Numerous Trigger-like Interactions of Kinases/Protein Phosphatases in Human Skeletal Muscles Can Underlie Transient Processes in Activation of Signaling Pathways during Exercise
by Alexander Yu. Vertyshev, Ilya R. Akberdin and Fedor A. Kolpakov
Int. J. Mol. Sci. 2023, 24(13), 11223; https://doi.org/10.3390/ijms241311223 - 07 Jul 2023
Viewed by 1134
Abstract
Optimizing physical training regimens to increase muscle aerobic capacity requires an understanding of the internal processes that occur during exercise that initiate subsequent adaptation. During exercise, muscle cells undergo a series of metabolic events that trigger downstream signaling pathways and induce the expression [...] Read more.
Optimizing physical training regimens to increase muscle aerobic capacity requires an understanding of the internal processes that occur during exercise that initiate subsequent adaptation. During exercise, muscle cells undergo a series of metabolic events that trigger downstream signaling pathways and induce the expression of many genes in working muscle fibers. There are a number of studies that show the dependence of changes in the activity of AMP-activated protein kinase (AMPK), one of the mediators of cellular signaling pathways, on the duration and intensity of single exercises. The activity of various AMPK isoforms can change in different directions, increasing for some isoforms and decreasing for others, depending on the intensity and duration of the load. This review summarizes research data on changes in the activity of AMPK, Ca2+/calmodulin-dependent protein kinase II (CaMKII), and other components of the signaling pathways in skeletal muscles during exercise. Based on these data, we hypothesize that the observed changes in AMPK activity may be largely related to metabolic and signaling transients rather than exercise intensity per se. Probably, the main events associated with these transients occur at the beginning of the exercise in a time window of about 1–10 min. We hypothesize that these transients may be partly due to putative trigger-like kinase/protein phosphatase interactions regulated by feedback loops. In addition, numerous dynamically changing factors, such as [Ca2+], metabolite concentration, and reactive oxygen and nitrogen species (RONS), can shift the switching thresholds and change the states of these triggers, thereby affecting the activity of kinases (in particular, AMPK and CaMKII) and phosphatases. The review considers the putative molecular mechanisms underlying trigger-like interactions. The proposed hypothesis allows for a reinterpretation of the experimental data available in the literature as well as the generation of ideas to optimize future training regimens. Full article
(This article belongs to the Special Issue The Physiology of Striated Muscle Tissue 2.0)
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14 pages, 7402 KiB  
Article
Bacterial Outer Membrane Vesicles Loaded with Perhexiline Suppress Tumor Development by Regulating Tumor-Associated Macrophages Repolarization in a Synergistic Way
by Shoujin Jiang, Wei Fu, Sijia Wang, Guanshu Zhu, Jufang Wang and Yi Ma
Int. J. Mol. Sci. 2023, 24(13), 11222; https://doi.org/10.3390/ijms241311222 - 07 Jul 2023
Cited by 1 | Viewed by 1210
Abstract
Tumor-associated macrophages (TAMs) promote tumor development and metastasis and are categorized into M1-like macrophages, suppressing tumor cells, and M2-like macrophages. M2-like macrophages, occupying a major role in TAMs, can be repolarized into anti-tumoral phenotypes. In this study, outer membrane vesicles (OMVs) secreted by [...] Read more.
Tumor-associated macrophages (TAMs) promote tumor development and metastasis and are categorized into M1-like macrophages, suppressing tumor cells, and M2-like macrophages. M2-like macrophages, occupying a major role in TAMs, can be repolarized into anti-tumoral phenotypes. In this study, outer membrane vesicles (OMVs) secreted by Escherichia coli Nissle 1917 carry perhexiline (OMV@Perhx) to explore the influence of OMVs and perhexiline on TAM repolarization. OMV@Perhx was internalized by macrophages and regulated the phenotype of TAMs from M2-like to M1-like efficiently to increase the level of tumor suppressor accordingly. Re-polarized macrophages promoted apoptosis and inhibited the mobility of tumor, cells including invasion and migration. The results indicate that OMVs improve the efficacy of perhexiline and also represent a promising natural immunomodulator. Combining OMVs with perhexiline treatments shows powerfully synergistic anti-tumor effects through co-culturing with re-polarized macrophages. This work is promising to exploit the extensive applications of OMVs and chemical drugs, therefore developing a meaningful drug carrier and immunomodulator as well as expanding the purposes of traditional chemical drugs. Full article
(This article belongs to the Section Molecular Nanoscience)
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15 pages, 3453 KiB  
Article
Transcription Factor Nrf2 Modulates Lipopolysaccharide-Induced Injury in Bovine Endometrial Epithelial Cells
by Pengjie Song, Chen Liu, Mingkun Sun, Jianguo Liu, Pengfei Lin, Huatao Chen, Dong Zhou, Keqiong Tang, Aihua Wang and Yaping Jin
Int. J. Mol. Sci. 2023, 24(13), 11221; https://doi.org/10.3390/ijms241311221 - 07 Jul 2023
Viewed by 1303
Abstract
Endometritis in high-yield dairy cows adversely affects lactation length, milk quality, and the economics of dairy products. Endoplasmic reticulum stress (ERS) in bovine endometrial epithelial cells (BEECs) occurs as a consequence of diverse post-natal stressors, and plays a key role in a variety [...] Read more.
Endometritis in high-yield dairy cows adversely affects lactation length, milk quality, and the economics of dairy products. Endoplasmic reticulum stress (ERS) in bovine endometrial epithelial cells (BEECs) occurs as a consequence of diverse post-natal stressors, and plays a key role in a variety of inflammatory diseases. Nuclear-factor-erythroid-2-related factor 2 (Nrf2) is an important protective regulatory factor in numerous inflammatory responses. However, the mechanism by which Nrf2 modulates inflammation by participating in ERS remains unclear. The objective of the present study was to explore the role of Nrf2 in lipopolysaccharide (LPS)-induced injury to BEECs and to decipher the underlying molecular mechanisms of this injury. The expression of Nrf2- and ERS-related genes increased significantly in bovine uteri with endometritis. Isolated BEECs were treated with LPS to stimulate the inflammatory response. The expression of Nrf2 was significantly higher in cells exposed to LPS, which also induced ERS in BEECs. Activation of Nrf2 led to enhanced expression of the genes for the inflammation markers TNF-α, p65, IL-6, and IL-8 in BEECs. Moreover, stimulation of Nrf2 was accompanied by activation of ERS. In contrast, Nrf2 knockdown reduced the expression of TNF-α, p65, IL-6, and IL-8. Additionally, Nrf2 knockdown decreased expression of ERS-related genes for the GRP78, PERK, eIF2α, ATF4, and CHOP proteins. Collectively, our findings demonstrate that Nrf2 and ERS are activated during inflammation in BEECs. Furthermore, Nrf2 promotes the inflammatory response by activating the PERK pathway in ERS and inducing apoptosis in BEECs. Full article
(This article belongs to the Section Molecular Immunology)
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16 pages, 10457 KiB  
Article
Preparation of Xanthene-TEMPO Dyads: Synthesis and Study of the Radical Enhanced Intersystem Crossing
by Wenhui Zhu, Yanran Wu, Yiyan Zhang, Andrey A. Sukhanov, Yuqi Chu, Xue Zhang, Jianzhang Zhao and Violeta K. Voronkova
Int. J. Mol. Sci. 2023, 24(13), 11220; https://doi.org/10.3390/ijms241311220 - 07 Jul 2023
Viewed by 990
Abstract
We prepared a rhodamine-TEMPO chromophore-radical dyad (RB-TEMPO) to study the radical enhanced intersystem crossing (REISC). The visible light-harvesting chromophore rhodamine is connected with the TEMPO (a nitroxide radical) via a C–N bond. The UV-vis absorption spectrum indicates negligible electron interaction between the two [...] Read more.
We prepared a rhodamine-TEMPO chromophore-radical dyad (RB-TEMPO) to study the radical enhanced intersystem crossing (REISC). The visible light-harvesting chromophore rhodamine is connected with the TEMPO (a nitroxide radical) via a C–N bond. The UV-vis absorption spectrum indicates negligible electron interaction between the two units at the ground state. Interestingly, the fluorescence of the rhodamine moiety is strongly quenched in RB-TEMPO, and the fluorescence lifetime of the rhodamine moiety is shortened to 0.29 ns, from the lifetime of 3.17 ns. We attribute this quenching effect to the intramolecular electron spin–spin interaction between the nitroxide radical and the photoexcited rhodamine chromophore. Nanosecond transient absorption spectra confirm the REISC in RB-TEMPO, indicated by the detection of the rhodamine chromophore triplet excited state; the lifetime was determined as 128 ns, which is shorter than the native rhodamine triplet state lifetime (0.58 μs). The zero-field splitting (ZFS) parameters of the triplet state of the chromophore were determined with the pulsed laser excited time-resolved electron paramagnetic resonance (TREPR) spectra. RB-TEMPO was used as a photoinitiator for the photopolymerization of pentaerythritol triacrylate (PETA). These studies are useful for the design of heavy atom-free triplet photosensitizers, the study of the ISC, and the electron spin dynamics of the radical-chromophore systems upon photoexcitation. Full article
(This article belongs to the Special Issue Recent Advances in Free Radicals, Radical Ions and Radical Pairs)
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15 pages, 3076 KiB  
Communication
Neurodegenerative Disease Associated Pathways in the Brains of Triple Transgenic Alzheimer’s Model Mice Are Reversed Following Two Weeks of Peripheral Administration of Fasudil
by Richard Killick, Christina Elliott, Elena Ribe, Martin Broadstock, Clive Ballard, Dag Aarsland and Gareth Williams
Int. J. Mol. Sci. 2023, 24(13), 11219; https://doi.org/10.3390/ijms241311219 - 07 Jul 2023
Cited by 2 | Viewed by 1536
Abstract
The pan Rho-associated coiled-coil-containing protein kinase (ROCK) inhibitor fasudil acts as a vasodilator and has been used as a medication for post-cerebral stroke for the past 29 years in Japan and China. More recently, based on the involvement of ROCK inhibition in synaptic [...] Read more.
The pan Rho-associated coiled-coil-containing protein kinase (ROCK) inhibitor fasudil acts as a vasodilator and has been used as a medication for post-cerebral stroke for the past 29 years in Japan and China. More recently, based on the involvement of ROCK inhibition in synaptic function, neuronal survival, and processes associated with neuroinflammation, it has been suggested that the drug may be repurposed for neurodegenerative diseases. Indeed, fasudil has demonstrated preclinical efficacy in many neurodegenerative disease models. To facilitate an understanding of the wider biological processes at play due to ROCK inhibition in the context of neurodegeneration, we performed a global gene expression analysis on the brains of Alzheimer’s disease model mice treated with fasudil via peripheral IP injection. We then performed a comparative analysis of the fasudil-driven transcriptional profile with profiles generated from a meta-analysis of multiple neurodegenerative diseases. Our results show that fasudil tends to drive gene expression in a reverse sense to that seen in brains with post-mortem neurodegenerative disease. The results are most striking in terms of pathway enrichment analysis, where pathways perturbed in Alzheimer’s and Parkinson’s diseases are overwhelmingly driven in the opposite direction by fasudil treatment. Thus, our results bolster the repurposing potential of fasudil by demonstrating an anti-neurodegenerative phenotype in a disease context and highlight the potential of in vivo transcriptional profiling of drug activity. Full article
(This article belongs to the Special Issue Neurodegenerative Diseases: Molecular Mechanisms and Therapies)
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16 pages, 3076 KiB  
Review
Reviewing PTBP1 Domain Modularity in the Pre-Genomic Era: A Foundation to Guide the Next Generation of Exploring PTBP1 Structure–Function Relationships
by Christine Carico and William J. Placzek
Int. J. Mol. Sci. 2023, 24(13), 11218; https://doi.org/10.3390/ijms241311218 - 07 Jul 2023
Viewed by 1152
Abstract
Polypyrimidine tract binding protein 1 (PTBP1) is one of the most well-described RNA binding proteins, known initially for its role as a splicing repressor before later studies revealed its numerous roles in RNA maturation, stability, and translation. While PTBP1’s various biological roles have [...] Read more.
Polypyrimidine tract binding protein 1 (PTBP1) is one of the most well-described RNA binding proteins, known initially for its role as a splicing repressor before later studies revealed its numerous roles in RNA maturation, stability, and translation. While PTBP1’s various biological roles have been well-described, it remains unclear how its four RNA recognition motif (RRM) domains coordinate these functions. The early PTBP1 literature saw extensive effort placed in detailing structures of each of PTBP1’s RRMs, as well as their individual RNA sequence and structure preferences. However, limitations in high-throughput and high-resolution genomic approaches (i.e., next-generation sequencing had not yet been developed) precluded the functional translation of these findings into a mechanistic understanding of each RRM’s contribution to overall PTBP1 function. With the emergence of new technologies, it is now feasible to begin elucidating the individual contributions of each RRM to PTBP1 biological functions. Here, we review all the known literature describing the apo and RNA bound structures of each of PTBP1’s RRMs, as well as the emerging literature describing the dependence of specific RNA processing events on individual RRM domains. Our goal is to provide a framework of the structure–function context upon which to facilitate the interpretation of future studies interrogating the dynamics of PTBP1 function. Full article
(This article belongs to the Section Biochemistry)
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21 pages, 1127 KiB  
Review
Investigating the Crime Scene—Molecular Signatures in Inflammatory Bowel Disease
by Vibeke Andersen, Tue B. Bennike, Corinna Bang, John D. Rioux, Isabelle Hébert-Milette, Toshiro Sato, Axel K. Hansen and Ole H. Nielsen
Int. J. Mol. Sci. 2023, 24(13), 11217; https://doi.org/10.3390/ijms241311217 - 07 Jul 2023
Cited by 3 | Viewed by 1670
Abstract
Inflammatory bowel diseases (IBD) are without cure and troublesome to manage because of the considerable diversity between patients and the lack of reliable biomarkers. Several studies have demonstrated that diet, gut microbiota, genetics and other patient factors are essential for disease occurrence and [...] Read more.
Inflammatory bowel diseases (IBD) are without cure and troublesome to manage because of the considerable diversity between patients and the lack of reliable biomarkers. Several studies have demonstrated that diet, gut microbiota, genetics and other patient factors are essential for disease occurrence and progression. Understanding the link between these factors is crucial for identifying molecular signatures that identify biomarkers to advance the management of IBD. Recent technological breakthroughs and data integration have fuelled the intensity of this research. This research demonstrates that the effect of diet depends on patient factors and gut microbial activity. It also identifies a range of potential biomarkers for IBD management, including mucosa-derived cytokines, gasdermins and neutrophil extracellular traps, all of which need further evaluation before clinical translation. This review provides an update on cutting-edge research in IBD that aims to improve disease management and patient quality of life. Full article
(This article belongs to the Special Issue Inflammatory Bowel Disease: From Pre-clinial Models into Translation)
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15 pages, 2608 KiB  
Article
In Vitro Evaluation of the Antiamoebic Activity of Kaempferol against Trophozoites of Entamoeba histolytica and in the Interactions of Amoebae with Hamster Neutrophils
by David Levaro-Loquio, Jesús Serrano-Luna, Maritza Velásquez-Torres, Germán Higuera-Martínez, Ivonne Maciel Arciniega-Martínez, Aldo Arturo Reséndiz-Albor, Nadia Mabel Pérez-Vielma and Judith Pacheco-Yépez
Int. J. Mol. Sci. 2023, 24(13), 11216; https://doi.org/10.3390/ijms241311216 - 07 Jul 2023
Viewed by 946
Abstract
Entamoeba histolytica (E. histolytica) is a parasite in humans that provokes amoebiasis. The most employed drug is metronidazole (MTZ); however, some studies have reported that this drug induces genotoxic effects. Therefore, it is necessary to explore new compounds without toxicity that [...] Read more.
Entamoeba histolytica (E. histolytica) is a parasite in humans that provokes amoebiasis. The most employed drug is metronidazole (MTZ); however, some studies have reported that this drug induces genotoxic effects. Therefore, it is necessary to explore new compounds without toxicity that can eliminate E. histolytica. Flavonoids are polyphenolic compounds that have demonstrated inhibition of growth and dysregulation of amoebic proteins. Despite the knowledge acquired to date, action mechanisms are not completely understood. The present work evaluates the effect of kaempferol against E. histolytica trophozoites and in the interactions with neutrophils from hamster, which is a susceptibility model. Our study demonstrated a significant reduction in the amoebic viability of trophozoites incubated with kaempferol at 150 μM for 90 min. The gene expression analysis showed a significant downregulation of Pr (peroxiredoxin), Rr (rubrerythrin), and TrxR (thioredoxin reductase). In interactions with amoebae and neutrophils for short times, we observed a reduction in ROS (reactive oxygen species), NO (nitric oxide), and MPO (myeloperoxidase) neutrophil activities. In conclusion, we confirmed that kaempferol is an effective drug against E. histolytica through the decrease in E. histolytica antioxidant enzyme expression and a regulator of several neutrophil mechanisms, such as MPO activity and the regulation of ROS and NO. Full article
(This article belongs to the Special Issue Neutrophil in Cell Biology and Diseases 2.0)
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16 pages, 3087 KiB  
Article
Cathepsin B Is Not an Intrinsic Factor Related to Asparaginase Resistance of the Acute Lymphoblastic Leukemia REH Cell Line
by Iris Munhoz Costa, Brian Effer, Tales Alexandre Costa-Silva, Chen Chen, Michael F. Ciccone, Adalberto Pessoa, Camila O. dos Santos and Gisele Monteiro
Int. J. Mol. Sci. 2023, 24(13), 11215; https://doi.org/10.3390/ijms241311215 - 07 Jul 2023
Viewed by 1085
Abstract
L-Asparaginase (ASNase) is a biopharmaceutical used as an essential drug in the treatment of acute lymphoblastic leukemia (ALL). Yet, some cases of ALL are naturally resistant to ASNase treatment, which results in poor prognosis. The REH ALL cell line, used as a model [...] Read more.
L-Asparaginase (ASNase) is a biopharmaceutical used as an essential drug in the treatment of acute lymphoblastic leukemia (ALL). Yet, some cases of ALL are naturally resistant to ASNase treatment, which results in poor prognosis. The REH ALL cell line, used as a model for studying the most common subtype of ALL, is considered resistant to treatment with ASNase. Cathepsin B (CTSB) is one of the proteases involved in the regulation of in vivo ASNase serum half-life and it has also been associated with the progression and resistance to treatment of several solid tumors. Previous works have shown that, in vitro, ASNase is degraded when incubated with REH cell lysate, which is prevented by a specific CTSB inhibitor, suggesting a function of this protease in the ASNase resistance of REH cells. In this work, we utilized a combination of CRISPR/Cas9 gene targeting and enzymatic measurements to investigate the relevance of CTSB on ASNase treatment resistance in the ALL model cell line. We found that deletion of CTSB in REH ALL cells did not confer ASNase treatment sensitivity, thus suggesting that intrinsic expression of CTSB is not a mechanism that drives the resistant nature of these ALL cells to enzymes used as the first-line treatment against leukemia. Full article
(This article belongs to the Special Issue State-of-the-Art Molecular Oncology in Brazil 2.0)
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22 pages, 5106 KiB  
Article
Dopamine D3 Receptor Modulates Akt/mTOR and ERK1/2 Pathways Differently during the Reinstatement of Cocaine-Seeking Behavior Induced by Psychological versus Physiological Stress
by Aurelio Franco-García, Rocío Guerrero-Bautista, Juana María Hidalgo, Victoria Gómez-Murcia, María Victoria Milanés and Cristina Núñez
Int. J. Mol. Sci. 2023, 24(13), 11214; https://doi.org/10.3390/ijms241311214 - 07 Jul 2023
Viewed by 940
Abstract
Stress triggers relapses in cocaine use that engage the activity of memory-related nuclei, such as the basolateral amygdala (BLA) and dentate gyrus (DG). Preclinical research suggests that D3 receptor (D3R) antagonists may be a promising means to attenuate cocaine reward and relapse. As [...] Read more.
Stress triggers relapses in cocaine use that engage the activity of memory-related nuclei, such as the basolateral amygdala (BLA) and dentate gyrus (DG). Preclinical research suggests that D3 receptor (D3R) antagonists may be a promising means to attenuate cocaine reward and relapse. As D3R regulates the activity of the Akt/mTOR and MEK/ERK1/2 pathways, we assessed the effects of SB-277011-A, a D3R antagonist, on the activity of these kinases during the reinstatement of cocaine-induced conditioned place preference (CPP) induced by psychological (restraint) and physiological (tail pinch) stress. Both stimuli reactivated an extinguished cocaine-CPP, but only restrained animals decreased their locomotor activity during reinstatement. Cocaine-seeking behavior reactivation was correlated with decreased p-Akt, p-mTOR, and p-ERK1/2 activation in both nuclei of restrained animals. While a D3R blockade prevented stress-induced CPP reinstatement and plasma corticosterone enhancement, SB-277011-A distinctly modulated Akt, mTOR, and ERK1/2 activation depending on the stressor and the dose used. Our data support the involvement of corticosterone in the SB-277011-A effects in restrained animals. Additionally, the ratios p-mTOR/mTOR and/or p-ERK1/2 /ERK1/2 in the BLA during stress-induced relapse seem to be related to the locomotor activity of animals receiving 48 mg/kg of the antagonist. Hence, our study indicates the D3R antagonist’s efficacy to prevent stress-induced relapses in drug use through distinct modulation of Akt/mTOR and MEK/ERK1/2 pathways in memory-processing nuclei. Full article
(This article belongs to the Special Issue Role of Dopamine in Health and Disease: Biological Aspect 2.0)
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22 pages, 7910 KiB  
Article
Identification of Regulatory Molecular “Hot Spots” for LH/PLOD Collagen Glycosyltransferase Activity
by Daiana Mattoteia, Antonella Chiapparino, Marco Fumagalli, Matteo De Marco, Francesca De Giorgi, Lisa Negro, Alberta Pinnola, Silvia Faravelli, Tony Roscioli, Luigi Scietti and Federico Forneris
Int. J. Mol. Sci. 2023, 24(13), 11213; https://doi.org/10.3390/ijms241311213 - 07 Jul 2023
Cited by 1 | Viewed by 1550
Abstract
Hydroxylysine glycosylations are post-translational modifications (PTMs) essential for the maturation and homeostasis of fibrillar and non-fibrillar collagen molecules. The multifunctional collagen lysyl hydroxylase 3 (LH3/PLOD3) and the collagen galactosyltransferase GLT25D1 are the human enzymes that have been identified as being responsible for the [...] Read more.
Hydroxylysine glycosylations are post-translational modifications (PTMs) essential for the maturation and homeostasis of fibrillar and non-fibrillar collagen molecules. The multifunctional collagen lysyl hydroxylase 3 (LH3/PLOD3) and the collagen galactosyltransferase GLT25D1 are the human enzymes that have been identified as being responsible for the glycosylation of collagen lysines, although a precise description of the contribution of each enzyme to these essential PTMs has not yet been provided in the literature. LH3/PLOD3 is thought to be capable of performing two chemically distinct collagen glycosyltransferase reactions using the same catalytic site: an inverting beta-1,O-galactosylation of hydroxylysines (Gal-T) and a retaining alpha-1,2-glucosylation of galactosyl hydroxylysines (Glc-T). In this work, we have combined indirect luminescence-based assays with direct mass spectrometry-based assays and molecular structure studies to demonstrate that LH3/PLOD3 only has Glc-T activity and that GLT25D1 only has Gal-T activity. Structure-guided mutagenesis confirmed that the Glc-T activity is defined by key residues in the first-shell environment of the glycosyltransferase catalytic site as well as by long-range contributions from residues within the same glycosyltransferase (GT) domain. By solving the molecular structures and characterizing the interactions and solving the molecular structures of human LH3/PLOD3 in complex with different UDP-sugar analogs, we show how these studies could provide insights for LH3/PLOD3 glycosyltransferase inhibitor development. Collectively, our data provide new tools for the direct investigation of collagen hydroxylysine PTMs and a comprehensive overview of the complex network of shapes, charges, and interactions that enable LH3/PLOD3 glycosyltransferase activities, expanding the molecular framework and facilitating an improved understanding and manipulation of glycosyltransferase functions in biomedical applications. Full article
(This article belongs to the Special Issue Recent Advances in Collagen Proteins)
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17 pages, 1710 KiB  
Review
The Role of Autophagy and Apoptosis in Affected Skin and Lungs in Patients with Systemic Sclerosis
by Vesna Spasovski, Marina Andjelkovic, Marina Parezanovic, Jovana Komazec, Milena Ugrin, Kristel Klaassen and Maja Stojiljkovic
Int. J. Mol. Sci. 2023, 24(13), 11212; https://doi.org/10.3390/ijms241311212 - 07 Jul 2023
Viewed by 1200
Abstract
Systemic sclerosis (SSc) is a complex autoimmune inflammatory disorder with multiple organ involvement. Skin changes present the hallmark of SSc and coincide with poor prognosis. Interstitial lung diseases (ILD) are the most widely reported complications in SSc patients and the primary cause of [...] Read more.
Systemic sclerosis (SSc) is a complex autoimmune inflammatory disorder with multiple organ involvement. Skin changes present the hallmark of SSc and coincide with poor prognosis. Interstitial lung diseases (ILD) are the most widely reported complications in SSc patients and the primary cause of death. It has been proposed that the processes of autophagy and apoptosis could play a significant role in the pathogenesis and clinical course of different autoimmune diseases, and accordingly in SSc. In this manuscript, we review the current knowledge of autophagy and apoptosis processes in the skin and lungs of patients with SSc. Profiling of markers involved in these processes in skin cells can be useful to recognize the stage of fibrosis and can be used in the clinical stratification of patients. Furthermore, the knowledge of the molecular mechanisms underlying these processes enables the repurposing of already known drugs and the development of new biological therapeutics that aim to reverse fibrosis by promoting apoptosis and regulate autophagy in personalized treatment approach. In SSc-ILD patients, the molecular signature of the lung tissues of each patient could be a distinctive criterion in order to establish the correct lung pattern, which directly impacts the course and prognosis of the disease. In this case, resolving the role of tissue-specific markers, which could be detected in the circulation using sensitive molecular methods, would be an important step toward development of non-invasive diagnostic procedures that enable early and precise diagnosis and preventing the high mortality of this rare disease. Full article
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17 pages, 3762 KiB  
Article
Transcriptome Analysis of Diurnal and Nocturnal-Warmed Plants, the Molecular Mechanism Underlying Cold Deacclimation Response in Deschampsia antarctica
by Dariel López, Giovanni Larama, Patricia L. Sáez and León A. Bravo
Int. J. Mol. Sci. 2023, 24(13), 11211; https://doi.org/10.3390/ijms241311211 - 07 Jul 2023
Cited by 2 | Viewed by 1132
Abstract
Warming in the Antarctic Peninsula is one of the fastest on earth, and is predicted to become more asymmetric in the near future. Warming has already favored the growth and reproduction of Antarctic plant species, leading to a decrease in their freezing tolerance [...] Read more.
Warming in the Antarctic Peninsula is one of the fastest on earth, and is predicted to become more asymmetric in the near future. Warming has already favored the growth and reproduction of Antarctic plant species, leading to a decrease in their freezing tolerance (deacclimation). Evidence regarding the effects of diurnal and nocturnal warming on freezing tolerance-related gene expression in D. antarctica is negligible. We hypothesized that freezing tolerance-related gene (such as CBF-regulon) expression is reduced mainly by nocturnal warming rather than diurnal temperature changes in D. antarctica. The present work aimed to determine the effects of diurnal and nocturnal warming on cold deacclimation and its associated gene expression in D. antarctica, under laboratory conditions. Fully cold-acclimated plants (8 °C/0 °C), with 16h/8h thermoperiod and photoperiod duration, were assigned to four treatments for 14 days: one control (8 °C/0 °C) and three with different warming conditions (diurnal (14 °C/0 °C), nocturnal (8 °C/6 °C), and diurnal-nocturnal (14 °C/6 °C). RNA-seq was performed and differential gene expression was analyzed. Nocturnal warming significantly down-regulated the CBF transcription factors expression and associated cold stress response genes and up-regulated photosynthetic and growth promotion genes. Consequently, nocturnal warming has a greater effect than diurnal warming on the cold deacclimation process in D. antarctica. The eco-physiological implications are discussed. Full article
(This article belongs to the Special Issue Abiotic Stresses in Plants: From Molecules to Environment)
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26 pages, 5380 KiB  
Article
LncRNA 220: A Novel Long Non-Coding RNA Regulates Autophagy and Apoptosis in Kupffer Cells via the miR-5101/PI3K/AKT/mTOR Axis in LPS-Induced Endotoxemic Liver Injury in Mice
by Ying Yang, Tian Tian, Shan Li, Nanhong Li, Haihua Luo and Yong Jiang
Int. J. Mol. Sci. 2023, 24(13), 11210; https://doi.org/10.3390/ijms241311210 - 07 Jul 2023
Cited by 1 | Viewed by 1228
Abstract
Sepsis is a severe medical condition distinguished by immune systematic dysfunction and multiple organic injury, or even failure, resulting from an acute systemic inflammatory response. Acute liver injury (ALI) could be considered as a notable inflammatory outcome of sepsis. Studies have demonstrated the [...] Read more.
Sepsis is a severe medical condition distinguished by immune systematic dysfunction and multiple organic injury, or even failure, resulting from an acute systemic inflammatory response. Acute liver injury (ALI) could be considered as a notable inflammatory outcome of sepsis. Studies have demonstrated the essential roles played by long non-coding RNAs (lncRNAs) in mediating the processes of various diseases, including their ability to engage in interactions with microRNAs (miRNAs) as complexes of competing endogenous RNA (ceRNA) to modulate signaling pathways. In this study, a newly discovered lncRNA, named 220, was identified to function in regulating autophagy and apoptosis in Kupffer cells treated with lipopolysaccharide (LPS). This was achieved through sponging miR-5101 as a ceRNA complex, as identified via high-throughput sequencing. The expression of 220 was found to be significantly different in the hepatic tissues of endotoxemic mice that were treated with LPS for 8 h, ultimately modulating the ALI process. Our studies have collectively demonstrated that 220 is a novel regulator that acts on LPS-induced autophagy and apoptosis in Kupffer cells, thereby mediating the ALI process induced by LPS. Furthermore, the validation of our findings using clinical databases suggests that 220 could potentially serve as a molecular target of clinical, diagnostic, and therapeutic significance in septic liver injury. Full article
(This article belongs to the Special Issue Immuno-Metabolism of Sepsis)
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17 pages, 3342 KiB  
Article
Albuminuria-Related Genetic Biomarkers: Replication and Predictive Evaluation in Individuals with and without Diabetes from the UK Biobank
by Marisa Cañadas-Garre, Andrew T. Kunzmann, Kerry Anderson, Eoin P. Brennan, Ross Doyle, Christopher C. Patterson, Catherine Godson, Alexander P. Maxwell and Amy Jayne McKnight
Int. J. Mol. Sci. 2023, 24(13), 11209; https://doi.org/10.3390/ijms241311209 - 07 Jul 2023
Viewed by 1377
Abstract
Increased albuminuria indicates underlying glomerular pathology and is associated with worse renal disease outcomes, especially in diabetic kidney disease. Many single nucleotide polymorphisms (SNPs), associated with albuminuria, could be potentially useful to construct polygenic risk scores (PRSs) for kidney disease. We investigated the [...] Read more.
Increased albuminuria indicates underlying glomerular pathology and is associated with worse renal disease outcomes, especially in diabetic kidney disease. Many single nucleotide polymorphisms (SNPs), associated with albuminuria, could be potentially useful to construct polygenic risk scores (PRSs) for kidney disease. We investigated the diagnostic accuracy of SNPs, previously associated with albuminuria-related traits, on albuminuria and renal injury in the UK Biobank population, with a particular interest in diabetes. Multivariable logistic regression was used to evaluate the influence of 91 SNPs on urine albumin-to-creatinine ratio (UACR)-related traits and kidney damage (any pathology indicating renal injury), stratifying by diabetes. Weighted PRSs for microalbuminuria and UACR from previous studies were used to calculate the area under the receiver operating characteristic curve (AUROC). CUBN-rs1801239 and DDR1-rs116772905 were associated with all the UACR-derived phenotypes, in both the overall and non-diabetic cohorts, but not with kidney damage. Several SNPs demonstrated different effects in individuals with diabetes compared to those without. SNPs did not improve the AUROC over currently used clinical variables. Many SNPs are associated with UACR or renal injury, suggesting a role in kidney dysfunction, dependent on the presence of diabetes in some cases. However, individual SNPs or PRSs did not improve the diagnostic accuracy for albuminuria or renal injury compared to standard clinical variables. Full article
(This article belongs to the Section Molecular Informatics)
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10 pages, 11095 KiB  
Communication
Conjugated Linoleic Acid-Mediated Connexin-43 Remodeling and Sudden Arrhythmic Death in Myocardial Infarction
by Natia Qipshidze Kelm, Jane C. Solinger, Kellianne M. Piell and Marsha P. Cole
Int. J. Mol. Sci. 2023, 24(13), 11208; https://doi.org/10.3390/ijms241311208 - 07 Jul 2023
Cited by 1 | Viewed by 901
Abstract
Connexin 43 (Cx43) is expressed in the left and right ventricles and is primarily responsible for conducting physiological responses in microvasculature. Studies have demonstrated that NADPH oxidase (NOX) enzymes are essential in cardiac redox biology and are responsible for the generation of reactive [...] Read more.
Connexin 43 (Cx43) is expressed in the left and right ventricles and is primarily responsible for conducting physiological responses in microvasculature. Studies have demonstrated that NADPH oxidase (NOX) enzymes are essential in cardiac redox biology and are responsible for the generation of reactive oxygen species (ROS). NOX2 is linked to left ventricular remodeling following myocardial infarction (MI). It was hypothesized that conjugated linoleic acid (cLA) treatment increases NOX-2 levels in heart tissue and disrupts connexins between the myocytes in the ventricle. Data herein demonstrate that cLA treatment significantly decreases survival in a murine model of MI. The observance of cLA-induced ventricular tachyarrhythmia’s (VT) led to the subsequent investigation of the underlying mechanism in this MI model. Mice were treated with cLA for 12 h, 24 h, 48 h, or 72 h to determine possible time-dependent changes in NOX and Cx43 signaling pathways in isolated left ventricles (LV) extracted from cardiac tissue. The results suggest that ROS generation, through the stimulation of NOX2 in the LV, triggers a decrease in Cx43 levels, causing dysfunction of the gap junctions following treatment with cLA. This cascade of events may initiate VT and subsequent death during MI. Taken together, individuals at risk of MI should use caution regarding cLA consumption. Full article
(This article belongs to the Section Molecular Biology)
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13 pages, 2348 KiB  
Article
Atomic Layer Deposition of Alumina-Coated Thin-Film Cathodes for Lithium Microbatteries
by Aaron O’Donoghue, Micheál Shine, Ian M. Povey and James F. Rohan
Int. J. Mol. Sci. 2023, 24(13), 11207; https://doi.org/10.3390/ijms241311207 - 07 Jul 2023
Cited by 1 | Viewed by 1156
Abstract
This work shows the electrochemical performance of sputter-deposited, binder-free lithium cobalt oxide thin films with an alumina coating deposited via atomic layer deposition for use in lithium-metal-based microbatteries. The Al2O3 coating can improve the charge–discharge kinetics and suppress the phase [...] Read more.
This work shows the electrochemical performance of sputter-deposited, binder-free lithium cobalt oxide thin films with an alumina coating deposited via atomic layer deposition for use in lithium-metal-based microbatteries. The Al2O3 coating can improve the charge–discharge kinetics and suppress the phase transition that occurs at higher potential limits where the crystalline structure of the lithium cobalt oxide is damaged due to the formation of Co4+, causing irreversible capacity loss. The electrochemical performance of the thin film is analysed by imposing 4.2, 4.4 and 4.5 V upper potential limits, which deliver improved performances for 3 nm of Al2O3, while also highlighting evidence of Al doping. Al2O3-coated lithium cobalt oxide of 3 nm is cycled at 147 µA cm−2 (~2.7 C) to an upper potential limit of 4.4 V with an initial capacity of 132 mAh g−1 (65.7 µAh cm−2 µm−1) and a capacity retention of 87% and 70% at cycle 100 and 400, respectively. This shows the high-rate capability and cycling benefits of a 3 nm Al2O3 coating. Full article
(This article belongs to the Special Issue Material Design and Mechanisms of Lithium-Ion Batteries)
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20 pages, 1265 KiB  
Review
A Cross-Talk about Radioresistance in Lung Cancer—How to Improve Radiosensitivity According to Chinese Medicine and Medicaments That Commonly Occur in Pharmacies
by Paulina Nowak, Iwona Bil-Lula and Mariola Śliwińska-Mossoń
Int. J. Mol. Sci. 2023, 24(13), 11206; https://doi.org/10.3390/ijms241311206 - 07 Jul 2023
Cited by 2 | Viewed by 1595
Abstract
Lung cancer is one of the most common cancers in the population and is characterized by non-specific symptoms that delay the diagnosis and reduce the effectiveness of oncological treatment. Due to the difficult placement of the tumor, one of the main methods of [...] Read more.
Lung cancer is one of the most common cancers in the population and is characterized by non-specific symptoms that delay the diagnosis and reduce the effectiveness of oncological treatment. Due to the difficult placement of the tumor, one of the main methods of lung cancer treatment is radiotherapy, which damages the DNA of cancer cells, inducing their apoptosis. However, resistance to ionizing radiation may develop during radiotherapy cycles, leading to an increase in the number of DNA points of control that protect cells from apoptosis. Cancer stem cells are essential for radioresistance, and due to their ability to undergo epithelial–mesenchymal transition, they modify the phenotype, bypassing the genotoxic effect of radiotherapy. It is therefore necessary to search for new methods that could improve the cytotoxic effect of cells through new mechanisms of action. Chinese medicine, with several thousand years of tradition, offers a wide range of possibilities in the search for compounds that could be used in conventional medicine. This review introduces the potential candidates that may present a radiosensitizing effect on lung cancer cells, breaking their radioresistance. Additionally, it includes candidates taken from conventional medicine—drugs commonly available in pharmacies, which may also be significant candidates. Full article
(This article belongs to the Special Issue Radiation Damage in Biomolecules and Cells 3.0)
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15 pages, 2198 KiB  
Review
SLO3: A Conserved Regulator of Sperm Membrane Potential
by Maximilian D. Lyon, Juan J. Ferreira, Ping Li, Shweta Bhagwat, Alice Butler, Kelsey Anderson, Maria Polo and Celia M. Santi
Int. J. Mol. Sci. 2023, 24(13), 11205; https://doi.org/10.3390/ijms241311205 - 07 Jul 2023
Cited by 1 | Viewed by 2147
Abstract
Sperm cells must undergo a complex maturation process after ejaculation to be able to fertilize an egg. One component of this maturation is hyperpolarization of the membrane potential to a more negative value. The ion channel responsible for this hyperpolarization, SLO3, was first [...] Read more.
Sperm cells must undergo a complex maturation process after ejaculation to be able to fertilize an egg. One component of this maturation is hyperpolarization of the membrane potential to a more negative value. The ion channel responsible for this hyperpolarization, SLO3, was first cloned in 1998, and since then much progress has been made to determine how the channel is regulated and how its function intertwines with various signaling pathways involved in sperm maturation. Although Slo3 was originally thought to be present only in the sperm of mammals, recent evidence suggests that a primordial form of the gene is more widely expressed in some fish species. Slo3, like many reproductive genes, is rapidly evolving with low conservation between closely related species and different regulatory and pharmacological profiles. Despite these differences, SLO3 appears to have a conserved role in regulating sperm membrane potential and driving large changes in response to stimuli. The effect of this hyperpolarization of the membrane potential may vary among mammalian species just as the regulation of the channel does. Recent discoveries have elucidated the role of SLO3 in these processes in human sperm and provided tools to target the channel to affect human fertility. Full article
(This article belongs to the Special Issue Recent Advances in the Physiology of Ion Channels in Sperm Cells)
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16 pages, 5206 KiB  
Article
Exploring the Pathophysiologic Cascade Leading to Osteoclastogenic Activation in Gaucher Disease Monocytes Generated via CRISPR/Cas9 Technology
by Maximiliano Emanuel Ormazabal, Eleonora Pavan, Emilio Vaena, Dania Ferino, Jessica Biasizzo, Juan Marcos Mucci, Fabrizio Serra, Adriana Cifù, Maurizio Scarpa, Paula Adriana Rozenfeld and Andrea Elena Dardis
Int. J. Mol. Sci. 2023, 24(13), 11204; https://doi.org/10.3390/ijms241311204 - 07 Jul 2023
Viewed by 1313
Abstract
Gaucher disease (GD) is caused by biallelic pathogenic variants in the acid β-glucosidase gene (GBA1), leading to a deficiency in the β-glucocerebrosidase (GCase) enzyme activity resulting in the intracellular accumulation of sphingolipids. Skeletal alterations are one of the most disabling features [...] Read more.
Gaucher disease (GD) is caused by biallelic pathogenic variants in the acid β-glucosidase gene (GBA1), leading to a deficiency in the β-glucocerebrosidase (GCase) enzyme activity resulting in the intracellular accumulation of sphingolipids. Skeletal alterations are one of the most disabling features in GD patients. Although both defective bone formation and increased bone resorption due to osteoblast and osteoclast dysfunction contribute to GD bone pathology, the molecular bases are not fully understood, and bone disease is not completely resolved with currently available specific therapies. For this reason, using editing technology, our group has developed a reliable, isogenic, and easy-to-handle cellular model of GD monocytes (GBAKO-THP1) to facilitate GD pathophysiology studies and high-throughput drug screenings. In this work, we further characterized the model showing an increase in proinflammatory cytokines (Interleukin-1β and Tumor Necrosis Factor-α) release and activation of osteoclastogenesis. Furthermore, our data suggest that GD monocytes would display an increased osteoclastogenic potential, independent of their interaction with the GD microenvironment or other GD cells. Both proinflammatory cytokine production and osteoclastogenesis were restored at least, in part, by treating cells with the recombinant human GCase, a substrate synthase inhibitor, a pharmacological chaperone, and an anti-inflammatory compound. Besides confirming that this model would be suitable to perform high-throughput screening of therapeutic molecules that act via different mechanisms and on different phenotypic features, our data provided insights into the pathogenic cascade, leading to osteoclastogenesis exacerbation and its contribution to bone pathology in GD. Full article
(This article belongs to the Collection Feature Papers in “Molecular Biology”)
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14 pages, 2549 KiB  
Article
The Combined Use of Copper Sulfate and Trichlorfon Exerts Stronger Toxicity on the Liver of Zebrafish
by Jianlu Zhang, Mingzhen Zhu, Qijun Wang and Hui Yang
Int. J. Mol. Sci. 2023, 24(13), 11203; https://doi.org/10.3390/ijms241311203 - 07 Jul 2023
Cited by 2 | Viewed by 1134
Abstract
In aquaculture, copper sulphate and trichlorfon are commonly used as disinfectants and insecticide, sometimes in combination. However, improper use can result in biotoxicity and increased ecological risks. The liver plays a crucial role in detoxification, lipid metabolism, nutrient storage, and immune function in [...] Read more.
In aquaculture, copper sulphate and trichlorfon are commonly used as disinfectants and insecticide, sometimes in combination. However, improper use can result in biotoxicity and increased ecological risks. The liver plays a crucial role in detoxification, lipid metabolism, nutrient storage, and immune function in fish. Selecting the liver as the main target organ for research helps to gain an in-depth understanding of various aspects of fish physiology, health, and adaptability. In the present study, zebrafish were exposed to Cu (0.5 mg/L) and Tri (0.5 mg/L) alone and in combination for 21 days. The results demonstrate that both Cu and Tri caused hepatocyte structure damage in zebrafish after 21 days of exposure, with the combination showing an even greater toxicity. Additionally, the antioxidant and immune enzyme activities in zebrafish liver were significantly induced on both day 7 and day 21. A transcriptome analysis revealed that Cu and Tri, alone and in combination, impacted various physiological activities differently, including metabolism, growth, and immunity. Overall, Cu and Tri, either individually or in combination, can induce tissue damage by generating oxidative stress in the body, and the longer the exposure duration, the stronger the toxic effects. Moreover, the combined exposure to Cu and Tri exhibits enhanced toxicity. This study provides a theoretical foundation for the combined use of heavy metal disinfectants and other drugs. Full article
(This article belongs to the Special Issue Molecular Toxicity of Drugs in Human and Animal Organs)
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