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Int. J. Mol. Sci., Volume 24, Issue 21 (November-1 2023) – 520 articles

Cover Story (view full-size image): Pro-inflammatory cytokines such as tumor necrosis factor alpha (TNFa) mediate the response to acute airway inflammation. In human airway smooth muscle (hASM) cells, TNFa induces an accumulation of unfolded proteins in the endoplasmic reticulum (ER), which trigger the autophosphorylation of inositol-requiring enzyme 1a (pIRE1a S724) with downstream splicing of X-box binding protein 1 (XBP1s) (ER stress response). In isolated hASM cells, we found that chemical chaperone (e.g., 4-phenylbutyric acid - 4-PBA) treatment mitigated the TNFa-induced pIRE1a S724/XBP1s ER stress response. These results indicate that chemical chaperones may be effective in treating the pathophysiology of acute airway inflammation. View this paper
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11 pages, 250 KiB  
Editorial
Cellular and Molecular Mechanisms in Oxidative Stress-Related Diseases 2.0/3.0
by Alessia Remigante and Rossana Morabito
Int. J. Mol. Sci. 2023, 24(21), 16018; https://doi.org/10.3390/ijms242116018 - 06 Nov 2023
Viewed by 795
Abstract
Oxidative stress is frequently described as the balance between the production of reactive species (including oxygen and nitrogen) in biological systems and the ability of the latter to defend itself through the sophisticated antioxidant machinery [...] Full article
13 pages, 4418 KiB  
Article
Whole-Genome Sequencing-Based Profiling of Antimicrobial Resistance Genes and Core-Genome Multilocus Sequence Typing of Campylobacter jejuni from Different Sources in Lithuania
by Jurgita Aksomaitiene, Aleksandr Novoslavskij and Mindaugas Malakauskas
Int. J. Mol. Sci. 2023, 24(21), 16017; https://doi.org/10.3390/ijms242116017 - 06 Nov 2023
Viewed by 1158
Abstract
Campylobacter jejuni is known as one of the main causative agents of gastroenteritis in humans worldwide, and the rise of antimicrobial resistance (AMR) in Campylobacter is a growing public health challenge of special concern. Whole-genome sequencing (WGS) was used to characterize genetic determinants [...] Read more.
Campylobacter jejuni is known as one of the main causative agents of gastroenteritis in humans worldwide, and the rise of antimicrobial resistance (AMR) in Campylobacter is a growing public health challenge of special concern. Whole-genome sequencing (WGS) was used to characterize genetic determinants of AMR in 53 C. jejuni isolates from dairy cattle, broiler products, wild birds, and humans in Lithuania. The WGS-based study revealed 26 C. jejuni AMR markers that conferred resistance to various antimicrobials. Genetic markers associated with resistance to beta-lactamases, tetracycline, and aminoglycosides were found in 79.3%, 28.3%, and 9.4% of C. jejuni isolates, respectively. Additionally, genetic markers associated with multidrug resistance (MDR) were found in 90.6% of C. jejuni isolates. The WGS data analysis revealed that a common mutation in the quinolone resistance-determining region (QRDR) was R285K (854G > A) at 86.8%, followed by A312T (934G > A) at 83% and T86I (257C > T) at 71.7%. The phenotypic resistance analysis performed with the agar dilution method revealed that ciprofloxacin (CIP) (90.6%), ceftriaxone (CRO) (67.9%), and tetracycline (TET) (45.3%) were the predominant AMR patterns. MDR was detected in 41.5% (22/53) of the isolates tested. Fifty-seven virulence genes were identified in all C. jejuni isolates; most of these genes were associated with motility (n = 28) and chemotaxis (n = 10). Additionally, all C. jejuni isolates harbored virulence genes related to adhesion, invasion, LOS, LPS, CPS, transportation, and CDT. In total, 16 sequence types (STs) and 11 clonal complexes (CC) were identified based on core-genome MLST (cgMLST) analysis. The data analysis revealed distinct diversity depending on phenotypic and genotypic antimicrobial resistance of C. jejuni. Full article
(This article belongs to the Special Issue Antibacterial Activity of Drug-Resistant Strains)
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16 pages, 2703 KiB  
Article
Synergy of the microRNA Ratio as a Promising Diagnosis Biomarker for Mucinous Borderline and Malignant Ovarian Tumors
by Enora Dolivet, Léopold Gaichies, Corinne Jeanne, Céline Bazille, Mélanie Briand, Mégane Vernon, Florence Giffard, Frédéric Leprêtre, Laurent Poulain, Christophe Denoyelle, Nicolas Vigneron and Raffaèle Fauvet
Int. J. Mol. Sci. 2023, 24(21), 16016; https://doi.org/10.3390/ijms242116016 - 06 Nov 2023
Viewed by 990
Abstract
Epithelial ovarian cancers (EOCs) are a heterogeneous collection of malignancies, each with their own developmental origin, clinical behavior and molecular profile. With less than 5% of EOC cases, mucinous ovarian carcinoma is a rare form with a poor prognosis and a 5-year survival [...] Read more.
Epithelial ovarian cancers (EOCs) are a heterogeneous collection of malignancies, each with their own developmental origin, clinical behavior and molecular profile. With less than 5% of EOC cases, mucinous ovarian carcinoma is a rare form with a poor prognosis and a 5-year survival of 11% for advanced stages (III/IV). At the early stages, these malignant forms are clinically difficult to distinguish from borderline (15%) and benign (80%) forms with a better prognosis due to the large size and heterogeneity of mucinous tumors. Improving their diagnosis is therefore a challenge with regard to the risk of under-treating a malignant form or of unnecessarily undertaking radical surgical excision. The involvement of microRNAs (miRNAs) in tumor progression and their potential as biomarkers of diagnosis are becoming increasingly recognized. In this study, the comparison of miRNA microarray expression profiles between malignant and borderline tumor FFPE samples identified 10 down-regulated and 5 up-regulated malignant miRNAs, which were validated by individual RT-qPCR. To overcome normalization issues and to improve the accuracy of the results, a ratio analysis combining paired up-regulated and down-regulated miRNAs was performed. Although 21/50 miRNA expression ratios were significantly different between malignant and borderline tumor samples, any ratio could perfectly discriminate the two groups. However, a combination of 14 pairs of miRNA ratios (double ratio) showed high discriminatory potential, with 100% of accuracy in distinguishing malignant and borderline ovarian tumors, which suggests that miRNAs may hold significant clinical potential as a diagnostic tool. In summary, these ratio miRNA-based signatures may help to improve the precision of histological diagnosis, likely to provide a preoperative diagnosis in order to adapt surgical procedures. Full article
(This article belongs to the Special Issue Interrelation between MicroRNA & Cancer)
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17 pages, 4519 KiB  
Article
Interrogating the Role of miR-125b and Its 3′isomiRs in Protection against Hypoxia
by Lee Lee Wong, Azizah Binti Fadzil, Qiying Chen, Miriam T. Rademaker, Christopher J. Charles, Arthur Mark Richards and Peipei Wang
Int. J. Mol. Sci. 2023, 24(21), 16015; https://doi.org/10.3390/ijms242116015 - 06 Nov 2023
Cited by 1 | Viewed by 927
Abstract
MiR-125b has therapeutic potential in the amelioration of myocardial ischemic injury. MicroRNA isomiRs, with either 5′ or 3′ addition or deletion of nucleotide(s), have been reported from next-generation sequencing data (NGS). However, due to technical challenges, validation and functional studies of isomiRs are [...] Read more.
MiR-125b has therapeutic potential in the amelioration of myocardial ischemic injury. MicroRNA isomiRs, with either 5′ or 3′ addition or deletion of nucleotide(s), have been reported from next-generation sequencing data (NGS). However, due to technical challenges, validation and functional studies of isomiRs are few. In this study, we discovered using NGS, four 3′isomiRs of miR-125b, i.e., addition of A (adenosine), along with deletions of A, AG (guanosine) and AGU (uridine) from rat and sheep heart. These findings were validated using RT-qPCR. Comprehensive functional studies were carried out in the H9C2 hypoxia model. After miR-125b, isomiRs of Plus A, Trim A, AG and AGU mimic transfection, the H9C2 cells were subjected to hypoxic challenge. As assessed using cell viability, apoptosis, CCK-8 and LDH release, miR-125b and isomiRs were all protective against hypoxia. However, Plus A and Trim A were more effective than miR-125b, whilst Trim AG and Trim AGU had far weaker effects than miR-125b. Interestingly, both the gene regulation profile and apoptotic gene validation indicated a major overlap among miR-125b, Plus A and Trim A, whilst Trims AG and AGU revealed a different profile compared to miR-125b. Conclusions: miR-125b and its 3′ isomiRs are expressed stably in the heart. miR-125b and isomiRs with addition or deletion of A might function concurrently and concordantly under specific physiological and pathophysiological conditions. In-depth understanding of isomiRs’ metabolism and function will contribute to better miRNA therapeutic drug design. Full article
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27 pages, 3408 KiB  
Review
Addressing Key Questions in Organoid Models: Who, Where, How, and Why?
by María Gómez-Álvarez, Marcos Agustina-Hernández, Emilio Francés-Herrero, Adolfo Rodríguez-Eguren, Clara Bueno-Fernandez and Irene Cervelló
Int. J. Mol. Sci. 2023, 24(21), 16014; https://doi.org/10.3390/ijms242116014 - 06 Nov 2023
Viewed by 1737
Abstract
Organoids are three-dimensional cellular structures designed to recreate the biological characteristics of the body’s native tissues and organs in vitro. There has been a recent surge in studies utilizing organoids due to their distinct advantages over traditional two-dimensional in vitro approaches. However, there [...] Read more.
Organoids are three-dimensional cellular structures designed to recreate the biological characteristics of the body’s native tissues and organs in vitro. There has been a recent surge in studies utilizing organoids due to their distinct advantages over traditional two-dimensional in vitro approaches. However, there is no consensus on how to define organoids. This literature review aims to clarify the concept of organoids and address the four fundamental questions pertaining to organoid models: (i) What constitutes organoids?—The cellular material. (ii) Where do organoids grow?—The extracellular scaffold. (iii) How are organoids maintained in vitro?—Via the culture media. (iv) Why are organoids suitable in vitro models?—They represent reproducible, stable, and scalable models for biological applications. Finally, this review provides an update on the organoid models employed within the female reproductive tract, underscoring their relevance in both basic biology and clinical applications. Full article
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19 pages, 7726 KiB  
Article
An In Silico Study for Expanding the Utility of Cannabidiol in Alzheimer’s Disease Therapeutic Development
by Kyudam Choi, Yurim Lee and Cheongwon Kim
Int. J. Mol. Sci. 2023, 24(21), 16013; https://doi.org/10.3390/ijms242116013 - 06 Nov 2023
Viewed by 1123
Abstract
Cannabidiol (CBD), a major non-psychoactive component of the cannabis plant, has shown therapeutic potential in Alzheimer’s disease (AD). In this study, we identified potential CBD targets associated with AD using a drug-target binding affinity prediction model and generated CBD analogs using a genetic [...] Read more.
Cannabidiol (CBD), a major non-psychoactive component of the cannabis plant, has shown therapeutic potential in Alzheimer’s disease (AD). In this study, we identified potential CBD targets associated with AD using a drug-target binding affinity prediction model and generated CBD analogs using a genetic algorithm combined with a molecular docking system. As a result, we identified six targets associated with AD: Endothelial NOS (ENOS), Myeloperoxidase (MPO), Apolipoprotein E (APOE), Amyloid-beta precursor protein (APP), Disintegrin and metalloproteinase domain-containing protein 10 (ADAM10), and Presenilin-1 (PSEN1). Furthermore, we generated CBD analogs for each target that optimize for all desired drug-likeness properties and physicochemical property filters, resulting in improved pIC50 values and docking scores compared to CBD. Molecular dynamics (MD) simulations were applied to analyze each target’s CBD and highest-scoring CBD analogs. The MD simulations revealed that the complexes of ENOS, MPO, and ADAM10 with CBD exhibited high conformational stability, and the APP and PSEN1 complexes with CBD analogs demonstrated even higher conformational stability and lower interaction energy compared to APP and PSEN1 complexes with CBD. These findings demonstrated the capable binding of the six identified targets with CBD and the enhanced binding stability achieved with the developed CBD analogs for each target. Full article
(This article belongs to the Special Issue Machine Learning Applications in Bioinformatics and Biomedicine)
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9 pages, 1184 KiB  
Article
Persistent Hypogammaglobulinemia after Receiving Rituximab Post-HSCT Is Not Caused by an Intrinsic B Cell Defect
by Lisa M. Ott de Bruin, Ingrid Pico-Knijnenburg, Monique M. van Ostaijen-ten Dam, Thomas J. Weitering, Dagmar Berghuis, Robbert G. M. Bredius, Arjan C. Lankester and Mirjam van der Burg
Int. J. Mol. Sci. 2023, 24(21), 16012; https://doi.org/10.3390/ijms242116012 - 06 Nov 2023
Viewed by 1429
Abstract
In the setting of hematopoietic stem cell transplantation (HSCT), Rituximab (RTX) is used for the treatment and prevention of EBV-associated post-transplantation lymphoproliferative disease or autoimmune phenomena such as autoimmune hemolytic anemia (AIHA). Persistent hypogammaglobulinemia and immunoglobulin substitution dependence has been observed in several [...] Read more.
In the setting of hematopoietic stem cell transplantation (HSCT), Rituximab (RTX) is used for the treatment and prevention of EBV-associated post-transplantation lymphoproliferative disease or autoimmune phenomena such as autoimmune hemolytic anemia (AIHA). Persistent hypogammaglobulinemia and immunoglobulin substitution dependence has been observed in several patients after RTX treatment despite the normalization of total B cell numbers. We aimed to study whether this is a B cell intrinsic phenomenon. We analyzed four patients with different primary diseases who were treated with myeloablative conditioning and matched unrelated donor HSCT who developed persistent hypogammaglobulinemia after receiving RTX treatment. They all received RTX early after HSCT to treat EBV infection or AIHA post-HSCT. All patients showed normalized total B cell numbers but absent to very low IgG positive memory B cells, and three lacked IgA positive memory B cells. All of the patients had full donor chimerism, and none had encountered graft-versus-host disease. Sorted peripheral blood naïve B cells from these patients, when stimulated with CD40L, IL21, IL10 and anti-IgM, demonstrated intact B cell differentiation including the formation of class-switched memory B cells and IgA and IgG production. Peripheral blood T cell numbers including CD4 follicular T-helper (Tfh) cells were all within the normal reference range. In conclusion, in these four HSCT patients, the persistent hypogammaglobulinemia observed after RTX cannot be attributed to an acquired intrinsic B cell problem nor to a reduction in Tfh cell numbers. Full article
(This article belongs to the Special Issue Advanced Research in Stem Cell and Exosome-Based Therapy)
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15 pages, 4104 KiB  
Article
Auraptene Enhances AMP-Activated Protein Kinase Phosphorylation and Thereby Inhibits the Proliferation, Migration and Expression of Androgen Receptors and Prostate-Specific Antigens in Prostate Cancer Cells
by Yasuyuki Akasaka, Shun Hasei, Yukino Ohata, Machi Kanna, Yusuke Nakatsu, Hideyuki Sakoda, Midori Fujishiro, Akifumi Kushiyama, Hiraku Ono, Akio Matsubara, Nobuyuki Hinata, Tomoichiro Asano and Takeshi Yamamotoya
Int. J. Mol. Sci. 2023, 24(21), 16011; https://doi.org/10.3390/ijms242116011 - 06 Nov 2023
Viewed by 1086
Abstract
Citrus hassaku extract reportedly activates AMPK. Because this extract contains an abundance of auraptene, we investigated whether pure auraptene activates AMPK and inhibits proliferation using prostate cancer cell lines. Indeed, auraptene inhibited the proliferation and migration of LNCaP cells and induced phosphorylation of [...] Read more.
Citrus hassaku extract reportedly activates AMPK. Because this extract contains an abundance of auraptene, we investigated whether pure auraptene activates AMPK and inhibits proliferation using prostate cancer cell lines. Indeed, auraptene inhibited the proliferation and migration of LNCaP cells and induced phosphorylation of AMPK or its downstream ACC in LNCaP, PC3, and HEK-293 cells, but not in DU145 cells not expressing LKB1. In addition, the mTOR-S6K pathway, located downstream from activated AMPK, was also markedly suppressed by auraptene treatment. Importantly, it was shown that auraptene reduced androgen receptor (AR) and prostate-specific antigen (PSA) expressions at both the protein and the mRNA level. This auraptene-induced downregulation of PSA was partially but significantly reversed by treatment with AMPK siRNA or the AMPK inhibitor compound C, suggesting AMPK activation to, at least partially, be causative. Finally, in DU145 cells lacking the LKB1 gene, exogenously induced LKB1 expression restored AMPK phosphorylation by auraptene, indicating the essential role of LKB1. In summary, auraptene is a potent AMPK activator that acts by elevating the AMP/ATP ratio, thereby potentially suppressing prostate cancer progression, via at least three molecular mechanisms, including suppression of the mTOR-S6K pathway, reduced lipid synthesis, and AR downregulation caused by AMPK activation. Full article
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29 pages, 2753 KiB  
Review
Unraveling the Potential of miRNAs from CSCs as an Emerging Clinical Tool for Breast Cancer Diagnosis and Prognosis
by Raquel Nogueras Pérez, Noelia Heredia-Nicolás, Laura de Lara-Peña, Julia López de Andrés, Juan Antonio Marchal, Gema Jiménez and Carmen Griñán-Lisón
Int. J. Mol. Sci. 2023, 24(21), 16010; https://doi.org/10.3390/ijms242116010 - 06 Nov 2023
Viewed by 1223
Abstract
Breast cancer (BC) is the most diagnosed cancer in women and the second most common cancer globally. Significant advances in BC research have led to improved early detection and effective therapies. One of the key challenges in BC is the presence of BC [...] Read more.
Breast cancer (BC) is the most diagnosed cancer in women and the second most common cancer globally. Significant advances in BC research have led to improved early detection and effective therapies. One of the key challenges in BC is the presence of BC stem cells (BCSCs). This small subpopulation within the tumor possesses unique characteristics, including tumor-initiating capabilities, contributes to treatment resistance, and plays a role in cancer recurrence and metastasis. In recent years, microRNAs (miRNAs) have emerged as potential regulators of BCSCs, which can modulate gene expression and influence cellular processes like BCSCs’ self-renewal, differentiation, and tumor-promoting pathways. Understanding the miRNA signatures of BCSCs holds great promise for improving BC diagnosis and prognosis. By targeting BCSCs and their associated miRNAs, researchers aim to develop more effective and personalized treatment strategies that may offer better outcomes for BC patients, minimizing tumor recurrence and metastasis. In conclusion, the investigation of miRNAs as regulators of BCSCs opens new directions for advancing BC research through the use of bioinformatics and the development of innovative therapeutic approaches. This review summarizes the most recent and innovative studies and clinical trials on the role of BCSCs miRNAs as potential tools for early diagnosis, prognosis, and resistance. Full article
(This article belongs to the Special Issue Interrelation between MicroRNA & Cancer)
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12 pages, 1394 KiB  
Article
Comparison of Evolutionary Relationships between Branchiostoma floridae, Ciona intestinalis, and Homo sapiens Globins Provide Evidence of Gene Co-Option and Convergent Evolution
by Nanako Yano, Toshifumi Minamoto, Hirosi Yamaguchi, Toshiyuki Goto and Takahito Nishikata
Int. J. Mol. Sci. 2023, 24(21), 16009; https://doi.org/10.3390/ijms242116009 - 06 Nov 2023
Viewed by 1028
Abstract
Globins have been studied as model proteins to elucidate the principles of protein evolution. This was achieved by understanding the relationship between amino acid sequence, three-dimensional structure, physicochemical properties, and physiological function. Previous molecular phylogenies of chordate globin genes revealed the monophyletic evolution [...] Read more.
Globins have been studied as model proteins to elucidate the principles of protein evolution. This was achieved by understanding the relationship between amino acid sequence, three-dimensional structure, physicochemical properties, and physiological function. Previous molecular phylogenies of chordate globin genes revealed the monophyletic evolution of urochordate globins and suggested convergent evolution. However, to provide evidence of convergent evolution, it is necessary to determine the physicochemical and functional similarities between vertebrates and urochordate globins. In this study, we determined the expression patterns of Ciona globin genes using real-time RT-PCR. Two genes (Gb-1 and Gb-2) were predominantly expressed in the branchial sac, heart, and hemocytes and were induced under hypoxia. Combined with the sequence analysis, our findings suggest that Gb-1/-2 correspond to vertebrate hemoglobin-α/-β. However, we did not find a robust similarity between Gb-3, Gb-4, and vertebrate globins. These results suggested that, even though Ciona globins obtained their unique functions differently from vertebrate globins, the two of them shared some physicochemical features and physiological functions. Our findings offer a good example for understanding the molecular mechanisms underlying gene co-option and convergence, which could lead to evolutionary innovations. Full article
(This article belongs to the Special Issue Ascidian Early Development)
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15 pages, 3691 KiB  
Article
CD38 Deficiency Alleviates Diabetic Cardiomyopathy by Coordinately Inhibiting Pyroptosis and Apoptosis
by Ling-Fang Wang, Qian Li, Ke Wen, Qi-Hang Zhao, Ya-Ting Zhang, Jia-Le Zhao, Qi Ding, Xiao-Hui Guan, Yun-Fei Xiao, Ke-Yu Deng and Hong-Bo Xin
Int. J. Mol. Sci. 2023, 24(21), 16008; https://doi.org/10.3390/ijms242116008 - 06 Nov 2023
Cited by 2 | Viewed by 1329
Abstract
Diabetic cardiomyopathy is one of the diabetes mellitus-induced cardiovascular complications that can result in heart failure in severe cases, which is characterized by cardiomyocyte apoptosis, local inflammation, oxidative stress, and myocardial fibrosis. CD38, a main hydrolase of NAD+ in mammals, plays an [...] Read more.
Diabetic cardiomyopathy is one of the diabetes mellitus-induced cardiovascular complications that can result in heart failure in severe cases, which is characterized by cardiomyocyte apoptosis, local inflammation, oxidative stress, and myocardial fibrosis. CD38, a main hydrolase of NAD+ in mammals, plays an important role in various cardiovascular diseases, according to our previous studies. However, the role of CD38 in diabetes-induced cardiomyopathy is still unknown. Here, we report that global deletion of the CD38 gene significantly prevented diabetic cardiomyopathy induced by high-fat diet plus streptozotocin (STZ) injection in CD38 knockout (CD38-KO) mice. We observed that CD38 expression was up-regulated, whereas the expression of Sirt3 was down-regulated in the hearts of diabetic mice. CD38 deficiency significantly promoted glucose metabolism and improved cardiac functions, exemplified by increased left ventricular ejection fraction and fractional shortening. In addition, we observed that CD38 deficiency markedly decreased diabetes or high glucose and palmitic acid (HG + PA)-induced pyroptosis and apoptosis in CD38 knockout hearts or cardiomyocytes, respectively. Furthermore, we found that the expression levels of Sirt3, mainly located in mitochondria, and its target gene FOXO3a were increased in CD38-deficient hearts and cardiomyocytes with CD38 knockdown under diabetic induction conditions. In conclusion, we demonstrated that CD38 deficiency protected mice from diabetes-induced diabetic cardiomyopathy by reducing pyroptosis and apoptosis via activating NAD+/Sirt3/FOXO3a signaling pathways. Full article
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12 pages, 1205 KiB  
Article
Correlational Study of Aminopeptidase Activities between Left or Right Frontal Cortex versus the Hypothalamus, Pituitary, Adrenal Axis of Spontaneously Hypertensive Rats Treated with Hypotensive or Hypertensive Agents
by Isabel Prieto, Ana Belén Segarra, Inmaculada Banegas, Magdalena Martínez-Cañamero, Raquel Durán, Francisco Vives, Germán Domínguez-Vías and Manuel Ramírez-Sánchez
Int. J. Mol. Sci. 2023, 24(21), 16007; https://doi.org/10.3390/ijms242116007 - 06 Nov 2023
Viewed by 726
Abstract
It has been suggested that the neuro-visceral integration works asymmetrically and that this asymmetry is dynamic and modifiable by physio-pathological influences. Aminopeptidases of the renin–angiotensin system (angiotensinases) have been shown to be modifiable under such conditions. This article analyzes the interactions of these [...] Read more.
It has been suggested that the neuro-visceral integration works asymmetrically and that this asymmetry is dynamic and modifiable by physio-pathological influences. Aminopeptidases of the renin–angiotensin system (angiotensinases) have been shown to be modifiable under such conditions. This article analyzes the interactions of these angiotensinases between the left or right frontal cortex (FC) and the same enzymes in the hypothalamus (HT), pituitary (PT), adrenal (AD) axis (HPA) in control spontaneously hypertensive rats (SHR), in SHR treated with a hypotensive agent in the form of captopril (an angiotensin-converting enzyme inhibitor), and in SHR treated with a hypertensive agent in the form of the L-Arginine hypertensive analogue L-NG-Nitroarginine Methyl Ester (L-NAME). In the control SHR, there were significant negative correlations between the right FC with HPA and positive correlations between the left FC and HPA. In the captopril group, the predominance of negative correlations between the right FC and HPA and positive correlations between the HPA and left FC was maintained. In the L-NAME group, a radical change in all types of interactions was observed; particularly, there was an inversion in the predominance of negative correlations between the HPA and left FC. These results indicated a better balance of neuro-visceral interactions after captopril treatment and an increase in these interactions in the hypertensive animals, especially in those treated with L-NAME. Full article
(This article belongs to the Collection State-of-the-Art Molecular Endocrinology and Metabolism in Spain)
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60 pages, 30540 KiB  
Review
Cationic Materials for Gene Therapy: A Look Back to the Birth and Development of 2,2-Bis-(hydroxymethyl)Propanoic Acid-Based Dendrimer Scaffolds
by Silvana Alfei
Int. J. Mol. Sci. 2023, 24(21), 16006; https://doi.org/10.3390/ijms242116006 - 06 Nov 2023
Cited by 2 | Viewed by 1077
Abstract
Gene therapy is extensively studied as a realistic and promising therapeutic approach for treating inherited and acquired diseases by repairing defective genes through introducing (transfection) the “healthy” genetic material in the diseased cells. To succeed, the proper DNA or RNA fragments need efficient [...] Read more.
Gene therapy is extensively studied as a realistic and promising therapeutic approach for treating inherited and acquired diseases by repairing defective genes through introducing (transfection) the “healthy” genetic material in the diseased cells. To succeed, the proper DNA or RNA fragments need efficient vectors, and viruses are endowed with excellent transfection efficiency and have been extensively exploited. Due to several drawbacks related to their use, nonviral cationic materials, including lipidic, polymeric, and dendrimer vectors capable of electrostatically interacting with anionic phosphate groups of genetic material, represent appealing alternative options to viral carriers. Particularly, dendrimers are highly branched, nanosized synthetic polymers characterized by a globular structure, low polydispersity index, presence of internal cavities, and a large number of peripheral functional groups exploitable to bind cationic moieties. Dendrimers are successful in several biomedical applications and are currently extensively studied for nonviral gene delivery. Among dendrimers, those derived by 2,2-bis(hydroxymethyl)propanoic acid (b-HMPA), having, unlike PAMAMs, a neutral polyester-based scaffold, could be particularly good-looking due to their degradability in vivo. Here, an overview of gene therapy, its objectives and challenges, and the main cationic materials studied for transporting and delivering genetic materials have been reported. Subsequently, due to their high potential for application in vivo, we have focused on the biodegradable dendrimer scaffolds, telling the history of the birth and development of b-HMPA-derived dendrimers. Finally, thanks to a personal experience in the synthesis of b-HMPA-based dendrimers, our contribution to this field has been described. In particular, we have enriched this work by reporting about the b-HMPA-based derivatives peripherally functionalized with amino acids prepared by us in recent years, thus rendering this paper original and different from the existing reviews. Full article
(This article belongs to the Special Issue Bioactive Nanoparticles: Synthesis and Potential Applications)
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15 pages, 4575 KiB  
Article
Identification and Expressional Analysis of siRNAs Responsive to Fusarium graminearum Infection in Wheat
by Kai Fu, Qianhui Wu, Ning Jiang, Sijia Hu, Hongyan Ye, Yi Hu, Lei Li, Tao Li and Zhengxi Sun
Int. J. Mol. Sci. 2023, 24(21), 16005; https://doi.org/10.3390/ijms242116005 - 06 Nov 2023
Viewed by 995
Abstract
The outbreak of Fusarium head blight (FHB) poses a serious threat to wheat production as it leads to both significant yield losses and accumulation of several mycotoxins including deoxynivalenol (DON) in the grains, which are harmful to human and livestock. To date, hundreds [...] Read more.
The outbreak of Fusarium head blight (FHB) poses a serious threat to wheat production as it leads to both significant yield losses and accumulation of several mycotoxins including deoxynivalenol (DON) in the grains, which are harmful to human and livestock. To date, hundreds of FHB-resistance-related quantitative trait loci (QTLs) have been reported, but only a few of them have been cloned and used for breeding. Small interfering RNAs (siRNA) have been reported in plants to mediate host defense against pathogens, but they have rarely been reported in wheat-FHB interaction. In order to identify the key siRNAs that can potentially be used in the improvement of resistance to FHB, siRNAs from the spikes of an FHB-resistant variety Sumai 3 and an FHB-susceptible variety of Chinese Spring (CS) were sequenced after F. graminearum infection and mock inoculation, respectively. The expression patterns of the siRNAs of interest were analyzed. A total of 4019 siRNAs of high-confidence were identified, with 131 being CS-specific, 309 Sumai 3-specific and 3071 being common in both varieties. More than 87% of these siRNAs were 24 nt in length. An overall down-regulation trend was found for siRNAs in the spikes of both varieties after being infected with F. graminearum. The expression patterns for Triticum aestivum Dicer-like 3 (TaDCL3) that synthesizes 24 nt siRNAs were validated by qRT-PCR, which were positively correlated with those of the siRNAs. A total of 85% of the differentially expressed genes putatively targeted by the siRNAs were significantly up-regulated after infection, showing a negative correlation with the overall down-regulated expression of siRNAs. Interestingly, the majority of the up-regulated genes are annotated as disease resistance. These results suggested that the inhibition of siRNA by F. graminearum up-regulated the disease resistance genes, which were putatively suppressed by siRNAs through RNA-directed DNA methylation (RdDM). Consequently, the resistant capability to F. graminearum infection was enhanced. This study provides novel clues for investigating the function of siRNA in wheat-F. graminearum interaction. Full article
(This article belongs to the Special Issue Wheat Genetics and Genomics 2.0)
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19 pages, 4536 KiB  
Article
Vasculoprotective Potential of Baicalein in Angiotensin II-Infused Abdominal Aortic Aneurysms through Inhibiting Inflammation and Oxidative Stress
by Erna Sulistyowati, Shang-En Huang, Tsung-Lin Cheng, Yu-Ying Chao, Chia-Yang Li, Ching-Wen Chang, Meng-Xuan Lin, Ming-Chung Lin and Jwu-Lai Yeh
Int. J. Mol. Sci. 2023, 24(21), 16004; https://doi.org/10.3390/ijms242116004 - 06 Nov 2023
Cited by 1 | Viewed by 1170
Abstract
Aortic wall inflammation, abnormal oxidative stress and progressive degradation of extracellular matrix proteins are the main characteristics of abdominal aortic aneurysms (AAAs). The nucleotide-binding oligomerization domain-like receptor family pyrin domain containing 3 (NLRP3) inflammasome dysregulation plays a crucial role in aortic damage and [...] Read more.
Aortic wall inflammation, abnormal oxidative stress and progressive degradation of extracellular matrix proteins are the main characteristics of abdominal aortic aneurysms (AAAs). The nucleotide-binding oligomerization domain-like receptor family pyrin domain containing 3 (NLRP3) inflammasome dysregulation plays a crucial role in aortic damage and disease progression. The first aim of this study was to examine the effect of baicalein (5,6,7-trihydroxy-2-phenyl-4H-1-benzopyran-4-one) on AAA formation in apolipoprotein E-deficient (ApoE−/−) mice. The second aim was to define whether baicalein attenuates aberrant vascular smooth muscle cell (VSMC) proliferation and inflammation in VSMC culture. For male ApoE−/− mice, a clinically relevant AAA model was randomly divided into four groups: saline infusion, baicalein intraperitoneal injection, Angiotensin II (Ang II) infusion and Ang II + baicalein. Twenty-seven days of treatment with baicalein markedly decreased Ang II-infused AAA incidence and aortic diameter, reduced collagen-fiber formation, preserved elastic structure and density and prevented smooth muscle cell contractile protein degradation. Baicalein inhibited rat VSMC proliferation and migration following the stimulation of VSMC cultures with Ang II while blocking the Ang II-inducible cell cycle progression from G0/G1 to the S phase in the synchronized cells. Cal-520 AM staining showed that baicalein decreased cellular calcium in Ang II-induced VSMCs; furthermore, a Western blot assay indicated that baicalein inhibited the expression of PCNA and significantly lowered levels of phospho-Akt and phospho-ERK, along with an increase in baicalein concentration in Ang II-induced VSMCs. Immunofluorescence staining showed that baicalein pretreatment reduced NF-κB nuclear translocation in Ang II-induced VSMCs and furthered the protein expressions of NLRP3 while ASC and caspase-1 were suppressed in a dose-dependent manner. Baicalein pretreatment upregulated Nrf2/HO-1 signaling in Ang II-induced VSMCs. Thus, 2′,7′-dichlorodihydrofluorescein diacetate (DCFH-DA) staining showed that its reactive oxygen species (ROS) production decreased, along with the baicalein pretreatment. Our overall results indicate that baicalein could have therapeutic potential in preventing aneurysm development. Full article
(This article belongs to the Special Issue Pharmacological Modulation of Oxidative Stress)
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13 pages, 2520 KiB  
Article
Paradigm Shift in Gastric Cancer Prevention: Harnessing the Potential of Aristolochia olivieri Extract
by Matteo Micucci, Anna Stella Bartoletti, Fuad O. Abdullah, Sabrina Burattini, Ilaria Versari, Matteo Canale, Federico D’Agostino, Davide Roncarati, Diletta Piatti, Gianni Sagratini, Giovanni Caprioli, Michele Mari, Michele Retini, Irene Faenza, Michela Battistelli and Sara Salucci
Int. J. Mol. Sci. 2023, 24(21), 16003; https://doi.org/10.3390/ijms242116003 - 06 Nov 2023
Viewed by 1038
Abstract
Gastric cancer, particularly adenocarcinoma, is a significant global health concern. Environmental risk factors, such as Helicobacter pylori infection and diet, play a role in its development. This study aimed to characterize the chemical composition and evaluate the in vitro antibacterial and antitumor activities [...] Read more.
Gastric cancer, particularly adenocarcinoma, is a significant global health concern. Environmental risk factors, such as Helicobacter pylori infection and diet, play a role in its development. This study aimed to characterize the chemical composition and evaluate the in vitro antibacterial and antitumor activities of an Aristolochia olivieri Colleg. ex Boiss. Leaves’ methanolic extract (AOME). Additionally, morphological changes in gastric cancer cell lines were analyzed. AOME was analyzed using HPLC-MS/MS, and its antibacterial activity against H. pylori was assessed using the broth microdilution method. MIC and MBC values were determined, and positive and negative controls were included in the evaluation. Anticancer effects were assessed through in vitro experiments using AGS, KATO-III, and SNU-1 cancer cell lines. The morphological changes were examined through SEM and TEM analyses. AOME contained several compounds, including caffeic acid, rutin, and hyperoside. The extract displayed significant antimicrobial effects against H. pylori, with consistent MIC and MBC values of 3.70 ± 0.09 mg/mL. AOME reduced cell viability in all gastric cancer cells in a dose- and time-dependent manner. Morphological analyses revealed significant ultrastructural changes in all tumor cell lines, suggesting the occurrence of cellular apoptosis. This study demonstrated that AOME possesses antimicrobial activity against H. pylori and potent antineoplastic properties in gastric cancer cell lines. AOME holds promise as a natural resource for innovative nutraceutical approaches in gastric cancer management. Further research and in vivo studies are warranted to validate its potential clinical applications. Full article
(This article belongs to the Special Issue Helicobacter: Infection, Diagnosis and Treatment 2.0)
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18 pages, 2368 KiB  
Article
Exploring the Effects of Rearing Densities on Epigenetic Modifications in the Zebrafish Gonads
by Alejandro Valdivieso, Marta Caballero-Huertas, Javier Moraleda-Prados, Francesc Piferrer and Laia Ribas
Int. J. Mol. Sci. 2023, 24(21), 16002; https://doi.org/10.3390/ijms242116002 - 06 Nov 2023
Viewed by 1268
Abstract
Rearing density directly impacts fish welfare, which, in turn, affects productivity in aquaculture. Previous studies have indicated that high-density rearing during sexual development in fish can induce stress, resulting in a tendency towards male-biased sex ratios in the populations. In recent years, research [...] Read more.
Rearing density directly impacts fish welfare, which, in turn, affects productivity in aquaculture. Previous studies have indicated that high-density rearing during sexual development in fish can induce stress, resulting in a tendency towards male-biased sex ratios in the populations. In recent years, research has defined the relevance of the interactions between the environment and epigenetics playing a key role in the final phenotype. However, the underlying epigenetic mechanisms of individuals exposed to confinement remain elucidated. By using zebrafish (Danio rerio), the DNA methylation promotor region and the gene expression patterns of six genes, namely dnmt1, cyp19a1a, dmrt1, cyp11c1, hsd17b1, and hsd11b2, involved in the DNA maintenance methylation, reproduction, and stress were assessed. Zebrafish larvae were subjected to two high-density conditions (9 and 66 fish/L) during two periods of overlapping sex differentiation of this species (7 to 18 and 18 to 45 days post-fertilization, dpf). Results showed a significant masculinization in the populations of fish subjected to high densities from 18 to 45 dpf. In adulthood, the dnmt1 gene was differentially hypomethylated in ovaries and its expression was significantly downregulated in the testes of fish exposed to high-density. Further, the cyp19a1a gene showed downregulation of gene expression in the ovaries of fish subjected to elevated density, as previously observed in other studies. We proposed dnmt1 as a potential testicular epimarker and the expression of ovarian cyp19a1a as a potential biomarker for predicting stress originated from high densities during the early stages of development. These findings highlight the importance of rearing densities by long-lasting effects in adulthood conveying cautions for stocking protocols in fish hatcheries. Full article
(This article belongs to the Special Issue Fish Genomics and Developmental Biology)
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27 pages, 11876 KiB  
Article
Targeting NADPH Oxidase and Integrin α5β1 to Inhibit Neutrophil Extracellular Traps-Mediated Metastasis in Colorectal Cancer
by Wenyuan Zhu, Siqi Yang, Delan Meng, Qingsong Wang and Jianguo Ji
Int. J. Mol. Sci. 2023, 24(21), 16001; https://doi.org/10.3390/ijms242116001 - 06 Nov 2023
Cited by 1 | Viewed by 1166
Abstract
Metastasis leads to a high mortality rate in colorectal cancer (CRC). Increased neutrophil extracellular traps (NETs) formation is one of the main causes of metastasis. However, the mechanism of NETs-mediated metastasis remains unclear and effective treatments are lacking. In this study, we found [...] Read more.
Metastasis leads to a high mortality rate in colorectal cancer (CRC). Increased neutrophil extracellular traps (NETs) formation is one of the main causes of metastasis. However, the mechanism of NETs-mediated metastasis remains unclear and effective treatments are lacking. In this study, we found neutrophils from CRC patients have enhanced NETs formation capacity and increased NETs positively correlate with CRC progression. By quantitative proteomic analysis of clinical samples and cell lines, we found that decreased secreted protein acidic and rich in cysteine (SPARC) results in massive NETs formation and integrin α5β1 is the hub protein of NETs-tumor cell interaction. Mechanistically, SPARC regulates the activation of the nicotinamide adenine dinucleotide phosphate oxidase (NADPH oxidase) pathway by interacting with the receptor for activated C kinase 1 (RACK1). Over-activated NADPH oxidase generates more reactive oxygen species (ROS), leading to the release of NETs. Then, NETs upregulate the expression of integrin α5β1 in tumor cells, which enhances adhesion and activates the downstream signaling pathways to promote proliferation and migration. The combination of NADPH oxidase inhibitor diphenyleneiodonium chloride (DPI) and integrin α5β1 inhibitor ATN-161 (Ac-PHSCN-NH2) effectively suppresses tumor progression in vivo. Our work reveals the mechanistic link between NETs and tumor progression and suggests a combination therapy against NETs-mediated metastasis for CRC. Full article
(This article belongs to the Section Molecular Biology)
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13 pages, 1892 KiB  
Article
Integrating Embeddings from Multiple Protein Language Models to Improve Protein O-GlcNAc Site Prediction
by Suresh Pokharel, Pawel Pratyush, Hamid D. Ismail, Junfeng Ma and Dukka B. KC
Int. J. Mol. Sci. 2023, 24(21), 16000; https://doi.org/10.3390/ijms242116000 - 06 Nov 2023
Cited by 1 | Viewed by 1878
Abstract
O-linked β-N-acetylglucosamine (O-GlcNAc) is a distinct monosaccharide modification of serine (S) or threonine (T) residues of nucleocytoplasmic and mitochondrial proteins. O-GlcNAc modification (i.e., O-GlcNAcylation) is involved in the regulation of diverse cellular processes, including transcription, epigenetic [...] Read more.
O-linked β-N-acetylglucosamine (O-GlcNAc) is a distinct monosaccharide modification of serine (S) or threonine (T) residues of nucleocytoplasmic and mitochondrial proteins. O-GlcNAc modification (i.e., O-GlcNAcylation) is involved in the regulation of diverse cellular processes, including transcription, epigenetic modifications, and cell signaling. Despite the great progress in experimentally mapping O-GlcNAc sites, there is an unmet need to develop robust prediction tools that can effectively locate the presence of O-GlcNAc sites in protein sequences of interest. In this work, we performed a comprehensive evaluation of a framework for prediction of protein O-GlcNAc sites using embeddings from pre-trained protein language models. In particular, we compared the performance of three protein sequence-based large protein language models (pLMs), Ankh, ESM-2, and ProtT5, for prediction of O-GlcNAc sites and also evaluated various ensemble strategies to integrate embeddings from these protein language models. Upon investigation, the decision-level fusion approach that integrates the decisions of the three embedding models, which we call LM-OGlcNAc-Site, outperformed the models trained on these individual language models as well as other fusion approaches and other existing predictors in almost all of the parameters evaluated. The precise prediction of O-GlcNAc sites will facilitate the probing of O-GlcNAc site-specific functions of proteins in physiology and diseases. Moreover, these findings also indicate the effectiveness of combined uses of multiple protein language models in post-translational modification prediction and open exciting avenues for further research and exploration in other protein downstream tasks. LM-OGlcNAc-Site’s web server and source code are publicly available to the community. Full article
(This article belongs to the Special Issue Glycoconjugates Function and Metabolism)
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12 pages, 3882 KiB  
Article
Branched-Chain Amino Acid Assembly into Amyloid-like Fibrils Provides a New Paradigm for Maple Syrup Urine Disease Pathology
by Topaz Kreiser, Ilana Sogolovsky-Bard, Dor Zaguri, Shira Shaham-Niv, Dana Laor Bar-Yosef and Ehud Gazit
Int. J. Mol. Sci. 2023, 24(21), 15999; https://doi.org/10.3390/ijms242115999 - 06 Nov 2023
Viewed by 920
Abstract
Inborn error of metabolism disorders (IEMs) are a family of diseases resulting from single-gene mutations that lead to the accumulation of metabolites that are usually toxic or interfere with normal cell function. The etiological link between metabolic alteration and the symptoms of IEMs [...] Read more.
Inborn error of metabolism disorders (IEMs) are a family of diseases resulting from single-gene mutations that lead to the accumulation of metabolites that are usually toxic or interfere with normal cell function. The etiological link between metabolic alteration and the symptoms of IEMs is still elusive. Several metabolites, which accumulate in IEMs, were shown to self-assemble to form ordered structures. These structures display the same biophysical, biochemical, and biological characteristics as proteinaceous amyloid fibrils. Here, we have demonstrated, for the first time, the ability of each of the branched-chain amino acids (BCAAs) that accumulate in maple syrup urine disease (MSUD) to self-assemble into amyloid-like fibrils depicted by characteristic morphology, binding to indicative amyloid-specific dyes and dose-dependent cytotoxicity by a late apoptosis mechanism. We could also detect the presence of the assemblies in living cells. In addition, by employing several in vitro techniques, we demonstrated the ability of known polyphenols to inhibit the formation of the BCAA fibrils. Our study implies that BCAAs possess a pathological role in MSUD, extends the paradigm-shifting concept regarding the toxicity of metabolite amyloid-like structures, and suggests new pathological targets that may lead to highly needed novel therapeutic opportunities for this orphan disease. Full article
(This article belongs to the Special Issue Pathological and Functional Amyloid Fibrils 2.0)
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16 pages, 964 KiB  
Review
Measurement of Cardiac-Specific Biomarkers in the Emergency Department: New Insight in Risk Evaluation
by Nadia Aspromonte, Martina Zaninotto, Alberto Aimo, Isabella Fumarulo, Mario Plebani and Aldo Clerico
Int. J. Mol. Sci. 2023, 24(21), 15998; https://doi.org/10.3390/ijms242115998 - 06 Nov 2023
Viewed by 1246
Abstract
The aim of this article review is to analyze some models and clinical issues related to the implementation of accelerated diagnostic protocols based on specific cardiac biomarkers in patients admitted to the emergency department (ED) with symptoms compatible with acute cardiac disorders. Four [...] Read more.
The aim of this article review is to analyze some models and clinical issues related to the implementation of accelerated diagnostic protocols based on specific cardiac biomarkers in patients admitted to the emergency department (ED) with symptoms compatible with acute cardiac disorders. Four specific clinical issues will be discussed in detail: (a) pathophysiological and clinical interpretations of circulating hs-cTnI and hs-cTnT levels; (b) the clinical relevance and estimation of the biological variation of biomarkers in patients admitted to the ED with acute and severe diseases; (c) the role and advantages of the point-of-care testing (POCT) methods for cardiac-specific biomarkers in pre-hospital and hospital clinical practice; and (d) the clinical role of specific cardiac biomarkers in patients with acute heart failure (AHF). In order to balance the risk between a hasty discharge versus the potential harms caused by a cardiac assessment in patients admitted to the ED with suspected acute cardiovascular disease, the measurement of specific cardiac biomarkers is essential for the early identification of the presence of myocardial dysfunction and/or injury and to significantly reduce the length and costs of hospitalization. Moreover, specific cardiac biomarkers (especially hs-cTnI and hs-cTnT) are useful predictors of mortality and major adverse cardiovascular events (MACE) in patients admitted to the ED with suspected acute cardiovascular disease. To guide the implementation of the most rapid algorithms for the diagnosis of Non-ST-Elevation Myocardial Infarction (NSTEMI) into routine clinical practice, clinical scientific societies and laboratory medicine societies should promote collaborative studies specifically designed for the evaluation of the analytical performance and, especially, the cost/benefit ratio resulting from the use of these clinical protocols and POCT methods in the ED clinical practice. Full article
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14 pages, 2214 KiB  
Article
Modelled-Microgravity Reduces Virulence Factor Production in Staphylococcus aureus through Downregulation of agr-Dependent Quorum Sensing
by Macauley J. Green, Ewan J. Murray, Paul Williams, Amir M. Ghaemmaghami, Jonathan W. Aylott and Philip M. Williams
Int. J. Mol. Sci. 2023, 24(21), 15997; https://doi.org/10.3390/ijms242115997 - 06 Nov 2023
Viewed by 1021
Abstract
Bacterial contamination during space missions is problematic for human health and damages filters and other vital support systems. Staphylococcus aureus is both a human commensal and an opportunistic pathogen that colonizes human tissues and causes acute and chronic infections. Virulence and colonization factors [...] Read more.
Bacterial contamination during space missions is problematic for human health and damages filters and other vital support systems. Staphylococcus aureus is both a human commensal and an opportunistic pathogen that colonizes human tissues and causes acute and chronic infections. Virulence and colonization factors are positively and negatively regulated, respectively, by bacterial cell-to-cell communication (quorum sensing) via the agr (accessory gene regulator) system. When cultured under low-shear modelled microgravity conditions (LSMMG), S. aureus has been reported to maintain a colonization rather than a pathogenic phenotype. Here, we show that the modulation of agr expression via reduced production of autoinducing peptide (AIP) signal molecules was responsible for this behavior. In an LSMMG environment, the S. aureus strains JE2 (methicillin-resistant) and SH1000 (methicillin-sensitive) both exhibited reduced cytotoxicity towards the human leukemia monocytic cell line (THP-1) and increased fibronectin binding. Using S. aureus agrP3::lux reporter gene fusions and mass spectrometry to quantify the AIP concentrations, the activation of agr, which depends on the binding of AIP to the transcriptional regulator AgrC, was delayed in the strains with an intact autoinducible agr system. This was because AIP production was reduced under these growth conditions compared with the ground controls. Under LSMMG, S. aureus agrP3::lux reporter strains that cannot produce endogenous AIPs still responded to exogenous AIPs. Provision of exogenous AIPs to S. aureus USA300 during microgravity culture restored the cytotoxicity of culture supernatants for the THP-1 cells. These data suggest that microgravity does not affect AgrC-AIP interactions but more likely the generation of AIPs. Full article
(This article belongs to the Special Issue Cellular and Molecular Signaling Meet the Space Environment 2.0)
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16 pages, 3642 KiB  
Article
Stimulation of the Pro-Resolving Receptor Fpr2 Reverses Inflammatory Microglial Activity by Suppressing NFκB Activity
by Edward S. Wickstead, Bradley T. Elliott, Sarah Pokorny, Christopher Biggs, Stephen J. Getting and Simon McArthur
Int. J. Mol. Sci. 2023, 24(21), 15996; https://doi.org/10.3390/ijms242115996 - 06 Nov 2023
Cited by 1 | Viewed by 1315
Abstract
Neuroinflammation driven primarily by microglia directly contributes to neuronal death in many neurodegenerative diseases. Classical anti-inflammatory approaches aim to suppress pro-inflammatory mediator production, but exploitation of inflammatory resolution may also be of benefit. A key driver of peripheral inflammatory resolution, formyl peptide receptor [...] Read more.
Neuroinflammation driven primarily by microglia directly contributes to neuronal death in many neurodegenerative diseases. Classical anti-inflammatory approaches aim to suppress pro-inflammatory mediator production, but exploitation of inflammatory resolution may also be of benefit. A key driver of peripheral inflammatory resolution, formyl peptide receptor 2 (Fpr2), is expressed by microglia, but its therapeutic potential in neurodegeneration remains unclear. Here, we studied whether targeting of Fpr2 could reverse inflammatory microglial activation induced by the potent bacterial inflammogen lipopolysaccharide (LPS). Exposure of murine primary or immortalised BV2 microglia to LPS triggered pro-inflammatory phenotypic change and activation of ROS production, effects significantly attenuated by subsequent treatment with the Fpr2 agonist C43. Mechanistic studies showed C43 to act through p38 MAPK phosphorylation and reduction of LPS-induced NFκB nuclear translocation via prevention of IκBα degradation. Here, we provide proof-of-concept data highlighting Fpr2 as a potential target for control of microglial pro-inflammatory activity, suggesting that it may be a promising therapeutic target for the treatment of neuroinflammatory disease. Full article
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34 pages, 6220 KiB  
Review
Application of Luteolin in Neoplasms and Nonneoplastic Diseases
by Katarzyna Rakoczy, Justyna Kaczor, Adam Sołtyk, Natalia Szymańska, Jakub Stecko, Jakub Sleziak, Julita Kulbacka and Dagmara Baczyńska
Int. J. Mol. Sci. 2023, 24(21), 15995; https://doi.org/10.3390/ijms242115995 - 06 Nov 2023
Viewed by 1825
Abstract
Researchers are amazed at the multitude of biological effects of 3′,4′,5,7-tetrahydroxyflavone, more commonly known as luteolin, as it simultaneously has antioxidant and pro-oxidant, as well as antimicrobial, anti-inflammatory, and cancer-preventive, properties. The anticancer properties of luteolin constitute a mosaic of pathways due to [...] Read more.
Researchers are amazed at the multitude of biological effects of 3′,4′,5,7-tetrahydroxyflavone, more commonly known as luteolin, as it simultaneously has antioxidant and pro-oxidant, as well as antimicrobial, anti-inflammatory, and cancer-preventive, properties. The anticancer properties of luteolin constitute a mosaic of pathways due to which this flavonoid influences cancer cells. Not only is it able to induce apoptosis and inhibit cancer cell proliferation, but it also suppresses angiogenesis and metastasis. Moreover, luteolin succeeds in cancer cell sensitization to therapeutically induced cytotoxicity. Nevertheless, apart from its promising role in chemoprevention, luteolin exhibits numerous potential utilizations in patients with conditions other than neoplasms, which include inflammatory skin diseases, diabetes mellitus, and COVID-19. This review aims to present the multidimensionality of the luteolin’s impact on both neoplastic and nonneoplastic diseases. When it comes to neoplasms, we intend to describe the complexity of the molecular mechanisms that underlay luteolin’s anticancer effectiveness, as well as to prove the usefulness of integrating this flavonoid in cancer therapy via the analysis of recent research on breast, colon, and lung cancer. Regarding nonneoplastic diseases, this review aims to emphasize the importance of researching the potential of luteolin in areas such as diabetology, virology, and dermatology as it summarizes the most important discoveries in those fields regarding its application. Full article
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10 pages, 1217 KiB  
Article
Regulatory Roles of Histone Deacetylation in Metabolic Stress-Induced Expression of Caspase Recruitment Domain-Containing Protein 9 (CARD9) in Pancreatic β-Cells
by Mirabela Hali, Nelson Pinto, Noah Gleason and Anjaneyulu Kowluru
Int. J. Mol. Sci. 2023, 24(21), 15994; https://doi.org/10.3390/ijms242115994 - 06 Nov 2023
Viewed by 1484
Abstract
CARD9, a scaffolding protein, has been implicated in the pathogenesis of metabolic diseases, including obesity and diabetes. We recently reported novel roles for CARD9 in islet β-cell dysregulation under duress of gluco (HG)- and glucolipotoxic (GLT) stress. CARD9 expression was also increased in [...] Read more.
CARD9, a scaffolding protein, has been implicated in the pathogenesis of metabolic diseases, including obesity and diabetes. We recently reported novel roles for CARD9 in islet β-cell dysregulation under duress of gluco (HG)- and glucolipotoxic (GLT) stress. CARD9 expression was also increased in β-cells following exposure to HG and GLT stress. The current study is aimed at understanding the putative roles of histone deacetylation in HG- and GLT-induced expression of CARD9. Using two structurally distinct inhibitors of histone deacetylases (HDACs), namely trichostatin (TSA) and suberoylanilide hydroxamic acid (SAHA), we provide the first evidence to suggest that the increased expression of CARD9 seen under duress of HG and GLT stress is under the regulatory control of histone deacetylation. Interestingly, the expression of protein kinase Cδ (PKCδ), a known upstream regulator of CARD9 activation, is also increased under conditions of metabolic stress. However, it is resistant to TSA and SAHA, suggesting that it is not regulated via histone deacetylation. Based on these data, we propose that targeting the appropriate HDACs, which mediate the expression (and function) of CARD9, might be the next step to further enhance our current understanding of the roles of CARD9 in islet dysfunction under metabolic stress and diabetes. Full article
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21 pages, 5709 KiB  
Article
Study on the Treatment of ITP Mice with IVIG Sourced from Distinct Sex-Special Plasma (DSP-IVIG)
by Wei Zhang, Xin Yuan, Zongkui Wang, Jixuan Xu, Shengliang Ye, Peng Jiang, Xi Du, Fengjuan Liu, Fangzhao Lin, Rong Zhang, Li Ma and Changqing Li
Int. J. Mol. Sci. 2023, 24(21), 15993; https://doi.org/10.3390/ijms242115993 - 06 Nov 2023
Cited by 1 | Viewed by 1322
Abstract
Intravenous immunoglobulin (IVIG) is a first-line drug prepared from human plasma for the treatment of autoimmune diseases (AIDs), especially immune thrombocytopenia (ITP). Significant differences exist in protein types and expression levels between male and female plasma, and the prevalence of autoimmune diseases varies [...] Read more.
Intravenous immunoglobulin (IVIG) is a first-line drug prepared from human plasma for the treatment of autoimmune diseases (AIDs), especially immune thrombocytopenia (ITP). Significant differences exist in protein types and expression levels between male and female plasma, and the prevalence of autoimmune diseases varies between sexes. The present study seeks to explore potential variations in IVIG sourced from distinct sex-specific plasma (DSP-IVIG), including IVIG sourced from female plasma (F-IVIG), IVIG sourced from male plasma (M-IVIG), and IVIG sourced from a blend of male and female plasma (Mix-IVIG). To address this question, we used an ITP mouse model and a monocyte–macrophage inflammation model treated with DSP IVIG. The analysis of proteomics in mice suggested that the pathogenesis and treatment of ITP may involve FcγRs mediated phagocytosis, apoptosis, Th17, cytokines, chemokines, and more. Key indicators, including the mouse spleen index, CD16+ macrophages, M1, M2, IL-6, IL-27, and IL-13, all indicated that the efficacy in improving ITP was highest for M-IVIG. Subsequent cell experiments revealed that M-IVIG exhibited a more potent ability to inhibit monocyte phagocytosis. It induced more necrotic M2 cells and fewer viable M2, resulting in weaker M2 phagocytosis. M-IVIG also demonstrated superiority in the downregulation of surface makers CD36, CD68, and CD16 on M1 macrophages, a weaker capacity to activate complement, and a stronger binding ability to FcγRs on the THP-1 surface. In summary, DSP-IVIG effectively mitigated inflammation in ITP mice and monocytes and macrophages. However, M-IVIG exhibited advantages in improving the spleen index, regulating the number and typing of M1 and M2 macrophages, and inhibiting macrophage-mediated inflammation compared to F-IVIG and Mix-IVIG. Full article
(This article belongs to the Special Issue Autoimmune Diseases: A Swing Dance of Immune Cells 2.0)
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24 pages, 1139 KiB  
Review
“Alphabet” Selenoproteins: Their Characteristics and Physiological Roles
by Carmen Beatrice Dogaru, Corina Muscurel, Carmen Duță and Irina Stoian
Int. J. Mol. Sci. 2023, 24(21), 15992; https://doi.org/10.3390/ijms242115992 - 06 Nov 2023
Cited by 1 | Viewed by 1397
Abstract
Selenium (Se) is a metalloid that is recognized as one of the vital trace elements in our body and plays multiple biological roles, largely mediated by proteins containing selenium—selenoproteins. Selenoproteins mainly have oxidoreductase functions but are also involved in many different molecular signaling [...] Read more.
Selenium (Se) is a metalloid that is recognized as one of the vital trace elements in our body and plays multiple biological roles, largely mediated by proteins containing selenium—selenoproteins. Selenoproteins mainly have oxidoreductase functions but are also involved in many different molecular signaling pathways, physiological roles, and complex pathogenic processes (including, for example, teratogenesis, neurodegenerative, immuno-inflammatory, and obesity development). All of the selenoproteins contain one selenocysteine (Sec) residue, with only one notable exception, the selenoprotein P (SELENOP), which has 10 Sec residues. Although these mechanisms have been studied intensely and in detail, the characteristics and functions of many selenoproteins remain unknown. This review is dedicated to the recent data describing the identity and the functions of several selenoproteins that are less known than glutathione peroxidases (Gpxs), iodothyronine deiodinases (DIO), thioredoxin reductases (TRxRs), and methionine sulfoxide reductases (Msrs) and which are named after alphabetical letters (i.e., F, H, I, K, M, N, O, P, R, S, T, V, W). These “alphabet” selenoproteins are involved in a wide range of physiological and pathogenetic processes such as antioxidant defense, anti-inflammation, anti-apoptosis, regulation of immune response, regulation of oxidative stress, endoplasmic reticulum (ER) stress, immune and inflammatory response, and toxin antagonism. In selenium deficiency, the “alphabet” selenoproteins are affected hierarchically, both with respect to the particular selenoprotein and the tissue of expression, as the brain or endocrine glands are hardly affected by Se deficiency due to their equipment with LRP2 or LRP8. Full article
(This article belongs to the Topic Metalloproteins and Metalloenzymes)
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12 pages, 3805 KiB  
Article
Effects of Factors Influencing Scar Formation on the Scar Microbiome in Patients with Burns
by Yeongyun Jung, Hui Song Cui, Eun Kyung Lee, So Young Joo, Cheong Hoon Seo and Yoon Soo Cho
Int. J. Mol. Sci. 2023, 24(21), 15991; https://doi.org/10.3390/ijms242115991 - 06 Nov 2023
Viewed by 1076
Abstract
Skin microbiome dysbiosis has deleterious effects, and the factors influencing burn scar formation, which affects the scar microbiome composition, are unknown. Therefore, we investigated the effects of various factors influencing scar formation on the scar microbiome composition in patients with burns. We collected [...] Read more.
Skin microbiome dysbiosis has deleterious effects, and the factors influencing burn scar formation, which affects the scar microbiome composition, are unknown. Therefore, we investigated the effects of various factors influencing scar formation on the scar microbiome composition in patients with burns. We collected samples from the burn scar center and margin of 40 patients with burns, subgrouped by factors influencing scar formation. Scar microbiome composition-influencing factors were analyzed using univariate and multivariate analyses. Skin graft, hospitalization period, intensive care unit (ICU) admission, burn degree, sex, age, total body surface area burned (TBSA), time post-injury, transepidermal water loss, the erythrocyte sedimentation rate, and C-reactive protein levels were identified as factors influencing burn scar microbiome composition. Only TBSA and ICU admission were associated with significant differences in alpha diversity. Alpha diversity significantly decreased with an increase in TBSA and was significantly lower in patients admitted to the ICU than in those not admitted to the ICU. Furthermore, we identified microorganisms associated with various explanatory variables. Our cross-sectional systems biology study confirmed that various variables influence the scar microbiome composition in patients with burns, each of which is associated with various microorganisms. Therefore, these factors should be considered during the application of skin microbiota for burn scar management. Full article
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14 pages, 10731 KiB  
Article
Chitinase 3-like-1 Expression in the Microenvironment Is Associated with Neutrophil Infiltration in Bladder Cancer
by Ling-Yi Xiao, Yu-Li Su, Shih-Yu Huang, Yi-Hua Chen and Po-Ren Hsueh
Int. J. Mol. Sci. 2023, 24(21), 15990; https://doi.org/10.3390/ijms242115990 - 05 Nov 2023
Cited by 1 | Viewed by 1147
Abstract
Bladder cancer is a common cancer with well-established therapeutic strategies. However, recurrence occurs in 50% of patients with non-muscle-invasive bladder cancer, and 20% of patients progress to muscle-invasive bladder cancer. The 5-year survival rate for muscle-invasive bladder cancer patients is disappointingly low, ranging [...] Read more.
Bladder cancer is a common cancer with well-established therapeutic strategies. However, recurrence occurs in 50% of patients with non-muscle-invasive bladder cancer, and 20% of patients progress to muscle-invasive bladder cancer. The 5-year survival rate for muscle-invasive bladder cancer patients is disappointingly low, ranging from 36% to 48%. A molecular marker of interest is chitinase 3-like-1 (CHI3L1), which is elevated in various cancers, including bladder cancer. In addition to its role in cancer cells, CHI3L1 also has regulatory abilities in immune cells. Neutrophil infiltration has been shown to positively correlate with overall survival, progression-free survival, and relapse-free survival in bladder cancer patients. However, the relationship between CHI3L1 and neutrophils remain poorly understood. Therefore, this study investigated the relationship between CHI3L1 level and protumor neutrophil infiltration in bladder cancer. We analyzed the GSE128959 dataset and the data of a bladder cancer cohort undergoing chemotherapy. We observed higher expression of CHI3L1 in bladder cancer patients with invasive or chemotherapy-resistance. Our results revealed a positive correlation between CHI3L1 expression and protumor neutrophil infiltration. Elevated CHI3L1 expression was associated with genes which were related to the recruitment and infiltration of neutrophils. Consequently, CHI3L1 may serve as a novel evaluation factor for the degree of neutrophil infiltration in advanced bladder cancer in those scheduled for chemotherapy. Full article
(This article belongs to the Section Molecular Oncology)
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16 pages, 2604 KiB  
Article
Mice Lacking PLAP-1/Asporin Show Alteration of Periodontal Ligament Structures and Acceleration of Bone Loss in Periodontitis
by Masaki Kinoshita, Satoru Yamada, Junichi Sasaki, Shigeki Suzuki, Tetsuhiro Kajikawa, Tomoaki Iwayama, Chiharu Fujihara, Satoshi Imazato and Shinya Murakami
Int. J. Mol. Sci. 2023, 24(21), 15989; https://doi.org/10.3390/ijms242115989 - 05 Nov 2023
Cited by 2 | Viewed by 1057
Abstract
Periodontal ligament-associated protein 1 (PLAP-1), also known as Asporin, is an extracellular matrix protein expressed in the periodontal ligament and plays a crucial role in periodontal tissue homeostasis. Our previous research demonstrated that PLAP-1 may inhibit TLR2/4-mediated inflammatory responses, thereby exerting a protective [...] Read more.
Periodontal ligament-associated protein 1 (PLAP-1), also known as Asporin, is an extracellular matrix protein expressed in the periodontal ligament and plays a crucial role in periodontal tissue homeostasis. Our previous research demonstrated that PLAP-1 may inhibit TLR2/4-mediated inflammatory responses, thereby exerting a protective function against periodontitis. However, the precise roles of PLAP-1 in the periodontal ligament (PDL) and its relationship to periodontitis have not been fully explored. In this study, we employed PLAP-1 knockout mice to investigate its roles and contributions to PDL tissue and function in a ligature-induced periodontitis model. Mandibular bone samples were collected from 10-week-old male C57BL/6 (WT) and PLAP-1 knockout (KO) mice. These samples were analyzed through micro-computed tomography (μCT) scanning, hematoxylin and eosin (HE) staining, picrosirius red staining, and fluorescence immunostaining using antibodies targeting extracellular matrix proteins. Additionally, the structure of the PDL collagen fibrils was examined using transmission electron microscopy (TEM). We also conducted tooth extraction and ligature-induced periodontitis models using both wild-type and PLAP-1 KO mice. PLAP-1 KO mice did not exhibit any changes in alveolar bone resorption up to the age of 10 weeks, but they did display an enlarged PDL space, as confirmed by μCT and histological analyses. Fluorescence immunostaining revealed increased expression of extracellular matrix proteins, including Col3, BGN, and DCN, in the PDL tissues of PLAP-1 KO mice. TEM analysis demonstrated an increase in collagen diameter within the PDL of PLAP-1 KO mice. In line with these findings, the maximum stress required for tooth extraction was significantly lower in PLAP-1 KO mice in the tooth extraction model compared to WT mice (13.89 N ± 1.34 and 16.51 N ± 1.31, respectively). In the ligature-induced periodontitis model, PLAP-1 knockout resulted in highly severe alveolar bone resorption, with a higher number of collagen fiber bundle tears and significantly more osteoclasts in the periodontium. Our results demonstrate that mice lacking PLAP-1/Asporin show alteration of periodontal ligament structures and acceleration of bone loss in periodontitis. This underscores the significant role of PLAP-1 in maintaining collagen fibrils in the PDL and suggests the potential of PLAP-1 as a therapeutic target for periodontal diseases. Full article
(This article belongs to the Special Issue Wound Repair and Regeneration 2023)
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