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Int. J. Mol. Sci., Volume 22, Issue 23 (December-1 2021) – 561 articles

Cover Story (view full-size image): Reductive radical stress represents the other side of the redox spectrum, less studied but equally important compared to oxidative stress. Reactions of hydrogen atoms (H.) and hydrated electrons (e–aq) with peptides/proteins induce chemical transformations of methionine and cystine residues into α-aminobutyric acid and alanine, respectively. Desulfurization processes and formation of diffusible sulfur-centered radicals, such as CH3S. and HS., are the key steps. Sulfur-centered radicals generated from proteins can trigger cis–trans isomerization of unsaturated lipids in membranes, as demonstrated in biomimetic models of proteo-liposomes. In pharmaceutical and pharmacological contexts novel perspectives of such reactivity involve stability of formulations and mode of action of drugs. View this paper.
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42 pages, 987 KiB  
Review
Mechanisms and Regulation of Cellular Senescence
by Lauréline Roger, Fanny Tomas and Véronique Gire
Int. J. Mol. Sci. 2021, 22(23), 13173; https://doi.org/10.3390/ijms222313173 - 6 Dec 2021
Cited by 152 | Viewed by 19581
Abstract
Cellular senescence entails a state of an essentially irreversible proliferative arrest in which cells remain metabolically active and secrete a range of pro-inflammatory and proteolytic factors as part of the senescence-associated secretory phenotype. There are different types of senescent cells, and senescence can [...] Read more.
Cellular senescence entails a state of an essentially irreversible proliferative arrest in which cells remain metabolically active and secrete a range of pro-inflammatory and proteolytic factors as part of the senescence-associated secretory phenotype. There are different types of senescent cells, and senescence can be induced in response to many DNA damage signals. Senescent cells accumulate in different tissues and organs where they have distinct physiological and pathological functions. Despite this diversity, all senescent cells must be able to survive in a nondividing state while protecting themselves from positive feedback loops linked to the constant activation of the DNA damage response. This capacity requires changes in core cellular programs. Understanding how different cell types can undergo extensive changes in their transcriptional programs, metabolism, heterochromatin patterns, and cellular structures to induce a common cellular state is crucial to preventing cancer development/progression and to improving health during aging. In this review, we discuss how senescent cells continuously evolve after their initial proliferative arrest and highlight the unifying features that define the senescent state. Full article
(This article belongs to the Special Issue Aging and Senescence 2.0)
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22 pages, 3238 KiB  
Article
Soybean miR159-GmMYB33 Regulatory Network Involved in Gibberellin-Modulated Resistance to Heterodera glycines
by Piao Lei, Nawei Qi, Yuan Zhou, Yuanyuan Wang, Xiaofeng Zhu, Yuanhu Xuan, Xiaoyu Liu, Haiyan Fan, Lijie Chen and Yuxi Duan
Int. J. Mol. Sci. 2021, 22(23), 13172; https://doi.org/10.3390/ijms222313172 - 6 Dec 2021
Cited by 16 | Viewed by 3556
Abstract
Soybean cyst nematode (SCN, Heterodera glycines) is an obligate sedentary biotroph that poses major threats to soybean production globally. Recently, multiple miRNAome studies revealed that miRNAs participate in complicated soybean-SCN interactions by regulating their target genes. However, the functional roles of miRNA [...] Read more.
Soybean cyst nematode (SCN, Heterodera glycines) is an obligate sedentary biotroph that poses major threats to soybean production globally. Recently, multiple miRNAome studies revealed that miRNAs participate in complicated soybean-SCN interactions by regulating their target genes. However, the functional roles of miRNA and target genes regulatory network are still poorly understood. In present study, we firstly investigated the expression patterns of miR159 and targeted GmMYB33 genes. The results showed miR159-3p downregulation during SCN infection; conversely, GmMYB33 genes upregulated. Furthermore, miR159 overexpressing and silencing soybean hairy roots exhibited strong resistance and susceptibility to H. glycines, respectively. In particular, miR159-GAMYB genes are reported to be involve in GA signaling and metabolism. Therefore, we then investigated the effects of GA application on the expression of miR159-GAMYB module and the development of H. glycines. We found that GA directly controls the miR159-GAMYB module, and exogenous GA application enhanced endogenous biologically active GA1 and GA3, the abundance of miR159, lowered the expression of GmMYB33 genes and delayed the development of H. glycines. Moreover, SCN infection also results in endogenous GA content decreased in soybean roots. In summary, the soybean miR159-GmMYB33 module was directly involved in the GA-modulated soybean resistance to H. glycines. Full article
(This article belongs to the Special Issue Small RNA and Hormone Cross Talk in Plants)
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13 pages, 8754 KiB  
Article
Azobenzene/Tetraethyl Ammonium Photochromic Potassium Channel Blockers: Scope and Limitations for Design of Para-Substituted Derivatives with Specific Absorption Band Maxima and Thermal Isomerization Rate
by Daniil M. Strashkov, Vladimir N. Mironov, Dmitrii M. Nikolaev, Maxim S. Panov, Stanislav A. Linnik, Andrey S. Mereshchenko, Vladimir A. Kochemirovsky, Andrey V. Vasin and Mikhail N. Ryazantsev
Int. J. Mol. Sci. 2021, 22(23), 13171; https://doi.org/10.3390/ijms222313171 - 6 Dec 2021
Cited by 3 | Viewed by 3161
Abstract
Azobenzene/tetraethyl ammonium photochromic ligands (ATPLs) are photoactive compounds with a large variety of photopharmacological applications such as nociception control or vision restoration. Absorption band maximum and lifetime of the less stable isomer are important characteristics that determine the applicability of ATPLs. Substituents allow [...] Read more.
Azobenzene/tetraethyl ammonium photochromic ligands (ATPLs) are photoactive compounds with a large variety of photopharmacological applications such as nociception control or vision restoration. Absorption band maximum and lifetime of the less stable isomer are important characteristics that determine the applicability of ATPLs. Substituents allow to adjust these characteristics in a range limited by the azobenzene/tetraethyl ammonium scaffold. The aim of the current study is to find the scope and limitations for the design of ATPLs with specific spectral and kinetic properties by introducing para substituents with different electronic effects. To perform this task we synthesized ATPLs with various electron acceptor and electron donor functional groups and studied their spectral and kinetic properties using flash photolysis and conventional spectroscopy techniques as well as quantum chemical modeling. As a result, we obtained diagrams that describe correlations between spectral and kinetic properties of ATPLs (absorption maxima of E and Z isomers of ATPLs, the thermal lifetime of their Z form) and both the electronic effect of substituents described by Hammett constants and structural parameters obtained from quantum chemical calculations. The provided results can be used for the design of ATPLs with properties that are optimal for photopharmacological applications. Full article
(This article belongs to the Special Issue Advances in Photopharmacology)
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16 pages, 33869 KiB  
Article
(20S) Ginsenoside Rh2 Exerts Its Anti-Tumor Effect by Disrupting the HSP90A-Cdc37 System in Human Liver Cancer Cells
by Chen Chen, Yu-Shi Wang, En-Ting Zhang, Gang-Ao Li, Wen-Yuan Liu, Yang Li and Ying-Hua Jin
Int. J. Mol. Sci. 2021, 22(23), 13170; https://doi.org/10.3390/ijms222313170 - 6 Dec 2021
Cited by 17 | Viewed by 3681
Abstract
(20S) ginsenoside Rh2 (G-Rh2), a major bioactive metabolite of ginseng, effectively inhibits the survival and proliferation of human liver cancer cells. However, its molecular targets and working mechanism remain largely unknown. Excitingly, we screened out heat shock protein 90 alpha (HSP90A), a key [...] Read more.
(20S) ginsenoside Rh2 (G-Rh2), a major bioactive metabolite of ginseng, effectively inhibits the survival and proliferation of human liver cancer cells. However, its molecular targets and working mechanism remain largely unknown. Excitingly, we screened out heat shock protein 90 alpha (HSP90A), a key regulatory protein associated with liver cancer, as a potential target of (20S) G-Rh2 by phage display analysis and mass spectrometry. The molecular docking and thermal shift analyses demonstrated that (20S) G-Rh2 directly bound to HSP90A, and this binding was confirmed to inhibit the interaction between HSP90A and its co-chaperone, cell division cycle control protein 37 (Cdc37). It is well-known that the HSP90A-Cdc37 system aids in the folding and maturation of cyclin-dependent kinases (CDKs). As expected, CDK4 and CDK6, the two G0-G1 phase promoting kinases as well as CDK2, a key G1-S phase transition promoting kinase, were significantly downregulated with (20S) G-Rh2 treatment, and these downregulations were mediated by the proteasome pathway. In the same condition, the cell cycle was arrested at the G0-G1 phase and cell growth was inhibited significantly by (20S) G-Rh2 treatment. Taken together, this study for the first time reveals that (20S) G-Rh2 exerts its anti-tumor effect by targeting HSP90A and consequently disturbing the HSP90A-Cdc37 chaperone system. HSP90A is frequently overexpressed in human hepatoma cells and the higher expression is closely correlated to the poor prognosis of liver cancer patients. Thus, (20S) G-Rh2 might become a promising alternative drug for liver cancer therapy. Full article
(This article belongs to the Special Issue Natural Organic Compounds: Cellular Pathways and Effects)
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12 pages, 2475 KiB  
Article
Stimuli-Responsive Drug Delivery of Doxorubicin Using Magnetic Nanoparticle Conjugated Poly(ethylene glycol)-g-Chitosan Copolymer
by Hyun-Min Yoon, Min-Su Kang, Go-Eun Choi, Young-Joon Kim, Chang-Hyu Bae, Young-Bob Yu and Young-IL Jeong
Int. J. Mol. Sci. 2021, 22(23), 13169; https://doi.org/10.3390/ijms222313169 - 6 Dec 2021
Cited by 24 | Viewed by 3069
Abstract
Stimuli-responsive nanoparticles are regarded as an ideal candidate for anticancer drug targeting. We synthesized glutathione (GSH) and magnetic-sensitive nanocomposites for a dual-targeting strategy. To achieve this goal, methoxy poly (ethylene glycol) (MePEG) was grafted to water-soluble chitosan (abbreviated as ChitoPEG). Then doxorubicin (DOX) [...] Read more.
Stimuli-responsive nanoparticles are regarded as an ideal candidate for anticancer drug targeting. We synthesized glutathione (GSH) and magnetic-sensitive nanocomposites for a dual-targeting strategy. To achieve this goal, methoxy poly (ethylene glycol) (MePEG) was grafted to water-soluble chitosan (abbreviated as ChitoPEG). Then doxorubicin (DOX) was conjugated to the backbone of chitosan via disulfide linkage. Iron oxide (IO) magnetic nanoparticles were also conjugated to the backbone of chitosan to provide magnetic sensitivity. In morphological observation, images from a transmission electron microscope (TEM) showed that IO nanoparticles were embedded in the ChitoPEG/DOX/IO nanocomposites. In a drug release study, GSH addition accelerated DOX release rate from nanocomposites, indicating that nanocomposites have redox-responsiveness. Furthermore, external magnetic stimulus concentrated nanocomposites in the magnetic field and then provided efficient internalization of nanocomposites into cancer cells in cell culture experiments. In an animal study with CT26 cell-bearing mice, nanocomposites showed superior magnetic sensitivity and then preferentially targeted tumor tissues in the field of external magnetic stimulus. Nanocomposites composed of ChitoPEG/DOX/IO nanoparticle conjugates have excellent anticancer drug targeting properties. Full article
(This article belongs to the Special Issue Nanotechnology in Targeted Drug Delivery)
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24 pages, 1232 KiB  
Review
A Review of the Current Mammalian Models of Alzheimer’s Disease and Challenges That Need to Be Overcome
by Natasha Elizabeth Mckean, Renee Robyn Handley and Russell Grant Snell
Int. J. Mol. Sci. 2021, 22(23), 13168; https://doi.org/10.3390/ijms222313168 - 6 Dec 2021
Cited by 38 | Viewed by 5992
Abstract
Alzheimer’s disease (AD) is one of the looming health crises of the near future. Increasing lifespans and better medical treatment for other conditions mean that the prevalence of this disease is expected to triple by 2050. The impact of AD includes both the [...] Read more.
Alzheimer’s disease (AD) is one of the looming health crises of the near future. Increasing lifespans and better medical treatment for other conditions mean that the prevalence of this disease is expected to triple by 2050. The impact of AD includes both the large toll on individuals and their families as well as a large financial cost to society. So far, we have no way to prevent, slow, or cure the disease. Current medications can only alleviate some of the symptoms temporarily. Many animal models of AD have been created, with the first transgenic mouse model in 1995. Mouse models have been beset by challenges, and no mouse model fully captures the symptomatology of AD without multiple genetic mutations and/or transgenes, some of which have never been implicated in human AD. Over 25 years later, many mouse models have been given an AD-like disease and then ‘cured’ in the lab, only for the treatments to fail in clinical trials. This review argues that small animal models are insufficient for modelling complex disorders such as AD. In order to find effective treatments for AD, we need to create large animal models with brains and lifespan that are closer to humans, and underlying genetics that already predispose them to AD-like phenotypes. Full article
(This article belongs to the Special Issue Alzheimer's disease: From Molecular Basis to Therapy)
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15 pages, 589 KiB  
Review
PPARγ—A Factor Linking Metabolically Unhealthy Obesity with Placental Pathologies
by Sebastian Kwiatkowski, Anna Kajdy, Katarzyna Stefańska, Magdalena Bednarek-Jędrzejek, Sylwia Dzidek, Piotr Tousty, Małgorzata Sokołowska and Ewa Kwiatkowska
Int. J. Mol. Sci. 2021, 22(23), 13167; https://doi.org/10.3390/ijms222313167 - 6 Dec 2021
Cited by 3 | Viewed by 2899
Abstract
Obesity is a known factor in the development of preeclampsia. This paper links adipose tissue pathologies with aberrant placental development and the resulting preeclampsia. PPARγ, a transcription factor from the ligand-activated nuclear hormone receptor family, appears to be one common aspect of both [...] Read more.
Obesity is a known factor in the development of preeclampsia. This paper links adipose tissue pathologies with aberrant placental development and the resulting preeclampsia. PPARγ, a transcription factor from the ligand-activated nuclear hormone receptor family, appears to be one common aspect of both pathologies. It is the master regulator of adipogenesis in humans. At the same time, its aberrantly low activity has been observed in placental pathologies. Overweight and obesity are very serious health problems worldwide. They have negative effects on the overall mortality rate. Very importantly, they are also conducive to diseases linked to impaired placental development, including preeclampsia. More and more people in Europe are suffering from overweight (35.2%) and obesity (16%) (EUROSTAT 2021 data), some of them young women planning pregnancy. As a result, we will be increasingly encountering obese pregnant women with a considerable risk of placental development disorders, including preeclampsia. An appreciation of the mechanisms shared by these two conditions may assist in their prevention and treatment. Clearly, it should not be forgotten that health education concerning the need for a proper diet and physical activity is of utmost importance here. Full article
(This article belongs to the Topic Pathogenesis of Pregnancy-Related Complications)
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16 pages, 2119 KiB  
Review
Gut Microbiota Extracellular Vesicles as Signaling Molecules Mediating Host-Microbiota Communications
by Salma Sultan, Walid Mottawea, JuDong Yeo and Riadh Hammami
Int. J. Mol. Sci. 2021, 22(23), 13166; https://doi.org/10.3390/ijms222313166 - 6 Dec 2021
Cited by 20 | Viewed by 12779
Abstract
Over the past decade, gut microbiota dysbiosis has been linked to many health disorders; however, the detailed mechanism of this correlation remains unclear. Gut microbiota can communicate with the host through immunological or metabolic signalling. Recently, microbiota-released extracellular vesicles (MEVs) have emerged as [...] Read more.
Over the past decade, gut microbiota dysbiosis has been linked to many health disorders; however, the detailed mechanism of this correlation remains unclear. Gut microbiota can communicate with the host through immunological or metabolic signalling. Recently, microbiota-released extracellular vesicles (MEVs) have emerged as significant mediators in the intercellular signalling mechanism that could be an integral part of microbiota-host communications. MEVs are small membrane-bound vesicles that encase a broad spectrum of biologically active compounds (i.e., proteins, mRNA, miRNA, DNA, carbohydrates, and lipids), thus mediating the horizontal transfer of their cargo across intra- and intercellular space. In this study, we provide a comprehensive and in-depth discussion of the biogenesis of microbial-derived EVs, their classification and routes of production, as well as their role in inter-bacterial and inter-kingdom signaling. Full article
(This article belongs to the Special Issue The Interplay of Microbiome and Immune Response in Health and Diseases-2nd Edition)
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13 pages, 3155 KiB  
Article
Poly(aspartic acid) Biohydrogel as the Base of a New Hybrid Conducting Material
by Adrián Fontana-Escartín, Guillem Ruano, Fiorella M. Silva, Francesc Estrany, Jordi Puiggalí, Carlos Alemán and Juan Torras
Int. J. Mol. Sci. 2021, 22(23), 13165; https://doi.org/10.3390/ijms222313165 - 6 Dec 2021
Cited by 5 | Viewed by 2888
Abstract
In the present study, a composite made of conducting polymer, poly(3,4-ethylenedioxythiophene) (PEDOT), and a biodegradable hydrogel of poly(aspartic acid) (PASP) were electrochemically interpenetrated with poly(hydroxymethyl-3,4-ethylenedioxythiophene) (PHMeDOT) to prepare a new interpenetrated polymer network (IPN). Different cross-linker and PEDOT MPs contents, as well as [...] Read more.
In the present study, a composite made of conducting polymer, poly(3,4-ethylenedioxythiophene) (PEDOT), and a biodegradable hydrogel of poly(aspartic acid) (PASP) were electrochemically interpenetrated with poly(hydroxymethyl-3,4-ethylenedioxythiophene) (PHMeDOT) to prepare a new interpenetrated polymer network (IPN). Different cross-linker and PEDOT MPs contents, as well as different electropolymerization times, were studied to optimize the structural and electrochemical properties. The properties of the new material, being electrically conductive, biocompatible, bioactive, and biodegradable, make it suitable for possible uses in biomedical applications. Full article
(This article belongs to the Special Issue Conducting and Biodegradable Polymers, a New Concept for Current and Future Biomedical Applications)
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27 pages, 1906 KiB  
Review
Influence of Risk Factors for Male Infertility on Sperm Protein Composition
by Marie Bisconti, Jean-François Simon, Sarah Grassi, Baptiste Leroy, Baptiste Martinet, Vanessa Arcolia, Vladimir Isachenko and Elise Hennebert
Int. J. Mol. Sci. 2021, 22(23), 13164; https://doi.org/10.3390/ijms222313164 - 6 Dec 2021
Cited by 24 | Viewed by 5943
Abstract
Male infertility is a common health problem that can be influenced by a host of lifestyle risk factors such as environment, nutrition, smoking, stress, and endocrine disruptors. These effects have been largely demonstrated on sperm parameters (e.g., motility, numeration, vitality, DNA integrity). In [...] Read more.
Male infertility is a common health problem that can be influenced by a host of lifestyle risk factors such as environment, nutrition, smoking, stress, and endocrine disruptors. These effects have been largely demonstrated on sperm parameters (e.g., motility, numeration, vitality, DNA integrity). In addition, several studies showed the deregulation of sperm proteins in relation to some of these factors. This review inventories the literature related to the identification of sperm proteins showing abundance variations in response to the four risk factors for male infertility that are the most investigated in this context: obesity, diabetes, tobacco smoking, and exposure to bisphenol-A (BPA). First, we provide an overview of the techniques used to identify deregulated proteins. Then, we summarise the main results obtained in the different studies and provide a compiled list of deregulated proteins in relation to each risk factor. Gene ontology analysis of these deregulated proteins shows that oxidative stress and immune and inflammatory responses are common mechanisms involved in sperm alterations encountered in relation to the risk factors. Full article
(This article belongs to the Special Issue Ejaculated and Testicular Spermatozoa: Molecular Biological Research of Morphology, Physiology and Spermatogenesis)
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14 pages, 4471 KiB  
Article
Neochlorogenic Acid Attenuates Hepatic Lipid Accumulation and Inflammation via Regulating miR-34a In Vitro
by Meng-Hsun Yu, Tung-Wei Hung, Chi-Chih Wang, Sheng-Wen Wu, Tzu-Wei Yang, Ching-Yu Yang, Tsui-Hwa Tseng and Chau-Jong Wang
Int. J. Mol. Sci. 2021, 22(23), 13163; https://doi.org/10.3390/ijms222313163 - 6 Dec 2021
Cited by 38 | Viewed by 3561
Abstract
Neochlorogenic acid (5-Caffeoylquinic acid; 5-CQA), a major phenolic compound isolated from mulberry leaves, possesses anti-oxidative and anti-inflammatory effects. Although it modulates lipid metabolism, the molecular mechanism is unknown. Using an in-vitro model of nonalcoholic fatty liver disease (NAFLD) in which oleic acid (OA) [...] Read more.
Neochlorogenic acid (5-Caffeoylquinic acid; 5-CQA), a major phenolic compound isolated from mulberry leaves, possesses anti-oxidative and anti-inflammatory effects. Although it modulates lipid metabolism, the molecular mechanism is unknown. Using an in-vitro model of nonalcoholic fatty liver disease (NAFLD) in which oleic acid (OA) induced lipid accumulation in HepG2 cells, we evaluated the alleviation effect of 5-CQA. We observed that 5-CQA improved OA-induced intracellular lipid accumulation by downregulating sterol regulatory element-binding protein 1 (SREBP1) and fatty acid synthase (FASN) expression, which regulates the fatty acid synthesis, as well as SREBP2 and HMG-CoA reductases (HMG-CoR) expressions, which regulate cholesterol synthesis. Treatment with 5-CQA also increased the expression of fatty acid β-oxidation enzymes. Remarkably, 5-CQA attenuated OA-induced miR-34a expression. A transfection assay with an miR-34a mimic or miR-34a inhibitor revealed that miR-34a suppressed Moreover, Sirtuin 1 (SIRT1) expression and inactivated 5’ adenosine monophosphate-activated protein kinase (AMPK). Our results suggest that 5-CQA alleviates lipid accumulation by downregulating miR-34a, leading to activation of the SIRT1/AMPK pathway. Full article
(This article belongs to the Special Issue Plant-Food-Derived Bioactives for Disorders Related to Oxidative Stress and Inflammation)
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14 pages, 937 KiB  
Review
Dystroglycanopathy: From Elucidation of Molecular and Pathological Mechanisms to Development of Treatment Methods
by Motoi Kanagawa
Int. J. Mol. Sci. 2021, 22(23), 13162; https://doi.org/10.3390/ijms222313162 - 6 Dec 2021
Cited by 25 | Viewed by 3709
Abstract
Dystroglycanopathy is a collective term referring to muscular dystrophies with abnormal glycosylation of dystroglycan. At least 18 causative genes of dystroglycanopathy have been identified, and its clinical symptoms are diverse, ranging from severe congenital to adult-onset limb-girdle types. Moreover, some cases are associated [...] Read more.
Dystroglycanopathy is a collective term referring to muscular dystrophies with abnormal glycosylation of dystroglycan. At least 18 causative genes of dystroglycanopathy have been identified, and its clinical symptoms are diverse, ranging from severe congenital to adult-onset limb-girdle types. Moreover, some cases are associated with symptoms involving the central nervous system. In the 2010s, the structure of sugar chains involved in the onset of dystroglycanopathy and the functions of its causative gene products began to be identified as if they were filling the missing pieces of a jigsaw puzzle. In parallel with these discoveries, various dystroglycanopathy model mice had been created, which led to the elucidation of its pathological mechanisms. Then, treatment strategies based on the molecular basis of glycosylation began to be proposed after the latter half of the 2010s. This review briefly explains the sugar chain structure of dystroglycan and the functions of the causative gene products of dystroglycanopathy, followed by introducing the pathological mechanisms involved as revealed from analyses of dystroglycanopathy model mice. Finally, potential therapeutic approaches based on the pathological mechanisms involved are discussed. Full article
(This article belongs to the Special Issue Myogenesis and Muscular Disorders)
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17 pages, 1941 KiB  
Article
Oxidation of Various Kraft Lignins with a Bacterial Laccase Enzyme
by Sebastian A. Mayr, Raditya Subagia, Renate Weiss, Nikolaus Schwaiger, Hedda K. Weber, Johannes Leitner, Doris Ribitsch, Gibson S. Nyanhongo and Georg M. Guebitz
Int. J. Mol. Sci. 2021, 22(23), 13161; https://doi.org/10.3390/ijms222313161 - 6 Dec 2021
Cited by 16 | Viewed by 4083
Abstract
Modification of kraft lignin (KL), traditionally uses harsh and energy-demanding physical and chemical processes. In this study, the potential of the bacterial laccase CotA (spore coating protein A) for oxidation of KL under mild conditions was assessed. Thereby, the efficiency of CotA to [...] Read more.
Modification of kraft lignin (KL), traditionally uses harsh and energy-demanding physical and chemical processes. In this study, the potential of the bacterial laccase CotA (spore coating protein A) for oxidation of KL under mild conditions was assessed. Thereby, the efficiency of CotA to oxidize both softwood and hardwood KL of varying purity at alkaline conditions was examined. For the respective type of wood, the highest oxidation activity by CotA was determined for the medium ash content softwood KL (MA_S) and the medium ash content hardwood KL (MA_H), respectively. By an up to 95% decrease in fluorescence and up to 65% in phenol content coupling of the structural lignin units was indicated. These results correlated with an increase in viscosity and molecular weight, which increased nearly 2 and 20-fold for MA_H and about 1.3 and 6.0-fold for MA_S, respectively. Thus, this study confirms that the CotA laccase can oxidize a variety of KL at alkaline conditions, while the origin and purity of KL were found to have a major impact on the efficiency of oxidation. Under the herein tested conditions, it was observed that the MA_H KL showed the highest susceptibility to CotA oxidation when compared to the other hardwood KLs and the softwood KLs. Therefore, this could be a viable method to produce sustainable resins and adhesives. Full article
(This article belongs to the Special Issue Smart Biobased Polymers and Composites: Current Challenges and Opportunities)
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26 pages, 3860 KiB  
Review
Design of Biopolymer-Based Interstitial Therapies for the Treatment of Glioblastoma
by Erik S. Pena, Elizabeth G. Graham-Gurysh, Eric M. Bachelder and Kristy M. Ainslie
Int. J. Mol. Sci. 2021, 22(23), 13160; https://doi.org/10.3390/ijms222313160 - 6 Dec 2021
Cited by 21 | Viewed by 6468
Abstract
Glioblastoma multiforme (GBM) is the most common form of primary brain cancer and has the highest morbidity rate and current treatments result in a bleak 5-year survival rate of 5.6%. Interstitial therapy is one option to increase survival. Drug delivery by interstitial therapy [...] Read more.
Glioblastoma multiforme (GBM) is the most common form of primary brain cancer and has the highest morbidity rate and current treatments result in a bleak 5-year survival rate of 5.6%. Interstitial therapy is one option to increase survival. Drug delivery by interstitial therapy most commonly makes use of a polymer implant encapsulating a drug which releases as the polymer degrades. Interstitial therapy has been extensively studied as a treatment option for GBM as it provides several advantages over systemic administration of chemotherapeutics. Primarily, it can be applied behind the blood–brain barrier, increasing the number of possible chemotherapeutic candidates that can be used and reducing systemic levels of the therapy while concentrating it near the cancer source. With interstitial therapy, multiple drugs can be released locally into the brain at the site of resection as the polymer of the implant degrades, and the release profile of these drugs can be tailored to optimize combination therapy or maintain synergistic ratios. This can bypass the blood–brain barrier, alleviate systemic toxicity, and resolve drug resistance in the tumor. However, tailoring drug release requires appropriate consideration of the complex relationship between the drug, polymer, and formulation method. Drug physicochemical properties can result in intermolecular bonding with the polymeric matrix and affect drug distribution in the implant depending on the formulation method used. This review is focused on current works that have applied interstitial therapy towards GBM, discusses polymer and formulation methods, and provides design considerations for future implantable biodegradable materials. Full article
(This article belongs to the Special Issue Glioblastoma: Recapitulating the Key Breakthroughs and Future Perspective)
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12 pages, 1673 KiB  
Article
Detection of CpG Methylation in G-Quadruplex Forming Sequences Using G-Quadruplex Ligands
by Hijiri Hasegawa, Ikkei Sasaki, Kaori Tsukakoshi, Yue Ma, Kazuo Nagasawa, Shusuke Numata, Yuuki Inoue, Yeji Kim and Kazunori Ikebukuro
Int. J. Mol. Sci. 2021, 22(23), 13159; https://doi.org/10.3390/ijms222313159 - 6 Dec 2021
Cited by 3 | Viewed by 3148
Abstract
Genomic DNA methylation is involved in many diseases and is expected to be a specific biomarker for even the pre-symptomatic diagnosis of many diseases. Thus, a rapid and inexpensive detection method is required for disease diagnosis. We have previously reported that cytosine methylation [...] Read more.
Genomic DNA methylation is involved in many diseases and is expected to be a specific biomarker for even the pre-symptomatic diagnosis of many diseases. Thus, a rapid and inexpensive detection method is required for disease diagnosis. We have previously reported that cytosine methylation in G-quadruplex (G4)-forming oligonucleotides develops different G4 topologies. In this study, we developed a method for detecting CpG methylation in G4-forming oligonucleotides based on the structural differences between methylated and unmethylated G4 DNAs. The differences in G4 topologies due to CpG methylation can be discriminated by G4 ligands. We performed a binding assay between methylated or unmethylated G4 DNAs and G4 ligands. The binding abilities of fluorescent G4 ligands to BCL-2, HRAS1, HRAS2, VEGF G4-forming sequences were examined by fluorescence-based microtiter plate assay. The differences in fluorescence intensities between methylated and unmethylated G4 DNAs were statistically significant. In addition to fluorescence detection, the binding of G4 ligand to DNA was detected by chemiluminescence. A significant difference was also detected in chemiluminescence intensity between methylated and unmethylated DNA. This is the first study on the detection of CpG methylation in G4 structures, focusing on structural changes using G4 ligands. Full article
(This article belongs to the Special Issue The Polymorphic World of G-Quadruplexes: From Structural Insights to Functional Activity-2nd Edition)
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10 pages, 889 KiB  
Review
A Brief Journey through Protein Misfolding in Transthyretin Amyloidosis (ATTR Amyloidosis)
by Alejandra Gonzalez-Duarte and Alfredo Ulloa-Aguirre
Int. J. Mol. Sci. 2021, 22(23), 13158; https://doi.org/10.3390/ijms222313158 - 6 Dec 2021
Cited by 16 | Viewed by 4285
Abstract
Transthyretin (TTR) amyloidogenesis involves the formation, aggregation, and deposition of amyloid fibrils from tetrameric TTR in different organs and tissues. While the result of amyloidoses is the accumulation of amyloid fibrils resulting in end-organ damage, the nature, and sequence of the molecular causes [...] Read more.
Transthyretin (TTR) amyloidogenesis involves the formation, aggregation, and deposition of amyloid fibrils from tetrameric TTR in different organs and tissues. While the result of amyloidoses is the accumulation of amyloid fibrils resulting in end-organ damage, the nature, and sequence of the molecular causes leading to amyloidosis may differ between the different variants. In addition, fibril accumulation and toxicity vary between different mutations. Structural changes in amyloidogenic TTR have been difficult to identify through X-ray crystallography; but nuclear magnetic resonance spectroscopy has revealed different chemical shifts in the backbone structure of mutated and wild-type TTR, resulting in diverse responses to the cellular conditions or proteolytic stress. Toxic mechanisms of TTR amyloidosis have different effects on different tissues. Therapeutic approaches have evolved from orthotopic liver transplants to novel disease-modifying therapies that stabilize TTR tetramers and gene-silencing agents like small interfering RNA and antisense oligonucleotide therapies. The underlying molecular mechanisms of the different TTR variants could be responsible for the tropisms to specific organs, the age at onset, treatment responses, or disparities in the prognosis. Full article
(This article belongs to the Special Issue Protein Folding Diseases—Molecular Mechanisms and Therapeutic Approaches)
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15 pages, 873 KiB  
Review
The Important Role of Endothelium and Extracellular Vesicles in the Cellular Mechanism of Aortic Aneurysm Formation
by Klaudia Mikołajczyk, Dominika Spyt, Wioletta Zielińska, Agnieszka Żuryń, Inaz Faisal, Murtaz Qamar, Piotr Świniarski, Alina Grzanka and Maciej Gagat
Int. J. Mol. Sci. 2021, 22(23), 13157; https://doi.org/10.3390/ijms222313157 - 6 Dec 2021
Cited by 16 | Viewed by 3893
Abstract
Homeostasis is a fundamental property of biological systems consisting of the ability to maintain a dynamic balance of the environment of biochemical processes. The action of endogenous and exogenous factors can lead to internal balance disorder, which results in the activation of the [...] Read more.
Homeostasis is a fundamental property of biological systems consisting of the ability to maintain a dynamic balance of the environment of biochemical processes. The action of endogenous and exogenous factors can lead to internal balance disorder, which results in the activation of the immune system and the development of inflammatory response. Inflammation determines the disturbances in the structure of the vessel wall, connected with the change in their diameter. These disorders consist of accumulation in the space between the endothelium and the muscle cells of low-density lipoproteins (LDL), resulting in the formation of fatty streaks narrowing the lumen and restricting the blood flow in the area behind the structure. The effect of inflammation may also be pathological dilatation of the vessel wall associated with the development of aneurysms. Described disease entities strongly correlate with the increased migration of immune cells. Recent scientific research indicates the secretion of specific vesicular structures during migration activated by the inflammation. The review focuses on the link between endothelial dysfunction and the inflammatory response and the impact of these processes on the development of disease entities potentially related to the secretion of extracellular vesicles (EVs). Full article
(This article belongs to the Special Issue Advances in Endothelial Cell Biology 2.0)
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27 pages, 9763 KiB  
Article
Depletion of Lipocalin 2 (LCN2) in Mice Leads to Dysbiosis and Persistent Colonization with Segmented Filamentous Bacteria
by Patrick Klüber, Steffen K. Meurer, Jessica Lambertz, Roman Schwarz, Silke Zechel-Gran, Till Braunschweig, Sabine Hurka, Eugen Domann and Ralf Weiskirchen
Int. J. Mol. Sci. 2021, 22(23), 13156; https://doi.org/10.3390/ijms222313156 - 5 Dec 2021
Cited by 24 | Viewed by 4699
Abstract
Lipocalin 2 (LCN2) mediates key roles in innate immune responses. It has affinity for many lipophilic ligands and binds various siderophores, thereby limiting bacterial growth by iron sequestration. Furthermore, LCN2 protects against obesity and metabolic syndrome by interfering with the composition of gut [...] Read more.
Lipocalin 2 (LCN2) mediates key roles in innate immune responses. It has affinity for many lipophilic ligands and binds various siderophores, thereby limiting bacterial growth by iron sequestration. Furthermore, LCN2 protects against obesity and metabolic syndrome by interfering with the composition of gut microbiota. Consequently, complete or hepatocyte-specific ablation of the Lcn2 gene is associated with higher susceptibility to bacterial infections. In the present study, we comparatively profiled microbiota in fecal samples of wild type and Lcn2 null mice and show, in contrast to previous reports, that the quantity of DNA in feces of Lcn2 null mice is significantly lower than that in wild type mice (p < 0.001). By using the hypervariable V4 region of the 16S rDNA gene and Next-Generation Sequencing methods, we found a statistically significant change in 16 taxonomic units in Lcn2-/- mice, including eight gender-specific deviations. In particular, members of Clostridium, Escherichia, Helicobacter, Lactococcus, Prevotellaceae_UCG-001 and Staphylococcus appeared to expand in the intestinal tract of knockout mice. Interestingly, the proportion of Escherichia (200-fold) and Staphylococcus (10-fold) as well as the abundance of intestinal bacteria encoding the LCN2-sensitive siderphore enterobactin (entA) was significantly increased in male Lcn2 null mice (743-fold, p < 0.001). This was accompanied by significant higher immune cell infiltration in the ileum as demonstrated by increased immunoreactivity against the pan-leukocyte protein CD45, the lymphocyte transcription factor MUM-1/IRF4, and the macrophage antigen CD68/Macrosialin. In addition, we found a higher expression of mucosal mast cell proteases indicating a higher number of those innate immune cells. Finally, the ileum of Lcn2 null mice displayed a high abundance of segmented filamentous bacteria, which are intimately associated with the mucosal cell layer, provoking epithelial antimicrobial responses and affecting T-helper cell polarization. Full article
(This article belongs to the Special Issue The Research of Neutrophil)
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19 pages, 1441 KiB  
Article
Modulation of Prostanoids Profile and Counter-Regulation of SDF-1α/CXCR4 and VIP/VPAC2 Expression by Sitagliptin in Non-Diabetic Rat Model of Hepatic Ischemia-Reperfusion Injury
by Małgorzata Krzystek-Korpacka, Mariusz G. Fleszar, Paulina Fortuna, Kinga Gostomska-Pampuch, Łukasz Lewandowski, Tomasz Piasecki, Bogna Kosyk, Adam Szeląg and Małgorzata Trocha
Int. J. Mol. Sci. 2021, 22(23), 13155; https://doi.org/10.3390/ijms222313155 - 5 Dec 2021
Cited by 2 | Viewed by 2738
Abstract
Molecular mechanisms underlying the beneficial effect of sitagliptin repurposed for hepatic ischemia-reperfusion injury (IRI) are poorly understood. We aimed to evaluate the impact of IRI and sitagliptin on the hepatic profile of eicosanoids (LC-MS/MS) and expression/concentration (RTqPCR/ELISA) of GLP-1/GLP-1R, SDF-1α/CXCR4 and VIP/VPAC1, VPAC2, [...] Read more.
Molecular mechanisms underlying the beneficial effect of sitagliptin repurposed for hepatic ischemia-reperfusion injury (IRI) are poorly understood. We aimed to evaluate the impact of IRI and sitagliptin on the hepatic profile of eicosanoids (LC-MS/MS) and expression/concentration (RTqPCR/ELISA) of GLP-1/GLP-1R, SDF-1α/CXCR4 and VIP/VPAC1, VPAC2, and PAC1 in 36 rats. Animals were divided into four groups and subjected to ischemia (60 min) and reperfusion (24 h) with or without pretreatment with sitagliptin (5 mg/kg) (IR and SIR) or sham-operated with or without sitagliptin pretreatment (controls and sitagliptin). PGI2, PGE2, and 13,14-dihydro-PGE1 were significantly upregulated in IR but not SIR, while sitagliptin upregulated PGD2 and 15-deoxy-12,14-PGJ2. IR and sitagliptin non-significantly upregulated GLP-1 while Glp1r expression was borderline detectable. VIP concentration and Vpac2 expression were downregulated in IR but not SIR, while Vpac1 was significantly downregulated solely in SIR. IRI upregulated both CXCR4 expression and concentration, and sitagliptin pretreatment abrogated receptor overexpression and downregulated Sdf1. In conclusion, hepatic IRI is accompanied by an elevation in proinflammatory prostanoids and overexpression of CXCR4, combined with downregulation of VIP/VPAC2. Beneficial effects of sitagliptin during hepatic IRI might be mediated by drug-induced normalization of proinflammatory prostanoids and upregulation of PGD2 and by concomitant downregulation of SDF-1α/CXCR4 and reinstating VIP/VCAP2 signaling. Full article
(This article belongs to the Special Issue Liver Damage and Repair 2.0)
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21 pages, 3367 KiB  
Article
Caulerpin Mitigates Helicobacter pylori-Induced Inflammation via Formyl Peptide Receptors
by Paola Cuomo, Chiara Medaglia, Ivana Allocca, Angela Michela Immacolata Montone, Fabrizia Guerra, Serena Cabaro, Ernesto Mollo, Daniela Eletto, Marina Papaianni and Rosanna Capparelli
Int. J. Mol. Sci. 2021, 22(23), 13154; https://doi.org/10.3390/ijms222313154 - 5 Dec 2021
Cited by 4 | Viewed by 3132
Abstract
The identification of novel strategies to control Helicobacter pylori (Hp)-associated chronic inflammation is, at present, a considerable challenge. Here, we attempt to combat this issue by modulating the innate immune response, targeting formyl peptide receptors (FPRs), G-protein coupled receptors that play [...] Read more.
The identification of novel strategies to control Helicobacter pylori (Hp)-associated chronic inflammation is, at present, a considerable challenge. Here, we attempt to combat this issue by modulating the innate immune response, targeting formyl peptide receptors (FPRs), G-protein coupled receptors that play key roles in both the regulation and the resolution of the innate inflammatory response. Specifically, we investigated, in vitro, whether Caulerpin—a bis-indole alkaloid isolated from algae of the genus Caulerpa—could act as a molecular antagonist scaffold of FPRs. We showed that Caulerpin significantly reduces the immune response against Hp culture filtrate, by reverting the FPR2-related signaling cascade and thus counteracting the inflammatory reaction triggered by Hp peptide Hp(2–20). Our study suggests Caulerpin to be a promising therapeutic or adjuvant agent for the attenuation of inflammation triggered by Hp infection, as well as its related adverse clinical outcomes. Full article
(This article belongs to the Special Issue Old and New Players in Inflammatory Disorders—in Memory of Dr. Nadia Ferlazzo)
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16 pages, 930 KiB  
Review
Differential Actions of Muscarinic Receptor Subtypes in Gastric, Pancreatic, and Colon Cancer
by Alyssa Schledwitz, Margaret H. Sundel, Madeline Alizadeh, Shien Hu, Guofeng Xie and Jean-Pierre Raufman
Int. J. Mol. Sci. 2021, 22(23), 13153; https://doi.org/10.3390/ijms222313153 - 5 Dec 2021
Cited by 18 | Viewed by 4159
Abstract
Cancers arising from gastrointestinal epithelial cells are common, aggressive, and difficult to treat. Progress in this area resulted from recognizing that the biological behavior of these cancers is highly dependent on bioactive molecules released by neurocrine, paracrine, and autocrine mechanisms within the tumor [...] Read more.
Cancers arising from gastrointestinal epithelial cells are common, aggressive, and difficult to treat. Progress in this area resulted from recognizing that the biological behavior of these cancers is highly dependent on bioactive molecules released by neurocrine, paracrine, and autocrine mechanisms within the tumor microenvironment. For many decades after its discovery as a neurotransmitter, acetylcholine was thought to be synthesized and released uniquely from neurons and considered the sole physiological ligand for muscarinic receptor subtypes, which were believed to have similar or redundant actions. In the intervening years, we learned this former dogma is not tenable. (1) Acetylcholine is not produced and released only by neurons. The cellular machinery required to synthesize and release acetylcholine is present in immune, cancer, and other cells, as well as in lower organisms (e.g., bacteria) that inhabit the gut. (2) Acetylcholine is not the sole physiological activator of muscarinic receptors. For example, selected bile acids can modulate muscarinic receptor function. (3) Muscarinic receptor subtypes anticipated to have overlapping functions based on similar G protein coupling and downstream signaling may have unexpectedly diverse actions. Here, we review the relevant research findings supporting these conclusions and discuss how the complexity of muscarinic receptor biology impacts health and disease, focusing on their role in the initiation and progression of gastric, pancreatic, and colon cancers. Full article
(This article belongs to the Special Issue Biological Interfaces in Gastrointestinal Cancer 2.0)
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11 pages, 1824 KiB  
Article
Adsorption of 1,2-Dichlorobenzene from the Aqueous Phase onto Activated Carbons and Modified Carbon Nanotubes
by Martyna Jurkiewicz and Robert Pełech
Int. J. Mol. Sci. 2021, 22(23), 13152; https://doi.org/10.3390/ijms222313152 - 5 Dec 2021
Cited by 10 | Viewed by 2669
Abstract
This study aimed to describe the adsorption process of ortho-dichlorobenzene (o-DCB) onto activated carbons (ACs) and modified carbon nanotubes (CNTs) from the aqueous phase. The starting material NC_7000 carbon nanotubes were modified by chlorination (NC_C) and then by the introduction of hydroxyl groups [...] Read more.
This study aimed to describe the adsorption process of ortho-dichlorobenzene (o-DCB) onto activated carbons (ACs) and modified carbon nanotubes (CNTs) from the aqueous phase. The starting material NC_7000 carbon nanotubes were modified by chlorination (NC_C) and then by the introduction of hydroxyl groups (NC_C_B). The concentration of o-DCB in solutions was performed by UV-VIS spectrophotometry. After adsorption, the activated carbons were regenerated by extraction with organic solvents such as acetone, methanol, ethanol, and 1-propanol; the carbon nanotubes were regenerated by methanol. The degree of adsorbate recovery was determined by gas chromatography (GC) with flame ionization detection, using ethylbenzene as an internal standard. The equilibrium isotherm data of adsorption were satisfactorily fitted by the Langmuir equations. The results indicate that carbon adsorbents are effective porous materials for removing o-DCB from the aqueous phase. Additionally, activated carbons are more regenerative adsorbents than carbon nanotubes. The recoveries of o-DCB from ACs were in the range of 76–85%, whereas the recoveries from CNTs were in the range of 23–46%. Modifications of CNTs affect the improvement of their adsorption properties towards o-DCB compared to unmodified CNTs. However, the introduction of new functional groups on carbon nanotube surfaces makes the regeneration process less effective. Full article
(This article belongs to the Special Issue Advanced Applications of Carbon-Based Adsorbents)
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13 pages, 3216 KiB  
Article
Functional Significance of Selective Expression of ERα and ERβ in Mammary Gland Organ Culture
by Rajendra G. Mehta
Int. J. Mol. Sci. 2021, 22(23), 13151; https://doi.org/10.3390/ijms222313151 - 5 Dec 2021
Cited by 3 | Viewed by 1842
Abstract
Thoracic pair of mammary glands from steroid hormone-pretreated mice respond to hormones structurally and functionally in organ culture. A short exposure of glands for 24 h to 7,12 Dimethylbenz(a)anthracene (DMBA) during a 24-day culture period induced alveolar or ductal lesions. Methods: To differentiate [...] Read more.
Thoracic pair of mammary glands from steroid hormone-pretreated mice respond to hormones structurally and functionally in organ culture. A short exposure of glands for 24 h to 7,12 Dimethylbenz(a)anthracene (DMBA) during a 24-day culture period induced alveolar or ductal lesions. Methods: To differentiate the functional significance of ERα and ERβ, we employed estrogen receptor (ER) knockout mice. We compared the effects of DMBA on the development of preneoplastic lesions in the glands in the absence of ERα (αERKO) and ERβ (βERKO) using an MMOC protocol. Glands were also subjected to microarray analyses. We showed that estradiol can be replaced by EGF for pretreatment of mice. The carcinogen-induced lesions developed under both steroids and EGF pretreatment protocols. The glands from αERKO did not develop any lesions, whereas in βERKO mice in which ERα is intact, mammary alveolar lesions developed. Comparison of microarrays of control, αERKO and βERKO mice showed that ERα was largely responsible for proliferation and the MAP kinase pathways, whereas ERβ regulated steroid metabolism-related genes. The results indicate that ERα is essential for the development of precancerous lesions. Both subtypes, ERα and Erβ, differentially regulated gene expression in mammary glands in organ cultures. Full article
(This article belongs to the Special Issue Cancer Cell Models for the Development of Anti-cancer Drugs)
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18 pages, 5498 KiB  
Article
AS1411 Nucleolin-Specific Binding Aptamers Reduce Pathological Angiogenesis through Inhibition of Nucleolin Phosphorylation
by Emilio Iturriaga-Goyon, Oscar Vivanco-Rojas, Fátima Sofía Magaña-Guerrero, Beatriz Buentello-Volante, Ilse Castro-Salas, José Eduardo Aguayo-Flores, Isabel Gracia-Mora, Marisol Rivera-Huerta, Francisco Sánchez-Bartés and Yonathan Garfias
Int. J. Mol. Sci. 2021, 22(23), 13150; https://doi.org/10.3390/ijms222313150 - 5 Dec 2021
Cited by 9 | Viewed by 3157
Abstract
Proliferative retinopathies produces an irreversible type of blindness affecting working age and pediatric population of industrialized countries. Despite the good results of anti-VEGF therapy, intraocular and systemic complications are often associated after its intravitreal use, hence novel therapeutic approaches are needed. The aim [...] Read more.
Proliferative retinopathies produces an irreversible type of blindness affecting working age and pediatric population of industrialized countries. Despite the good results of anti-VEGF therapy, intraocular and systemic complications are often associated after its intravitreal use, hence novel therapeutic approaches are needed. The aim of the present study is to test the effect of the AS1411, an antiangiogenic nucleolin-binding aptamer, using in vivo, ex vivo and in vitro models of angiogenesis and propose a mechanistic insight. Our results showed that AS1411 significantly inhibited retinal neovascularization in the oxygen induced retinopathy (OIR) in vivo model, as well as inhibited branch formation in the rat aortic ex vivo assay, and, significantly reduced proliferation, cell migration and tube formation in the HUVEC in vitro model. Importantly, phosphorylated NCL protein was significantly abolished in HUVEC in the presence of AS1411 without affecting NFκB phosphorylation and -21 and 221-angiomiRs, suggesting that the antiangiogenic properties of this molecule are partially mediated by a down regulation in NCL phosphorylation. In sum, this new research further supports the NCL role in the molecular etiology of pathological angiogenesis and identifies AS1411 as a novel anti-angiogenic treatment. Full article
(This article belongs to the Special Issue Advances in Molecular Activity of Potential Drugs)
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15 pages, 846 KiB  
Review
Overview of Drug Transporters in Human Placenta
by Michiko Yamashita and Udo R. Markert
Int. J. Mol. Sci. 2021, 22(23), 13149; https://doi.org/10.3390/ijms222313149 - 5 Dec 2021
Cited by 14 | Viewed by 4883
Abstract
The transport of drugs across the placenta is a point of great importance in pharmacotherapy during pregnancy. However, the knowledge of drug transport in pregnancy is mostly based on experimental clinical data, and the underlying biological mechanisms are not fully understood. In this [...] Read more.
The transport of drugs across the placenta is a point of great importance in pharmacotherapy during pregnancy. However, the knowledge of drug transport in pregnancy is mostly based on experimental clinical data, and the underlying biological mechanisms are not fully understood. In this review, we summarize the current knowledge of drug transporters in the human placenta. We only refer to human data since the placenta demonstrates great diversity among species. In addition, we describe the experimental models that have been used in human placental transport studies and discuss their availability. A better understanding of placental drug transporters will be beneficial for the health of pregnant women who need drug treatment and their fetuses. Full article
(This article belongs to the Special Issue Reproductive and Developmental Toxicology 2.0)
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13 pages, 2383 KiB  
Article
Antimicrobial Properties and Cytotoxic Effect of Imidazolium Geminis with Tunable Hydrophobicity
by Syumbelya K. Amerkhanova, Alexandra D. Voloshina, Alla B. Mirgorodskaya, Anna P. Lyubina, Darya A. Kuznetsova, Rushana A. Kushnazarova, Vasilii A. Mikhailov and Lucia Ya. Zakharova
Int. J. Mol. Sci. 2021, 22(23), 13148; https://doi.org/10.3390/ijms222313148 - 5 Dec 2021
Cited by 16 | Viewed by 2334
Abstract
Antimicrobial, membranotropic and cytotoxic properties of dicationic imidazolium surfactants of n-s-n (Im) series with variable length of alkyl group (n = 8, 10, 12, 14, 16) and spacer fragment (s = 2, 3, 4) were explored and compared with monocationic analogues. Their activity [...] Read more.
Antimicrobial, membranotropic and cytotoxic properties of dicationic imidazolium surfactants of n-s-n (Im) series with variable length of alkyl group (n = 8, 10, 12, 14, 16) and spacer fragment (s = 2, 3, 4) were explored and compared with monocationic analogues. Their activity against a representative range of Gram-positive and Gram-negative bacteria, and also fungi, is characterized. The relationship between the biological activity and the structural features of these compounds is revealed, with the hydrophobicity emphasized as a key factor. Among dicationic surfactants, decyl derivatives showed highest antimicrobial effect, while for monocationic analogues, the maximum activity is observed in the case of tetradecyl tail. The leading compounds are 2–4 times higher in activity compared to reference antibiotics and prove effective against resistant strains. It has been shown that the antimicrobial effect is not associated with the destruction of the cell membrane, but is due to specific interactions of surfactants and cell components. Importantly, they show strong selectivity for microorganism cells while being of low harm to healthy human cells, with a SI ranging from 30 to 100. Full article
(This article belongs to the Special Issue The Self-Assembly and Design of Polyfunctional Nanosystems 3.0)
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19 pages, 4160 KiB  
Article
Impact of Cigarette Smoking on the Expression of Oxidative Stress-Related Genes in Cumulus Cells Retrieved from Healthy Women Undergoing IVF
by Fani Konstantinidou, Maria Cristina Budani, Annalina Sarra, Liborio Stuppia, Gian Mario Tiboni and Valentina Gatta
Int. J. Mol. Sci. 2021, 22(23), 13147; https://doi.org/10.3390/ijms222313147 - 5 Dec 2021
Cited by 11 | Viewed by 2898
Abstract
The female reproductive system represents a sensitive target of the harmful effects of cigarette smoke, with folliculogenesis as one of the ovarian processes most affected by this exposure. The aim of this study was to analyze the impact of tobacco smoking on expression [...] Read more.
The female reproductive system represents a sensitive target of the harmful effects of cigarette smoke, with folliculogenesis as one of the ovarian processes most affected by this exposure. The aim of this study was to analyze the impact of tobacco smoking on expression of oxidative stress-related genes in cumulus cells (CCs) from smoking and non-smoking women undergoing IVF techniques. Real time PCR technology was used to analyze the gene expression profile of 88 oxidative stress genes enclosed in a 96-well plate array. Statistical significance was assessed by one-way ANOVA. The biological functions and networks/pathways of modulated genes were evidenced by ingenuity pathway analysis software. Promoter methylation analysis was performed by pyrosequencing. Our results showed a down-regulation of 24 genes and an up-regulation of 2 genes (IL6 and SOD2, respectively) involved in defense against oxidative damage, cell cycle regulation, as well as inflammation in CCs from smoking women. IL-6 lower promoter methylation was found in CCs of the smokers group. In conclusion, the disclosed overall downregulation suggests an oxidant-antioxidant imbalance in CCs triggered by cigarette smoking exposure. This evidence adds a piece to the puzzle of the molecular basis of female reproduction and could help underlay the importance of antioxidant treatments for smoking women undergoing IVF protocols. Full article
(This article belongs to the Section Molecular Toxicology)
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16 pages, 2833 KiB  
Article
Evaluation of the Physico-Chemical Properties of Liposomes Assembled from Bioconjugates of Anisic Acid with Phosphatidylcholine
by Hanna Pruchnik, Anna Gliszczyńska and Aleksandra Włoch
Int. J. Mol. Sci. 2021, 22(23), 13146; https://doi.org/10.3390/ijms222313146 - 5 Dec 2021
Cited by 8 | Viewed by 2751
Abstract
The aim of this work was the evaluation of the physico-chemical properties of a new type of liposomes that are composed of DPPC and bioconjugates of anisic acid with phosphatidylcholine. In particular, the impact of modified anisic acid phospholipids on the thermotropic parameters [...] Read more.
The aim of this work was the evaluation of the physico-chemical properties of a new type of liposomes that are composed of DPPC and bioconjugates of anisic acid with phosphatidylcholine. In particular, the impact of modified anisic acid phospholipids on the thermotropic parameters of liposomes was determined, which is crucial for using them as potential carriers of active substances in cancer therapies. Their properties were determined using three biophysical methods, namely differential scanning calorimetry (DSC), steady-state fluorimetry and attenuated total reflectance Fourier transform infrared spectroscopy (ATR-FTIR). Moreover, temperature studies of liposomes composed of DPPC and bioconjugates of anisic acid with phosphatidylcholine provided information about the phase transition, fluidity regarding chain order, hydration and dynamics. The DSC results show that the main phase transition peak for conjugates of anisic acid with phosphatidylcholine molecules was broadened and shifted to a lower temperature in a concentration- and structure-dependent manner. The ATR-FTIR results and the results of measurements conducted using fluorescent probes located at different regions in the lipid bilayer are in line with DSC. The results show that the new bioconjugates with phosphatidylcholine have a significant impact on the physico-chemical properties of a membrane and cause a decrease in the temperature of the main phase transition. The consequence of this is greater fluidity of the lipid bilayer. Full article
(This article belongs to the Collection Feature Papers in Molecular Biophysics)
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10 pages, 1690 KiB  
Article
An Easy Route to Aziridine Ketones and Carbinols
by Boriss Strumfs, Jekaterina Hermane, Sergey Belyakov, Artjoms Sobolevs, Kirils Velikijs, Romans Uljanovs, Peteris Trapencieris and Ilze Strumfa
Int. J. Mol. Sci. 2021, 22(23), 13145; https://doi.org/10.3390/ijms222313145 - 5 Dec 2021
Cited by 1 | Viewed by 1780
Abstract
N,N-Dimethylaziridine-2-carboxamides react with organolithium reagents yielding 2-aziridinylketones. The reaction with one equivalent of organolithium compound is selective to amide carbonyl at a low (−78 °C) temperature. These ketones, in reaction with organolithium reagents, give symmetrical and unsymmetrical aziridinyl carbinols. The usage of [...] Read more.
N,N-Dimethylaziridine-2-carboxamides react with organolithium reagents yielding 2-aziridinylketones. The reaction with one equivalent of organolithium compound is selective to amide carbonyl at a low (−78 °C) temperature. These ketones, in reaction with organolithium reagents, give symmetrical and unsymmetrical aziridinyl carbinols. The usage of excess phenyllithium may serve as a special N-Boc-protecting group cleavage method for acid-sensitive substrates. Full article
(This article belongs to the Special Issue Heterocyclic Compounds: Advanced Syntheses and Applications)
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17 pages, 2273 KiB  
Article
A Cancer-Related microRNA Signature Shows Biomarker Utility in Multiple Myeloma
by Aristea-Maria Papanota, Paraskevi Karousi, Christos K. Kontos, Pinelopi I. Artemaki, Christine-Ivy Liacos, Maria-Alexandra Papadimitriou, Tina Bagratuni, Evangelos Eleutherakis-Papaiakovou, Panagiotis Malandrakis, Ioannis Ntanasis-Stathopoulos, Maria Gavriatopoulou, Efstathios Kastritis, Margaritis Avgeris, Meletios-Athanasios Dimopoulos, Andreas Scorilas and Evangelos Terpos
Int. J. Mol. Sci. 2021, 22(23), 13144; https://doi.org/10.3390/ijms222313144 - 5 Dec 2021
Cited by 13 | Viewed by 2997
Abstract
Multiple myeloma (MM) is the second most common hematological malignancy, arising from terminally differentiated B cells, namely plasma cells. miRNAs are small non-coding RNAs that participate in the post-transcriptional regulation of gene expression. In this study, we investigated the role of nine miRNAs [...] Read more.
Multiple myeloma (MM) is the second most common hematological malignancy, arising from terminally differentiated B cells, namely plasma cells. miRNAs are small non-coding RNAs that participate in the post-transcriptional regulation of gene expression. In this study, we investigated the role of nine miRNAs in MM. CD138+ plasma cells were selected from bone marrow aspirates from MM and smoldering MM (sMM) patients. Total RNA was extracted and in vitro polyadenylated. Next, first-strand cDNA synthesis was performed using an oligo-dT–adapter primer. For the relative quantification of the investigated miRNAs, an in-house real-time quantitative PCR (qPCR) assay was developed. A functional in silico analysis of the miRNAs was also performed. miR-16-5p and miR-155-5p expression was significantly lower in the CD138+ plasma cells of MM patients than in those of sMM patients. Furthermore, lower levels of miR-15a-5p, miR-16-5p, and miR-222-3p were observed in the CD138+ plasma cells of MM patients with osteolytic bone lesions, compared to those without. miR-125b-5p was also overexpressed in the CD138+ plasma cells of MM patients with bone disease that presented with skeletal-related events (SREs). Furthermore, lower levels of miR-223-3p were associated with significantly worse overall survival in MM patients. In conclusion, we propose a miRNA signature with putative clinical utility in MM. Full article
(This article belongs to the Special Issue Multiple Myeloma: Focus on Molecular and Epigenetic Aspects)
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