International Journal of Molecular Sciences

3 pages, 169 KiB

Open AccessEditorial

Molecular Pathology, Diagnostics and Therapeutics: A Story of Success in 2022

by Stephen A. Bustin

Int. J. Mol. Sci. 2023, 24(5), 5063; https://doi.org/10.3390/ijms24055063 - 06 Mar 2023

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Molecular pathology, diagnostics and therapeutics are three closely related topics of critical importance in medical research and clinical practice [...] Full article

(This article belongs to the Section Molecular Pathology, Diagnostics, and Therapeutics)

15 pages, 2786 KiB

Open AccessArticle

Loss of Blood-Brain Barrier Integrity in an In Vitro Model Subjected to Intermittent Hypoxia: Is Reversion Possible with a HIF-1α Pathway Inhibitor?

by Anne Cloé Voirin, Morgane Chatard, Anne Briançon-Marjollet, Jean Louis Pepin, Nathalie Perek and Frederic Roche

Int. J. Mol. Sci. 2023, 24(5), 5062; https://doi.org/10.3390/ijms24055062 - 06 Mar 2023

Cited by 3 | Viewed by 1918

Abstract

Several sleep-related breathing disorders provoke repeated hypoxia stresses, which potentially lead to neurological diseases, such as cognitive impairment. Nevertheless, consequences of repeated intermittent hypoxia on the blood-brain barrier (BBB) are less recognized. This study compared two methods of intermittent hypoxia induction on the [...] Read more.

Several sleep-related breathing disorders provoke repeated hypoxia stresses, which potentially lead to neurological diseases, such as cognitive impairment. Nevertheless, consequences of repeated intermittent hypoxia on the blood-brain barrier (BBB) are less recognized. This study compared two methods of intermittent hypoxia induction on the cerebral endothelium of the BBB: one using hydralazine and the other using a hypoxia chamber. These cycles were performed on an endothelial cell and astrocyte coculture model. Na-Fl permeability, tight junction protein, and ABC transporters (P-gp and MRP-1) content were evaluated with or without HIF-1 inhibitors YC-1. Our results demonstrated that hydralazine as well as intermittent physical hypoxia progressively altered BBB integrity, as shown by an increase in Na-Fl permeability. This alteration was accompanied by a decrease in concentration of tight junction proteins ZO-1 and claudin-5. In turn, microvascular endothelial cells up-regulated the expression of P-gp and MRP-1. An alteration was also found under hydralazine after the third cycle. On the other hand, the third intermittent hypoxia exposure showed a preservation of BBB characteristics. Furthermore, inhibition of HIF-1α with YC-1 prevented BBB dysfunction after hydralazine treatment. In the case of physical intermittent hypoxia, we observed an incomplete reversion suggesting that other biological mechanisms may be involved in BBB dysfunction. In conclusion, intermittent hypoxia led to an alteration of the BBB model with an adaptation observed after the third cycle. Full article

(This article belongs to the Special Issue Pathophysiological and Molecular Signaling Impacts of Chronic Hypoxia and Intermittent Hypoxia)

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36 pages, 3697 KiB

Open AccessArticle

Genetic Structure Analysis of 155 Transboundary and Local Populations of Cattle (Bos taurus, Bos indicus and Bos grunniens) Based on STR Markers

by Evgenia Solodneva, Gulnara Svishcheva, Rodion Smolnikov, Sergey Bazhenov, Evgenii Konorov, Vera Mukhina and Yurii Stolpovsky

Int. J. Mol. Sci. 2023, 24(5), 5061; https://doi.org/10.3390/ijms24055061 - 06 Mar 2023

Cited by 1 | Viewed by 2083

Abstract

Every week, 1–2 breeds of farm animals, including local cattle, disappear in the world. As the keepers of rare allelic variants, native breeds potentially expand the range of genetic solutions to possible problems of the future, which means that the study of the [...] Read more.

Every week, 1–2 breeds of farm animals, including local cattle, disappear in the world. As the keepers of rare allelic variants, native breeds potentially expand the range of genetic solutions to possible problems of the future, which means that the study of the genetic structure of these breeds is an urgent task. Providing nomadic herders with valuable resources necessary for life, domestic yaks have also become an important object of study. In order to determine the population genetic characteristics, and clarify the phylogenetic relationships of modern representatives of 155 cattle populations from different regions of the world, we collected a large set of STR data (10,250 individuals), including unique native cattle, 12 yak populations from Russia, Mongolia and Kyrgyzstan, as well as zebu breeds. Estimation of main population genetic parameters, phylogenetic analysis, principal component analysis and Bayesian cluster analysis allowed us to refine genetic structure and provided insights in relationships of native populations, transboundary breeds and populations of domestic yak. Our results can find practical application in conservation programs of endangered breeds, as well as become the basis for future fundamental research. Full article

(This article belongs to the Special Issue Bioinformatics of Gene Regulations and Structure - 2022)

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15 pages, 3164 KiB

Open AccessArticle

A Novel Wall-Associated Kinase TaWAK-5D600 Positively Participates in Defense against Sharp Eyespot and Fusarium Crown Rot in Wheat

by Haijun Qi, Xiuliang Zhu, Wenbiao Shen and Zengyan Zhang

Int. J. Mol. Sci. 2023, 24(5), 5060; https://doi.org/10.3390/ijms24055060 - 06 Mar 2023

Cited by 1 | Viewed by 1820

Abstract

Sharp eyespot and Fusarium crown rot, mainly caused by soil-borne fungi Rhizoctonia cerealis and Fusarium pseudograminearum, are destructive diseases of major cereal crops including wheat (Triticum aestivum). However, the mechanisms underlying wheat-resistant responses to the two pathogens are largely elusive. [...] Read more.

Sharp eyespot and Fusarium crown rot, mainly caused by soil-borne fungi Rhizoctonia cerealis and Fusarium pseudograminearum, are destructive diseases of major cereal crops including wheat (Triticum aestivum). However, the mechanisms underlying wheat-resistant responses to the two pathogens are largely elusive. In this study, we performed a genome-wide analysis of wall-associated kinase (WAK) family in wheat. As a result, a total of 140 TaWAK (not TaWAKL) candidate genes were identified from the wheat genome, each of which contains an N-terminal signal peptide, a galacturonan binding domain, an EGF-like domain, a calcium binding EGF domain (EGF-Ca), a transmembrane domain, and an intracellular Serine/Threonine protein kinase domain. By analyzing the RNA-sequencing data of wheat inoculated with R. cerealis and F. pseudograminearum, we found that transcript abundance of TaWAK-5D600 (TraesCS5D02G268600) on chromosome 5D was significantly upregulated, and that its upregulated transcript levels in response to both pathogens were higher compared with other TaWAK genes. Importantly, knock-down of TaWAK-5D600 transcript impaired wheat resistance against the fungal pathogens R. cerealis and F. pseudograminearum, and significantly repressed expression of defense-related genes in wheat, TaSERK1, TaMPK3, TaPR1, TaChitinase3, and TaChitinase4. Thus, this study proposes TaWAK-5D600 as a promising gene for improving wheat broad resistance to sharp eyespot and Fusarium crown rot (FCR) in wheat. Full article

(This article belongs to the Special Issue Molecular Insights into Plant-Biotic Interactions and Crop Yield)

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19 pages, 6634 KiB

Open AccessArticle

Ginsenoside Rb1 Improves Post-Cardiac Arrest Myocardial Stunning and Cerebral Outcomes by Regulating the Keap1/Nrf2 Pathway

by Long Chen, Na Geng, Taiwei Chen, Qingqing Xiao, Hengyuan Zhang, Huanhuan Huo, Lisheng Jiang, Qin Shao and Ben He

Int. J. Mol. Sci. 2023, 24(5), 5059; https://doi.org/10.3390/ijms24055059 - 06 Mar 2023

Cited by 4 | Viewed by 1970

Abstract

The prognosis of cardiac arrest (CA) is dismal despite the ongoing progress in cardiopulmonary resuscitation (CPR). ginsenoside Rb1 (Gn-Rb1) has been verified to be cardioprotective in cardiac remodeling and cardiac ischemia/reperfusion (I/R) injury, but its role is less known in CA. After 15 [...] Read more.

The prognosis of cardiac arrest (CA) is dismal despite the ongoing progress in cardiopulmonary resuscitation (CPR). ginsenoside Rb1 (Gn-Rb1) has been verified to be cardioprotective in cardiac remodeling and cardiac ischemia/reperfusion (I/R) injury, but its role is less known in CA. After 15 min of potassium chloride-induced CA, male C57BL/6 mice were resuscitated. Gn-Rb1 was blindly randomized to mice after 20 s of CPR. We assessed the cardiac systolic function before CA and 3 h after CPR. Mortality rates, neurological outcome, mitochondrial homeostasis, and the levels of oxidative stress were evaluated. We found that Gn-Rb1 improved the long-term survival during the post-resuscitation period but did not affect the ROSC rate. Further mechanistic investigations revealed that Gn-Rb1 ameliorated CA/CPR-induced mitochondrial destabilization and oxidative stress, partially via the activation of Keap1/Nrf2 axis. Gn-Rb1 improved the neurological outcome after resuscitation partially by balancing the oxidative stress and suppressing apoptosis. In sum, Gn-Rb1 protects against post-CA myocardial stunning and cerebral outcomes via the induction of the Nrf2 signaling pathway, which may offer a new insight into therapeutic strategies for CA. Full article

(This article belongs to the Section Molecular Pathology, Diagnostics, and Therapeutics)

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12 pages, 4787 KiB

Open AccessCommunication

Transcriptome Sequencing Reveals the Mechanism behind Chemically Induced Oral Mucositis in a 3D Cell Culture Model

by Maria Lambros, Jonathan Moreno, Qinqin Fei, Cyrus Parsa, Robert Orlando and Lindsey Van Haute

Int. J. Mol. Sci. 2023, 24(5), 5058; https://doi.org/10.3390/ijms24055058 - 06 Mar 2023

Viewed by 1621

Abstract

Oral mucositis is a common side effect of cancer treatment, and in particular of treatment with the mTORC1 inhibitor everolimus. Current treatment methods are not efficient enough and a better understanding of the causes and mechanisms behind oral mucositis is necessary to find [...] Read more.

Oral mucositis is a common side effect of cancer treatment, and in particular of treatment with the mTORC1 inhibitor everolimus. Current treatment methods are not efficient enough and a better understanding of the causes and mechanisms behind oral mucositis is necessary to find potential therapeutic targets. Here, we treated an organotypic 3D oral mucosal tissue model consisting of human keratinocytes grown on top of human fibroblasts with a high or low dose of everolimus for 40 or 60 h and investigated (1) the effect of everolimus on microscopic sections of the 3D cell culture for evidence of morphologic changes and (2) changes in the transcriptome by high throughput RNA-Seq analysis. We show that the most affected pathways are cornification, cytokine expression, glycolysis, and cell proliferation and we provide further details. This study provides a good resource towards a better understanding of the development of oral mucositis. It gives a detailed overview of the different molecular pathways that are involved in mucositis. This in turn provides information about potential therapeutic targets, which is an important step towards preventing or managing this common side effect of cancer treatment. Full article

(This article belongs to the Special Issue Design, Discovery and Development of Modulators Targeting Protein-Protein Interactions)

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15 pages, 4958 KiB

Open AccessArticle

The CCCH-Type Zinc-Finger Protein GhC3H20 Enhances Salt Stress Tolerance in Arabidopsis thaliana and Cotton through ABA Signal Transduction Pathway

by Qi Zhang, Jingjing Zhang, Fei Wei, Xiaokang Fu, Hengling Wei, Jianhua Lu, Liang Ma and Hantao Wang

Int. J. Mol. Sci. 2023, 24(5), 5057; https://doi.org/10.3390/ijms24055057 - 06 Mar 2023

Cited by 4 | Viewed by 1679

Abstract

The CCCH zinc-finger protein contains a typical C3H-type motif widely existing in plants, and it plays an important role in plant growth, development, and stress responses. In this study, a CCCH zinc-finger gene, GhC3H20, was isolated and thoroughly characterized to regulate salt [...] Read more.

The CCCH zinc-finger protein contains a typical C3H-type motif widely existing in plants, and it plays an important role in plant growth, development, and stress responses. In this study, a CCCH zinc-finger gene, GhC3H20, was isolated and thoroughly characterized to regulate salt stress in cotton and Arabidopsis. The expression of GhC3H20 was up-regulated under salt, drought, and ABA treatments. GUS activity was detected in the root, stem, leaves, and flowers of ProGhC3H20::GUS transgenic Arabidopsis. Compared with the control, the GUS activity of ProGhC3H20::GUS transgenic Arabidopsis seedlings under NaCl treatment was stronger. Through the genetic transformation of Arabidopsis, three transgenic lines of 35S-GhC3H20 were obtained. Under NaCl and mannitol treatments, the roots of the transgenic lines were significantly longer than those of the wild-type (WT) Arabidopsis. The leaves of the WT turned yellow and wilted under high-concentration salt treatment at the seedling stage, while the leaves of the transgenic Arabidopsis lines did not. Further investigation showed that compared with the WT, the content of catalase (CAT) in the leaves of the transgenic lines was significantly higher. Therefore, compared with the WT, overexpression of GhC3H20 enhanced the salt stress tolerance of transgenic Arabidopsis. A virus-induced gene silencing (VIGS) experiment showed that compared with the control, the leaves of pYL156-GhC3H20 plants were wilted and dehydrated. The content of chlorophyll in pYL156-GhC3H20 leaves was significantly lower than those of the control. Therefore, silencing of GhC3H20 reduced salt stress tolerance in cotton. Two interacting proteins (GhPP2CA and GhHAB1) of GhC3H20 have been identified through a yeast two-hybrid assay. The expression levels of PP2CA and HAB1 in transgenic Arabidopsis were higher than those in the WT, and pYL156-GhC3H20 had expression levels lower than those in the control. GhPP2CA and GhHAB1 are the key genes involved in the ABA signaling pathway. Taken together, our findings demonstrate that GhC3H20 may interact with GhPP2CA and GhHAB1 to participate in the ABA signaling pathway to enhance salt stress tolerance in cotton. Full article

(This article belongs to the Special Issue Genes Function and Mechanism Identification in Plant Stress Resistance)

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17 pages, 3816 KiB

Open AccessArticle

Ceria Nanoparticles Alleviated Osteoarthritis through Attenuating Senescence and Senescence-Associated Secretory Phenotype in Synoviocytes

by Xunshan Ren, Huangming Zhuang, Fuze Jiang, Yuelong Zhang and Panghu Zhou

Int. J. Mol. Sci. 2023, 24(5), 5056; https://doi.org/10.3390/ijms24055056 - 06 Mar 2023

Cited by 2 | Viewed by 2015

Abstract

Accumulation of senescent cells is the prominent risk factor for osteoarthritis (OA), accelerating the progression of OA through a senescence-associated secretory phenotype (SASP). Recent studies emphasized the existence of senescent synoviocytes in OA and the therapeutic effect of removing senescent synoviocytes. Ceria nanoparticles [...] Read more.

Accumulation of senescent cells is the prominent risk factor for osteoarthritis (OA), accelerating the progression of OA through a senescence-associated secretory phenotype (SASP). Recent studies emphasized the existence of senescent synoviocytes in OA and the therapeutic effect of removing senescent synoviocytes. Ceria nanoparticles (CeNP) have exhibited therapeutic effects in multiple age-related diseases due to their unique capability of ROS scavenging. However, the role of CeNP in OA remains unknown. Our results revealed that CeNP could inhibit the expression of senescence and SASP biomarkers in multiple passaged and hydrogen-peroxide-treated synoviocytes by removing ROS. In vivo, the concentration of ROS in the synovial tissue was remarkably suppressed after the intra-articular injection of CeNP. Likewise, CeNP reduced the expression of senescence and SASP biomarkers as determined by immunohistochemistry analysis. The mechanistic study showed that CeNP inactivated the NFκB pathway in senescent synoviocytes. Finally, safranin O–fast green staining showed milder destruction of articular cartilage in the CeNP-treated group compared with the OA group. Overall, our study suggested that CeNP attenuated senescence and protected cartilage from degeneration via scavenging ROS and inactivating the NFκB signaling pathway. This study has potentially significant implications in the field of OA as it provides a novel strategy for OA treatment. Full article

(This article belongs to the Special Issue Novel Strategies in the Development of New Anti-inflammatory Drug Substances and Therapies)

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19 pages, 1299 KiB

Open AccessArticle

Cannabidiol as a Promising Therapeutic Option in IC/BPS: In Vitro Evaluation of Its Protective Effects against Inflammation and Oxidative Stress

by Tadeja Kuret, Mateja Erdani Kreft, Rok Romih and Peter Veranič

Int. J. Mol. Sci. 2023, 24(5), 5055; https://doi.org/10.3390/ijms24055055 - 06 Mar 2023

Cited by 3 | Viewed by 2171

Abstract

Several animal studies have described the potential effect of cannabidiol (CBD) in alleviating the symptoms of interstitial cystitis/bladder pain syndrome (IC/BPS), a chronic inflammatory disease of the urinary bladder. However, the effects of CBD, its mechanism of action, and modulation of downstream signaling [...] Read more.

Several animal studies have described the potential effect of cannabidiol (CBD) in alleviating the symptoms of interstitial cystitis/bladder pain syndrome (IC/BPS), a chronic inflammatory disease of the urinary bladder. However, the effects of CBD, its mechanism of action, and modulation of downstream signaling pathways in urothelial cells, the main effector cells in IC/BPS, have not been fully elucidated yet. Here, we investigated the effect of CBD against inflammation and oxidative stress in an in vitro model of IC/BPS comprised of TNFα-stimulated human urothelial cells SV-HUC1. Our results show that CBD treatment of urothelial cells significantly decreased TNFα-upregulated mRNA and protein expression of IL1α, IL8, CXCL1, and CXCL10, as well as attenuated NFκB phosphorylation. In addition, CBD treatment also diminished TNFα-driven cellular reactive oxygen species generation (ROS), by increasing the expression of the redox-sensitive transcription factor Nrf2, the antioxidant enzymes superoxide dismutase 1 and 2, and hem oxygenase 1. CBD-mediated effects in urothelial cells may occur by the activation of the PPARγ receptor since inhibition of PPARγ resulted in significantly diminished anti-inflammatory and antioxidant effects of CBD. Our observations provide new insights into the therapeutic potential of CBD through modulation of PPARγ/Nrf2/NFκB signaling pathways, which could be further exploited in the treatment of IC/BPS. Full article

(This article belongs to the Special Issue Inflammation in Health and Disease: New Insights and Therapeutic Avenues 3.0)

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12 pages, 2982 KiB

Open AccessArticle

Properties of a Single Amino Acid Residue in the Third Transmembrane Domain Determine the Kinetics of Ambient Light-Sensitive Channelrhodopsin

by Akito Hatakeyama, Eriko Sugano, Tatsuki Sayama, Yoshito Watanabe, Tomoya Suzuki, Kitako Tabata, Yuka Endo, Tetsuya Sakajiri, Tomokazu Fukuda, Taku Ozaki and Hiroshi Tomita

Int. J. Mol. Sci. 2023, 24(5), 5054; https://doi.org/10.3390/ijms24055054 - 06 Mar 2023

Cited by 1 | Viewed by 1267

Abstract

Channelrhodopsins have been utilized in gene therapy to restore vision in patients with retinitis pigmentosa and their channel kinetics are an important factor to consider in such applications. We investigated the channel kinetics of ComV1 variants with different amino acid residues at the [...] Read more.

Channelrhodopsins have been utilized in gene therapy to restore vision in patients with retinitis pigmentosa and their channel kinetics are an important factor to consider in such applications. We investigated the channel kinetics of ComV1 variants with different amino acid residues at the 172nd position. Patch clamp methods were used to record the photocurrents induced by stimuli from diodes in HEK293 cells transfected with plasmid vectors. The channel kinetics (τon and τoff) were considerably altered by the replacement of the 172nd amino acid and was dependent on the amino acid characteristics. The size of amino acids at this position correlated with τon and decay, whereas the solubility correlated with τon and τoff. Molecular dynamic simulation indicated that the ion tunnel constructed by H172, E121, and R306 widened due to H172A variant, whereas the interaction between A172 and the surrounding amino acids weakened compared with H172. The bottleneck radius of the ion gate constructed with the 172nd amino acid affected the photocurrent and channel kinetics. The 172nd amino acid in ComV1 is a key residue for determining channel kinetics as its properties alter the radius of the ion gate. Our findings can be used to improve the channel kinetics of channelrhodopsins. Full article

(This article belongs to the Special Issue Retinal Diseases and Cell Signaling)

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17 pages, 1409 KiB

Open AccessReview

Female Reproductive Aging and Oxidative Stress: Mesenchymal Stem Cell Conditioned Medium as a Promising Antioxidant

by Kihae Ra, Se Chang Park and Byeong Chun Lee

Int. J. Mol. Sci. 2023, 24(5), 5053; https://doi.org/10.3390/ijms24055053 - 06 Mar 2023

Cited by 10 | Viewed by 2808

Abstract

The recent tendency to delay pregnancy has increased the incidence of age-related infertility, as female reproductive competence decreases with aging. Along with aging, a lowered capacity of antioxidant defense causes a loss of normal function in the ovaries and uterus due to oxidative [...] Read more.

The recent tendency to delay pregnancy has increased the incidence of age-related infertility, as female reproductive competence decreases with aging. Along with aging, a lowered capacity of antioxidant defense causes a loss of normal function in the ovaries and uterus due to oxidative damage. Therefore, advancements have been made in assisted reproduction to resolve infertility caused by reproductive aging and oxidative stress, following an emphasis on their use. The application of mesenchymal stem cells (MSCs) with intensive antioxidative properties has been extensively validated as a regenerative therapy, and proceeding from original cell therapy, the therapeutic effects of stem cell conditioned medium (CM) containing paracrine factors secreted during cell culture have been reported to be as effective as that of direct treatment of source cells. In this review, we summarized the current understanding of female reproductive aging and oxidative stress and present MSC-CM, which could be developed as a promising antioxidant intervention for assisted reproductive technology. Full article

(This article belongs to the Special Issue Advanced Research on Reproductive System Disease 2022)

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16 pages, 41816 KiB

Open AccessArticle

Finding miRNA–RNA Network Biomarkers for Predicting Metastasis and Prognosis in Cancer

by Seokwoo Lee, Myounghoon Cho, Byungkyu Park and Kyungsook Han

Int. J. Mol. Sci. 2023, 24(5), 5052; https://doi.org/10.3390/ijms24055052 - 06 Mar 2023

Viewed by 1486

Abstract

Despite remarkable progress in cancer research and treatment over the past decades, cancer ranks as a leading cause of death worldwide. In particular, metastasis is the major cause of cancer deaths. After an extensive analysis of miRNAs and RNAs in tumor tissue samples, [...] Read more.

Despite remarkable progress in cancer research and treatment over the past decades, cancer ranks as a leading cause of death worldwide. In particular, metastasis is the major cause of cancer deaths. After an extensive analysis of miRNAs and RNAs in tumor tissue samples, we derived miRNA–RNA pairs with substantially different correlations from those in normal tissue samples. Using the differential miRNA–RNA correlations, we constructed models for predicting metastasis. A comparison of our model to other models with the same data sets of solid cancer showed that our model is much better than the others in both lymph node metastasis and distant metastasis. The miRNA–RNA correlations were also used in finding prognostic network biomarkers in cancer patients. The results of our study showed that miRNA–RNA correlations and networks consisting of miRNA–RNA pairs were more powerful in predicting prognosis as well as metastasis. Our method and the biomarkers obtained using the method will be useful for predicting metastasis and prognosis, which in turn will help select treatment options for cancer patients and targets of anti-cancer drug discovery. Full article

(This article belongs to the Special Issue Network Medicine in Human Diseases)

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16 pages, 2253 KiB

Open AccessArticle

Gene Expression Analysis of Immune Regulatory Genes in Circulating Tumour Cells and Peripheral Blood Mononuclear Cells in Patients with Colorectal Carcinoma

by Sharmin Aktar, Faysal Bin Hamid, Sujani Madhurika Kodagoda Gamage, Tracie Cheng, Nahal Pakneshan, Cu Tai Lu, Farhadul Islam, Vinod Gopalan and Alfred King-yin Lam

Int. J. Mol. Sci. 2023, 24(5), 5051; https://doi.org/10.3390/ijms24055051 - 06 Mar 2023

Cited by 3 | Viewed by 2087 | Correction

Abstract

Information regarding genetic alterations of driver cancer genes in circulating tumour cells (CTCs) and their surrounding immune microenvironment nowadays can be employed as a real-time monitoring platform for translational applications such as patient response to therapeutic targets, including immunotherapy. This study aimed to [...] Read more.

Information regarding genetic alterations of driver cancer genes in circulating tumour cells (CTCs) and their surrounding immune microenvironment nowadays can be employed as a real-time monitoring platform for translational applications such as patient response to therapeutic targets, including immunotherapy. This study aimed to investigate the expression profiling of these genes along with immunotherapeutic target molecules in CTCs and peripheral blood mononuclear cells (PBMCs) in patients with colorectal carcinoma (CRC). Expression of p53, APC, KRAS, c-Myc, and immunotherapeutic target molecules PD-L1, CTLA-4, and CD47 in CTCs and PBMCs were analysed by qPCR. Their expression in high versus low CTC-positive patients with CRC was compared and clinicopathological correlations between these patient groups were analysed. CTCs were detected in 61% (38 of 62) of patients with CRC. The presence of higher numbers of CTCs was significantly correlated with advanced cancer stages (p = 0.045) and the subtypes of adenocarcinoma (conventional vs. mucinous, p = 0.019), while being weakly correlated with tumour size (p = 0.051). Patients with lower numbers of CTCs had higher expression of KRAS. Higher KRAS expression in CTCs was negatively correlated with tumour perforation (p = 0.029), lymph node status (p = 0.037), distant metastasis (p = 0.046) and overall staging (p = 0.004). CTLA-4 was highly expressed in both CTCs and PBMCs. In addition, CTLA-4 expression was positively correlated with KRAS (r = 0.6878, p = 0.002) in the enriched CTC fraction. Dysregulation of KRAS in CTCs might evade the immune system by altering the expression of CTLA-4, providing new insights into the selection of therapeutic targets at the onset of the disease. Monitoring CTCs counts, as well as gene expression profiling of PBMCs, can be helpful in predicting tumour progression, patient outcome and treatment. Full article

(This article belongs to the Special Issue Heterogeneity and Precision Oncology in Circulating Tumor Cells)

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17 pages, 3031 KiB

Open AccessArticle

Identification and Functional Analysis of Two Mitoferrins, CsMIT1 and CsMIT2, Participating in Iron Homeostasis in Cucumber

by Karolina Małas and Katarzyna Kabała

Int. J. Mol. Sci. 2023, 24(5), 5050; https://doi.org/10.3390/ijms24055050 - 06 Mar 2023

Viewed by 1383

Abstract

Mitochondria are one of the major iron sinks in plant cells. Mitochondrial iron accumulation involves the action of ferric reductase oxidases (FRO) and carriers located in the inner mitochondrial membrane. It has been suggested that among these transporters, mitoferrins (mitochondrial iron transporters, MITs) [...] Read more.

Mitochondria are one of the major iron sinks in plant cells. Mitochondrial iron accumulation involves the action of ferric reductase oxidases (FRO) and carriers located in the inner mitochondrial membrane. It has been suggested that among these transporters, mitoferrins (mitochondrial iron transporters, MITs) belonging to the mitochondrial carrier family (MCF) function as mitochondrial iron importers. In this study, two cucumber proteins, CsMIT1 and CsMIT2, with high homology to Arabidopsis, rice and yeast MITs were identified and characterized. CsMIT1 and CsMIT2 were expressed in all organs of the two-week-old seedlings. Under Fe-limited conditions as well as Fe excess, the mRNA levels of CsMIT1 and CsMIT2 were altered, suggesting their regulation by iron availability. Analyses using Arabidopsis protoplasts confirmed the mitochondrial localization of cucumber mitoferrins. Expression of CsMIT1 and CsMIT2 restored the growth of the Δmrs3Δmrs4 mutant (defective in mitochondrial Fe transport), but not in mutants sensitive to other heavy metals. Moreover, the altered cytosolic and mitochondrial Fe concentrations, observed in the Δmrs3Δmrs4 strain, were recovered almost to the levels of WT yeast by expressing CsMIT1 or CsMIT2. These results indicate that cucumber proteins are involved in the iron transport from the cytoplasm to the mitochondria. Full article

(This article belongs to the Special Issue Iron and Sulfur in Plants 3.0)

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15 pages, 2771 KiB

Open AccessArticle

Effect of Chitosan-Diosgenin Combination on Wound Healing

by Lubomir Petrov, Olya Stoilova, Georgi Pramatarov, Hristiyana Kanzova, Elina Tsvetanova, Madlena Andreeva, Almira Georgieva, Dimitrinka Atanasova, Stanislav Philipov and Albena Alexandrova

Int. J. Mol. Sci. 2023, 24(5), 5049; https://doi.org/10.3390/ijms24055049 - 06 Mar 2023

Cited by 2 | Viewed by 1547

Abstract

The difficult-to-heal wounds continue to be a problem for modern medicine. Chitosan and diosgenin possess anti-inflammatory and antioxidant effects making them relevant substances for wound treatment. That is why this work aimed to study the effect of the combined application of chitosan and [...] Read more.

The difficult-to-heal wounds continue to be a problem for modern medicine. Chitosan and diosgenin possess anti-inflammatory and antioxidant effects making them relevant substances for wound treatment. That is why this work aimed to study the effect of the combined application of chitosan and diosgenin on a mouse skin wound model. For the purpose, wounds (6 mm diameter) were made on mice’s backs and were treated for 9 days with one of the following: 50% ethanol (control), polyethylene glycol (PEG) in 50% ethanol, chitosan and PEG in 50% ethanol (Chs), diosgenin and PEG in 50% ethanol (Dg) and chitosan, diosgenin and PEG in 50% ethanol (ChsDg). Before the first treatment and on the 3rd, 6th and 9th days, the wounds were photographed and their area was determined. On the 9th day, animals were euthanized and wounds’ tissues were excised for histological analysis. In addition, the lipid peroxidation (LPO), protein oxidation (POx) and total glutathione (tGSH) levels were measured. The results showed that ChsDg had the most pronounced overall effect on wound area reduction, followed by Chs and PEG. Moreover, the application of ChsDg maintained high levels of tGSH in wound tissues, compared to other substances. It was shown that all tested substances, except ethanol, reduced POx comparable to intact skin levels. Therefore, the combined application of chitosan and diosgenin is a very promising and effective medication for wound healing. Full article

(This article belongs to the Special Issue The Emerging Role of Polymeric Materials in Pharmaceutical Designs and Applications)

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16 pages, 4051 KiB

Open AccessArticle

Discovering the Biological Significance and Therapeutic Potential of miR-29b-3p in Triple-Negative Breast Cancer

by Ancuta Jurj, Oana Zanoaga, Lajos Raduly, Vlad Morhan, Zsofia Papi, Cristina Ciocan, Laura-Ancuta Pop, Ioana Berindan-Neagoe and Cornelia Braicu

Int. J. Mol. Sci. 2023, 24(5), 5048; https://doi.org/10.3390/ijms24055048 - 06 Mar 2023

Cited by 1 | Viewed by 1844

Abstract

The lack of estrogen or progesterone receptors and absence of HER2 amplification/overexpression in triple-negative breast cancer (TNBC) restricts therapeutic options used in clinical management. MicroRNAs (miRNAs) are small, non-coding transcripts which affect important cellular mechanisms by regulating gene expression at the post-transcriptional level. [...] Read more.

The lack of estrogen or progesterone receptors and absence of HER2 amplification/overexpression in triple-negative breast cancer (TNBC) restricts therapeutic options used in clinical management. MicroRNAs (miRNAs) are small, non-coding transcripts which affect important cellular mechanisms by regulating gene expression at the post-transcriptional level. Among this class, attention was focused on miR-29b-3p with a high profile in TNBC and correlated with the overall survival rates, as TCGA data revealed. This study aims to investigate the implication of the miR-29b-3p inhibitor in TNBC cell lines by identifying a potential therapeutic transcript, improving the clinical outcomes of this disease. The experiments were performed on two TNBC cell lines (MDA-MB-231 and BT549) as in vitro models. An established dose of 50 nM was used for all functional assays performed on the miR-29b-3p inhibitor. A decreased level of miR-29b-3p determined a significant reduction in cell proliferation and colony-forming capacity. At the same time, the changes occurring at the molecular and cellular levels were highlighted. We observed that, when inhibiting the expression level of miR-29b-3p, processes such as apoptosis and autophagy were activated. Further, microarray data revealed that the miRNA expression pattern was altered after miR-29b-3p inhibition, pointing out 8 overexpressed and 11 downregulated miRNAs specific for BT549 cells and 33 upregulated and 10 downregulated miRNAs that were specific for MDA-MB-231 cells. As a common signature for both cell lines, three transcripts were observed, two downregulated, miR-29b-3p and miR-29a, and one upregulated, miR-1229-5p. According to DIANA miRPath, the main predicted targets are related to ECM (extracellular matrix) receptor interaction and TP53 signaling. An additional validation step through qRT-PCR was performed, which showed an upregulation of MCL1 and TGFB1. By inhibiting the expression level of miR-29b-3p, it was shown that complex regulatory pathways targeted this transcript in TNBC cells. Full article

(This article belongs to the Special Issue Breast Cancer Mechanistic Insights and Targeted Therapies)

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25 pages, 4116 KiB

Open AccessArticle

Parental Preconception and Pre-Hatch Exposure to a Developmental Insult Alters Offspring’s Gene Expression and Epigenetic Regulations: An Avian Model

by Issam Rimawi, Gadi Turgeman, Nataly Avital-Cohen, Israel Rozenboim and Joseph Yanai

Int. J. Mol. Sci. 2023, 24(5), 5047; https://doi.org/10.3390/ijms24055047 - 06 Mar 2023

Cited by 2 | Viewed by 1800

Abstract

Parental exposure to insults was initially considered safe if stopped before conception. In the present investigation, paternal or maternal preconception exposure to the neuroteratogen chlorpyrifos was investigated in a well-controlled avian model (Fayoumi) and compared to pre-hatch exposure focusing on molecular [...] Read more.

Parental exposure to insults was initially considered safe if stopped before conception. In the present investigation, paternal or maternal preconception exposure to the neuroteratogen chlorpyrifos was investigated in a well-controlled avian model (Fayoumi) and compared to pre-hatch exposure focusing on molecular alterations. The investigation included the analysis of several neurogenesis, neurotransmission, epigenetic and microRNA genes. A significant decrease in the vesicular acetylcholine transporter (SLC18A3) expression was detected in the female offspring in the three investigated models: paternal (57.7%, p < 0.05), maternal (36%, p < 0.05) and pre-hatch (35.6%, p < 0.05). Paternal exposure to chlorpyrifos also led to a significant increase in brain-derived neurotrophic factor (BDNF) gene expression mainly in the female offspring (27.6%, p < 0.005), while its targeting microRNA, miR-10a, was similarly decreased in both female (50.5%, p < 0.05) and male (56%, p < 0.05) offspring. Doublecortin’s (DCX) targeting microRNA, miR-29a, was decreased in the offspring after maternal preconception exposure to chlorpyrifos (39.8%, p < 0.05). Finally, pre-hatch exposure to chlorpyrifos led to a significant increase in protein kinase C beta (PKCß; 44.1%, p < 0.05), methyl-CpG-binding domain protein 2 (MBD2; 44%, p < 0.01) and 3 (MBD3; 33%, p < 0.05) genes expression in the offspring. Although extensive studies are required to establish a mechanism–phenotype relationship, it should be noted that the current investigation does not include phenotype assessment in the offspring. Full article

(This article belongs to the Special Issue Regulation and Function of Adult Neurogenesis)

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17 pages, 1513 KiB

Open AccessReview

The Functions of TRIM56 in Antiviral Innate Immunity and Tumorigenesis

by Lin Fu, Xiaotong Zhou, Qian Jiao and Xi Chen

Int. J. Mol. Sci. 2023, 24(5), 5046; https://doi.org/10.3390/ijms24055046 - 06 Mar 2023

Cited by 10 | Viewed by 2249

Abstract

As a member of the TRIM (tripartite motif) protein family, TRIM56 can function as an E3 ubiquitin ligase. In addition, TRIM56 has been shown to possess deubiquitinase activity and the ability to bind RNA. This adds to the complexity of the regulatory mechanism [...] Read more.

As a member of the TRIM (tripartite motif) protein family, TRIM56 can function as an E3 ubiquitin ligase. In addition, TRIM56 has been shown to possess deubiquitinase activity and the ability to bind RNA. This adds to the complexity of the regulatory mechanism of TRIM56. TRIM56 was initially found to be able to regulate the innate immune response. In recent years, its role in direct antiviral and tumor development has also attracted the interest of researchers, but there is no systematic review on TRIM56. Here, we first summarize the structural features and expression of TRIM56. Then, we review the functions of TRIM56 in TLR and cGAS-STING pathways of innate immune response, the mechanisms and structural specificity of TRIM56 against different types of viruses, and the dual roles of TRIM56 in tumorigenesis. Finally, we discuss the future research directions regarding TRIM56. Full article

(This article belongs to the Section Molecular Immunology)

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17 pages, 837 KiB

Open AccessReview

Impacts of Environmental Pollution on Brain Tumorigenesis

by Cristina Pagano, Giovanna Navarra, Laura Coppola, Beatrice Savarese, Giorgio Avilia, Antonella Giarra, Giovanni Pagano, Alessandra Marano, Marco Trifuoggi, Maurizio Bifulco and Chiara Laezza

Int. J. Mol. Sci. 2023, 24(5), 5045; https://doi.org/10.3390/ijms24055045 - 06 Mar 2023

Cited by 4 | Viewed by 4074

Abstract

Pollutants consist of several components, known as direct or indirect mutagens, that can be associated with the risk of tumorigenesis. The increased incidence of brain tumors, observed more frequently in industrialized countries, has generated a deeper interest in examining different pollutants that could [...] Read more.

Pollutants consist of several components, known as direct or indirect mutagens, that can be associated with the risk of tumorigenesis. The increased incidence of brain tumors, observed more frequently in industrialized countries, has generated a deeper interest in examining different pollutants that could be found in food, air, or water supply. These compounds, due to their chemical nature, alter the activity of biological molecules naturally found in the body. The bioaccumulation leads to harmful effects for humans, increasing the risk of the onset of several pathologies, including cancer. Environmental components often combine with other risk factors, such as the individual genetic component, which increases the chance of developing cancer. The objective of this review is to discuss the impact of environmental carcinogens on modulating the risk of brain tumorigenesis, focusing our attention on certain categories of pollutants and their sources. Full article

(This article belongs to the Special Issue Latest Review Papers in Molecular Oncology 2023)

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20 pages, 12533 KiB

Open AccessArticle

Integrating Multi-Omics Analysis Reveals the Regulatory Mechanisms of White–Violet Mutant Flowers in Grape Hyacinth (Muscari latifolium)

by Junren Ma, Zhi Li and Yali Liu

Int. J. Mol. Sci. 2023, 24(5), 5044; https://doi.org/10.3390/ijms24055044 - 06 Mar 2023

Viewed by 1595

Abstract

Grape hyacinth (Muscari spp.) is a famous bulbous blue flower; however, few bicolor varieties are available in the market. Therefore, the discovery of bicolor varieties and understanding of their mechanisms are crucial to the breeding of new varieties. In this study, we [...] Read more.

Grape hyacinth (Muscari spp.) is a famous bulbous blue flower; however, few bicolor varieties are available in the market. Therefore, the discovery of bicolor varieties and understanding of their mechanisms are crucial to the breeding of new varieties. In this study, we report a significant bicolor mutant with white upper and violet lower portions, with both parts belonging to a single raceme. Ionomics showed that pH and metal element contents were not responsible for the bicolor formation. Targeted metabolomics illustrated that the content of the 24 color-related compounds was significantly lower in the upper part than that in the lower part. Moreover, full-length transcriptomics combined with second-generation transcriptomics revealed 12,237 differentially expressed genes in which anthocyanin synthesis gene expression of the upper part was noted to be significantly lower than that of the lower part. Transcription factor differential expression analysis was used to describe the presence of a pair of MaMYB113a/b sequences, with low levels of expression in the upper part and high expression in the lower part. Furthermore, tobacco transformation confirmed that overexpression of MaMYB113a/b can promote anthocyanin accumulation in tobacco leaves. Accordingly, the differential expression of MaMYB113a/b contributes the formation of a bicolor mutant in Muscari latifolium. Full article

(This article belongs to the Section Molecular Plant Sciences)

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21 pages, 14902 KiB

Open AccessReview

Polyoxometalates Impact as Anticancer Agents

by Fátima Carvalho and Manuel Aureliano

Int. J. Mol. Sci. 2023, 24(5), 5043; https://doi.org/10.3390/ijms24055043 - 06 Mar 2023

Cited by 16 | Viewed by 4486

Abstract

Polyoxometalates (POMs) are oxoanions of transition metal ions, such as V, Mo, W, Nb, and Pd, forming a variety of structures with a wide range of applications. Herein, we analyzed recent studies on the effects of polyoxometalates as anticancer agents, particularly their effects [...] Read more.

Polyoxometalates (POMs) are oxoanions of transition metal ions, such as V, Mo, W, Nb, and Pd, forming a variety of structures with a wide range of applications. Herein, we analyzed recent studies on the effects of polyoxometalates as anticancer agents, particularly their effects on the cell cycle. To this end, a literature search was carried out between March and June 2022, using the keywords “polyoxometalates” and “cell cycle”. The effects of POMs on selected cell lines can be diverse, such as their effects in the cell cycle, protein expression, mitochondrial effects, reactive oxygen species (ROS) production, cell death and cell viability. The present study focused on cell viability and cell cycle arrest. Cell viability was analyzed by dividing the POMs into sections according to the constituent compound, namely polyoxovanadates (POVs), polyoxomolybdates (POMos), polyoxopaladates (POPds) and polyoxotungstates (POTs). When comparing and sorting the IC₅₀ values in ascending order, we obtained first POVs, then POTs, POPds and, finally, POMos. When comparing clinically approved drugs and POMs, better results of POMs in relation to drugs were observed in many cases, since the dose required to have an inhibitory concentration of 50% is 2 to 200 times less, depending on the POMs, highlighting that these compounds could become in the future an alternative to existing drugs in cancer therapy. Full article

(This article belongs to the Special Issue Novel Biosystems in Toxicology and Pharmacology)

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35 pages, 1530 KiB

Open AccessReview

Role of Dopamine in the Heart in Health and Disease

by Joachim Neumann, Britt Hofmann, Stefan Dhein and Ulrich Gergs

Int. J. Mol. Sci. 2023, 24(5), 5042; https://doi.org/10.3390/ijms24055042 - 06 Mar 2023

Cited by 10 | Viewed by 6475

Abstract

Dopamine has effects on the mammalian heart. These effects can include an increase in the force of contraction, and an elevation of the beating rate and the constriction of coronary arteries. Depending on the species studied, positive inotropic effects were strong, very modest, [...] Read more.

Dopamine has effects on the mammalian heart. These effects can include an increase in the force of contraction, and an elevation of the beating rate and the constriction of coronary arteries. Depending on the species studied, positive inotropic effects were strong, very modest, or absent, or even negative inotropic effects occurred. We can discern five dopamine receptors. In addition, the signal transduction by dopamine receptors and the regulation of the expression of cardiac dopamine receptors will be of interest to us, because this might be a tempting area of drug development. Dopamine acts in a species-dependent fashion on these cardiac dopamine receptors, but also on cardiac adrenergic receptors. We will discuss the utility of drugs that are currently available as tools to understand cardiac dopamine receptors. The molecule dopamine itself is present in the mammalian heart. Therefore, cardiac dopamine might act as an autocrine or paracrine compound in the mammalian heart. Dopamine itself might cause cardiac diseases. Moreover, the cardiac function of dopamine and the expression of dopamine receptors in the heart can be altered in diseases such as sepsis. Various drugs for cardiac and non-cardiac diseases are currently in the clinic that are, at least in part, agonists or antagonists at dopamine receptors. We define the research needs in order to understand dopamine receptors in the heart better. All in all, an update on the role of dopamine receptors in the human heart appears to be clinically relevant, and is thus presented here. Full article

(This article belongs to the Collection Feature Paper Collection in Biochemistry)

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10 pages, 252 KiB

Open AccessReview

Ovarian Cancer and Glutamine Metabolism

by Zacharias Fasoulakis, Antonios Koutras, Thomas Ntounis, Ioannis Prokopakis, Paraskevas Perros, Athanasios Chionis, Ioakeim Sapantzoglou, Alexandros Katrachouras, Kyriakos Konis, Athina A. Samara, Asimina Valsamaki, Vasileios-Chrysovalantis Palios, Panagiotis Symeonidis, Konstantinos Nikolettos, Athanasios Pagkalos, Sotirios Sotiriou, Marianna Theodora, Panos Antsaklis, Georgios Daskalakis and Emmanuel N. Kontomanolis

Int. J. Mol. Sci. 2023, 24(5), 5041; https://doi.org/10.3390/ijms24055041 - 06 Mar 2023

Cited by 5 | Viewed by 2326

Abstract

Cancer cells are known to have a distinct metabolic profile and to exhibit significant changes in a variety of metabolic mechanisms compared to normal cells, particularly glycolysis and glutaminolysis, in order to cover their increased energy requirements. There is mounting evidence that there [...] Read more.

Cancer cells are known to have a distinct metabolic profile and to exhibit significant changes in a variety of metabolic mechanisms compared to normal cells, particularly glycolysis and glutaminolysis, in order to cover their increased energy requirements. There is mounting evidence that there is a link between glutamine metabolism and the proliferation of cancer cells, demonstrating that glutamine metabolism is a vital mechanism for all cellular processes, including the development of cancer. Detailed knowledge regarding its degree of engagement in numerous biological processes across distinct cancer types is still lacking, despite the fact that such knowledge is necessary for comprehending the differentiating characteristics of many forms of cancer. This review aims to examine data on glutamine metabolism and ovarian cancer and identify possible therapeutic targets for ovarian cancer treatment. Full article

(This article belongs to the Special Issue Molecular and Cellular Mechanisms of Gynecologic Malignancies, Benign Diseases, and Their Medications)

14 pages, 1159 KiB

Open AccessReview

Sepsis-Associated Muscle Wasting: A Comprehensive Review from Bench to Bedside

by Ikumi Yoshihara, Yutaka Kondo, Ken Okamoto and Hiroshi Tanaka

Int. J. Mol. Sci. 2023, 24(5), 5040; https://doi.org/10.3390/ijms24055040 - 06 Mar 2023

Cited by 3 | Viewed by 4377

Abstract

Sepsis-associated muscle wasting (SAMW) is characterized by decreased muscle mass, reduced muscle fiber size, and decreased muscle strength, resulting in persistent physical disability accompanied by sepsis. Systemic inflammatory cytokines are the main cause of SAMW, which occurs in 40–70% of patients with sepsis. [...] Read more.

Sepsis-associated muscle wasting (SAMW) is characterized by decreased muscle mass, reduced muscle fiber size, and decreased muscle strength, resulting in persistent physical disability accompanied by sepsis. Systemic inflammatory cytokines are the main cause of SAMW, which occurs in 40–70% of patients with sepsis. The pathways associated with the ubiquitin–proteasome and autophagy systems are particularly activated in the muscle tissues during sepsis and may lead to muscle wasting. Additionally, expression of muscle atrophy-related genes Atrogin-1 and MuRF-1 are seemingly increased via the ubiquitin–proteasome pathway. In clinical settings, electrical muscular stimulation, physiotherapy, early mobilization, and nutritional support are used for patients with sepsis to prevent or treat SAMW. However, there are no pharmacological treatments for SAMW, and the underlying mechanisms are still unknown. Therefore, research is urgently required in this field. Full article

(This article belongs to the Special Issue Muscle Atrophy: From Bench to Bedside)

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16 pages, 4699 KiB

Open AccessArticle

Effects of Terahertz Radiation on the Aggregation of Alzheimer’s Aβ42 Peptide

by Lei Wang, Yuanyuan Cheng, Wenxia Wang, Jinwu Zhao, Yinsong Wang, Xumei Zhang, Meng Wang, Tianhe Shan and Mingxia He

Int. J. Mol. Sci. 2023, 24(5), 5039; https://doi.org/10.3390/ijms24055039 - 06 Mar 2023

Cited by 1 | Viewed by 1864

Abstract

The pathophysiology of Alzheimer’s disease is thought to be directly linked to the abnormal aggregation of β-amyloid (Aβ) in the nervous system as a common neurodegenerative disease. Consequently, researchers in many areas are actively looking for factors that affect Aβ aggregation. Numerous investigations [...] Read more.

The pathophysiology of Alzheimer’s disease is thought to be directly linked to the abnormal aggregation of β-amyloid (Aβ) in the nervous system as a common neurodegenerative disease. Consequently, researchers in many areas are actively looking for factors that affect Aβ aggregation. Numerous investigations have demonstrated that, in addition to chemical induction of Aβ aggregation, electromagnetic radiation may also affect Aβ aggregation. Terahertz waves are an emerging form of non-ionizing radiation that has the potential to affect the secondary bonding networks of biological systems, which in turn could affect the course of biochemical reactions by altering the conformation of biological macromolecules. As the primary radiation target in this investigation, the in vitro modeled Aβ42 aggregation system was examined using fluorescence spectrophotometry, supplemented by cellular simulations and transmission electron microscopy, to see how it responded to 3.1 THz radiation in various aggregation phases. The results demonstrated that in the nucleation aggregation stage, 3.1 THz electromagnetic waves promote Aβ42 monomer aggregation and that this promoting effect gradually diminishes with the exacerbation of the degree of aggregation. However, by the stage of oligomer aggregation into the original fiber, 3.1 THz electromagnetic waves exhibited an inhibitory effect. This leads us to the conclusion that terahertz radiation has an impact on the stability of the Aβ42 secondary structure, which in turn affects how Aβ42 molecules are recognized during the aggregation process and causes a seemingly aberrant biochemical response. Molecular dynamics simulation was employed to support the theory based on the aforementioned experimental observations and inferences. Full article

(This article belongs to the Special Issue Alzheimer’s Disease: Role and Structure of Soluble Oligomers)

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3 pages, 185 KiB

Open AccessEditorial

Genetic Variation in Transcription Factor Binding Sites

by Gabriel Santpere

Int. J. Mol. Sci. 2023, 24(5), 5038; https://doi.org/10.3390/ijms24055038 - 06 Mar 2023

Cited by 1 | Viewed by 1270

Abstract

The interaction between transcription factors (TFs) and DNA is the core process that determines the state of a cell’s transcriptome [...] Full article

(This article belongs to the Special Issue The Role of Genetic Variation on Transcription Factor Binding Sites in Evolution and Disease)

17 pages, 2248 KiB

Open AccessArticle

[4+2]-Cycloaddition to 5-Methylidene-Hydantoins and 5-Methylidene-2-Thiohydantoins in the Synthesis of Spiro-2-Chalcogenimidazolones

by Dmitry E. Shybanov, Maxim E. Kukushkin, Yanislav S. Hrytseniuk, Yuri K. Grishin, Vitaly A. Roznyatovsky, Viktor A. Tafeenko, Dmitry A. Skvortsov, Nikolai V. Zyk and Elena K. Beloglazkina

Int. J. Mol. Sci. 2023, 24(5), 5037; https://doi.org/10.3390/ijms24055037 - 06 Mar 2023

Cited by 3 | Viewed by 1438

Abstract

Novel hydantion and thiohydantoin-based spiro-compounds were prepared via theDiels–Alder reactions between 5-methylidene-hydantoins or 5-methylidene-2-thiohydantoins and 1,3-dienes (cyclopentadiene, cyclohexadiene, 2,3-dimethylbutadiene, isoprene). It was shown that the cycloaddition reactions proceed regioselectively and stereoselectively with the formation of exo-isomers in the reactions with cyclic dienes andthe [...] Read more.

Novel hydantion and thiohydantoin-based spiro-compounds were prepared via theDiels–Alder reactions between 5-methylidene-hydantoins or 5-methylidene-2-thiohydantoins and 1,3-dienes (cyclopentadiene, cyclohexadiene, 2,3-dimethylbutadiene, isoprene). It was shown that the cycloaddition reactions proceed regioselectively and stereoselectively with the formation of exo-isomers in the reactions with cyclic dienes andthe less sterically hindered products in the reactions with isoprene. Reactions of methylideneimidazolones with cyclopentadiene proceed viaco-heating the reactants; reactions with cyclohexadiene, 2,3-dimethylbutadiene, and isoprene require catalysis by Lewis acids. It was demonstrated that ZnI₂ is an effective catalyst in the Diels–Alder reactions of methylidenethiohydantoins with non-activated dienes. The possibility of alkylation and acylation of the obtained spiro-hydantoinsat the N(1)nitrogen atoms with PhCH₂Cl or Boc₂O and the alkylation of the spiro-thiohydantoinsat the S atoms with MeI or PhCH₂Cl in high yields have been demonstrated. The preparativetransformation of spiro-thiohydantoins into corresponding spiro-hydantoinsin mild conditions by treating with 35% aqueous H₂O₂ or nitrile oxide has been carried out. The obtained compounds show moderate cytotoxicity in the MTT test on MCF7, A549, HEK293T, and VA13 cell lines. Some of the tested compounds demonstrated some antibacterial effect against Escherichia coli (E. coli) BW25113 DTC-pDualrep2 but were almost inactive against E. coli BW25113 LPTD-pDualrep2. Full article

(This article belongs to the Special Issue Development and Synthesis of Biologically Active Compounds)

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15 pages, 51753 KiB

Open AccessArticle

Fabrication of Silane-Grafted Cellulose Nanocrystals and Their Effects on the Structural, Thermal, Mechanical, and Hysteretic Behavior of Thermoplastic Polyurethane

by Xuenan Sun, Xinze Yang, Jiajing Zhang, Bin Shang, Pei Lyu, Chunhua Zhang, Xin Liu and Liangjun Xia

Int. J. Mol. Sci. 2023, 24(5), 5036; https://doi.org/10.3390/ijms24055036 - 06 Mar 2023

Cited by 2 | Viewed by 1402

Abstract

Reinforcement of polymer nanocomposites can be achieved by the selection of the appropriate fabrication method, surface modification, and orientation of the filler. Herein, we present a nonsolvent-induced phase separation method with ternary solvents to prepare thermoplastic polyurethane (TPU) composite films with excellent mechanical [...] Read more.

Reinforcement of polymer nanocomposites can be achieved by the selection of the appropriate fabrication method, surface modification, and orientation of the filler. Herein, we present a nonsolvent-induced phase separation method with ternary solvents to prepare thermoplastic polyurethane (TPU) composite films with excellent mechanical properties using 3-Glycidyloxypropyltrimethoxysilane-modified cellulose nanocrystals (GLCNCs). ATR-IR and SEM analyses of the GLCNCs confirmed that GL was successfully coated on the surface of the nanocrystals. The incorporation of GLCNCs in TPU resulted in the enhancement of the tensile strain and toughness of pure TPU owing to the enhanced interfacial interactions between them. The GLCNC–TPU composite film had tensile strain and toughness values of 1740.42% and 90.01 MJ/m³, respectively. Additionally, GLCNC–TPU exhibited a good elastic recovery rate. CNCs were readily aligned along the fiber axis after the spinning and drawing of the composites into fibers, which further improved the mechanical properties of the composites. The stress, strain, and toughness of the GLCNC–TPU composite fiber increased by 72.60%, 10.25%, and 103.61%, respectively, compared to those of the pure TPU film. This study demonstrates a facile and effective strategy for fabricating mechanically enhanced TPU composites. Full article

(This article belongs to the Special Issue Recent Advances in Cellulose Chemistry)

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14 pages, 3136 KiB

Open AccessReview

Role of Omega-Hydroxy Ceramides in Epidermis: Biosynthesis, Barrier Integrity and Analyzing Method

by Fei Ge, Keyan Sun, Zhenlin Hu and Xin Dong

Int. J. Mol. Sci. 2023, 24(5), 5035; https://doi.org/10.3390/ijms24055035 - 06 Mar 2023

Cited by 4 | Viewed by 2141

Abstract

Attached to the outer surface of the corneocyte lipid envelope (CLE), omega-hydroxy ceramides (ω-OH-Cer) link to involucrin and function as lipid components of the stratum corneum (SC). The integrity of the skin barrier is highly dependent on the lipid components of SC, especially [...] Read more.

Attached to the outer surface of the corneocyte lipid envelope (CLE), omega-hydroxy ceramides (ω-OH-Cer) link to involucrin and function as lipid components of the stratum corneum (SC). The integrity of the skin barrier is highly dependent on the lipid components of SC, especially on ω-OH-Cer. Synthetic ω-OH-Cer supplementation has been utilized in clinical practice for epidermal barrier injury and related surgeries. However, the mechanism discussion and analyzing methods are not keeping pace with its clinical application. Though mass spectrometry (MS) is the primary choice for biomolecular analysis, method modifications for ω-OH-Cer identification are lacking in progress. Therefore, finding conclusions on ω-OH-Cer biological function, as well as on its identification, means it is vital to remind further researchers of how the following work should be done. This review summarizes the important role of ω-OH-Cer in epidermal barrier functions and the forming mechanism of ω-OH-Cer. Recent identification methods for ω-OH-Cer are also discussed, which could provide new inspirations for study on both ω-OH-Cer and skin care development. Full article

(This article belongs to the Section Molecular Neurobiology)

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20 pages, 1439 KiB

Open AccessReview

Neutrophil Extracellular Traps in Airway Diseases: Pathological Roles and Therapeutic Implications

by Ara Jo and Dae Woo Kim

Int. J. Mol. Sci. 2023, 24(5), 5034; https://doi.org/10.3390/ijms24055034 - 06 Mar 2023

Cited by 11 | Viewed by 4770

Abstract

Neutrophils are important effector cells of the innate immune response that fight pathogens by phagocytosis and degranulation. Neutrophil extracellular traps (NETs) are released into the extracellular space to defend against invading pathogens. Although NETs play a defensive role against pathogens, excessive NETs can [...] Read more.

Neutrophils are important effector cells of the innate immune response that fight pathogens by phagocytosis and degranulation. Neutrophil extracellular traps (NETs) are released into the extracellular space to defend against invading pathogens. Although NETs play a defensive role against pathogens, excessive NETs can contribute to the pathogenesis of airway diseases. NETs are known to be directly cytotoxic to the lung epithelium and endothelium, highly involved in acute lung injury, and implicated in disease severity and exacerbation. This review describes the role of NET formation in airway diseases, including chronic rhinosinusitis, and suggests that targeting NETs could be a therapeutic strategy for airway diseases. Full article

(This article belongs to the Special Issue Chronic Rhinosinusitis: Aetiology, Immunology and Treatment)

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