Biomolecules

15 pages, 2900 KiB

Open AccessArticle

Regulation of CRISPR-Associated Genes by Rv1776c (CasR) in Mycobacterium tuberculosis

by Wenping Wei, Xiaofang Jiang, Li Zhang, Yunjun Yan, Jinyong Yan, Li Xu, Chun-Hui Gao and Min Yang

Biomolecules 2023, 13(2), 400; https://doi.org/10.3390/biom13020400 - 20 Feb 2023

Cited by 2 | Viewed by 1676

Abstract

The CRISPR-Cas system is an adaptive immune system for many bacteria and archaea to defend against foreign nucleic acid invasion, and this system is conserved in the genome of M. tuberculosis (Mtb). Although the CRISPR-Cas system-mediated immune defense mechanism has been [...] Read more.

The CRISPR-Cas system is an adaptive immune system for many bacteria and archaea to defend against foreign nucleic acid invasion, and this system is conserved in the genome of M. tuberculosis (Mtb). Although the CRISPR-Cas system-mediated immune defense mechanism has been revealed in Mtb, the regulation of cas gene expression is poorly understood. In this study, we identified a transcription factor, CasR (CRISPR-associated protein repressor, encoded by Rv1776c), and it could bind to the upstream DNA sequence of the CRISPR-Cas gene cluster and regulate the expression of cas genes. EMSA and ChIP assays confirmed that CasR could interact with the upstream sequence of the csm6 promoter, both in vivo and in vitro. Furthermore, DNA footprinting assay revealed that CasR recognized a 20 bp palindromic sequence motif and negatively regulated the expression of csm6. In conclusion, our research elucidates the regulatory effect of CasR on the expression of CRISPR-associated genes in mycobacteria, thus providing insight into gene expression regulation of the CRISPR-Cas system. Full article

(This article belongs to the Special Issue Virulence Factors in Mycobacterium tuberculosis Infection: Structural and Functional Studies)

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25 pages, 9337 KiB

Open AccessArticle

Single-Cell RNA-Seq Analysis Reveals Macrophages Are Involved in the Pathogenesis of Human Sporadic Acute Type A Aortic Dissection

by Bin Zhang, Kuan Zeng, Rui-Cong Guan, Hui-Qi Jiang, Yong-Jia Qiang, Qing Zhang, Mo Yang, Bao-Ping Deng and Yan-Qi Yang

Biomolecules 2023, 13(2), 399; https://doi.org/10.3390/biom13020399 - 20 Feb 2023

Cited by 7 | Viewed by 3605

Abstract

Macrophages play an important role in the progression of sporadic acute type A aortic dissection (ATAAD). The aim of this study was to characterize the cellular heterogeneity of macrophages in ATAAD tissues by scRNA-seq. Ascending aortic wall tissue from six ATAAD patients and [...] Read more.

Macrophages play an important role in the progression of sporadic acute type A aortic dissection (ATAAD). The aim of this study was to characterize the cellular heterogeneity of macrophages in ATAAD tissues by scRNA-seq. Ascending aortic wall tissue from six ATAAD patients and three heart transplant donors was assessed by scRNA-seq and then analyzed and validated by various bioinformatic algorithms and histopathology experiments. The results revealed that the proportion of macrophages in ATAAD tissues (24.51%) was significantly higher than that in normal tissues (13.69%). Among the six macrophage subclusters, pro-inflammatory macrophages accounted for 14.96% of macrophages in the AD group and 0.18% in the normal group. Chemokine- and inflammation-related genes (CCL2, CCL20, S100A8, and S100A9) were expressed more intensively in macrophages in ATAAD tissue than in those in normal tissue. Additionally, intercellular communication analysis and transcription factor analysis indicated the activation of inflammation and degradation of the extracellular matrix in ATAAD tissue. Finally, immunohistochemistry, immunofluorescence, and Western blot experiments confirmed the overexpression of macrophage marker genes (CD68 and CD163) and matrix metalloproteinases (MMP9 and MMP2) in ATAAD tissue. Collectively, our study provides a preliminary evaluation of the role of macrophages in ATAAD, and the results could aid in the development of therapeutic options in the future. Full article

(This article belongs to the Section Bioinformatics and Systems Biology)

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22 pages, 2712 KiB

Open AccessReview

Regulation of the Epithelial to Mesenchymal Transition in Osteosarcoma

by Kristin Hinton, Andrew Kirk, Paulose Paul and Sujata Persad

Biomolecules 2023, 13(2), 398; https://doi.org/10.3390/biom13020398 - 20 Feb 2023

Cited by 5 | Viewed by 2401

Abstract

The epithelial to mesenchymal transition (EMT) is a cellular process that has been linked to the promotion of aggressive cellular features in many cancer types. It is characterized by the loss of the epithelial cell phenotype and a shift to a more mesenchymal [...] Read more.

The epithelial to mesenchymal transition (EMT) is a cellular process that has been linked to the promotion of aggressive cellular features in many cancer types. It is characterized by the loss of the epithelial cell phenotype and a shift to a more mesenchymal phenotype and is accompanied by an associated change in cell markers. EMT is highly complex and regulated via multiple signaling pathways. While the importance of EMT is classically described for carcinomas—cancers of epithelial origin—it has also been clearly demonstrated in non-epithelial cancers, including osteosarcoma (OS), a primary bone cancer predominantly affecting children and young adults. Recent studies examining EMT in OS have highlighted regulatory roles for multiple proteins, non-coding nucleic acids, and components of the tumor micro-environment. This review serves to summarize these experimental findings, identify key families of regulatory molecules, and identify potential therapeutic targets specific to the EMT process in OS. Full article

(This article belongs to the Special Issue EMT and Cancer II)

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5 pages, 231 KiB

Open AccessComment

Imaging the Vulnerable Carotid Plaque with CT: Caveats to Consider. Comment on Wang et al. Identification Markers of Carotid Vulnerable Plaques: An Update. Biomolecules 2022, 12, 1192

by David C. Rotzinger, Salah D. Qanadli and Guillaume Fahrni

Biomolecules 2023, 13(2), 397; https://doi.org/10.3390/biom13020397 - 20 Feb 2023

Viewed by 964

Abstract

We read with great interest the review by Wang et al. entitled “Identification Markers of Carotid Vulnerable Plaques: An Update”, recently published in Biomolecules [...] Full article

20 pages, 1533 KiB

Open AccessEditor’s ChoiceReview

Cellular Pathogenesis of Hepatic Encephalopathy: An Update

by Kaihui Lu

Biomolecules 2023, 13(2), 396; https://doi.org/10.3390/biom13020396 - 19 Feb 2023

Cited by 7 | Viewed by 6093

Abstract

Hepatic encephalopathy (HE) is a neuropsychiatric syndrome derived from metabolic disorders due to various liver failures. Clinically, HE is characterized by hyperammonemia, EEG abnormalities, and different degrees of disturbance in sensory, motor, and cognitive functions. The molecular mechanism of HE has not been [...] Read more.

Hepatic encephalopathy (HE) is a neuropsychiatric syndrome derived from metabolic disorders due to various liver failures. Clinically, HE is characterized by hyperammonemia, EEG abnormalities, and different degrees of disturbance in sensory, motor, and cognitive functions. The molecular mechanism of HE has not been fully elucidated, although it is generally accepted that HE occurs under the influence of miscellaneous factors, especially the synergistic effect of toxin accumulation and severe metabolism disturbance. This review summarizes the recently discovered cellular mechanisms involved in the pathogenesis of HE. Among the existing hypotheses, ammonia poisoning and the subsequent oxidative/nitrosative stress remain the mainstream theories, and reducing blood ammonia is thus the main strategy for the treatment of HE. Other pathological mechanisms mainly include manganese toxicity, autophagy inhibition, mitochondrial damage, inflammation, and senescence, proposing new avenues for future therapeutic interventions. Full article

(This article belongs to the Special Issue The Contribution of Astrocytes to Neuropathology)

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13 pages, 922 KiB

Open AccessArticle

FK506-Binding Protein like (FKBPL) Has an Important Role in Heart Failure with Preserved Ejection Fraction Pathogenesis with Potential Diagnostic Utility

by Michael Chhor, Hao Chen, Djurdja Jerotić, Milorad Tešić, Valentina N. Nikolić, Milan Pavlović, Rada M. Vučić, Benjamin Rayner, Chris J. Watson, Mark Ledwidge, Kenneth McDonald, Tracy Robson, Kristine C. McGrath and Lana McClements

Biomolecules 2023, 13(2), 395; https://doi.org/10.3390/biom13020395 - 18 Feb 2023

Cited by 2 | Viewed by 2202

Abstract

Heart failure (HF) is the leading cause of hospitalisations worldwide, with only 35% of patients surviving the first 5 years after diagnosis. The pathogenesis of HF with preserved ejection fraction (HFpEF) is still unclear, impeding the implementation of effective treatments. FK506-binding protein like [...] Read more.

Heart failure (HF) is the leading cause of hospitalisations worldwide, with only 35% of patients surviving the first 5 years after diagnosis. The pathogenesis of HF with preserved ejection fraction (HFpEF) is still unclear, impeding the implementation of effective treatments. FK506-binding protein like (FKBPL) and its therapeutic peptide mimetic, AD-01, are critical mediators of angiogenesis and inflammation. Thus, in this study, we investigated—for the first time—FKBPL’s role in the pathogenesis and as a biomarker of HFpEF. In vitro models of cardiac hypertrophy following exposure to a hypertensive stimulus, angiotensin-II (Ang-II, 100 nM), and/or AD-01 (100 nM), for 24 and 48 h were employed as well as human plasma samples from people with different forms of HFpEF and controls. Whilst the FKBPL peptide mimetic, AD-01, induced cardiomyocyte hypertrophy in a similar manner to Ang-II (p < 0.0001), when AD-01 and Ang-II were combined together, this process was abrogated (p < 0.01–0.0001). This mechanism appears to involve a negative feedback loop related to FKBPL (p < 0.05). In human plasma samples, FKBPL concentration was increased in HFpEF compared to controls (p < 0.01); however, similar to NT-proBNP and Gal-3, it was unable to stratify between different forms of HFpEF: acute HFpEF, chronic HFpEF and hypertrophic cardiomyopathy (HCM). FKBPL may be explored for its biomarker and therapeutic target potential in HFpEF. Full article

(This article belongs to the Special Issue Cardiovascular Diseases and Biomarkers)

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Graphical abstract

17 pages, 1512 KiB

Open AccessReview

Promiscuity, a Driver of Plant Cytochrome P450 Evolution?

by Danièle Werck-Reichhart

Biomolecules 2023, 13(2), 394; https://doi.org/10.3390/biom13020394 - 18 Feb 2023

Cited by 8 | Viewed by 2152

Abstract

Plant cytochrome P450 monooxygenases were long considered to be highly substrate-specific, regioselective and stereoselective enzymes, in this respect differing from their animal counterparts. The functional data that have recently accumulated clearly counter this initial dogma. Highly promiscuous P450 enzymes have now been reported, [...] Read more.

Plant cytochrome P450 monooxygenases were long considered to be highly substrate-specific, regioselective and stereoselective enzymes, in this respect differing from their animal counterparts. The functional data that have recently accumulated clearly counter this initial dogma. Highly promiscuous P450 enzymes have now been reported, mainly in terpenoid pathways with functions in plant adaptation, but also some very versatile xenobiotic/herbicide metabolizers. An overlap and predictable interference between endogenous and herbicide metabolism are starting to emerge. Both substrate preference and permissiveness vary between plant P450 families, with high promiscuity seemingly favoring retention of gene duplicates and evolutionary blooms. Yet significant promiscuity can also be observed in the families under high negative selection and with essential functions, usually enhanced after gene duplication. The strategies so far implemented, to systematically explore P450 catalytic capacity, are described and discussed. Full article

(This article belongs to the Special Issue New Insights into Cytochrome P450s)

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13 pages, 3868 KiB

Open AccessArticle

Predicting Potent Compounds Using a Conditional Variational Autoencoder Based upon a New Structure–Potency Fingerprint

by Tiago Janela, Kosuke Takeuchi and Jürgen Bajorath

Biomolecules 2023, 13(2), 393; https://doi.org/10.3390/biom13020393 - 18 Feb 2023

Cited by 1 | Viewed by 1738

Abstract

Prediction of the potency of bioactive compounds generally relies on linear or nonlinear quantitative structure–activity relationship (QSAR) models. Nonlinear models are generated using machine learning methods. We introduce a novel approach for potency prediction that depends on a newly designed molecular fingerprint (FP) [...] Read more.

Prediction of the potency of bioactive compounds generally relies on linear or nonlinear quantitative structure–activity relationship (QSAR) models. Nonlinear models are generated using machine learning methods. We introduce a novel approach for potency prediction that depends on a newly designed molecular fingerprint (FP) representation. This structure–potency fingerprint (SPFP) combines different modules accounting for the structural features of active compounds and their potency values in a single bit string, hence unifying structure and potency representation. This encoding enables the derivation of a conditional variational autoencoder (CVAE) using SPFPs of training compounds and apply the model to predict the SPFP potency module of test compounds using only their structure module as input. The SPFP–CVAE approach correctly predicts the potency values of compounds belonging to different activity classes with an accuracy comparable to support vector regression (SVR), representing the state-of-the-art in the field. In addition, highly potent compounds are predicted with very similar accuracy as SVR and deep neural networks. Full article

(This article belongs to the Special Issue Computer Aided Drug Discovery)

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14 pages, 2318 KiB

Open AccessArticle

High-Intensity Focused Ultrasound Decreases Subcutaneous Fat Tissue Thickness by Increasing Apoptosis and Autophagy

by Kyung-A Byun, Hyun Jun Park, Seyeon Oh, Sosorburam Batsukh, Hye Jin Sun, Taehui Kim, Sunggeun Kim, Donghwan Kang, Kuk Hui Son and Kyunghee Byun

Biomolecules 2023, 13(2), 392; https://doi.org/10.3390/biom13020392 - 18 Feb 2023

Cited by 2 | Viewed by 1890

Abstract

High-intensity focused ultrasound (HIFU) leads to decreased subcutaneous adipose tissue (SAT) thickness via heat-induced adipocyte necrosis. Heat can induce adipocyte apoptosis and autophagy, and it is known that nuclear or mitochondrial p53 is involved in apoptosis and autophagy. However, whether HIFU leads to [...] Read more.

High-intensity focused ultrasound (HIFU) leads to decreased subcutaneous adipose tissue (SAT) thickness via heat-induced adipocyte necrosis. Heat can induce adipocyte apoptosis and autophagy, and it is known that nuclear or mitochondrial p53 is involved in apoptosis and autophagy. However, whether HIFU leads to apoptosis or autophagy is unclear. We evaluated whether HIFU decreases SAT thickness via p53-related apoptosis or autophagy in high-fat diet (HFD)-fed animals. The expression of nuclear and mitochondrial p53 was increased by HIFU. HIFU also led to decreased expression of BCL2/BCL-xL (an antiapoptotic signal), increased expression of BAX/BAK (an apoptotic signal), increased levels of cleaved caspase 3/9, and increased numbers of apoptotic cells as evaluated by TUNEL assay. Furthermore, HIFU led to increased levels of ATG5, BECN1, and LC3II/LC3I, and decreased levels of p62, a marker of increased autophagy. The thickness of SAT was decreased by HIFU. In conclusion, HIFU led to nuclear and mitochondrial p53 expression, which led to apoptosis and autophagy, and eventually decreased SAT thickness in HFD-fed animals. Full article

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12 pages, 724 KiB

Open AccessArticle

A Vegetarian Diet Significantly Changes Plasma Kynurenine Concentrations

by Anne-Lise Bjørke-Monsen, Kristin Varsi, Arve Ulvik, Sunniva Todnem Sakkestad and Per Magne Ueland

Biomolecules 2023, 13(2), 391; https://doi.org/10.3390/biom13020391 - 18 Feb 2023

Cited by 2 | Viewed by 1688

Abstract

Tryptophan is an essential amino acid and a precursor of a number of physiologically important metabolites, including serotonin, melatonin, tryptamine, and kynurenines. We assessed tryptophan, kynurenines, and vitamin B2 and B6, as well as biomarkers of liver function and inflammation, in a group [...] Read more.

Tryptophan is an essential amino acid and a precursor of a number of physiologically important metabolites, including serotonin, melatonin, tryptamine, and kynurenines. We assessed tryptophan, kynurenines, and vitamin B2 and B6, as well as biomarkers of liver function and inflammation, in a group of 158 female omnivores and vegetarians aged 18–40 years. The majority of women were omnivores, and 22% were vegetarians. Vegetarians had 25% lower serum ALT, significantly higher pyridoxal concentrations, and significantly lower plasma concentrations of most kynurenines, varying from 8% lower concentrations of median plasma kynurenine to 42% lower concentrations of plasma xanthurenic acid, compared to omnivores. No significant differences were observed in vitamin B2 status or in inflammation markers, C-reactive protein and neopterin between the groups. Vegetarians had lower levels of several plasma kynurenines compared to omnivores. The reason for this is unknown; however, lower ALT concentrations, suggesting a better liver status, and a more favourable vitamin B6 status might be contributing factors. Full article

(This article belongs to the Special Issue Biochemistry in Medicine—Honorary Special Issue Commemorating Research and Work of Professors Jan O. Aaseth and Jan Alexander)

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17 pages, 30353 KiB

Open AccessArticle

Preliminary Transcriptome Analysis of Long Noncoding RNA in Hypothalamic-Pituitary-Mammary Gland Axis of Dairy Cows under Heat Stress

by Hanfang Zeng, Shujie Li, Yunfei Zhai, Haomiao Chang and Zhaoyu Han

Biomolecules 2023, 13(2), 390; https://doi.org/10.3390/biom13020390 - 18 Feb 2023

Cited by 3 | Viewed by 1456

Abstract

Heat stress (HS) is directly correlated to mammary gland dysfunction in dairy cows, especially in summer. The hypothalamic−pituitary−mammary gland axis (HPM axis) plays an important role in the regulation of stress response and lactation physiology in heat−stressed dairy cows. The aim of this [...] Read more.

Heat stress (HS) is directly correlated to mammary gland dysfunction in dairy cows, especially in summer. The hypothalamic−pituitary−mammary gland axis (HPM axis) plays an important role in the regulation of stress response and lactation physiology in heat−stressed dairy cows. The aim of this study was to explore the lncRNA profile, and the competitive endogenous RNA (ceRNA) regulatory network in hypothalamus, pituitary, and mammary gland tissues of heat−stressed and normal dairy cows. We performed RNA sequencing (RNA−seq) to identify differentially expressed (DE) lncRNAs, and the ceRNA regulatory network was established in HPM−axis−related tissues. Our results showed that a total of 13, 702 and 202 DE lncRNAs were identified in hypothalamus, pituitary, and mammary glands, respectively. Of lncRNAs, 8, 209 and 45 were up−regulated, and 5, 493 and 157 lncRNAs were down−regulated. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses indicated that DE lncRNAs target genes that might play a role in hormone synthesis, secretion and action, apoptosis, mitogen−activated protein kinase (MAPK), AMP−activated protein kinase (AMPK), and mechanistic target of rapamycin (mTOR) signaling pathway. Moreover, the ceRNA regulatory network associated with the MAPK signaling pathway in HPM−axis−related tissues contains 3286 lncRNA–mRNA pairs. Furthermore, the ceRNA regulatory network associated with apoptosis, prolactin, AMPK, and mTOR signaling pathway in the mammary gland contains 772 lncRNA–mRNA pairs. Thus, some lncRNAs may be involved in the regulation of stress response and the physiological process of lactation. The changes in lncRNA expression profiles and ceRNAs (lncRNA–miRNA–mRNA) in HPM−axis−related tissues are the key to affect the stress response and lactation physiology of dairy cows under HS, which provide a theoretical basis for the molecular mechanism in the stress response of HPM−axis−related tissues in dairy cows under HS. Full article

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12 pages, 529 KiB

Open AccessArticle

Predictive Value of Collagen Biomarkers in Advanced Chronic Kidney Disease Patients

by Carina Ureche, Gianina Dodi, Adela Mihaela Șerban, Andreea Simona Covic, Luminița Voroneanu, Simona Hogaș, Radu Andy Sascău, Cristian Stătescu and Adrian Covic

Biomolecules 2023, 13(2), 389; https://doi.org/10.3390/biom13020389 - 18 Feb 2023

Cited by 3 | Viewed by 1334

Abstract

Patients with chronic kidney disease have an increased risk of all-cause death. The value of collagen biomarkers such as procollagen type I carboxy-terminal propeptide (PICP) and procollagen type III N-terminal peptide (P3NP), in end-stage renal disease (ESRD), has not yet been defined (in [...] Read more.

Patients with chronic kidney disease have an increased risk of all-cause death. The value of collagen biomarkers such as procollagen type I carboxy-terminal propeptide (PICP) and procollagen type III N-terminal peptide (P3NP), in end-stage renal disease (ESRD), has not yet been defined (in the literature and in clinics). The purpose of this study was to determine the potential value of these new biomarkers in the prediction of mortality in this population. Plasma PICP and P3NP levels were determined in 140 patients with ESRD, not yet on dialysis, who were followed up for 36 ± 5.3 months. During follow-up, 58 deaths were recorded (41.4%), with the majority of them being cardiovascular deaths (43, 74.13%). Using the ROC curve, the cut-off value for the prediction of mortality for PICP was 297.31 µg/L, while for P3NP, the cut-off value was 126.67 µg/L. In univariate analysis, a value of PICP above the cut-off point was associated with a fivefold increased risk of mortality (hazard ratio (HR) 5.071, 95% confidence interval 1.935–13.29, p = 0.001) and a value of P3NP above the cut-off point was associated with a twofold increased risk of mortality (HR 2.089, 95% CI 1.044–4.178, p = 0.002). In a multivariable Cox proportional hazards model, PICP values remained independent predictors of mortality (HR 1.22, 95% CI 1.1–1.31, p < 0.0001). Our data suggest that the collagen biomarker PICP is an independent predictor of mortality in ESRD patients who are not yet on dialysis. Full article

(This article belongs to the Special Issue Pharmacology of Cardiovascular Disease)

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14 pages, 1452 KiB

Open AccessEditor’s ChoiceReview

Granzyme B in Autoimmune Skin Disease

by Anna Gleave and David J. Granville

Biomolecules 2023, 13(2), 388; https://doi.org/10.3390/biom13020388 - 18 Feb 2023

Cited by 4 | Viewed by 2786

Abstract

Autoimmune diseases often present with cutaneous symptoms that contribute to dysfunction, disfigurement, and in many cases, reduced quality-of-life. Unfortunately, treatment options for many autoimmune skin diseases are limited. Local and systemic corticosteroids remain the current standard-of-care but are associated with significant adverse effects. [...] Read more.

Autoimmune diseases often present with cutaneous symptoms that contribute to dysfunction, disfigurement, and in many cases, reduced quality-of-life. Unfortunately, treatment options for many autoimmune skin diseases are limited. Local and systemic corticosteroids remain the current standard-of-care but are associated with significant adverse effects. Hence, there is an unmet need for novel therapies that block molecular drivers of disease in a local and/or targeted manner. Granzyme B (GzmB) is a serine protease with known cytotoxic activity and emerging extracellular functions, including the cleavage of cell–cell junctions, basement membranes, cell receptors, and other structural proteins. While minimal to absent in healthy skin, GzmB is markedly elevated in alopecia areata, interface dermatitis, pemphigoid disease, psoriasis, systemic sclerosis, and vitiligo. This review will discuss the role of GzmB in immunity, blistering, apoptosis, and barrier dysfunction in the context of autoimmune skin disease. GzmB plays a causal role in the development of pemphigoid disease and carries diagnostic and prognostic significance in cutaneous lupus erythematosus, vitiligo, and alopecia areata. Taken together, these data support GzmB as a promising therapeutic target for autoimmune skin diseases impacted by impaired barrier function, inflammation, and/or blistering. Full article

(This article belongs to the Special Issue Pathogenesis and Drug Development for Non-communicable Inflammatory Skin Diseases)

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23 pages, 2110 KiB

Open AccessEditor’s ChoiceArticle

Using GPT-3 to Build a Lexicon of Drugs of Abuse Synonyms for Social Media Pharmacovigilance

by Kristy A. Carpenter and Russ B. Altman

Biomolecules 2023, 13(2), 387; https://doi.org/10.3390/biom13020387 - 18 Feb 2023

Cited by 7 | Viewed by 4084

Abstract

Drug abuse is a serious problem in the United States, with over 90,000 drug overdose deaths nationally in 2020. A key step in combating drug abuse is detecting, monitoring, and characterizing its trends over time and location, also known as pharmacovigilance. While federal [...] Read more.

Drug abuse is a serious problem in the United States, with over 90,000 drug overdose deaths nationally in 2020. A key step in combating drug abuse is detecting, monitoring, and characterizing its trends over time and location, also known as pharmacovigilance. While federal reporting systems accomplish this to a degree, they often have high latency and incomplete coverage. Social-media-based pharmacovigilance has zero latency, is easily accessible and unfiltered, and benefits from drug users being willing to share their experiences online pseudo-anonymously. However, unlike highly structured official data sources, social media text is rife with misspellings and slang, making automated analysis difficult. Generative Pretrained Transformer 3 (GPT-3) is a large autoregressive language model specialized for few-shot learning that was trained on text from the entire internet. We demonstrate that GPT-3 can be used to generate slang and common misspellings of terms for drugs of abuse. We repeatedly queried GPT-3 for synonyms of drugs of abuse and filtered the generated terms using automated Google searches and cross-references to known drug names. When generated terms for alprazolam were manually labeled, we found that our method produced 269 synonyms for alprazolam, 221 of which were new discoveries not included in an existing drug lexicon for social media. We repeated this process for 98 drugs of abuse, of which 22 are widely-discussed drugs of abuse, building a lexicon of colloquial drug synonyms that can be used for pharmacovigilance on social media. Full article

(This article belongs to the Special Issue Biomolecular Data Science—in Honor of Professor Philip E. Bourne)

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30 pages, 928 KiB

Open AccessReview

Biomolecules from Macroalgae—Nutritional Profile and Bioactives for Novel Food Product Development

by Laura E. Healy, Xianglu Zhu, Milica Pojić, Carl Sullivan, Uma Tiwari, James Curtin and Brijesh K. Tiwari

Biomolecules 2023, 13(2), 386; https://doi.org/10.3390/biom13020386 - 17 Feb 2023

Cited by 14 | Viewed by 3862

Abstract

Seaweed is in the spotlight as a promising source of nutrition for humans as the search for sustainable food production systems continues. Seaweed has a well-documented rich nutritional profile containing compounds such as polyphenols, carotenoids and polysaccharides as well as proteins, fatty acids [...] Read more.

Seaweed is in the spotlight as a promising source of nutrition for humans as the search for sustainable food production systems continues. Seaweed has a well-documented rich nutritional profile containing compounds such as polyphenols, carotenoids and polysaccharides as well as proteins, fatty acids and minerals. Seaweed processing for the extraction of functional ingredients such as alginate, agar, and carrageenan is well-established. Novel pretreatments such as ultrasound assisted extraction or high-pressure processing can be incorporated to more efficiently extract these targeted ingredients. The scope of products that can be created using seaweed are wide ranging: from bread and noodles to yoghurt and milk and even as an ingredient to enhance the nutritional profile and stability of meat products. There are opportunities for food producers in this area to develop novel food products using seaweed. This review paper discusses the unique properties of seaweed as a food, the processes involved in seaweed aquaculture, and the products that can be developed from this marine biomass. Challenges facing the industry such as consumer hesitation around seaweed products, the safety of seaweed, and processing hurdles will also be discussed. Full article

(This article belongs to the Special Issue Lipids, Proteins and Bioactive Peptides in Food: A Themed Issue Dedicated to Dr. José M. Lorenzo)

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28 pages, 4277 KiB

Open AccessFeature PaperArticle

Improved Assessment of Globularity of Protein Structures and the Ellipsoid Profile of the Biological Assemblies from the PDB

by Mateusz Banach

Biomolecules 2023, 13(2), 385; https://doi.org/10.3390/biom13020385 - 17 Feb 2023

Cited by 1 | Viewed by 1399

Abstract

In this paper, we present an update to the ellipsoid profile algorithm (EP), a simple technique for the measurement of the globularity of protein structures without the calculation of molecular surfaces. The globularity property is understood in this context as the ability of [...] Read more.

In this paper, we present an update to the ellipsoid profile algorithm (EP), a simple technique for the measurement of the globularity of protein structures without the calculation of molecular surfaces. The globularity property is understood in this context as the ability of the molecule to fill a minimum volume enclosing ellipsoid (MVEE) that approximates its assumed globular shape. The more of the interior of this ellipsoid is occupied by the atoms of the protein, the better are its globularity metrics. These metrics are derived from the comparison of the volume of the voxelized representation of the atoms and the volume of all voxels that can fit inside that ellipsoid (a uniform unit Å cube lattice). The so-called ellipsoid profile shows how the globularity changes with the distance from the center. Two of its values, the so-called ellipsoid indexes, are used to classify the structure as globular, semi-globular or non-globular. Here, we enhance the workflow of the EP algorithm via an improved outlier detection subroutine based on principal component analysis. It is capable of robust distinguishing between the dense parts of the molecules and, for example, disordered chain fragments fully exposed to the solvent. The PCA-based method replaces the current approach based on kernel density estimation. The improved EP algorithm was tested on 2124 representatives of domain superfamilies from SCOP 2.08. The second part of this work is dedicated to the survey of globularity of 3594 representatives of biological assemblies from molecules currently deposited in the PDB and analyzed by the 3DComplex database (monomers and complexes up to 60 chains). Full article

(This article belongs to the Collection Biomolecules In Silico: Contemporary Advances in Computational Approaches to Investigating the Molecular Dynamics of Biological Systems)

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13 pages, 2500 KiB

Open AccessFeature PaperArticle

Using Microphysiological System for the Development of Treatments for Joint Inflammation and Associated Cartilage Loss—A Pilot Study

by Meagan J. Makarczyk, Sophie Hines, Haruyo Yagi, Zhong Alan Li, Alyssa M. Aguglia, Justin Zbikowski, Anne-Marie Padget, Qi Gao, Bruce A. Bunnell, Stuart B. Goodman and Hang Lin

Biomolecules 2023, 13(2), 384; https://doi.org/10.3390/biom13020384 - 17 Feb 2023

Cited by 5 | Viewed by 2695

Abstract

Osteoarthritis (OA) is a painful and disabling joint disease affecting millions worldwide. The lack of clinically relevant models limits our ability to predict therapeutic outcomes prior to clinical trials, where most drugs fail. Therefore, there is a need for a model that accurately [...] Read more.

Osteoarthritis (OA) is a painful and disabling joint disease affecting millions worldwide. The lack of clinically relevant models limits our ability to predict therapeutic outcomes prior to clinical trials, where most drugs fail. Therefore, there is a need for a model that accurately recapitulates the whole-joint disease nature of OA in humans. Emerging microphysiological systems provide a new opportunity. We recently established a miniature knee joint system, known as the miniJoint, in which human bone-marrow-derived mesenchymal stem cells (hBMSCs) were used to create an osteochondral complex, synovial-like fibrous tissue, and adipose tissue analogs. In this study, we explored the potential of the miniJoint in developing novel treatments for OA by testing the hypothesis that co-treatment with anti-inflammation and chondroinducing agents can suppress joint inflammation and associated cartilage degradation. Specifically, we created a “synovitis”-relevant OA model in the miniJoint by treating synovial-like tissues with interleukin-1β (IL-1β), and then a combined treatment of oligodeoxynucleotides (ODNs) suppressing the nuclear factor kappa beta (NF-κB) genetic pathway and bone morphogenic protein-7 (BMP-7) was introduced. The combined treatment with BMP-7 and ODNs reduced inflammation in the synovial-like fibrous tissue and showed an increase in glycosaminoglycan formation in the cartilage portion of the osteochondral complex. For the first time, this study demonstrated the potential of the miniJoint in developing disease-modifying OA drugs. The therapeutic efficacy of co-treatment with NF-κB ODNs and BMP-7 can be further validated in future clinical studies. Full article

(This article belongs to the Special Issue Extracellular Factors of Connective Tissues: Regulation of Cell Fate and Disease Modelling Perspectives)

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24 pages, 2578 KiB

Open AccessCommunication

Applied Clinical Tandem Mass Spectrometry-Based Quantification Methods for Lipid-Derived Biomarkers, Steroids and Cannabinoids: Fit-for-Purpose Validation Methods

by Isabelle Matias, Ilaria Belluomo, Pierre-Louis Raux and Monique Vallée

Biomolecules 2023, 13(2), 383; https://doi.org/10.3390/biom13020383 - 17 Feb 2023

Cited by 2 | Viewed by 1608

Abstract

The emergence of metabolomics and quantification approaches is revealing new biomarkers applied to drug discovery. In this context, tandem mass spectrometry is the method of choice, requiring a specific validation process for preclinical and clinical applications. Research on the two classes of lipid [...] Read more.

The emergence of metabolomics and quantification approaches is revealing new biomarkers applied to drug discovery. In this context, tandem mass spectrometry is the method of choice, requiring a specific validation process for preclinical and clinical applications. Research on the two classes of lipid mediators, steroids and cannabinoids, has revealed a potential interaction in cannabis addiction and metabolism-related disorders. Here we present the development of GC-MS/MS and LC-MS/MS methods for routine quantification of targeted steroids and cannabinoids, respectively. The methods were developed using an isotopic approach, including validation for linearity, selectivity, LLOQ determination, matrix effect, carryover, between- and within-run accuracy and precision, and stability tests to measure 11 steroids and seven cannabinoids in human plasma. These methods were satisfactory for most validity conditions, although not all met the acceptance criteria for all analytes. A comparison of calibration curves in biological and surrogate matrices and in methanol showed that the latter condition was more applicable for our quantification of endogenous compounds. In conclusion, the validation of our methods met the criteria for GLP-qualified rather than GLP-validated methods, which can be used for routine analytical studies for dedicated preclinical and clinical purposes, by combining appropriate system suitability testing, including quality controls in the biological matrix. Full article

(This article belongs to the Special Issue Recent Advances in Steroid Research and Nervous System Function)

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15 pages, 807 KiB

Open AccessArticle

Early Use of Corticosteroids following CAR T-Cell Therapy Correlates with Reduced Risk of High-Grade CRS without Negative Impact on Neurotoxicity or Treatment Outcome

by Tim Lakomy, Dilara Akhoundova, Henning Nilius, Marie-Noëlle Kronig, Urban Novak, Michael Daskalakis, Ulrike Bacher and Thomas Pabst

Biomolecules 2023, 13(2), 382; https://doi.org/10.3390/biom13020382 - 17 Feb 2023

Cited by 10 | Viewed by 2531

Abstract

Background: Chimeric antigen receptor T-cell therapy (CAR T-cell therapy) is associated with potentially life-threatening toxicities, most commonly cytokine release syndrome (CRS) and immune-effector-cell-associated neurotoxicity syndrome (ICANS). These frequent adverse events are managed with the IL-6 receptor antagonist tocilizumab and/or corticosteroids. The prophylactic and [...] Read more.

Background: Chimeric antigen receptor T-cell therapy (CAR T-cell therapy) is associated with potentially life-threatening toxicities, most commonly cytokine release syndrome (CRS) and immune-effector-cell-associated neurotoxicity syndrome (ICANS). These frequent adverse events are managed with the IL-6 receptor antagonist tocilizumab and/or corticosteroids. The prophylactic and early use of corticosteroids for CRS and ICANS have previously been reported, but eventual negative impacts on CAR T-cell efficacy are feared. Methods: Retrospective comparative analysis of two patient cohorts with hematological malignancies treated with CAR T-cell therapy: 43 patients received early administration of 10 mg dexamethasone preceding each dose of tocilizumab (“early corticosteroid/ tocilizumab”, EcsTcz cohort) vs. 40 patients who received tocilizumab alone (“tocilizumab alone”, Tcz cohort) for treatment of low-grade CRS. Results: Despite overall higher CRS incidence (91% vs. 70%; p = 0.0249), no high-grade CRS was observed (0% vs. 10%; p = 0.0497) among patients receiving early corticosteroids in combination with tocilizumab. In terms of neurotoxicity, no worsening regarding incidence of ICANS (30% vs. 33%; p = 0.8177) or high-grade ICANS (20% vs. 14%; p = 0.5624) was observed in the EcsTcz cohort. Moreover, overall response rates (80% vs. 77%; p = 0.7936), complete response rates (50% vs. 44%; p = 0.6628), progression-free survival (p = 0.6345) and overall survival (p = 0.1215) were comparable for both cohorts. Conclusions: Our study suggests that the early use of corticosteroids in combination with the standard tocilizumab schedule for low-grade CRS following CAR T-cell therapy may significantly reduce the risk of high-grade CRS without negative impact on neurotoxicity or treatment outcome. Full article

(This article belongs to the Special Issue Immunotherapy and Cancer)

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16 pages, 2376 KiB

Open AccessReview

The Role of Inflammation in The Cellular and Molecular Mechanisms of Cardiopulmonary Complications of Sickle Cell Disease

by Oluwabukola T. Gbotosho, Jahnavi Gollamudi and Hyacinth I. Hyacinth

Biomolecules 2023, 13(2), 381; https://doi.org/10.3390/biom13020381 - 17 Feb 2023

Cited by 3 | Viewed by 2632

Abstract

Cardiopulmonary complications remain the major cause of mortality despite newer therapies and improvements in the lifespan of patients with sickle cell disease (SCD). Inflammation has been identified as a major risk modifier in the pathogenesis of SCD-associated cardiopulmonary complications in recent mechanistic and [...] Read more.

Cardiopulmonary complications remain the major cause of mortality despite newer therapies and improvements in the lifespan of patients with sickle cell disease (SCD). Inflammation has been identified as a major risk modifier in the pathogenesis of SCD-associated cardiopulmonary complications in recent mechanistic and observational studies. In this review, we discuss recent cellular and molecular mechanisms of cardiopulmonary complications in SCD and summarize the most recent evidence from clinical and laboratory studies. We emphasize the role of inflammation in the onset and progression of these complications to better understand the underlying pathobiological processes. We also discuss future basic and translational research in addressing questions about the complex role of inflammation in the development of SCD cardiopulmonary complications, which may lead to promising therapies and reduce morbidity and mortality in this vulnerable population. Full article

(This article belongs to the Special Issue Recent Advances in Cellular and Molecular Mechanisms of Cardiovascular and Metabolic Diseases)

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16 pages, 3340 KiB

Open AccessArticle

Structural Characterization of Nanobodies during Germline Maturation

by Clarissa A. Seidler, Janik Kokot, Monica L. Fernández-Quintero and Klaus R. Liedl

Biomolecules 2023, 13(2), 380; https://doi.org/10.3390/biom13020380 - 17 Feb 2023

Viewed by 1541

Abstract

Camelid heavy-chain antibody variable domains (V_HH), nanobodies, are the smallest-known functional antibody fragments with high therapeutic potential. In this study, we investigate a V_HH binding to hen egg-white lysozyme (HEL). We structurally and dynamically characterized the conformational diversity of [...] Read more.

Camelid heavy-chain antibody variable domains (V_HH), nanobodies, are the smallest-known functional antibody fragments with high therapeutic potential. In this study, we investigate a V_HH binding to hen egg-white lysozyme (HEL). We structurally and dynamically characterized the conformational diversity of four V_HH variants to elucidate the antigen-binding process. For two of these antibodies, not only are the dissociation constants known, but also the experimentally determined crystal structures of the V_HH in complex with HEL are available. We performed well-tempered metadynamics simulations in combination with molecular dynamics simulations to capture a broad conformational space and to reconstruct the thermodynamics and kinetics of conformational transitions in the antigen-binding site, the paratope. By kinetically characterizing the loop movements of the paratope, we found that, with an increase in affinity, the state populations shift towards the binding competent conformation. The contacts contributing to antigen binding, and those who contribute to the overall stability, show a clear trend towards less variable but more intense contacts. Additionally, these investigated nanobodies clearly follow the conformational selection paradigm, as the binding competent conformation pre-exists within the structural ensembles without the presence of the antigen. Full article

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24 pages, 6204 KiB

Open AccessArticle

nWASP Inhibition Increases Wound Healing via TrKb/PLCγ Signalling

by Bethan A. Frugtniet, Fiona Ruge, Andrew J. Sanders, Sioned Owen, Keith G. Harding, Wen G. Jiang and Tracey A. Martin

Biomolecules 2023, 13(2), 379; https://doi.org/10.3390/biom13020379 - 17 Feb 2023

Viewed by 1820

Abstract

(1) Background: Chronic wounds represent a major burden to patients and healthcare systems and identifying new therapeutic targets to encourage wound healing is a significant challenge. This study evaluated nWASP as a new therapeutic target in human wound healing and determined how this [...] Read more.

(1) Background: Chronic wounds represent a major burden to patients and healthcare systems and identifying new therapeutic targets to encourage wound healing is a significant challenge. This study evaluated nWASP as a new therapeutic target in human wound healing and determined how this can be regulated. (2) Methods: Clinical cohorts from patients with chronic wounds were tested for the expression of nWASP and cell models were employed to evaluate the influence of nWASP on cellular functions that are key to the healing process following knockdown and/or the use of nWASP-specific inhibitors. (3) Results: nWASP was significantly elevated at transcript levels in human non-healing chronic wounds versus healing tissues. nWASP inhibitors, wiskostatin and 187-1, along with the knockdown of nWASP, modified both HaCaT and HECV cell behaviour. We then identified two signalling pathways affected by nWASP inhibition: TrkB signalling and downstream PLCγ1 phosphorylation were impaired by nWASP inhibition in HaCaT cells. The healing of wounds in a diabetic murine model was significantly improved with an nWASP inhibitor treatment. (4) Conclusions: This study showed that nWASP activity was related to the non-healing behaviour of chronic wounds and together with the findings in the in vivo models, it strongly suggested nWASP as a therapeutic target in non-healing wounds that are regulated via TrkB and PLCγ1 signalling. Full article

(This article belongs to the Collection Feature Papers in Biological Factors)

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22 pages, 1726 KiB

Open AccessEditor’s ChoiceReview

Mitochondrial Neurodegeneration: Lessons from Drosophila melanogaster Models

by Michele Brischigliaro, Erika Fernandez-Vizarra and Carlo Viscomi

Biomolecules 2023, 13(2), 378; https://doi.org/10.3390/biom13020378 - 16 Feb 2023

Cited by 5 | Viewed by 4880

Abstract

The fruit fly—i.e., Drosophila melanogaster—has proven to be a very useful model for the understanding of basic physiological processes, such as development or ageing. The availability of straightforward genetic tools that can be used to produce engineered individuals makes this model extremely [...] Read more.

The fruit fly—i.e., Drosophila melanogaster—has proven to be a very useful model for the understanding of basic physiological processes, such as development or ageing. The availability of straightforward genetic tools that can be used to produce engineered individuals makes this model extremely interesting for the understanding of the mechanisms underlying genetic diseases in physiological models. Mitochondrial diseases are a group of yet-incurable genetic disorders characterized by the malfunction of the oxidative phosphorylation system (OXPHOS), which is the highly conserved energy transformation system present in mitochondria. The generation of D. melanogaster models of mitochondrial disease started relatively recently but has already provided relevant information about the molecular mechanisms and pathological consequences of mitochondrial dysfunction. Here, we provide an overview of such models and highlight the relevance of D. melanogaster as a model to study mitochondrial disorders. Full article

(This article belongs to the Special Issue Mitochondria and Central Nervous System Disorders II)

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15 pages, 2604 KiB

Open AccessEditor’s ChoiceReview

Opposing Roles of FACT for Euchromatin and Heterochromatin in Yeast

by Shinya Takahata and Yota Murakami

Biomolecules 2023, 13(2), 377; https://doi.org/10.3390/biom13020377 - 16 Feb 2023

Cited by 1 | Viewed by 2309

Abstract

DNA is stored in the nucleus of a cell in a folded state; however, only the necessary genetic information is extracted from the required group of genes. The key to extracting genetic information is chromatin ambivalence. Depending on the chromosomal region, chromatin is [...] Read more.

DNA is stored in the nucleus of a cell in a folded state; however, only the necessary genetic information is extracted from the required group of genes. The key to extracting genetic information is chromatin ambivalence. Depending on the chromosomal region, chromatin is characterized into low-density “euchromatin” and high-density “heterochromatin”, with various factors being involved in its regulation. Here, we focus on chromatin regulation and gene expression by the yeast FACT complex, which functions in both euchromatin and heterochromatin. FACT is known as a histone H2A/H2B chaperone and was initially reported as an elongation factor associated with RNA polymerase II. In budding yeast, FACT activates promoter chromatin by interacting with the transcriptional activators SBF/MBF via the regulation of G1/S cell cycle genes. In fission yeast, FACT plays an important role in the formation of higher-order chromatin structures and transcriptional repression by binding to Swi6, an HP1 family protein, at heterochromatin. This FACT property, which refers to the alternate chromatin-regulation depending on the binding partner, is an interesting phenomenon. Further analysis of nucleosome regulation within heterochromatin is expected in future studies. Full article

(This article belongs to the Special Issue Yeast Models for Gene Regulation)

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12 pages, 2622 KiB

Open AccessArticle

Therapeutic Potential of Phytocannabinoid Cannabigerol for Multiple Sclerosis: Modulation of Microglial Activation In Vitro and In Vivo

by Sigal Fleisher-Berkovich, Yvonne Ventura, Maya Amoyal, Arik Dahan, Valeria Feinshtein, Leenor Alfahel, Adrian Israelson, Nirit Bernstein, Jonathan Gorelick and Shimon Ben-Shabat

Biomolecules 2023, 13(2), 376; https://doi.org/10.3390/biom13020376 - 16 Feb 2023

Cited by 3 | Viewed by 1990

Abstract

Multiple sclerosis (MS) is a widespread chronic neuroinflammatory and neurodegenerative disease. Microglia play a crucial role in the pathogenesis of MS via the release of cytokines and reactive oxygen species, e.g., nitric oxide. Research involving the role of phytocannabinoids in neuroinflammation is currently [...] Read more.

Multiple sclerosis (MS) is a widespread chronic neuroinflammatory and neurodegenerative disease. Microglia play a crucial role in the pathogenesis of MS via the release of cytokines and reactive oxygen species, e.g., nitric oxide. Research involving the role of phytocannabinoids in neuroinflammation is currently receiving much attention. Cannabigerol is a main phytocannabinoid, which has attracted significant pharmacological interest due to its non-psychotropic nature. In this research, we studied the effects of cannabigerol on microglial inflammation in vitro, followed by an in vivo study. Cannabigerol attenuated the microglial production of nitric oxide in BV2 microglia and primary glial cells; concomitant treatment of the cells with cannabigerol and telmisartan (a neuroprotective angiotensin receptor blocker) decreased nitric oxide production additively. Inducible nitric oxide synthase (iNOS) expression was also reduced by cannabigerol. Moreover, tumor necrosis factor-α (TNF-α), a major cytokine involved in MS, was significantly reduced by cannabigerol in both cell cultures. Next, we studied the effects of cannabigerol in vivo using a mice model of MS, experimental autoimmune encephalomyelitis (EAE). The clinical scores of EAE mice were attenuated upon cannabigerol treatment; additionally, lumbar sections of EAE mice showed enhanced neuronal loss (relative to control mice), which was restored by cannabigerol treatment. Altogether, the set of experiments presented in this work indicates that cannabigerol possesses an appealing therapeutic potential for the treatment of MS. Full article

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

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13 pages, 2419 KiB

Open AccessFeature PaperArticle

IgG N-Glycosylation Is Altered in Coronary Artery Disease

by Barbara Radovani, Frano Vučković, Aldo P. Maggioni, Ele Ferrannini, Gordan Lauc and Ivan Gudelj

Biomolecules 2023, 13(2), 375; https://doi.org/10.3390/biom13020375 - 16 Feb 2023

Cited by 7 | Viewed by 2543

Abstract

Coronary artery disease (CAD) is the most common cardiovascular disease (CVD), and previous studies have shown a significant association between N-glycosylation, a highly regulated posttranslational modification, and the development of atherosclerotic plaques. Our aim was to determine whether the N-glycome of immunoglobulin G [...] Read more.

Coronary artery disease (CAD) is the most common cardiovascular disease (CVD), and previous studies have shown a significant association between N-glycosylation, a highly regulated posttranslational modification, and the development of atherosclerotic plaques. Our aim was to determine whether the N-glycome of immunoglobulin G (IgG) is associated with CAD, as N-glycans are known to alter the effector functions of IgG, which may enhance the inflammatory response in CAD. Therefore, in this study, we isolated IgG from subjects with coronary atherosclerosis (CAD+) and from subjects with clean coronaries (CAD−). The purified IgGs were denatured and enzymatically deglycosylated, and the released and fluorescently labelled N-glycans were analysed by ultra-high performance liquid chromatography based on hydrophilic interactions with fluorescence detection (HILIC-UHPLC-FLR). Sex-stratified analysis of 316 CAD− and 156 CAD+ cases revealed differences in IgG N-glycome composition. The most notable differences were observed in women, where the presence of sialylated N-glycan structures was negatively associated with CAD. The obtained chromatograms provide insight into the IgG N-glycome composition in CAD as well as the biomarker potential of IgG N-glycans in CAD. Full article

(This article belongs to the Special Issue Protein Glycosylation and Human Diseases)

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10 pages, 440 KiB

Open AccessReview

Metabolic Activation of PARP as a SARS-CoV-2 Therapeutic Target—Is It a Bait for the Virus or the Best Deal We Could Ever Make with the Virus? Is AMBICA the Potential Cure?

by Prasanth Puthanveetil

Biomolecules 2023, 13(2), 374; https://doi.org/10.3390/biom13020374 - 16 Feb 2023

Cited by 1 | Viewed by 1590

Abstract

The COVID-19 pandemic has had a great impact on global health and is an economic burden. Even with vaccines and anti-viral medications we are still scrambling to get a balance. In this perspective, we have shed light upon an extremely feasible approach by [...] Read more.

The COVID-19 pandemic has had a great impact on global health and is an economic burden. Even with vaccines and anti-viral medications we are still scrambling to get a balance. In this perspective, we have shed light upon an extremely feasible approach by which we can control the SARS-CoV-2 infection and the associated complications, bringing some solace to this ongoing turmoil. We are providing some insights regarding an ideal agent which could prevent SARS-CoV-2 multiplication. If we could identify an agent which is an activator of metabolism and is also bioactive, we could prevent corona activation (AMBICA). Some naturally occurring lipid molecules best fit this identity as an agent which has the capacity to replenish our host cells, specifically immune cells, with ATP. It could also act as a source for providing a substrate for host cell PARP family members for MARylation and PARylation processes, leading to manipulation of the viral macro domain function, resulting in curbing the virulence and propagation of SARS-CoV-2. Identification of the right lipid molecule or combination of lipid molecules will fulfill the criteria. This perspective has focused on a unique angle of host-pathogen interaction and will open up a new dimension in treating COVID-19 infection. Full article

(This article belongs to the Special Issue Metabolic Pathways and COVID-19: Mechanisms and Clinical Implications)

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15 pages, 3239 KiB

Open AccessFeature PaperArticle

Melatonin Activates Anti-Inflammatory Features in Microglia in a Multicellular Context: Evidence from Organotypic Brain Slices and HMC3 Cells

by Sara Merlo, Grazia Ilaria Caruso, Dhwani Sunil Korde, Alla Khodorovska, Christian Humpel and Maria Angela Sortino

Biomolecules 2023, 13(2), 373; https://doi.org/10.3390/biom13020373 - 16 Feb 2023

Cited by 2 | Viewed by 1976

Abstract

Melatonin (MEL) is a neurohormone endowed with neuroprotective activity, exerted both directly on neuronal cells and indirectly through modulation of responsive glial cells. In particular, MEL’s effects on microglia are receptor-mediated and in part dependent on SIRT1 activation. In the present study, we [...] Read more.

Melatonin (MEL) is a neurohormone endowed with neuroprotective activity, exerted both directly on neuronal cells and indirectly through modulation of responsive glial cells. In particular, MEL’s effects on microglia are receptor-mediated and in part dependent on SIRT1 activation. In the present study, we exploited the highly preserved cytoarchitecture of organotypic brain cultures (OC) to explore the effects of MEL on hippocampal microglia in a 3D context as compared to a single cell type context represented by the human HMC3 cell line. We first evaluated the expression of MEL receptor MT1 and SIRT1 and then investigated MEL action against an inflammatory stimulation with LPS: OCs were cultured for a total of 2 weeks and during this time exposed to 0.1 μg/mL of LPS for 24 h either on day 1 (LPS 1°) or on day 11 (LPS 11°). MEL was added immediately after plating and kept for the entire experiment. Under these conditions, both MEL and LPS induced amoeboid microglia. However, the same round phenotype matched different polarization features. LPS increased the number of nuclear-NF-kB+ round cells and MEL alone or in combination with LPS increased BDNF+ round microglia. In addition, MEL contrasted LPS effects on NF-kB expression. Data from HMC3 microglia confirmed MEL’s anti-inflammatory effects against LPS in terms of CASP1 induction and BDNF release, identifying SIRT1 as a mediator. However, no effects were evident for MEL alone on HMC3 microglia. Overall, our results point to the importance of the multicellular context for full MEL activity, especially in a preventive view, and support the use of OCs as a favorable model to explore inflammatory responses. Full article

(This article belongs to the Collection Feature Papers in Biochemistry)

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19 pages, 2944 KiB

Open AccessEditor’s ChoiceReview

Schizophrenia Animal Modeling with Epidermal Growth Factor and Its Homologs: Their Connections to the Inflammatory Pathway and the Dopamine System

by Hidekazu Sotoyama, Hisaaki Namba, Manavu Tohmi and Hiroyuki Nawa

Biomolecules 2023, 13(2), 372; https://doi.org/10.3390/biom13020372 - 15 Feb 2023

Cited by 3 | Viewed by 2640

Abstract

Epidermal growth factor (EGF) and its homologs, such as neuregulins, bind to ErbB (Her) receptor kinases and regulate glial differentiation and dopaminergic/GABAergic maturation in the brain and are therefore implicated in schizophrenia neuropathology involving these cell abnormalities. In this review, we summarize the [...] Read more.

Epidermal growth factor (EGF) and its homologs, such as neuregulins, bind to ErbB (Her) receptor kinases and regulate glial differentiation and dopaminergic/GABAergic maturation in the brain and are therefore implicated in schizophrenia neuropathology involving these cell abnormalities. In this review, we summarize the biological activities of the EGF family and its neuropathologic association with schizophrenia, mainly overviewing our previous model studies and the related articles. Transgenic mice as well as the rat/monkey models established by perinatal challenges of EGF or its homologs consistently exhibit various behavioral endophenotypes relevant to schizophrenia. In particular, post-pubertal elevation in baseline dopaminergic activity may illustrate the abnormal behaviors relevant to positive and negative symptoms as well as to the timing of this behavioral onset. With the given molecular interaction and transactivation of ErbB receptor kinases with Toll-like receptors (TLRs), EGF/ErbB signals are recruited by viral infection and inflammatory diseases such as COVID-19-mediated pneumonia and poxvirus-mediated fibroma and implicated in the immune–inflammatory hypothesis of schizophrenia. Finally, we also discuss the interaction of clozapine with ErbB receptor kinases as well as new antipsychotic development targeting these receptors. Full article

(This article belongs to the Special Issue Neurotrophic Factors and Growth Factors - Historical Perspective and New Directions for Medical Use)

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17 pages, 5379 KiB

Open AccessArticle

Transcriptomic Effects on the Mouse Heart Following 30 Days on the International Space Station

by Alicia L. Veliz, Lana Mamoun, Lorelei Hughes, Richard Vega, Bailey Holmes, Andrea Monteon, Jillian Bray, Michael J. Pecaut and Mary Kearns-Jonker

Biomolecules 2023, 13(2), 371; https://doi.org/10.3390/biom13020371 - 15 Feb 2023

Cited by 3 | Viewed by 2491

Abstract

Efforts to understand the impact of spaceflight on the human body stem from growing interest in long-term space travel. Multiple organ systems are affected by microgravity and radiation, including the cardiovascular system. Previous transcriptomic studies have sought to reveal the changes in gene [...] Read more.

Efforts to understand the impact of spaceflight on the human body stem from growing interest in long-term space travel. Multiple organ systems are affected by microgravity and radiation, including the cardiovascular system. Previous transcriptomic studies have sought to reveal the changes in gene expression after spaceflight. However, little is known about the impact of long-term spaceflight on the mouse heart in vivo. This study focuses on the transcriptomic changes in the hearts of female C57BL/6J mice flown on the International Space Station (ISS) for 30 days. RNA was isolated from the hearts of three flight and three comparable ground control mice and RNA sequencing was performed. Our analyses showed that 1147 transcripts were significantly regulated after spaceflight. The MAPK, PI3K-Akt, and GPCR signaling pathways were predicted to be activated. Transcripts related to cytoskeleton breakdown and organization were upregulated, but no significant change in the expression of extracellular matrix (ECM) components or oxidative stress pathway-associated transcripts occurred. Our results indicate an absence of cellular senescence, and a significant upregulation of transcripts associated with the cell cycle. Transcripts related to cellular maintenance and survival were most affected by spaceflight, suggesting that cardiovascular transcriptome initiates an adaptive response to long-term spaceflight. Full article

(This article belongs to the Special Issue Effects of Weightlessness on Molecular Changes in Cellular Organisms, Animals and Plants)

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