International Journal of Molecular Sciences

15 pages, 2579 KiB

Open AccessArticle

Unhealthy Diets Induce Distinct and Regional Effects on Intestinal Inflammatory Signalling Pathways and Long-Lasting Metabolic Dysfunction in Rats

by Sofia Nogueira, Joana Barbosa, Juliana Faria, Susana I. Sá, Armando Cardoso, Raquel Soares, Bruno M. Fonseca and Sandra Leal

Int. J. Mol. Sci. 2022, 23(18), 10984; https://doi.org/10.3390/ijms231810984 - 19 Sep 2022

Viewed by 4188

Abstract

The intestinal epithelium is a principal site for environmental agents’ detection. Several inflammation- and stress-related signalling pathways have been identified as key players in these processes. However, it is still unclear how the chronic intake of inadequate nutrients triggers inflammatory signalling pathways in [...] Read more.

The intestinal epithelium is a principal site for environmental agents’ detection. Several inflammation- and stress-related signalling pathways have been identified as key players in these processes. However, it is still unclear how the chronic intake of inadequate nutrients triggers inflammatory signalling pathways in different intestinal regions. We aimed to evaluate the impact of unhealthy dietary patterns, starting at a younger age, and the association with metabolic dysfunction, intestinal inflammatory response, and obesity in adulthood. A rat model was used to evaluate the effects of the consumption of sugary beverages (HSD) and a Western diet (WD), composed of ultra-processed foods. Both diets showed a positive correlation with adiposity index, but a positive correlation was found between the HSD diet and the levels of blood glucose and triglycerides, whereas the WD diet correlated positively with triglyceride levels. Moreover, a distinct inflammatory response was associated with either the WD or HSD diets. The WD induced an increase in TLR2, TLR4, and nuclear factor-kappa B (NF-κB) intestinal gene expression, with higher levels in the colon and overexpression of the inducible nitric oxide synthase. In turn, the HSD diet induced activation of the TLR2-mediated NF-κB signalling pathway in the small intestine. Altogether, these findings support the concept that early intake of unhealthy foods and nutrients are a main exogenous signal for disturbances of intestinal immune mechanisms and in a region-specific manner, ultimately leading to obesity-related disorders in later life. Full article

(This article belongs to the Special Issue Gut Microbiota and Metabolic Diseases)

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14 pages, 3505 KiB

Open AccessArticle

Dual-Functional Nanofibrous Patches for Accelerating Wound Healing

by Dan Xia, Yuan Liu, Wuxiu Cao, Junwei Gao, Donghui Wang, Mengxia Lin, Chunyong Liang, Ning Li and Ruodan Xu

Int. J. Mol. Sci. 2022, 23(18), 10983; https://doi.org/10.3390/ijms231810983 - 19 Sep 2022

Cited by 15 | Viewed by 2902

Abstract

Bacterial infections and inflammation are two main factors for delayed wound healing. Coaxial electrospinning nanofibrous patches, by co-loading and sequential co-delivering of anti-bacterial and anti-inflammation agents, are promising wound dressing for accelerating wound healing. Herein, curcumin (Cur) was loaded into the polycaprolactone (PCL) [...] Read more.

Bacterial infections and inflammation are two main factors for delayed wound healing. Coaxial electrospinning nanofibrous patches, by co-loading and sequential co-delivering of anti-bacterial and anti-inflammation agents, are promising wound dressing for accelerating wound healing. Herein, curcumin (Cur) was loaded into the polycaprolactone (PCL) core, and broad-spectrum antibacterial tetracycline hydrochloride (TH) was loaded into gelatin (GEL) shell to prepare PCL-Cur/GEL-TH core-shell nanofiber membranes. The fibers showed a clear co-axial structure and good water absorption capacity, hydrophilicity and mechanical properties. In vitro drug release results showed sequential release of Cur and TH, in which the coaxial mat showed good antioxidant activity by DPPH test and excellent antibacterial activity was demonstrated by a disk diffusion method. The coaxial mats showed superior biocompatibility toward human immortalized keratinocytes. This study indicates a coaxial nanofiber membrane combining anti-bacterial and anti-inflammation agents has great potential as a wound dressing for promoting wound repair. Full article

(This article belongs to the Special Issue Wound Healing and Hypertrophic Scar)

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23 pages, 3331 KiB

Open AccessArticle

Investigation of TLR2 and TLR4 Polymorphisms and Sepsis Susceptibility: Computational and Experimental Approaches

by Mohammed Y. Behairy, Ali A. Abdelrahman, Eman A. Toraih, Emad El-Deen A. Ibrahim, Marwa M. Azab, Anwar A. Sayed and Hany R. Hashem

Int. J. Mol. Sci. 2022, 23(18), 10982; https://doi.org/10.3390/ijms231810982 - 19 Sep 2022

Cited by 12 | Viewed by 2504

Abstract

Toll-like receptors (TLR) play an eminent role in the regulation of immune responses to invading pathogens during sepsis. TLR genetic variants might influence individual susceptibility to developing sepsis. The current study aimed to investigate the association of genetic polymorphisms of the TLR2 and [...] Read more.

Toll-like receptors (TLR) play an eminent role in the regulation of immune responses to invading pathogens during sepsis. TLR genetic variants might influence individual susceptibility to developing sepsis. The current study aimed to investigate the association of genetic polymorphisms of the TLR2 and TLR4 with the risk of developing sepsis with both a pilot study and in silico tools. Different in silico tools were used to predict the impact of our SNPs on protein structure, stability, and function. Furthermore, in our prospective study, all patients matching the inclusion criteria in the intensive care units (ICU) were included and followed up, and DNA samples were genotyped using real-time polymerase chain reaction (RT-PCR) technology. There was a significant association between TLR2 Arg753Gln polymorphisms and sepsis under the over-dominant model (p = 0.043). In contrast, we did not find a significant difference with the TLR4 Asp299Gly polymorphism with sepsis. However, there was a significant association between TLR4 Asp299Gly polymorphisms and Acinetobacter baumannii infection which is quite a virulent organism in ICU (p = 0.001) and post-surgical cohorts (p = 0.033). Our results conclude that the TLR2 genotype may be a risk factor for sepsis in adult patients. Full article

(This article belongs to the Special Issue The Role of Toll-Like Receptors (TLR) in Infection and Inflammation)

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12 pages, 3855 KiB

Open AccessArticle

Alpha-Lipoic Acid Attenuates Apoptosis and Ferroptosis in Cisplatin-Induced Ototoxicity via the Reduction of Intracellular Lipid Droplets

by Sam Cho, Seok Jin Hong, Sung Hun Kang, YongKeun Park and Sung Kyun Kim

Int. J. Mol. Sci. 2022, 23(18), 10981; https://doi.org/10.3390/ijms231810981 - 19 Sep 2022

Cited by 12 | Viewed by 3397

Abstract

Alpha-lipoic acid (α-LA) is a potent antioxidant that can prevent apoptosis associated with cisplatin-induced ototoxicity through ROS. Ferroptosis is defined as an iron-dependent cell death pathway that has recently been highlighted and is associated with the accumulation of intracellular lipid droplets (LDs) due [...] Read more.

Alpha-lipoic acid (α-LA) is a potent antioxidant that can prevent apoptosis associated with cisplatin-induced ototoxicity through ROS. Ferroptosis is defined as an iron-dependent cell death pathway that has recently been highlighted and is associated with the accumulation of intracellular lipid droplets (LDs) due to an inflammatory process. Herein, we investigated the impact of α-LA on ferroptosis and analyzed the characteristics of LDs in auditory hair cells treated with cisplatin using high-resolution 3D quantitative-phase imaging with reconstruction of the refractive index (RI) distribution. HEI-OC1 cells were treated with 500 μM α-LA for 24 h and then with 15 μM cisplatin for 48 h. With 3D optical diffraction tomography (3D-ODT), the RI values of treated cells were analyzed. Regions with high RI values were considered to be LDs and labelled to measure the count, mass, and volume of LDs. The expression of LC3-B, P62, GPX4, 4-hydroxynonenal (4-HNE), and xCT was evaluated by Western blotting. HEI-OC1 cells damaged by cisplatin showed lipid peroxidation, depletion of xCT, and abnormal accumulation of 4-HNE. Additionally, the count, mass, and volume of LDs increased in the cells. Cells treated with α-LA had inhibited expression of 4-HNE, while the expression of xCT and GPX4 was recovered, which restored LDs to a level that was similar to that in the control group. Our research on LDs with 3D-ODT offers biological evidence of ferroptosis and provides insights on additional approaches for investigating the molecular pathways. Full article

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

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13 pages, 1645 KiB

Open AccessArticle

Bile Salt Hydrolases with Extended Substrate Specificity Confer a High Level of Resistance to Bile Toxicity on Atopobiaceae Bacteria

by Kana Morinaga, Hiroyuki Kusada and Hideyuki Tamaki

Int. J. Mol. Sci. 2022, 23(18), 10980; https://doi.org/10.3390/ijms231810980 - 19 Sep 2022

Cited by 17 | Viewed by 3370

Abstract

The bile resistance of intestinal bacteria is among the key factors responsible for their successful colonization of and survival in the mammalian gastrointestinal tract. In this study, we demonstrated that lactate-producing Atopobiaceae bacteria (Leptogranulimonas caecicola TOC12^T and Granulimonas faecalis OPF53^T [...] Read more.

The bile resistance of intestinal bacteria is among the key factors responsible for their successful colonization of and survival in the mammalian gastrointestinal tract. In this study, we demonstrated that lactate-producing Atopobiaceae bacteria (Leptogranulimonas caecicola TOC12^T and Granulimonas faecalis OPF53^T) isolated from mouse intestine showed high resistance to mammalian bile extracts, due to significant bile salt hydrolase (BSH) activity. We further succeeded in isolating BSH proteins (designated LcBSH and GfBSH) from L. caecicola TOC12^T and G. faecalis OPF53^T, respectively, and characterized their enzymatic features. Interestingly, recombinant LcBSH and GfBSH proteins exhibited BSH activity against 12 conjugated bile salts, indicating that LcBSH and GfBSH have much broader substrate specificity than the previously identified BSHs from lactic acid bacteria, which are generally known to hydrolyze six bile salt isomers. Phylogenetic analysis showed that LcBSH and GfBSH had no affinities with any known BSH subgroup and constituted a new BSH subgroup in the phylogeny. In summary, we discovered functional BSHs with broad substrate specificity from Atopobiaceae bacteria and demonstrated that these BSH enzymes confer bile resistance to L. caecicola TOC12^T and G. faecalis OPF53^T. Full article

(This article belongs to the Special Issue Overview of the Molecular Mechanism of Bacterial Environmental Adaptation by Comprehensive Analysis)

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19 pages, 6710 KiB

Open AccessArticle

Ultrasonic-Assisted Synthesis of Benzofuran Appended Oxadiazole Molecules as Tyrosinase Inhibitors: Mechanistic Approach through Enzyme Inhibition, Molecular Docking, Chemoinformatics, ADMET and Drug-Likeness Studies

by Ali Irfan, Ameer Fawad Zahoor, Shagufta Kamal, Mubashir Hassan and Andrzej Kloczkowski

Int. J. Mol. Sci. 2022, 23(18), 10979; https://doi.org/10.3390/ijms231810979 - 19 Sep 2022

Cited by 14 | Viewed by 2825

Abstract

Furan-oxadiazole structural hybrids belong to the most promising and biologically active classes of oxygen and nitrogen containing five member heterocycles which have expanded therapeutic scope and potential in the fields of pharmacology, medicinal chemistry and pharmaceutics. A novel series 5a–j of benzofuran-oxadiazole molecules [...] Read more.

Furan-oxadiazole structural hybrids belong to the most promising and biologically active classes of oxygen and nitrogen containing five member heterocycles which have expanded therapeutic scope and potential in the fields of pharmacology, medicinal chemistry and pharmaceutics. A novel series 5a–j of benzofuran-oxadiazole molecules incorporating S-alkylated amide linkage have been synthesized using ultrasonic irradiation and screened for bacterial tyrosinase inhibition activity. Most of the synthesized furan-oxadiazole structural motifs exhibited significant tyrosinase inhibition activity in the micromolar range, with one of the derivatives being more potent than the standard drug ascorbic acid. Among the tested compounds, the scaffold 5a displayed more tyrosinase inhibition efficacy IC₅₀ (11 ± 0.25 μM) than the ascorbic acid IC₅₀ (11.5 ± 0.1 μM). Compounds 5b, 5c and 5d efficiently inhibited bacterial tyrosinase with IC₅₀ values in the range of 12.4 ± 0.0–15.5 ± 0.0 μM. The 2-fluorophenylacetamide containing furan-oxadiazole compound 5a may be considered as a potential lead for tyrosinase inhibition with lesser side effects as a skin whitening and malignant melanoma anticancer agent. Full article

(This article belongs to the Special Issue Polynitrogen and Nitrogen-Oxygen Molecular Systems: Synthesis, Reactivity and Application)

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13 pages, 4003 KiB

Open AccessArticle

Asiatic Acid Attenuates Inflammation Induced by Salmonella via Upregulating LncRNA TVX1 in Microglia

by Wenshu Zou, Jingyan Zhang, Kai Zhang, Zhiping Peng, Ruihua Xin, Lei Wang and Jianxi Li

Int. J. Mol. Sci. 2022, 23(18), 10978; https://doi.org/10.3390/ijms231810978 - 19 Sep 2022

Cited by 5 | Viewed by 2269

Abstract

Salmonella typhimurium (S.T) induces damage to the central nervous system; however, the role of Asiatic acid (AA) in this is still unknown. Microglia play a role as macrophages to recognize the invaded pathogenic microbes in the brain. The aim of this study was [...] Read more.

Salmonella typhimurium (S.T) induces damage to the central nervous system; however, the role of Asiatic acid (AA) in this is still unknown. Microglia play a role as macrophages to recognize the invaded pathogenic microbes in the brain. The aim of this study was to investigate the protective effect and mechanism of AA on the central nervous system through an in vitro model of S.T infection in microglia. We pre-treated microglia with AA before S.T infection and explored the anti-infection mechanism of AA by sequencing, quantitative reverse transcription PCR (RT-qPCR), and Western blotting. Long non-coding RNA (lncRNA) sequencing demonstrated that inflammation is a major factor in S.T infection of microglia. RT-qPCR data demonstrated that AA inhibited S.T-induced increases in the mRNA levels of the pro-inflammatory factors interleukin (IL)-1β, IL-6, and IL-18. Western blotting demonstrated that AA inhibited S.T-induced activation of the nuclear factor (NF)-κB pathway and activation of the NLR family, pyrin domain-containing 3 (NLRP3) inflammasome. Expression of the lncRNA TVX1 in microglia was decreased by S.T infection and increased by pretreatment with AA. Inhibition of TVX1 expression reversed the anti-inflammatory effect of AA, and overexpression of TVX1 in microglia suppressed S.T-induced inflammation. In conclusion, AA attenuated S.T-induced microglial inflammation by upregulating the expression of the lncRNA TVX1. Full article

(This article belongs to the Special Issue Current Trends of Natural Bioactive Molecules in Regulation of Cell Signaling Pathways in Different Diseases)

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11 pages, 2298 KiB

Open AccessArticle

Highly Bright Silica-Coated InP/ZnS Quantum Dot-Embedded Silica Nanoparticles as Biocompatible Nanoprobes

by Kyeong-Min Ham, Minhee Kim, Sungje Bock, Jaehi Kim, Wooyeon Kim, Heung Su Jung, Jaehyun An, Hobeom Song, Jung-Won Kim, Hyung-Mo Kim, Won-Yeop Rho, Sang Hun Lee, Seung-min Park, Dong-Eun Kim and Bong-Hyun Jun

Int. J. Mol. Sci. 2022, 23(18), 10977; https://doi.org/10.3390/ijms231810977 - 19 Sep 2022

Cited by 8 | Viewed by 3570

Abstract

Quantum dots (QDs) have outstanding optical properties such as strong fluorescence, excellent photostability, broad absorption spectra, and narrow emission bands, which make them useful for bioimaging. However, cadmium (Cd)-based QDs, which have been widely studied, have potential toxicity problems. Cd-free QDs have also [...] Read more.

Quantum dots (QDs) have outstanding optical properties such as strong fluorescence, excellent photostability, broad absorption spectra, and narrow emission bands, which make them useful for bioimaging. However, cadmium (Cd)-based QDs, which have been widely studied, have potential toxicity problems. Cd-free QDs have also been studied, but their weak photoluminescence (PL) intensity makes their practical use in bioimaging challenging. In this study, Cd-free QD nanoprobes for bioimaging were fabricated by densely embedding multiple indium phosphide/zinc sulfide (InP/ZnS) QDs onto silica templates and coating them with a silica shell. The fabricated silica-coated InP/ZnS QD-embedded silica nanoparticles (SiO₂@InP QDs@SiO₂ NPs) exhibited hydrophilic properties because of the surface silica shell. The quantum yield (QY), maximum emission peak wavelength, and full-width half-maximum (FWHM) of the final fabricated SiO₂@InP QDs@SiO₂ NPs were 6.61%, 527.01 nm, and 44.62 nm, respectively. Moreover, the brightness of the particles could be easily controlled by adjusting the amount of InP/ZnS QDs in the SiO₂@InP QDs@SiO₂ NPs. When SiO₂@InP QDs@SiO₂ NPs were administered to tumor syngeneic mice, the fluorescence signal was prominently detected in the tumor because of the preferential distribution of the SiO₂@InP QDs@SiO₂ NPs, demonstrating their applicability in bioimaging with NPs. Thus, SiO₂@InP QDs@SiO₂ NPs have the potential to successfully replace Cd-based QDs as highly bright and biocompatible fluorescent nanoprobes. Full article

(This article belongs to the Special Issue Advanced Optical Materials: From Materials to Applications)

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14 pages, 1163 KiB

Open AccessReview

Dosage Compensation in Drosophila: Its Canonical and Non-Canonical Mechanisms

by Yuri Y. Shevelyov, Sergey V. Ulianov, Mikhail S. Gelfand, Stepan N. Belyakin and Sergey V. Razin

Int. J. Mol. Sci. 2022, 23(18), 10976; https://doi.org/10.3390/ijms231810976 - 19 Sep 2022

Cited by 3 | Viewed by 4135

Abstract

Dosage compensation equalizes gene expression in a single male X chromosome with that in the pairs of autosomes and female X chromosomes. In the fruit fly Drosophila, canonical dosage compensation is implemented by the male-specific lethal (MSL) complex functioning in all male [...] Read more.

Dosage compensation equalizes gene expression in a single male X chromosome with that in the pairs of autosomes and female X chromosomes. In the fruit fly Drosophila, canonical dosage compensation is implemented by the male-specific lethal (MSL) complex functioning in all male somatic cells. This complex contains acetyl transferase males absent on the first (MOF), which performs H4K16 hyperacetylation specifically in the male X chromosome, thus facilitating transcription of the X-linked genes. However, accumulating evidence points to an existence of additional, non-canonical dosage compensation mechanisms operating in somatic and germline cells. In this review, we discuss current advances in the understanding of both canonical and non-canonical mechanisms of dosage compensation in Drosophila. Full article

(This article belongs to the Special Issue Chromatin Organization during Cell Differentiation)

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45 pages, 3335 KiB

Open AccessReview

Recent Advances of Chitosan Formulations in Biomedical Applications

by Mohammed A. S. Abourehab, Sheersha Pramanik, Mohamed A. Abdelgawad, Bassam M. Abualsoud, Ammar Kadi, Mohammad Javed Ansari and A. Deepak

Int. J. Mol. Sci. 2022, 23(18), 10975; https://doi.org/10.3390/ijms231810975 - 19 Sep 2022

Cited by 107 | Viewed by 7833

Abstract

Chitosan, a naturally abundant cationic polymer, is chemically composed of cellulose-based biopolymers derived by deacetylating chitin. It offers several attractive characteristics such as renewability, hydrophilicity, biodegradability, biocompatibility, non-toxicity, and a broad spectrum of antimicrobial activity towards gram-positive and gram-negative bacteria as well as [...] Read more.

Chitosan, a naturally abundant cationic polymer, is chemically composed of cellulose-based biopolymers derived by deacetylating chitin. It offers several attractive characteristics such as renewability, hydrophilicity, biodegradability, biocompatibility, non-toxicity, and a broad spectrum of antimicrobial activity towards gram-positive and gram-negative bacteria as well as fungi, etc., because of which it is receiving immense attention as a biopolymer for a plethora of applications including drug delivery, protective coating materials, food packaging films, wastewater treatment, and so on. Additionally, its structure carries reactive functional groups that enable several reactions and electrochemical interactions at the biomolecular level and improves the chitosan’s physicochemical properties and functionality. This review article highlights the extensive research about the properties, extraction techniques, and recent developments of chitosan-based composites for drug, gene, protein, and vaccine delivery applications. Its versatile applications in tissue engineering and wound healing are also discussed. Finally, the challenges and future perspectives for chitosan in biomedical applications are elucidated. Full article

(This article belongs to the Special Issue Multifunctional Application of Biopolymers and Biomaterials)

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11 pages, 2034 KiB

Open AccessArticle

MicroRNA and Hemostasis Profile of Carotid Atherosclerosis

by Anton A. Raskurazhev, Polina I. Kuznetsova, Alla A. Shabalina and Marine M. Tanashyan

Int. J. Mol. Sci. 2022, 23(18), 10974; https://doi.org/10.3390/ijms231810974 - 19 Sep 2022

Cited by 5 | Viewed by 2292

Abstract

Carotid atherosclerosis (CA) is an important risk factor for ischemic stroke. We described the miRNA and hemostasis profile of patients with moderate and advanced stages of carotid atherosclerosis and elucidated potential correlations with hemostatic activation. A prospective case-control study included 61 patients with [...] Read more.

Carotid atherosclerosis (CA) is an important risk factor for ischemic stroke. We described the miRNA and hemostasis profile of patients with moderate and advanced stages of carotid atherosclerosis and elucidated potential correlations with hemostatic activation. A prospective case-control study included 61 patients with evidence of carotid atherosclerosis (via ultrasound). The study population was divided into groups depending on the degree of carotid artery stenosis: 60% or more (advanced) and <60% (moderate). All patients underwent the following blood tests: general blood test, hemostatic parameters and microRNA. Extraction of microRNA was performed using Leukocyte RNA Purification Kit (NORGEN Biotec Corp., Thorold, ON, Canada); miRNA quantification was performed via RT-PCR. Statistical analysis was performed in R programming language (v. 4.1.0) using RSudio. MicroRNA expression profile was different depending on CA degree. MiR-33a-5p/3p levels were higher in patients with ≥60% carotid stenosis (42.70 and 42.45 versus 38.50 and 38.50, respectively, p < 0.05). Almost complete separation can be visualized with the levels of miR-126-5p: 9.50 in the moderate CA group versus 5.25 in the advanced CA (p < 0.001). MiR-29-5p was higher in the moderate CA group: 28.60 [25.50;33.05] than in advanced CA group: 25.75 [24.38;29.50] (p = 0.086); miR-29-3p was also higher in the moderate CA group: 10.36 [8.60;14.99] than in advanced CA group: 8.46 [7.47;10.3] (p = 0.001). By-group pairwise correlation analyses revealed at least three clusters with significant positive correlations in the moderate CA group: miR-29-3p with factors V and XII (r = 0.53 and r = 0.37, respectively, p < 0.05); miR-21-5p with ADAMTS13, erythrocyte sedimentation rate and D-dimer (r = 0.42, r = 0.36 and r = 0.44, respectively, p < 0.05); stenosis degree with miR-33a-5p/3p and factor VIII levels (r = 0.43 (both) and r = 0.62, respectively, p < 0.05). Hemostasis parameters did not reveal significant changes in CA patients: the only statistically significant differences concerned factor VIII, plasminogen and (marginally significant) ADAMTS-13 and protein C. Down-regulation of miR-126-5p expression has been identified as a promising biomarker of advanced carotid atherosclerosis with high specificity and sensitivity. Correlation cluster analysis showed potential interplay between miRNAs and hemostatic activation in the setting of carotid atherosclerosis. Full article

(This article belongs to the Special Issue Immunopathology of Atherosclerosis and Related Diseases: Focus on Molecular Biology 2.0)

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19 pages, 2539 KiB

Open AccessArticle

Insights into the Mechanism of Pre-mRNA Splicing of Tiny Introns from the Genome of a Giant Ciliate Stentor coeruleus

by Jirayu Nuadthaisong, Tanaporn Phetruen, Chanakan Techawisutthinan and Sittinan Chanarat

Int. J. Mol. Sci. 2022, 23(18), 10973; https://doi.org/10.3390/ijms231810973 - 19 Sep 2022

Cited by 4 | Viewed by 2421

Abstract

Stentor coeruleus is a ciliate known for its regenerative ability. Recent genome sequencing reveals that its spliceosomal introns are exceptionally small. We wondered whether the multimegadalton spliceosome has any unique characteristics for removal of the tiny introns. First, we analyzed intron features and [...] Read more.

Stentor coeruleus is a ciliate known for its regenerative ability. Recent genome sequencing reveals that its spliceosomal introns are exceptionally small. We wondered whether the multimegadalton spliceosome has any unique characteristics for removal of the tiny introns. First, we analyzed intron features and identified spliceosomal RNA/protein components. We found that all snRNAs are present, whereas many proteins are conserved but slightly reduced in size. Some regulators, such as Serine/Arginine-rich proteins, are noticeably undetected. Interestingly, while most parts of spliceosomal proteins, including Prp8′s positively charged catalytic cavity, are conserved, regions of branching factors projecting to the active site are not. We conjecture that steric-clash avoidance between spliceosomal proteins and a sharply looped lariat might occur, and splicing regulation may differ from other species. Full article

(This article belongs to the Section Biochemistry)

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19 pages, 1859 KiB

Open AccessReview

Mesenchymal Stem Cell-Derived Exosomes: A Promising Therapeutic Agent for the Treatment of Liver Diseases

by Yi Ding, Qiulin Luo, Hanyun Que, Nan Wang, Puyang Gong and Jian Gu

Int. J. Mol. Sci. 2022, 23(18), 10972; https://doi.org/10.3390/ijms231810972 - 19 Sep 2022

Cited by 19 | Viewed by 4455

Abstract

Liver disease has become a major global health and economic burden due to its broad spectrum of diseases, multiple causes and difficult treatment. Most liver diseases progress to end-stage liver disease, which has a large amount of matrix deposition that makes it difficult [...] Read more.

Liver disease has become a major global health and economic burden due to its broad spectrum of diseases, multiple causes and difficult treatment. Most liver diseases progress to end-stage liver disease, which has a large amount of matrix deposition that makes it difficult for the liver and hepatocytes to regenerate. Liver transplantation is the only treatment for end-stage liver disease, but the shortage of suitable organs, expensive treatment costs and surgical complications greatly reduce patient survival rates. Therefore, there is an urgent need for an effective treatment modality. Cell-free therapy has become a research hotspot in the field of regenerative medicine. Mesenchymal stem cell (MSC)-derived exosomes have regulatory properties and transport functional “cargo” through physiological barriers to target cells to exert communication and regulatory activities. These exosomes also have little tumorigenic risk. MSC-derived exosomes promote hepatocyte proliferation and repair damaged liver tissue by participating in intercellular communication and regulating signal transduction, which supports their promise as a new strategy for the treatment of liver diseases. This paper reviews the physiological functions of exosomes and highlights the physiological changes and alterations in signaling pathways related to MSC-derived exosomes for the treatment of liver diseases in some relevant clinical studies. We also summarize the advantages of exosomes as drug delivery vehicles and discuss the challenges of exosome treatment of liver diseases in the future. Full article

(This article belongs to the Section Molecular Pathology, Diagnostics, and Therapeutics)

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24 pages, 974 KiB

Open AccessArticle

Proteomic Characterization of Virulence Factors and Related Proteins in Enterococcus Strains from Dairy and Fermented Food Products

by Ana G. Abril, Marcos Quintela-Baluja, Tomás G. Villa, Pilar Calo-Mata, Jorge Barros-Velázquez and Mónica Carrera

Int. J. Mol. Sci. 2022, 23(18), 10971; https://doi.org/10.3390/ijms231810971 - 19 Sep 2022

Cited by 15 | Viewed by 3484

Abstract

Enterococcus species are Gram-positive bacteria that are normal gastrointestinal tract inhabitants that play a beneficial role in the dairy and meat industry. However, Enterococcus species are also the causative agents of health care-associated infections that can be found in dairy and fermented food [...] Read more.

Enterococcus species are Gram-positive bacteria that are normal gastrointestinal tract inhabitants that play a beneficial role in the dairy and meat industry. However, Enterococcus species are also the causative agents of health care-associated infections that can be found in dairy and fermented food products. Enterococcal infections are led by strains of Enterococcus faecalis and Enterococcus faecium, which are often resistant to antibiotics and biofilm formation. Enterococci virulence factors attach to host cells and are also involved in immune evasion. LC-MS/MS-based methods offer several advantages compared with other approaches because one can directly identify microbial peptides without the necessity of inferring conclusions based on other approaches such as genomics tools. The present study describes the use of liquid chromatography–electrospray ionization tandem mass spectrometry (LC–ESI–MS/MS) to perform a global shotgun proteomics characterization for opportunistic pathogenic Enterococcus from different dairy and fermented food products. This method allowed the identification of a total of 1403 nonredundant peptides, representing 1327 proteins. Furthermore, 310 of those peptides corresponded to proteins playing a direct role as virulence factors for Enterococcus pathogenicity. Virulence factors, antibiotic sensitivity, and proper identification of the enterococcal strain are required to propose an effective therapy. Data are available via ProteomeXchange with identifier PXD036435. Label-free quantification (LFQ) demonstrated that the majority of the high-abundance proteins corresponded to E. faecalis species. Therefore, the global proteomic repository obtained here can be the basis for further research into pathogenic Enterococcus species, thus facilitating the development of novel therapeutics. Full article

(This article belongs to the Special Issue Food Safety - Transcriptomics and Proteomics)

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37 pages, 4734 KiB

Open AccessReview

Genetics, Functions, and Clinical Impact of Presenilin-1 (PSEN1) Gene

by Jaya Bagaria, Eva Bagyinszky and Seong Soo A. An

Int. J. Mol. Sci. 2022, 23(18), 10970; https://doi.org/10.3390/ijms231810970 - 19 Sep 2022

Cited by 35 | Viewed by 6998

Abstract

Presenilin-1 (PSEN1) has been verified as an important causative factor for early onset Alzheimer’s disease (EOAD). PSEN1 is a part of γ-secretase, and in addition to amyloid precursor protein (APP) cleavage, it can also affect other processes, such as Notch signaling, β-cadherin processing, [...] Read more.

Presenilin-1 (PSEN1) has been verified as an important causative factor for early onset Alzheimer’s disease (EOAD). PSEN1 is a part of γ-secretase, and in addition to amyloid precursor protein (APP) cleavage, it can also affect other processes, such as Notch signaling, β-cadherin processing, and calcium metabolism. Several motifs and residues have been identified in PSEN1, which may play a significant role in γ-secretase mechanisms, such as the WNF, GxGD, and PALP motifs. More than 300 mutations have been described in PSEN1; however, the clinical phenotypes related to these mutations may be diverse. In addition to classical EOAD, patients with PSEN1 mutations regularly present with atypical phenotypic symptoms, such as spasticity, seizures, and visual impairment. In vivo and in vitro studies were performed to verify the effect of PSEN1 mutations on EOAD. The pathogenic nature of PSEN1 mutations can be categorized according to the ACMG-AMP guidelines; however, some mutations could not be categorized because they were detected only in a single case, and their presence could not be confirmed in family members. Genetic modifiers, therefore, may play a critical role in the age of disease onset and clinical phenotypes of PSEN1 mutations. This review introduces the role of PSEN1 in γ-secretase, the clinical phenotypes related to its mutations, and possible significant residues of the protein. Full article

(This article belongs to the Special Issue Molecular Biomarkers in Neurological Diseases)

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16 pages, 1671 KiB

Open AccessArticle

The Efficacy and Biopharmaceutical Properties of a Fixed-Dose Combination of Disulfiram and Benzyl Benzoate

by Maria Lajarin-Reinares, Elia Martinez-Esteve, Eloy Pena-Rodríguez, Mariona Cañellas-Santos, Sanja Bulut, Kostas Karabelas, Adam Clauss, Carles Nieto, Mireia Mallandrich and Francisco Fernandez-Campos

Int. J. Mol. Sci. 2022, 23(18), 10969; https://doi.org/10.3390/ijms231810969 - 19 Sep 2022

Cited by 6 | Viewed by 4358

Abstract

Scabies and hair lice are parasitic diseases that affect human skin and hair, respectively. The incidence and resistances of these infections are increasing. Tenutex^® (disulfiram and benzyl benzoate emulsion) is an alternative to standard insecticides to avoid resistances. The aim of the [...] Read more.

Scabies and hair lice are parasitic diseases that affect human skin and hair, respectively. The incidence and resistances of these infections are increasing. Tenutex^® (disulfiram and benzyl benzoate emulsion) is an alternative to standard insecticides to avoid resistances. The aim of the work is to evaluate the transdermal absorption and the in vitro efficacy against scabies and hair lice after different exposition times. Dermatomed human skin was used to assess the dermal absorption using a validated High Performance Liquid Chromatography (HPLC) method. HEK001 keratinocytes were used to evaluate the cytotoxicity of benzyl benzoate. Only benzyl benzoate was able to cross the skin, but it did not show cytotoxicity at any of the tested concentrations. The product efficacy was tested on Psoroptes ovis after direct contact and after administration on sheep skin explants at different contact times. Permethrin/malathion-resistant strains of Pediculus humanis capitis adults and eggs were directly exposed to Tenutex, and the vitality and hatchability, respectively, were evaluated. The anti-scabies study demonstrated that exposure for 6 or 24 h completely eradicated the parasite. The pediculicidal activity of Tenutex exhibited superior efficacy than standard treatment on resistant lice. The positive results obtained suggest that Tenutex^® is a good treatment option, especially in drug resistance situations. Full article

(This article belongs to the Special Issue Recent Advances on Small Molecule for Multitarget-Based Treatment of Human Diseases 2.0)

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26 pages, 3187 KiB

Open AccessReview

Correlation between Type I Interferon Associated Factors and COVID-19 Severity

by Dóra Bencze, Tünde Fekete and Kitti Pázmándi

Int. J. Mol. Sci. 2022, 23(18), 10968; https://doi.org/10.3390/ijms231810968 - 19 Sep 2022

Cited by 10 | Viewed by 3402

Abstract

Antiviral type I interferons (IFN) produced in the early phase of viral infections effectively inhibit viral replication, prevent virus-mediated tissue damages and promote innate and adaptive immune responses that are all essential to the successful elimination of viruses. As professional type I IFN [...] Read more.

Antiviral type I interferons (IFN) produced in the early phase of viral infections effectively inhibit viral replication, prevent virus-mediated tissue damages and promote innate and adaptive immune responses that are all essential to the successful elimination of viruses. As professional type I IFN producing cells, plasmacytoid dendritic cells (pDC) have the ability to rapidly produce waste amounts of type I IFNs. Therefore, their low frequency, dysfunction or decreased capacity to produce type I IFNs might increase the risk of severe viral infections. In accordance with that, declined pDC numbers and delayed or inadequate type I IFN responses could be observed in patients with severe coronavirus disease (COVID-19) caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), as compared to individuals with mild or no symptoms. Thus, besides chronic diseases, all those conditions, which negatively affect the antiviral IFN responses lengthen the list of risk factors for severe COVID-19. In the current review, we would like to briefly discuss the role and dysregulation of pDC/type I IFN axis in COVID-19, and introduce those type I IFN-dependent factors, which account for an increased risk of COVID-19 severity and thus are responsible for the different magnitude of individual immune responses to SARS-CoV-2. Full article

(This article belongs to the Section Molecular Pathology, Diagnostics, and Therapeutics)

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20 pages, 4120 KiB

Open AccessArticle

Gene Expression and DNA Methylation in Human Papillomavirus Positive and Negative Head and Neck Squamous Cell Carcinomas

by Snežana Hinić, April Rich, Nicole V. Anayannis, Stephanie Cabarcas-Petroski, Laura Schramm and Patricio I. Meneses

Int. J. Mol. Sci. 2022, 23(18), 10967; https://doi.org/10.3390/ijms231810967 - 19 Sep 2022

Cited by 6 | Viewed by 2466

Abstract

High-risk human papillomaviruses (HPV) are important agents, responsible for a large percentage of the 745,000 cases of head and neck squamous cell carcinomas (HNSCC), which were identified worldwide in 2020. In addition to being virally induced, tobacco and heavy alcohol consumption are believed [...] Read more.

High-risk human papillomaviruses (HPV) are important agents, responsible for a large percentage of the 745,000 cases of head and neck squamous cell carcinomas (HNSCC), which were identified worldwide in 2020. In addition to being virally induced, tobacco and heavy alcohol consumption are believed to cause DNA damage contributing to the high number of HNSCC cases. Gene expression and DNA methylation differ between HNSCC based on HPV status. We used publicly available gene expression and DNA methylation profiles from the Cancer Genome Atlas and compared HPV positive and HPV negative HNSCC groups. We used differential gene expression analysis, differential methylation analysis, and a combination of these two analyses to identify the differences. Differential expression analysis identified 1854 differentially expressed genes, including PCNA, TNFRSF14, TRAF1, TRAF2, BCL2, and BIRC3. SYCP2 was identified as one of the top deregulated genes in the differential methylation analysis and in the combined differential expression and methylation analyses. Additionally, pathway and ontology analyses identified the extracellular matrix and receptor interaction pathway as the most altered between HPV negative and HPV positive HNSCC groups. Combining gene expression and DNA methylation can help in elucidating the genes involved in HPV positive HNSCC tumorigenesis, such as SYCP2 and TAF7L. Full article

(This article belongs to the Special Issue Genetic and Epigenetic Control of Disease Occurrence)

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13 pages, 1652 KiB

Open AccessArticle

New Insights into the Thermal Stability of 1-Butyl-3-methylimidazolium-Based Ionic Liquids

by Artyom V. Belesov, Natalya V. Shkaeva, Mark S. Popov, Tatyana E. Skrebets, Anna V. Faleva, Nikolay V. Ul’yanovskii and Dmitry S. Kosyakov

Int. J. Mol. Sci. 2022, 23(18), 10966; https://doi.org/10.3390/ijms231810966 - 19 Sep 2022

Cited by 7 | Viewed by 2841

Abstract

One of the most promising applications of ionic liquids (ILs) with 1-butyl-3-methylimidazolium (bmim) cation is based on their unique ability to dissolve and fractionate lignocellulosic biomass, allowing for the development of green biorefining technologies. A complete dissolution of lignocellulose requires prolonged treatment at [...] Read more.

One of the most promising applications of ionic liquids (ILs) with 1-butyl-3-methylimidazolium (bmim) cation is based on their unique ability to dissolve and fractionate lignocellulosic biomass, allowing for the development of green biorefining technologies. A complete dissolution of lignocellulose requires prolonged treatment at elevated temperatures, which can cause the partial degradation of ILs. In the present study, a combination of various analytical techniques (GC-MS, HPLC-HRMS, 2D-NMR, synchronous thermal analysis) was used for the comprehensive characterization of bmim acetate, chloride, and methyl sulfate degradation products formed at 150 °C during 6- and 24-h thermal treatment. A number of volatile and non-volatile products, including monomeric and dimeric alkyl substituted imidazoles, alcohols, alkyl amines, methyl and butyl acetates, and N-alkylamides, was identified. By thermal lability, ILs can be arranged in the following sequence, coinciding with the decrease in basicity of the anion: [bmim]OAc > [bmim]Cl > [bmim]MeSO₄. The accumulation of thermal degradation products in ILs, in turn, affects their physico-chemical properties and thermal stability, and leads to a decrease in the decomposition temperature, a change in the shape of the thermogravimetric curves, and the formation of carbon residue during pyrolysis. Full article

(This article belongs to the Special Issue Advances in Ionic Liquids and Their Various Applications)

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24 pages, 2230 KiB

Open AccessReview

Flavones: Six Selected Flavones and Their Related Signaling Pathways That Induce Apoptosis in Cancer

by Se Hyo Jeong, Hun Hwan Kim, Sang Eun Ha, Min Young Park, Pritam Bhagwan Bhosale, Abuyaseer Abusaliya, Kwang Il Park, Jeong Doo Heo, Hyun Wook Kim and Gon Sup Kim

Int. J. Mol. Sci. 2022, 23(18), 10965; https://doi.org/10.3390/ijms231810965 - 19 Sep 2022

Cited by 17 | Viewed by 3572

Abstract

Cancer is a horrific disease that, to date, has no cure. It is caused by various factors and takes many lives. Apoptosis is a programmed cell death mechanism and if it does not function correctly in cancer cells, it can lead to severe [...] Read more.

Cancer is a horrific disease that, to date, has no cure. It is caused by various factors and takes many lives. Apoptosis is a programmed cell death mechanism and if it does not function correctly in cancer cells, it can lead to severe disease. There are various signaling pathways for regulating apoptosis in cancer cells. Flavonoids are non-artificial natural bioactive compounds that are gaining attention as being capable of for inducing apoptosis in cancer cells. Among these, in this study, we focus on flavones. Flavones are a subclass of the numerous available flavonoids and possess several bioactive functions. Some of the most reported and well-known critical flavones, namely apigenin, acacetin, baicalein, luteolin, tangeretin, and wogonin, are discussed in depth in this review. Our main aim is to investigate the effects of the selected flavones on apoptosis and cell signaling pathways that contribute to death due to various types of cancers. Full article

(This article belongs to the Special Issue Therapeutic Effects of Plant Based Bioactive Compounds on Cancer 2.0)

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18 pages, 4065 KiB

Open AccessArticle

BR-Mediated Protein S-Nitrosylation Alleviated Low-Temperature Stress in Mini Chinese Cabbage (Brassica rapa ssp. pekinensis)

by Xueqin Gao, Jizhong Ma, Jianzhong Tie, Yutong Li, Linli Hu and Jihua Yu

Int. J. Mol. Sci. 2022, 23(18), 10964; https://doi.org/10.3390/ijms231810964 - 19 Sep 2022

Cited by 8 | Viewed by 2186

Abstract

Brassinosteroids (BRs), a novel plant hormone, are widely involved in plant growth and stress response processes. Nitric oxide (NO), as an important gas signaling molecule, can regulate target protein activity, subcellular localization and function in response to various stresses through post-translational S-nitrosylation [...] Read more.

Brassinosteroids (BRs), a novel plant hormone, are widely involved in plant growth and stress response processes. Nitric oxide (NO), as an important gas signaling molecule, can regulate target protein activity, subcellular localization and function in response to various stresses through post-translational S-nitrosylation modifications. However, the relationship between BR and NO in alleviating low-temperature stress of mini Chinese cabbage remains unclear. The hydroponic experiment combined with the pharmacological and molecular biological method was conducted to study the alleviating mechanism of BR at low temperature in mini Chinese cabbage. The results showed that low temperature inhibited the growth of mini Chinese cabbage seedlings, as evidenced by dwarf plants and yellow leaves. Treatment with 0.05 mg/L BR and 50 µM NO donor S-nitrosoglutathione (GSNO) significantly increased the leaf area, stem diameter, chlorophyll content, dry and fresh weight and proline content. Meanwhile, the malondialdehyde (MDA) content in 0.05 mg/L BR- and 50 µM GSNO-treated leaves were significantly lower than those in other treated leaves under low-temperature conditions. In addition, BR and GSNO applications induced an increase in NO and S-nitrosothiol (SNO) levels in vivo under low-temperature stress. Similarly, spraying BR after the elimination of NO also increased the level of S-nitrosylation in vivo, while spraying GSNO after inhibiting BR biosynthesis decreased the level of NO and SNO in vivo. In contrast, the S-nitrosoglutathione reductase (BrGSNOR) relative expression level and GSNOR enzyme activity were downregulated and inhibited by BR treatment, GSNO treatment and spraying BR after NO clearance, while the relative expression level of BrGSNOR was upregulated and GSNOR enzyme activity was also increased when spraying GSNO after inhibiting BR synthesis. Meanwhile, the biotin switch assay showed that exogenous BR increased the level of total nitrosylated protein in vivo under low-temperature stress. These results suggested that BR might act as an upstream signal of NO, induced the increase of NO content in vivo and then induced the protein S-nitrosylation modification to alleviate the damage of mini Chinese cabbage seedlings under low-temperature stress. Full article

(This article belongs to the Special Issue Crop Biotic and Abiotic Stress Tolerance 2.0)

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22 pages, 6532 KiB

Open AccessArticle

Spontaneous Transformation of Biomedical Polymeric Silver Salt into a Nanocomposite: Physical–Chemical and Antimicrobial Properties Dramatically Depend on the Initial Preparation State

by Klavdia A. Abzaeva, Boris G. Sukhov, Spartak S. Khutsishvili, Elena B. Tarabukina, Lev E. Zelenkov, Anna V. Nevezhina and Tat’yana V. Fadeeva

Int. J. Mol. Sci. 2022, 23(18), 10963; https://doi.org/10.3390/ijms231810963 - 19 Sep 2022

Viewed by 2690

Abstract

An antimicrobial polyacrylic silver salt (freshly prepared, stored for one year and model-aged) was studied by physical–chemical techniques for nanoparticle detection. In all cases, this salt represents a composite of radical-enriched macromolecules and silver(0) nanoparticles. As time passed, the initial small spherical nanoparticles [...] Read more.

An antimicrobial polyacrylic silver salt (freshly prepared, stored for one year and model-aged) was studied by physical–chemical techniques for nanoparticle detection. In all cases, this salt represents a composite of radical-enriched macromolecules and silver(0) nanoparticles. As time passed, the initial small spherical nanoparticles were converted into larger non-spherical silver nanoparticles. The initial highly water-soluble antimicrobial solid nanocomposite almost loses its solubility in water and cannot be used as an antimicrobial agent. Unlike insoluble solid silver polyacrylate, its freshly prepared aqueous solution retains a liquid-phase consistency after one year as well as pronounced antimicrobial properties. The mechanism of these spontaneous and model-simulated processes was proposed. These results have attracted attention for officinal biomedicinal silver salts as complex radical-enriched nanocomposite substances; they also indicate contrasting effects of silver polymeric salt storing in solid and solution forms that dramatically influence antimicrobial activity. Full article

(This article belongs to the Collection Feature Papers in Materials Science)

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4 pages, 207 KiB

Open AccessEditorial

Angiogenesis in Disease

by Diego La Mendola, Maria Letizia Trincavelli and Claudia Martini

Int. J. Mol. Sci. 2022, 23(18), 10962; https://doi.org/10.3390/ijms231810962 - 19 Sep 2022

Cited by 19 | Viewed by 3475

Abstract

Angiogenesis is a multi-step process by which new blood capillaries are formed starting from preexisting functional vessels [...] Full article

(This article belongs to the Special Issue Angiogenesis in Disease)

12 pages, 1900 KiB

Open AccessArticle

Copper(II) Etioporphyrinate as a Promising Photoluminescent and Electroluminescent Temperature Sensor

by Andrey Yu. Chernyadyev, Alexey E. Aleksandrov, Dmitry A. Lypenko and Aslan Yu. Tsivadze

Int. J. Mol. Sci. 2022, 23(18), 10961; https://doi.org/10.3390/ijms231810961 - 19 Sep 2022

Cited by 6 | Viewed by 1671

Abstract

Luminescent temperature sensors are of great interest because they allow remote determination of temperature in transparent media, such as living tissues, as well as on scattering or transparent surfaces of materials. This study analyzes the luminescent properties of copper(II) etioporphyrinate (Cu-EtioP) in a [...] Read more.

Luminescent temperature sensors are of great interest because they allow remote determination of temperature in transparent media, such as living tissues, as well as on scattering or transparent surfaces of materials. This study analyzes the luminescent properties of copper(II) etioporphyrinate (Cu-EtioP) in a polystyrene film upon variation of temperature from −195 °C to +65 °C in a cryostat. It is shown that the ratio of intensities of phosphorescence transitions in the red spectral region of such a material varies significantly, that is, the material has thermosensory properties. The phosphorescence decay curves of copper(II) etioporphyrinate in a polystyrene film are analyzed. The quantum yield of phosphorescence of copper(II) etioporphyrinate determined by the absolute method was 3.15%. It was also found that the electroluminescence (EL) spectra of copper(II) etioporphyrinate in a poly(9-vinylcarbazole) (PVK) matrix demonstrated a similar change in the spectra in the temperature range −3 °C to +80 °C. That is, copper(II) etioporphyrinate can also be used as a luminescent temperature sensor as part of an active OLED layer. Full article

(This article belongs to the Special Issue Functional Optical Nano/Micromaterials)

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23 pages, 3974 KiB

Open AccessArticle

Estrogen Receptor Subtypes Elicit a Distinct Gene Expression Profile of Endothelial-Derived Factors Implicated in Atherosclerotic Plaque Vulnerability

by Narjes Nasiri-Ansari, Eliana Spilioti, Ioannis Kyrou, Vassiliki Kalotychou, Antonios Chatzigeorgiou, Despina Sanoudou, Karin Dahlman-Wright, Harpal S. Randeva, Athanasios G. Papavassiliou, Paraskevi Moutsatsou and Eva Kassi

Int. J. Mol. Sci. 2022, 23(18), 10960; https://doi.org/10.3390/ijms231810960 - 19 Sep 2022

Cited by 8 | Viewed by 2777

Abstract

In the presence of established atherosclerosis, estrogens are potentially harmful. MMP-2 and MMP-9, their inhibitors (TIMP-2 and TIMP-1), RANK, RANKL, OPG, MCP-1, lysyl oxidase (LOX), PDGF-β, and ADAMTS-4 play critical roles in plaque instability/rupture. We aimed to investigate (i) the effect of estradiol [...] Read more.

In the presence of established atherosclerosis, estrogens are potentially harmful. MMP-2 and MMP-9, their inhibitors (TIMP-2 and TIMP-1), RANK, RANKL, OPG, MCP-1, lysyl oxidase (LOX), PDGF-β, and ADAMTS-4 play critical roles in plaque instability/rupture. We aimed to investigate (i) the effect of estradiol on the expression of the abovementioned molecules in endothelial cells, (ii) which type(s) of estrogen receptors mediate these effects, and (iii) the role of p21 in the estrogen-mediated regulation of the aforementioned factors. Human aortic endothelial cells (HAECs) were cultured with estradiol in the presence or absence of TNF-α. The expression of the aforementioned molecules was assessed by qRT-PCR and ELISA. Zymography was also performed. The experiments were repeated in either ERα- or ERβ-transfected HAECs and after silencing p21. HAECs expressed only the GPR-30 estrogen receptor. Estradiol, at low concentrations, decreased MMP-2 activity by 15-fold, increased LOX expression by 2-fold via GPR-30, and reduced MCP-1 expression by 3.5-fold via ERβ. The overexpression of ERα increased MCP-1 mRNA expression by 2.5-fold. In a low-grade inflammation state, lower concentrations of estradiol induced the mRNA expression of MCP-1 (3.4-fold) and MMP-9 (7.5-fold) and increased the activity of MMP-2 (1.7-fold) via GPR-30. Moreover, p21 silencing resulted in equivocal effects on the expression of the abovementioned molecules. Estradiol induced different effects regarding atherogenic plaque instability through different ERs. The balance of the expression of the various ER subtypes may play an important role in the paradoxical characterization of estrogens as both beneficial and harmful. Full article

(This article belongs to the Special Issue Atherosclerotic and Cardiometabolic Disease: From Molecular Basis to Therapeutic Advances)

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19 pages, 984 KiB

Open AccessReview

From Floral Induction to Blooming: The Molecular Mysteries of Flowering in Woody Plants

by Liyong Sun, Tangjie Nie, Yao Chen and Zengfang Yin

Int. J. Mol. Sci. 2022, 23(18), 10959; https://doi.org/10.3390/ijms231810959 - 19 Sep 2022

Cited by 12 | Viewed by 4636

Abstract

Flowering is a pivotal developmental process in response to the environment and determines the start of a new life cycle in plants. Woody plants usually possess a long juvenile nonflowering phase followed by an adult phase with repeated flowering cycles. The molecular mechanism [...] Read more.

Flowering is a pivotal developmental process in response to the environment and determines the start of a new life cycle in plants. Woody plants usually possess a long juvenile nonflowering phase followed by an adult phase with repeated flowering cycles. The molecular mechanism underlying flowering regulation in woody plants is believed to be much more complex than that in annual herbs. In this review, we briefly describe the successive but distinct flowering processes in perennial trees, namely the vegetative phase change, the floral transition, floral organogenesis, and final blooming, and summarize in detail the most recent advances in understanding how woody plants regulate flowering through dynamic gene expression. Notably, the florigen gene FLOWERING LOCUS T(FT) and its antagonistic gene TERMINAL FLOWER 1 (TFL1) seem to play a central role in various flowering transition events. Flower development in different taxa requires interactions between floral homeotic genes together with AGL6 conferring floral organ identity. Finally, we illustrate the issues and corresponding measures of flowering regulation investigation. It is of great benefit to the future study of flowering in perennial trees. Full article

(This article belongs to the Section Molecular Plant Sciences)

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16 pages, 2354 KiB

Open AccessArticle

Human Milk Oligosaccharide 2′-Fucosyllactose Modulates Local Viral Immune Defense by Supporting the Regulatory Functions of Intestinal Epithelial and Immune Cells

by Veronica Ayechu-Muruzabal, Bente Poelmann, Alinda J. Berends, Nienke Kettelarij, Johan Garssen, Belinda van’t Land and Linette E. M. Willemsen

Int. J. Mol. Sci. 2022, 23(18), 10958; https://doi.org/10.3390/ijms231810958 - 19 Sep 2022

Cited by 5 | Viewed by 2567

Abstract

Human milk contains bioactive components that provide protection against viral infections in early life. In particular, intestinal epithelial cells (IEC) have key regulatory roles in the prevention of enteric viral infections. Here we established an in vitro model to study the modulation of [...] Read more.

Human milk contains bioactive components that provide protection against viral infections in early life. In particular, intestinal epithelial cells (IEC) have key regulatory roles in the prevention of enteric viral infections. Here we established an in vitro model to study the modulation of host responses against enteric viruses mimicked by poly I:C (pIC). The effects of 2′-fucosyllactose (2′FL), abundantly present in human milk, were studied on IEC and/or innate immune cells, and the subsequent functional response of the adaptive immune cells. IEC were pre-incubated with 2′FL and stimulated with naked or Lyovec™-complexed pIC (LV-pIC). Additionally, monocyte-derived dendritic cells (moDC) alone or in co-culture with IEC were stimulated with LV-pIC. Then, conditioned-moDC were co-cultured with naïve CD4⁺ T helper (Th)-cells. IEC stimulation with naked or LV-pIC promoted pro-inflammatory IL-8, CCL20, GROα and CXCL10 cytokine secretion. However, only exposure to LV-pIC additionally induced IFNβ, IFNλ1 and CCL5 secretion. Pre-incubation with 2′FL further increased pIC induced CCL20 secretion and LV-pIC induced CXCL10 secretion. LV-pIC-exposed IEC/moDC and moDC cultures showed increased secretion of IL-8, GROα, IFNλ1 and CXCL10, and in the presence of 2′FL galectin-4 and -9 were increased. The LV-pIC-exposed moDC showed a more pronounced secretion of CCL20, CXCL10 and CCL5. The moDC from IEC/moDC cultures did not drive T-cell development in moDC/T-cell cultures, while moDC directly exposed to LV-pIC secreted Th1 driving IL-12p70 and promoted IFNγ secretion by Th-cells. Hereby, a novel intestinal model was established to study mucosal host-defense upon a viral trigger. IEC may support intestinal homeostasis, regulating local viral defense which may be modulated by 2′FL. These results provide insights regarding the protective capacity of human milk components in early life. Full article

(This article belongs to the Special Issue Immune Modulation of Mucosal Inflammation 2.0)

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15 pages, 703 KiB

Open AccessReview

The Emerging Role of Venetoclax-Based Treatments in Acute Lymphoblastic Leukemia

by Shlomzion Aumann, Adir Shaulov, Arnon Haran, Noa Gross Even-Zohar, Vladimir Vainstein and Boaz Nachmias

Int. J. Mol. Sci. 2022, 23(18), 10957; https://doi.org/10.3390/ijms231810957 - 19 Sep 2022

Cited by 21 | Viewed by 4556

Abstract

Venetoclax, a B-cell lymphoma (BCL-2) inhibitor, in combination with hypomethylating agents has become the new standard of care in elderly and unfit patients with acute myeloid leukemia, with significantly improved overall survival and quality of life. Studies of venetoclax combined with high-dose chemotherapy [...] Read more.

Venetoclax, a B-cell lymphoma (BCL-2) inhibitor, in combination with hypomethylating agents has become the new standard of care in elderly and unfit patients with acute myeloid leukemia, with significantly improved overall survival and quality of life. Studies of venetoclax combined with high-dose chemotherapy are emerging with evidence of higher rates of molecular remission. Recently, a growing number of publications bring forth the use of venetoclax in patients with acute lymphoblastic leukemia (ALL). In the current review, we present the biological rationale of BCL-2 inhibition in ALL, how the interplay of BH3 proteins modulate the response and the current clinical experience with various combinations. Full article

(This article belongs to the Special Issue Cellular and Molecular Mechanisms of Lymphomas and Leukemia)

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13 pages, 2042 KiB

Open AccessArticle

The CFTR Amplifier Nesolicaftor Rescues TGF-β1 Inhibition of Modulator-Corrected F508del CFTR Function

by Charles Bengtson, Neerupma Silswal, Nathalie Baumlin, Makoto Yoshida, John Dennis, Sireesha Yerrathota, Michael Kim and Matthias Salathe

Int. J. Mol. Sci. 2022, 23(18), 10956; https://doi.org/10.3390/ijms231810956 - 19 Sep 2022

Cited by 9 | Viewed by 2445

Abstract

Highly effective cystic fibrosis transmembrane conductance regulator (CFTR) modulators have led to dramatic improvements in lung function in many people with cystic fibrosis (PwCF). However, the efficacy of CFTR modulators may be hindered by persistent airway inflammation. The cytokine transforming growth factor-beta1 (TGF-β1) [...] Read more.

Highly effective cystic fibrosis transmembrane conductance regulator (CFTR) modulators have led to dramatic improvements in lung function in many people with cystic fibrosis (PwCF). However, the efficacy of CFTR modulators may be hindered by persistent airway inflammation. The cytokine transforming growth factor-beta1 (TGF-β1) is associated with worse pulmonary disease in PwCF and can diminish modulator efficacy. Thus, strategies to augment the CFTR response to modulators in an inflammatory environment are needed. Here, we tested whether the CFTR amplifier nesolicaftor (or PTI-428) could rescue the effects of TGF-β1 on CFTR function and ciliary beating in primary human CF bronchial epithelial (CFBE) cells. CFBE cells homozygous for F508del were treated with the combination of elexacaftor/tezacaftor/ivacaftor (ETI) and TGF-β1 in the presence and absence of nesolicaftor. Nesolicaftor augmented the F508del CFTR response to ETI and reversed TGF-β1-induced reductions in CFTR conductance by increasing the expression of CFTR mRNA. Nesolicaftor further rescued the reduced ciliary beating and increased expression of the cytokines IL-6 and IL-8 caused by TGF-β1. Finally, nesolicaftor augmented the F508del CFTR response to ETI in CFBE cells overexpressing miR-145, a negative regulator of CFTR expression. Thus, CFTR amplifiers, but only when used with highly effective modulators, may provide benefit in an inflamed environment. Full article

(This article belongs to the Special Issue Cystic Fibrosis and CFTR Interactions)

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23 pages, 4235 KiB

Open AccessArticle

Semi-Empirical Calculation of Bodipy Aggregate Spectroscopic Properties through Direct Sampling of Configurational Ensembles

by Sergey Usoltsev, Artem Shagurin and Yuriy Marfin

Int. J. Mol. Sci. 2022, 23(18), 10955; https://doi.org/10.3390/ijms231810955 - 19 Sep 2022

Cited by 2 | Viewed by 1894

Abstract

Efficient prediction of the aggregation-induced callback of organic chromophores for utilization in molecular sensorics is a desirable development goal in modern computational chemistry. Dye aggregates are complicated to study when utilizing conventional quantum chemistry approaches, since they are usually composed of too many [...] Read more.

Efficient prediction of the aggregation-induced callback of organic chromophores for utilization in molecular sensorics is a desirable development goal in modern computational chemistry. Dye aggregates are complicated to study when utilizing conventional quantum chemistry approaches, since they are usually composed of too many atoms to be effectively analyzed, even with high-throughput parallel systems. Here, we present a successful attempt to develop a protocol to assess the spectroscopic changes happening in BODIPY dyes upon aggregation from the first principles utilizing extended tight-binding (XTB) and Zerner’s intermediate neglect of differential overlap (ZINDO) Hamiltonians. The developed sampling technique for aggregate configurational space scanning was found to be sufficient to both reproduce peculiarities and justify experimental data on the spectroscopic behavior of chromophore aggregates. The sTDA, sTD-DFT (GFN2-XTB) and CIS (ZINDO) approaches were assessed, and then sources of errors and benefits were outlined. Importantly, our goal was to keep any of the mentioned calculations within a computational cost feasible for a single workstation, whereas scaling was possible at any point in time. Finally, several aggregate structures were investigated in the external field to try to achieve distributions similar to the ones observed in the electrostatic potential of the air–water interface to assess the borderlines of practical applicability of the suggested scheme. Full article

(This article belongs to the Special Issue Feature Papers in Physical Chemistry and Chemical Physics 2022)

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