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Int. J. Mol. Sci., Volume 24, Issue 11 (June-1 2023) – 672 articles

Cover Story (view full-size image): During the hyperacute and acute phases of a stroke, damaged neurons release several soluble mediators that induce an M1-like phenotype in the microglia. Primed microglia release ROS, MMPs, miRNAs-charged EVs and pro-inflammatory cytokines that activate ECs and astrocytes. These also secrete pro-inflammatory mediators that further promote ECs activation, TJs degradation and BBB disruption. Activated ECs express adhesion molecules for leukocytes that infiltrate the ischemic lesion. In the chronic phase of a stroke, ECs and astrocytes promote a beneficial anti-inflammatory M2-like phenotype in microglia via the secretion of VEGF and TGF-β, respectively. The release of TGF-β from astrocytes is stimulated by IL-10 derived from M2-like microglia in a positive feedback loop. View this paper
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24 pages, 2175 KiB  
Review
Upgrading Treatment and Molecular Diagnosis in Endometrial Cancer—Driving New Tools for Endometrial Preservation?
by Miriam Dellino, Marco Cerbone, Antonio Simone Laganà, Amerigo Vitagliano, Antonella Vimercati, Marco Marinaccio, Giorgio Maria Baldini, Antonio Malvasi, Ettore Cicinelli, Gianluca Raffaello Damiani, Gerardo Cazzato and Eliano Cascardi
Int. J. Mol. Sci. 2023, 24(11), 9780; https://doi.org/10.3390/ijms24119780 - 05 Jun 2023
Cited by 4 | Viewed by 2703
Abstract
One emerging problem for onco-gynecologists is the incidence of premenopausal patients under 40 years of age diagnosed with stage I Endometrial Cancer (EC) who want to preserve their fertility. Our review aims to define a primary risk assessment that can help fertility experts [...] Read more.
One emerging problem for onco-gynecologists is the incidence of premenopausal patients under 40 years of age diagnosed with stage I Endometrial Cancer (EC) who want to preserve their fertility. Our review aims to define a primary risk assessment that can help fertility experts and onco-gynecologists tailor personalized treatment and fertility-preserving strategies for fertile patients wishing to have children. We confirm that risk factors such as myometrial invasion and The International Federation of Gynecology and Obstetrics (FIGO) staging should be integrated into the novel molecular classification provided by The Cancer Genome Atlas (TCGA). We also corroborate the influence of classical risk factors such as obesity, Polycystic ovarian syndrome (PCOS), and diabetes mellitus to assess fertility outcomes. The fertility preservation options are inadequately discussed with women with a diagnosis of gynecological cancer. A multidisciplinary team of gynecologists, oncologists, and fertility specialists could increase patient satisfaction and improve fertility outcomes. The incidence and death rates of endometrial cancer are rising globally. International guidelines recommend radical hysterectomy and bilateral salpingo-oophorectomy as the standard of care for this cancer; however, fertility-sparing alternatives should be tailored to motivated women of reproductive age, establishing an appropriate cost–benefit balance between childbearing desire and cancer risk. New molecular classifications such as that of TCGA provide a robust supplementary risk assessment tool that can tailor the treatment options to the patient’s needs, curtail over- and under-treatment, and contribute to the spread of fertility-preserving strategies. Full article
(This article belongs to the Special Issue Cancer Prevention with Molecular Target Therapies 4.0)
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11 pages, 1512 KiB  
Article
A dePEGylated Lipopeptide-Based Pan-Coronavirus Fusion Inhibitor Exhibits Potent and Broad-Spectrum Anti-HIV-1 Activity without Eliciting Anti-PEG Antibodies
by Ling Xu, Chao Wang, Wei Xu, Lixiao Xing, Jie Zhou, Jing Pu, Mingming Fu, Lu Lu, Shibo Jiang and Qian Wang
Int. J. Mol. Sci. 2023, 24(11), 9779; https://doi.org/10.3390/ijms24119779 - 05 Jun 2023
Cited by 1 | Viewed by 1229
Abstract
We previously identified a lipopeptide, EK1C4, by linking cholesterol to EK1, a pan-CoV fusion inhibitory peptide via a polyethylene glycol (PEG) linker, which showed potent pan-CoV fusion inhibitory activity. However, PEG can elicit antibodies to PEG in vivo, which will attenuate its antiviral [...] Read more.
We previously identified a lipopeptide, EK1C4, by linking cholesterol to EK1, a pan-CoV fusion inhibitory peptide via a polyethylene glycol (PEG) linker, which showed potent pan-CoV fusion inhibitory activity. However, PEG can elicit antibodies to PEG in vivo, which will attenuate its antiviral activity. Therefore, we designed and synthesized a dePEGylated lipopeptide, EKL1C, by replacing the PEG linker in EK1C4 with a short peptide. Similar to EK1C4, EKL1C displayed potent inhibitory activity against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and other coronaviruses. In this study, we found that EKL1C also exhibited broad-spectrum fusion inhibitory activity against human immunodeficiency virus type 1 (HIV-1) infection by interacting with the N-terminal heptad repeat 1 (HR1) of viral gp41 to block six-helix bundle (6-HB) formation. These results suggest that HR1 is a common target for the development of broad-spectrum viral fusion inhibitors and EKL1C has potential clinical application as a candidate therapeutic or preventive agent against infection by coronavirus, HIV-1, and possibly other class I enveloped viruses. Full article
(This article belongs to the Collection Feature Papers in Molecular Immunology)
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21 pages, 6357 KiB  
Article
Perfluoroalkyl Chain Length Effect on Crystal Packing and [LnO8] Coordination Geometry in Lanthanide-Lithium β-Diketonates: Luminescence and Single-Ion Magnet Behavior
by Kristina A. Smirnova, Yulia O. Edilova, Mikhail A. Kiskin, Artem S. Bogomyakov, Yulia S. Kudyakova, Marina S. Valova, Galina V. Romanenko, Pavel A. Slepukhin, Victor I. Saloutin and Denis N. Bazhin
Int. J. Mol. Sci. 2023, 24(11), 9778; https://doi.org/10.3390/ijms24119778 - 05 Jun 2023
Cited by 1 | Viewed by 1375
Abstract
Functionalized perfluoroalkyl lithium β-diketonates (LiL) react with lanthanide(III) salts (Ln = Eu, Gd, Tb, Dy) in methanol to give heterobimetallic Ln-Li complexes of general formula [(LnL3)(LiL)(MeOH)]. The length of fluoroalkyl substituent in ligand was found to affect the crystal packing of [...] Read more.
Functionalized perfluoroalkyl lithium β-diketonates (LiL) react with lanthanide(III) salts (Ln = Eu, Gd, Tb, Dy) in methanol to give heterobimetallic Ln-Li complexes of general formula [(LnL3)(LiL)(MeOH)]. The length of fluoroalkyl substituent in ligand was found to affect the crystal packing of complexes. Photoluminescent and magnetic properties of heterobimetallic β-diketonates in the solid state are reported. The effect of the geometry of the [LnO8] coordination environment of heterometallic β-diketonates on the luminescent properties (quantum yields, phosphorescence lifetimes for Eu, Tb, Dy complexes) and single-ion magnet behavior (Ueff for Dy complexes) is revealed. Full article
(This article belongs to the Special Issue Synthesis and Applications of Advanced Inorganic Materials)
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9 pages, 1046 KiB  
Brief Report
Zooming into Gut Dysbiosis in Parkinson’s Disease: New Insights from Functional Mapping
by Luigia Turco, Nicola Opallo, Elisabetta Buommino, Carmen De Caro, Claudio Pirozzi, Giuseppina Mattace Raso, Francesca Lembo and Lorena Coretti
Int. J. Mol. Sci. 2023, 24(11), 9777; https://doi.org/10.3390/ijms24119777 - 05 Jun 2023
Viewed by 1199
Abstract
Gut dysbiosis has been involved in the pathogenesis and progression of Parkinson’s disease (PD), but the mechanisms through which gut microbiota (GM) exerts its influences deserve further study. Recently, we proposed a two-hit mouse model of PD in which ceftriaxone (CFX)-induced dysbiosis amplifies [...] Read more.
Gut dysbiosis has been involved in the pathogenesis and progression of Parkinson’s disease (PD), but the mechanisms through which gut microbiota (GM) exerts its influences deserve further study. Recently, we proposed a two-hit mouse model of PD in which ceftriaxone (CFX)-induced dysbiosis amplifies the neurodegenerative phenotype generated by striatal 6-hydroxydopamine (6-OHDA) injection in mice. Low GM diversity and the depletion of key gut colonizers and butyrate producers were the main signatures of GM alteration in this model. Here, we used the phylogenetic investigation of communities by reconstruction of unobserved states (PICRUSt2) to unravel candidate pathways of cell-to-cell communication associated with dual-hit mice and potentially involved in PD progression. We focused our analysis on short-chain fatty acids (SCFAs) metabolism and quorum sensing (QS) signaling. Based on linear discriminant analysis, combined with the effect size results, we found increased functions linked to pyruvate utilization and a depletion of acetate and butyrate production in 6-OHDA+CFX mice. The specific arrangement of QS signaling as a possible result of the disrupted GM structure was also observed. With this exploratory study, we suggested a scenario in which SCFAs metabolism and QS signaling might represent the effectors of gut dysbiosis potentially involved in the designation of the functional outcomes that contribute to the exacerbation of the neurodegenerative phenotype in the dual-hit animal model of PD. Full article
(This article belongs to the Special Issue Molecular Mechanisms of Neuronal Death in Neurodegeneration)
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15 pages, 4850 KiB  
Article
CD11b Deficiency Favors Cartilage Calcification via Increased Matrix Vesicles, Apoptosis, and Lysyl Oxidase Activity
by Ilaria Bernabei, Uwe Hansen, Driss Ehirchiou, Jürgen Brinckmann, Veronique Chobaz, Nathalie Busso and Sonia Nasi
Int. J. Mol. Sci. 2023, 24(11), 9776; https://doi.org/10.3390/ijms24119776 - 05 Jun 2023
Viewed by 1416
Abstract
Pathological cartilage calcification is a hallmark feature of osteoarthritis, a common degenerative joint disease, characterized by cartilage damage, progressively causing pain and loss of movement. The integrin subunit CD11b was shown to play a protective role against cartilage calcification in a mouse model [...] Read more.
Pathological cartilage calcification is a hallmark feature of osteoarthritis, a common degenerative joint disease, characterized by cartilage damage, progressively causing pain and loss of movement. The integrin subunit CD11b was shown to play a protective role against cartilage calcification in a mouse model of surgery-induced OA. Here, we investigated the possible mechanism by which CD11b deficiency could favor cartilage calcification by using naïve mice. First, we found by transmission electron microscopy (TEM) that CD11b KO cartilage from young mice presented early calcification spots compared with WT. CD11b KO cartilage from old mice showed progression of calcification areas. Mechanistically, we found more calcification-competent matrix vesicles and more apoptosis in both cartilage and chondrocytes isolated from CD11b-deficient mice. Additionally, the extracellular matrix from cartilage lacking the integrin was dysregulated with increased collagen fibrils with smaller diameters. Moreover, we revealed by TEM that CD11b KO cartilage had increased expression of lysyl oxidase (LOX), the enzyme that catalyzes matrix crosslinks. We confirmed this in murine primary CD11b KO chondrocytes, where Lox gene expression and crosslinking activity were increased. Overall, our results suggest that CD11b integrin regulates cartilage calcification through reduced MV release, apoptosis, LOX activity, and matrix crosslinking. As such, CD11b activation might be a key pathway for maintaining cartilage integrity. Full article
(This article belongs to the Special Issue Osteoarthritis: From Pathogenesis to Treatment)
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16 pages, 3548 KiB  
Article
Genome-Wide Identification of Detoxification Genes in Wild Silkworm Antheraea pernyi and Transcriptional Response to Coumaphos
by Dong-Bin Chen, Run-Xi Xia, Qun Li, Yu-Ping Li, Hui-Ying Cao and Yan-Qun Liu
Int. J. Mol. Sci. 2023, 24(11), 9775; https://doi.org/10.3390/ijms24119775 - 05 Jun 2023
Viewed by 1143
Abstract
For a half-century, the commercial wild silkworm, Antheraea pernyi, has been protected by coumaphos, which is an internal organophosphorus insecticide used to kill the potential parasitic fly larvae inside. Knowledge about the detoxification genes of A. pernyi as well as the detoxification [...] Read more.
For a half-century, the commercial wild silkworm, Antheraea pernyi, has been protected by coumaphos, which is an internal organophosphorus insecticide used to kill the potential parasitic fly larvae inside. Knowledge about the detoxification genes of A. pernyi as well as the detoxification mechanism for this species remains severely limited. In this study, we identified 281 detoxification genes (32 GSTs, 48 ABCs, 104 CYPs, and 97 COEs) in the genome of this insect, which are unevenly distributed over 46 chromosomes. When compared to the domesticated silkworm, Bombyx mori, a lepidopteran model species, A. pernyi has a similar number of ABCs, but a greater number of GSTs, CYPs, and COEs. By transcriptome-based expression analysis, we found that coumaphos at a safe concentration level significantly changed the pathways related to ATPase complex function and the transporter complex in A. pernyi. KEGG functional enrichment analysis indicated that protein processing in the endoplasmic reticulum was the most affected pathway after coumaphos treatment. Finally, we identified four significantly up-regulated detoxification genes (ABCB1, ABCB3, ABCG11, and ae43) and one significantly down-regulated detoxification gene (CYP6AE9) in response to coumaphos treatment, suggesting that these five genes may contribute to detoxification of coumaphos in A. pernyi. Our study provides the first set of detoxification genes for wild silkworms from Saturniidae and highlights the importance of detoxification gene repertoire in insect pesticide tolerance. Full article
(This article belongs to the Section Molecular Genetics and Genomics)
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15 pages, 2705 KiB  
Article
Effect of Achillea fragrantissima Extract on Excision Wound Biofilms of MRSA and Pseudomonas aeruginosa in Diabetic Mice
by Yasir Almuhanna, Mohammed Hussein Alqasmi, Hamood AlSudais, Mohammed Alrouji, Fahd A. Kuriri, Mohammed Alissa, Meshari A. Alsuwat, Mohammed Asad and Babu Joseph
Int. J. Mol. Sci. 2023, 24(11), 9774; https://doi.org/10.3390/ijms24119774 - 05 Jun 2023
Cited by 2 | Viewed by 1260
Abstract
Achillea fragrantissima, a desert plant commonly known as yarrow, is traditionally used as an antimicrobial agent in folklore medicine in Saudi Arabia. The current study was undertaken to determine its antibiofilm activity against methicillin-resistant Staphylococcus aureus (MRSA) and multi-drug-resistant Pseudomonas aeruginosa (MDR- [...] Read more.
Achillea fragrantissima, a desert plant commonly known as yarrow, is traditionally used as an antimicrobial agent in folklore medicine in Saudi Arabia. The current study was undertaken to determine its antibiofilm activity against methicillin-resistant Staphylococcus aureus (MRSA) and multi-drug-resistant Pseudomonas aeruginosa (MDR-P. aeruginosa) using in vitro and in vivo studies. A biofilm model induced through an excision wound in diabetic mice was used to evaluate its effect in vivo. The skin irritation and cytotoxic effects of the extract were determined using mice and HaCaT cell lines, respectively. The Achillea fragrantissima methanolic extract was analyzed with LC-MS to detect different phytoconstituents, which revealed the presence of 47 different phytoconstituents. The extract inhibited the growth of both tested pathogens in vitro. It also increased the healing of biofilm-formed excision wounds, demonstrating its antibiofilm, antimicrobial, and wound-healing action in vivo. The effect of the extract was concentration-dependent, and its activity was stronger against MRSA than MDR-P. aeruginosa. The extract formulation was devoid of a skin irritation effect in vivo and cytotoxic effect on HaCaT cell lines in vitro. Full article
(This article belongs to the Special Issue Advanced Therapies and Functional Materials for Wound Healing)
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14 pages, 2336 KiB  
Article
Reduced Striatal Dopamine Transporter Availability and Heightened Response to Natural and Pharmacological Stimulation in CCK-1R-Deficient Obese Rats
by Sevag Hamamah, Andras Hajnal and Mihai Covasa
Int. J. Mol. Sci. 2023, 24(11), 9773; https://doi.org/10.3390/ijms24119773 - 05 Jun 2023
Cited by 1 | Viewed by 1079
Abstract
Alterations in dopamine neurotransmission are associated with obesity and food preferences. Otsuka Long-Evans Tokushima Fatty (OLETF) rats that lack functional cholecystokinin receptor type-1 (CCK-1R), due to a natural mutation, exhibit impaired satiation, are hyperphagic, and become obese. In addition, compared to lean control [...] Read more.
Alterations in dopamine neurotransmission are associated with obesity and food preferences. Otsuka Long-Evans Tokushima Fatty (OLETF) rats that lack functional cholecystokinin receptor type-1 (CCK-1R), due to a natural mutation, exhibit impaired satiation, are hyperphagic, and become obese. In addition, compared to lean control Long-Evans Tokushima (LETO) rats, OLETF rats have pronounced avidity for over-consuming palatable sweet solutions, have greater dopamine release to psychostimulants, reduced dopamine 2 receptor (D2R) binding, and exhibit increased sensitivity to sucrose reward. This supports altered dopamine function in this strain and its general preference for palatable solutions such as sucrose. In this study, we examined the relationship between OLETF’s hyperphagic behavior and striatal dopamine signaling by investigating basal and amphetamine stimulated motor activity in prediabetic OLETF rats before and after access to sucrose solution (0.3 M) compared to non-mutant control LETO rats, as well as availability of dopamine transporter (DAT) using autoradiography. In the sucrose tests, one group of OLETF rats received ad libitum access to sucrose while the other group received an amount of sucrose equal to that consumed by the LETO. OLETFs with ad libitum access consumed significantly more sucrose than LETOs. Sucrose exerted a biphasic effect on basal activity in both strains, i.e., reduced activity for 1 week followed by increased activity in weeks 2 and 3. Basal locomotor activity was reduced (−17%) in OLETFs prior to sucrose, compared to LETOs. Withdrawal of sucrose resulted in increased locomotor activity in both strains. The magnitude of this effect was greater in OLETFs and the activity was increased in restricted compared to ad-libitum-access OLETFs. Sucrose access augmented AMPH-responses in both strains with a greater sensitization to AMPH during week 1, an effect that was a function of the amount of sucrose consumed. One week of sucrose withdrawal sensitized AMPH-induced ambulatory activity in both strains. In OLETF with restricted access to sucrose, withdrawal resulted in no further sensitization to AMPH. DAT availability in the nucleus accumbens shell was significantly reduced in OLETF compared with aged-matched LETO. Together, these findings show that OLETF rats have reduced basal DA transmission and a heightened response to natural and pharmacological stimulation. Full article
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11 pages, 1315 KiB  
Review
Role of SNAREs and Rabs in Myelin Regulation
by Azzurra Margiotta
Int. J. Mol. Sci. 2023, 24(11), 9772; https://doi.org/10.3390/ijms24119772 - 05 Jun 2023
Viewed by 2010
Abstract
The myelin sheath is an insulating layer around the nerves of the brain and spinal cord which allows a fast and efficient nerve conduction. Myelin is made of protein and fatty substances and gives protection for the propagation of the electrical impulse. The [...] Read more.
The myelin sheath is an insulating layer around the nerves of the brain and spinal cord which allows a fast and efficient nerve conduction. Myelin is made of protein and fatty substances and gives protection for the propagation of the electrical impulse. The myelin sheath is formed by oligodendrocytes in the central nervous system (CNS) and by Schwann cells in the peripheral nervous system (PNS). The myelin sheath presents a highly organized structure and expands both radially and longitudinally, but in a different way and with a different composition. Myelin alterations determine the onset of several neuropathies, as the electrical signal can be slowed or stopped. Soluble N-ethylmaleimide-sensitive factor attachment protein receptors (SNAREs) and ras (rat sarcoma)-associated binding proteins (rabs) have been proved to contribute to several aspects regarding the formation of myelin or dysmyelination. Here, I will describe the role of these proteins in regulating membrane trafficking and nerve conduction, myelin biogenesis and maintenance. Full article
(This article belongs to the Special Issue Channels and Transporters in Cells and Tissue 4.0)
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22 pages, 1207 KiB  
Review
Mast Cells in Upper and Lower Airway Diseases: Sentinels in the Front Line
by Giovanni Costanzo, Giulia Anna Maria Luigia Costanzo, Lorenzo Del Moro, Emanuele Nappi, Corrado Pelaia, Francesca Puggioni, Giorgio Walter Canonica, Enrico Heffler and Giovanni Paoletti
Int. J. Mol. Sci. 2023, 24(11), 9771; https://doi.org/10.3390/ijms24119771 - 05 Jun 2023
Cited by 2 | Viewed by 2905
Abstract
Mast cells (MCs) are fascinating cells of the innate immune system involved not only in allergic reaction but also in tissue homeostasis, response to infection, wound healing, protection against kidney injury, the effects of pollution and, in some circumstances, cancer. Indeed, exploring their [...] Read more.
Mast cells (MCs) are fascinating cells of the innate immune system involved not only in allergic reaction but also in tissue homeostasis, response to infection, wound healing, protection against kidney injury, the effects of pollution and, in some circumstances, cancer. Indeed, exploring their role in respiratory allergic diseases would give us, perhaps, novel therapy targets. Based on this, there is currently a great demand for therapeutic regimens to enfeeble the damaging impact of MCs in these pathological conditions. Several strategies can accomplish this at different levels in response to MC activation, including targeting individual mediators released by MCs, blockade of receptors for MC-released compounds, inhibition of MC activation, limiting mast cell growth, or inducing mast cell apoptosis. The current work focuses on and summarizes the mast cells’ role in pathogenesis and as a personalized treatment target in allergic rhinitis and asthma; even these supposed treatments are still at the preclinical stage. Full article
(This article belongs to the Special Issue Mast Cells in Immunity and Diseases)
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14 pages, 2312 KiB  
Review
Human Placental Adaptive Changes in Response to Maternal Obesity: Sex Specificities
by Esther Dos Santos, Marta Hita Hernández, Valérie Sérazin, François Vialard and Marie-Noëlle Dieudonné
Int. J. Mol. Sci. 2023, 24(11), 9770; https://doi.org/10.3390/ijms24119770 - 05 Jun 2023
Cited by 4 | Viewed by 1419
Abstract
Maternal obesity is increasingly prevalent and is associated with elevated morbidity and mortality rates in both mothers and children. At the interface between the mother and the fetus, the placenta mediates the impact of the maternal environment on fetal development. Most of the [...] Read more.
Maternal obesity is increasingly prevalent and is associated with elevated morbidity and mortality rates in both mothers and children. At the interface between the mother and the fetus, the placenta mediates the impact of the maternal environment on fetal development. Most of the literature presents data on the effects of maternal obesity on placental functions and does not exclude potentially confounding factors such as metabolic diseases (e.g., gestational diabetes). In this context, the focus of this review mainly lies on the impact of maternal obesity (in the absence of gestational diabetes) on (i) endocrine function, (ii) morphological characteristics, (iii) nutrient exchanges and metabolism, (iv) inflammatory/immune status, (v) oxidative stress, and (vi) transcriptome. Moreover, some of those placental changes in response to maternal obesity could be supported by fetal sex. A better understanding of sex-specific placental responses to maternal obesity seems to be crucial for improving pregnancy outcomes and the health of mothers and children. Full article
(This article belongs to the Special Issue Recent Advances in Placental Pathophysiology)
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31 pages, 7018 KiB  
Hypothesis
The Midbrain Preisthmus: A Poorly Known Effect of the Isthmic Organizer
by Luis Puelles and Matias Hidalgo-Sánchez
Int. J. Mol. Sci. 2023, 24(11), 9769; https://doi.org/10.3390/ijms24119769 - 05 Jun 2023
Cited by 1 | Viewed by 1003
Abstract
This essay reexamines molecular evidence supporting the existence of the ‘preisthmus’, a caudal midbrain domain present in vertebrates (studied here in the mouse). It is thought to derive from the embryonic m2 mesomere and appears intercalated between the isthmus (caudally) and the inferior [...] Read more.
This essay reexamines molecular evidence supporting the existence of the ‘preisthmus’, a caudal midbrain domain present in vertebrates (studied here in the mouse). It is thought to derive from the embryonic m2 mesomere and appears intercalated between the isthmus (caudally) and the inferior colliculus (rostrally). Among a substantial list of gene expression mappings examined from the Allen Developing and Adult Brain Atlases, a number of quite consistent selective positive markers, plus some neatly negative markers, were followed across embryonic stages E11.5, E13.5, E15.5, E18.5, and several postnatal stages up to the adult brain. Both alar and basal subdomains of this transverse territory were explored and illustrated. It is argued that the peculiar molecular and structural profile of the preisthmus is due to its position as rostrally adjacent to the isthmic organizer, where high levels of both FGF8 and WNT1 morphogens must exist at early embryonic stages. Isthmic patterning of the midbrain is discussed in this context. Studies of the effects of the isthmic morphogens usually do not attend to the largely unknown preisthmic complex. The adult alar derivatives of the preisthmus were confirmed to comprise a specific preisthmic sector of the periaqueductal gray, an intermediate stratum represented by the classic cuneiform nucleus, and a superficial stratum containing the subbrachial nucleus. The basal derivatives, occupying a narrow retrorubral domain intercalated between the oculomotor and trochlear motor nuclei, include dopaminergic and serotonergic neurons, as well as a variety of peptidergic neuron types. Full article
(This article belongs to the Special Issue Common Molecular Mechanisms in Embryonic Development)
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20 pages, 3216 KiB  
Article
Novel 2-alkythio-4-chloro-N-[imino(heteroaryl)methyl]benzenesulfonamide Derivatives: Synthesis, Molecular Structure, Anticancer Activity and Metabolic Stability
by Beata Żołnowska, Jarosław Sławiński, Mariusz Belka, Tomasz Bączek, Jarosław Chojnacki and Anna Kawiak
Int. J. Mol. Sci. 2023, 24(11), 9768; https://doi.org/10.3390/ijms24119768 - 05 Jun 2023
Cited by 1 | Viewed by 1957
Abstract
A series of novel 2-alkythio-4-chloro-N-[imino-(heteroaryl)methyl]benzenesulfonamide derivatives, 824, were synthesized in the reaction of the N-(benzenesulfonyl)cyanamide potassium salts 17 with the appropriate mercaptoheterocycles. All the synthesized compounds were evaluated for their anticancer activity in HeLa, HCT-116 [...] Read more.
A series of novel 2-alkythio-4-chloro-N-[imino-(heteroaryl)methyl]benzenesulfonamide derivatives, 824, were synthesized in the reaction of the N-(benzenesulfonyl)cyanamide potassium salts 17 with the appropriate mercaptoheterocycles. All the synthesized compounds were evaluated for their anticancer activity in HeLa, HCT-116 and MCF-7 cell lines. The most promising compounds, 1113, molecular hybrids containing benzenesulfonamide and imidazole moieties, selectively showed a high cytotoxic effect in HeLa cancer cells (IC50: 6–7 μM) and exhibited about three times less cytotoxicity against the non-tumor cell line HaCaT cells (IC50: 18–20 μM). It was found that the anti-proliferative effects of 11, 12 and 13 were associated with their ability to induce apoptosis in HeLa cells. The compounds increased the early apoptotic population of cells, elevated the percentage of cells in the sub-G1 phase of the cell cycle and induced apoptosis through caspase activation in HeLa cells. For the most active compounds, susceptibility to undergo first-phase oxidation reactions in human liver microsomes was assessed. The results of the in vitro metabolic stability experiments indicated values of the factor t½ for 1113 in the range of 9.1–20.3 min and suggested the hypothetical oxidation of these compounds to sulfenic and subsequently sulfinic acids as metabolites. Full article
(This article belongs to the Section Biochemistry)
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10 pages, 4879 KiB  
Article
Effects of Red LED Irradiation in Enhancing the Mineralization of Human Dental Pulp Cells In Vitro
by Ying Yang, Ok-Su Kim, Guo Liu, Bin-Na Lee, Danyang Liu, Wenqi Fu, Siyu Zhu, Jae-Seok Kang, Byunggook Kim and Okjoon Kim
Int. J. Mol. Sci. 2023, 24(11), 9767; https://doi.org/10.3390/ijms24119767 - 05 Jun 2023
Cited by 1 | Viewed by 1065
Abstract
Dentin regeneration is the preferred method used to preserve dental pulp vitality after pulp exposure due to caries. Red light-emitting diode irradiation (LEDI), which is based on photobiomodulation (PBM), has been used to promote hard-tissue regeneration. However, the underlying mechanism still needs elucidation. [...] Read more.
Dentin regeneration is the preferred method used to preserve dental pulp vitality after pulp exposure due to caries. Red light-emitting diode irradiation (LEDI), which is based on photobiomodulation (PBM), has been used to promote hard-tissue regeneration. However, the underlying mechanism still needs elucidation. This study aimed to explore the mechanism involved in red LEDI affecting dentin regeneration. Alizarin red S (ARS) staining revealed that red LEDI induced mineralization of human dental pulp cells (HDPCs) in vitro. We further distinguished the cell proliferation (0–6 d), differentiation (6–12 d), and mineralization (12–18 d) of HDPCs in vitro and treated cells either with or without red LEDI in each stage. The results showed that red LEDI treatment in the mineralization stage, but not the proliferation or differentiation stages, increased mineralized nodule formation around HDPCs. Western blot also indicated that red LEDI treatment in the mineralization stage, but not the proliferation or differentiation stages, upregulated the expression of dentin matrix marker proteins (dentin sialophosphoprotein, DSPP; dentin matrix protein 1, DMP1; osteopontin, OPN) and an intracellular secretory vesicle marker protein (lysosomal-associated membrane protein 1, LAMP1). Therefore, the red LEDI might enhance the matrix vesicle secretion of HDPCs. On the molecular level, red LEDI enhanced mineralization by activating the mitogen-activated protein kinase (MAPK) signaling pathways (ERK and P38). ERK and P38 inhibition reduced mineralized nodule formation and the expression of relevant marker proteins. In summary, red LEDI enhanced the mineralization of HDPCs by functioning to produce a positive effect in the mineralization stage in vitro. Full article
(This article belongs to the Section Molecular Biophysics)
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19 pages, 9352 KiB  
Article
ZIM1 Combined with Hydrogel Inhibits Senescence of Primary PαS Cells during In Vitro Expansion
by Yueming Tian, Menglong Hu, Xuenan Liu, Xu Wang, Dazhuang Lu, Zheng Li, Yunsong Liu, Ping Zhang and Yongsheng Zhou
Int. J. Mol. Sci. 2023, 24(11), 9766; https://doi.org/10.3390/ijms24119766 - 05 Jun 2023
Viewed by 1309
Abstract
Bone marrow stem cells (BMSCs) are a promising source of seed cells in bone tissue engineering, which needs a great quantity of cells. Cell senescence occurs as they are passaged, which could affect the therapeutic effects of cells. Therefore, this study aims to [...] Read more.
Bone marrow stem cells (BMSCs) are a promising source of seed cells in bone tissue engineering, which needs a great quantity of cells. Cell senescence occurs as they are passaged, which could affect the therapeutic effects of cells. Therefore, this study aims to explore the transcriptomic differences among the uncultured and passaged cells, finding a practical target gene for anti-aging. We sorted PαS (PDGFR-α+SCA-1+CD45-TER119-) cells as BMSCs by flow cytometry analysis. The changes in cellular senescence phenotype (Counting Kit-8 (CCK-8) assay, reactive oxygen species (ROS) test, senescence-associated β-galactosidase (SA-β-Gal) activity staining, expression of aging-related genes, telomere-related changes and in vivo differentiation potential) and associated transcriptional alterations during three important cell culture processes (in vivo, first adherence in vitro, first passage, and serial passage in vitro) were studied. Overexpression plasmids of potential target genes were made and examed. Gelatin methacryloyl (GelMA) was applied to explore the anti-aging effects combined with the target gene. Aging-related genes and ROS levels increased, telomerase activity and average telomere length decreased, and SA-β-Gal activities increased as cells were passaged. RNA-seq offered that imprinted zinc-finger gene 1 (Zim1) played a critical role in anti-aging during cell culture. Further, Zim1 combined with GelMA reduced the expression of P16/P53 and ROS levels with doubled telomerase activities. Few SA-β-Gal positive cells were found in the above state. These effects are achieved at least by the activation of Wnt/β-catenin signaling through the regulation of Wnt2. The combined application of Zim1 and hydrogel could inhibit the senescence of BMSCs during in vitro expansion, which may benefit clinical application. Full article
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13 pages, 1478 KiB  
Review
Cyanidin-3-O-glucoside as a Nutrigenomic Factor in Type 2 Diabetes and Its Prominent Impact on Health
by Iga Bartel, Magdalena Koszarska, Nina Strzałkowska, Nikolay T. Tzvetkov, Dongdong Wang, Jarosław O. Horbańczuk, Agnieszka Wierzbicka, Atanas G. Atanasov and Artur Jóźwik
Int. J. Mol. Sci. 2023, 24(11), 9765; https://doi.org/10.3390/ijms24119765 - 05 Jun 2023
Cited by 2 | Viewed by 1850
Abstract
Type 2 diabetes (T2D) accounts for a global health problem. It is a complex disease as a result of the combination of environmental as well as genetic factors. Morbidity is still increasing across the world. One of the possibilities for the prevention and [...] Read more.
Type 2 diabetes (T2D) accounts for a global health problem. It is a complex disease as a result of the combination of environmental as well as genetic factors. Morbidity is still increasing across the world. One of the possibilities for the prevention and mitigation of the negative consequences of type 2 diabetes is a nutritional diet rich in bioactive compounds such as polyphenols. This review is focused on cyanidin-3-O-glucosidase (C3G), which belongs to the anthocyanins subclass, and its anti-diabetic properties. There are numerous pieces of evidence that C3G exerts positive effects on diabetic parameters, including in vitro and in vivo studies. It is involved in alleviating inflammation, reducing blood glucose, controlling postprandial hyperglycemia, and gene expression related to the development of T2D. C3G is one of the beneficial polyphenolic compounds that may help to overcome the public health problems associated with T2D. Full article
(This article belongs to the Special Issue Natural Compounds and Oxidative Stress)
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10 pages, 1012 KiB  
Article
Thermochemical Study of the Interaction of Cytosine and Uracil with Peptides in a Buffered Saline: Complex Formation with beta-Endorphin 30-31 (Human), L-Glutathion (Reduced) and α-L-Alanyl-L-Tyrosine
by Vladimir P. Barannikov, Valeriy I. Smirnov, Igor N. Mezhevoi and Damir R. Koltyshev
Int. J. Mol. Sci. 2023, 24(11), 9764; https://doi.org/10.3390/ijms24119764 - 05 Jun 2023
Cited by 1 | Viewed by 885
Abstract
The complex formation of uracil and cytosine with glycyl-L-glutamic acid (β-endorphin 30-31), γ-L-glutamyl-L-cysteinyl-glycine (glutathione reduced), α-L-alanyl-L-tyrosine, and α-L-alanyl-α-L-alanine in a buffered saline has been studied using dissolution calorimetry. The values of the reaction constant, the change in Gibbs energy, enthalpy, and entropy were [...] Read more.
The complex formation of uracil and cytosine with glycyl-L-glutamic acid (β-endorphin 30-31), γ-L-glutamyl-L-cysteinyl-glycine (glutathione reduced), α-L-alanyl-L-tyrosine, and α-L-alanyl-α-L-alanine in a buffered saline has been studied using dissolution calorimetry. The values of the reaction constant, the change in Gibbs energy, enthalpy, and entropy were obtained. It is shown that the ratio of the enthalpy and entropy factors depends on the charge of the peptide ion, and the number of H-bond acceptors in the peptide structure. The contributions of interaction between charged groups and polar fragments, hydrogen bonding, and stacking interaction are discussed, taking into account the effect of solvent reorganization around the reactant molecules. Full article
(This article belongs to the Section Physical Chemistry and Chemical Physics)
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12 pages, 699 KiB  
Review
Periodontitis Disease in Farmed Ruminants—Current State of Research
by Arkadiusz Grzeczka, Marianna Lech, Gracjan Wozniak, Szymon Graczyk, Pawel Kordowitzki, Małgorzata Olejnik, Marek Gehrke and Jędrzej Maria Jaśkowski
Int. J. Mol. Sci. 2023, 24(11), 9763; https://doi.org/10.3390/ijms24119763 - 05 Jun 2023
Cited by 2 | Viewed by 1384
Abstract
Periodontal disease in ruminants is common and occurs in farmed and wild animals. Periodontal lesions can result from the secretion of endotoxins by pathogenic bacteria and as consequences of immune system activity. Three main types of periodontitis have been described. The first is [...] Read more.
Periodontal disease in ruminants is common and occurs in farmed and wild animals. Periodontal lesions can result from the secretion of endotoxins by pathogenic bacteria and as consequences of immune system activity. Three main types of periodontitis have been described. The first is chronic inflammation involving mainly premolars and molars—periodontitis (PD). The second type is an acute inflammatory reaction occurring with calcification of the periosteum of the jawbone and swelling of the surrounding soft tissues (Cara inchada, CI—“swollen face”). Finally, a third type, similar to the first but located in the incisor area, is called “broken mouth” (BM). Etiological variation between the different types of periodontitis is indicated. This particularly manifests in the composition of the microbiome, which is characteristic of the different forms of periodontitis. The widespread detection of lesions has drawn attention to the current nature of the problem. Full article
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19 pages, 19940 KiB  
Article
Insights into S. aureus-Induced Bone Deformation in a Mouse Model of Chronic Osteomyelitis Using Fluorescence and Raman Imaging
by Shibarjun Mandal, Astrid Tannert, Christina Ebert, Rustam R. Guliev, Yvonne Ozegowski, Lina Carvalho, Britt Wildemann, Simone Eiserloh, Sina M. Coldewey, Bettina Löffler, Luís Bastião Silva, Verena Hoerr, Lorena Tuchscherr and Ute Neugebauer
Int. J. Mol. Sci. 2023, 24(11), 9762; https://doi.org/10.3390/ijms24119762 - 05 Jun 2023
Cited by 1 | Viewed by 1705
Abstract
Osteomyelitis is an infection of the bone that is often difficult to treat and causes a significant healthcare burden. Staphylococcus aureus is the most common pathogen causing osteomyelitis. Osteomyelitis mouse models have been established to gain further insights into the pathogenesis and host [...] Read more.
Osteomyelitis is an infection of the bone that is often difficult to treat and causes a significant healthcare burden. Staphylococcus aureus is the most common pathogen causing osteomyelitis. Osteomyelitis mouse models have been established to gain further insights into the pathogenesis and host response. Here, we use an established S. aureus hematogenous osteomyelitis mouse model to investigate morphological tissue changes and bacterial localization in chronic osteomyelitis with a focus on the pelvis. X-ray imaging was performed to follow the disease progression. Six weeks post infection, when osteomyelitis had manifested itself with a macroscopically visible bone deformation in the pelvis, we used two orthogonal methods, namely fluorescence imaging and label-free Raman spectroscopy, to characterise tissue changes on a microscopic scale and to localise bacteria in different tissue regions. Hematoxylin and eosin as well as Gram staining were performed as a reference method. We could detect all signs of a chronically florid tissue infection with osseous and soft tissue changes as well as with different inflammatory infiltrate patterns. Large lesions dominated in the investigated tissue samples. Bacteria were found to form abscesses and were distributed in high numbers in the lesion, where they could occasionally also be detected intracellularly. In addition, bacteria were found in lower numbers in surrounding muscle tissue and even in lower numbers in trabecular bone tissue. The Raman spectroscopic imaging revealed a metabolic state of the bacteria with reduced activity in agreement with small cell variants found in other studies. In conclusion, we present novel optical methods to characterise bone infections, including inflammatory host tissue reactions and bacterial adaptation. Full article
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14 pages, 3494 KiB  
Article
Hypoxia with or without Treadmill Exercises Affects Slow-Twitch Muscle Atrophy and Joint Destruction in a Rat Model of Rheumatoid Arthritis
by Yoichiro Kamada, Yuji Arai, Shogo Toyama, Atsuo Inoue, Shuji Nakagawa, Yuta Fujii, Kenta Kaihara, Ryota Cha, Osam Mazda and Kenji Takahashi
Int. J. Mol. Sci. 2023, 24(11), 9761; https://doi.org/10.3390/ijms24119761 - 05 Jun 2023
Cited by 1 | Viewed by 968
Abstract
The effects of treadmill running under hypoxic conditions on joints and muscles of collagen-induced arthritis (CIA) rats were investigated. CIA rats were divided into normoxia no-exercise, hypoxia no-exercise (Hypo-no), and hypoxia exercise (Hypo-ex) groups. Changes were examined on days 2 and 44 of [...] Read more.
The effects of treadmill running under hypoxic conditions on joints and muscles of collagen-induced arthritis (CIA) rats were investigated. CIA rats were divided into normoxia no-exercise, hypoxia no-exercise (Hypo-no), and hypoxia exercise (Hypo-ex) groups. Changes were examined on days 2 and 44 of hypoxia with or without treadmill exercises. In the early stage of hypoxia, the expression of hypoxia-inducible factor (HIF)-1α increased in the Hypo-no and Hypo-ex groups. The expression of the egl-9 family hypoxia-inducible factor 1 (EGLN1) and vascular endothelial growth factor (VEGF) in the Hypo-ex group also increased. Under sustained hypoxia, the Hypo-no and Hypo-ex groups did not show increased expression of HIF-1α or VEGF, but p70S6K levels were elevated. Histologically, joint destruction was alleviated in the Hypo-no group, the loss of muscle weight in slow-twitch muscles was prevented, and muscle fibrosis was suppressed. In the Hypo-ex group, the preventive effect of a reduction in the slow-twitch muscle cross-sectional area was enhanced. Thus, chronic hypoxia in an animal model of rheumatoid arthritis controlled arthritis and joint destruction and prevented slow-twitch muscle atrophy and fibrosis. The combination of hypoxia with treadmill running further enhanced the preventive effects on slow-twitch muscle atrophy. Full article
(This article belongs to the Section Molecular Pathology, Diagnostics, and Therapeutics)
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16 pages, 1736 KiB  
Review
A Critical View over the Newest Antidiabetic Molecules in Light of Efficacy—A Systematic Review and Meta-Analysis
by Teodor Salmen, Liviu-Ionut Serbanoiu, Ioana-Cristina Bica, Cristian Serafinceanu, Emir Muzurović, Andrej Janez, Stefan Busnatu, Maciej Banach, Ali Abbas Rizvi, Manfredi Rizzo and Anca Pantea Stoian
Int. J. Mol. Sci. 2023, 24(11), 9760; https://doi.org/10.3390/ijms24119760 - 05 Jun 2023
Cited by 4 | Viewed by 2528
Abstract
The increase in life expectancy without a decrease in the years lived without disability leads to the rise of the population aged over 65 years prone to polypharmacy. The novel antidiabetic drugs can improve this global therapeutic and health problem in patients with [...] Read more.
The increase in life expectancy without a decrease in the years lived without disability leads to the rise of the population aged over 65 years prone to polypharmacy. The novel antidiabetic drugs can improve this global therapeutic and health problem in patients with diabetes mellitus (DM). We aimed to establish the efficacy (A1c hemoglobin reduction) and safety of the newest antidiabetic drugs (considered so due to their novelty in medical practice use), specifically DPP-4i, SGLT-2i, GLP-1 Ra, and tirzepatide. The present meta-analysis followed the protocol registered at Prospero with the CRD42022330442 registration number. The reduction in HbA1c in the DPP4-i class for tenegliptin was 95% CI −0.54 [−1.1, 0.01], p = 0.06; in the SGLT2-iclass for ipragliflozin 95% CI −0.2 [−0.87, 0.47], p = 0.55; and for tofogliflozin 95% CI 3.13 [−12.02, 18.28], p = 0.69, while for tirzepatide it was 0.15, 95% CI [−0.50, 0.80] (p = 0.65). The guidelines for treatment in type 2 DM are provided from cardiovascular outcome trials that report mainly major adverse cardiovascular events and data about efficacy. The newest antidiabetic non-insulinic drugs are reported to be efficient in lowering HbA1c, but this effect depends between classes, molecules, or patients’ age. The newest antidiabetic drugs are proven to be efficient molecules in terms of HbA1c decrease, weight reduction, and safety, but more studies are needed in order to characterize exactly their efficacy and safety profiles. Full article
(This article belongs to the Special Issue New Advances in Type 2 Diabetes and Its Complications)
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18 pages, 792 KiB  
Review
Plant Growth Promotion Using Bacillus cereus
by Iryna Kulkova, Jakub Dobrzyński, Paweł Kowalczyk, Grzegorz Bełżecki and Karol Kramkowski
Int. J. Mol. Sci. 2023, 24(11), 9759; https://doi.org/10.3390/ijms24119759 - 05 Jun 2023
Cited by 16 | Viewed by 2824
Abstract
Plant growth-promoting bacteria (PGPB) appear to be a sensible competitor to conventional fertilization, including mineral fertilizers and chemical plant protection products. Undoubtedly, one of the most interesting bacteria exhibiting plant-stimulating traits is, more widely known as a pathogen, Bacillus cereus. To date, [...] Read more.
Plant growth-promoting bacteria (PGPB) appear to be a sensible competitor to conventional fertilization, including mineral fertilizers and chemical plant protection products. Undoubtedly, one of the most interesting bacteria exhibiting plant-stimulating traits is, more widely known as a pathogen, Bacillus cereus. To date, several environmentally safe strains of B. cereus have been isolated and described, including B. cereus WSE01, MEN8, YL6, SA1, ALT1, ERBP, GGBSTD1, AK1, AR156, C1L, and T4S. These strains have been studied under growth chamber, greenhouse, and field conditions and have shown many significant traits, including indole-3-acetic acid (IAA) and aminocyclopropane-1-carboxylic acid (ACC) deaminase production or phosphate solubilization, which allows direct plant growth promotion. It includes an increase in biometrics traits, chemical element content (e.g., N, P, and K), and biologically active substances content or activity, e.g., antioxidant enzymes and total soluble sugar. Hence, B. cereus has supported the growth of plant species such as soybean, maize, rice, and wheat. Importantly, some B. cereus strains can also promote plant growth under abiotic stresses, including drought, salinity, and heavy metal pollution. In addition, B. cereus strains produced extracellular enzymes and antibiotic lipopeptides or triggered induced systemic resistance, which allows indirect stimulation of plant growth. As far as biocontrol is concerned, these PGPB can suppress the development of agriculturally important phytopathogens, including bacterial phytopathogens (e.g., Pseudomonas syringae, Pectobacterium carotovorum, and Ralstonia solanacearum), fungal phytopathogens (e.g., Fusarium oxysporum, Botrytis cinerea, and Rhizoctonia solani), and other phytopathogenic organisms (e.g., Meloidogyne incognita (Nematoda) and Plasmodiophora brassicae (Protozoa)). In conclusion, it should be noted that there are still few studies on the effectiveness of B. cereus under field conditions, particularly, there is a lack of comprehensive analyses comparing the PGP effects of B. cereus and mineral fertilizers, which should be reduced in favor of decreasing the use of mineral fertilizers. It is also worth mentioning that there are still very few studies on the impact of B. cereus on the indigenous microbiota and its persistence after application to soil. Further studies would help to understand the interactions between B. cereus and indigenous microbiota, subsequently contributing to increasing its effectiveness in promoting plant growth. Full article
(This article belongs to the Special Issue Molecular Insights into Plant-Biotic Interactions and Crop Yield)
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14 pages, 1867 KiB  
Article
Effectiveness of Albumin-Fused Thioredoxin against 6-Hydroxydopamine-Induced Neurotoxicity In Vitro
by Okina Sakakibara, Mikako Shimoda, Gaku Yamamoto, Youichirou Higashi, Mayumi Ikeda-Imafuku, Yu Ishima, Masahiro Kawahara and Ken-ichiro Tanaka
Int. J. Mol. Sci. 2023, 24(11), 9758; https://doi.org/10.3390/ijms24119758 - 05 Jun 2023
Cited by 2 | Viewed by 1269
Abstract
Parkinson’s disease (PD) is a neurodegenerative disorder caused by oxidative stress-dependent loss of dopaminergic neurons in the substantia nigra and elevated microglial inflammatory responses. Recent studies show that cell loss also occurs in the hypothalamus in PD. However, effective treatments for the disorder [...] Read more.
Parkinson’s disease (PD) is a neurodegenerative disorder caused by oxidative stress-dependent loss of dopaminergic neurons in the substantia nigra and elevated microglial inflammatory responses. Recent studies show that cell loss also occurs in the hypothalamus in PD. However, effective treatments for the disorder are lacking. Thioredoxin is the major protein disulfide reductase in vivo. We previously synthesized an albumin–thioredoxin fusion protein (Alb–Trx), which has a longer plasma half-life than thioredoxin, and reported its effectiveness in the treatment of respiratory and renal diseases. Moreover, we reported that the fusion protein inhibits trace metal-dependent cell death in cerebrovascular dementia. Here, we investigated the effectiveness of Alb–Trx against 6-hydroxydopamine (6-OHDA)-induced neurotoxicity in vitro. Alb–Trx significantly inhibited 6-OHDA-induced neuronal cell death and the integrated stress response. Alb–Trx also markedly inhibited 6-OHDA-induced reactive oxygen species (ROS) production, at a concentration similar to that inhibiting cell death. Exposure to 6-OHDA perturbed the mitogen-activated protein kinase pathway, with increased phosphorylated Jun N-terminal kinase and decreased phosphorylated extracellular signal-regulated kinase levels. Alb–Trx pretreatment ameliorated these changes. Furthermore, Alb–Trx suppressed 6-OHDA-induced neuroinflammatory responses by inhibiting NF-κB activation. These findings suggest that Alb–Trx reduces neuronal cell death and neuroinflammatory responses by ameliorating ROS-mediated disruptions in intracellular signaling pathways. Thus, Alb–Trx may have potential as a novel therapeutic agent for PD. Full article
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16 pages, 38314 KiB  
Article
Hyaluronan with Different Molecular Weights Can Affect the Gut Microbiota and Pathogenetic Progression of Post-Intensive Care Syndrome Mice in Different Ways
by Lu Li, Yuanyuan Jiang, Qianqian Zhu, Dawei Liu, Mingkai Chang, Yongzhe Wang, Ruitong Xi and Wenfei Wang
Int. J. Mol. Sci. 2023, 24(11), 9757; https://doi.org/10.3390/ijms24119757 - 05 Jun 2023
Cited by 2 | Viewed by 1145
Abstract
Post-intensive care syndrome (PICS) poses a serious threat to the health of intensive care unit (ICU) survivors, and effective treatment options are currently lacking. With increasing survival rates of ICU patients worldwide, there is a rising interest in developing methods to alleviate PICS [...] Read more.
Post-intensive care syndrome (PICS) poses a serious threat to the health of intensive care unit (ICU) survivors, and effective treatment options are currently lacking. With increasing survival rates of ICU patients worldwide, there is a rising interest in developing methods to alleviate PICS symptoms. This study aimed to explore the potential of using Hyaluronan (HA) with different molecular weights as potential drugs for treating PICS in mice. Cecal ligation and puncture (CLP) were used to establish a PICS mice model, and high molecular weight HA (HMW-HA) or oligo-HA were used as therapeutic agents. Pathological and physiological changes of PICS mice in each group were monitored. 16S rRNA sequencing was performed to dissect gut microbiota discrepancies. The results showed that both molecular weights of HA could increase the survival rate of PICS mice at the experimental endpoint. Specifically, 1600 kDa-HA can alleviate PICS in a short time. In contrast, 3 kDa-HA treatment decreased PICS model survivability in the early stages of the experiment. Further, via 16S rRNA sequence analysis, we observed the changes in the gut microbiota in PICS mice, thereby impairing intestinal structure and increasing inflammation. Additionally, both types of HA can reverse this change. Moreover, compared to 1600 kDa-HA, 3 kDa-HA can significantly elevate the proportion of probiotics and reduce the abundance of pathogenic bacteria (Desulfovibrionaceae and Enterobacteriaceae). In conclusion, HA holds the advantage of being a potential therapeutic drug for PICS, but different molecular weights can lead to varying effects. Moreover, 1600 kDa-HA showed promise as a protective agent in PICS mice, and caution should be taken to its timing when considering using 3 kDa-HA. Full article
(This article belongs to the Section Molecular Microbiology)
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15 pages, 8226 KiB  
Article
Modulation of Dietary Choline Uptake in a Mouse Model of Acid Sphingomyelinase Deficiency
by Ángel Gaudioso, Pilar Moreno-Huguet, Josefina Casas, Edward H. Schuchman and María Dolores Ledesma
Int. J. Mol. Sci. 2023, 24(11), 9756; https://doi.org/10.3390/ijms24119756 - 05 Jun 2023
Viewed by 1316
Abstract
Acid sphingomyelinase deficiency (ASMD) is a lysosomal storage disorder caused by mutations in the gene-encoding acid sphingomyelinase (ASM). ASMD impacts peripheral organs in all patients, including the liver and spleen. The infantile and chronic neurovisceral forms of the disease also lead to neuroinflammation [...] Read more.
Acid sphingomyelinase deficiency (ASMD) is a lysosomal storage disorder caused by mutations in the gene-encoding acid sphingomyelinase (ASM). ASMD impacts peripheral organs in all patients, including the liver and spleen. The infantile and chronic neurovisceral forms of the disease also lead to neuroinflammation and neurodegeneration for which there is no effective treatment. Cellular accumulation of sphingomyelin (SM) is a pathological hallmark in all tissues. SM is the only sphingolipid comprised of a phosphocholine group linked to ceramide. Choline is an essential nutrient that must be obtained from the diet and its deficiency promotes fatty liver disease in a process dependent on ASM activity. We thus hypothesized that choline deprivation could reduce SM production and have beneficial effects in ASMD. Using acid sphingomyelinase knock-out (ASMko) mice, which mimic neurovisceral ASMD, we have assessed the safety of a choline-free diet and its effects on liver and brain pathological features such as altered sphingolipid and glycerophospholipid composition, inflammation and neurodegeneration. We found that the choline-free diet was safe in our experimental conditions and reduced activation of macrophages and microglia in the liver and brain, respectively. However, there was no significant impact on sphingolipid levels and neurodegeneration was not prevented, arguing against the potential of this nutritional strategy to assist in the management of neurovisceral ASMD patients. Full article
(This article belongs to the Special Issue Bioactive Lipids and Their Derivatives in Biomedical Applications)
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18 pages, 1253 KiB  
Review
RNA Interference Past and Future Applications in Plants
by Sarah Koeppe, Lawrence Kawchuk and Melanie Kalischuk
Int. J. Mol. Sci. 2023, 24(11), 9755; https://doi.org/10.3390/ijms24119755 - 05 Jun 2023
Cited by 8 | Viewed by 4032
Abstract
Antisense RNA was observed to elicit plant disease resistance and post-translational gene silencing (PTGS). The universal mechanism of RNA interference (RNAi) was shown to be induced by double-stranded RNA (dsRNA), an intermediate produced during virus replication. Plant viruses with a single-stranded positive-sense RNA [...] Read more.
Antisense RNA was observed to elicit plant disease resistance and post-translational gene silencing (PTGS). The universal mechanism of RNA interference (RNAi) was shown to be induced by double-stranded RNA (dsRNA), an intermediate produced during virus replication. Plant viruses with a single-stranded positive-sense RNA genome have been instrumental in the discovery and characterization of systemic RNA silencing and suppression. An increasing number of applications for RNA silencing have emerged involving the exogenous application of dsRNA through spray-induced gene silencing (SIGS) that provides specificity and environmentally friendly options for crop protection and improvement. Full article
(This article belongs to the Special Issue RNA Interference-Based Tools for Plant Improvement and Protection 2.0)
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19 pages, 4541 KiB  
Article
Application of Box–Behnken Design to Optimize Phosphate Adsorption Conditions from Water onto Novel Adsorbent CS-ZL/ZrO/Fe3O4: Characterization, Equilibrium, Isotherm, Kinetic, and Desorption Studies
by Endar Hidayat, Nur Maisarah Binti Mohamad Sarbani, Seiichiro Yonemura, Yoshiharu Mitoma and Hiroyuki Harada
Int. J. Mol. Sci. 2023, 24(11), 9754; https://doi.org/10.3390/ijms24119754 - 05 Jun 2023
Cited by 2 | Viewed by 1032
Abstract
Phosphate (PO43−) is an essential nutrient in agriculture; however, it is hazardous to the environment if discharged in excess as in wastewater discharge and runoff from agriculture. Moreover, the stability of chitosan under acidic conditions remains a concern. To address [...] Read more.
Phosphate (PO43−) is an essential nutrient in agriculture; however, it is hazardous to the environment if discharged in excess as in wastewater discharge and runoff from agriculture. Moreover, the stability of chitosan under acidic conditions remains a concern. To address these problems, CS-ZL/ZrO/Fe3O4 was synthesized using a crosslinking method as a novel adsorbent for the removal of phosphate (PO43−) from water and to increase the stability of chitosan. The response surface methodology (RSM) with a Box–Behnken design (BBD)-based analysis of variance (ANOVA) was implemented. The ANOVA results clearly showed that the adsorption of PO43− onto CS-ZL/ZrO/Fe3O4 was significant (p ≤ 0.05), with good mechanical stability. pH, dosage, and time were the three most important factors for the removal of PO43−. Freundlich isotherm and pseudo-second-order kinetic models generated the best equivalents for PO43− adsorption. The presence of coexisting ions for PO43− removal was also studied. The results indicated no significant effect on PO43− removal (p ≤ 0.05). After adsorption, PO43− was easily released by 1 M NaOH, reaching 95.77% and exhibiting a good capability over three cycles. Thus, this concept is effective for increasing the stability of chitosan and is an alternative adsorbent for the removal of PO43− from water. Full article
(This article belongs to the Special Issue Multifunctional Application of Biopolymers and Biomaterials)
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13 pages, 2054 KiB  
Communication
Potentiating the Cross-Reactive IFN-γ T Cell and Polyfunctional T Cell Responses by Heterologous GX-19N DNA Booster in Mice Primed with Either a COVID-19 mRNA Vaccine or Inactivated Vaccine
by Yong Bok Seo, Ara Ko, Duckhyang Shin, Junyoung Kim, You Suk Suh, Juyoung Na, Ji In Ryu, Suyeon Lee, Min Ji Oh and Young Chul Sung
Int. J. Mol. Sci. 2023, 24(11), 9753; https://doi.org/10.3390/ijms24119753 - 05 Jun 2023
Viewed by 1216
Abstract
Waning vaccine-induced immunity, coupled with the emergence of SARS-CoV-2 variants, has inspired the widespread implementation of COVID-19 booster vaccinations. Here, we evaluated the potential of the GX-19N DNA vaccine as a heterologous booster to enhance the protective immune response to SARS-CoV-2 in mice [...] Read more.
Waning vaccine-induced immunity, coupled with the emergence of SARS-CoV-2 variants, has inspired the widespread implementation of COVID-19 booster vaccinations. Here, we evaluated the potential of the GX-19N DNA vaccine as a heterologous booster to enhance the protective immune response to SARS-CoV-2 in mice primed with either an inactivated virus particle (VP) or an mRNA vaccine. We found that in the VP-primed condition, GX-19N enhanced the response of both vaccine-specific antibodies and cross-reactive T Cells to the SARS-CoV-2 variant of concern (VOC), compared to the homologous VP vaccine prime-boost. Under the mRNA-primed condition, GX-19N induced higher vaccine-induced T Cell responses but lower antibody responses than the homologous mRNA vaccine prime-boost. Furthermore, the heterologous GX-19N boost induced higher S-specific polyfunctional CD4+ and CD8+ T cell responses than the homologous VP or mRNA prime-boost vaccinations. Our results provide new insights into booster vaccination strategies for the management of novel COVID-19 variants. Full article
(This article belongs to the Special Issue COVID-19 and Future Pathogens)
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15 pages, 4539 KiB  
Article
Unleashing the Influence of cAMP Receptor Protein: The Master Switch of Bacteriocin Export in Pectobacterium carotovorum subsp. carotovorum
by Chung-Pei Chang, Ruchi Briam James Sersenia Lagitnay, Tzu-Rong Li, Wei-Ting Lai, Reymund Calanga Derilo and Duen-Yau Chuang
Int. J. Mol. Sci. 2023, 24(11), 9752; https://doi.org/10.3390/ijms24119752 - 05 Jun 2023
Cited by 1 | Viewed by 1365
Abstract
Pectobacterium carotovorum subsp. carotovorum (Pcc) is a Gram-negative phytopathogenic bacterium that produces carocin, a low-molecular-weight bacteriocin that can kill related strains in response to factors in the environment such as UV exposure or nutritional deficiency. The function of the catabolite activator [...] Read more.
Pectobacterium carotovorum subsp. carotovorum (Pcc) is a Gram-negative phytopathogenic bacterium that produces carocin, a low-molecular-weight bacteriocin that can kill related strains in response to factors in the environment such as UV exposure or nutritional deficiency. The function of the catabolite activator protein (CAP), also known as the cyclic AMP receptor protein (CRP), as a regulator of carocin synthesis was examined. The crp gene was knocked out as part of the investigation, and the outcomes were assessed both in vivo and in vitro. Analysis of the DNA sequence upstream of the translation initiation site of carocin S3 revealed two putative binding sites for CRP that were confirmed using a biotinylated probe pull-down experiment. This study revealed that the deletion of crp inhibited genes involved in extracellular bacteriocin export via the flagellar type III secretion system and impacted the production of many low-molecular-weight bacteriocins. The biotinylated probe pull-down test demonstrated that when UV induction was missing, CRP preferentially attached to one of the two CAP sites while binding to both when UV induction was present. In conclusion, our research aimed to simulate the signal transduction system that controls the expression of the carocin gene in response to UV induction. Full article
(This article belongs to the Special Issue Peptide Antimicrobial Agents 3.0)
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15 pages, 3304 KiB  
Article
Comparison of Osteoconductive Ability of Two Types of Cholesterol-Bearing Pullulan (CHP) Nanogel-Hydrogels Impregnated with BMP-2 and RANKL-Binding Peptide: Bone Histomorphometric Study in a Murine Calvarial Defect Model
by Cangyou Xie, Fatma Rashed, Yosuke Sasaki, Masud Khan, Jia Qi, Yuri Kubo, Yoshiro Matsumoto, Shinichi Sawada, Yoshihiro Sasaki, Takashi Ono, Tohru Ikeda, Kazunari Akiyoshi and Kazuhiro Aoki
Int. J. Mol. Sci. 2023, 24(11), 9751; https://doi.org/10.3390/ijms24119751 - 05 Jun 2023
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Abstract
The receptor activator of NF-κB ligand (RANKL)-binding peptide is known to accelerate bone morphogenetic protein (BMP)-2-induced bone formation. Cholesterol-bearing pullulan (CHP)-OA nanogel-crosslinked PEG gel (CHP-OA nanogel-hydrogel) was shown to release the RANKL-binding peptide sustainably; however, an appropriate scaffold for peptide-accelerated bone formation is [...] Read more.
The receptor activator of NF-κB ligand (RANKL)-binding peptide is known to accelerate bone morphogenetic protein (BMP)-2-induced bone formation. Cholesterol-bearing pullulan (CHP)-OA nanogel-crosslinked PEG gel (CHP-OA nanogel-hydrogel) was shown to release the RANKL-binding peptide sustainably; however, an appropriate scaffold for peptide-accelerated bone formation is not determined yet. This study compares the osteoconductivity of CHP-OA hydrogel and another CHP nanogel, CHP-A nanogel-crosslinked PEG gel (CHP-A nanogel–hydrogel), in the bone formation induced by BMP-2 and the peptide. A calvarial defect model was performed in 5-week-old male mice, and scaffolds were placed in the defect. In vivo μCT was performed every week. Radiological and histological analyses after 4 weeks of scaffold placement revealed that the calcified bone area and the bone formation activity at the defect site in the CHP-OA hydrogel were significantly lower than those in the CHP-A hydrogel when the scaffolds were impregnated with both BMP-2 and the RANKL-binding peptide. The amount of induced bone was similar in both CHP-A and CHP-OA hydrogels when impregnated with BMP-2 alone. In conclusion, CHP-A hydrogel could be an appropriate scaffold compared to the CHP-OA hydrogel when the local bone formation was induced by the combination of RANKL-binding peptide and BMP-2, but not by BMP-2 alone. Full article
(This article belongs to the Special Issue Rational Design and Application of Functional Hydrogels)
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