International Journal of Molecular Sciences

15 pages, 5917 KiB

Open AccessArticle

Properties of Transport Mediated by the Human Organic Cation Transporter 2 Studied in a Polarized Three-Dimensional Epithelial Cell Culture Model

by Tim N. Koepp, Alexander Tokaj, Pavel I. Nedvetsky, Ana Carolina Conchon Costa, Beatrice Snieder, Rita Schröter and Giuliano Ciarimboli

Int. J. Mol. Sci. 2021, 22(17), 9658; https://doi.org/10.3390/ijms22179658 - 6 Sep 2021

Cited by 8 | Viewed by 2770

Abstract

The renal secretory clearance for organic cations (neurotransmitters, metabolism products and drugs) is mediated by transporters specifically expressed in the basolateral and apical plasma membrane domains of proximal tubule cells. Here, human organic cation transporter 2 (hOCT2) is the main transporter for organic [...] Read more.

The renal secretory clearance for organic cations (neurotransmitters, metabolism products and drugs) is mediated by transporters specifically expressed in the basolateral and apical plasma membrane domains of proximal tubule cells. Here, human organic cation transporter 2 (hOCT2) is the main transporter for organic cations in the basolateral membrane domain. In this study, we stably expressed hOCT2 in Madin-Darby Canine Kidney (MDCK) cells and cultivated these cells in the presence of an extracellular matrix to obtain three-dimensional (3D) structures (cysts). The transport properties of hOCT2 expressed in MDCK cysts were compared with those measured using human embryonic kidney cells (HEK293) stably transfected with hOCT2 (hOCT2-HEK cells). In the MDCK cysts, hOCT2 was expressed in the basolateral membrane domain and showed a significant uptake of the fluorescent organic cation 4-(4-(dimethylamino)styryl)-N-methylpyridinium (ASP⁺) with an affinity (K_m) of 3.6 ± 1.2 µM, similar to what was measured in the hOCT2-HEK cells (K_m = 3.1 ± 0.2 µM). ASP⁺ uptake was inhibited by tetraethylammonium (TEA⁺), tetrapentylammonium (TPA⁺), metformin and baricitinib both in the hOCT2-HEK cells and the hOCT2- MDCK cysts, even though the apparent affinities of TEA⁺ and baricitinib were dependent on the expression system. Then, hOCT2 was subjected to the same rapid regulation by inhibition of p56^lck tyrosine kinase or calmodulin in the hOCT2-HEK cells and hOCT2- MDCK cysts. However, inhibition of casein kinase II regulated only activity of hOCT2 expressed in MDCK cysts and not in HEK cells. Taken together, these results suggest that the 3D cell culture model is a suitable tool for the functional analysis of hOCT2 transport properties, depending on cell polarization. Full article

(This article belongs to the Special Issue Physiology, Biochemistry, and Pharmacology of Transporters for Organic Cations 2.0)

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20 pages, 25014 KiB

Open AccessArticle

K-Mer Analyses Reveal Different Evolutionary Histories of Alpha, Beta, and Gamma Papillomaviruses

by Zigui Chen, Filippo Utro, Daniel Platt, Rob DeSalle, Laxmi Parida, Paul K. S. Chan and Robert D. Burk

Int. J. Mol. Sci. 2021, 22(17), 9657; https://doi.org/10.3390/ijms22179657 - 6 Sep 2021

Cited by 11 | Viewed by 3369

Abstract

Papillomaviruses (PVs) are a heterogeneous group of DNA viruses that can infect fish, birds, reptiles, and mammals. PVs infecting humans (HPVs) phylogenetically cluster into five genera (Alpha-, Beta-, Gamma-, Mu- and Nu-PV), with differences in tissue tropism and carcinogenicity. The evolutionary features associated [...] Read more.

Papillomaviruses (PVs) are a heterogeneous group of DNA viruses that can infect fish, birds, reptiles, and mammals. PVs infecting humans (HPVs) phylogenetically cluster into five genera (Alpha-, Beta-, Gamma-, Mu- and Nu-PV), with differences in tissue tropism and carcinogenicity. The evolutionary features associated with the divergence of Papillomaviridae are not well understood. Using a combination of k-mer distributions, genetic metrics, and phylogenetic algorithms, we sought to evaluate the characteristics and differences of Alpha-, Beta- and Gamma-PVs constituting the majority of HPV genomes. A total of 640 PVs including 442 HPV types, 27 non-human primate PV types, and 171 non-primate animal PV types were evaluated. Our analyses revealed the highest genetic diversity amongst Gamma-PVs compared to the Alpha and Beta PVs, suggesting reduced selective pressures on Gamma-PVs. Using a sequence alignment-free trimer (k = 3) phylogeny algorithm, we reconstructed a phylogeny that grouped most HPV types into a monophyletic clade that was further split into three branches similar to alignment-based classifications. Interestingly, a subset of low-risk Alpha HPVs (the species Alpha-2, 3, 4, and 14) split from other HPVs and were clustered with non-human primate PVs. Surprisingly, the trimer-constructed phylogeny grouped the Gamma-6 species types originally isolated from the cervicovaginal region with the main Alpha-HPV clade. These data indicate that characterization of papillomavirus heterogeneity via orthogonal approaches reveals novel insights into the biological understanding of HPV genomes. Full article

(This article belongs to the Special Issue Human Papillomavirus from Lab to Life: Insights from Molecular Researches)

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21 pages, 1235 KiB

Open AccessReview

Molecular Mechanisms of Nitric Oxide (NO) Signaling and Reactive Oxygen Species (ROS) Homeostasis during Abiotic Stresses in Plants

by Kaiser Iqbal Wani, M. Naeem, Christian Danve M. Castroverde, Hazem M. Kalaji, Mohammed Albaqami and Tariq Aftab

Int. J. Mol. Sci. 2021, 22(17), 9656; https://doi.org/10.3390/ijms22179656 - 6 Sep 2021

Cited by 70 | Viewed by 6858

Abstract

Abiotic stressors, such as drought, heavy metals, and high salinity, are causing huge crop losses worldwide. These abiotic stressors are expected to become more extreme, less predictable, and more widespread in the near future. With the rapidly growing human population and changing global [...] Read more.

Abiotic stressors, such as drought, heavy metals, and high salinity, are causing huge crop losses worldwide. These abiotic stressors are expected to become more extreme, less predictable, and more widespread in the near future. With the rapidly growing human population and changing global climate conditions, it is critical to prevent global crop losses to meet the increasing demand for food and other crop products. The reactive gaseous signaling molecule nitric oxide (NO) is involved in numerous plant developmental processes as well as plant responses to various abiotic stresses through its interactions with various molecules. Together, these interactions lead to the homeostasis of reactive oxygen species (ROS), proline and glutathione biosynthesis, post-translational modifications such as S-nitrosylation, and modulation of gene and protein expression. Exogenous application of various NO donors positively mitigates the negative effects of various abiotic stressors. In view of the multidimensional role of this signaling molecule, research over the past decade has investigated its potential in alleviating the deleterious effects of various abiotic stressors, particularly in ROS homeostasis. In this review, we highlight the recent molecular and physiological advances that provide insights into the functional role of NO in mediating various abiotic stress responses in plants. Full article

(This article belongs to the Special Issue ROS and Abiotic Stress in Plants 2.0)

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13 pages, 1281 KiB

Open AccessReview

ER-SURF: Riding the Endoplasmic Reticulum Surface to Mitochondria

by Christian Koch, Maya Schuldiner and Johannes M. Herrmann

Int. J. Mol. Sci. 2021, 22(17), 9655; https://doi.org/10.3390/ijms22179655 - 6 Sep 2021

Cited by 18 | Viewed by 6637

Abstract

Most mitochondrial proteins are synthesized in the cytosol and targeted to the mitochondrial surface in a post-translational manner. The surface of the endoplasmic reticulum (ER) plays an active role in this targeting reaction. ER-associated chaperones interact with certain mitochondrial membrane protein precursors and [...] Read more.

Most mitochondrial proteins are synthesized in the cytosol and targeted to the mitochondrial surface in a post-translational manner. The surface of the endoplasmic reticulum (ER) plays an active role in this targeting reaction. ER-associated chaperones interact with certain mitochondrial membrane protein precursors and transfer them onto receptor proteins of the mitochondrial surface in a process termed ER-SURF. ATP-driven proteins in the membranes of mitochondria (Msp1, ATAD1) and the ER (Spf1, P5A-ATPase) serve as extractors for the removal of mislocalized proteins. If the re-routing to mitochondria fails, precursors can be degraded by ER or mitochondria-associated degradation (ERAD or MAD respectively) in a proteasome-mediated reaction. This review summarizes the current knowledge about the cooperation of the ER and mitochondria in the targeting and quality control of mitochondrial precursor proteins. Full article

(This article belongs to the Special Issue Mechanisms of ER Protein Import)

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14 pages, 3128 KiB

Open AccessArticle

In Search of Monocot Phosphodiesterases: Identification of a Calmodulin Stimulated Phosphodiesterase from Brachypodium distachyon

by Mateusz Kwiatkowski, Aloysius Wong, Anna Kozakiewicz-Piekarz, Christoph Gehring and Krzysztof Jaworski

Int. J. Mol. Sci. 2021, 22(17), 9654; https://doi.org/10.3390/ijms22179654 - 6 Sep 2021

Cited by 9 | Viewed by 2489

Abstract

In plants, rapid and reversible biological responses to environmental cues may require complex cellular reprograming. This is enabled by signaling molecules such as the cyclic nucleotide monophosphates (cNMPs) cAMP and cGMP, as well as Ca²⁺. While the roles and synthesis of [...] Read more.

In plants, rapid and reversible biological responses to environmental cues may require complex cellular reprograming. This is enabled by signaling molecules such as the cyclic nucleotide monophosphates (cNMPs) cAMP and cGMP, as well as Ca²⁺. While the roles and synthesis of cAMP and cGMP in plants are increasingly well-characterized, the “off signal” afforded by cNMP-degrading enzymes, the phosphodiesterases (PDEs), is, however, poorly understood, particularly so in monocots. Here, we identified a candidate PDE from the monocot Brachypodium distachyon (BDPDE1) and showed that it can hydrolyze cNMPs to 5′NMPs but with a preference for cAMP over cGMP in vitro. Notably, the PDE activity was significantly enhanced by Ca²⁺ only in the presence of calmodulin (CaM), which interacts with BDPDE1, most likely at a predicted CaM-binding site. Finally, based on our biochemical, mutagenesis and structural analyses, we constructed a comprehensive amino acid consensus sequence extracted from the catalytic centers of annotated and/or experimentally validated PDEs across species to enable a broad application of this search motif for the identification of similar active sites in eukaryotes and prokaryotes. Full article

(This article belongs to the Special Issue New Horizons in Plant Cell Signaling)

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20 pages, 5855 KiB

Open AccessArticle

Entropy-Enthalpy Compensations Fold Proteins in Precise Ways

by Jiacheng Li, Chengyu Hou, Xiaoliang Ma, Shuai Guo, Hongchi Zhang, Liping Shi, Chenchen Liao, Bing Zheng, Lin Ye, Lin Yang and Xiaodong He

Int. J. Mol. Sci. 2021, 22(17), 9653; https://doi.org/10.3390/ijms22179653 - 6 Sep 2021

Cited by 13 | Viewed by 4361

Abstract

Exploring the protein-folding problem has been a longstanding challenge in molecular biology and biophysics. Intramolecular hydrogen (H)-bonds play an extremely important role in stabilizing protein structures. To form these intramolecular H-bonds, nascent unfolded polypeptide chains need to escape from hydrogen bonding with surrounding [...] Read more.

Exploring the protein-folding problem has been a longstanding challenge in molecular biology and biophysics. Intramolecular hydrogen (H)-bonds play an extremely important role in stabilizing protein structures. To form these intramolecular H-bonds, nascent unfolded polypeptide chains need to escape from hydrogen bonding with surrounding polar water molecules under the solution conditions that require entropy-enthalpy compensations, according to the Gibbs free energy equation and the change in enthalpy. Here, by analyzing the spatial layout of the side-chains of amino acid residues in experimentally determined protein structures, we reveal a protein-folding mechanism based on the entropy-enthalpy compensations that initially driven by laterally hydrophobic collapse among the side-chains of adjacent residues in the sequences of unfolded protein chains. This hydrophobic collapse promotes the formation of the H-bonds within the polypeptide backbone structures through the entropy-enthalpy compensation mechanism, enabling secondary structures and tertiary structures to fold reproducibly following explicit physical folding codes and forces. The temperature dependence of protein folding is thus attributed to the environment dependence of the conformational Gibbs free energy equation. The folding codes and forces in the amino acid sequence that dictate the formation of β-strands and α-helices can be deciphered with great accuracy through evaluation of the hydrophobic interactions among neighboring side-chains of an unfolded polypeptide from a β-strand-like thermodynamic metastable state. The folding of protein quaternary structures is found to be guided by the entropy-enthalpy compensations in between the docking sites of protein subunits according to the Gibbs free energy equation that is verified by bioinformatics analyses of a dozen structures of dimers. Protein folding is therefore guided by multistage entropy-enthalpy compensations of the system of polypeptide chains and water molecules under the solution conditions. Full article

(This article belongs to the Special Issue The Multiple and Dynamic Faces of Protein Structure: Folded States, Intrinsically Unfolded States, and Aggregates/Fibrils)

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93 pages, 37405 KiB

Open AccessReview

Advances in Chitosan-Based Nanoparticles for Drug Delivery

by Veronika Mikušová and Peter Mikuš

Int. J. Mol. Sci. 2021, 22(17), 9652; https://doi.org/10.3390/ijms22179652 - 6 Sep 2021

Cited by 252 | Viewed by 14943

Abstract

Nanoparticles (NPs) have an outstanding position in pharmaceutical, biological, and medical disciplines. Polymeric NPs based on chitosan (CS) can act as excellent drug carriers because of some intrinsic beneficial properties including biocompatibility, biodegradability, non-toxicity, bioactivity, easy preparation, and targeting specificity. Drug transport and [...] Read more.

Nanoparticles (NPs) have an outstanding position in pharmaceutical, biological, and medical disciplines. Polymeric NPs based on chitosan (CS) can act as excellent drug carriers because of some intrinsic beneficial properties including biocompatibility, biodegradability, non-toxicity, bioactivity, easy preparation, and targeting specificity. Drug transport and release from CS-based particulate systems depend on the extent of cross-linking, morphology, size, and density of the particulate system, as well as physicochemical properties of the drug. All these aspects have to be considered when developing new CS-based NPs as potential drug delivery systems. This comprehensive review is summarizing and discussing recent advances in CS-based NPs being developed and examined for drug delivery. From this point of view, an enhancement of CS properties by its modification is presented. An enhancement in drug delivery by CS NPs is discussed in detail focusing on (i) a brief summarization of basic characteristics of CS NPs, (ii) a categorization of preparation procedures used for CS NPs involving also recent improvements in production schemes of conventional as well as novel CS NPs, (iii) a categorization and evaluation of CS-based-nanocomposites involving their production schemes with organic polymers and inorganic material, and (iv) very recent implementations of CS NPs and nanocomposites in drug delivery. Full article

(This article belongs to the Special Issue Chitosan Functionalizations, Formulations and Composites 2.0)

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17 pages, 6130 KiB

Open AccessArticle

Genome-Wide Identification and Analysis of the Metallothionein Genes in Oryza Genus

by Mingxing Cheng, Huanran Yuan, Ruihua Wang, Jianing Zou, Ting Liang, Fang Yang and Shaoqing Li

Int. J. Mol. Sci. 2021, 22(17), 9651; https://doi.org/10.3390/ijms22179651 - 6 Sep 2021

Cited by 11 | Viewed by 3366

Abstract

Metallothionein (MT) proteins are low molecular mass, cysteine-rich, and metal-binding proteins that play an important role in maintaining metal homeostasis and stress response. However, the evolutionary relationships and functional differentiation of MT in the Oryza genus remain unclear. Here we identified 53 MT [...] Read more.

Metallothionein (MT) proteins are low molecular mass, cysteine-rich, and metal-binding proteins that play an important role in maintaining metal homeostasis and stress response. However, the evolutionary relationships and functional differentiation of MT in the Oryza genus remain unclear. Here we identified 53 MT genes from six Oryza genera, including O. sativa ssp. japonica, O. rufipogon, O. sativa ssp. indica, O. nivara, O. glumaepatula, and O. barthii. The MT genes were clustered into four groups based on phylogenetic analysis. MT genes are unevenly distributed on chromosomes; almost half of the MT genes were clustered on chromosome 12, which may result from a fragment duplication containing the MT genes on chromosome 12. Five pairs of segmental duplication events and ten pairs of tandem duplication events were found in the rice MT family. The Ka/Ks values of the fifteen duplicated MT genes indicated that the duplicated MT genes were under a strong negative selection during evolution. Next, combining the promoter activity assay with gene expression analysis revealed different expression patterns of MT genes. In addition, the expression of OsMT genes was induced under different stresses, including NaCl, CdCl₂, ABA, and MeJ treatments. Additionally, we found that OsMT genes were mainly located in chloroplasts. These results imply that OsMT genes play different roles in response to these stresses. All results provide important insights into the evolution of the MT gene family in the Oryza genus, and will be helpful to further study the function of MT genes. Full article

(This article belongs to the Special Issue Plant Genomics and Genome Editing)

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18 pages, 1979 KiB

Open AccessArticle

Multiple Imputation Approaches Applied to the Missing Value Problem in Bottom-Up Proteomics

by Miranda L. Gardner and Michael A. Freitas

Int. J. Mol. Sci. 2021, 22(17), 9650; https://doi.org/10.3390/ijms22179650 - 6 Sep 2021

Cited by 15 | Viewed by 4635

Abstract

Analysis of differential abundance in proteomics data sets requires careful application of missing value imputation. Missing abundance values widely vary when performing comparisons across different sample treatments. For example, one would expect a consistent rate of “missing at random” (MAR) across batches of [...] Read more.

Analysis of differential abundance in proteomics data sets requires careful application of missing value imputation. Missing abundance values widely vary when performing comparisons across different sample treatments. For example, one would expect a consistent rate of “missing at random” (MAR) across batches of samples and varying rates of “missing not at random” (MNAR) depending on the inherent difference in sample treatments within the study. The missing value imputation strategy must thus be selected that best accounts for both MAR and MNAR simultaneously. Several important issues must be considered when deciding the appropriate missing value imputation strategy: (1) when it is appropriate to impute data; (2) how to choose a method that reflects the combinatorial manner of MAR and MNAR that occurs in an experiment. This paper provides an evaluation of missing value imputation strategies used in proteomics and presents a case for the use of hybrid left-censored missing value imputation approaches that can handle the MNAR problem common to proteomics data. Full article

(This article belongs to the Section Biochemistry)

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15 pages, 2202 KiB

Open AccessReview

JNK Signaling in Drosophila Aging and Longevity

by Tian Gan, Lixia Fan, Long Zhao, Mala Misra, Min Liu, Min Zhang and Ying Su

Int. J. Mol. Sci. 2021, 22(17), 9649; https://doi.org/10.3390/ijms22179649 - 6 Sep 2021

Cited by 10 | Viewed by 5944

Abstract

The evolutionarily conserved c-Jun N-terminal kinase (JNK) signaling pathway is a critical genetic determinant in the control of longevity. In response to extrinsic and intrinsic stresses, JNK signaling is activated to protect cells from stress damage and promote survival. In Drosophila, global [...] Read more.

The evolutionarily conserved c-Jun N-terminal kinase (JNK) signaling pathway is a critical genetic determinant in the control of longevity. In response to extrinsic and intrinsic stresses, JNK signaling is activated to protect cells from stress damage and promote survival. In Drosophila, global JNK upregulation can delay aging and extend lifespan, whereas tissue/organ-specific manipulation of JNK signaling impacts lifespan in a context-dependent manner. In this review, focusing on several tissues/organs that are highly associated with age-related diseases—including metabolic organs (intestine and fat body), neurons, and muscles—we summarize the distinct effects of tissue/organ-specific JNK signaling on aging and lifespan. We also highlight recent progress in elucidating the molecular mechanisms underlying the tissue-specific effects of JNK activity. Together, these studies highlight an important and comprehensive role for JNK signaling in the regulation of longevity in Drosophila. Full article

(This article belongs to the Special Issue Function and Mechanisms of JNK Pathway)

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13 pages, 1927 KiB

Open AccessArticle

Deletion of Cdk5 in Macrophages Ameliorates Anti-Inflammatory Response during Endotoxemia through Induction of C-Maf and Il-10

by Pauline Pfänder, Ann-Kathrin Eiers, Ute Burret and Sabine Vettorazzi

Int. J. Mol. Sci. 2021, 22(17), 9648; https://doi.org/10.3390/ijms22179648 - 6 Sep 2021

Cited by 7 | Viewed by 2996

Abstract

Immune response control is critical as excessive cytokine production can be detrimental and damage the host. Interleukin-10 (Il-10), an anti-inflammatory cytokine produced primarily by macrophages, is a key regulator that counteracts and controls excessive inflammatory response. Il-10 expression is regulated through the transcription [...] Read more.

Immune response control is critical as excessive cytokine production can be detrimental and damage the host. Interleukin-10 (Il-10), an anti-inflammatory cytokine produced primarily by macrophages, is a key regulator that counteracts and controls excessive inflammatory response. Il-10 expression is regulated through the transcription factor c-Maf. Another regulator of Il-10 production is p35, an activator of the cyclin-dependent kinase 5 (Cdk5), which decreases Il-10 production in macrophages, thus increasing inflammation. However, Cdk5 regulation of c-Maf and the involvement of Il-10 production in macrophages has not yet been investigated. We used in vitro primary bone marrow-derived macrophages (BMDMs) lacking Cdk5, stimulated them with lipopolysaccharid (LPS) and observed increased levels of c-Maf and Il-10. In an in vivo mouse model of LPS-induced endotoxemia, mice lacking Cdk5 in macrophages showed increased levels of c-Maf and elevated levels of Il-10 in lungs as well as in plasma, resulting in ameliorated survival. Taken together, we identified Cdk5 as a potential novel regulator of Il-10 production through c-Maf in macrophages under inflammatory conditions. Our results suggest that inhibition of Cdk5 enhances the c-Maf-Il-10 axis and thus potentiates improvement of anti-inflammatory therapy. Full article

(This article belongs to the Special Issue Regulation of Inflammatory Reactions in Health and Disease)

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17 pages, 2233 KiB

Open AccessArticle

Characterization of Protocatechuate 4,5-Dioxygenase from Pseudarthrobacter phenanthrenivorans Sphe3 and In Situ Reaction Monitoring in the NMR Tube

by Epameinondas Tsagogiannis, Elpiniki Vandera, Alexandra Primikyri, Stamatia Asimakoula, Andreas G. Tzakos, Ioannis P. Gerothanassis and Anna-Irini Koukkou

Int. J. Mol. Sci. 2021, 22(17), 9647; https://doi.org/10.3390/ijms22179647 - 6 Sep 2021

Cited by 13 | Viewed by 3604

Abstract

The current study aims at the functional and kinetic characterization of protocatechuate (PCA) 4,5-dioxygenase (PcaA) from Pseudarthrobacter phenanthrenivorans Sphe3. This is the first single subunit Type II dioxygenase characterized in Actinobacteria. RT-PCR analysis demonstrated that pcaA and the adjacent putative genes implicated [...] Read more.

The current study aims at the functional and kinetic characterization of protocatechuate (PCA) 4,5-dioxygenase (PcaA) from Pseudarthrobacter phenanthrenivorans Sphe3. This is the first single subunit Type II dioxygenase characterized in Actinobacteria. RT-PCR analysis demonstrated that pcaA and the adjacent putative genes implicated in the PCA meta-cleavage pathway comprise a single transcriptional unit. The recombinant PcaA is highly specific for PCA and exhibits Michaelis–Menten kinetics with K_m and V_max values of 21 ± 1.6 μM and 44.8 ± 4.0 U × mg⁻¹, respectively, in pH 9.5 and at 20 °C. PcaA also converted gallate from a broad range of substrates tested. The enzymatic reaction products were identified and characterized, for the first time, through in situ biotransformation monitoring inside an NMR tube. The PCA reaction product demonstrated a keto-enol tautomerization, whereas the gallate reaction product was present only in the keto form. Moreover, the transcriptional levels of pcaA and pcaR (gene encoding a LysR-type regulator of the pathway) were also determined, showing an induction when cells were grown on PCA and phenanthrene. Studying key enzymes in biodegradation pathways is significant for bioremediation and for efficient biocatalysts development. Full article

(This article belongs to the Section Molecular Microbiology)

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11 pages, 3650 KiB

Open AccessArticle

The Reactivity of Azidonitrobenzofuroxans towards 1,3-Dicarbonyl Compounds: Unexpected Formation of Amino Derivative via the Regitz Diazo Transfer and Tautomerism Study

by Elena Chugunova, Almir Gazizov, Daut Islamov, Alexander Burilov, Alena Tulesinova, Sergey Kharlamov, Victor Syakaev, Vasily Babaev, Nurgali Akylbekov, Nurbol Appazov, Konstantin Usachev and Rakhmetulla Zhapparbergenov

Int. J. Mol. Sci. 2021, 22(17), 9646; https://doi.org/10.3390/ijms22179646 - 6 Sep 2021

Cited by 3 | Viewed by 2521

Abstract

Herein, we report on the reaction of nitro-substituted azidobenzofuroxans with 1,3-dicarbonyl compounds in basic media. The known reactions of benzofuroxans and azidofuroxans with 1,3-dicarbonyl compounds in the presence of bases are the 1,3-dipolar cycloaddition and the Beirut reaction. In contrast with this, azidonitrobenzofuroxan [...] Read more.

Herein, we report on the reaction of nitro-substituted azidobenzofuroxans with 1,3-dicarbonyl compounds in basic media. The known reactions of benzofuroxans and azidofuroxans with 1,3-dicarbonyl compounds in the presence of bases are the 1,3-dipolar cycloaddition and the Beirut reaction. In contrast with this, azidonitrobenzofuroxan reacts with 1,3-carbonyl compounds through Regitz diazo transfer, which is the first example of this type of reaction for furoxan derivatives. This difference is seemingly due to the strong electron-withdrawing effect of the superelectrophilic azidonitrobenzofuroxan, which serves as the azido transfer agent rather than 1,3-dipole in this case. Full article

(This article belongs to the Special Issue Bioactive Oxadiazoles 2.0)

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25 pages, 7016 KiB

Open AccessArticle

In Silico Screening of Novel α1-GABA_A Receptor PAMs towards Schizophrenia Based on Combined Modeling Studies of Imidazo [1,2-a]-Pyridines

by Xiaojiao Zheng, Chenchen Wang, Na Zhai, Xiaogang Luo, Genyan Liu and Xiulian Ju

Int. J. Mol. Sci. 2021, 22(17), 9645; https://doi.org/10.3390/ijms22179645 - 6 Sep 2021

Cited by 12 | Viewed by 3712

Abstract

The ionotropic GABA_A receptor (GABA_AR) has been proven to be an important target of atypical antipsychotics. A novel series of imidazo [1,2-a]-pyridine derivatives, as selective positive allosteric modulators (PAMs) of α1-containing GABA_ARs with potent antipsychotic activities, have been [...] Read more.

The ionotropic GABA_A receptor (GABA_AR) has been proven to be an important target of atypical antipsychotics. A novel series of imidazo [1,2-a]-pyridine derivatives, as selective positive allosteric modulators (PAMs) of α1-containing GABA_ARs with potent antipsychotic activities, have been reported recently. To better clarify the pharmacological essentiality of these PAMs and explore novel antipsychotics hits, three-dimensional quantitative structure–activity relationships (3D-QSAR), molecular docking, pharmacophore modeling, and molecular dynamics (MD) were performed on 33 imidazo [1,2-a]-pyridines. The constructed 3D-QSAR models exhibited good predictive abilities. The dockings results and MD simulations demonstrated that hydrogen bonds, π–π stackings, and hydrophobic interactions play essential roles in the binding of these novel PAMs in the GABA_AR binding pocket. Four hit compounds (DS01–04) were then screened out by the combination of the constructed models and computations, including the pharmacophore model, Topomer Search, molecular dockings, ADME/T predictions, and MD simulations. The compounds DS03 and DS04, with higher docking scores and better predicted activities, were also found to be relatively stable in the binding pocket by MD simulations. These results might provide a significant theoretical direction or information for the rational design and development of novel α1-GABA_AR PAMs with antipsychotic activities. Full article

(This article belongs to the Special Issue QSAR and Chemoinformatics in Molecular Modeling and Drug Design 2.0)

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20 pages, 1178 KiB

Open AccessReview

New Advances in the Research of Resistance to Neoadjuvant Chemotherapy in Breast Cancer

by Junsha An, Cheng Peng, Hailin Tang, Xiuxiu Liu and Fu Peng

Int. J. Mol. Sci. 2021, 22(17), 9644; https://doi.org/10.3390/ijms22179644 - 6 Sep 2021

Cited by 45 | Viewed by 5896

Abstract

Breast cancer has an extremely high incidence in women, and its morbidity and mortality rank first among female tumors. With the increasing development of medicine today, the clinical application of neoadjuvant chemotherapy has brought new hope to the treatment of breast cancer. Although [...] Read more.

Breast cancer has an extremely high incidence in women, and its morbidity and mortality rank first among female tumors. With the increasing development of medicine today, the clinical application of neoadjuvant chemotherapy has brought new hope to the treatment of breast cancer. Although the efficacy of neoadjuvant chemotherapy has been confirmed, drug resistance is one of the main reasons for its treatment failure, contributing to the difficulty in the treatment of breast cancer. This article focuses on multiple mechanisms of action and expounds a series of recent research advances that mediate drug resistance in breast cancer cells. Drug metabolizing enzymes can mediate a catalytic reaction to inactivate chemotherapeutic drugs and develop drug resistance. The drug efflux system can reduce the drug concentration in breast cancer cells. The combination of glutathione detoxification system and platinum drugs can cause breast cancer cells to be insensitive to drugs. Changes in drug targets have led to poorer efficacy of HER2 receptor inhibitors. Moreover, autophagy, epithelial–mesenchymal transition, and tumor microenvironment can all contribute to the development of resistance in breast cancer cells. Based on the relevant research on the existing drug resistance mechanism, the current treatment plan for reversing the resistance of breast cancer to neoadjuvant chemotherapy is explored, and the potential drug targets are analyzed, aiming to provide a new idea and strategy to reverse the resistance of neoadjuvant chemotherapy drugs in breast cancer. Full article

(This article belongs to the Special Issue Molecular Research and Treatment of Breast Cancer)

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26 pages, 501 KiB

Open AccessReview

Bleeding and Thrombosis: Insights into Pathophysiology of Bothrops Venom-Related Hemostasis Disorders

by Sébastien Larréché, Jean-Philippe Chippaux, Lucie Chevillard, Simon Mathé, Dabor Résière, Virginie Siguret and Bruno Mégarbane

Int. J. Mol. Sci. 2021, 22(17), 9643; https://doi.org/10.3390/ijms22179643 - 6 Sep 2021

Cited by 37 | Viewed by 4048

Abstract

Toxins from Bothrops venoms targeting hemostasis are responsible for a broad range of clinical and biological syndromes including local and systemic bleeding, incoagulability, thrombotic microangiopathy and macrothrombosis. Beyond hemostais disorders, toxins are also involved in the pathogenesis of edema and in most complications [...] Read more.

Toxins from Bothrops venoms targeting hemostasis are responsible for a broad range of clinical and biological syndromes including local and systemic bleeding, incoagulability, thrombotic microangiopathy and macrothrombosis. Beyond hemostais disorders, toxins are also involved in the pathogenesis of edema and in most complications such as hypovolemia, cardiovascular collapse, acute kidney injury, myonecrosis, compartmental syndrome and superinfection. These toxins can be classified as enzymatic proteins (snake venom metalloproteinases, snake venom serine proteases, phospholipases A₂ and L-amino acid oxidases) and non-enzymatic proteins (desintegrins and C-type lectin proteins). Bleeding is due to a multifocal toxicity targeting vessels, platelets and coagulation factors. Vessel damage due to the degradation of basement membrane and the subsequent disruption of endothelial cell integrity under hydrostatic pressure and tangential shear stress is primarily responsible for bleeding. Hemorrhage is promoted by thrombocytopenia, platelet hypoaggregation, consumption coagulopathy and fibrin(ogen)olysis. Onset of thrombotic microangiopathy is probably due to the switch of endothelium to a prothrombotic phenotype with overexpression of tissue factor and other pro-aggregating biomarkers in association with activation of platelets and coagulation. Thrombosis involving large-caliber vessels in B. lanceolatus envenomation remains a unique entity, which exact pathophysiology remains poorly understood. Full article

(This article belongs to the Special Issue Venom Proteomics and Transcriptomics 2.0)

20 pages, 7053 KiB

Open AccessArticle

Tissue-Specific Proteome and Subcellular Microscopic Analyses Reveal the Effect of High Salt Concentration on Actin Cytoskeleton and Vacuolization in Aleurone Cells during Early Germination of Barley

by Georgi Dermendjiev, Madeleine Schnurer, Jakob Weiszmann, Sarah Wilfinger, Emanuel Ott, Claudia Gebert, Wolfram Weckwerth and Verena Ibl

Int. J. Mol. Sci. 2021, 22(17), 9642; https://doi.org/10.3390/ijms22179642 - 6 Sep 2021

Cited by 7 | Viewed by 3091

Abstract

Cereal grain germination provides the basis for crop production and requires a tissue-specific interplay between the embryo and endosperm during heterotrophic germination involving signalling, protein secretion, and nutrient uptake until autotrophic growth is possible. High salt concentrations in soil are one of the [...] Read more.

Cereal grain germination provides the basis for crop production and requires a tissue-specific interplay between the embryo and endosperm during heterotrophic germination involving signalling, protein secretion, and nutrient uptake until autotrophic growth is possible. High salt concentrations in soil are one of the most severe constraints limiting the germination of crop plants, affecting the metabolism and redox status within the tissues of germinating seed. However, little is known about the effect of salt on seed storage protein mobilization, the endomembrane system, and protein trafficking within and between these tissues. Here, we used mass spectrometry analyses to investigate the protein dynamics of the embryo and endosperm of barley (Hordeum vulgare, L.) at five different early points during germination (0, 12, 24, 48, and 72 h after imbibition) in germinated grains subjected to salt stress. The expression of proteins in the embryo as well as in the endosperm was temporally regulated. Seed storage proteins (SSPs), peptidases, and starch-digesting enzymes were affected by salt. Additionally, microscopic analyses revealed an altered assembly of actin bundles and morphology of protein storage vacuoles (PSVs) in the aleurone layer. Our results suggest that besides the salt-induced protein expression, intracellular trafficking and actin cytoskeleton assembly are responsible for germination delay under salt stress conditions. Full article

(This article belongs to the Special Issue Morphology and Physiology of Seeds and Other Plant Storage Tissues)

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26 pages, 592 KiB

Open AccessReview

The Role of the Gut Microbiome in Diabetes and Obesity-Related Kidney Disease

by Amgad Zaky, Sarah J. Glastras, May Y. W. Wong, Carol A. Pollock and Sonia Saad

Int. J. Mol. Sci. 2021, 22(17), 9641; https://doi.org/10.3390/ijms22179641 - 6 Sep 2021

Cited by 97 | Viewed by 10824

Abstract

Diabetic kidney disease (DKD) is a progressive disorder, which is increasing globally in prevalence due to the increased incidence of obesity and diabetes mellitus. Despite optimal clinical management, a significant number of patients with diabetes develop DKD. Hence, hitherto unrecognized factors are likely [...] Read more.

Diabetic kidney disease (DKD) is a progressive disorder, which is increasing globally in prevalence due to the increased incidence of obesity and diabetes mellitus. Despite optimal clinical management, a significant number of patients with diabetes develop DKD. Hence, hitherto unrecognized factors are likely to be involved in the initiation and progression of DKD. An extensive number of studies have demonstrated the role of microbiota in health and disease. Dysregulation in the microbiota resulting in a deficiency of short chain fatty acids (SCFAs) such as propionate, acetate, and butyrate, by-products of healthy gut microbiota metabolism, have been demonstrated in obesity, type 1 and type 2 diabetes. However, it is not clear to date whether such changes in the microbiota are causative or merely associated with the diseases. It is also not clear which microbiota have protective effects on humans. Few studies have investigated the centrality of reduced SCFA in DKD development and progression or the potential therapeutic effects of supplemental SCFAs on insulin resistance, inflammation, and metabolic changes. SCFA receptors are expressed in the kidneys, and emerging data have demonstrated that intestinal dysbiosis activates the renal renin-angiotensin system, which contributes to the development of DKD. In this review, we will summarize the complex relationship between the gut microbiota and the kidney, examine the evidence for the role of gut dysbiosis in diabetes and obesity-related kidney disease, and explore the mechanisms involved. In addition, we will describe the role of potential therapies that modulate the gut microbiota to prevent or reduce kidney disease progression. Full article

(This article belongs to the Special Issue Early Life Nutrition and the Development of Offspring Metabolic Health)

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15 pages, 12649 KiB

Open AccessReview

The Roles of c-Jun N-Terminal Kinase (JNK) in Infectious Diseases

by Jing Chen, Chao Ye, Chao Wan, Gang Li, Lianci Peng, Yuanyi Peng and Rendong Fang

Int. J. Mol. Sci. 2021, 22(17), 9640; https://doi.org/10.3390/ijms22179640 - 6 Sep 2021

Cited by 29 | Viewed by 4571

Abstract

c-Jun N-terminal kinases (JNKs) are among the most crucial mitogen-activated protein kinases (MAPKs) and regulate various cellular processes, including cell proliferation, apoptosis, autophagy, and inflammation. Microbes heavily rely on cellular signaling pathways for their effective replication; hence, JNKs may play important roles in [...] Read more.

c-Jun N-terminal kinases (JNKs) are among the most crucial mitogen-activated protein kinases (MAPKs) and regulate various cellular processes, including cell proliferation, apoptosis, autophagy, and inflammation. Microbes heavily rely on cellular signaling pathways for their effective replication; hence, JNKs may play important roles in infectious diseases. In this review, we describe the basic signaling properties of MAPKs and JNKs in apoptosis, autophagy, and inflammasome activation. Furthermore, we discuss the roles of JNKs in various infectious diseases induced by viruses, bacteria, fungi, and parasites, as well as their potential to serve as targets for the development of therapeutic agents for infectious diseases. We expect this review to expand our understanding of the JNK signaling pathway’s role in infectious diseases and provide important clues for the prevention and treatment of infectious diseases. Full article

(This article belongs to the Section Biochemistry)

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21 pages, 6473 KiB

Open AccessArticle

NK Cells Lose Their Cytotoxicity Function against Cancer Stem Cell-Rich Radiotherapy-Resistant Breast Cancer Cell Populations

by Hana Jin and Hye Jung Kim

Int. J. Mol. Sci. 2021, 22(17), 9639; https://doi.org/10.3390/ijms22179639 - 6 Sep 2021

Cited by 11 | Viewed by 4048

Abstract

Cancer stem cells (CSCs) can be induced from differentiated cancer cells in the tumor microenvironment or in response to treatments and exhibit chemo- and radioresistance, leading to tumor recurrence and metastasis. We previously reported that triple negative breast cancer (TNBC) cells with acquired [...] Read more.

Cancer stem cells (CSCs) can be induced from differentiated cancer cells in the tumor microenvironment or in response to treatments and exhibit chemo- and radioresistance, leading to tumor recurrence and metastasis. We previously reported that triple negative breast cancer (TNBC) cells with acquired radioresistance exhibited more aggressive features due to an increased CSC population. Therefore, here, we isolated CSCs from radiotherapy-resistant (RT-R)-TNBC cells and investigated the effects of these CSCs on tumor progression and NK cell-mediated cytotoxicity. Compared to MDA-MB-231 and RT-R-MDA-MB-231 cells, CD24^−/low/CD44⁺ cells isolated from RT-R-MDA-MB-231 cells showed increased proliferation, migration and invasion abilities, and induced expression of tumor progression-related molecules. Moreover, similar to MDA-MB-231 cells, CD24^−/low/CD44⁺ cells recruited NK cells but suppressed NK cell cytotoxicity by regulating ligands for NK cell activation. In an in vivo model, CD24^−/low/CD44⁺ cell-injected mice showed enhanced tumor progression and lung metastasis via upregulation of tumor progression-related molecules and altered host immune responses. Specifically, NK cells were recruited into the peritumoral area tumor but lost their cytotoxicity due to the altered expression of activating and inhibitory ligands on tumors. These results suggest that CSCs may cause tumor evasion of immune cells, resulting in tumor progression. Full article

(This article belongs to the Special Issue Cancer Stem Cells)

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12 pages, 3673 KiB

Open AccessArticle

Application of Immunoprofiling Using Multiplexed Immunofluorescence Staining Identifies the Prognosis of Patients with High-Grade Serous Ovarian Cancer

by Shin-Wha Lee, Ha-Young Lee, Sung Wan Kang, Min Je Kim, Young-Jae Lee, Chang Ohk Sung and Yong-Man Kim

Int. J. Mol. Sci. 2021, 22(17), 9638; https://doi.org/10.3390/ijms22179638 - 6 Sep 2021

Cited by 6 | Viewed by 2668

Abstract

Immunoprofiling has an established impact on the prognosis of several cancers; however, its role and definition in high-grade serous ovarian cancer (HGSOC) are mostly unknown. This study is to investigate immunoprofiling which could be a prognostic factor in HGSOC. We produced tumor microarrays [...] Read more.

Immunoprofiling has an established impact on the prognosis of several cancers; however, its role and definition in high-grade serous ovarian cancer (HGSOC) are mostly unknown. This study is to investigate immunoprofiling which could be a prognostic factor in HGSOC. We produced tumor microarrays of 187 patients diagnosed with HGSOC. We performed a multiplexed immunofluorescence staining using Opal Multiplex IHC kit and quantitative analysis with Vectra-Inform system. The expression intensities of programmed death-ligand 1 (PD-L1), CD4, CD8, CD20, FoxP3, and CK in whole tumor tissues were evaluated. The enrolled patients showed general characteristics, mostly FIGO stage III/IV and responsive to chemotherapy. Each immune marker showed diverse positive densities, and each tumor sample represented its immune characteristics as an inflamed tumor or noninflamed tumor. No marker was associated with survival as a single one. Interestingly, high ratios of CD8 to FoxP3 and CD8 to PD-L1 were related to the favorable overall survival (77 vs. 39 months, 84 vs. 47 months, respectively), and CD8 to PD-L1 ratio was also a significant prognostic factor (HR 0.621, 95% CI 0.420–0.917, p = 0.017) along with well-known clinical prognostic factors. Additionally, CD8 to PD-L1 ratio was found to be higher in the chemosensitive group (p = 0.034). In conclusion, the relative expression levels of CD8, FoxP3, and PD-L1 were significantly related to the clinical outcome of patients with HGSOC, which could be a kind of significant immunoprofiling of ovarian cancer patients to apply for treatment. Full article

(This article belongs to the Special Issue The Promise of Precision Oncology 2.0: Molecular Strategies, Methods, Pharmacogenomics and Informatics)

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16 pages, 4267 KiB

Open AccessArticle

Fabrication of Hydroxyapatite with Bioglass Nanocomposite for Human Wharton’s-Jelly-Derived Mesenchymal Stem Cell Growing Substrate

by Shamsi Ebrahimi, Yusoff Umul Hanim, Coswald Stephen Sipaut, Norsazlina binti Ahmad Jan, Sazmal E. Arshad and Siew Eng How

Int. J. Mol. Sci. 2021, 22(17), 9637; https://doi.org/10.3390/ijms22179637 - 6 Sep 2021

Cited by 10 | Viewed by 2534

Abstract

Recently, composite scaffolding has found many applications in hard tissue engineering due to a number of desirable features. In this present study, hydroxyapatite/bioglass (HAp/BG) nanocomposite scaffolds were prepared in different ratios using a hydrothermal approach. The aim of this research was to evaluate [...] Read more.

Recently, composite scaffolding has found many applications in hard tissue engineering due to a number of desirable features. In this present study, hydroxyapatite/bioglass (HAp/BG) nanocomposite scaffolds were prepared in different ratios using a hydrothermal approach. The aim of this research was to evaluate the adhesion, growth, viability, and osteoblast differentiation behavior of human Wharton’s-jelly-derived mesenchymal stem cells (hWJMSCs) on HAp/BG in vitro as a scaffold for application in bone tissue engineering. Particle size and morphology were investigated by TEM and bioactivity was assessed and proven using SEM analysis with hWJMSCs in contact with the HAp/BG nanocomposite. Viability was evaluated using PrestoBlue^TM assay and early osteoblast differentiation and mineralization behaviors were investigated by ALP activity and EDX analysis simultaneously. TEM results showed that the prepared HAp/BG nanocomposite had dimensions of less than 40 nm. The morphology of hWJMSCs showed a fibroblast-like shape, with a clear filopodia structure. The viability of hWJMSCs was highest for the HAp/BG nanocomposite with a 70:30 ratio of HAp to BG (HAp70/BG30). The in vitro biological results confirmed that HAp/BG composite was not cytotoxic. It was also observed that the biological performance of HAp70/BG30 was higher than HAp scaffold alone. In summary, HAp/BG scaffold combined with mesenchymal stem cells showed significant potential for bone repair applications in tissue engineering. Full article

(This article belongs to the Special Issue Patient-Derived Organoids in Personalized Medicine)

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10 pages, 2138 KiB

Open AccessArticle

Analyses of the Mode of Action of an Alpha-Adrenoceptor Blocker in Substantia Gelatinosa Neurons in Rats

by Daisuke Uta, Tsuyoshi Hattori and Megumu Yoshimura

Int. J. Mol. Sci. 2021, 22(17), 9636; https://doi.org/10.3390/ijms22179636 - 6 Sep 2021

Viewed by 2223

Abstract

To elucidate why naftopidil increases the frequency of spontaneous synaptic currents in only some substantia gelatinosa (SG) neurons, post-hoc analyses were performed. Blind patch-clamp recording was performed using slice preparations of SG neurons from the spinal cords of adult rats. Spontaneous inhibitory and [...] Read more.

To elucidate why naftopidil increases the frequency of spontaneous synaptic currents in only some substantia gelatinosa (SG) neurons, post-hoc analyses were performed. Blind patch-clamp recording was performed using slice preparations of SG neurons from the spinal cords of adult rats. Spontaneous inhibitory and excitatory postsynaptic currents (sIPSCs and sEPSCs, respectively) were recorded. The ratios of the frequency and amplitude of the sIPSCs and sEPSCs following the introduction of naftopidil compared with baseline, and after the application of naftopidil, serotonin (5-HT), and prazosin, compared with noradrenaline (NA) were evaluated. First, the sIPSC analysis indicated that SG neurons reached their full response ratio for NA at 50 μM. Second, they responded to 5-HT (50 μM) with a response ratio similar to that for NA, but prazosin (10 μM) did not change the sEPSCs and sIPSCs. Third, the highest concentration of naftopidil (100 μM) led to two types of response in the SG neurons, which corresponded with the reactions to 5-HT and prazosin. These results indicate that not all neurons were necessarily activated by naftopidil, and that the micturition reflex may be regulated in a sophisticated manner by inhibitory mechanisms in these interneurons. Full article

(This article belongs to the Special Issue GABAergic and Glycinergic Neurons)

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14 pages, 2417 KiB

Open AccessArticle

Aggregation Condition–Structure Relationship of Mouse Prion Protein Fibrils

by Jēkabs Fridmanis, Zigmantas Toleikis, Tomas Sneideris, Mantas Ziaunys, Raitis Bobrovs, Vytautas Smirnovas and Kristaps Jaudzems

Int. J. Mol. Sci. 2021, 22(17), 9635; https://doi.org/10.3390/ijms22179635 - 6 Sep 2021

Cited by 5 | Viewed by 2643

Abstract

Prion diseases are associated with conformational conversion of cellular prion protein into a misfolded pathogenic form, which resembles many properties of amyloid fibrils. The same prion protein sequence can misfold into different conformations, which are responsible for variations in prion disease phenotypes (prion [...] Read more.

Prion diseases are associated with conformational conversion of cellular prion protein into a misfolded pathogenic form, which resembles many properties of amyloid fibrils. The same prion protein sequence can misfold into different conformations, which are responsible for variations in prion disease phenotypes (prion strains). In this work, we use atomic force microscopy, FTIR spectroscopy and magic-angle spinning NMR to devise structural models of mouse prion protein fibrils prepared in three different denaturing conditions. We find that the fibril core region as well as the structure of its N- and C-terminal parts is almost identical between the three fibrils. In contrast, the central part differs in length of β-strands and the arrangement of charged residues. We propose that the denaturant ionic strength plays a major role in determining the structure of fibrils obtained in a particular condition by stabilizing fibril core interior-facing glutamic acid residues. Full article

(This article belongs to the Special Issue The Role of Environment in Amyloid Aggregation)

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17 pages, 4770 KiB

Open AccessArticle

Modification of a Single Atom Affects the Physical Properties of Double Fluorinated Fmoc-Phe Derivatives

by Moran Aviv, Dana Cohen-Gerassi, Asuka A. Orr, Rajkumar Misra, Zohar A. Arnon, Linda J. W. Shimon, Yosi Shacham-Diamand, Phanourios Tamamis and Lihi Adler-Abramovich

Int. J. Mol. Sci. 2021, 22(17), 9634; https://doi.org/10.3390/ijms22179634 - 6 Sep 2021

Cited by 12 | Viewed by 3526

Abstract

Supramolecular hydrogels formed by the self-assembly of amino-acid based gelators are receiving increasing attention from the fields of biomedicine and material science. Self-assembled systems exhibit well-ordered functional architectures and unique physicochemical properties. However, the control over the kinetics and mechanical properties of the [...] Read more.

Supramolecular hydrogels formed by the self-assembly of amino-acid based gelators are receiving increasing attention from the fields of biomedicine and material science. Self-assembled systems exhibit well-ordered functional architectures and unique physicochemical properties. However, the control over the kinetics and mechanical properties of the end-products remains puzzling. A minimal alteration of the chemical environment could cause a significant impact. In this context, we report the effects of modifying the position of a single atom on the properties and kinetics of the self-assembly process. A combination of experimental and computational methods, used to investigate double-fluorinated Fmoc-Phe derivatives, Fmoc-3,4F-Phe and Fmoc-3,5F-Phe, reveals the unique effects of modifying the position of a single fluorine on the self-assembly process, and the physical properties of the product. The presence of significant physical and morphological differences between the two derivatives was verified by molecular-dynamics simulations. Analysis of the spontaneous phase-transition of both building blocks, as well as crystal X-ray diffraction to determine the molecular structure of Fmoc-3,4F-Phe, are in good agreement with known changes in the Phe fluorination pattern and highlight the effect of a single atom position on the self-assembly process. These findings prove that fluorination is an effective strategy to influence supramolecular organization on the nanoscale. Moreover, we believe that a deep understanding of the self-assembly process may provide fundamental insights that will facilitate the development of optimal amino-acid-based low-molecular-weight hydrogelators for a wide range of applications. Full article

(This article belongs to the Special Issue Functional Nanomaterials and Polymer Nanocomposites: Current Uses and Potential Applications)

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19 pages, 4414 KiB

Open AccessArticle

Impact of Amyloid-β on Platelet Mitochondrial Function and Platelet–Mediated Amyloid Aggregation in Alzheimer’s Disease

by Lili Donner, Tobias Feige, Carolin Freiburg, Laura Mara Toska, Andreas S. Reichert, Madhumita Chatterjee and Margitta Elvers

Int. J. Mol. Sci. 2021, 22(17), 9633; https://doi.org/10.3390/ijms22179633 - 6 Sep 2021

Cited by 21 | Viewed by 3332

Abstract

Background: Alzheimer’s disease (AD) is characterized by an accumulation of amyloid β (Aβ) peptides in the brain and mitochondrial dysfunction. Platelet activation is enhanced in AD and platelets contribute to AD pathology by their ability to facilitate soluble Aβ to form Aβ aggregates. [...] Read more.

Background: Alzheimer’s disease (AD) is characterized by an accumulation of amyloid β (Aβ) peptides in the brain and mitochondrial dysfunction. Platelet activation is enhanced in AD and platelets contribute to AD pathology by their ability to facilitate soluble Aβ to form Aβ aggregates. Thus, anti-platelet therapy reduces the formation of cerebral amyloid angiopathy in AD transgenic mice. Platelet mitochondrial dysfunction plays a regulatory role in thrombotic response, but its significance in AD is unknown and explored herein. Methods: The effects of Aβ-mediated mitochondrial dysfunction in platelets were investigated in vitro. Results: Aβ40 stimulation of human platelets led to elevated reactive oxygen species (ROS) and superoxide production, while reduced mitochondrial membrane potential and oxygen consumption rate. Enhanced mitochondrial dysfunction triggered platelet-mediated Aβ40 aggregate formation through GPVI-mediated ROS production, leading to enhanced integrin αII_bβ₃ activation during synergistic stimulation from ADP and Aβ40. Aβ40 aggregate formation of human and murine (APP23) platelets were comparable to controls and could be reduced by the antioxidant vitamin C. Conclusions: Mitochondrial dysfunction contributes to platelet-mediated Aβ aggregate formation and might be a promising target to limit platelet activation exaggerated pathological manifestations in AD. Full article

(This article belongs to the Special Issue Molecular Research on Platelet Function in Disease)

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23 pages, 4634 KiB

Open AccessArticle

Targeted Disruption of the Inhibitor of DNA Binding 4 (Id4) Gene Alters Photic Entrainment of the Circadian Clock

by Giles E. Duffield, Maricela Robles-Murguia, Tim Y. Hou and Kathleen A. McDonald

Int. J. Mol. Sci. 2021, 22(17), 9632; https://doi.org/10.3390/ijms22179632 - 6 Sep 2021

Cited by 2 | Viewed by 2366

Abstract

Inhibitor of DNA binding (Id) genes comprise a family of four helix–loop–helix (HLH) transcriptional inhibitors. Our earlier studies revealed a role for ID2 within the circadian system, contributing to input, output, and core clock function through its interaction with CLOCK and [...] Read more.

Inhibitor of DNA binding (Id) genes comprise a family of four helix–loop–helix (HLH) transcriptional inhibitors. Our earlier studies revealed a role for ID2 within the circadian system, contributing to input, output, and core clock function through its interaction with CLOCK and BMAL1. Here, we explore the contribution of ID4 to the circadian system using a targeted disruption of the Id4 gene. Attributes of the circadian clock were assessed by monitoring the locomotor activity of Id4−/− mice, and they revealed disturbances in its operation. Id4-mutant mice expressed a shorter circadian period length, attenuated phase shifts in responses to continuous and discrete photic cues, and an advanced phase angle of entrainment under a 12:12 light:dark cycle and under short and long photoperiods. To understand the basis for these properties, suprachiasmatic nucleus (SCN) and retinal structures were examined. Anatomical analysis reveals a smaller Id4−/− SCN in the width dimension, which is a finding consistent with its smaller brain. As a result of this feature, anterograde tracing in Id4−/− mice revealed retinal afferents innovate a disproportionally larger SCN area. The Id4−/− photic entrainment responses are unlikely to be due to an impaired function of the retinal pathways since Id4−/− retinal anatomy and function tested by pupillometry were similar to wild-type mice. Furthermore, these circadian characteristics are opposite to those exhibited by the Id2−/− mouse, suggesting an opposing influence of the ID4 protein within the circadian system; or, the absence of ID4 results in changes in the expression or activity of other members of the Id gene family. Expression analysis of the Id genes within the Id4−/− SCN revealed a time-of-day specific elevated Id1. It is plausible that the increased Id1 and/or absence of ID4 result in changes in interactions with bHLH canonical clock components or with targets upstream and/or downstream of the clock, thereby resulting in abnormal properties of the circadian clock and its entrainment. Full article

(This article belongs to the Special Issue Molecular and Cellular Mechanisms of Synchronization within the Mammalian Circadian System)

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11 pages, 10304 KiB

Open AccessArticle

Flame Retardant Functionalization of Microcrystalline Cellulose by Phosphorylation Reaction with Phytic Acid

by Hua-Bin Yuan, Ren-Cheng Tang and Cheng-Bing Yu

Int. J. Mol. Sci. 2021, 22(17), 9631; https://doi.org/10.3390/ijms22179631 - 6 Sep 2021

Cited by 29 | Viewed by 4321

Abstract

The functionalization of microcrystalline cellulose (MCC) is an important strategy for broadening its application fields. In the present work, MCC was functionalized by phosphorylation reaction with phytic acid (PA) for enhanced flame retardancy. The conditions of phosphorylation reaction including PA concentration, MCC/PA weight [...] Read more.

The functionalization of microcrystalline cellulose (MCC) is an important strategy for broadening its application fields. In the present work, MCC was functionalized by phosphorylation reaction with phytic acid (PA) for enhanced flame retardancy. The conditions of phosphorylation reaction including PA concentration, MCC/PA weight ratio and temperature were discussed, and the thermal degradation, heat release and char-forming properties of the resulting PA modified MCC were studied by thermogravimetric analysis and pyrolysis combustion flow calorimetry. The PA modified MCC, which was prepared at 90 °C, 50%PA and 1:3 weight ratio of MCC to PA, exhibited early thermal dehydration with rapid char formation as well as low heat release capability. This work suggests a novel strategy for the phosphorylation of cellulose using PA and reveals that the PA phosphorylated MCC can act as a promising flame retardant material. Full article

(This article belongs to the Special Issue Cellulose and Its Applications)

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20 pages, 1034 KiB

Open AccessReview

Perspectives on hiPSC-Derived Muscle Cells as Drug Discovery Models for Muscular Dystrophies

by Elena Abati, Emanuele Sclarandi, Giacomo Pietro Comi, Valeria Parente and Stefania Corti

Int. J. Mol. Sci. 2021, 22(17), 9630; https://doi.org/10.3390/ijms22179630 - 6 Sep 2021

Cited by 4 | Viewed by 3178

Abstract

Muscular dystrophies are a heterogeneous group of inherited diseases characterized by the progressive degeneration and weakness of skeletal muscles, leading to disability and, often, premature death. To date, no effective therapies are available to halt or reverse the pathogenic process, and meaningful treatments [...] Read more.

Muscular dystrophies are a heterogeneous group of inherited diseases characterized by the progressive degeneration and weakness of skeletal muscles, leading to disability and, often, premature death. To date, no effective therapies are available to halt or reverse the pathogenic process, and meaningful treatments are urgently needed. From this perspective, it is particularly important to establish reliable in vitro models of human muscle that allow the recapitulation of disease features as well as the screening of genetic and pharmacological therapies. We herein review and discuss advances in the development of in vitro muscle models obtained from human induced pluripotent stem cells, which appear to be capable of reproducing the lack of myofiber proteins as well as other specific pathological hallmarks, such as inflammation, fibrosis, and reduced muscle regenerative potential. In addition, these platforms have been used to assess genetic correction strategies such as gene silencing, gene transfer and genome editing with clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 (Cas9), as well as to evaluate novel small molecules aimed at ameliorating muscle degeneration. Furthermore, we discuss the challenges related to in vitro drug testing and provide a critical view of potential therapeutic developments to foster the future clinical translation of preclinical muscular dystrophy studies. Full article

(This article belongs to the Special Issue hiPSC-Derived Cells as Models for Drug Discovery 2.0)

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14 pages, 654 KiB

Open AccessReview

The Ubiquitin System: An Emerging Therapeutic Target for Lung Cancer

by Jun-O Jin, Nidhi Puranik, Quyen Thu Bui, Dhananjay Yadav and Peter Chang-Whan Lee

Int. J. Mol. Sci. 2021, 22(17), 9629; https://doi.org/10.3390/ijms22179629 - 6 Sep 2021

Cited by 24 | Viewed by 4487

Abstract

The ubiquitin system, present in all eukaryotes, contributes to regulating multiple types of cellular protein processes such as cell signaling, cell cycle, and receptor trafficking, and it affects the immune response. In most types of cancer, unusual events in ubiquitin-mediated signaling pathway modulation [...] Read more.

The ubiquitin system, present in all eukaryotes, contributes to regulating multiple types of cellular protein processes such as cell signaling, cell cycle, and receptor trafficking, and it affects the immune response. In most types of cancer, unusual events in ubiquitin-mediated signaling pathway modulation can lead to a variety of clinical outcomes, including tumor formation and metastasis. Similarly, ubiquitination acts as a core component, which contributes to the alteration of cell signaling activity, dictating biosignal turnover and protein fates. As lung cancer acquires the most commonly mutated proteins, changes in the ubiquitination of the proteins contribute to the development of lung cancer. Various inhibitors targeting the ubiquitin system have been developed for clinical applications in lung cancer treatment. In this review, we summarize the current research advances in therapeutics for lung cancer by targeting the ubiquitin system. Full article

(This article belongs to the Special Issue Ubiquitination and Deubiquitination in Cellular Homeostasis)

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