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Int. J. Mol. Sci., Volume 23, Issue 1 (January-1 2022) – 578 articles

Cover Story (view full-size image): Polyethylene terephthalate (PET) is one of the most abundant polyesters in the world. Only 25–30% of PET waste is recycled, while most of this polymer is incinerated or disposed of in landfills, posing several threats to ecosystems and human health. The discovery and subsequent improvement by protein engineering of polyester hydrolyzing enzymes, such as the PET hydrolase from I. sakaiensis (IsPETase), represent the first step to fostering innovative and cost-efficient processes for the degradation and upcycling of PET within the context of a plastics circular economy. The evolved stable and efficient variant of IsPETase we produced (named TS-ΔIsPET) represents a useful tool in enzyme-based PET recycling processes: such a procedure would considerably decrease the environmental impact of PET manufacturing (also reducing its CO2 footprint) and create additional socioeconomic benefits. View this paper
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25 pages, 2201 KiB  
Review
Nuclear Cytoskeleton in Virus Infection
by Lenka Horníková, Kateřina Bruštíková, Sandra Huérfano and Jitka Forstová
Int. J. Mol. Sci. 2022, 23(1), 578; https://doi.org/10.3390/ijms23010578 - 05 Jan 2022
Cited by 3 | Viewed by 6046
Abstract
The nuclear lamina is the main component of the nuclear cytoskeleton that maintains the integrity of the nucleus. However, it represents a natural barrier for viruses replicating in the cell nucleus. The lamina blocks viruses from being trafficked to the nucleus for replication, [...] Read more.
The nuclear lamina is the main component of the nuclear cytoskeleton that maintains the integrity of the nucleus. However, it represents a natural barrier for viruses replicating in the cell nucleus. The lamina blocks viruses from being trafficked to the nucleus for replication, but it also impedes the nuclear egress of the progeny of viral particles. Thus, viruses have evolved mechanisms to overcome this obstacle. Large viruses induce the assembly of multiprotein complexes that are anchored to the inner nuclear membrane. Important components of these complexes are the viral and cellular kinases phosphorylating the lamina and promoting its disaggregation, therefore allowing virus egress. Small viruses also use cellular kinases to induce lamina phosphorylation and the subsequent disruption in order to facilitate the import of viral particles during the early stages of infection or during their nuclear egress. Another component of the nuclear cytoskeleton, nuclear actin, is exploited by viruses for the intranuclear movement of their particles from the replication sites to the nuclear periphery. This study focuses on exploitation of the nuclear cytoskeleton by viruses, although this is just the beginning for many viruses, and promises to reveal the mechanisms and dynamic of physiological and pathological processes in the nucleus. Full article
(This article belongs to the Special Issue Cytoskeleton: At the Heart of Pathogen Invasion and Host Manipulation)
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15 pages, 7602 KiB  
Article
Heat Shock Protein 60 Restricts Release of Mitochondrial dsRNA to Suppress Hepatic Inflammation and Ameliorate Non-Alcoholic Fatty Liver Disease in Mice
by Ying-Hsien Huang, Feng-Sheng Wang, Pei-Wen Wang, Hung-Yu Lin, Sheng-Dean Luo and Ya-Ling Yang
Int. J. Mol. Sci. 2022, 23(1), 577; https://doi.org/10.3390/ijms23010577 - 05 Jan 2022
Cited by 9 | Viewed by 5359
Abstract
Non-alcoholic fatty liver disease (NAFLD), the most common cause of chronic liver disease, consists of fat deposited (steatosis) in the liver due to causes besides excessive alcohol use. The folding activity of heat shock protein 60 (HSP60) has been shown to protect mitochondria [...] Read more.
Non-alcoholic fatty liver disease (NAFLD), the most common cause of chronic liver disease, consists of fat deposited (steatosis) in the liver due to causes besides excessive alcohol use. The folding activity of heat shock protein 60 (HSP60) has been shown to protect mitochondria from proteotoxicity under various types of stress. In this study, we investigated whether HSP60 could ameliorate experimental high-fat diet (HFD)-induced obesity and hepatitis and explored the potential mechanism in mice. The results uncovered that HSP60 gain not only alleviated HFD-induced body weight gain, fat accumulation, and hepatocellular steatosis, but also glucose tolerance and insulin resistance according to intraperitoneal glucose tolerance testing and insulin tolerance testing in HSP60 transgenic (HSP60Tg) compared to wild-type (WT) mice by HFD. Furthermore, overexpression of HSP60 in the HFD group resulted in inhibited release of mitochondrial dsRNA (mt-dsRNA) compared to WT mice. In addition, overexpression of HSP60 also inhibited the activation of toll-like receptor 3 (TLR3), melanoma differentiation-associated gene 5 (MDA5), and phosphorylated-interferon regulatory factor 3 (p-IRF3), as well as inflammatory biomarkers such as mRNA of il-1β and il-6 expression in the liver in response to HFD. The in vitro study also confirmed that the addition of HSP-60 mimics in HepG2 cells led to upregulated expression level of HSP60 and restricted release of mt-dsRNA, as well as downregulated expression levels of TLR3, MDA5, and pIRF3. This study provides novel insight into a hepatoprotective effect, whereby HSP60 inhibits the release of dsRNA to repress the TLR3/MDA5/pIRF3 pathway in the context of NAFLD or hepatic inflammation. Therefore, HSP60 may serve as a possible therapeutic target for improving NAFLD. Full article
(This article belongs to the Special Issue Molecular Link between Steatosis and Obesity)
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23 pages, 5408 KiB  
Article
Regulation of Heterogenous LexA Expression in Staphylococcus aureus by an Antisense RNA Originating from Transcriptional Read-Through upon Natural Mispairings in the sbrB Intrinsic Terminator
by Laurène Bastet, Pilar Bustos-Sanmamed, Arancha Catalan-Moreno, Carlos J. Caballero, Sergio Cuesta, Leticia Matilla-Cuenca, Maite Villanueva, Jaione Valle, Iñigo Lasa and Alejandro Toledo-Arana
Int. J. Mol. Sci. 2022, 23(1), 576; https://doi.org/10.3390/ijms23010576 - 05 Jan 2022
Cited by 2 | Viewed by 3849
Abstract
Bacterial genomes are pervasively transcribed, generating a wide variety of antisense RNAs (asRNAs). Many of them originate from transcriptional read-through events (TREs) during the transcription termination process. Previous transcriptome analyses revealed that the lexA gene from Staphylococcus aureus, which encodes the main [...] Read more.
Bacterial genomes are pervasively transcribed, generating a wide variety of antisense RNAs (asRNAs). Many of them originate from transcriptional read-through events (TREs) during the transcription termination process. Previous transcriptome analyses revealed that the lexA gene from Staphylococcus aureus, which encodes the main SOS response regulator, is affected by the presence of an asRNA. Here, we show that the lexA antisense RNA (lexA-asRNA) is generated by a TRE on the intrinsic terminator (TTsbrB) of the sbrB gene, which is located downstream of lexA, in the opposite strand. Transcriptional read-through occurs by a natural mutation that destabilizes the TTsbrB structure and modifies the efficiency of the intrinsic terminator. Restoring the mispairing mutation in the hairpin of TTsbrB prevented lexA-asRNA transcription. The level of lexA-asRNA directly correlated with cellular stress since the expressions of sbrB and lexA-asRNA depend on the stress transcription factor SigB. Comparative analyses revealed strain-specific nucleotide polymorphisms within TTsbrB, suggesting that this TT could be prone to accumulating natural mutations. A genome-wide analysis of TREs suggested that mispairings in TT hairpins might provide wider transcriptional connections with downstream genes and, ultimately, transcriptomic variability among S. aureus strains. Full article
(This article belongs to the Special Issue Bacterial Non-coding RNA)
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13 pages, 2337 KiB  
Article
Evaluating a Targeted Cancer Therapy Approach Mediated by RNA trans-Splicing In Vitro and in a Xenograft Model for Epidermolysis Bullosa-Associated Skin Cancer
by Katharina Woess, Yuchen Sun, Hanae Morio, Anna Stierschneider, Anna Kaufmann, Stefan Hainzl, Lisa Trattner, Thomas Kocher, Birgit Tockner, Victoria Leb-Reichl, Markus Steiner, Gabriele Brachtl, Andrew P. South, Johann W. Bauer, Julia Reichelt, Tomomi Furihata, Verena Wally, Ulrich Koller, Josefina Piñón Hofbauer and Christina Guttmann-Gruber
Int. J. Mol. Sci. 2022, 23(1), 575; https://doi.org/10.3390/ijms23010575 - 05 Jan 2022
Cited by 4 | Viewed by 4636
Abstract
Conventional anti-cancer therapies based on chemo- and/or radiotherapy represent highly effective means to kill cancer cells but lack tumor specificity and, therefore, result in a wide range of iatrogenic effects. A promising approach to overcome this obstacle is spliceosome-mediated RNA trans-splicing (SMaRT), [...] Read more.
Conventional anti-cancer therapies based on chemo- and/or radiotherapy represent highly effective means to kill cancer cells but lack tumor specificity and, therefore, result in a wide range of iatrogenic effects. A promising approach to overcome this obstacle is spliceosome-mediated RNA trans-splicing (SMaRT), which can be leveraged to target tumor cells while leaving normal cells unharmed. Notably, a previously established RNA trans-splicing molecule (RTM44) showed efficacy and specificity in exchanging the coding sequence of a cancer target gene (Ct-SLCO1B3) with the suicide gene HSV1-thymidine kinase in a colorectal cancer model, thereby rendering tumor cells sensitive to the prodrug ganciclovir (GCV). In the present work, we expand the application of this approach, using the same RTM44 in aggressive skin cancer arising in the rare genetic skin disease recessive dystrophic epidermolysis bullosa (RDEB). Stable expression of RTM44, but not a splicing-deficient control (NC), in RDEB-SCC cells resulted in expression of the expected fusion product at the mRNA and protein level. Importantly, systemic GCV treatment of mice bearing RTM44-expressing cancer cells resulted in a significant reduction in tumor volume and weight compared with controls. Thus, our results demonstrate the applicability of RTM44-mediated targeting of the cancer gene Ct-SLCO1B3 in a different malignancy. Full article
(This article belongs to the Special Issue Molecular Research and Treatment of Skin Diseases)
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19 pages, 3790 KiB  
Review
Carbamylated Proteins in Renal Disease: Aggravating Factors or Just Biomarkers?
by Laëtitia Gorisse, Stéphane Jaisson, Christine Piétrement and Philippe Gillery
Int. J. Mol. Sci. 2022, 23(1), 574; https://doi.org/10.3390/ijms23010574 - 05 Jan 2022
Cited by 5 | Viewed by 3729
Abstract
Carbamylation is a nonenzymatic post-translational modification resulting from the reaction between cyanate, a urea by-product, and proteins. In vivo and in vitro studies have demonstrated that carbamylation modifies protein structures and functions, triggering unfavourable molecular and cellular responses. An enhanced formation of carbamylation-derived [...] Read more.
Carbamylation is a nonenzymatic post-translational modification resulting from the reaction between cyanate, a urea by-product, and proteins. In vivo and in vitro studies have demonstrated that carbamylation modifies protein structures and functions, triggering unfavourable molecular and cellular responses. An enhanced formation of carbamylation-derived products (CDPs) is observed in pathological contexts, especially during chronic kidney disease (CKD), because of increased blood urea. Significantly, studies have reported a positive correlation between serum CDPs and the evolutive state of renal failure. Further, serum concentrations of carbamylated proteins are characterized as strong predictors of mortality in end-stage renal disease patients. Over time, it is likely that these modified compounds become aggravating factors and promote long-term complications, including cardiovascular disorders and inflammation or immune system dysfunctions. These poor clinical outcomes have led researchers to consider strategies to prevent or slow down CDP formation. Even if growing evidence suggests the involvement of carbamylation in the pathophysiology of CKD, the real relevance of carbamylation is still unclear: is it a causal phenomenon, a metabolic consequence or just a biological feature? In this review, we discuss how carbamylation, a consequence of renal function decline, may become a causal phenomenon of kidney disease progression and how CDPs may be used as biomarkers. Full article
(This article belongs to the Special Issue Recent Advances in Molecular Mechanisms of Kidney Injury and Repair)
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17 pages, 1547 KiB  
Review
Targeting Cancer with CRISPR/Cas9-Based Therapy
by Katarzyna Balon, Adam Sheriff, Joanna Jacków and Łukasz Łaczmański
Int. J. Mol. Sci. 2022, 23(1), 573; https://doi.org/10.3390/ijms23010573 - 05 Jan 2022
Cited by 18 | Viewed by 6977
Abstract
Cancer is a devastating condition characterised by the uncontrolled division of cells with many forms remaining resistant to current treatment. A hallmark of cancer is the gradual accumulation of somatic mutations which drive tumorigenesis in cancerous cells, creating a mutation landscape distinctive to [...] Read more.
Cancer is a devastating condition characterised by the uncontrolled division of cells with many forms remaining resistant to current treatment. A hallmark of cancer is the gradual accumulation of somatic mutations which drive tumorigenesis in cancerous cells, creating a mutation landscape distinctive to a cancer type, an individual patient or even a single tumour lesion. Gene editing with CRISPR/Cas9-based tools now enables the precise and permanent targeting of mutations and offers an opportunity to harness this technology to target oncogenic mutations. However, the development of safe and effective gene editing therapies for cancer relies on careful design to spare normal cells and avoid introducing other mutations. This article aims to describe recent advancements in cancer-selective treatments based on the CRISPR/Cas9 system, especially focusing on strategies for targeted delivery of the CRISPR/Cas9 machinery to affected cells, controlling Cas9 expression in tissues of interest and disrupting cancer-specific genes to result in selective death of malignant cells. Full article
(This article belongs to the Special Issue Gene and Cell-Based Cancer Therapies)
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18 pages, 27118 KiB  
Article
The Heat Stress Transcription Factor LlHsfA4 Enhanced Basic Thermotolerance through Regulating ROS Metabolism in Lilies (Lilium Longiflorum)
by Chengpeng Wang, Yunzhuan Zhou, Xi Yang, Bing Zhang, Fuxiang Xu, Yue Wang, Cunxu Song, Mingfang Yi, Nan Ma, Xiaofeng Zhou and Junna He
Int. J. Mol. Sci. 2022, 23(1), 572; https://doi.org/10.3390/ijms23010572 - 05 Jan 2022
Cited by 23 | Viewed by 3621
Abstract
Heat stress severely affects the annual agricultural production. Heat stress transcription factors (HSFs) represent a critical regulatory juncture in the heat stress response (HSR) of plants. The HsfA1-dependent pathway has been explored well, but the regulatory mechanism of the HsfA1-independent pathway is still [...] Read more.
Heat stress severely affects the annual agricultural production. Heat stress transcription factors (HSFs) represent a critical regulatory juncture in the heat stress response (HSR) of plants. The HsfA1-dependent pathway has been explored well, but the regulatory mechanism of the HsfA1-independent pathway is still under-investigated. In the present research, HsfA4, an important gene of the HsfA1-independent pathway, was isolated from lilies (Lilium longiflorum) using the RACE method, which encodes 435 amino acids. LlHsfA4 contains a typical domain of HSFs and belongs to the HSF A4 family, according to homology comparisons and phylogenetic analysis. LlHsfA4 was mainly expressed in leaves and was induced by heat stress and H2O2 using qRT-PCR and GUS staining in transgenic Arabidopsis. LlHsfA4 had transactivation activity and was located in the nucleus and cytoplasm through a yeast one hybrid system and through transient expression in lily protoplasts. Over expressing LlHsfA4 in Arabidopsis enhanced its basic thermotolerance, but acquired thermotolerance was not achieved. Further research found that heat stress could increase H2O2 content in lily leaves and reduced H2O2 accumulation in transgenic plants, which was consistent with the up-regulation of HSR downstream genes such as Heat stress proteins (HSPs), Galactinol synthase1 (GolS1), WRKY DNA binding protein 30 (WRKY30), Zinc finger of Arabidopsis thaliana 6 (ZAT6) and the ROS-scavenging enzyme Ascorbate peroxidase 2 (APX2). In conclusion, these results indicate that LlHsfA4 plays important roles in heat stress response through regulating the ROS metabolism in lilies. Full article
(This article belongs to the Section Molecular Plant Sciences)
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14 pages, 3975 KiB  
Article
Interleukin-4 Aggravates LPS-Induced Striatal Neurodegeneration In Vivo via Oxidative Stress and Polarization of Microglia/Macrophages
by Jaegeun Jang, Ahreum Hong, Youngcheul Chung and Byungkwan Jin
Int. J. Mol. Sci. 2022, 23(1), 571; https://doi.org/10.3390/ijms23010571 - 05 Jan 2022
Cited by 7 | Viewed by 2975
Abstract
The present study investigated the effects of interleukin (IL)-4 on striatal neurons in lipopolysaccharide (LPS)-injected rat striatum in vivo. Either LPS or PBS as a control was unilaterally injected into the striatum, and brain tissues were processed for immunohistochemical and Nissl staining or [...] Read more.
The present study investigated the effects of interleukin (IL)-4 on striatal neurons in lipopolysaccharide (LPS)-injected rat striatum in vivo. Either LPS or PBS as a control was unilaterally injected into the striatum, and brain tissues were processed for immunohistochemical and Nissl staining or for hydroethidine histochemistry at the indicated time points after LPS injection. Analysis by NeuN and Nissl immunohistochemical staining showed a significant loss of striatal neurons at 1, 3, and 7 days post LPS. In parallel, IL-4 immunoreactivity was upregulated as early as 1 day, reached a peak at 3 days, and was sustained up to 7 days post LPS. Increased levels of IL-4 immunoreactivity were exclusively detected in microglia/macrophages, but not in neurons nor astrocytes. The neutralizing antibody (NA) for IL-4 significantly protects striatal neurons against LPS-induced neurotoxicity in vivo. Accompanying neuroprotection, IL-4NA inhibited activation of microglia/macrophages, production of reactive oxygen species (ROS), ROS-derived oxidative damage and nitrosative stress, and produced polarization of microglia/macrophages shifted from M1 to M2. These results suggest that endogenous IL-4 expressed in LPS-activated microglia/macrophages contributes to striatal neurodegeneration in which oxidative/nitrosative stress and M1/M2 polarization are implicated. Full article
(This article belongs to the Special Issue Molecular Signals and Genetic Regulations of Neurological Disorders)
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15 pages, 18584 KiB  
Article
Brain-Derived Neurotrophic Factor Suppressed Proinflammatory Cytokines Secretion and Enhanced MicroRNA(miR)-3168 Expression in Macrophages
by Hui-Chun Yu, Hsien-Bin Huang, Hsien-Yu Huang Tseng and Ming-Chi Lu
Int. J. Mol. Sci. 2022, 23(1), 570; https://doi.org/10.3390/ijms23010570 - 05 Jan 2022
Cited by 8 | Viewed by 2841
Abstract
We investigated the role of brain-derived neurotrophic factor (BDNF) and its signaling pathway in the proinflammatory cytokines production of macrophages. The effects of different concentrations of BDNF on proinflammatory cytokines expression and secretion in U937 cell-differentiated macrophages, and human monocyte-derived macrophages were analyzed [...] Read more.
We investigated the role of brain-derived neurotrophic factor (BDNF) and its signaling pathway in the proinflammatory cytokines production of macrophages. The effects of different concentrations of BDNF on proinflammatory cytokines expression and secretion in U937 cell-differentiated macrophages, and human monocyte-derived macrophages were analyzed using enzyme-linked immunosorbent assay and real-time polymerase chain reaction. The CRISPR-Cas9 system was used to knockout p75 neurotrophin receptor (p75NTR), one of the BDNF receptors. Next-generation sequencing (NGS) was conducted to search for BDNF-regulated microRNA. A very low concentration of BDNF (1 ng/mL) could suppress the secretion of interleukin (IL)-1β, tumor necrosis factor (TNF)-α, and IL-6 in lipopolysaccharide (LPS)-stimulated macrophages but did not change their mRNA expression. BDNF suppressed IL-1β and IL-6 secretion in human monocyte-derived macrophages. In U937 cells, BDNF suppressed the phosphorylation of JNK and c-Jun. The p75NTR knockout strongly suppressed IL-1β, IL-6, and TNF-α secretion in macrophages and LPS-stimulated macrophages. BDNF regulated the expression of miR-3168 with Ras-related protein Rab-11A as its target. In conclusion, BDNF suppressed proinflammatory cytokines secretion in macrophages and inhibited the phosphorylation of JNK. Knockout of p75NTR suppressed proinflammatory cytokines expression and secretion. BDNF upregulated the expression of miR-3168. The inhibition of p75NTR could be a potential strategy to control inflammation. Full article
(This article belongs to the Special Issue Human and Animal Monocytes and Macrophages in Homeostasis and Disease 2.0)
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23 pages, 7429 KiB  
Article
Gene Co-Expression Analysis Reveals Transcriptome Divergence between Wild and Cultivated Sugarcane under Drought Stress
by Peiting Li, Pingping Lin, Zhenli Zhao, Zihong Li, Yanming Liu, Chaohua Huang, Guoqiang Huang, Liangnian Xu, Zuhu Deng, Yu Zhang and Xinwang Zhao
Int. J. Mol. Sci. 2022, 23(1), 569; https://doi.org/10.3390/ijms23010569 - 05 Jan 2022
Cited by 22 | Viewed by 3444
Abstract
Drought is the main abiotic stress that constrains sugarcane growth and production. To understand the molecular mechanisms that govern drought stress, we performed a comprehensive comparative analysis of physiological changes and transcriptome dynamics related to drought stress of highly drought-resistant (ROC22, cultivated genotype) [...] Read more.
Drought is the main abiotic stress that constrains sugarcane growth and production. To understand the molecular mechanisms that govern drought stress, we performed a comprehensive comparative analysis of physiological changes and transcriptome dynamics related to drought stress of highly drought-resistant (ROC22, cultivated genotype) and weakly drought-resistant (Badila, wild genotype) sugarcane, in a time-course experiment (0 h, 4 h, 8 h, 16 h and 32 h). Physiological examination reviewed that ROC22, which shows superior drought tolerance relative to Badila, has high performance photosynthesis and better anti-oxidation defenses under drought conditions. The time series dataset enabled the identification of important hubs and connections of gene expression networks. We identified 36,956 differentially expressed genes (DEGs) in response to drought stress. Of these, 15,871 DEGs were shared by the two genotypes, and 16,662 and 4423 DEGs were unique to ROC22 and Badila, respectively. Abscisic acid (ABA)-activated signaling pathway, response to water deprivation, response to salt stress and photosynthesis-related processes showed significant enrichment in the two genotypes under drought stress. At 4 h of drought stress, ROC22 had earlier stress signal transduction and specific up-regulation of the processes response to ABA, L-proline biosynthesis and MAPK signaling pathway–plant than Badila. WGCNA analysis used to compile a gene regulatory network for ROC22 and Badila leaves exposed to drought stress revealed important candidate genes, including several classical transcription factors: NAC87, JAMYB, bHLH84, NAC21/22, HOX24 and MYB102, which are related to some antioxidants and trehalose, and other genes. These results provide new insights and resources for future research and cultivation of drought-tolerant sugarcane varieties. Full article
(This article belongs to the Section Molecular Plant Sciences)
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18 pages, 7070 KiB  
Article
Tracking of Endothelial Cell Migration and Stiffness Measurements Reveal the Role of Cytoskeletal Dynamics
by Dominick J. Romano, Jesus M. Gomez-Salinero, Zoran Šunić, Antonio Checco and Sina Y. Rabbany
Int. J. Mol. Sci. 2022, 23(1), 568; https://doi.org/10.3390/ijms23010568 - 05 Jan 2022
Cited by 3 | Viewed by 2859
Abstract
Cell migration is a complex, tightly regulated multistep process in which cytoskeletal reorganization and focal adhesion redistribution play a central role. Core to both individual and collective migration is the persistent random walk, which is characterized by random force generation and resistance to [...] Read more.
Cell migration is a complex, tightly regulated multistep process in which cytoskeletal reorganization and focal adhesion redistribution play a central role. Core to both individual and collective migration is the persistent random walk, which is characterized by random force generation and resistance to directional change. We first discuss a model that describes the stochastic movement of ECs and characterizes EC persistence in wound healing. To that end, we pharmacologically disrupted cytoskeletal dynamics, cytochalasin D for actin and nocodazole for tubulin, to understand its contributions to cell morphology, stiffness, and motility. As such, the use of Atomic Force Microscopy (AFM) enabled us to probe the topography and stiffness of ECs, while time lapse microscopy provided observations in wound healing models. Our results suggest that actin and tubulin dynamics contribute to EC shape, compressive moduli, and directional organization in collective migration. Insights from the model and time lapse experiment suggest that EC speed and persistence are directionally organized in wound healing. Pharmacological disruptions suggest that actin and tubulin dynamics play a role in collective migration. Current insights from both the model and experiment represent an important step in understanding the biomechanics of EC migration as a therapeutic target. Full article
(This article belongs to the Special Issue Molecular Studies on Tissue-Specific Endothelial Cells in Development, Homeostasis and Disease)
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14 pages, 2452 KiB  
Article
A Glutathione Peroxidase Gene from Litopenaeus vannamei Is Involved in Oxidative Stress Responses and Pathogen Infection Resistance
by Jinquan Fan, Binbin Li, Qianming Hong, Zeyu Yan, Xinjun Yang, Kecheng Lu, Guoliang Chen, Lei Wang and Yihong Chen
Int. J. Mol. Sci. 2022, 23(1), 567; https://doi.org/10.3390/ijms23010567 - 05 Jan 2022
Cited by 16 | Viewed by 2381
Abstract
In shrimp, several glutathione peroxidase (GPX) genes have been cloned and functionally studied. Increasing evidence suggests the genes’ involvement in white spot syndrome virus (WSSV)- or Vibrio alginolyticus-infection resistance. In the present study, a novel GXP gene (LvGPX3) was cloned [...] Read more.
In shrimp, several glutathione peroxidase (GPX) genes have been cloned and functionally studied. Increasing evidence suggests the genes’ involvement in white spot syndrome virus (WSSV)- or Vibrio alginolyticus-infection resistance. In the present study, a novel GXP gene (LvGPX3) was cloned in Litopenaeus vannamei. Promoter of LvGPX3 was activated by NF-E2-related factor 2. Further study showed that LvGPX3 expression was evidently accelerated by oxidative stress or WSSV or V. alginolyticus infection. Consistently, downregulated expression of LvGPX3 increased the cumulative mortality of WSSV- or V. alginolyticus-infected shrimp. Similar results occurred in shrimp suffering from oxidative stress. Moreover, LvGPX3 was important for enhancing Antimicrobial peptide (AMP) gene expression in S2 cells with lipopolysaccharide treatment. Further, knockdown of LvGPX3 expression significantly suppressed expression of AMPs, such as Penaeidins 2a, Penaeidins 3a and anti-lipopolysaccharide factor 1 in shrimp. AMPs have been proven to be engaged in shrimp WSSV- or V. alginolyticus-infection resistance; it was inferred that LvGPX3 might enhance shrimp immune response under immune challenges, such as increasing expression of AMPs. The regulation mechanism remains to be further studied. Full article
(This article belongs to the Section Biochemistry)
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18 pages, 3032 KiB  
Article
Metabolic Rewiring by Human Placenta-Derived Mesenchymal Stem Cell Therapy Promotes Rejuvenation in Aged Female Rats
by Kyeoung-Hwa Kim and Kyung-Ah Lee
Int. J. Mol. Sci. 2022, 23(1), 566; https://doi.org/10.3390/ijms23010566 - 05 Jan 2022
Cited by 4 | Viewed by 2957
Abstract
Aging is a degenerative process involving cell function deterioration, leading to altered metabolic pathways, increased metabolite diversity, and dysregulated metabolism. Previously, we reported that human placenta-derived mesenchymal stem cells (hPD-MSCs) have therapeutic effects on ovarian aging. This study aimed to identify hPD-MSC therapy-induced [...] Read more.
Aging is a degenerative process involving cell function deterioration, leading to altered metabolic pathways, increased metabolite diversity, and dysregulated metabolism. Previously, we reported that human placenta-derived mesenchymal stem cells (hPD-MSCs) have therapeutic effects on ovarian aging. This study aimed to identify hPD-MSC therapy-induced responses at the metabolite and protein levels and serum biomarker(s) of aging and/or rejuvenation. We observed weight loss after hPD-MSC therapy. Importantly, insulin-like growth factor-I (IGF-I), known prolongs healthy life spans, were markedly elevated in serum. Capillary electrophoresis-time-of-flight mass spectrometry (CE-TOF/MS) analysis identified 176 metabolites, among which the levels of 3-hydroxybutyric acid, glycocholic acid, and taurine, which are associated with health and longevity, were enhanced after hPD-MSC stimulation. Furthermore, after hPD-MSC therapy, the levels of vitamin B6 and its metabolite pyridoxal 5′-phosphate were markedly increased in the serum and liver, respectively. Interestingly, hPD-MSC therapy promoted serotonin production due to increased vitamin B6 metabolism rates. Increased liver serotonin levels after multiple-injection therapy altered the expression of mRNAs and proteins associated with hepatocyte proliferation and mitochondrial biogenesis. Changes in metabolites in circulation after hPD-MSC therapy can be used to identify biomarker(s) of aging and/or rejuvenation. In addition, serotonin is a valuable therapeutic target for reversing aging-associated liver degeneration. Full article
(This article belongs to the Special Issue Anti-aging: Molecular Mechanisms and Rejuvenation Strategies)
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17 pages, 6350 KiB  
Article
Runx1 Messenger RNA Delivered by Polyplex Nanomicelles Alleviate Spinal Disc Hydration Loss in a Rat Disc Degeneration Model
by Cheng-Chung Chang, Hsi-Kai Tsou, Hsu-Hsin Chang, Long Yi Chan, Guan-Yu Zhuo, Tomoji Maeda and Chin-Yu Lin
Int. J. Mol. Sci. 2022, 23(1), 565; https://doi.org/10.3390/ijms23010565 - 05 Jan 2022
Cited by 13 | Viewed by 2715
Abstract
Vertebral disc degenerative disease (DDD) affects millions of people worldwide and is a critical factor leading to low back and neck pain and consequent disability. Currently, no strategy has addressed curing DDD from fundamental aspects, because the pathological mechanism leading to DDD is [...] Read more.
Vertebral disc degenerative disease (DDD) affects millions of people worldwide and is a critical factor leading to low back and neck pain and consequent disability. Currently, no strategy has addressed curing DDD from fundamental aspects, because the pathological mechanism leading to DDD is still controversial. One possible mechanism points to the homeostatic status of extracellular matrix (ECM) anabolism, and catabolism in the disc may play a vital role in the disease’s progression. If the damaged disc receives an abundant amount of cartilage, anabolic factors may stimulate the residual cells in the damaged disc to secrete the ECM and mitigate the degeneration process. To examine this hypothesis, a cartilage anabolic factor, Runx1, was expressed by mRNA through a sophisticated polyamine-based PEG-polyplex nanomicelle delivery system in the damaged disc in a rat model. The mRNA medicine and polyamine carrier have favorable safety characteristics and biocompatibility for regenerative medicine. The endocytosis of mRNA-loaded polyplex nanomicelles in vitro, mRNA delivery efficacy, hydration content, disc shrinkage, and ECM in the disc in vivo were also examined. The data revealed that the mRNA-loaded polyplex nanomicelle was promptly engulfed by cellular late endosome, then spread into the cytosol homogeneously at a rate of less than 20 min post-administration of the mRNA medicine. The mRNA expression persisted for at least 6-days post-injection in vivo. Furthermore, the Runx1 mRNA delivered by polyplex nanomicelles increased hydration content by ≈43% in the punctured disc at 4-weeks post-injection (wpi) compared with naked Runx1 mRNA administration. Meanwhile, the disc space and ECM production were also significantly ameliorated in the polyplex nanomicelle group. This study demonstrated that anabolic factor administration by polyplex nanomicelle-protected mRNA medicine, such as Runx1, plays a key role in alleviating the progress of DDD, which is an imbalance scenario of disc metabolism. This platform could be further developed as a promising strategy applied to regenerative medicine. Full article
(This article belongs to the Special Issue Molecular Imaging in Nanomedical Research 2.0)
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16 pages, 5135 KiB  
Article
A NAC Transcription Factor TuNAC69 Contributes to ANK-NLR-WRKY NLR-Mediated Stripe Rust Resistance in the Diploid Wheat Triticum urartu
by Yang Xu, Shenghao Zou, Hao Zeng, Wei Wang, Bin Wang, Huan Wang and Dingzhong Tang
Int. J. Mol. Sci. 2022, 23(1), 564; https://doi.org/10.3390/ijms23010564 - 05 Jan 2022
Cited by 10 | Viewed by 2790
Abstract
Stripe rust is one of the most devastating diseases in wheat. Nucleotide-binding site (NBS) and leucine-rich repeat (LRR) domain receptors (NLRs) recognize pathogenic effectors and trigger plant immunity. We previously identified a unique NLR protein YrU1 in the diploid wheat Triticum urartu, [...] Read more.
Stripe rust is one of the most devastating diseases in wheat. Nucleotide-binding site (NBS) and leucine-rich repeat (LRR) domain receptors (NLRs) recognize pathogenic effectors and trigger plant immunity. We previously identified a unique NLR protein YrU1 in the diploid wheat Triticum urartu, which contains an N-terminal ANK domain and a C-terminal WRKY domain and confers disease resistance to stripe rust fungus Puccinia striiformis f. sp. Tritici (Pst). However, how YrU1 functions in disease resistance is not clear. In this study, through the RNA-seq analysis, we found that the expression of a NAC member TuNAC69 was significantly up-regulated after inoculation with Pst in the presence of YrU1. TuNAC69 was mainly localized in the nucleus and showed transcriptional activation in yeast. Knockdown TuNAC69 in diploid wheat Triticum urartu PI428309 that contains YrU1 by virus-induced gene silencing reduced the resistance to stripe rust. In addition, overexpression of TuNAC69 in Arabidopsis enhanced the resistance to powdery mildew Golovinomyces cichoracearum. In summary, our study indicates that TuNAC69 participates in the immune response mediated by NLR protein YrU1, and likely plays an important role in disease resistance to other pathogens. Full article
(This article belongs to the Special Issue Plant-Microbe Interactions)
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14 pages, 4600 KiB  
Article
Investigation of the Antibacterial Properties of Silver-Doped Amorphous Carbon Coatings Produced by Low Pressure Magnetron Assisted Acetylene Discharges
by Valentin Job, Julie Laloy, Vincent Maloteau, Emile Haye, Stéphane Lucas and Sébastien Penninckx
Int. J. Mol. Sci. 2022, 23(1), 563; https://doi.org/10.3390/ijms23010563 - 05 Jan 2022
Cited by 2 | Viewed by 2014
Abstract
Hospital-acquired infections are responsible for a significant part of morbidity and mortality. Among the possible modes of transmission, this study focuses on environmental surfaces by developing innovative antibacterial coatings that can be applied on interior fittings in hospitals. This work aims to optimize [...] Read more.
Hospital-acquired infections are responsible for a significant part of morbidity and mortality. Among the possible modes of transmission, this study focuses on environmental surfaces by developing innovative antibacterial coatings that can be applied on interior fittings in hospitals. This work aims to optimize a coating made of an amorphous carbon matrix doped with silver (a-C:H:Ag) produced by a hybrid PVD/PECVD process and to evaluate its antibacterial activity. We present a coating characterization (chemical composition and morphology) as well as its stability in an ageing process and after multiple exposures to bacteria. The antibacterial activity of the coatings is demonstrated against Escherichia coli (Gram-negative) and Staphylococcus aureus (Gram-positive) bacteria through several bioassays. Moreover, the data suggest a crucial role of silver diffusion towards the surface and nanoparticle formation to explain the very promising anti-bacterial activities reported in this work. Full article
(This article belongs to the Special Issue Advances in Nanotechnology: Nanomaterials and Nanobiocatalyst)
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16 pages, 1148 KiB  
Review
Affinity, Specificity, and Cooperativity of DNA Binding by Bacterial Gene Regulatory Proteins
by Jannette Carey
Int. J. Mol. Sci. 2022, 23(1), 562; https://doi.org/10.3390/ijms23010562 - 05 Jan 2022
Cited by 9 | Viewed by 2442
Abstract
Nearly all of biology depends on interactions between molecules: proteins with small molecules, proteins with other proteins, nucleic acids with small molecules, and nucleic acids with proteins that regulate gene expression, our concern in this Special Issue. All those kinds of interactions, and [...] Read more.
Nearly all of biology depends on interactions between molecules: proteins with small molecules, proteins with other proteins, nucleic acids with small molecules, and nucleic acids with proteins that regulate gene expression, our concern in this Special Issue. All those kinds of interactions, and others, constitute the vast majority of biology at the molecular level. An understanding of those interactions requires that we quantify them to learn how they interact: How strongly? With which partners? How—and how well—are different partners distinguished? This review addresses the evolution of our current understanding of the molecular origins of affinity and specificity in regulatory protein–DNA interactions, and suggests that both these properties can be modulated by cooperativity. Full article
(This article belongs to the Special Issue Bacterial Regulatory Proteins)
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20 pages, 6946 KiB  
Article
Bidirectional lncRNA Transfer between Cuscuta Parasites and Their Host Plant
by Yuguo Wu, Dong Luo, Longfa Fang, Qiang Zhou, Wenxian Liu and Zhipeng Liu
Int. J. Mol. Sci. 2022, 23(1), 561; https://doi.org/10.3390/ijms23010561 - 05 Jan 2022
Cited by 7 | Viewed by 2650
Abstract
Dodder species (Cuscuta spp.) are holoparasites that have extensive material exchange with their host plants through vascular connections. Recent studies on cross-species transfer have provided breakthrough insights, but little is known about the interaction mechanisms of the inter-plant mobile substances in parasitic [...] Read more.
Dodder species (Cuscuta spp.) are holoparasites that have extensive material exchange with their host plants through vascular connections. Recent studies on cross-species transfer have provided breakthrough insights, but little is known about the interaction mechanisms of the inter-plant mobile substances in parasitic systems. We sequenced the transcriptomes of dodder growing on soybean hosts to characterize the long non-coding RNA (lncRNA) transfer between the two species, and found that lncRNAs can move in high numbers (365 dodder lncRNAs and 14 soybean lncRNAs) in a bidirectional manner. Reverse transcription-polymerase chain reaction further confirmed that individual lncRNAs were trafficked in the dodder–soybean parasitic system. To reveal the potential functions of mobile transcripts, the Gene Ontology terms of mobile lncRNA target genes were predicted, and mobile dodder target genes were found to be mainly enriched in “metabolic process”, “catalytic activity”, “signaling”, and “response to stimulus” categories, whereas mobile soybean target genes were enriched in organelle-related categories, indicating that specific mobile lncRNAs may be important in regulating dodder parasitism. Our findings reveal that lncRNAs are transferred between dodder and its host soybean plants, which may act as critical regulators to coordinate the host–dodder interaction at the whole parasitic level. Full article
(This article belongs to the Collection Recent Advances in Plant Molecular Science in China 2021)
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18 pages, 2462 KiB  
Article
Loss of SDHB Induces a Metabolic Switch in the hPheo1 Cell Line toward Enhanced OXPHOS
by Mouna Tabebi, Ravi Kumar Dutta, Camilla Skoglund, Peter Söderkvist and Oliver Gimm
Int. J. Mol. Sci. 2022, 23(1), 560; https://doi.org/10.3390/ijms23010560 - 05 Jan 2022
Cited by 10 | Viewed by 2888
Abstract
Background: Enzymes of tricarboxylic acid (TCA) have recently been recognized as tumor suppressors. Mutations in the SDHB subunit of succinate dehydrogenase (SDH) cause pheochromocytomas and paragangliomas (PCCs/PGLs) and predispose patients to malignant disease with poor prognosis. Methods: Using the human pheochromocytoma cell line [...] Read more.
Background: Enzymes of tricarboxylic acid (TCA) have recently been recognized as tumor suppressors. Mutations in the SDHB subunit of succinate dehydrogenase (SDH) cause pheochromocytomas and paragangliomas (PCCs/PGLs) and predispose patients to malignant disease with poor prognosis. Methods: Using the human pheochromocytoma cell line (hPheo1), we knocked down SDHB gene expression using CRISPR-cas9 technology. Results: Microarray gene expression analysis showed that >500 differentially expressed gene targets, about 54%, were upregulated in response to SDHB knock down. Notably, genes involved in glycolysis, hypoxia, cell proliferation, and cell differentiation were up regulated, whereas genes involved in oxidative phosphorylation (OXPHOS) were downregulated. In vitro studies show that hPheo1 proliferation is not affected negatively and the cells that survive by shifting their metabolism to the use of glutamine as an alternative energy source and promote OXPHOS activity. Knock down of SDHB expression results in a significant increase in GLUD1 expression in hPheo1 cells cultured as monolayer or as 3D culture. Analysis of TCGA data confirms the enhancement of GLUD1 in SDHB mutated/low expressed PCCs/PGLs. Conclusions: Our data suggest that the downregulation of SDHB in PCCs/PGLs results in increased GLUD1 expression and may represent a potential biomarker and therapeutic target in SDHB mutated tumors and SDHB loss of activity-dependent diseases. Full article
(This article belongs to the Collection 21st Anniversary of IJMS: Advances in Molecular Endocrinology and Metabolism)
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15 pages, 1904 KiB  
Article
TRAPing Ghrelin-Activated Circuits: A Novel Tool to Identify, Target and Control Hormone-Responsive Populations in TRAP2 Mice
by Iris Stoltenborg, Fiona Peris-Sampedro, Erik Schéle, Marie V. Le May, Roger A. H. Adan and Suzanne L. Dickson
Int. J. Mol. Sci. 2022, 23(1), 559; https://doi.org/10.3390/ijms23010559 - 05 Jan 2022
Cited by 2 | Viewed by 4960
Abstract
The availability of Cre-based mouse lines for visualizing and targeting populations of hormone-sensitive cells has helped identify the neural circuitry driving hormone effects. However, these mice have limitations and may not even be available. For instance, the development of the first ghrelin receptor [...] Read more.
The availability of Cre-based mouse lines for visualizing and targeting populations of hormone-sensitive cells has helped identify the neural circuitry driving hormone effects. However, these mice have limitations and may not even be available. For instance, the development of the first ghrelin receptor (Ghsr)-IRES-Cre model paved the way for using the Cre-lox system to identify and selectively manipulate ghrelin-responsive populations. The insertion of the IRES-Cre cassette, however, interfered with Ghsr expression, resulting in defective GHSR signaling and a pronounced phenotype in the homozygotes. As an alternative strategy to target ghrelin-responsive cells, we hereby utilize TRAP2 (targeted recombination in active populations) mice in which it is possible to gain genetic access to ghrelin-activated populations. In TRAP2 mice crossed with a reporter strain, we visualized ghrelin-activated cells and found, as expected, much activation in the arcuate nucleus (Arc). We then stimulated this population using a chemogenetic approach and found that this was sufficient to induce an orexigenic response of similar magnitude to that induced by peripheral ghrelin injection. The stimulation of this population also impacted food choice. Thus, the TRAPing of hormone-activated neurons (here exemplified by ghrelin-activated pathways) provides a complimentary/alternative technique to visualize, access and control discrete pathways, linking hormone action to circuit function. Full article
(This article belongs to the Special Issue Transgenic Mice in Human Diseases: Insights from Molecular Research 2.0)
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19 pages, 6004 KiB  
Article
Metformin-Incorporated Gelatin/Nano-Hydroxyapatite Scaffolds Promotes Bone Regeneration in Critical Size Rat Alveolar Bone Defect Model
by Chih-Hsiang Fang, Chung-Kai Sun, Yi-Wen Lin, Min-Chih Hung, Hung-Ying Lin, Ching-Hung Li, I-Ping Lin, Hung-Chen Chang, Jui-Sheng Sun and Jenny Zwei-Chieng Chang
Int. J. Mol. Sci. 2022, 23(1), 558; https://doi.org/10.3390/ijms23010558 - 05 Jan 2022
Cited by 14 | Viewed by 3751
Abstract
In this study, we fabricated gelatin/nano-hydroxyapatite/metformin scaffold (GHMS) and compared its effectiveness in bone regeneration with extraction-only, Sinbone, and Bio-Oss Collagen® groups in a critical size rat alveolar bone defect model. GHMS was synthesized by co-precipitating calcium hydroxide and orthophosphoric acid within [...] Read more.
In this study, we fabricated gelatin/nano-hydroxyapatite/metformin scaffold (GHMS) and compared its effectiveness in bone regeneration with extraction-only, Sinbone, and Bio-Oss Collagen® groups in a critical size rat alveolar bone defect model. GHMS was synthesized by co-precipitating calcium hydroxide and orthophosphoric acid within gelatin solution, incorporating metformin, and cross-linked by microbial transglutaminase. The morphology, characterization, and biocompatibility of scaffold were examined. The in vitro effects of GHMS on osteogenic gene and protein expressions were evaluated. In vivo bone formation was assessed in a critical size rat alveolar bone defect model with micro-computed tomography and histological examination by comparing GHMS with extraction-only, Sinbone, and Bio-Oss Collagen®. The synthesized GHMS had a highly interconnected porous structure with a mean pore size of 81.85 ± 13.8 µm. GHMS exhibited good biocompatibility; promoted ALPL, RUNX2, SP7, BGLAP, SPARC and Col1a1 gene expressions; and upregulated the synthesis of osteogenic proteins, including osteonectin, osteocalcin, and collagen type I. In critical size rat alveolar bone defects, GHMS showed superior bone regeneration compared to extraction-only, Sinbone, and Bio-Oss Collagen® groups as manifested by greater alveolar ridge preservation, while more bone formation with a lower percentage of connective tissue and residual scaffold at the defect sites grafted with GHMS in histological staining. The GHMS presented in this study may be used as a potential bone substitute to regenerate alveolar bone. The good biocompatibility, relatively fast degradation, interconnected pores allowing vascularization, and higher bioactivity properties of the components of the GHMS (gelatin, nHA, and metformin) may contribute to direct osteogenesis. Full article
(This article belongs to the Special Issue Bone Development and Regeneration 2.0)
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7 pages, 556 KiB  
Article
Glycosylation of Receptor Binding Domain of SARS-CoV-2 S-Protein Influences on Binding to Immobilized DNA Aptamers
by Fedor Grabovenko, Liudmila Nikiforova, Bogdan Yanenko, Andrey Ulitin, Eugene Loktyushov, Timofei Zatsepin, Elena Zavyalova and Maria Zvereva
Int. J. Mol. Sci. 2022, 23(1), 557; https://doi.org/10.3390/ijms23010557 - 05 Jan 2022
Cited by 9 | Viewed by 2371
Abstract
Nucleic acid aptamers specific to S-protein and its receptor binding domain (RBD) of SARS-CoV-2 (severe acute respiratory syndrome-related coronavirus 2) virions are of high interest as potential inhibitors of viral infection and recognizing elements in biosensors. Development of specific therapy and biosensors is [...] Read more.
Nucleic acid aptamers specific to S-protein and its receptor binding domain (RBD) of SARS-CoV-2 (severe acute respiratory syndrome-related coronavirus 2) virions are of high interest as potential inhibitors of viral infection and recognizing elements in biosensors. Development of specific therapy and biosensors is complicated by an emergence of new viral strains bearing amino acid substitutions and probable differences in glycosylation sites. Here, we studied affinity of a set of aptamers to two Wuhan-type RBD of S-protein expressed in Chinese hamster ovary cell line and Pichia pastoris that differ in glycosylation patterns. The expression system for the RBD protein has significant effects, both on values of dissociation constants and relative efficacy of the aptamer binding. We propose glycosylation of the RBD as the main force for observed differences. Moreover, affinity of a several aptamers was affected by a site of biotinylation. Thus, the robustness of modified aptamers toward new virus variants should be carefully tested. Full article
(This article belongs to the Collection Feature Papers in Molecular Pathology, Diagnostics, and Therapeutics)
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19 pages, 4275 KiB  
Article
The Beneficial Effects of Combining Anti-Aβ Antibody NP106 and Curcumin Analog TML-6 on the Treatment of Alzheimer’s Disease in APP/PS1 Mice
by Ih-Jen Su, Chia-Yu Hsu, Santai Shen, Po-Kuan Chao, John Tsu-An Hsu, Jung-Tsung Hsueh, Jia-Jun Liang, Ying-Ting Hsu and Feng-Shiun Shie
Int. J. Mol. Sci. 2022, 23(1), 556; https://doi.org/10.3390/ijms23010556 - 05 Jan 2022
Cited by 5 | Viewed by 2657
Abstract
Alzheimer’s disease (AD) is a progressive neurodegenerative disease with a multifactorial etiology. A multitarget treatment that modulates multifaceted biological functions might be more effective than a single-target approach. Here, the therapeutic efficacy of combination treatment using anti-Aβ antibody NP106 and curcumin analog TML-6 [...] Read more.
Alzheimer’s disease (AD) is a progressive neurodegenerative disease with a multifactorial etiology. A multitarget treatment that modulates multifaceted biological functions might be more effective than a single-target approach. Here, the therapeutic efficacy of combination treatment using anti-Aβ antibody NP106 and curcumin analog TML-6 versus monotherapy was investigated in an APP/PS1 mouse model of AD. Our data demonstrate that both combination treatment and monotherapy attenuated brain Aβ and improved the nesting behavioral deficit to varying degrees. Importantly, the combination treatment group had the lowest Aβ levels, and insoluble forms of Aβ were reduced most effectively. The nesting performance of APP/PS1 mice receiving combination treatment was better than that of other APP/PS1 groups. Further findings indicate that enhanced microglial Aβ phagocytosis and lower levels of proinflammatory cytokines were concurrent with the aforementioned effects of NP106 in combination with TML-6. Intriguingly, combination treatment also normalized the gut microbiota of APP/PS1 mice to levels resembling the wild-type control. Taken together, combination treatment outperformed NP106 or TML-6 monotherapy in ameliorating Aβ pathology and the nesting behavioral deficit in APP/PS1 mice. The superior effect might result from a more potent modulation of microglial function, cerebral inflammation, and the gut microbiota. This innovative treatment paradigm confers a new avenue to develop more efficacious AD treatments. Full article
(This article belongs to the Collection Feature Papers in Molecular Pathology, Diagnostics, and Therapeutics)
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15 pages, 3481 KiB  
Article
IL-17 Pathway Members as Potential Biomarkers of Effective Systemic Treatment and Cardiovascular Disease in Patients with Moderate-to-Severe Psoriasis
by Xing Wang, Hannah Kaiser, Amanda Kvist-Hansen, Benjamin D. McCauley, Lone Skov, Peter Riis Hansen and Christine Becker
Int. J. Mol. Sci. 2022, 23(1), 555; https://doi.org/10.3390/ijms23010555 - 05 Jan 2022
Cited by 13 | Viewed by 2913
Abstract
Psoriasis is a chronic inflammatory condition associated with atherosclerotic cardiovascular disease (CVD). Systemic anti-psoriatic treatments mainly include methotrexate and biological therapies targeting TNF, IL-12/23 and IL-17A. We profiled plasma proteins from patients with moderate-to-severe psoriasis to explore potential biomarkers of effective systemic treatment [...] Read more.
Psoriasis is a chronic inflammatory condition associated with atherosclerotic cardiovascular disease (CVD). Systemic anti-psoriatic treatments mainly include methotrexate and biological therapies targeting TNF, IL-12/23 and IL-17A. We profiled plasma proteins from patients with moderate-to-severe psoriasis to explore potential biomarkers of effective systemic treatment and their relationship to CVD. We found that systemically well-treated patients (PASI < 3.0, n = 36) had lower circulating levels of IL-17 pathway proteins compared to untreated patients (PASI > 10, n = 23). Notably, IL-17C and PI3 were decreased with all four examined systemic treatment types. Furthermore, in patients without CVD, we observed strong correlations among IL-17C/PI3/PASI (r ≥ 0.82, p ≤ 1.5 × 10−12) pairs or between IL-17A/PASI (r = 0.72, p = 9.3 × 10−8). In patients with CVD, the IL-17A/PASI correlation was abolished (r = 0.2, p = 0.24) and the other correlations were decreased, e.g., IL-17C/PI3 (r = 0.61, p = 4.5 × 10−5). Patients with moderate-to-severe psoriasis and CVD had lower levels of IL-17A compared to those without CVD (normalized protein expression [NPX] 2.02 vs. 2.55, p = 0.013), and lower IL-17A levels (NPX < 2.3) were associated with higher incidence of CVD (OR = 24.5, p = 0.0028, 95% CI 2.1–1425.1). As a result, in patients with moderate-to-severe psoriasis, we propose circulating IL-17C and PI3 as potential biomarkers of effective systemic anti-psoriatic treatment, and IL-17A as potential marker of CVD. Full article
(This article belongs to the Special Issue Interconnecting Cytokine-Associated Molecular Pathways and Pathogenesis of Inflammatory Skin Diseases)
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10 pages, 1446 KiB  
Article
The microRNA-455 Null Mouse Has Memory Deficit and Increased Anxiety, Targeting Key Genes Involved in Alzheimer’s Disease
by Tracey E. Swingler, Lingzi Niu, Matthew G. Pontifex, David Vauzour and Ian M. Clark
Int. J. Mol. Sci. 2022, 23(1), 554; https://doi.org/10.3390/ijms23010554 - 05 Jan 2022
Cited by 7 | Viewed by 2886
Abstract
The complete molecular mechanisms underlying the pathophysiology of Alzheimer’s disease (AD) remain to be elucidated. Recently, microRNA-455-3p has been identified as a circulating biomarker of early AD, with increased expression in post-mortem brain tissue of AD patients. MicroRNA-455-3p also directly targets and down-regulates [...] Read more.
The complete molecular mechanisms underlying the pathophysiology of Alzheimer’s disease (AD) remain to be elucidated. Recently, microRNA-455-3p has been identified as a circulating biomarker of early AD, with increased expression in post-mortem brain tissue of AD patients. MicroRNA-455-3p also directly targets and down-regulates APP, with the overexpression of miR-455-3p suppressing its toxic effects. Here, we show that miR-455-3p expression decreases with age in the brains of wild-type mice. We generated a miR-455 null mouse utilising CRISPR-Cas9 to explore its function further. Loss of miR-455 resulted in increased weight gain, potentially indicative of metabolic disturbances. Furthermore, performance on the novel object recognition task diminished significantly in miR-455 null mice (p = 0.004), indicating deficits in recognition memory. A slight increase in anxiety was also captured on the open field test. BACE1 and TAU were identified as new direct targets for miR-455-3p, with overexpression of miR-455-3p leading to a reduction in the expression of APP, BACE1 and TAU in neuroblastoma cells. In the hippocampus of miR-455 null mice at 14 months of age, the levels of protein for APP, BACE1 and TAU were all increased. Such findings reinforce the involvement of miR-455 in AD progression and demonstrate its action on cognitive performance. Full article
(This article belongs to the Topic Emerging Translational Research in Neurological and Psychiatric Diseases: From In Vitro to In Vivo Models)
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15 pages, 3907 KiB  
Article
Indigo Pulverata Levis (Chung-Dae, Persicaria tinctoria) Alleviates Atopic Dermatitis-like Inflammatory Responses In Vivo and In Vitro
by Ga-Yul Min, Ji-Hye Kim, Tae-In Kim, Won-Kyung Cho, Ju-Hye Yang and Jin-Yeul Ma
Int. J. Mol. Sci. 2022, 23(1), 553; https://doi.org/10.3390/ijms23010553 - 05 Jan 2022
Cited by 7 | Viewed by 3022
Abstract
Atopic dermatitis (AD) is a chronic inflammatory skin disease associated with a type 2 T helper cell (Th2) immune response. The IndigoPulverata Levis extract (CHD) is used in traditional Southeast Asian medicine; however, its beneficial effects on AD remain uninvestigated. Therefore, we [...] Read more.
Atopic dermatitis (AD) is a chronic inflammatory skin disease associated with a type 2 T helper cell (Th2) immune response. The IndigoPulverata Levis extract (CHD) is used in traditional Southeast Asian medicine; however, its beneficial effects on AD remain uninvestigated. Therefore, we investigated the therapeutic effects of CHD in 2,4-dinitrochlorobenzene (DNCB)-induced BALB/c mice and tumor necrosis factor (TNF)-α- and interferon gamma (IFN)-γ-stimulated HaCaT cells. We evaluated immune cell infiltration, skin thickness, and the serum IgE and TNF-α levels in DNCB-induced AD mice. Moreover, we measured the expression levels of pro-inflammatory cytokines, mitogen-activated protein kinase (MAPK), and the nuclear factor-kappa B (NF-κB) in the mice dorsal skin. We also studied the effect of CHD on the translocation of NF-κB p65 and inflammatory chemokines in HaCaT cells. Our in vivo results revealed that CHD reduced the dermis and epidermis thicknesses and inhibited immune cell infiltration. Furthermore, it suppressed the proinflammatory cytokine expression and MAPK and NF-κB phosphorylations in the skin tissue and decreased serum IgE and TNF-α levels. In vitro results indicated that CHD downregulated inflammatory chemokines and blocked NF-κB p65 translocation. Thus, we deduced that CHD is a potential drug candidate for AD treatment. Full article
(This article belongs to the Special Issue Biological Interactions of Bioactive Natural Products)
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39 pages, 4273 KiB  
Review
Genetics of Autosomal Recessive Spastic Ataxia of Charlevoix-Saguenay (ARSACS) and Role of Sacsin in Neurodegeneration
by Jaya Bagaria, Eva Bagyinszky and Seong Soo A. An
Int. J. Mol. Sci. 2022, 23(1), 552; https://doi.org/10.3390/ijms23010552 - 04 Jan 2022
Cited by 9 | Viewed by 7393
Abstract
Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) is an early-onset neurodegenerative disease that was originally discovered in the population from the Charlevoix-Saguenay-Lac-Saint-Jean (CSLSJ) region in Quebec. Although the disease progression of ARSACS may start in early childhood, cases with later onset have also [...] Read more.
Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) is an early-onset neurodegenerative disease that was originally discovered in the population from the Charlevoix-Saguenay-Lac-Saint-Jean (CSLSJ) region in Quebec. Although the disease progression of ARSACS may start in early childhood, cases with later onset have also been observed. Spasticity and ataxia could be common phenotypes, and retinal optic nerve hypermyelination is detected in the majority of patients. Other symptoms, such as pes cavus, ataxia and limb deformities, are also frequently observed in affected individuals. More than 200 mutations have been discovered in the SACS gene around the world. Besides French Canadians, SACS genetics have been extensively studied in Tunisia or Japan. Recently, emerging studies discovered SACS mutations in several other countries. SACS mutations could be associated with pathogenicity either in the homozygous or compound heterozygous stages. Sacsin has been confirmed to be involved in chaperon activities, controlling the microtubule balance or cell migration. Additionally, sacsin may also play a crucial role in regulating the mitochondrial functions. Through these mechanisms, it may share common mechanisms with other neurodegenerative diseases. Further studies are needed to define the exact functions of sacsin. This review introduces the genetic mutations discovered in the SACS gene and discusses its pathomechanisms and its possible involvement in other neurodegenerative diseases. Full article
(This article belongs to the Special Issue Molecular Genetics in Neurodegenerative Disorders)
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22 pages, 2914 KiB  
Article
Thymosin β4 Is an Endogenous Iron Chelator and Molecular Switcher of Ferroptosis
by Joanna I. Lachowicz, Giusi Pichiri, Marco Piludu, Sara Fais, Germano Orrù, Terenzio Congiu, Monica Piras, Gavino Faa, Daniela Fanni, Gabriele Dalla Torre, Xabier Lopez, Kousik Chandra, Kacper Szczepski, Lukasz Jaremko, Mitra Ghosh, Abdul-Hamid Emwas, Massimo Castagnola, Mariusz Jaremko, Ewald Hannappel and Pierpaolo Coni
Int. J. Mol. Sci. 2022, 23(1), 551; https://doi.org/10.3390/ijms23010551 - 04 Jan 2022
Cited by 16 | Viewed by 3517
Abstract
Thymosin β4 (Tβ4) was extracted forty years agofrom calf thymus. Since then, it has been identified as a G-actin binding protein involved in blood clotting, tissue regeneration, angiogenesis, and anti-inflammatory processes. Tβ4 has also been implicated in tumor metastasis and neurodegeneration. However, the [...] Read more.
Thymosin β4 (Tβ4) was extracted forty years agofrom calf thymus. Since then, it has been identified as a G-actin binding protein involved in blood clotting, tissue regeneration, angiogenesis, and anti-inflammatory processes. Tβ4 has also been implicated in tumor metastasis and neurodegeneration. However, the precise roles and mechanism(s) of action of Tβ4 in these processes remain largely unknown, with the binding of the G-actin protein being insufficient to explain these multi-actions. Here we identify for the first time the important role of Tβ4 mechanism in ferroptosis, an iron-dependent form of cell death, which leads to neurodegeneration and somehow protects cancer cells against cell death. Specifically, we demonstrate four iron2+ and iron3+ binding regions along the peptide and show that the presence of Tβ4 in cell growing medium inhibits erastin and glutamate-induced ferroptosis in the macrophage cell line. Moreover, Tβ4 increases the expression of oxidative stress-related genes, namely BAX, hem oxygenase-1, heat shock protein 70 and thioredoxin reductase 1, which are downregulated during ferroptosis. We state the hypothesis that Tβ4 is an endogenous iron chelator and take part in iron homeostasis in the ferroptosis process. We discuss the literature data of parallel involvement of Tβ4 and ferroptosis in different human pathologies, mainly cancer and neurodegeneration. Our findings confronted with literature data show that controlled Tβ4 release could command on/off switching of ferroptosis and may provide novel therapeutic opportunities in cancer and tissue degeneration pathologies. Full article
(This article belongs to the Section Biochemistry)
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18 pages, 1868 KiB  
Article
Insights into the Structure and Protein Composition of Moorella thermoacetica Spores Formed at Different Temperatures
by Tiffany Malleck, Fatima Fekraoui, Isabelle Bornard, Céline Henry, Eloi Haudebourg, Stella Planchon and Véronique Broussolle
Int. J. Mol. Sci. 2022, 23(1), 550; https://doi.org/10.3390/ijms23010550 - 04 Jan 2022
Cited by 1 | Viewed by 2244
Abstract
The bacterium Moorella thermoacetica produces the most heat-resistant spores of any spoilage-causing microorganism known in the food industry. Previous work by our group revealed that the resistance of these spores to wet heat and biocides was lower when spores were produced at a [...] Read more.
The bacterium Moorella thermoacetica produces the most heat-resistant spores of any spoilage-causing microorganism known in the food industry. Previous work by our group revealed that the resistance of these spores to wet heat and biocides was lower when spores were produced at a lower temperature than the optimal temperature. Here, we used electron microcopy to characterize the ultrastructure of the coat of the spores formed at different sporulation temperatures; we found that spores produced at 55 °C mainly exhibited a lamellar inner coat tightly associated with a diffuse outer coat, while spores produced at 45 °C showed an inner and an outer coat separated by a less electron-dense zone. Moreover, misarranged coat structures were more frequently observed when spores were produced at the lower temperature. We then analyzed the proteome of the spores obtained at either 45 °C or 55 °C with respect to proteins putatively involved in the spore coat, exosporium, or in spore resistance. Some putative spore coat proteins, such as CotSA, were only identified in spores produced at 55 °C; other putative exosporium and coat proteins were significantly less abundant in spores produced at 45 °C. Altogether, our results suggest that sporulation temperature affects the structure and protein composition of M. thermoacetica spores. Full article
(This article belongs to the Special Issue Bacterial Endospores: Stress Resistance and Germination)
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Article
Biological Evaluation and Molecular Docking Studies of Novel 1,3,4-Oxadiazole Derivatives of 4,6-Dimethyl-2-sulfanylpyridine-3-carboxamide
by Piotr Świątek, Teresa Glomb, Agnieszka Dobosz, Tomasz Gębarowski, Kamil Wojtkowiak, Aneta Jezierska, Jarosław J. Panek, Małgorzata Świątek and Małgorzata Strzelecka
Int. J. Mol. Sci. 2022, 23(1), 549; https://doi.org/10.3390/ijms23010549 - 04 Jan 2022
Cited by 7 | Viewed by 3218
Abstract
To date, chronic inflammation is involved in most main human pathologies such as cancer, and autoimmune, cardiovascular or neurodegenerative disorders. Studies suggest that different prostanoids, especially prostaglandin E2, and their own synthase (cyclooxygenase enzyme-COX) can promote tumor growth by activating signaling [...] Read more.
To date, chronic inflammation is involved in most main human pathologies such as cancer, and autoimmune, cardiovascular or neurodegenerative disorders. Studies suggest that different prostanoids, especially prostaglandin E2, and their own synthase (cyclooxygenase enzyme-COX) can promote tumor growth by activating signaling pathways which control cell proliferation, migration, apoptosis, and angiogenesis. Non-steroidal anti-inflammatory drugs (NSAIDs) are used, alongside corticosteroids, to treat inflammatory symptoms particularly in all chronic diseases. However, their toxicity from COX inhibition and the suppression of physiologically important prostaglandins limits their use. Therefore, in continuation of our efforts in the development of potent, safe, non-toxic chemopreventive compounds, we report herein the design, synthesis, biological evaluation of new series of Schiff base-type hybrid compounds containing differently substituted N-acyl hydrazone moieties, 1,3,4-oxadiazole ring, and 4,6-dimethylpyridine core. The anti-COX-1/COX-2, antioxidant and anticancer activities were studied. Schiff base 13, containing 2-bromobenzylidene residue inhibited the activity of both isoenzymes, COX-1 and COX-2 at a lower concentration than standard drugs, and its COX-2/COX-1 selectivity ratio was similar to meloxicam. Furthermore, the results of cytotoxicity assay indicated that all of the tested compounds exhibited potent anti-cancer activity against A549, MCF-7, LoVo, and LoVo/Dx cell lines, compared with piroxicam and meloxicam. Moreover, our experimental study was supported by density functional theory (DFT) and molecular docking to describe the binding mode of new structures to cyclooxygenase. Full article
(This article belongs to the Special Issue Bioactive Oxadiazoles 2.0)
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