International Journal of Molecular Sciences

15 pages, 3005 KiB

Open AccessArticle

Statins Aggravate the Risk of Insulin Resistance in Human Muscle

by Stefanie A. Grunwald, Stefanie Haafke, Ulrike Grieben, Ursula Kassner, Elisabeth Steinhagen-Thiessen and Simone Spuler

Int. J. Mol. Sci. 2022, 23(4), 2398; https://doi.org/10.3390/ijms23042398 - 21 Feb 2022

Cited by 15 | Viewed by 5051

Abstract

Beside their beneficial effects on cardiovascular events, statins are thought to contribute to insulin resistance and type-2 diabetes. It is not known whether these effects are long-term events from statin-treatment or already triggered with the first statin-intake. Skeletal muscle is considered the main [...] Read more.

Beside their beneficial effects on cardiovascular events, statins are thought to contribute to insulin resistance and type-2 diabetes. It is not known whether these effects are long-term events from statin-treatment or already triggered with the first statin-intake. Skeletal muscle is considered the main site for insulin-stimulated glucose uptake and therefore, a primary target for insulin resistance in the human body. We analyzed localization and expression of proteins related to GLUT4 mediated glucose uptake via AMPKα or AKT in human skeletal muscle tissue from patients with statin-intake >6 months and in primary human myotubes after 96 h statin treatment. The ratio for AMPKα activity significantly increased in human skeletal muscle cells treated with statins for long- and short-term. Furthermore, the insulin-stimulated counterpart, AKT, significantly decreased in activity and protein level, while GSK3ß and mTOR protein expression reduced in statin-treated primary human myotubes, only. However, GLUT4 was normally distributed whereas CAV3 was internalized from plasma membrane around the nucleus in statin-treated primary human myotubes. Statin-treatment activates AMPKα-dependent glucose uptake and remains active after long-term statin treatment. Permanent blocking of its insulin-dependent counterpart AKT activation may lead to metabolic inflexibility and insulin resistance in the long run and may be a direct consequence of statin-treatment. Full article

(This article belongs to the Special Issue Highlights in Pathophysiology of the Musculoskeletal System)

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28 pages, 1088 KiB

Open AccessReview

Diabetes and Ischemic Stroke: An Old and New Relationship an Overview of the Close Interaction between These Diseases

by Carlo Domenico Maida, Mario Daidone, Gaetano Pacinella, Rosario Luca Norrito, Antonio Pinto and Antonino Tuttolomondo

Int. J. Mol. Sci. 2022, 23(4), 2397; https://doi.org/10.3390/ijms23042397 - 21 Feb 2022

Cited by 62 | Viewed by 13609

Abstract

Diabetes mellitus is a comprehensive expression to identify a condition of chronic hyperglycemia whose causes derive from different metabolic disorders characterized by altered insulin secretion or faulty insulin effect on its targets or often both mechanisms. Diabetes and atherosclerosis are, from the point [...] Read more.

Diabetes mellitus is a comprehensive expression to identify a condition of chronic hyperglycemia whose causes derive from different metabolic disorders characterized by altered insulin secretion or faulty insulin effect on its targets or often both mechanisms. Diabetes and atherosclerosis are, from the point of view of cardio- and cerebrovascular risk, two complementary diseases. Beyond shared aspects such as inflammation and oxidative stress, there are multiple molecular mechanisms by which they feed off each other: chronic hyperglycemia and advanced glycosylation end-products (AGE) promote ‘accelerated atherosclerosis’ through the induction of endothelial damage and cellular dysfunction. These diseases impact the vascular system and, therefore, the risk of developing cardio- and cerebrovascular events is now evident, but the observation of this significant correlation has its roots in past decades. Cerebrovascular complications make diabetic patients 2–6 times more susceptible to a stroke event and this risk is magnified in younger individuals and in patients with hypertension and complications in other vascular beds. In addition, when patients with diabetes and hyperglycemia experience an acute ischemic stroke, they are more likely to die or be severely disabled and less likely to benefit from the one FDA-approved therapy, intravenous tissue plasminogen activator. Experimental stroke models have revealed that chronic hyperglycemia leads to deficits in cerebrovascular structure and function that may explain some of the clinical observations. Increased edema, neovascularization, and protease expression as well as altered vascular reactivity and tone may be involved and point to potential therapeutic targets. Further study is needed to fully understand this complex disease state and the breadth of its manifestation in the cerebrovasculature. Full article

(This article belongs to the Section Molecular Endocrinology and Metabolism)

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16 pages, 3527 KiB

Open AccessArticle

Chitosan Functionalized with Carboxyl Groups as a Recyclable Biomaterial for the Adsorption of Cu (II) and Zn (II) Ions in Aqueous Media

by Asmaa M. Abu El-Soad, Giuseppe Lazzara, Mahmoud O. Abd El-Magied, Giuseppe Cavallaro, Jamelah S. Al-Otaibi, M. I. Sayyed and Elena G. Kovaleva

Int. J. Mol. Sci. 2022, 23(4), 2396; https://doi.org/10.3390/ijms23042396 - 21 Feb 2022

Cited by 20 | Viewed by 3405

Abstract

The modification of chitosan represents a challenging task in obtaining biopolymeric materials with enhanced removal capacity for heavy metals. In the present work, the adsorption characteristics of chitosan modified with carboxyl groups (CTS-CAA) towards copper (II) and zinc (II) ions have been tested. [...] Read more.

The modification of chitosan represents a challenging task in obtaining biopolymeric materials with enhanced removal capacity for heavy metals. In the present work, the adsorption characteristics of chitosan modified with carboxyl groups (CTS-CAA) towards copper (II) and zinc (II) ions have been tested. The efficacy of the synthesis of CTS-CAA has been evaluated by studying various properties of the modified chitosan. Specifically, the functionalized chitosan has been characterized by using several techniques, including thermal analyses (differential scanning calorimetry and thermogravimetry), spectroscopies (FT-IR, XRD), elemental analysis, and scanning electron microscopy. The kinetics and the adsorption isotherms of CTS-CAA towards both Cu (II) and Zn (II) have been determined in the aqueous solvent under variable pH. The obtained results have been analyzed by using different adsorption models. In addition, the experiments have been conducted at variable temperatures to explore the thermodynamics of the adsorption process. The regeneration of CTS-CAA has been investigated by studying the desorption process using different eluents. This paper reports an efficient protocol to synthesize chitosan-based material perspective as regenerative adsorbents for heavy metals. Full article

(This article belongs to the Section Materials Science)

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28 pages, 4098 KiB

Open AccessArticle

The Effects of a Meldonium Pre-Treatment on the Course of the LPS-Induced Sepsis in Rats

by Siniša Đurašević, Aleksandra Ružičić, Iva Lakić, Tomislav Tosti, Saša Đurović, Sofija Glumac, Snežana Pejić, Ana Todorović, Dunja Drakulić, Sanja Stanković, Nebojša Jasnić, Jelena Đorđević and Zoran Todorović

Int. J. Mol. Sci. 2022, 23(4), 2395; https://doi.org/10.3390/ijms23042395 - 21 Feb 2022

Cited by 9 | Viewed by 3714

Abstract

A dysregulated and overwhelming response to an infection accompanied by the exaggerated pro-inflammatory state and metabolism disturbance leads to the fatal outcome in sepsis. Previously we showed that meldonium, an anti-ischemic drug clinically used to treat myocardial and cerebral ischemia, strongly increases mortality [...] Read more.

A dysregulated and overwhelming response to an infection accompanied by the exaggerated pro-inflammatory state and metabolism disturbance leads to the fatal outcome in sepsis. Previously we showed that meldonium, an anti-ischemic drug clinically used to treat myocardial and cerebral ischemia, strongly increases mortality in faecal-induced peritonitis (FIP) in rats. We postulated that the same mechanism that is responsible for the otherwise strong anti-inflammatory effects of meldonium could be the culprit of the increased mortality. In the present study, we applied the LPS-induced model of sepsis to explore the presence of any differences from and/or similarities to the FIP model. When it comes to energy production, despite some shared similarities, it is evident that LPS and FIP models of sepsis differ greatly. A different profile of sympathoadrenal activation may account for this observation, as it was lacking in the FIP model, whereas in the LPS model it was strong enough to overcome the effects of meldonium. Therefore, choosing the appropriate model of sepsis induction is of great importance, especially if energy homeostasis is the main focus of the study. Even when differences in the experimental design of the two models are acknowledged, the role of different patterns of energy production cannot be excluded. On that account, our results draw attention to the importance of uninterrupted energy production in sepsis but also call for much-needed revisions of the current recommendations for its treatment. Full article

(This article belongs to the Collection Feature Papers in Molecular Toxicology)

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17 pages, 10807 KiB

Open AccessArticle

Biological Determinants of Metabolic Syndrome in Visceral and Subcutaneous Adipose Tissue from Severely Obese Women

by Óscar Osorio-Conles, Arturo Vega-Beyhart, Ainitze Ibarzabal, José María Balibrea, Josep Vidal and Ana de Hollanda

Int. J. Mol. Sci. 2022, 23(4), 2394; https://doi.org/10.3390/ijms23042394 - 21 Feb 2022

Cited by 1 | Viewed by 3388

Abstract

The metabolic syndrome (MetS) is a cluster of the most dangerous heart attack risk factors: diabetes or raised fasting plasma glucose, abdominal obesity, high cholesterol and high blood pressure. The goal of this study is to compare the state of the main features [...] Read more.

The metabolic syndrome (MetS) is a cluster of the most dangerous heart attack risk factors: diabetes or raised fasting plasma glucose, abdominal obesity, high cholesterol and high blood pressure. The goal of this study is to compare the state of the main features of obesity-associated white adipose tissue (WAT) dysfunction in 66 women with severe obesity without (MetS−) or with MetS (MetS+). Fat cell area, adipocyte size distribution and histological fibrosis were analysed in visceral (VAT) and abdominal subcutaneous WAT (SAT) in 33 age- and BMI-matched pairs of MetS− and MetS+ subjects. The mRNA expression of 93 genes implicated in obesity-associated WAT dysfunction was analysed by RT-qPCR in both fat depots. MetS+ females showed higher adipocyte hypertrophy in both fat depots and increased fibrosis and expression of macrophage and hypoxia markers in SAT. Transcriptional data suggest increased fatty acid oxidation in SAT and impaired thermogenesis and extracellular matrix remodelling in VAT from MetS+ subjects. A sPLS-DA model, including SAT expression of PPARA and LEPR genes identified MetS with an AUC = 0.87. Despite equal age, BMI and body composition, MetS+ females display morphological and transcriptional differences in both WAT depots, especially in SAT. These factors may contribute to the transition to MetS. Full article

(This article belongs to the Special Issue Metabolic Syndrome: From Molecular Mechanisms to Novel Therapies)

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16 pages, 2234 KiB

Open AccessArticle

Deficiency in RCAT-1 Function Causes Dopamine Metabolism Related Behavioral Disorders in Caenorhabditis elegans

by Haelim Jeong, Jun Young Park, Ji-Hyun Lee, Ja-Hyun Baik, Chae-Yeon Kim, Jin-Young Cho, Monica Driscoll and Young-Ki Paik

Int. J. Mol. Sci. 2022, 23(4), 2393; https://doi.org/10.3390/ijms23042393 - 21 Feb 2022

Cited by 3 | Viewed by 3490

Abstract

When animals are faced with food depletion, food search-associated locomotion is crucial for their survival. Although food search-associated locomotion is known to be regulated by dopamine, it has yet to investigate the potential molecular mechanisms governing the regulation of genes involved in dopamine [...] Read more.

When animals are faced with food depletion, food search-associated locomotion is crucial for their survival. Although food search-associated locomotion is known to be regulated by dopamine, it has yet to investigate the potential molecular mechanisms governing the regulation of genes involved in dopamine metabolism (e.g., cat-1, cat-2) and related behavioral disorders. During the studies of the pheromone ascaroside, a signal of starvation stress in C. elegans, we identified R02D3.7, renamed rcat-1 (regulator of cat genes-1), which had previously been shown to bind to regulatory sequences of both cat-1 and cat-2 genes. It was found that RCAT-1 (R02D3.7) is expressed in dopaminergic neurons and functions as a novel negative transcriptional regulator for cat-1 and cat-2 genes. When a food source becomes depleted, the null mutant, rcat-1(ok1745), exhibited an increased frequency of high-angled turns and intensified area restricted search behavior compared to the wild-type animals. Moreover, rcat-1(ok1745) also showed defects in state-dependent olfactory adaptation and basal slowing response, suggesting that the mutants are deficient in either sensing food or locomotion toward food. However, rcat-1(ok1745) has normal cuticular structures and locomotion genes. The discovery of rcat-1 not only identifies a new subtype of dopamine-related behaviors but also provides a potential therapeutic target in Parkinson’s disease. Full article

(This article belongs to the Special Issue Role of Dopamine in Health and Disease—Biological Aspect)

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12 pages, 6131 KiB

Open AccessArticle

Discovery of SARS-CoV-2 3CL^Pro Peptidomimetic Inhibitors through the Catalytic Dyad Histidine-Specific Protein–Ligand Interactions

by Yaxin Wang, Binghong Xu, Sen Ma, Hao Wang, Luqing Shang, Cheng Zhu and Sheng Ye

Int. J. Mol. Sci. 2022, 23(4), 2392; https://doi.org/10.3390/ijms23042392 - 21 Feb 2022

Cited by 7 | Viewed by 3244

Abstract

As the etiological agent for the coronavirus disease 2019, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) challenges the ongoing efforts of vaccine development and drug design. Due to the accumulating cases of breakthrough infections, there are urgent needs for broad-spectrum antiviral medicines. Here, [...] Read more.

As the etiological agent for the coronavirus disease 2019, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) challenges the ongoing efforts of vaccine development and drug design. Due to the accumulating cases of breakthrough infections, there are urgent needs for broad-spectrum antiviral medicines. Here, we designed and examined five new tetrapeptidomimetic anti-SARS-CoV-2 inhibitors targeting the 3C-Like protease (3CL^Pro), which is highly conserved among coronaviruses and essential for viral replications. We significantly improved the efficacy of a ketoamide lead compound based on high-resolution co-crystal structures, all-atom simulations, and binding energy calculations. The inhibitors successfully engaged the catalytic dyad histidine residue (H41) of 3CLPro as designed, and they exhibited nanomolar inhibitory capacity as well as mitigated the viral loads of SARS-CoV-2 in cellular assays. As a widely applicable design principle, our results revealed that the potencies of 3CL^Pro-specific drug candidates were determined by the interplay between 3CL^Pro H41 residue and the peptidomimetic inhibitors. Full article

(This article belongs to the Collection Computational Studies of Biomolecules)

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14 pages, 36195 KiB

Open AccessArticle

PTK7, a Catalytically Inactive Receptor Tyrosine Kinase, Increases Oncogenic Phenotypes in Xenograft Tumors of Esophageal Squamous Cell Carcinoma KYSE-30 Cells

by Won-Sik Shin, Mi-Kyung Park, Jae Hoon Kim, Si Won Oh, Ji-Yun Jang, Ho Lee and Seung-Taek Lee

Int. J. Mol. Sci. 2022, 23(4), 2391; https://doi.org/10.3390/ijms23042391 - 21 Feb 2022

Cited by 8 | Viewed by 3065

Abstract

Protein tyrosine kinase 7 (PTK7), a catalytically defective receptor protein tyrosine kinase, is upregulated in tumor tissues and cell lines of esophageal squamous cell carcinoma (ESCC). We showed that PTK7 plays an oncogenic role in various ESCC cell lines. However, its role as [...] Read more.

Protein tyrosine kinase 7 (PTK7), a catalytically defective receptor protein tyrosine kinase, is upregulated in tumor tissues and cell lines of esophageal squamous cell carcinoma (ESCC). We showed that PTK7 plays an oncogenic role in various ESCC cell lines. However, its role as an oncogene has not been demonstrated in vivo. Here, we examined the influence of PTK7 on the tumorigenic potential of ESCC KYSE-30 cells, which are known to establish xenograft tumors. Overexpression of PTK7 enhanced the proliferation, adhesion, wound healing, and migration of KYSE-30 cells, and these effects were reversed by the knockdown of PTK7. PTK7 overexpression and knockdown, respectively, increased and decreased the tyrosine phosphorylation of cellular proteins and the phosphorylation of ERK, AKT, and FAK, which are important for cell proliferation, survival, adhesion, and migration. Additionally, PTK7 overexpression and silencing, respectively, increased and decreased the weight, volume, and number of Ki-67-positive proliferating cells in xenograft tumors of KYSE-30 cells. Therefore, we propose that PTK7 plays an important role in the tumorigenesis of ESCC cells in vivo and is a potential therapeutic target for ESCC. Full article

(This article belongs to the Special Issue Cancer: Novel Approaches in the Discovery and Design of Targeted Therapies)

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17 pages, 2641 KiB

Open AccessReview

The Role of Natural Polymorphic Variants of DNA Polymerase β in DNA Repair

by Olga A. Kladova, Olga S. Fedorova and Nikita A. Kuznetsov

Int. J. Mol. Sci. 2022, 23(4), 2390; https://doi.org/10.3390/ijms23042390 - 21 Feb 2022

Cited by 13 | Viewed by 3160

Abstract

DNA polymerase β (Polβ) is considered the main repair DNA polymerase involved in the base excision repair (BER) pathway, which plays an important part in the repair of damaged DNA bases usually resulting from alkylation or oxidation. In general, BER involves consecutive actions [...] Read more.

DNA polymerase β (Polβ) is considered the main repair DNA polymerase involved in the base excision repair (BER) pathway, which plays an important part in the repair of damaged DNA bases usually resulting from alkylation or oxidation. In general, BER involves consecutive actions of DNA glycosylases, AP endonucleases, DNA polymerases, and DNA ligases. It is known that protein–protein interactions of Polβ with enzymes from the BER pathway increase the efficiency of damaged base repair in DNA. However natural single-nucleotide polymorphisms can lead to a substitution of functionally significant amino acid residues and therefore affect the catalytic activity of the enzyme and the accuracy of Polβ action. Up-to-date databases contain information about more than 8000 SNPs in the gene of Polβ. This review summarizes data on the in silico prediction of the effects of Polβ SNPs on DNA repair efficacy; available data on cancers associated with SNPs of Polβ; and experimentally tested variants of Polβ. Analysis of the literature indicates that amino acid substitutions could be important for the maintenance of the native structure of Polβ and contacts with DNA; others affect the catalytic activity of the enzyme or play a part in the precise and correct attachment of the required nucleotide triphosphate. Moreover, the amino acid substitutions in Polβ can disturb interactions with enzymes involved in BER, while the enzymatic activity of the polymorphic variant may not differ significantly from that of the wild-type enzyme. Therefore, investigation regarding the effect of Polβ natural variants occurring in the human population on enzymatic activity and protein–protein interactions is an urgent scientific task. Full article

(This article belongs to the Special Issue Recent Advances in Protein-Protein Interactions)

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10 pages, 1101 KiB

Open AccessArticle

Overexpression of Peroxisome-Localized GmABCA7 Promotes Seed Germination in Arabidopsis thaliana

by Jianchun Li, Zaihui Peng, Yan Liu, Meirong Lang, Yaohui Chen, Huihong Wang, Yingshuang Li, Banruo Shi, Weipeng Huang, Li Han, Yifeng Ma, Yu Zhang and Bangjun Wang

Int. J. Mol. Sci. 2022, 23(4), 2389; https://doi.org/10.3390/ijms23042389 - 21 Feb 2022

Cited by 5 | Viewed by 2437

Abstract

Peroxisome is one of the important organelles for intracellular lipid metabolism in plant cells and β-oxidation of fatty acids in peroxisomes provides the energy for oil-containing seed germination. In this study, we identified an ATP-binding cassette (ABC) transporter gene, GmABCA7 from soybean, which [...] Read more.

Peroxisome is one of the important organelles for intracellular lipid metabolism in plant cells and β-oxidation of fatty acids in peroxisomes provides the energy for oil-containing seed germination. In this study, we identified an ATP-binding cassette (ABC) transporter gene, GmABCA7 from soybean, which is highly expressed in the different developmental stages of seeds. Transient expression of GmABCA7 in tobacco epidermal cells showed that GmABCA7 was specifically localized at the peroxisomes. Overexpression of GmABCA7 in Arabidopsis does not change seed phenotypes, or the overall levels of lipid, protein and sugar stored in the seeds; however, the transgenic seeds produced more gluconeogenic pathway precursors such as succinate and malate and germinated earlier compared to the wild type seeds. These results suggest that GmABCA7 may affect the β-oxidation of fatty acids and play an important role in seed germination. Full article

(This article belongs to the Special Issue Morphology and Physiology of Seeds and Other Plant Storage Tissues 2.0)

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19 pages, 4883 KiB

Open AccessArticle

Neuroprotective Effects of the DPP4 Inhibitor Vildagliptin in In Vivo and In Vitro Models of Parkinson’s Disease

by Ramesh Pariyar, Tonking Bastola, Dae Ho Lee and Jungwon Seo

Int. J. Mol. Sci. 2022, 23(4), 2388; https://doi.org/10.3390/ijms23042388 - 21 Feb 2022

Cited by 23 | Viewed by 4247

Abstract

Parkinson’s disease (PD) is characterized by loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc) of the midbrain. Restoration of nigrostriatal dopamine neurons has been proposed as a potential therapeutic strategy for PD. Because currently used PD therapeutics only help relieve [...] Read more.

Parkinson’s disease (PD) is characterized by loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc) of the midbrain. Restoration of nigrostriatal dopamine neurons has been proposed as a potential therapeutic strategy for PD. Because currently used PD therapeutics only help relieve motor symptoms and do not treat the cause of the disease, highly effective drugs are needed. Vildagliptin, a dipeptidyl peptidase 4 (DPP4) inhibitor, is an anti-diabetic drug with various pharmacological properties including neuroprotective effects. However, the detailed effects of vildagliptin against PD are not fully understood. We investigated the effects of vildagliptin on PD and its underlying molecular mechanisms using a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced mouse model and a 1-methyl-4-phenylpyridium (MPP⁺)-induced cytotoxicity model. Vildagliptin (50 mg/kg) administration significantly attenuated MPTP-induced motor deficits as evidenced by rotarod, pole, and nest building tests. Immunohistochemistry and Western blot analysis revealed that vildagliptin increased tyrosine hydroxylase-positive cells in the SNpc and striatum, which was reduced by MPTP treatment. Furthermore, vildagliptin activated MPTP-decreased PI3k/Akt and mitigated MPTP-increased ERK and JNK signaling pathways in the striatum. Consistent with signaling transduction in the mouse striatum, vildagliptin reversed MPP⁺-induced dephosphorylation of PI3K/Akt and phosphorylation of ERK and JNK in SH-SY5Y cells. Moreover, vildagliptin attenuated MPP⁺-induced conversion of LC3B-II in SH-SY5Y cells, suggesting its role in autophagy inhibition. Taken together, these findings indicate that vildagliptin has protective effects against MPTP-induced motor dysfunction by inhibiting dopaminergic neuronal apoptosis, which is associated with regulation of PI3k/Akt, ERK, and JNK signaling transduction. Our findings suggest vildagliptin as a promising repurposing drug to treat PD. Full article

(This article belongs to the Special Issue Research in Parkinson's Disease)

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18 pages, 4442 KiB

Open AccessArticle

Pro- and Anti-Inflammatory Cytokines in the Context of NK Cell–Trophoblast Interactions

by Valentina Mikhailova, Polina Grebenkina, Evgeniia Khokhlova, Alina Davydova, Zeina Salloum, Elizaveta Tyshchuk, Valeria Zagainova, Kseniia Markova, Igor Kogan, Sergey Selkov and Dmitry Sokolov

Int. J. Mol. Sci. 2022, 23(4), 2387; https://doi.org/10.3390/ijms23042387 - 21 Feb 2022

Cited by 13 | Viewed by 4584

Abstract

During pregnancy, uterine NK cells interact with trophoblast cells. In addition to contact interactions, uterine NK cells are influenced by cytokines, which are secreted by the cells of the decidua microenvironment. Cytokines can affect the phenotypic characteristics of NK cells and change their [...] Read more.

During pregnancy, uterine NK cells interact with trophoblast cells. In addition to contact interactions, uterine NK cells are influenced by cytokines, which are secreted by the cells of the decidua microenvironment. Cytokines can affect the phenotypic characteristics of NK cells and change their functional activity. An imbalance of pro- and anti-inflammatory signals can lead to the development of reproductive pathology. The aim of this study was to assess the effects of cytokines on NK cells in the presence of trophoblast cells in an in vitro model. We used TNFα, IFNγ, TGFβ and IL-10; the NK-92 cell line; and peripheral blood NK cells (pNKs) from healthy, non-pregnant women. For trophoblast cells, the JEG-3 cell line was used. In the monoculture of NK-92 cells, TNFα caused a decrease in CD56 expression. In the coculture of NK cells with JEG-3 cells, TNFα increased the expression of NKG2C and NKG2A by NK-92 cells. Under the influence of TGFβ, the expression of CD56 increased and the expression of NKp30 decreased in the monoculture. After the preliminary cultivation of NK-92 cells in the presence of TGFβ, their cytotoxicity increased. In the case of adding TGFβ to the PBMC culture, as well as coculturing PBMCs and JEG-3 cells, the expression of CD56 and NKp44 by pNK cells was reduced. The differences in the effects of TGFβ in the model using NK-92 cells and pNK cells may be associated with the possible influence of monocytes or other lymphoid cells from the mononuclear fraction. Full article

(This article belongs to the Special Issue Natural Killer Cells and Immunotherapy)

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17 pages, 4074 KiB

Open AccessArticle

Smart Lipid–Polysaccharide Nanoparticles for Targeted Delivery of Doxorubicin to Breast Cancer Cells

by Manuela Curcio, Matteo Brindisi, Giuseppe Cirillo, Luca Frattaruolo, Antonella Leggio, Vittoria Rago, Fiore Pasquale Nicoletta, Anna Rita Cappello and Francesca Iemma

Int. J. Mol. Sci. 2022, 23(4), 2386; https://doi.org/10.3390/ijms23042386 - 21 Feb 2022

Cited by 16 | Viewed by 3556

Abstract

In this study, actively-targeted (CD44-receptors) and dual stimuli (pH/redox)-responsive lipid–polymer nanoparticles were proposed as a delivery vehicle of doxorubicin hydrochloride in triple negative breast cancer cell lines. A phosphatidylcholine lipid film was hydrated with a solution of oxidized hyaluronic acid and doxorubicin, chosen [...] Read more.

In this study, actively-targeted (CD44-receptors) and dual stimuli (pH/redox)-responsive lipid–polymer nanoparticles were proposed as a delivery vehicle of doxorubicin hydrochloride in triple negative breast cancer cell lines. A phosphatidylcholine lipid film was hydrated with a solution of oxidized hyaluronic acid and doxorubicin, chosen as model drug, followed by a crosslinking reaction with cystamine hydrochloride. The obtained spherical nanoparticles (mean diameter of 30 nm) were found to be efficiently internalized in cancer cells by a receptor-mediated endocytosis process, and to modulate the drug release depending on the pH and redox potential of the surrounding medium. In vitro cytotoxicity assays demonstrated the safety and efficacy of the nanoparticles in enhancing the cytotoxic effect of the free anticancer drug, with the IC₅₀ values being reduced by two and three times in MDA-MB-468 and MDA-MB-231, respectively. The combination of self-assembled phospholipid molecules with a polysaccharide counterpart acting as receptor ligand, and stimuli-responsive chemical moieties, was carried out on smart multifunctional nanoparticles able to actively target breast cancer cells and improve the in vitro anticancer activity of doxorubicin. Full article

(This article belongs to the Special Issue Biomolecule-Based Biomaterials and Their Application in Drug Delivery Systems)

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13 pages, 4617 KiB

Open AccessArticle

Generation and Characterization of a Zebrafish IL-2Rγc SCID Model

by Robert Sertori, Realla Jones, Faiza Basheer, Leni Rivera, Samantha Dawson, Stella Loke, Somayyeh Heidary, Amardeep Dhillon, Clifford Liongue and Alister C. Ward

Int. J. Mol. Sci. 2022, 23(4), 2385; https://doi.org/10.3390/ijms23042385 - 21 Feb 2022

Cited by 15 | Viewed by 2723

Abstract

The IL-2 family of cytokines act via receptor complexes that share the interleukin-2 receptor gamma common (IL-2Rγc) chain to play key roles in lymphopoiesis. Inactivating IL-2Rγc mutations results in severe combined immunodeficiency (SCID) in humans and other species. This study sought to generate [...] Read more.

The IL-2 family of cytokines act via receptor complexes that share the interleukin-2 receptor gamma common (IL-2Rγc) chain to play key roles in lymphopoiesis. Inactivating IL-2Rγc mutations results in severe combined immunodeficiency (SCID) in humans and other species. This study sought to generate an equivalent zebrafish SCID model. The zebrafish il2rga gene was targeted for genome editing using TALENs and presumed loss-of-function alleles analyzed with respect to immune cell development and impacts on intestinal microbiota and tumor immunity. Knockout of zebrafish Il-2rγc.a resulted in a SCID phenotype, including a significant reduction in T cells, with NK cells also impacted. This resulted in dysregulated intestinal microbiota and defective immunity to tumor xenotransplants. Collectively, this establishes a useful zebrafish SCID model. Full article

(This article belongs to the Special Issue Cytokine Receptors In Development, Homeostasis & Disease)

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18 pages, 4727 KiB

Open AccessArticle

Premarin Reduces Neurodegeneration and Promotes Improvement of Function in an Animal Model of Spinal Cord Injury

by Azizul Haque, Arabinda Das, Supriti Samantaray, Denise Matzelle, Mollie Capone, Gerald Wallace, Aarti N. Husarik, Saied Taheri, Russel J. Reiter, Abhay Varma, Swapan K. Ray and Naren L. Banik

Int. J. Mol. Sci. 2022, 23(4), 2384; https://doi.org/10.3390/ijms23042384 - 21 Feb 2022

Cited by 7 | Viewed by 2640

Abstract

Spinal cord injury (SCI) causes significant mortality and morbidity. Currently, no FDA-approved pharmacotherapy is available for treating SCI. Previously, low doses of estrogen (17β-estradiol, E2) were shown to improve the post-injury outcome in a rat SCI model. However, the range of associated side [...] Read more.

Spinal cord injury (SCI) causes significant mortality and morbidity. Currently, no FDA-approved pharmacotherapy is available for treating SCI. Previously, low doses of estrogen (17β-estradiol, E2) were shown to improve the post-injury outcome in a rat SCI model. However, the range of associated side effects makes advocating its therapeutic use difficult. Therefore, this study aimed at investigating the therapeutic efficacy of Premarin (PRM) in SCI. PRM is an FDA-approved E2 (10%) formulation, which is used for hormone replacement therapy with minimal risk of serious side effects. The effects of PRM on SCI were examined by magnetic resonance imaging, immunofluorescent staining, and western blot analysis in a rat model. SCI animals treated with vehicle alone, PRM, E2 receptor antagonist (ICI), or PRM + ICI were graded in a blinded way for locomotor function by using the Basso–Beattie–Bresnahan (BBB) locomotor scale. PRM treatment for 7 days decreased post-SCI lesion volume and attenuated neuronal cell death, inflammation, and axonal damage. PRM also altered the balance of pro- and anti-apoptotic proteins in favor of cell survival and improved angiogenesis and microvascular growth. Increased expression of estrogen receptors (ERs) ERα and ERβ following PRM treatment and their inhibition by ER inhibitor indicated that the neuroprotection associated with PRM treatment might be E2-receptor mediated. The attenuation of glial activation with decreased inflammation and cell death, and increased angiogenesis by PRM led to improved functional outcome as determined by the BBB locomotor scale. These results suggest that PRM treatment has significant therapeutic implications for the improvement of post-SCI outcome. Full article

(This article belongs to the Special Issue Advances in Research on Spinal Cord Injury)

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33 pages, 4045 KiB

Open AccessReview

Recent Advances in Copper-Based Solid Heterogeneous Catalysts for Azide–Alkyne Cycloaddition Reactions

by Noura Aflak, Hicham Ben El Ayouchia, Lahoucine Bahsis, Hafid Anane, Miguel Julve and Salah-Eddine Stiriba

Int. J. Mol. Sci. 2022, 23(4), 2383; https://doi.org/10.3390/ijms23042383 - 21 Feb 2022

Cited by 40 | Viewed by 5623

Abstract

The copper(I)-catalyzed azide−alkyne cycloaddition (CuAAC) reaction is considered to be the most representative ligation process within the context of the “click chemistry” concept. This CuAAC reaction, which yields compounds containing a 1,2,3-triazole core, has become relevant in the construction of biologically complex systems, [...] Read more.

The copper(I)-catalyzed azide−alkyne cycloaddition (CuAAC) reaction is considered to be the most representative ligation process within the context of the “click chemistry” concept. This CuAAC reaction, which yields compounds containing a 1,2,3-triazole core, has become relevant in the construction of biologically complex systems, bioconjugation strategies, and supramolecular and material sciences. Although many CuAAC reactions are performed under homogenous conditions, heterogenous copper-based catalytic systems are gaining exponential interest, relying on the easy removal, recovery, and reusability of catalytically copper species. The present review covers the most recently developed copper-containing heterogenous solid catalytic systems that use solid inorganic/organic hybrid supports, and which have been used in promoting CuAAC reactions. Due to the demand for 1,2,3-triazoles as non-classical bioisosteres and as framework-based drugs, the CuAAC reaction promoted by solid heterogenous catalysts has greatly improved the recovery and removal of copper species, usually by simple filtration. In so doing, the solving of the toxicity issue regarding copper particles in compounds of biological interest has been achieved. This protocol is also expected to produce a practical chemical process for accessing such compounds on an industrial scale. Full article

(This article belongs to the Collection Feature Papers in 'Macromolecules')

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14 pages, 2277 KiB

Open AccessArticle

Development and Validation of SNP and InDel Markers for Pod-Shattering Tolerance in Soybean

by Jeong-Hyun Seo, Sanjeev Kumar Dhungana, Beom-Kyu Kang, In-Youl Baek, Jung-Sook Sung, Jee-Yeon Ko, Chan-Sik Jung, Ki-Seung Kim and Tae-Hwan Jun

Int. J. Mol. Sci. 2022, 23(4), 2382; https://doi.org/10.3390/ijms23042382 - 21 Feb 2022

Cited by 11 | Viewed by 3608

Abstract

Pod-shattering causes a significant yield loss in many soybean cultivars. Shattering-tolerant cultivars provide the most effective approach to minimizing this loss. We developed molecular markers for pod-shattering and validated them in soybeans with diverse genetic backgrounds. The genes Glyma.16g141200, Glyma.16g141500, and [...] Read more.

Pod-shattering causes a significant yield loss in many soybean cultivars. Shattering-tolerant cultivars provide the most effective approach to minimizing this loss. We developed molecular markers for pod-shattering and validated them in soybeans with diverse genetic backgrounds. The genes Glyma.16g141200, Glyma.16g141500, and Glyma.16g076600, identified in our previous study by quantitative trait locus (QTL) mapping and whole-genome resequencing, were selected for marker development. The whole-genome resequencing of three parental lines (one shattering-tolerant and two shattering-susceptible) identified single nucleotide polymorphism (SNP) and/or insertion/deletion (InDel) regions within or near the selected genes. Two SNPs and one InDel were converted to Kompetitive Allele-Specific PCR (KASP) and InDel markers, respectively. The accuracy of the markers was examined in the two recombinant inbred line populations used for the QTL mapping, as well as the 120 varieties and elite lines, through allelic discrimination and phenotyping by the oven-drying method. Both types of markers successfully discriminated the pod shattering-tolerant and shattering-susceptible genotypes. The prediction accuracy, which was as high as 90.9% for the RILs and was 100% for the varieties and elite lines, also supported the accuracy and usefulness of these markers. Thus, the markers can be used effectively for genetic and genomic studies and the marker-assisted selection for pod-shattering tolerance in soybean. Full article

(This article belongs to the Special Issue Molecular Genetics and Plant Breeding 2.0)

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18 pages, 2788 KiB

Open AccessArticle

Common Molecular Targets of a Quinolone Based Bumped Kinase Inhibitor in Neospora caninum and Danio rerio

by Joachim Müller, Nicoleta Anghel, Dennis Imhof, Kai Hänggeli, Anne-Christine Uldry, Sophie Braga-Lagache, Manfred Heller, Kayode K. Ojo, Luis-Miguel Ortega-Mora, Wesley C. Van Voorhis and Andrew Hemphill

Int. J. Mol. Sci. 2022, 23(4), 2381; https://doi.org/10.3390/ijms23042381 - 21 Feb 2022

Cited by 8 | Viewed by 2343

Abstract

Neospora caninum is an apicomplexan parasite closely related to Toxoplasma gondii, and causes abortions, stillbirths and/or fetal malformations in livestock. Target-based drug development has led to the synthesis of calcium-dependent protein kinase 1 inhibitors, collectively named bumped kinase inhibitors (BKIs). Previous studies [...] Read more.

Neospora caninum is an apicomplexan parasite closely related to Toxoplasma gondii, and causes abortions, stillbirths and/or fetal malformations in livestock. Target-based drug development has led to the synthesis of calcium-dependent protein kinase 1 inhibitors, collectively named bumped kinase inhibitors (BKIs). Previous studies have shown that several BKIs have excellent efficacy against neosporosis in vitro and in vivo. However, several members of this class of compounds impair fertility in pregnant mouse models and cause embryonic malformation in a zebrafish (Danio rerio) model. Similar to the first-generation antiprotozoal drug quinine, some BKIs have a quinoline core structure. To identify common targets in both organisms, we performed differential affinity chromatography with cell-free extracts from N. caninum tachyzoites and D. rerio embryos using the 5-aminopyrazole-4-carboxamide (AC) compound BKI-1748 and quinine columns coupled to epoxy-activated sepharose followed by mass spectrometry. BKI-binding proteins of interest were identified in eluates from columns coupled to BKI-1748, or in eluates from BKI-1748 as well as quinine columns. In N. caninum, 12 proteins were bound specifically to BKI-1748 alone, and 105 proteins, including NcCDPK1, were bound to both BKI-1748 and quinine. For D. rerio, the corresponding numbers were 13 and 98 binding proteins, respectively. In both organisms, a majority of BKI-1748 binding proteins was involved in RNA binding and modification, in particular, splicing. Moreover, both datasets contained proteins involved in DNA binding or modification and key steps of intermediate metabolism. These results suggest that BKI-1748 interacts with not only specific targets in apicomplexans, such as CDPK1, but also with targets in other eukaryotes, which are involved in common, essential pathways. Full article

(This article belongs to the Section Molecular Biology)

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24 pages, 1582 KiB

Open AccessReview

Beyond Seizure Control: Treating Comorbidities in Epilepsy via Targeting of the P2X7 Receptor

by Beatriz Gil, Jonathon Smith, Yong Tang, Peter Illes and Tobias Engel

Int. J. Mol. Sci. 2022, 23(4), 2380; https://doi.org/10.3390/ijms23042380 - 21 Feb 2022

Cited by 17 | Viewed by 4379

Abstract

Epilepsy is one of the most common chronic diseases of the central nervous system (CNS). Treatment of epilepsy remains, however, a clinical challenge with over 30% of patients not responding to current pharmacological interventions. Complicating management of treatment, epilepsy comes with multiple comorbidities, [...] Read more.

Epilepsy is one of the most common chronic diseases of the central nervous system (CNS). Treatment of epilepsy remains, however, a clinical challenge with over 30% of patients not responding to current pharmacological interventions. Complicating management of treatment, epilepsy comes with multiple comorbidities, thereby further reducing the quality of life of patients. Increasing evidence suggests purinergic signalling via extracellularly released ATP as shared pathological mechanisms across numerous brain diseases. Once released, ATP activates specific purinergic receptors, including the ionotropic P2X7 receptor (P2X7R). Among brain diseases, the P2X7R has attracted particular attention as a therapeutic target. The P2X7R is an important driver of inflammation, and its activation requires high levels of extracellular ATP to be reached under pathological conditions. Suggesting the therapeutic potential of drugs targeting the P2X7R for epilepsy, P2X7R expression increases following status epilepticus and during epilepsy, and P2X7R antagonism modulates seizure severity and epilepsy development. P2X7R antagonism has, however, also been shown to be effective in treating conditions most commonly associated with epilepsy such as psychiatric disorders and cognitive deficits, which suggests that P2X7R antagonisms may provide benefits beyond seizure control. This review summarizes the evidence suggesting drugs targeting the P2X7R as a novel treatment strategy for epilepsy with a particular focus of its potential impact on epilepsy-associated comorbidities. Full article

(This article belongs to the Special Issue Purinergic Signaling in Neuroinflammation 2.0)

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11 pages, 3035 KiB

Open AccessArticle

Quantitative Trait Locus Mapping of Salt Tolerance in Wild Rice Oryza longistaminata

by Lei Yuan, Licheng Zhang, Xiao Wei, Ruihua Wang, Nannan Li, Gaili Chen, Fengfeng Fan, Shaoying Huang, Jianxiong Li and Shaoqing Li

Int. J. Mol. Sci. 2022, 23(4), 2379; https://doi.org/10.3390/ijms23042379 - 21 Feb 2022

Cited by 14 | Viewed by 2536

Abstract

Salt stress is one of the most severe adverse environments in rice production; increasing salinization is seriously endangering rice production around the world. In this study, a rice backcross inbred line (BIL) population derived from the cross of 9311 and wild rice Oryza [...] Read more.

Salt stress is one of the most severe adverse environments in rice production; increasing salinization is seriously endangering rice production around the world. In this study, a rice backcross inbred line (BIL) population derived from the cross of 9311 and wild rice Oryza longistaminata was employed to identify the favorable genetic loci of O. longistaminata for salt tolerance. A total of 27 quantitative trait loci (QTLs) related to salt tolerance were identified in 140 rice BILs, and 17 QTLs formed seven QTL clusters on different chromosomes, of which 18 QTLs were derived from O. longistaminata, and a QTL for salt injury score (SIS), water content of seedlings (WCS) under salt treatment, and relative water content of seedlings (RWCS) was repeatedly detected and colocalized at the same site on chromosome 2, and a cytochrome P450 86B1 (MH02t0466900) was suggested as the potential candidate gene responsible for the salt tolerance based on sequence and expression analysis. These findings laid the foundation for further improving rice salt tolerance through molecular breeding in the future. Full article

(This article belongs to the Topic Plant Responses and Tolerance to Salinity Stress)

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32 pages, 4924 KiB

Open AccessReview

Ferritinophagy and α-Synuclein: Pharmacological Targeting of Autophagy to Restore Iron Regulation in Parkinson’s Disease

by Matthew K. Boag, Angus Roberts, Vladimir N. Uversky, Linlin Ma, Des R. Richardson and Dean L. Pountney

Int. J. Mol. Sci. 2022, 23(4), 2378; https://doi.org/10.3390/ijms23042378 - 21 Feb 2022

Cited by 12 | Viewed by 4448

Abstract

A major hallmark of Parkinson’s disease (PD) is the fatal destruction of dopaminergic neurons within the substantia nigra pars compacta. This event is preceded by the formation of Lewy bodies, which are cytoplasmic inclusions composed of α-synuclein protein aggregates. A triad contribution [...] Read more.

A major hallmark of Parkinson’s disease (PD) is the fatal destruction of dopaminergic neurons within the substantia nigra pars compacta. This event is preceded by the formation of Lewy bodies, which are cytoplasmic inclusions composed of α-synuclein protein aggregates. A triad contribution of α-synuclein aggregation, iron accumulation, and mitochondrial dysfunction plague nigral neurons, yet the events underlying iron accumulation are poorly understood. Elevated intracellular iron concentrations up-regulate ferritin expression, an iron storage protein that provides cytoprotection against redox stress. The lysosomal degradation pathway, autophagy, can release iron from ferritin stores to facilitate its trafficking in a process termed ferritinophagy. Aggregated α-synuclein inhibits SNARE protein complexes and destabilizes microtubules to halt vesicular trafficking systems, including that of autophagy effectively. The scope of this review is to describe the physiological and pathological relationship between iron regulation and α-synuclein, providing a detailed understanding of iron metabolism within nigral neurons. The underlying mechanisms of autophagy and ferritinophagy are explored in the context of PD, identifying potential therapeutic targets for future investigation. Full article

(This article belongs to the Special Issue Alpha-Synuclein in Neurodegeneration)

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20 pages, 12238 KiB

Open AccessArticle

Amyloid Beta Pathology Exacerbates Weight Loss and Brain Cytokine Responses following Low-Dose Lipopolysaccharide in Aged Female Tg2576 Mice

by Rachel C. Knopp, Kristen K. Baumann, Miranda L. Wilson, William A. Banks and Michelle A. Erickson

Int. J. Mol. Sci. 2022, 23(4), 2377; https://doi.org/10.3390/ijms23042377 - 21 Feb 2022

Cited by 10 | Viewed by 3008

Abstract

Systemic inflammation has been implicated in the progression of Alzheimer’s disease (AD); however, less is understood about how existing AD pathology contributes to adverse outcomes following acute inflammatory insults. In the present study, our goal was to determine how AD-associated amyloid beta (Aβ) [...] Read more.

Systemic inflammation has been implicated in the progression of Alzheimer’s disease (AD); however, less is understood about how existing AD pathology contributes to adverse outcomes following acute inflammatory insults. In the present study, our goal was to determine how AD-associated amyloid beta (Aβ) pathology influences the acute neuroinflammatory and behavioral responses to a moderate systemic inflammatory insult. We treated 16–18-month-old female Tg2576 (Tg) mice, which overproduce human Aβ and develop plaques, and age-matched wild-type (WT) littermate mice with an intraperitoneal injection of 0.33 mg/kg lipopolysaccharide (LPS) or saline. Mice were then evaluated over the next 28 h for sickness/depressive-like behaviors (food intake, weight loss, locomotion, and sucrose preference), systemic inflammation (serum amyloid A, SAA), blood-brain barrier (BBB) disruption, astrogliosis (glial fibrillary acidic protein/GFAP), Aβ, and cytokine levels in the brain. We found that LPS caused a larger reduction in body weight in Tg vs. WT mice, but that other behavioral responses to LPS did not differ by genotype. BBB disruption was not apparent in either genotype following LPS. Concentrations of the systemic inflammatory marker, SAA, in the blood and brain were significantly increased with LPS but did not significantly differ by genotype. GFAP was increased in Tg mice vs. WT but was not significantly affected by LPS in either genotype. Finally, LPS-induced increases of eight cytokines (IL-1β, IL-6, IL-12 (p40), IL-10, IL-17A, MIP-1α/CCL3, MIP-1β/CCL4, and RANTES/CCL5) were found to be significantly higher in Tg mice vs. WT. In summary, our data show that Aβ pathology exacerbates the neuroinflammatory response to LPS and identifies cytokines that are selectively regulated by Aβ. The association of worse neuroinflammation with greater weight loss in Tg mice suggests that Aβ pathology could contribute to poor outcomes following a systemic inflammatory insult. Full article

(This article belongs to the Collection Feature Papers in Molecular Pathology, Diagnostics, and Therapeutics)

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15 pages, 5089 KiB

Open AccessReview

The Role of Bone-Derived Hormones in Glucose Metabolism, Diabetic Kidney Disease, and Cardiovascular Disorders

by Yuichi Takashi and Daiji Kawanami

Int. J. Mol. Sci. 2022, 23(4), 2376; https://doi.org/10.3390/ijms23042376 - 21 Feb 2022

Cited by 18 | Viewed by 4395

Abstract

Bone contributes to supporting the body, protecting the central nervous system and other organs, hematopoiesis, the regulation of mineral metabolism (mainly calcium and phosphate), and assists in respiration. Bone has many functions in the body. Recently, it was revealed that bone also works [...] Read more.

Bone contributes to supporting the body, protecting the central nervous system and other organs, hematopoiesis, the regulation of mineral metabolism (mainly calcium and phosphate), and assists in respiration. Bone has many functions in the body. Recently, it was revealed that bone also works as an endocrine organ and secretes several systemic humoral factors, including fibroblast growth factor 23 (FGF23), osteocalcin (OC), sclerostin, and lipocalin 2. Bone can communicate with other organs via these hormones. In particular, it has been reported that these bone-derived hormones are involved in glucose metabolism and diabetic complications. Some functions of these bone-derived hormones can become useful biomarkers that predict the incidence of diabetes and the progression of diabetic complications. Furthermore, other functions are considered to be targets for the prevention or treatment of diabetes and its complications. As is well known, diabetes is now a worldwide health problem, and many efforts have been made to treat diabetes. Thus, further investigations of the endocrine system through bone-derived hormones may provide us with new perspectives on the prediction, prevention, and treatment of diabetes. In this review, we summarize the role of bone-derived hormones in glucose metabolism, diabetic kidney disease, and cardiovascular disorders. Full article

(This article belongs to the Special Issue Prospective and Cutting-Edge Research for Diabetic Complications)

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24 pages, 1782 KiB

Open AccessReview

The Gut-Skin Microbiota Axis and Its Role in Diabetic Wound Healing—A Review Based on Current Literature

by Bharati Kadamb Patel, Kadamb Haribhai Patel, Ryan Yuki Huang, Chuen Neng Lee and Shabbir M. Moochhala

Int. J. Mol. Sci. 2022, 23(4), 2375; https://doi.org/10.3390/ijms23042375 - 21 Feb 2022

Cited by 35 | Viewed by 7081

Abstract

Diabetic foot ulcers (DFU) are a growing concern worldwide as they pose complications in routine clinical practices such as diagnosis and management. Bacterial interactions on the skin surface are vital to the pathophysiology of DFU and may control delayed wound healing. The microbiota [...] Read more.

Diabetic foot ulcers (DFU) are a growing concern worldwide as they pose complications in routine clinical practices such as diagnosis and management. Bacterial interactions on the skin surface are vital to the pathophysiology of DFU and may control delayed wound healing. The microbiota from our skin directly regulates cutaneous health and disease by interacting with the numerous cells involved in the wound healing mechanism. Commensal microbiota, in particular, interact with wound-repairing skin cells to enhance barrier regeneration. The observed microbes in DFU include Staphylococcus, Streptococcus, Corynebacterium, Pseudomonas, and several anaerobes. Skin commensal microbes, namely S. epidermidis, can regulate the gamma delta T cells and induce Perforin-2 expression. The increased expression of Perforin-2 by skin cells destroyed S. aureus within the cells, facilitating wound healing. Possible crosstalk between the human commensal microbiome and different cell types involved in cutaneous wound healing promotes the immune response and helps to maintain the barrier function in humans. Wound healing is a highly well-coordinated, complex mechanism; it can be devastating if interrupted. Skin microbiomes are being studied in relation to the gut-skin axis along with their effects on dermatologic conditions. The gut-skin axis illustrates the connection wherein the gut can impact skin health due to its immunological and metabolic properties. The precise mechanism underlying gut-skin microbial interactions is still unidentified, but the immune and endocrine systems are likely to be involved. Next-generation sequencing and the development of bioinformatics pipelines may considerably improve the understanding of the microbiome-skin axis involved in diabetic wound healing in a much more sophisticated way. We endeavor to shed light on the importance of these pathways in the pathomechanisms of the most prevalent inflammatory conditions including the diabetes wound healing, as well as how probiotics may intervene in the gut-skin axis. Full article

(This article belongs to the Section Biochemistry)

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11 pages, 1811 KiB

Open AccessReview

Current Studies of the Effects of Drought Stress on Root Exudates and Rhizosphere Microbiomes of Crop Plant Species

by Yalin Chen, Zongmu Yao, Yu Sun, Enze Wang, Chunjie Tian, Yang Sun, Juan Liu, Chunyu Sun and Lei Tian

Int. J. Mol. Sci. 2022, 23(4), 2374; https://doi.org/10.3390/ijms23042374 - 21 Feb 2022

Cited by 55 | Viewed by 9085

Abstract

With the warming global climate, drought stress is considered to be the most important abiotic factor limiting plant growth and yield in the world. Drought stress has serious impacts on crop production. Many researchers have studied the influences of drought stress on crop [...] Read more.

With the warming global climate, drought stress is considered to be the most important abiotic factor limiting plant growth and yield in the world. Drought stress has serious impacts on crop production. Many researchers have studied the influences of drought stress on crop production and plant physiology; however, few researchers have combined root exudates with root-associated microbiomes for their mutual effects under drought conditions. In this review, we systematically illustrate the impact of drought stress on root exudates and root-associated microbiomes, and then we discuss the mutual regulation of root-associated microbiomes and the host plant in helping the plant adapt to drought. Finally, we construct a framework for the mutual connections between the plant, root exudates, and the microbiome. We hope this review can provide some significant guidelines to promote the study of drought resistance in plants in association with the rhizosphere microbiota. Full article

(This article belongs to the Special Issue Plants Responses to Climate Change)

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20 pages, 3579 KiB

Open AccessArticle

A Zebrafish Model for a Rare Genetic Disease Reveals a Conserved Role for FBXL3 in the Circadian Clock System

by Shir Confino, Talya Dor, Adi Tovin, Yair Wexler, Zohar Ben-Moshe Livne, Michaela Kolker, Odelia Pisanty, Sohyun Kathy Park, Nathalie Geyer, Joel Reiter, Shimon Edvardson, Hagar Mor-Shaked, Orly Elpeleg, Daniela Vallone, Lior Appelbaum, Nicholas S. Foulkes and Yoav Gothilf

Int. J. Mol. Sci. 2022, 23(4), 2373; https://doi.org/10.3390/ijms23042373 - 21 Feb 2022

Cited by 4 | Viewed by 2888

Abstract

The circadian clock, which drives a wide range of bodily rhythms in synchrony with the day–night cycle, is based on a molecular oscillator that ticks with a period of approximately 24 h. Timed proteasomal degradation of clock components is central to the fine-tuning [...] Read more.

The circadian clock, which drives a wide range of bodily rhythms in synchrony with the day–night cycle, is based on a molecular oscillator that ticks with a period of approximately 24 h. Timed proteasomal degradation of clock components is central to the fine-tuning of the oscillator’s period. FBXL3 is a protein that functions as a substrate-recognition factor in the E3 ubiquitin ligase complex, and was originally shown in mice to mediate degradation of CRY proteins and thus contribute to the mammalian circadian clock mechanism. By exome sequencing, we have identified a FBXL3 mutation in patients with syndromic developmental delay accompanied by morphological abnormalities and intellectual disability, albeit with a normal sleep pattern. We have investigated the function of FBXL3 in the zebrafish, an excellent model to study both vertebrate development and circadian clock function and, like humans, a diurnal species. Loss of fbxl3a function in zebrafish led to disruption of circadian rhythms of promoter activity and mRNA expression as well as locomotor activity and sleep–wake cycles. However, unlike humans, no morphological effects were evident. These findings point to an evolutionary conserved role for FBXL3 in the circadian clock system across vertebrates and to the acquisition of developmental roles in humans. Full article

(This article belongs to the Special Issue Zebrafish as a Model for Neurological Disorders)

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27 pages, 5464 KiB

Open AccessArticle

Identification of Nifurtimox and Chrysin as Anti-Influenza Virus Agents by Clinical Transcriptome Signature Reversion

by Yijing Xin, Shubing Chen, Ke Tang, You Wu and Ying Guo

Int. J. Mol. Sci. 2022, 23(4), 2372; https://doi.org/10.3390/ijms23042372 - 21 Feb 2022

Cited by 4 | Viewed by 2997

Abstract

The rapid development in the field of transcriptomics provides remarkable biomedical insights for drug discovery. In this study, a transcriptome signature reversal approach was conducted to identify the agents against influenza A virus (IAV) infection through dissecting gene expression changes in response to [...] Read more.

The rapid development in the field of transcriptomics provides remarkable biomedical insights for drug discovery. In this study, a transcriptome signature reversal approach was conducted to identify the agents against influenza A virus (IAV) infection through dissecting gene expression changes in response to disease or compounds’ perturbations. Two compounds, nifurtimox and chrysin, were identified by a modified Kolmogorov–Smirnov test statistic based on the transcriptional signatures from 81 IAV-infected patients and the gene expression profiles of 1309 compounds. Their activities were verified in vitro with half maximal effective concentrations (EC₅₀s) from 9.1 to 19.1 μM against H1N1 or H3N2. It also suggested that the two compounds interfered with multiple sessions in IAV infection by reversing the expression of 28 IAV informative genes. Through network-based analysis of the 28 reversed IAV informative genes, a strong synergistic effect of the two compounds was revealed, which was confirmed in vitro. By using the transcriptome signature reversion (TSR) on clinical datasets, this study provides an efficient scheme for the discovery of drugs targeting multiple host factors regarding clinical signs and symptoms, which may also confer an opportunity for decelerating drug-resistant variant emergence. Full article

(This article belongs to the Special Issue Exploiting the Multitarget and Repositioned Drugs Approach)

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19 pages, 9693 KiB

Open AccessArticle

Serial Passaging of RAW 264.7 Cells Modulates Intracellular AGE Formation and Downregulates RANKL-Induced In Vitro Osteoclastogenesis

by Tanzima Tarannum Lucy, A. N. M. Mamun-Or-Rashid, Masayuki Yagi and Yoshikazu Yonei

Int. J. Mol. Sci. 2022, 23(4), 2371; https://doi.org/10.3390/ijms23042371 - 21 Feb 2022

Cited by 7 | Viewed by 3941

Abstract

The passage number of cells refers to the number of subculturing processes that the cells have undergone. The effect of passage number on morphological and phenotypical characteristics of cells is of great importance. Advanced glycation end products have also been associated with cell [...] Read more.

The passage number of cells refers to the number of subculturing processes that the cells have undergone. The effect of passage number on morphological and phenotypical characteristics of cells is of great importance. Advanced glycation end products have also been associated with cell functionality and characteristics. Murine monocyte RAW 264.7 cells differentiate into osteoclasts upon receptor activation caused by nuclear factor-kappa-Β ligand (RANKL) treatment. This study aims to identify the role of passage number on intracellular advanced glycation end products (AGEs) formation and osteoclastogenic differentiation of RAW 264.7 cells. Western blotting was performed to check intracellular AGE formation along with fluorometric analysis using a microplate reader. Tartrate-resistant acid phosphatase (TRAP) staining was performed to check osteoclastogenic differentiation, and qPCR was realized to check the responsible mRNA expression. Immunofluorescence was used to check the morphological changes. Intracellular AGE formation was increased with passaging, and the higher passage number inhibited multinucleated osteoclastogenic differentiation. Osteoclastogenic gene expression also showed a reducing trend in higher passages, along with a significant reduction in F-actin ring size and number. Lower passages should be used to avoid the effects of cell subculturing in in vitro osteoclastogenesis study using RAW 264.7 cells. Full article

(This article belongs to the Special Issue Osteoclastogenesis and Osteogenesis 2.0)

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11 pages, 6460 KiB

Open AccessReview

Bioadhesive Nanoparticles for Local Drug Delivery

by Liu Yu, Zewen Luo, Tian Chen, Yaqi Ouyang, Lingyun Xiao, Shu Liang, Zhangwen Peng, Yang Liu and Yang Deng

Int. J. Mol. Sci. 2022, 23(4), 2370; https://doi.org/10.3390/ijms23042370 - 21 Feb 2022

Cited by 25 | Viewed by 4278

Abstract

Local drug delivery is an effective strategy for achieving direct and instant therapeutic effects. Current clinical treatments have fallen short and are limited by traditional technologies. Bioadhesive nanoparticles (NPs), however, may be a promising carrier for optimized local drug delivery, offering prolonged drug [...] Read more.

Local drug delivery is an effective strategy for achieving direct and instant therapeutic effects. Current clinical treatments have fallen short and are limited by traditional technologies. Bioadhesive nanoparticles (NPs), however, may be a promising carrier for optimized local drug delivery, offering prolonged drug retention time and steadily maintained therapeutic concentrations. In addition, the possibility of clinical applications of this platform are abundant, as most polymers used for bioadhesion are both biodegradable and biocompatible. This review highlights the major advances in the investigations of polymer-based bioadhesive nanoparticles and their innumerable applications in local drug delivery. Full article

(This article belongs to the Special Issue Biomolecules for Nanodelivery)

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14 pages, 1650 KiB

Open AccessArticle

Tryptophan Metabolites Regulate Neuropentraxin 1 Expression in Endothelial Cells

by Romain Vial, Stéphane Poitevin, Nathalie McKay, Stéphane Burtey and Claire Cerini

Int. J. Mol. Sci. 2022, 23(4), 2369; https://doi.org/10.3390/ijms23042369 - 21 Feb 2022

Cited by 2 | Viewed by 2382

Abstract

In patients with chronic kidney disease (CKD) and in animal models of CKD, the transcription factor Aryl Hydrocabon Receptor (AhR) is overactivated. In addition to the canonical AhR targets constituting the AhR signature, numerous other genes are regulated by this factor. We identified [...] Read more.

In patients with chronic kidney disease (CKD) and in animal models of CKD, the transcription factor Aryl Hydrocabon Receptor (AhR) is overactivated. In addition to the canonical AhR targets constituting the AhR signature, numerous other genes are regulated by this factor. We identified neuronal pentraxin 1 (NPTX1) as a new AhR target. Belonging to the inflammatory protein family, NPTX1 seems of prime interest regarding the inflammatory state observed in CKD. Endothelial cells were exposed to tryptophan-derived toxins, indoxyl sulfate (IS) and indole-3-acetic acid (IAA). The adenine mouse model of CKD was used to analyze NPTX1 expression in the burden of uremia. NPTX1 expression was quantified by RT-PCR and western blot. AhR involvement was analyzed using silencing RNA. We found that IS and IAA upregulated NPTX1 expression in an AhR-dependent way. Furthermore, this effect was not restricted to uremic indolic toxins since the dioxin 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) and the tryptophan photoproduct 6-formylindolo[3,2-b]carbazole (FICZ) do the same. In CKD mice, NPTX1 expression was increased in the aorta. Therefore, NPTX1 is a new target of AhR and further work is necessary to elucidate its exact role during CKD. Full article

(This article belongs to the Special Issue Decoding the Complex Crossroad of Tryptophan Metabolic Pathways)

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