International Journal of Molecular Sciences

26 pages, 761 KiB

Open AccessReview

Protein Misfolding and Aggregation in the Brain: Common Pathogenetic Pathways in Neurodegenerative and Mental Disorders

by Aleksandra Ochneva, Yana Zorkina, Olga Abramova, Olga Pavlova, Valeriya Ushakova, Anna Morozova, Eugene Zubkov, Konstantin Pavlov, Olga Gurina and Vladimir Chekhonin

Int. J. Mol. Sci. 2022, 23(22), 14498; https://doi.org/10.3390/ijms232214498 - 21 Nov 2022

Cited by 6 | Viewed by 4184

Abstract

Mental disorders represent common brain diseases characterized by substantial impairments of social and cognitive functions. The neurobiological causes and mechanisms of psychopathologies still have not been definitively determined. Various forms of brain proteinopathies, which include a disruption of protein conformations and the formation [...] Read more.

Mental disorders represent common brain diseases characterized by substantial impairments of social and cognitive functions. The neurobiological causes and mechanisms of psychopathologies still have not been definitively determined. Various forms of brain proteinopathies, which include a disruption of protein conformations and the formation of protein aggregates in brain tissues, may be a possible cause behind the development of psychiatric disorders. Proteinopathies are known to be the main cause of neurodegeneration, but much less attention is given to the role of protein impairments in psychiatric disorders’ pathogenesis, such as depression and schizophrenia. For this reason, the aim of this review was to discuss the potential contribution of protein illnesses in the development of psychopathologies. The first part of the review describes the possible mechanisms of disruption to protein folding and aggregation in the cell: endoplasmic reticulum stress, dysfunction of chaperone proteins, altered mitochondrial function, and impaired autophagy processes. The second part of the review addresses the known proteins whose aggregation in brain tissue has been observed in psychiatric disorders (amyloid, tau protein, α-synuclein, DISC-1, disbindin-1, CRMP1, SNAP25, TRIOBP, NPAS3, GluA1, FABP, and ankyrin-G). Full article

(This article belongs to the Special Issue Intersection between Cognitive Impairment and Metabolic Alterations in the Molecular Mechanisms of Neurodegeneration)

► Show Figures

Figure 1

15 pages, 1439 KiB

Open AccessArticle

DFT Study of the Direct Radical Scavenging Potency of Two Natural Catecholic Compounds

by Ana Amić and Denisa Mastiľák Cagardová

Int. J. Mol. Sci. 2022, 23(22), 14497; https://doi.org/10.3390/ijms232214497 - 21 Nov 2022

Cited by 7 | Viewed by 2065

Abstract

To ascertain quercetin’s and rooperol’s potency of H-atom donation to CH₃OO^• and HOO^•, thermodynamics, kinetics and tunnelling, three forms of chemical reaction control, were theoretically examined. In lipid media, H-atom donation from quercetin’s catecholic OH groups via the [...] Read more.

To ascertain quercetin’s and rooperol’s potency of H-atom donation to CH₃OO^• and HOO^•, thermodynamics, kinetics and tunnelling, three forms of chemical reaction control, were theoretically examined. In lipid media, H-atom donation from quercetin’s catecholic OH groups via the proton-coupled electron transfer (PCET) mechanism, is more relevant than from C-ring enolic moiety. Amongst rooperol’s two catecholic moieties, H-atom donation from A-ring OH groups is favored. Allylic hydrogens of rooperol are poorly abstractable via the hydrogen atom transfer (HAT) mechanism. Kinetic analysis including tunnelling enables a more reliable prediction of the H-atom donation potency of quercetin and rooperol, avoiding the pitfalls of a solely thermodynamic approach. Obtained results contradict the increasing number of misleading statements about the high impact of C–H bond breaking on polyphenols’ antioxidant potency. In an aqueous environment at pH = 7.4, the 3-O⁻ phenoxide anion of quercetin and rooperol’s 4′-O⁻ phenoxide anion are preferred sites for CH₃OO^• and HOO^• inactivation via the single electron transfer (SET) mechanism. Full article

(This article belongs to the Special Issue Mechanisms Underlying Antioxidant Potency of Bioactive Compounds)

► Show Figures

Graphical abstract

13 pages, 2812 KiB

Open AccessReview

Soluble PD-L1 as a Prognostic Factor for Immunotherapy Treatment in Solid Tumors: Systematic Review and Meta-Analysis

by Fabio Scirocchi, Lidia Strigari, Alessandra Di Filippo, Chiara Napoletano, Angelica Pace, Hassan Rahimi, Andrea Botticelli, Aurelia Rughetti, Marianna Nuti and Ilaria Grazia Zizzari

Int. J. Mol. Sci. 2022, 23(22), 14496; https://doi.org/10.3390/ijms232214496 - 21 Nov 2022

Cited by 14 | Viewed by 2216

Abstract

Blocking the Programmed Cell Death Protein 1 (PD-1)/programmed death ligand-1 (PD-L1) axis has demonstrated great efficacy in cancer immunotherapy treatment and remains the central modality of immune targeting. To support the rational and tailored use of these drugs, it is important to identify [...] Read more.

Blocking the Programmed Cell Death Protein 1 (PD-1)/programmed death ligand-1 (PD-L1) axis has demonstrated great efficacy in cancer immunotherapy treatment and remains the central modality of immune targeting. To support the rational and tailored use of these drugs, it is important to identify reliable biomarkers related to survival. The role of the soluble form of the PD-L1 (sPD-L1) as a prognostic biomarker related to survival in solid cancer patients treated with immunotherapy has not yet been consistently evaluated. A systematic literature search of original articles in PubMed, MEDLINE and Scopus was conducted. Studies reporting hazard ratios (HRs) with a 95% confidence interval (CI) or Kaplan–Meier curves or individual patient data for overall survival (OS) or progression-free survival (PFS) associated with baseline levels of sPD-L1 in cancer patients undergoing immunotherapy treatment were considered eligible. Twelve studies involving 1076 patients and different tumor types treated with immunotherapy were included in the analysis. High blood levels of sPD-L1 correlated with poorer OS and PFS in cancer patients treated with immunotherapy (HR = 1.49, 95%CI: 1.15, 1.93, p < 0.01, I² = 77% for OS; HR = 1.59, 95%CI: 1.20, 2.12, p < 0.01, I² = 82% for PFS). A subgroup analysis highlighted that high levels of sPD-L1 were associated with worse survival in patients affected by NSCLC (HR = 1.81 95%CI: 1.09–3.00, p = 0.02, I² = 83% for OS; HR = 2.18, 95%CI: 1.27–3.76, p < 0.01, I² = 88% for PFS). An HR > 1 indicated that patients with low levels of sPD-L1 have the highest rates of OS/PFS. In this meta-analysis, we clarified the role of sPD-L1 in different solid cancers treated exclusively with Immune checkpoint inhibitors (ICIs). sPD-L1 could represent a non-invasive biomarker that is easily dosable in the blood of patients. The pooled data from the selected studies showed that a high circulating concentration of sPD-L1 in cancer patients correlates with worse survival, suggesting that it may be a helpful prognostic biomarker for the selection of cancer patients before immunotherapy, thus improving the efficacy of ICIs and avoiding unnecessary treatment. Full article

(This article belongs to the Special Issue Cancer Immunotherapy: Tumor Microenvironment, Biomarker Discovery and Immune Resistance)

► Show Figures

Figure 1

28 pages, 2231 KiB

Open AccessReview

Cosmetic Preservatives: Hazardous Micropollutants in Need of Greater Attention?

by Marta Nowak-Lange, Katarzyna Niedziałkowska and Katarzyna Lisowska

Int. J. Mol. Sci. 2022, 23(22), 14495; https://doi.org/10.3390/ijms232214495 - 21 Nov 2022

Cited by 9 | Viewed by 2974

Abstract

In recent years, personal care products (PCPs) have surfaced as a novel class of pollutants due to their release into wastewater treatment plants (WWTPs) and receiving environments by sewage effluent and biosolid-augmentation soil, which poses potential risks to non-target organisms. Among PCPs, there [...] Read more.

In recent years, personal care products (PCPs) have surfaced as a novel class of pollutants due to their release into wastewater treatment plants (WWTPs) and receiving environments by sewage effluent and biosolid-augmentation soil, which poses potential risks to non-target organisms. Among PCPs, there are preservatives that are added to cosmetics for protection against microbial spoilage. This paper presents a review of the occurrence in different environmental matrices, toxicological effects, and mechanisms of microbial degradation of four selected preservatives (triclocarban, chloroxylenol, methylisothiazolinone, and benzalkonium chloride). Due to the insufficient removal from WWTPs, cosmetic preservatives have been widely detected in aquatic environments and sewage sludge at concentrations mainly below tens of µg L^-1. These compounds are toxic to aquatic organisms, such as fish, algae, daphnids, and rotifers, as well as terrestrial organisms. A summary of the mechanisms of preservative biodegradation by micro-organisms and analysis of emerging intermediates is also provided. Formed metabolites are often characterized by lower toxicity compared to the parent compounds. Further studies are needed for an evaluation of environmental concentrations of preservatives in diverse matrices and toxicity to more species of aquatic and terrestrial organisms, and for an understanding of the mechanisms of microbial degradation. The research should focus on chloroxylenol and methylisothiazolinone because these compounds are the least understood. Full article

(This article belongs to the Section Molecular Toxicology)

► Show Figures

Figure 1

19 pages, 1980 KiB

Open AccessArticle

Probiogenomic In-Silico Analysis and Safety Assessment of Lactiplantibacillus plantarum DJF10 Strain Isolated from Korean Raw Milk

by Sujatha Kandasamy, Jayeon Yoo, Jeonghee Yun, Kil-Ho Lee, Han-Byul Kang, Ji-Eun Kim, Mi-Hwa Oh and Jun-Sang Ham

Int. J. Mol. Sci. 2022, 23(22), 14494; https://doi.org/10.3390/ijms232214494 - 21 Nov 2022

Cited by 10 | Viewed by 2222

Abstract

The whole genome sequence of Lactiplantibacillus plantarum DJF10, isolated from Korean raw milk, is reported, along with its genomic analysis of probiotics and safety features. The genome consists of 29 contigs with a total length of 3,385,113 bp and a GC content of [...] Read more.

The whole genome sequence of Lactiplantibacillus plantarum DJF10, isolated from Korean raw milk, is reported, along with its genomic analysis of probiotics and safety features. The genome consists of 29 contigs with a total length of 3,385,113 bp and a GC content of 44.3%. The average nucleotide identity and whole genome phylogenetic analysis showed the strain belongs to Lactiplantibacillus plantarum with 99% identity. Genome annotation using Prokka predicted a total of 3235 genes, including 3168 protein-coding sequences (CDS), 59 tRNAs, 7 rRNAs and 1 tmRNA. The functional annotation results by EggNOG and KEGG showed a high number of genes associated with genetic information and processing, transport and metabolism, suggesting the strain’s ability to adapt to several environments. Various genes conferring probiotic characteristics, including genes related to stress adaptation to the gastrointestinal tract, biosynthesis of vitamins, cell adhesion and production of bacteriocins, were identified. The CAZyme analysis detected 98 genes distributed under five CAZymes classes. In addition, several genes encoding carbohydrate transport and metabolism were identified. The genome also revealed the presence of insertion sequences, genomic islands, phage regions, CRISPR-cas regions, and the absence of virulence and toxin genes. However, the presence of hemolysin and antibiotic-resistance-related genes detected in the KEGG search needs further experimental validation to confirm the safety of the strain. The presence of two bacteriocin clusters, sactipeptide and plantaricin J, as detected by the BAGEL 4 webserver, confer the higher antimicrobial potential of DJF10. Altogether, the analyses in this study performed highlight this strain’s functional characteristics. However, further in vitro and in vivo studies are required on the safety assurance and potential application of L. plantarum DJF10 as a probiotic agent. Full article

(This article belongs to the Section Molecular Microbiology)

► Show Figures

Figure 1

13 pages, 2732 KiB

Open AccessArticle

MicroRNA Expression Profile in TSC Cell Lines and the Impact of mTOR Inhibitor

by Bartłomiej Pawlik, Szymon Grabia, Urszula Smyczyńska, Wojciech Fendler, Izabela Dróżdż, Ewa Liszewska, Jacek Jaworski, Katarzyna Kotulska, Sergiusz Jóźwiak, Wojciech Młynarski and Joanna Trelińska

Int. J. Mol. Sci. 2022, 23(22), 14493; https://doi.org/10.3390/ijms232214493 - 21 Nov 2022

Viewed by 1680

Abstract

The aim of this study was to assess the potential implication of microRNA on tuberous sclerosis (TSC) pathogenesis by performing microRNA profiling on cell lines silencing TSC1 or TSC2 genes using qPCR panels, before and after incubation with rapamycin. Significant differences in expression [...] Read more.

The aim of this study was to assess the potential implication of microRNA on tuberous sclerosis (TSC) pathogenesis by performing microRNA profiling on cell lines silencing TSC1 or TSC2 genes using qPCR panels, before and after incubation with rapamycin. Significant differences in expression were observed between samples before and after rapamycin treatment in nineteen miRNAs in TSC1, five miRNAs in TSC2 and seven miRNAs in controls. Of miRNAs dysregulated before rapamycin treatment, three normalized after treatment in the TSC1 group (miR-21-3p, miR-433-3p, let-7g-3p) and one normalized in the TSC2 group (miR-1224-3p). Of the miRNAs dysregulated before rapamycin treatment in the TSC1 and TSC2 groups, two did not normalize after treatment (miR-33a-3p, miR-29a-3p). The results of the possible targets indicated that there are four common genes with seed regions susceptible to regulation by those miRNAs: ZBTB20, PHACTR2, PLXNC1 and ATP1B4. Our data show no changes in mRNA expression of these targets after rapamycin treatment. In conclusion, results of our study indicate the involvement of miRNA dysregulation in the pathogenesis of TSC. Some of the miRNA might be used as markers of treatment efficacy and autonomic miRNA as a target for future therapy. Full article

(This article belongs to the Collection Feature Papers in Molecular Genetics and Genomics)

► Show Figures

Figure 1

22 pages, 3267 KiB

Open AccessReview

From Nucleus to Membrane: A Subcellular Map of the N-Acetylation Machinery in Plants

by Marlena Pożoga, Laura Armbruster and Markus Wirtz

Int. J. Mol. Sci. 2022, 23(22), 14492; https://doi.org/10.3390/ijms232214492 - 21 Nov 2022

Cited by 3 | Viewed by 2240

Abstract

N-terminal acetylation (NTA) is an ancient protein modification conserved throughout all domains of life. N-terminally acetylated proteins are present in the cytosol, the nucleus, the plastids, mitochondria and the plasma membrane of plants. The frequency of NTA differs greatly between these subcellular compartments. [...] Read more.

N-terminal acetylation (NTA) is an ancient protein modification conserved throughout all domains of life. N-terminally acetylated proteins are present in the cytosol, the nucleus, the plastids, mitochondria and the plasma membrane of plants. The frequency of NTA differs greatly between these subcellular compartments. While up to 80% of cytosolic and 20–30% of plastidic proteins are subject to NTA, NTA of mitochondrial proteins is rare. NTA alters key characteristics of proteins such as their three-dimensional structure, binding properties and lifetime. Since the majority of proteins is acetylated by five ribosome-bound N-terminal acetyltransferases (Nats) in yeast and humans, NTA was long perceived as an exclusively co-translational process in eukaryotes. The recent characterization of post-translationally acting plant Nats, which localize to the plasma membrane and the plastids, has challenged this view. Moreover, findings in humans, yeast, green algae and higher plants uncover differences in the cytosolic Nat machinery of photosynthetic and non-photosynthetic eukaryotes. These distinctive features of the plant Nat machinery might constitute adaptations to the sessile lifestyle of plants. This review sheds light on the unique role of plant N-acetyltransferases in development and stress responses as well as their evolution-driven adaptation to function in different cellular compartments. Full article

(This article belongs to the Special Issue Modifications of Protein Termini 2.0)

► Show Figures

Figure 1

17 pages, 5356 KiB

Open AccessArticle

Modeling RTT Syndrome by iPSC-Derived Neurons from Male and Female Patients with Heterogeneously Severe Hot-Spot MECP2 Variants

by Sara Perego, Valentina Alari, Gianluca Pietra, Andrea Lamperti, Alessandro Vimercati, Nicole Camporeale, Maria Garzo, Francesca Cogliati, Donatella Milani, Aglaia Vignoli, Angela Peron, Lidia Larizza, Tommaso Pizzorusso and Silvia Russo

Int. J. Mol. Sci. 2022, 23(22), 14491; https://doi.org/10.3390/ijms232214491 - 21 Nov 2022

Cited by 4 | Viewed by 1826

Abstract

Rett syndrome caused by MECP2 variants is characterized by a heterogenous clinical spectrum accounted for in 60% of cases by hot-spot variants. Focusing on the most frequent variants, we generated in vitro iPSC-neurons from the blood of RTT girls with p.Arg133Cys and p.Arg255*, [...] Read more.

Rett syndrome caused by MECP2 variants is characterized by a heterogenous clinical spectrum accounted for in 60% of cases by hot-spot variants. Focusing on the most frequent variants, we generated in vitro iPSC-neurons from the blood of RTT girls with p.Arg133Cys and p.Arg255*, associated to mild and severe phenotype, respectively, and of an RTT male harboring the close to p.Arg255*, p.Gly252Argfs*7 variant. Truncated MeCP2 proteins were revealed by Western blot and immunofluorescence analysis. We compared the mutant versus control neurons at 42 days for morphological parameters and at 120 days for electrophysiology recordings, including girls’ isogenic clones. A precocious reduced morphological complexity was evident in neurons with truncating variants, while in p.Arg133Cys neurons any significant differences were observed in comparison with the isogenic wild-type clones. Reduced nuclear size and branch number show up as the most robust biomarkers. Patch clamp recordings on mature neurons allowed the assessment of cell biophysical properties, V-gated currents, and spiking pattern in the mutant and control cells. Immature spiking, altered cell capacitance, and membrane resistance of RTT neurons, were particularly pronounced in the Arg255* and Gly252Argfs*7 mutants. The overall results indicate that the specific markers of in vitro cellular phenotype mirror the clinical severity and may be amenable to drug testing for translational purposes. Full article

(This article belongs to the Special Issue Rare Diseases—Molecular Mechanisms and Therapeutic Strategies (IV))

► Show Figures

Figure 1

19 pages, 2341 KiB

Open AccessArticle

Immunological Roles of TmToll-2 in Response to Escherichia coli Systemic Infection in Tenebrio molitor

by Maryam Ali Mohammadie Kojour, Ho Am Jang, Yong Seok Lee, Yong Hun Jo and Yeon Soo Han

Int. J. Mol. Sci. 2022, 23(22), 14490; https://doi.org/10.3390/ijms232214490 - 21 Nov 2022

Cited by 5 | Viewed by 1358

Abstract

The antimicrobial roles of Toll-like receptors have been mainly identified in mammalian models and Drosophila. However, its immunological function in other insects has yet to be fully clarified. Here, we determined the innate immune response involvement of TmToll-2 encountering Gram-negative, Gram-positive, and [...] Read more.

The antimicrobial roles of Toll-like receptors have been mainly identified in mammalian models and Drosophila. However, its immunological function in other insects has yet to be fully clarified. Here, we determined the innate immune response involvement of TmToll-2 encountering Gram-negative, Gram-positive, and fungal infection. Our data revealed that TmToll-2 expression could be induced by Escherichia coli, Staphylococcus aureus, and Candida albicans infections in the fat bodies, gut, Malpighian tubules, and hemolymph of Tenebrio molitor young larvae. However, TmToll-2 silencing via RNAi technology revealed that sole E. coli systemic infection caused mortality in the double-strand RNA TmToll-2-injected group compared with that in the control group. Further investigation indicated that in the absence of TmToll-2, the final effector of Toll signaling pathway, antimicrobial peptide (AMP) genes and relevant transcription factors were significantly downregulated, mainly E. coli post-insult. We showed that the expression of all AMP genes was suppressed in the main immune organ of insects, namely, fat bodies, in silenced individuals, while the relevant expressions were not affected after fungal infection. Thus, our research revealed the immunological roles of TmToll-2 in different organs of T. molitor in response to pathogenic insults. Full article

(This article belongs to the Section Molecular Biology)

► Show Figures

Figure 1

17 pages, 2466 KiB

Open AccessArticle

Essential Hypertension and Oxidative Stress: Novel Future Perspectives

by Caterina Franco, Edoardo Sciatti, Gaia Favero, Francesca Bonomini, Enrico Vizzardi and Rita Rezzani

Int. J. Mol. Sci. 2022, 23(22), 14489; https://doi.org/10.3390/ijms232214489 - 21 Nov 2022

Cited by 20 | Viewed by 4525

Abstract

Among cardiovascular diseases, hypertension is one of the main risk factors predisposing to fatal complications. Oxidative stress and chronic inflammation have been identified as potentially responsible for the development of endothelial damage and vascular stiffness, two of the primum movens of hypertension and [...] Read more.

Among cardiovascular diseases, hypertension is one of the main risk factors predisposing to fatal complications. Oxidative stress and chronic inflammation have been identified as potentially responsible for the development of endothelial damage and vascular stiffness, two of the primum movens of hypertension and cardiovascular diseases. Based on these data, we conducted an open-label randomized study, first, to evaluate the endothelial damage and vascular stiffness in hypertense patients; second, to test the effect of supplementation with a physiological antioxidant (melatonin 1 mg/day for 1 year) in patients with essential hypertension vs. hypertensive controls. Twenty-three patients of either gender were enrolled and randomized 1:1 in two groups (control and supplemented group). The plasmatic total antioxidant capacity (as a marker of oxidative stress), blood pressure, arterial stiffness, and peripheral endothelial function were evaluated at the beginning of the study and after 1 year in both groups. Our results showed that arterial stiffness improved significantly (p = 0.022) in supplemented patients. The endothelial function increased too, even if not significantly (p = 0.688), after 1 year of melatonin administration. Moreover, the supplemented group showed a significative reduction in TAC levels (p = 0.041) correlated with the improvement of arterial stiffness. These data suggest that melatonin may play an important role in reducing the serum levels of TAC and, consequently, in improving arterial stiffness. Full article

(This article belongs to the Special Issue Melatonin in Disease and Health 2.0)

► Show Figures

Graphical abstract

16 pages, 10643 KiB

Open AccessArticle

DNA Sequence-Dependent Properties of Nucleosome Positioning in Regions of Distinct Chromatin States in Mouse Embryonic Stem Cells

by Guoqing Liu, Zhi Zhang, Biyu Dong and Jia Liu

Int. J. Mol. Sci. 2022, 23(22), 14488; https://doi.org/10.3390/ijms232214488 - 21 Nov 2022

Viewed by 1387

Abstract

Chromatin architecture is orchestrated, and plays crucial roles during the developmental process by regulating gene expression. In embryonic stem cells (ESCs), three types of chromatin states, including active, repressive and poised states, were previously identified and characterized with specific chromatin modification marks and [...] Read more.

Chromatin architecture is orchestrated, and plays crucial roles during the developmental process by regulating gene expression. In embryonic stem cells (ESCs), three types of chromatin states, including active, repressive and poised states, were previously identified and characterized with specific chromatin modification marks and different transcription activity, but it is largely unknown how nucleosomes are organized in these chromatin states. In this study, by using a DNA deformation energy model, we investigated the sequence-dependent nucleosome organization within the chromatin states in mouse ESCs. The results revealed that: (1) compared with poised genes, active genes are characterized with a higher level of nucleosome occupancy around their transcription start sites (TSS) and transcription termination sites (TTS), and both types of genes do not have a nucleosome-depleted region at their TTS, contrasting with the MNase-seq based result; (2) based on our previous DNA bending energy model, we developed an improved model capable of predicting both rotational positioning and nucleosome occupancy determined by a chemical mapping approach; (3) DNA bending-energy-based analyses demonstrated that the fragile nucleosomes positioned at both gene ends could be explained largely by enhanced rotational positioning signals encoded in DNA, but nucleosome phasing around the TSS of active genes was not determined by sequence preference; (4) the nucleosome occupancy landscape around the binding sites of some developmentally important transcription factors known to bind with different chromatin contexts, was also successfully predicted; (5) the difference of nucleosome occupancy around the TSS between CpG-rich and CpG-poor promoters was partly captured by our sequence-dependent model. Taken together, by developing an improved deformation-energy-based model, we revealed some sequence-dependent properties of the nucleosome arrangements in regions of distinct chromatin states in mouse ESCs. Full article

(This article belongs to the Special Issue Positioning of Nucleosomes 2.0)

► Show Figures

Figure 1

23 pages, 3682 KiB

Open AccessArticle

Hispolon Cyclodextrin Complexes and Their Inclusion in Liposomes for Enhanced Delivery in Melanoma Cell Lines

by Ishwor Poudel, Manjusha Annaji, Fajar Setyo Wibowo, Robert D. Arnold, Oladiran Fasina, Brian Via, Vijaya Rangari, Maria Soledad Peresin, Forrest Smith, Muralikrishnan Dhanasekaran, Amit K. Tiwari and R. Jayachandra Babu

Int. J. Mol. Sci. 2022, 23(22), 14487; https://doi.org/10.3390/ijms232214487 - 21 Nov 2022

Cited by 3 | Viewed by 1737

Abstract

Hispolon, a phenolic pigment isolated from the mushroom species Phellinus linteus, has been investigated for anti-inflammatory, antioxidant, and anticancer properties; however, low solubility and poor bioavailability have limited its potential clinical translation. In this study, the inclusion complex of hispolon with Sulfobutylether-β-cyclodextrin [...] Read more.

Hispolon, a phenolic pigment isolated from the mushroom species Phellinus linteus, has been investigated for anti-inflammatory, antioxidant, and anticancer properties; however, low solubility and poor bioavailability have limited its potential clinical translation. In this study, the inclusion complex of hispolon with Sulfobutylether-β-cyclodextrin (SBEβCD) was characterized, and the Hispolon-SBEβCD Complex (HSC) was included within the sterically stabilized liposomes (SL) to further investigate its anticancer activity against melanoma cell lines. The HSC-trapped-Liposome (HSC-SL) formulation was investigated for its sustained drug delivery and enhanced cytotoxicity. The inclusion complex in the solid=state was confirmed by a Job’s plot analysis, molecular modeling, differential scanning calorimetry (DSC), Fourier transform infrared spectroscopy (FTIR), Proton nuclear magnetic resonance (NMR) spectroscopy, and scanning electron microscopy (SEM). The HSC-SL showed no appreciable deviation in size (<150 nm) and polydispersity index (<0.2) and improved drug encapsulation efficiency (>90%) as compared to control hispolon liposomes. Individually incorporated hispolon and SBEβCD in the liposomes (H-CD-SL) was not significant in loading the drug in the liposomes, compared to HSC-SL, as a substantial amount of free drug was separated during dialysis. The HSC-SL formulation showed a sustained release compared to hispolon liposomes (H-SLs) and Hispolon-SBEβCD liposomes (H-CD-SLs). The anticancer activity on melanoma cell lines (B16BL6) of HSC and HSC-SL was higher than in H-CD-SL and hispolon solution. These findings suggest that HSC inclusion in the HSC-SL liposomes stands out as a potential formulation approach for enhancing drug loading, encapsulation, and chemotherapeutic efficiency of hispolon and similar water insoluble drug molecules. Full article

(This article belongs to the Special Issue Application Progress of Liposomes in Drug Development 2.0)

► Show Figures

Graphical abstract

3 pages, 191 KiB

Open AccessEditorial

Nanostrategies: The Future Medicine for Fighting Cancer Progression and Drug Resistance 2.0

by Giovanni Luca Beretta

Int. J. Mol. Sci. 2022, 23(22), 14486; https://doi.org/10.3390/ijms232214486 - 21 Nov 2022

Viewed by 1090

Abstract

The attractiveness of the nanomaterials research field has persisted [...] Full article

(This article belongs to the Special Issue Nano-Strategies: The Future Medicine for Fighting Cancer Progression and Drug Resistance 2.0)

12 pages, 2572 KiB

Open AccessArticle

Nitrogen-Doped Bismuth Nanosheet as an Efficient Electrocatalyst to CO₂ Reduction for Production of Formate

by Sanxiu Li, Yufei Kang, Chenyang Mo, Yage Peng, Haijun Ma and Juan Peng

Int. J. Mol. Sci. 2022, 23(22), 14485; https://doi.org/10.3390/ijms232214485 - 21 Nov 2022

Cited by 5 | Viewed by 1879

Abstract

Electrochemical CO₂ reduction (CO₂RR) to produce high value-added chemicals or fuels is a promising technology to address the greenhouse effect and energy challenges. Formate is a desirable product of CO₂RR with great economic value. Here, nitrogen-doped bismuth nanosheets [...] Read more.

Electrochemical CO₂ reduction (CO₂RR) to produce high value-added chemicals or fuels is a promising technology to address the greenhouse effect and energy challenges. Formate is a desirable product of CO₂RR with great economic value. Here, nitrogen-doped bismuth nanosheets (N-BiNSs) were prepared by a facile one-step method. The N-BiNSs were used as efficient electrocatalysts for CO₂RR with selective formate production. The N-BiNSs exhibited a high formate Faradic efficiency (FE_formate) of 95.25% at −0.95 V (vs. RHE) with a stable current density of 33.63 mA cm⁻² in 0.5 M KHCO₃. Moreover, the N-BiNSs for CO₂RR yielded a large current density (300 mA cm⁻²) for formate production in a flow-cell measurement, achieving the commercial requirement. The FE_formate of 90% can maintain stability for 14 h of electrolysis. Nitrogen doping could induce charge transfer from the N atom to the Bi atom, thus modulating the electronic structure of N-Bi nanosheets. DFT results demonstrated the N-BiNSs reduced the adsorption energy of the *OCHO intermediate and promoted the mass transfer of charges, thereby improving the CO₂RR with high FE_formate. This study provides a valuable strategy to enhance the catalytic performance of bismuth-based catalysts for CO₂RR by using a nitrogen-doping strategy. Full article

(This article belongs to the Special Issue Molecular Aspects in Catalytic Materials for Pollution Elimination and Green Chemistry)

► Show Figures

Figure 1

27 pages, 8564 KiB

Open AccessArticle

Genome-Scale Investigation of GARP Family Genes Reveals Their Pivotal Roles in Nutrient Stress Resistance in Allotetraploid Rapeseed

by Ying-Peng Hua, Peng-Jia Wu, Tian-Yu Zhang, Hai-Li Song, Yi-Fan Zhang, Jun-Fan Chen, Cai-Peng Yue, Jin-Yong Huang, Tao Sun and Ting Zhou

Int. J. Mol. Sci. 2022, 23(22), 14484; https://doi.org/10.3390/ijms232214484 - 21 Nov 2022

Cited by 3 | Viewed by 1681

Abstract

The GARP genes are plant-specific transcription factors (TFs) and play key roles in regulating plant development and abiotic stress resistance. However, few systematic analyses of GARPs have been reported in allotetraploid rapeseed (Brassica napus L.) yet. In the present study, a total [...] Read more.

The GARP genes are plant-specific transcription factors (TFs) and play key roles in regulating plant development and abiotic stress resistance. However, few systematic analyses of GARPs have been reported in allotetraploid rapeseed (Brassica napus L.) yet. In the present study, a total of 146 BnaGARP members were identified from the rapeseed genome based on the sequence signature. The BnaGARP TFs were divided into five subfamilies: ARR, GLK, NIGT1/HRS1/HHO, KAN, and PHL subfamilies, and the members within the same subfamilies shared similar exon-intron structures and conserved motif configuration. Analyses of the Ka/Ks ratios indicated that the GARP family principally underwent purifying selection. Several cis-acting regulatory elements, essential for plant growth and diverse biotic and abiotic stresses, were identified in the promoter regions of BnaGARPs. Further, 29 putative miRNAs were identified to be targeting BnaGARPs. Differential expression of BnaGARPs under low nitrate, ammonium toxicity, limited phosphate, deficient boron, salt stress, and cadmium toxicity conditions indicated their potential involvement in diverse nutrient stress responses. Notably, BnaA9.HHO1 and BnaA1.HHO5 were simultaneously transcriptionally responsive to these nutrient stresses in both hoots and roots, which indicated that BnaA9.HHO1 and BnaA1.HHO5 might play a core role in regulating rapeseed resistance to nutrient stresses. Therefore, this study would enrich our understanding of molecular characteristics of the rapeseed GARPs and will provide valuable candidate genes for further in-depth study of the GARP-mediated nutrient stress resistance in rapeseed. Full article

(This article belongs to the Special Issue Alternative Splicing: From Abiotic Stress Tolerance to Evolutionary Genomics)

► Show Figures

Figure 1

20 pages, 2876 KiB

Open AccessArticle

New TMA (4,6,4′-Trimethyl angelicin) Analogues as Anti-Inflammatory Agents in the Treatment of Cystic Fibrosis Lung Disease

by Chiara Tupini, Adriana Chilin, Alice Rossi, Ida De Fino, Alessandra Bragonzi, Elisabetta D’Aversa, Lucia Carmela Cosenza, Christian Vaccarin, Gianni Sacchetti, Monica Borgatti, Anna Tamanini, Maria Cristina Dechecchi, Francesca Sanvito, Roberto Gambari, Giulio Cabrini and Ilaria Lampronti

Int. J. Mol. Sci. 2022, 23(22), 14483; https://doi.org/10.3390/ijms232214483 - 21 Nov 2022

Cited by 2 | Viewed by 1622

Abstract

A series of new-generation TMA (4,6,4′-trimethyl angelicin) analogues was projected and synthetized in order to ameliorate anti-inflammatory activity, with reduced or absent toxicity. Since the NF-κB transcription factor (TF) plays a critical role in the expression of IL-8 (Interluekin 8), a typical marker [...] Read more.

A series of new-generation TMA (4,6,4′-trimethyl angelicin) analogues was projected and synthetized in order to ameliorate anti-inflammatory activity, with reduced or absent toxicity. Since the NF-κB transcription factor (TF) plays a critical role in the expression of IL-8 (Interluekin 8), a typical marker of lung inflammation in Cystic Fibrosis (CF), the use of agents able to interfere with the NF-κB pathway represents an interesting therapeutic strategy. Through preliminary EMSA experiments, we identified several new TMA derivatives able to inhibit the NF-κB/DNA complex. The selected active molecules were then analyzed to evaluate the anti-inflammatory effect using both Pseudomonas aeruginosa (PAO1) infection and TNF-alpha stimulus on the CF IB3-1 cell line. It was demonstrated that mainly two TMA analogues, GY971a mesylate salt (6-p-minophenyl-4,4′-dimethyl-angelicin) and GY964 (4-phenyl-6,4′-dimethyl-angelicin), were able to decrease the IL-8 gene expression. At the same time, these molecules were found to have no pro-apoptotic, mutagenic and phototoxic effects, facilitating our decision to test the efficacy in vivo by using a mouse model of acute P. aeruginosa lung infection. The anti-inflammatory effect of GY971a was confirmed in vivo; this derivative was able to deeply decrease the total number of inflammatory cells, the neutrophil count and the cytokine/chemokine profile in the P. aeruginosa acute infection model, without evident toxicity. Considering all the obtained and reported in vitro and in vivo pre-clinical results, GY971a seems to have interesting anti-inflammatory effects, modulating the NF-κB pathway, as well as the starting lead compound TMA, but without side effects. Full article

(This article belongs to the Special Issue Rare Monogenic Diseases: Molecular Pathophysiology and Novel Therapies 2.0)

► Show Figures

Figure 1

15 pages, 2597 KiB

Open AccessArticle

Characterization of Mitochondrial Alterations in Aicardi–Goutières Patients Mutated in RNASEH2A and RNASEH2B Genes

by Francesca Dragoni, Jessica Garau, Daisy Sproviero, Simona Orcesi, Costanza Varesio, Silvia De Siervi, Stella Gagliardi, Cristina Cereda and Orietta Pansarasa

Int. J. Mol. Sci. 2022, 23(22), 14482; https://doi.org/10.3390/ijms232214482 - 21 Nov 2022

Cited by 4 | Viewed by 1680

Abstract

Aicardi–Goutières syndrome (AGS) is a rare encephalopathy characterized by neurological and immunological features. Mitochondrial dysfunctions may lead to mitochondrial DNA (mtDNA) release and consequent immune system activation. We investigated the role of mitochondria and mtDNA in AGS pathogenesis by studying patients mutated in [...] Read more.

Aicardi–Goutières syndrome (AGS) is a rare encephalopathy characterized by neurological and immunological features. Mitochondrial dysfunctions may lead to mitochondrial DNA (mtDNA) release and consequent immune system activation. We investigated the role of mitochondria and mtDNA in AGS pathogenesis by studying patients mutated in RNASEH2B and RNASEH2A genes. Lymphoblastoid cell lines (LCLs) from RNASEH2A- and RNASEH2B-mutated patients and healthy control were used. Transmission Electron Microscopy (TEM) and flow cytometry were used to assess morphological alterations, reactive oxygen species (ROS) production and mitochondrial membrane potential variations. Seahorse Analyzer was used to investigate metabolic alterations, and mtDNA oxidation and VDAC1 oligomerization were assessed by immunofluorescence. Western blot and RT-qPCR were used to quantify mtTFA protein and mtDNA release. Morphological alterations of mitochondria were observed in both mutated LCLs, and loss of physiological membrane potential was mainly identified in RNASEH2A LCLs. ROS production and 8-oxoGuanine levels were increased in RNASEH2B LCLs. Additionally, the VDAC1 signal was increased, suggesting a mitochondrial pore formation possibly determining mtDNA release. Indeed, higher cytoplasmic mtDNA levels were found in RNASEH2B LCLs. Metabolic alterations confirmed mitochondrial damage in both LCLs. Data highlighted mitochondrial alterations in AGS patients’ LCLs suggesting a pivotal role in AGS pathogenesis. Full article

(This article belongs to the Special Issue Biomarkers in Rare Diseases 3.0)

► Show Figures

Figure 1

19 pages, 2918 KiB

Open AccessArticle

Utility of a Molecular Signature for Predicting Recurrence and Progression in Non-Muscle-Invasive Bladder Cancer Patients: Comparison with the EORTC, CUETO and 2021 EAU Risk Groups

by Xuan-Mei Piao, Seon-Kyu Kim, Young Joon Byun, Chuang-Ming Zheng, Ho Won Kang, Won Tae Kim, Yong-June Kim, Sang-Cheol Lee, Wun-Jae Kim, Sung-Kwon Moon, Yung Hyun Choi and Seok Joong Yun

Int. J. Mol. Sci. 2022, 23(22), 14481; https://doi.org/10.3390/ijms232214481 - 21 Nov 2022

Cited by 2 | Viewed by 1485

Abstract

To evaluate the utility of different risk assessments in non-muscle-invasive bladder cancer (NMIBC) patients, a total of 178 NMIBC patients from Chungbuk National University Hospital (CBNUH) were enrolled, and the predictive value of the molecular signature-based subtype predictor (MSP888) and risk calculators based [...] Read more.

To evaluate the utility of different risk assessments in non-muscle-invasive bladder cancer (NMIBC) patients, a total of 178 NMIBC patients from Chungbuk National University Hospital (CBNUH) were enrolled, and the predictive value of the molecular signature-based subtype predictor (MSP888) and risk calculators based on clinicopathological factors (EORTC, CUETO and 2021 EAU risk scores) was compared. Of the 178 patients, 49 were newly analyzed by the RNA-sequencing, and their MSP888 subtype was evaluated. The ability of the EORTC, MSP888 and two molecular subtyping systems of bladder cancer (Lund and UROMOL subtypes) to predict progression of 460 NMIBC patients from the UROMOL project was assessed. Cox regression analyses showed that the MSP888 was an independent predictor of NMIBC progression in the CBNUH cohort (p = 0.043). Particularly in patients without an intravesical BCG immunotherapy, MSP888 significantly linked with risk of disease recurrence and progression (both p < 0.05). However, the EORTC, CUETO and 2021 EAU risk scores showed disappointing results with respect to estimating the NMIBC prognosis. In the UROMOL cohort, the MSP888, Lund and UROMOL subtypes demonstrated a similar capacity to predict NMIBC progression (all p < 0.05). Conclusively, the MSP888 is favorable for stratifying patients to facilitate optimal treatment. Full article

(This article belongs to the Section Molecular Oncology)

► Show Figures

Figure 1

29 pages, 7374 KiB

Open AccessReview

The Four Homeostasis Knights: In Balance upon Post-Translational Modifications

by Stefania Pieroni, Marilena Castelli, Danilo Piobbico, Simona Ferracchiato, Damiano Scopetti, Nicola Di-Iacovo, Maria Agnese Della-Fazia and Giuseppe Servillo

Int. J. Mol. Sci. 2022, 23(22), 14480; https://doi.org/10.3390/ijms232214480 - 21 Nov 2022

Cited by 1 | Viewed by 1849

Abstract

A cancer outcome is a multifactorial event that comes from both exogenous injuries and an endogenous predisposing background. The healthy state is guaranteed by the fine-tuning of genes controlling cell proliferation, differentiation, and development, whose alteration induces cellular behavioral changes finally leading to [...] Read more.

A cancer outcome is a multifactorial event that comes from both exogenous injuries and an endogenous predisposing background. The healthy state is guaranteed by the fine-tuning of genes controlling cell proliferation, differentiation, and development, whose alteration induces cellular behavioral changes finally leading to cancer. The function of proteins in cells and tissues is controlled at both the transcriptional and translational level, and the mechanism allowing them to carry out their functions is not only a matter of level. A major challenge to the cell is to guarantee that proteins are made, folded, assembled and delivered to function properly, like and even more than other proteins when referring to oncogenes and onco-suppressors products. Over genetic, epigenetic, transcriptional, and translational control, protein synthesis depends on additional steps of regulation. Post-translational modifications are reversible and dynamic processes that allow the cell to rapidly modulate protein amounts and function. Among them, ubiquitination and ubiquitin-like modifications modulate the stability and control the activity of most of the proteins that manage cell cycle, immune responses, apoptosis, and senescence. The crosstalk between ubiquitination and ubiquitin-like modifications and post-translational modifications is a keystone to quickly update the activation state of many proteins responsible for the orchestration of cell metabolism. In this light, the correct activity of post-translational machinery is essential to prevent the development of cancer. Here we summarize the main post-translational modifications engaged in controlling the activity of the principal oncogenes and tumor suppressors genes involved in the development of most human cancers. Full article

(This article belongs to the Special Issue Ubiquitin and Ubiquitin-Like Molecules in Cancer)

► Show Figures

Figure 1

15 pages, 1851 KiB

Open AccessCommunication

Salivary microRNA and Metabolic Profiles in a Mouse Model of Subchronic and Mild Social Defeat Stress

by Yuta Yoshida, Yuhei Yajima, Kina Kawakami, Shin-ichi Nakamura, Takamitsu Tsukahara, Katsutaka Oishi and Atsushi Toyoda

Int. J. Mol. Sci. 2022, 23(22), 14479; https://doi.org/10.3390/ijms232214479 - 21 Nov 2022

Cited by 2 | Viewed by 2566

Abstract

Identification of early biomarkers of stress is important for preventing mood and anxiety disorders. Saliva is an easy-to-collect and non-invasive diagnostic target. The aim of this study was to characterize the changes in salivary whole microRNAs (miRNAs) and metabolites in mice subjected to [...] Read more.

Identification of early biomarkers of stress is important for preventing mood and anxiety disorders. Saliva is an easy-to-collect and non-invasive diagnostic target. The aim of this study was to characterize the changes in salivary whole microRNAs (miRNAs) and metabolites in mice subjected to subchronic and mild social defeat stress (sCSDS). In this study, we identified seven upregulated and one downregulated miRNAs/PIWI-interacting RNA (piRNA) in the saliva of sCSDS mice. One of them, miR-208b-3p, which is reported as a reliable marker for myocardial infarction, was upregulated in the saliva of sCSDS mice. Histological analysis showed frequent myocardial interstitial fibrosis in the heart of such mice. In addition, gene ontology and pathway analyses suggested that the pathways related to energy metabolism, such as the oxidative phosphorylation and the pentose phosphate pathway, were significantly related to the miRNAs affected by sCSDS in saliva. In contrast, salivary metabolites were not significantly changed in the sCSDS mice, which is consistent with our previous metabolomic study on the plasma of sCSDS mice. Taken in the light of previous studies, the present study provides novel potential stress biomarkers for future diagnosis using saliva. Full article

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

► Show Figures

Figure 1

22 pages, 2936 KiB

Open AccessReview

Probiotics and Commensal Gut Microbiota as the Effective Alternative Therapy for Multiple Sclerosis Patients Treatment

by Angela Dziedzic and Joanna Saluk

Int. J. Mol. Sci. 2022, 23(22), 14478; https://doi.org/10.3390/ijms232214478 - 21 Nov 2022

Cited by 7 | Viewed by 3348

Abstract

The gut-brain axis (GBA) refers to the multifactorial interactions between the intestine microflora and the nervous, immune, and endocrine systems, connecting brain activity and gut functions. Alterations of the GBA have been revealed in people with multiple sclerosis (MS), suggesting a potential role [...] Read more.

The gut-brain axis (GBA) refers to the multifactorial interactions between the intestine microflora and the nervous, immune, and endocrine systems, connecting brain activity and gut functions. Alterations of the GBA have been revealed in people with multiple sclerosis (MS), suggesting a potential role in disease pathogenesis and making it a promising therapeutic target. Whilst research in this field is still in its infancy, a number of studies revealed that MS patients are more likely to exhibit modified microbiota, altered levels of short-chain fatty acids, and enhanced intestinal permeability. Both clinical and preclinical trials in patients with MS and animal models revealed that the administration of probiotic bacteria might improve cognitive, motor, and mental behaviors by modulation of GBA molecular pathways. According to the newest data, supplementation with probiotics may be associated with slower disability progression, reduced depressive symptoms, and improvements in general health in patients with MS. Herein, we give an overview of how probiotics supplementation may have a beneficial effect on the course of MS and its animal model. Hence, interference with the composition of the MS patient’s intestinal microbiota may, in the future, be a grip point for the development of diagnostic tools and personalized microbiota-based adjuvant therapy. Full article

(This article belongs to the Special Issue Comeback to Natural Therapeutics in Modern Age: Insights into Molecular Modes of Action of Natural Products)

► Show Figures

Figure 1

21 pages, 10450 KiB

Open AccessArticle

Platelet–Neutrophil Association in NETs-Rich Areas in the Retrieved AIS Patient Thrombi

by Ghulam Jeelani Pir, Aijaz Parray, Raheem Ayadathil, Sajitha V. Pananchikkal, Fayaz Ahmad Mir, Islam Muhammad, Ahmed Abubakar, Nueman Amir, Sohail Hussain, Khawaja H. Haroon, Ahmad Muhammad, Yahya Imam, Satya Narayana Patro, Naveed Akhtar, Aymen Zakaria and Saadat Kamran

Int. J. Mol. Sci. 2022, 23(22), 14477; https://doi.org/10.3390/ijms232214477 - 21 Nov 2022

Cited by 4 | Viewed by 2251

Abstract

Histological structure of thrombi is a strong determinant of the outcome of vascular recanalization therapy, the only treatment option for acute ischemic stroke (AIS) patients. A total of 21 AIS patients from this study after undergoing non-enhanced CT scan and multimodal MRI were [...] Read more.

Histological structure of thrombi is a strong determinant of the outcome of vascular recanalization therapy, the only treatment option for acute ischemic stroke (AIS) patients. A total of 21 AIS patients from this study after undergoing non-enhanced CT scan and multimodal MRI were treated with mechanical stent-based and manual aspiration thrombectomy, and thromboembolic retrieved from a cerebral artery. Complementary histopathological and imaging analyses were performed to understand their composition with a specific focus on fibrin, von Willebrand factor, and neutrophil extracellular traps (NETs). Though distinct RBC-rich and platelet-rich areas were found, AIS patient thrombi were overwhelmingly platelet-rich, with 90% of thrombi containing <40% total RBC-rich contents (1.5 to 37%). Structurally, RBC-rich areas were simple, consisting of tightly packed RBCs in thin fibrin meshwork with sparsely populated nucleated cells and lacked any substantial von Willebrand factor (VWF). Platelet-rich areas were structurally more complex with thick fibrin meshwork associated with VWF. Plenty of leukocytes populated the platelet-rich areas, particularly in the periphery and border areas between platelet-rich and RBC-rich areas. Platelet-rich areas showed abundant activated neutrophils (myeloperoxidase⁺ and neutrophil-elastase⁺) containing citrullinated histone-decorated DNA. Citrullinated histone-decorated DNA also accumulated extracellularly, pointing to NETosis by the activated neutrophils. Notably, NETs-containing areas showed strong reactivity to VWF, platelets, and high-mobility group box 1 (HMGB1), signifying a close interplay between these components. Full article

(This article belongs to the Special Issue Emerging Treatment for Cardiovascular Diseases)

► Show Figures

Figure 1

17 pages, 4042 KiB

Open AccessArticle

Competing Easy-Axis Anisotropies Impacting Magnetic Tunnel Junction-Based Molecular Spintronics Devices (MTJMSDs)

by Bishnu R. Dahal, Andrew Grizzle, Christopher D’Angelo, Vincent Lamberti and Pawan Tyagi

Int. J. Mol. Sci. 2022, 23(22), 14476; https://doi.org/10.3390/ijms232214476 - 21 Nov 2022

Viewed by 1386

Abstract

Molecular spintronics devices (MSDs) attempt to harness molecules’ quantum state, size, and configurable attributes for application in computer devices—a quest that began more than 70 years ago. In the vast number of theoretical studies and limited experimental attempts, MSDs have been found to [...] Read more.

Molecular spintronics devices (MSDs) attempt to harness molecules’ quantum state, size, and configurable attributes for application in computer devices—a quest that began more than 70 years ago. In the vast number of theoretical studies and limited experimental attempts, MSDs have been found to be suitable for application in memory devices and futuristic quantum computers. MSDs have recently also exhibited intriguing spin photovoltaic-like phenomena, signaling their potential application in cost-effective and novel solar cell technologies. The molecular spintronics field’s major challenge is the lack of mass-fabrication methods producing robust magnetic molecule connections with magnetic electrodes of different anisotropies. Another main challenge is the limitations of conventional theoretical methods for understanding experimental results and designing new devices. Magnetic tunnel junction-based molecular spintronics devices (MTJMSDs) are designed by covalently connecting paramagnetic molecules across an insulating tunneling barrier. The insulating tunneling barrier serves as a mechanical spacer between two ferromagnetic (FM) electrodes of tailorable magnetic anisotropies to allow molecules to undergo many intriguing phenomena. Our experimental studies showed that the paramagnetic molecules could produce strong antiferromagnetic coupling between two FM electrodes, leading to a dramatic large-scale impact on the magnetic electrode itself. Recently, we showed that the Monte Carlo Simulation (MCS) was effective in providing plausible insights into the observation of unusual magnetic domains based on the role of single easy-axis magnetic anisotropy. Here, we experimentally show that the response of a paramagnetic molecule is dramatically different when connected to FM electrodes of different easy-axis anisotropies. Motivated by our experimental studies, here, we report on an MCS study investigating the impact of the simultaneous presence of two easy-axis anisotropies on MTJMSD equilibrium properties. In-plane easy-axis anisotropy produced multiple magnetic phases of opposite spins. The multiple magnetic phases vanished at higher thermal energy, but the MTJMSD still maintained a higher magnetic moment because of anisotropy. The out-of-plane easy-axis anisotropy caused a dominant magnetic phase in the FM electrode rather than multiple magnetic phases. The simultaneous application of equal-magnitude in-plane and out-of-plane easy-axis anisotropies on the same electrode negated the anisotropy effect. Our experimental and MCS study provides insights for designing and understanding new spintronics-based devices. Full article

(This article belongs to the Special Issue Magnetic Materials and Their Various Applications)

► Show Figures

Figure 1

19 pages, 1719 KiB

Open AccessReview

Advances in Aptamers-Based Applications in Breast Cancer: Drug Delivery, Therapeutics, and Diagnostics

by Tooba Gholikhani, Shalen Kumar, Hadi Valizadeh, Somayeh Mahdinloo, Khosro Adibkia, Parvin Zakeri-Milani, Mohammad Barzegar-Jalali and Balam Jimenez

Int. J. Mol. Sci. 2022, 23(22), 14475; https://doi.org/10.3390/ijms232214475 - 21 Nov 2022

Cited by 4 | Viewed by 2342

Abstract

Aptamers are synthetic single-stranded oligonucleotides (such as RNA and DNA) evolved in vitro using Systematic Evolution of Ligands through Exponential enrichment (SELEX) techniques. Aptamers are evolved to have high affinity and specificity to targets; hence, they have a great potential for use in [...] Read more.

Aptamers are synthetic single-stranded oligonucleotides (such as RNA and DNA) evolved in vitro using Systematic Evolution of Ligands through Exponential enrichment (SELEX) techniques. Aptamers are evolved to have high affinity and specificity to targets; hence, they have a great potential for use in therapeutics as delivery agents and/or in treatment strategies. Aptamers can be chemically synthesized and modified in a cost-effective manner and are easy to hybridize to a variety of nano-particles and other agents which has paved a way for targeted therapy and diagnostics applications such as in breast tumors. In this review, we systematically explain different aptamer adoption approaches to therapeutic or diagnostic uses when addressing breast tumors. We summarize the current therapeutic techniques to address breast tumors including aptamer-base approaches. We discuss the next aptamer-based therapeutic and diagnostic approaches targeting breast tumors. Finally, we provide a perspective on the future of aptamer-based sensors for breast therapeutics and diagnostics. In this section, the therapeutic applications of aptamers will be discussed for the targeting therapy of breast cancer. Full article

(This article belongs to the Special Issue Molecular Insights into Breast Cancer: Advanced Development and Therapeutic Strategies)

► Show Figures

Figure 1

21 pages, 7422 KiB

Open AccessArticle

Bcl-2 Family Members Bcl-xL and Bax Cooperatively Contribute to Bortezomib Resistance in Mantle Cell Lymphoma

by Sudjit Luanpitpong, Montira Janan, Juthamas Yosudjai, Jirarat Poohadsuan, Pithi Chanvorachote and Surapol Issaragrisil

Int. J. Mol. Sci. 2022, 23(22), 14474; https://doi.org/10.3390/ijms232214474 - 21 Nov 2022

Cited by 3 | Viewed by 1639

Abstract

Mantle cell lymphoma (MCL) is an aggressive non-Hodgkin lymphoma with poor prognosis, due to the inevitable development of drug resistance. Despite being the first-in-class proteasome inhibitor for relapsed/refractory MCL, resistance to bortezomib (BTZ) in MCL patients remains a major hurdle of effective therapy, [...] Read more.

Mantle cell lymphoma (MCL) is an aggressive non-Hodgkin lymphoma with poor prognosis, due to the inevitable development of drug resistance. Despite being the first-in-class proteasome inhibitor for relapsed/refractory MCL, resistance to bortezomib (BTZ) in MCL patients remains a major hurdle of effective therapy, and relapse following BTZ is frequent. Understanding the mechanisms underlying BTZ resistance is, therefore, important for improving the clinical outcome and developing novel therapeutic strategies. Here, we established de novo BTZ-resistant human MCL-derived cells with the highest resistance index of 300-fold compared to parental cells. We provided compelling evidence that both Bcl-xL and Bax are key mediators in determining BTZ sensitivity in MCL cells. Overexpression of antiapoptotic Bcl-xL and depletion of proapoptotic Bax cooperatively protected MCL cells against BTZ-induced apoptosis, causing acquired BTZ resistance, likely by tilting the balance of Bcl-2 family proteins toward antiapoptotic signaling. Bioinformatics analyses suggested that high BCL2L1 (encoded Bcl-xL) and low BAX were, in part, associated with poor prognosis of MCL patients, e.g., when combined with low OGT, which regulates cellular O-GlcNAcylation. Our findings support recent strategies in small molecule drug discovery co-targeting antiapoptotic Bcl-2 family proteins using BH3 mimetics and Bax using Bax activators to overcome cancer drug resistance. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Targeted Therapy in Cancer)

► Show Figures

Figure 1

14 pages, 5900 KiB

Open AccessArticle

Self-Assembled BODIPY Derivative with A-D-A Structure as Organic Nanoparticles for Photodynamic/Photothermal Cancer Therapy

by Guojing Li, Mengqian Yang, Qilong Sha, Li Li, Xiaogang Luo and Fengshou Wu

Int. J. Mol. Sci. 2022, 23(22), 14473; https://doi.org/10.3390/ijms232214473 - 21 Nov 2022

Cited by 2 | Viewed by 1484

Abstract

Organic nanomaterials have attracted considerable attention in the area of photodynamic and photothermal therapy, owing to their outstanding biocompatibility, potential biodegradability, well-defined chemical structure, and easy functionalization. However, it is still a challenge to develop a single organic molecule that obtains both photothermal [...] Read more.

Organic nanomaterials have attracted considerable attention in the area of photodynamic and photothermal therapy, owing to their outstanding biocompatibility, potential biodegradability, well-defined chemical structure, and easy functionalization. However, it is still a challenge to develop a single organic molecule that obtains both photothermal and photodynamic effects. In this contribution, we synthesized a new boron-dipyrromethene (BODIPY)-based derivative (DPBDP) with an acceptor–donor–acceptor (A-D-A) structure by coupling 3,6-di(2-thienyl)-2,5-dihydropyrrolo [3,4-c] pyrrole-1,4-dione (DPP) and BODIPY. To enhance the hydrophilicity of the BODIPY derivative, the polyethylene glycol (PEG) chains were introduced to the meso- position of BODIPY core. The amphiphilic DPBDP was then self-assembled into related nanoparticles (DPBDP NPs) with improved hydrophilicity and enhanced absorbance in the NIR region. DPBDP NPs could simultaneously generate the singlet oxygen (¹O₂) and heat under the irradiation of a single laser (690 nm). The ¹O₂ quantum yield and photothermal conversion efficiency (PCE) of DPBDP NPs were calculated to be 14.2% and 26.1%, respectively. The biocompatibility and phototherapeutic effect of DPBDP NPs were evaluated through cell counting kit-8 (CCK-8) assay. Under irradiation of 690 nm laser (1.0 W/cm²), the half maximal inhibitory concentration (IC₅₀) of DPBDP NPs was calculated to be 16.47 µg/mL. Thus, the as-prepared DPBDP NPs could be acted as excellent candidates for synergistic photodynamic/photothermal therapy. Full article

(This article belongs to the Special Issue Bioluminescent: Fluorescent Biomolecules and Nanomaterials)

► Show Figures

Figure 1

16 pages, 2554 KiB

Open AccessArticle

OsMKKK70 Negatively Regulates Cold Tolerance at Booting Stage in Rice

by Enyang Mei, Jiaqi Tang, Mingliang He, Zhiqi Liu, Xiaojie Tian and Qingyun Bu

Int. J. Mol. Sci. 2022, 23(22), 14472; https://doi.org/10.3390/ijms232214472 - 21 Nov 2022

Cited by 2 | Viewed by 1404

Abstract

Cold stress at the booting stage leads to a lower seed setting rate and seriously threatens the production of rice (Oryza sativa L.), which has become a major yield-limiting factor in higher-altitude and -latitude regions. Because cold tolerance at the booting stage [...] Read more.

Cold stress at the booting stage leads to a lower seed setting rate and seriously threatens the production of rice (Oryza sativa L.), which has become a major yield-limiting factor in higher-altitude and -latitude regions. Because cold tolerance at the booting stage (CTB) is a complex trait and is controlled by multiple loci, only a few genes have been reported so far. In this study, a function of OsMKKK70 (Mitogen Activated Protein Kinase Kinase Kinase 70) in response to CTB was characterized. OsMKKK70 expression was rapidly induced by cold stress at the booting stage. OsMKKK70 overexpression (OsMKKK70-OE) plants were more sensitive to cold stress at the booting stage with a lower seed setting and pollen fertility, but there was no significant difference between the osmkkk70 mutant and WT. Considering the effect of functional redundancy, we further tested the CTB response of osmkkk62/70 and osmkkk55/62/70, the double and triple mutants of OsMKKK70 with its closest homologs OsMKKK62 and OsMKKK55, and found that osmkkk62/70 and osmkkk55/62/70 displayed significantly increased CTB with a higher seed setting and pollen fertility, indicating that OsMKKK70 negatively regulates rice CTB. Moreover, under the low-temperature (LT) condition, the osmkkk62/70 mutant had slightly higher Gibberellin (GA) contents, increased expression of GA biosynthesis genes, and lower protein level of OsSLR1 in anthers than those in WT. By contrast, OsMKKK70-OE anther had a lower GA biosynthesis than that of WT. Together, these findings suggest that OsMKKK70 negatively regulates rice CTB by fine-tuning GA levels in anthers. Full article

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

► Show Figures

Figure 1

20 pages, 6466 KiB

Open AccessArticle

Characterization of NLRP3 Inflammasome Activation in the Onset of Diabetic Retinopathy

by Charisse Y-J. Kuo, Jack J. Maran, Emma G. Jamieson, Ilva D. Rupenthal, Rinki Murphy and Odunayo O. Mugisho

Int. J. Mol. Sci. 2022, 23(22), 14471; https://doi.org/10.3390/ijms232214471 - 21 Nov 2022

Cited by 11 | Viewed by 2007

Abstract

The aim of this study was to characterize the role of nucleotide-binding oligomerization domain- (NOD-) like receptor (NLR) protein 3 (NLRP3) inflammasome activation in the onset of diabetic retinopathy (DR) using retina and vitreous from donors without diabetes mellitus (CTL), with diabetes mellitus [...] Read more.

The aim of this study was to characterize the role of nucleotide-binding oligomerization domain- (NOD-) like receptor (NLR) protein 3 (NLRP3) inflammasome activation in the onset of diabetic retinopathy (DR) using retina and vitreous from donors without diabetes mellitus (CTL), with diabetes mellitus alone (DM), and with DR. Retinal expression of glial fibrillary acidic protein (GFAP) and ionized calcium-binding adapter molecule 1 (Iba-1), the key markers of retinal inflammation, connexin43 (Cx43) which is involved in upstream inflammasome regulation, as well as NLRP3 and cleaved caspase-1, the main markers of inflammasome activation, were evaluated using immunohistochemistry and Western blotting. Vitreous interleukin (IL)-1β and IL-18, biomarkers of the activated inflammasome, were measured using a Luminex multiplex assay. Results showed a significant increase in the number and size of Iba-1⁺ cells and NLRP3 expression in DM, while a significant increase in GFAP, Cx43, cleaved caspase-1 and vitreous IL-18, as well as a further increase in Iba-1 and NLRP3 was found in DR. This suggests that the inflammasome is already primed in DM before its activation in DR. Furthermore, IL-18 may act as the major effector of inflammasome activation in DR while nuclear translocation of cleaved caspase-1 may play a role in gene transcription contributing to DR onset. Full article

(This article belongs to the Special Issue The Role of Inflammation in Diabetic Retinopathy)

► Show Figures

Figure 1

9 pages, 1686 KiB

Open AccessArticle

Drug Combination Studies of the Dipeptide Nitrile CD24 with Curcumin: A New Strategy to Synergistically Inhibit Rhodesain of Trypanosoma brucei rhodesiense

by Carla Di Chio, Santo Previti, Fabiola De Luca, Marta Bogacz, Collin Zimmer, Annika Wagner, Tanja Schirmeister, Maria Zappalà and Roberta Ettari

Int. J. Mol. Sci. 2022, 23(22), 14470; https://doi.org/10.3390/ijms232214470 - 21 Nov 2022

Cited by 1 | Viewed by 1140

Abstract

Rhodesain is a cysteine protease that is crucial for the life cycle of Trypanosoma brucei rhodesiense, a parasite causing the lethal form of Human African Trypanosomiasis. CD24 is a recently developed synthetic inhibitor of rhodesain, characterized by a nanomolar affinity towards the [...] Read more.

Rhodesain is a cysteine protease that is crucial for the life cycle of Trypanosoma brucei rhodesiense, a parasite causing the lethal form of Human African Trypanosomiasis. CD24 is a recently developed synthetic inhibitor of rhodesain, characterized by a nanomolar affinity towards the trypanosomal protease (K_i = 16 nM), and acting as a competitive inhibitor. In the present work, we carried out a combination study of CD24 with curcumin, the multitarget nutraceutical obtained from Curcuma longa L., which we demonstrated to inhibit rhodesain in a non-competitive manner. By applying the Chou and Talalay method, we obtained an initial additive effect at IC₅₀ (f_a = 0.5, Combination Index = 1), while for the most relevant f_a values, ranging from 0.6 to 1, i.e., from 60% to 100% of rhodesain inhibition, we obtained a combination index < 1, thus suggesting that an increasingly synergistic action occurred for the combination of the synthetic inhibitor CD24 and curcumin. Furthermore, the combination of the two inhibitors showed an antitrypanosomal activity better than that of CD24 alone (EC₅₀ = 4.85 µM and 10.1 µM for the combination and CD24, respectively), thus suggesting the use of the two inhibitors in combination is desirable. Full article

(This article belongs to the Special Issue Protease Inhibitors: A Promising Therapeutic Strategy for Human and Infectious Diseases)

► Show Figures

Graphical abstract

12 pages, 1922 KiB

Open AccessArticle

Cardio-Vascular Interaction Evaluated by Speckle-Tracking Echocardiography and Cardio-Ankle Vascular Index in Hypertensive Patients

by Tsuyoshi Tabata, Shuji Sato, Ruiko Ohno, Masahiro Iwakawa, Hajime Kiyokawa, Yukihiro Morinaga, Naoaki Tanji, Toshio Kinoshita and Kazuhiro Shimizu

Int. J. Mol. Sci. 2022, 23(22), 14469; https://doi.org/10.3390/ijms232214469 - 21 Nov 2022

Cited by 5 | Viewed by 3072

Abstract

Hypertension increases arterial stiffness, leading to dysfunction and structural changes in the left atrium (LA) and left ventricle (LV). However, the effects of hypertension on the right atrium (RA) and the right ventricle are still not fully understood. The purpose of this study [...] Read more.

Hypertension increases arterial stiffness, leading to dysfunction and structural changes in the left atrium (LA) and left ventricle (LV). However, the effects of hypertension on the right atrium (RA) and the right ventricle are still not fully understood. The purpose of this study was to clarify whether there is an interaction not only in the left ventricular system but also in the right ventricular system in hypertensive patients with preserved LV ejection fraction. The current retrospective observational study included patients (n = 858) with some risk of metabolic abnormalities (hypertension, diabetes, and dyslipidemia) who had visited our hospital and undergone echocardiography between 2015 and 2018. Among them, we retrospectively studied 165 consecutive hypertensive patients with preserved LV ejection fraction who had echocardiography performed on the same day as a cardio-ankle vascular index (CAVI) in our hospital. The phasic function of both atria was evaluated by two-dimensional speckle-tracking echocardiography. CAVI was measured using Vasela 1500 (Fukuda Denshi^®). In the univariate analysis, CAVI was significantly correlated with LA and RA conduit function (LA conduit function, r = −0.448, p = 0.0001; RA conduit function, r = −0.231, p = 0.003). A multivariate regression analysis revealed that LA and RA conduit function was independently associated with CAVI (LA, t = −5.418, p = 0.0001; RA, t = −2.113, p = 0.036). CAVI showed a possibility that the association between heart and vessels are contained from not only LA phasic function but also RA phasic function in hypertensive patients. Full article

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

► Show Figures

Figure 1

Journal Menu

Journal Browser

Int. J. Mol. Sci., Volume 23, Issue 22 (November-2 2022) – 835 articles

Further Information

Guidelines

MDPI Initiatives

Follow MDPI