International Journal of Molecular Sciences

16 pages, 1601 KiB

Open AccessArticle

Blood Metabolite Profiling of Antarctic Expedition Members: An ¹H NMR Spectroscopy-Based Study

by Laura Del Coco, Marco Greco, Alessandra Inguscio, Anas Munir, Antonio Danieli, Luca Cossa, Debora Musarò, Maria Rosaria Coscia, Francesco Paolo Fanizzi and Michele Maffia

Int. J. Mol. Sci. 2023, 24(9), 8459; https://doi.org/10.3390/ijms24098459 - 08 May 2023

Cited by 1 | Viewed by 1907

Abstract

Serum samples from eight participants during the XV winter-over at Concordia base (Antarctic expedition) collected at defined time points, including predeparture, constituted the key substrates for a specific metabolomics study. To ascertain acute changes and chronic adaptation to hypoxia, the metabolic profiles of [...] Read more.

Serum samples from eight participants during the XV winter-over at Concordia base (Antarctic expedition) collected at defined time points, including predeparture, constituted the key substrates for a specific metabolomics study. To ascertain acute changes and chronic adaptation to hypoxia, the metabolic profiles of the serum samples were analyzed using NMR spectroscopy, with principal components analysis (PCA) followed by partial least squares and orthogonal partial least squares discriminant analyses (PLS-DA and OPLS-DA) used as supervised classification methods. Multivariate data analyses clearly highlighted an adaptation period characterized by an increase in the levels of circulating glutamine and lipids, mobilized to supply the body energy needs. At the same time, a reduction in the circulating levels of glutamate and N-acetyl glycoproteins, stress condition indicators, and proinflammatory markers were also found in the NMR data investigation. Subsequent pathway analysis showed possible perturbations in metabolic processes, potentially related to the physiological adaptation, predominantly found by comparing the baseline (at sea level, before mission onset), the base arrival, and the mission ending collected values. Full article

(This article belongs to the Special Issue Adaptation to Hypoxia: Beyond the Chimera)

► Show Figures

Figure 1

18 pages, 2843 KiB

Open AccessArticle

GABA_A Receptor β3 Subunit Mutation N328D Heterozygous Knock-in Mice Have Lennox–Gastaut Syndrome

by Gerald Ikemefuna Nwosu, Wangzhen Shen, Kirill Zavalin, Sarah Poliquin, Karishma Randhave, Carson Flamm, Marshall Biven, Katherine Langer and Jing-Qiong Kang

Int. J. Mol. Sci. 2023, 24(9), 8458; https://doi.org/10.3390/ijms24098458 - 08 May 2023

Viewed by 1833

Abstract

Lennox–Gastaut Syndrome (LGS) is a developmental and epileptic encephalopathy (DEE) characterized by multiple seizure types, electroencephalogram (EEG) patterns, and cognitive decline. Its etiology has a prominent genetic component, including variants in GABRB3 that encodes the GABA_A receptor (GABA_AR) β₃ [...] Read more.

Lennox–Gastaut Syndrome (LGS) is a developmental and epileptic encephalopathy (DEE) characterized by multiple seizure types, electroencephalogram (EEG) patterns, and cognitive decline. Its etiology has a prominent genetic component, including variants in GABRB3 that encodes the GABA_A receptor (GABA_AR) β₃ subunit. LGS has an unknown pathophysiology, and few animal models are available for studying LGS. The objective of this study was to evaluate Gabrb3^+/N328D knock-in mice as a model for LGS. We generated a heterozygous knock-in mouse expressing Gabrb3 (c.A982G, p.N238D), a de novo mutation identified in a patient with LGS. We investigated Gabrb3^+/N328D mice for features of LGS. In 2–4-month-old male and female C57BL/J6 wild-type and Gabrb3^+/N328D mice, we investigated seizure severity using video-monitored EEG, cognitive impairment using a suite of behavioral tests, and profiled GABA_AR subunit expression by Western blot. Gabrb3^+/N328D mice showed spontaneous seizures and signs of cognitive impairment, including deficits in spatial learning, memory, and locomotion. Moreover, Gabrb3^+/N328D mice showed reduced β₃ subunit expression in the cerebellum, hippocampus, and thalamus. This phenotype of epilepsy and neurological impairment resembles the LGS patient phenotype. We conclude that Gabrb3^+/N328D mice provide a good model for investigating the pathophysiology and therapeutic intervention of LGS and DEEs. Full article

(This article belongs to the Special Issue Molecular and Cellular Mechanisms of Epilepsy 2.0)

► Show Figures

Figure 1

17 pages, 1339 KiB

Open AccessReview

Recent Developments in Combination Chemotherapy for Colorectal and Breast Cancers with Topoisomerase Inhibitors

by Jung Yoon Jang, Donghwan Kim and Nam Deuk Kim

Int. J. Mol. Sci. 2023, 24(9), 8457; https://doi.org/10.3390/ijms24098457 - 08 May 2023

Cited by 8 | Viewed by 2502

Abstract

DNA topoisomerases are important enzymes that stabilize DNA supercoiling and resolve entanglements. There are two main types of topoisomerases in all cells: type I, which causes single-stranded DNA breaks, and type II, which cuts double-stranded DNA. Topoisomerase activity is particularly increased in rapidly [...] Read more.

DNA topoisomerases are important enzymes that stabilize DNA supercoiling and resolve entanglements. There are two main types of topoisomerases in all cells: type I, which causes single-stranded DNA breaks, and type II, which cuts double-stranded DNA. Topoisomerase activity is particularly increased in rapidly dividing cells, such as cancer cells. Topoisomerase inhibitors have been an effective chemotherapeutic option for the treatment of several cancers. In addition, combination cancer therapy with topoisomerase inhibitors may increase therapeutic efficacy and decrease resistance or side effects. Topoisomerase inhibitors are currently being used worldwide, including in the United States, and clinical trials on the combination of topoisomerase inhibitors with other drugs are currently underway. The primary objective of this review was to comprehensively analyze the current clinical landscape concerning the combined application of irinotecan, an extensively investigated type I topoisomerase inhibitor for colorectal cancer, and doxorubicin, an extensively researched type II topoisomerase inhibitor for breast cancer, while presenting a novel approach for cancer therapy. Full article

(This article belongs to the Special Issue The Discovery, Synthesis and Development of Cancer Therapeutic Agents)

► Show Figures

Figure 1

22 pages, 1252 KiB

Open AccessReview

Protein Aggregates and Aggrephagy in Myopathies

by Sara Gibertini, Alessandra Ruggieri, Marta Cheli and Lorenzo Maggi

Int. J. Mol. Sci. 2023, 24(9), 8456; https://doi.org/10.3390/ijms24098456 - 08 May 2023

Cited by 4 | Viewed by 1837

Abstract

A number of muscular disorders are hallmarked by the aggregation of misfolded proteins within muscle fibers. A specialized form of macroautophagy, termed aggrephagy, is designated to remove and degrade protein aggregates. This review aims to summarize what has been studied so far about [...] Read more.

A number of muscular disorders are hallmarked by the aggregation of misfolded proteins within muscle fibers. A specialized form of macroautophagy, termed aggrephagy, is designated to remove and degrade protein aggregates. This review aims to summarize what has been studied so far about the direct involvement of aggrephagy and the activation of the key players, among others, p62, NBR1, Alfy, Tollip, Optineurin, TAX1BP1 and CCT2 in muscular diseases. In the first part of the review, we describe the aggrephagy pathway with the involved proteins; then, we illustrate the muscular disorder histologically characterized by protein aggregates, highlighting the role of aggrephagy pathway abnormalities in these muscular disorders. Full article

(This article belongs to the Special Issue Molecular and Tissue Engineering Approaches in Musculoskeletal Regenerative Medicine 4.0)

► Show Figures

Figure 1

13 pages, 1340 KiB

Open AccessArticle

Pathogenic Variants of SLC22A12 (URAT1) and SLC2A9 (GLUT9) in Spanish Patients with Renal Hypouricemia: Founder Effect of SLC2A9 Variant c.374C>T; p.(T125M)

by Ana Perdomo-Ramirez, Elizabeth Cordoba-Lanus, Carmen Jane Trujillo-Frias, Carolina Gonzalez-Navasa, Elena Ramos-Trujillo, Maria Isabel Luis-Yanes, Victor Garcia-Nieto and Felix Claverie-Martin

Int. J. Mol. Sci. 2023, 24(9), 8455; https://doi.org/10.3390/ijms24098455 - 08 May 2023

Cited by 1 | Viewed by 1644

Abstract

Renal hypouricemia (RHUC) is a rare inherited disorder characterized by impaired urate reabsorption in the proximal tubule resulting in low urate serum levels and increased urate excretion. Some patients may present severe complications such as exercise-induced acute renal failure and nephrolithiasis. RHUC is [...] Read more.

Renal hypouricemia (RHUC) is a rare inherited disorder characterized by impaired urate reabsorption in the proximal tubule resulting in low urate serum levels and increased urate excretion. Some patients may present severe complications such as exercise-induced acute renal failure and nephrolithiasis. RHUC is caused by inactivating mutations in the SLC22A12 (RHUC type 1) or SLC2A9 (RHUC type 2) genes, which encode urate transporters URAT1 and GLUT9, respectively. In this study, our goal was to identify mutations associated with twenty-one new cases with RHUC through direct sequencing of SLC22A12 and SLC2A9 coding exons. Additionally, we carried out an SNPs-haplotype analysis to determine whether the rare SLC2A9 variant c.374C>T; p.(T125M), which is recurrent in Spanish families with RHUC type 2, had a common-linked haplotype. Six intragenic informative SNPs were analyzed using PCR amplification from genomic DNA and direct sequencing. Our results showed that ten patients carried the SLC22A12 mutation c.1400C>T; p.(T467M), ten presented the SLC2A9 mutation c.374C>T, and one carried a new SLC2A9 heterozygous mutation, c.593G>A; p.(R198H). Patients carrying the SLC2A9 mutation c.374C>T share a common-linked haplotype, confirming that it emerged due to a founder effect. Full article

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

► Show Figures

Figure 1

24 pages, 8768 KiB

Open AccessArticle

Computational and Enzymatic Studies of Sartans in SARS-CoV-2 Spike RBD-ACE2 Binding: The Role of Tetrazole and Perspectives as Antihypertensive and COVID-19 Therapeutics

by Konstantinos Kelaidonis, Irene Ligielli, Spiros Letsios, Veroniki P. Vidali, Thomas Mavromoustakos, Niki Vassilaki, Graham J. Moore, Weronika Hoffmann, Katarzyna Węgrzyn, Harry Ridgway, Christos T. Chasapis and John M. Matsoukas

Int. J. Mol. Sci. 2023, 24(9), 8454; https://doi.org/10.3390/ijms24098454 - 08 May 2023

Cited by 1 | Viewed by 1803

Abstract

This study is an extension of current research into a novel class of synthetic antihypertensive drugs referred to as “bisartans”, which are bis-alkylated imidazole derivatives bearing two symmetric anionic biphenyltetrazoles. Research to date indicates that bisartans are superior to commercially available hypertension drugs, [...] Read more.

This study is an extension of current research into a novel class of synthetic antihypertensive drugs referred to as “bisartans”, which are bis-alkylated imidazole derivatives bearing two symmetric anionic biphenyltetrazoles. Research to date indicates that bisartans are superior to commercially available hypertension drugs, since the former undergo stronger docking to angiotensin-converting enzyme 2 (ACE2). ACE2 is the key receptor involved in SARS-CoV-2 entry, thus initiating COVID-19 infection and in regulating levels of vasoactive peptides such as angiotensin II and beneficial heptapeptides A(1-7) and Alamandine in the renin–angiotensin system (RAS). In previous studies using in vivo rabbit-iliac arterial models, we showed that Na⁺ or K⁺ salts of selected Bisartans initiate a potent dose–response inhibition of vasoconstriction. Furthermore, computational studies revealed that bisartans undergo stable binding to the vital interfacial region between ACE2 and the SARS-CoV-2 “receptor binding domain” (i.e., the viral RBD). Thus, bisartan homologs are expected to interfere with SARS-CoV-2 infection and/or suppress disease expression in humans. The primary goal of this study was to investigate the role of tetrazole in binding and the network of amino acids of SARS-CoV-2 Spike RBD-ACE2 complex involved in interactions with sartans. This study would, furthermore, allow the expansion of the synthetic space to create a diverse suite of new bisartans in conjunction with detailed computational and in vitro antiviral studies. A critical role for tetrazole was uncovered in this study, shedding light on the vital importance of this group in the binding of sartans and bisartans to the ACE2/Spike complex. The in silico data predicting an interaction of tetrazole-containing sartans with ACE2 were experimentally validated by the results of surface plasmon resonance (SPR) analyses performed with a recombinant human ACE2 protein. Full article

(This article belongs to the Special Issue Nutrient Metabolites and Their Receptors in Human Diseases)

► Show Figures

Figure 1

20 pages, 3716 KiB

Open AccessArticle

Inflammasome Coordinates Senescent Chronic Wound Induced by Thalassophryne nattereri Venom

by Carla Lima, Aline Ingrid Andrade-Barros, Fabiana Franco Carvalho, Maria Alice Pimentel Falcão and Monica Lopes-Ferreira

Int. J. Mol. Sci. 2023, 24(9), 8453; https://doi.org/10.3390/ijms24098453 - 08 May 2023

Viewed by 1365

Abstract

Thalassophryne nattereri toadfish (niquim) envenomation, common in the hands and feet of bathers and fishermen in the north and northeast regions of Brazil, is characterized by local symptoms such as immediate edema and intense pain. These symptoms progress to necrosis that lasts for [...] Read more.

Thalassophryne nattereri toadfish (niquim) envenomation, common in the hands and feet of bathers and fishermen in the north and northeast regions of Brazil, is characterized by local symptoms such as immediate edema and intense pain. These symptoms progress to necrosis that lasts for an extended period of time, with delayed healing. Wound healing is a complex process characterized by the interdependent role of keratinocytes, fibroblasts, and endothelial and innate cells such as neutrophils and macrophages. Macrophages and neutrophils are actively recruited to clear debris during the inflammatory phase of wound repair, promoting the production of pro-inflammatory mediators, and in the late stage, macrophages promote tissue repair. Our hypothesis is that injury caused by T. nattereri venom (VTn) leads to senescent wounds. In this study, we provide valuable information about the mechanism(s) behind the dysregulated inflammation in wound healing induced by VTn. We demonstrate in mouse paws injected with the venom the installation of γH2AX/p16^Ink4a-dependent senescence with persistent neutrophilic inflammation in the proliferation and remodeling phases. VTn induced an imbalance of M1/M2 macrophages by maintaining a high number of TNF-α-producing M1 macrophages in the wound but without the ability to eliminate the persistent neutrophils. Chronic neutrophilic inflammation and senescence were mediated by cytokines such as IL-1α and IL-1β in a caspase-1- and caspase-11-dependent manner. In addition, previous blocking with anti-IL-1α and anti-IL-β neutralizing antibodies and caspase-1 (Ac YVAD-CMK) and caspase-11 (Wedelolactone) inhibitors was essential to control the pro-inflammatory activity of M1 macrophages induced by VTn injection, skewing towards an anti-inflammatory state, and was sufficient to block neutrophil recruitment and senescence. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Animal Toxins, Venoms and Antivenoms)

► Show Figures

Figure 1

22 pages, 1404 KiB

Open AccessReview

Oxidative Stress Linking Obesity and Cancer: Is Obesity a ‘Radical Trigger’ to Cancer?

by Mirna Jovanović, Sanja Kovačević, Jelena Brkljačić and Ana Djordjevic

Int. J. Mol. Sci. 2023, 24(9), 8452; https://doi.org/10.3390/ijms24098452 - 08 May 2023

Cited by 4 | Viewed by 2396

Abstract

Obesity is on the rise worldwide, and consequently, obesity-related non-communicable diseases are as well. Nutritional overload induces metabolic adaptations in an attempt to restore the disturbed balance, and the byproducts of the mechanisms at hand include an increased generation of reactive species. Obesity-related [...] Read more.

Obesity is on the rise worldwide, and consequently, obesity-related non-communicable diseases are as well. Nutritional overload induces metabolic adaptations in an attempt to restore the disturbed balance, and the byproducts of the mechanisms at hand include an increased generation of reactive species. Obesity-related oxidative stress causes damage to vulnerable systems and ultimately contributes to neoplastic transformation. Dysfunctional obese adipose tissue releases cytokines and induces changes in the cell microenvironment, promoting cell survival and progression of the transformed cancer cells. Other than the increased risk of cancer development, obese cancer patients experience higher mortality rates and reduced therapy efficiency as well. The fact that obesity is considered the second leading preventable cause of cancer prioritizes the research on the mechanisms connecting obesity to cancerogenesis and finding the solutions to break the link. Oxidative stress is integral at different stages of cancer development and advancement in obese patients. Hypocaloric, balanced nutrition, and structured physical activity are some tools for relieving this burden. However, the sensitivity of simultaneously treating cancer and obesity poses a challenge. Further research on the obesity–cancer liaison would offer new perspectives on prevention programs and treatment development. Full article

(This article belongs to the Special Issue The Crosstalk between Adipose Tissue and Cancer)

► Show Figures

Figure 1

27 pages, 3966 KiB

Open AccessArticle

Beneficial Effects of Probiotic Bifidobacterium longum in a Lithium–Pilocarpine Model of Temporal Lobe Epilepsy in Rats

by Olga E. Zubareva, Alexandra V. Dyomina, Anna A. Kovalenko, Anna I. Roginskaya, Tigran B. Melik-Kasumov, Marina A. Korneeva, Alesya V. Chuprina, Alesya A. Zhabinskaya, Stepan A. Kolyhan, Maria V. Zakharova, Marusya O. Gryaznova and Aleksey V. Zaitsev

Int. J. Mol. Sci. 2023, 24(9), 8451; https://doi.org/10.3390/ijms24098451 - 08 May 2023

Cited by 5 | Viewed by 2112

Abstract

Epilepsy is a challenging brain disorder that is often difficult to treat with conventional therapies. The gut microbiota has been shown to play an important role in the development of neuropsychiatric disorders, including epilepsy. In this study, the effects of Bifidobacterium longum, [...] Read more.

Epilepsy is a challenging brain disorder that is often difficult to treat with conventional therapies. The gut microbiota has been shown to play an important role in the development of neuropsychiatric disorders, including epilepsy. In this study, the effects of Bifidobacterium longum, a probiotic, on inflammation, neuronal degeneration, and behavior are evaluated in a lithium–pilocarpine model of temporal lobe epilepsy (TLE) induced in young adult rats. B. longum was administered orally at a dose of 10⁹ CFU/rat for 30 days after pilocarpine injection. The results show that B. longum treatment has beneficial effects on the TLE-induced changes in anxiety levels, neuronal death in the amygdala, and body weight recovery. In addition, B. longum increased the expression of anti-inflammatory and neuroprotective genes, such as Il1rn and Pparg. However, the probiotic had little effect on TLE-induced astrogliosis and microgliosis and did not reduce neuronal death in the hippocampus and temporal cortex. The study suggests that B. longum may have a beneficial effect on TLE and may provide valuable insights into the role of gut bacteria in epileptogenesis. In addition, the results show that B. longum may be a promising drug for the comprehensive treatment of epilepsy. Full article

(This article belongs to the Special Issue Molecular and Cellular Mechanisms of Epilepsy 2.0)

► Show Figures

Figure 1

15 pages, 2825 KiB

Open AccessArticle

Structural Dynamics Predominantly Determine the Adaptability of Proteins to Amino Acid Deletions

by Anupam Banerjee and Ivet Bahar

Int. J. Mol. Sci. 2023, 24(9), 8450; https://doi.org/10.3390/ijms24098450 - 08 May 2023

Cited by 1 | Viewed by 1374

Abstract

The insertion or deletion (indel) of amino acids has a variety of effects on protein function, ranging from disease-forming changes to gaining new functions. Despite their importance, indels have not been systematically characterized towards protein engineering or modification goals. In the present work, [...] Read more.

The insertion or deletion (indel) of amino acids has a variety of effects on protein function, ranging from disease-forming changes to gaining new functions. Despite their importance, indels have not been systematically characterized towards protein engineering or modification goals. In the present work, we focus on deletions composed of multiple contiguous amino acids (mAA-dels) and their effects on the protein (mutant) folding ability. Our analysis reveals that the mutant retains the native fold when the mAA-del obeys well-defined structural dynamics properties: localization in intrinsically flexible regions, showing low resistance to mechanical stress, and separation from allosteric signaling paths. Motivated by the possibility of distinguishing the features that underlie the adaptability of proteins to mAA-dels, and by the rapid evaluation of these features using elastic network models, we developed a positive-unlabeled learning-based classifier that can be adopted for protein design purposes. Trained on a consolidated set of features, including those reflecting the intrinsic dynamics of the regions where the mAA-dels occur, the new classifier yields a high recall of 84.3% for identifying mAA-dels that are stably tolerated by the protein. The comparative examination of the relative contribution of different features to the prediction reveals the dominant role of structural dynamics in enabling the adaptation of the mutant to mAA-del without disrupting the native fold. Full article

(This article belongs to the Special Issue Artificial Intelligence & Deep Learning Approaches for Structural Bioinformatics)

► Show Figures

Figure 1

18 pages, 7937 KiB

Open AccessArticle

Comprehensive Transcriptomic and Metabolic Profiling of Agrobacterium-tumefaciens-Infected Immature Wheat Embryos

by Weiwei Wang, Jinliang Guo, Jiayang Ma, Zhulin Wang, Lining Zhang, Zixu Wang, Min Meng, Chao Zhang, Fengli Sun and Yajun Xi

Int. J. Mol. Sci. 2023, 24(9), 8449; https://doi.org/10.3390/ijms24098449 - 08 May 2023

Cited by 1 | Viewed by 2199

Abstract

The transformation efficiency (TE) was improved by a series of special chemical and physical methods using immature embryos from the cultivar Fielder, with the PureWheat technique. To analyze the reaction of immature embryos infected, which seemed to provide the necessary by Agrobacterium tumefaciens in [...] Read more.

The transformation efficiency (TE) was improved by a series of special chemical and physical methods using immature embryos from the cultivar Fielder, with the PureWheat technique. To analyze the reaction of immature embryos infected, which seemed to provide the necessary by Agrobacterium tumefaciens in PureWheat, a combination of scanning electron microscopy (SEM), complete transcriptome analysis, and metabolome analysis was conducted to understand the progress. The results of the SEM analysis revealed that Agrobacterium tumefaciens were deposited under the damaged cortex of immature embryos as a result of pretreatment and contacted the receptor cells to improve the TE. Transcriptome analysis indicated that the differentially expressed genes were mainly enriched in phenylpropanoid biosynthesis, starch and sucrose metabolism, plant–pathogen interaction, plant hormone signal transduction, and the MAPK (Mitogen-activated protein kinase) signaling pathway. By analyzing the correlation between differentially expressed genes and metabolites, the expression of many genes and the accumulation of metabolites were changed in glucose metabolism and the TCA cycle (Citrate cycle), as well as the amino acid metabolism; this suggests that the infection of wheat embryos with Agrobacterium is an energy-demanding process. The shikimate pathway may act as a hub between glucose metabolism and phenylpropanoid metabolism during Agrobacterium infection. The downregulation of the F5H gene and upregulation of the CCR gene led to the accumulation of lignin precursors through phenylpropanoid metabolism. In addition, several metabolic pathways and oxidases were found to be involved in the infection treatment, including melatonin biosynthesis, benzoxazinoid biosynthesis, betaine biosynthesis, superoxide dismutase, and peroxidase, suggesting that wheat embryos may be under the stress of Agrobacterium and, thus, undergo an oxidative stress response. These findings explore the physiological and molecular changes of immature embryos during the co-culture stage of the PureWheat technique and provide insights for Agrobacterium-mediated transgenic wheat experiments. Full article

(This article belongs to the Section Molecular Plant Sciences)

► Show Figures

Figure 1

13 pages, 1537 KiB

Open AccessArticle

Bacterial Community Survey of Wolbachia-Infected Parthenogenetic Parasitoid Trichogramma pretiosum (Hymenoptera: Trichogrammatidae) Treated with Antibiotics and High Temperature

by Wei Guo, Meijiao Zhang, Liangguan Lin, Chenxu Zeng, Yuping Zhang and Xiaofang He

Int. J. Mol. Sci. 2023, 24(9), 8448; https://doi.org/10.3390/ijms24098448 - 08 May 2023

Cited by 1 | Viewed by 1634

Abstract

Wolbachia has been shown to induce thelytokous parthenogenesis in Trichogramma species, which have been widely used as biological control agents around the world. Little is known about the changes of bacterial community after restoring arrhenotokous or bisexual reproduction in the T. pretiosum. [...] Read more.

Wolbachia has been shown to induce thelytokous parthenogenesis in Trichogramma species, which have been widely used as biological control agents around the world. Little is known about the changes of bacterial community after restoring arrhenotokous or bisexual reproduction in the T. pretiosum. Here, we investigate the emergence of males of T. pretiosum through curing experiments (antibiotics and high temperature), crossing experiments, and high-throughput 16S ribosomal RNA sequencing (rRNA-seq). The results of curing experiments showed that both antibiotics and high temperatures could cause the thelytokous T. pretiosum to produce male offspring. Wolbachia was dominant in the thelytokous T. pretiosum bacterial community with 99.01% relative abundance. With the relative abundance of Wolbachia being depleted by antibiotics, the diversity and relative content of other endosymbiotic bacteria increased, and the reproductive mode reverted from thelytoky to arrhenotoky in T. pretiosum. Although antibiotics did not eliminate Wolbachia in T. pretiosum, sulfadiazine showed an advantage in restoring entirely arrhenotokous and successive bisexual reproduction. This study was the first to demonstrate the bacterial communities in parthenogenetic Trichogramma before and after antibiotics or high-temperature treatment. Our findings supported the hypothesis that Wolbachia titer-dependence drives a reproduction switch in T. pretiosum between thelytoky and arrhenotoky. Full article

(This article belongs to the Special Issue Insects and Their Derived Products: Emerging Themes and Future Research Directions)

► Show Figures

Figure 1

16 pages, 1557 KiB

Open AccessReview

The Role of BDNF in Multiple Sclerosis Neuroinflammation

by Viviana Nociti and Marina Romozzi

Int. J. Mol. Sci. 2023, 24(9), 8447; https://doi.org/10.3390/ijms24098447 - 08 May 2023

Cited by 10 | Viewed by 2905

Abstract

Multiple sclerosis (MS) is a chronic, inflammatory, and degenerative disease of the central nervous system (CNS). Inflammation is observed in all stages of MS, both within and around the lesions, and can have beneficial and detrimental effects on MS pathogenesis. A possible mechanism [...] Read more.

Multiple sclerosis (MS) is a chronic, inflammatory, and degenerative disease of the central nervous system (CNS). Inflammation is observed in all stages of MS, both within and around the lesions, and can have beneficial and detrimental effects on MS pathogenesis. A possible mechanism for the neuroprotective effect in MS involves the release of brain-derived neurotrophic factor (BDNF) by immune cells in peripheral blood and inflammatory lesions, as well as by microglia and astrocytes within the CNS. BDNF is a neurotrophic factor that plays a key role in neuroplasticity and neuronal survival. This review aims to analyze the current understanding of the role that inflammation plays in MS, including the factors that contribute to both beneficial and detrimental effects. Additionally, it explores the potential role of BDNF in MS, as it may modulate neuroinflammation and provide neuroprotection. By obtaining a deeper understanding of the intricate relationship between inflammation and BDNF, new therapeutic strategies for MS may be developed. Full article

(This article belongs to the Special Issue Neuroinflammation: The Pathogenic Mechanism of Neurological Disorders 2.0)

► Show Figures

Figure 1

18 pages, 6467 KiB

Open AccessArticle

The Enzyme Lysine Malonylation of Calvin Cycle and Gluconeogenesis Regulated Glycometabolism in Nostoc flagelliforme to Adapt to Drought Stress

by Meng Wang, Qiang Zhu, Ning Yao, Wangli Liang, Xiaoxia Ma, Jingjing Li, Xiaoxu Li, Lingxia Wang and Wenyu Liang

Int. J. Mol. Sci. 2023, 24(9), 8446; https://doi.org/10.3390/ijms24098446 - 08 May 2023

Viewed by 1386

Abstract

Lysine malonylation (Kmal) is an evolutionarily conserved post-translational modification (PTM) that has been demonstrated to be involved in cellular and organismal metabolism. However, the role that Kmal plays in response to drought stress of the terrestrial cyanobacteria N. flagelliforme is still unknown. In [...] Read more.

Lysine malonylation (Kmal) is an evolutionarily conserved post-translational modification (PTM) that has been demonstrated to be involved in cellular and organismal metabolism. However, the role that Kmal plays in response to drought stress of the terrestrial cyanobacteria N. flagelliforme is still unknown. In this study, we performed the first proteomic analysis of Kmal in N. flagelliforme under different drought stresses using LC-MS/MS. In total, 421 malonylated lysine residues were found in 236 different proteins. GO and KEGG enrichment analysis indicated that these malonylated proteins were highly enriched in several metabolic pathways, including carbon metabolism and photosynthesis. Decreased malonylation levels were found to hinder the reception and transmission of light energy and CO₂ fixation, which led to a decrease in photosynthetic activity. Kmal was also shown to inhibit the flux of the TCA cycle and activate the gluconeogenesis pathway in response to drought stress. Furthermore, malonylated antioxidant enzymes and antioxidants were synergistically involved in reactive oxygen species (ROS) scavenging. Malonylation was involved in lipid degradation and amino acid biosynthesis as part of drought stress adaptation. This work represents the first comprehensive investigation of the role of malonylation in dehydrated N. flagelliforme, providing an important resource for understanding the drought tolerance mechanism of this organism. Full article

(This article belongs to the Section Molecular Plant Sciences)

► Show Figures

Graphical abstract

21 pages, 900 KiB

Open AccessReview

Non-Alcoholic Fatty Liver Disease and Bone Tissue Metabolism: Current Findings and Future Perspectives

by Oxana M. Drapkina, Anastasia Yu. Elkina, Anna F. Sheptulina and Anton R. Kiselev

Int. J. Mol. Sci. 2023, 24(9), 8445; https://doi.org/10.3390/ijms24098445 - 08 May 2023

Cited by 2 | Viewed by 2346

Abstract

Non-alcoholic fatty liver disease (NAFLD) is reaching epidemic proportions worldwide. Moreover, the prevalence of this liver disease is expected to increase rapidly in the near future, aligning with the rise in obesity and the aging of the population. The pathogenesis of NAFLD is [...] Read more.

Non-alcoholic fatty liver disease (NAFLD) is reaching epidemic proportions worldwide. Moreover, the prevalence of this liver disease is expected to increase rapidly in the near future, aligning with the rise in obesity and the aging of the population. The pathogenesis of NAFLD is considered to be complex and to include the interaction between genetic, metabolic, inflammatory, and environmental factors. It is now well documented that NAFLD is linked to the other conditions common to insulin resistance, such as abnormal lipid levels, metabolic syndrome, and type 2 diabetes mellitus. Additionally, it is considered that the insulin resistance may be one of the main mechanisms determining the disturbances in both bone tissue metabolism and skeletal muscles quality and functions in patients with NAFLD. To date, the association between NAFLD and osteoporosis has been described in several studies, though it worth noting that most of them included postmenopausal women or elderly patients and originated from Asia. However, taking into account the health and economic burdens of NAFLD, and the increasing prevalence of obesity in children and adolescents worldwide, further investigation of the relationship between osteopenia, osteoporosis and sarcopenia in NAFLD, including in young and middle-aged patients, is of great importance. In addition, this will help to justify active screening and surveillance of osteopenia and osteoporosis in patients with NAFLD. In this review, we will discuss various pathophysiological mechanisms and possible biologically active molecules that may interplay between NAFLD and bone tissue metabolism. Full article

(This article belongs to the Topic Clinical, Translational and Basic Research on Liver Diseases, 2nd Volume)

► Show Figures

Figure 1

23 pages, 1227 KiB

Open AccessReview

Autoimmunity: A New Focus on Nasal Polyps

by Jingyu Huang and Yu Xu

Int. J. Mol. Sci. 2023, 24(9), 8444; https://doi.org/10.3390/ijms24098444 - 08 May 2023

Cited by 3 | Viewed by 3153

Abstract

Chronic rhinosinusitis with nasal polyps (CRSwNP) has long been considered a benign, chronic inflammatory, and hyperplastic disease. Recent studies have shown that autoimmune-related mechanisms are involved in the pathology of nasal polyps. Activated plasma cells, eosinophils, basophils, innate type 2 lymphocytes, mast cells, [...] Read more.

Chronic rhinosinusitis with nasal polyps (CRSwNP) has long been considered a benign, chronic inflammatory, and hyperplastic disease. Recent studies have shown that autoimmune-related mechanisms are involved in the pathology of nasal polyps. Activated plasma cells, eosinophils, basophils, innate type 2 lymphocytes, mast cells, and proinflammatory cytokine in polyp tissue indicate the mobilization of innate and adaptive immune pathways during polyp formation. The discovery of a series of autoantibodies further supports the autoimmune nature of nasal polyps. Local homeostasis dysregulation, infection, and chronic inflammation may trigger autoimmunity through several mechanisms, including autoantigens overproduction, microbial translocation, molecular mimicry, superantigens, activation or inhibition of receptors, bystander activation, dysregulation of Toll-Like Receptors (TLRs), epitope spreading, autoantigens complementarity. In this paper, we elaborated on the microbiome-mediated mechanism, abnormal host immunity, and genetic changes to update the role of autoimmunity in the pathogenesis of chronic rhinosinusitis with nasal polyps. Full article

(This article belongs to the Special Issue Recent Advances in Autoimmune and Inflammatory Disorders)

► Show Figures

Figure 1

13 pages, 1760 KiB

Open AccessArticle

NSD Overexpression in the Fat Body Increases Antimicrobial Peptide Production by the Immune Deficiency Pathway in Drosophila

by Chihyun Won, Kyungju Nam, Donghee Ko, Byungjun Kang and Im-Soon Lee

Int. J. Mol. Sci. 2023, 24(9), 8443; https://doi.org/10.3390/ijms24098443 - 08 May 2023

Cited by 1 | Viewed by 1388

Abstract

Nuclear receptor-binding SET domain-containing protein 1 (NSD1) inactivation in tumor cells contributes to an immune-cold phenotype, indicating its potential association with immune disturbances. Drosophila NSD is a homolog of the human NSD1. Thus, in this study, we investigated the effect of NSD overexpression [...] Read more.

Nuclear receptor-binding SET domain-containing protein 1 (NSD1) inactivation in tumor cells contributes to an immune-cold phenotype, indicating its potential association with immune disturbances. Drosophila NSD is a homolog of the human NSD1. Thus, in this study, we investigated the effect of NSD overexpression in the fat body, the central organ involved in Drosophila immune responses. Upon ectopic expression of NSD in the fat body, the mRNA levels of antimicrobial peptides increased. Using reporter constructs containing deletions of various NF-κB sites in the Attacin-A (AttA) promoter, we found that transcriptional activation by NSD is mainly mediated via the IMD pathway by activating Relish. Since the IMD pathway is required to resist Gram-negative bacterial infections, we further examined the effect of fat body-specific NSD overexpression on Drosophila immune defenses. Upon oral ingestion of Gram-negative Pseudomonas entomophila, the survival rate of the NSD-overexpressing larvae was higher than that of the wild type, suggesting a positive role of NSD in immune responses. Taken together, these results suggest the association of NSD with the IMD pathway and is thus expected to contribute to the elucidation of the molecular mechanisms of immune malfunction in various NSD1-associated human diseases. Full article

(This article belongs to the Special Issue Role of Drosophila in Human Disease Research 3.0)

► Show Figures

Figure 1

18 pages, 2828 KiB

Open AccessArticle

Mechanism of ADP-Inhibited ATP Hydrolysis in Single Proton-Pumping F_oF₁-ATP Synthase Trapped in Solution

by Iván Pérez, Thomas Heitkamp and Michael Börsch

Int. J. Mol. Sci. 2023, 24(9), 8442; https://doi.org/10.3390/ijms24098442 - 08 May 2023

Cited by 3 | Viewed by 1848

Abstract

F_oF₁-ATP synthases in mitochondria, in chloroplasts, and in most bacteria are proton-driven membrane enzymes that supply the cells with ATP made from ADP and phosphate. Different control mechanisms exist to monitor and prevent the enzymes’ reverse chemical reaction of [...] Read more.

F_oF₁-ATP synthases in mitochondria, in chloroplasts, and in most bacteria are proton-driven membrane enzymes that supply the cells with ATP made from ADP and phosphate. Different control mechanisms exist to monitor and prevent the enzymes’ reverse chemical reaction of fast wasteful ATP hydrolysis, including mechanical or redox-based blockade of catalysis and ADP inhibition. In general, product inhibition is expected to slow down the mean catalytic turnover. Biochemical assays are ensemble measurements and cannot discriminate between a mechanism affecting all enzymes equally or individually. For example, all enzymes could work more slowly at a decreasing substrate/product ratio, or an increasing number of individual enzymes could be completely blocked. Here, we examined the effect of increasing amounts of ADP on ATP hydrolysis of single Escherichia coli F_oF₁-ATP synthases in liposomes. We observed the individual catalytic turnover of the enzymes one after another by monitoring the internal subunit rotation using single-molecule Förster resonance energy transfer (smFRET). Observation times of single FRET-labeled F_oF₁-ATP synthases in solution were extended up to several seconds using a confocal anti-Brownian electrokinetic trap (ABEL trap). By counting active versus inhibited enzymes, we revealed that ADP inhibition did not decrease the catalytic turnover of all F_oF₁-ATP synthases equally. Instead, increasing ADP in the ADP/ATP mixture reduced the number of remaining active enzymes that operated at similar catalytic rates for varying substrate/product ratios. Full article

(This article belongs to the Special Issue Proton Pumps: Molecular Mechanisms, Inhibitors and Activators of Proton Pumping)

► Show Figures

Figure 1

33 pages, 2010 KiB

Open AccessReview

Ubiquitination Links DNA Damage and Repair Signaling to Cancer Metabolism

by Seo-Young Koo, Eun-Ji Park, Hyun-Ji Noh, Su-Mi Jo, Bo-Kyoung Ko, Hyun-Jin Shin and Chang-Woo Lee

Int. J. Mol. Sci. 2023, 24(9), 8441; https://doi.org/10.3390/ijms24098441 - 08 May 2023

Cited by 3 | Viewed by 3077

Abstract

Changes in the DNA damage response (DDR) and cellular metabolism are two important factors that allow cancer cells to proliferate. DDR is a set of events in which DNA damage is recognized, DNA repair factors are recruited to the site of damage, the [...] Read more.

Changes in the DNA damage response (DDR) and cellular metabolism are two important factors that allow cancer cells to proliferate. DDR is a set of events in which DNA damage is recognized, DNA repair factors are recruited to the site of damage, the lesion is repaired, and cellular responses associated with the damage are processed. In cancer, DDR is commonly dysregulated, and the enzymes associated with DDR are prone to changes in ubiquitination. Additionally, cellular metabolism, especially glycolysis, is upregulated in cancer cells, and enzymes in this metabolic pathway are modulated by ubiquitination. The ubiquitin–proteasome system (UPS), particularly E3 ligases, act as a bridge between cellular metabolism and DDR since they regulate the enzymes associated with the two processes. Hence, the E3 ligases with high substrate specificity are considered potential therapeutic targets for treating cancer. A number of small molecule inhibitors designed to target different components of the UPS have been developed, and several have been tested in clinical trials for human use. In this review, we discuss the role of ubiquitination on overall cellular metabolism and DDR and confirm the link between them through the E3 ligases NEDD4, APC/C^CDH1, FBXW7, and Pellino1. In addition, we present an overview of the clinically important small molecule inhibitors and implications for their practical use. Full article

(This article belongs to the Special Issue DNA Damage, Repair, and Cancer Metabolism)

► Show Figures

Figure 1

25 pages, 7245 KiB

Open AccessArticle

Lateral Root Initiation in Cucumber (Cucumis sativus): What Does the Expression Pattern of Rapid Alkalinization Factor 34 (RALF34) Tell Us?

by Alexey S. Kiryushkin, Elena L. Ilina, Elizaveta D. Guseva, Katharina Pawlowski and Kirill N. Demchenko

Int. J. Mol. Sci. 2023, 24(9), 8440; https://doi.org/10.3390/ijms24098440 - 08 May 2023

Cited by 3 | Viewed by 1997

Abstract

In Arabidopsis, the small signaling peptide (peptide hormone) RALF34 is involved in the gene regulatory network of lateral root initiation. In this study, we aimed to understand the nature of the signals induced by RALF34 in the non-model plant cucumber (Cucumis sativus [...] Read more.

In Arabidopsis, the small signaling peptide (peptide hormone) RALF34 is involved in the gene regulatory network of lateral root initiation. In this study, we aimed to understand the nature of the signals induced by RALF34 in the non-model plant cucumber (Cucumis sativus), where lateral root primordia are induced in the apical meristem of the parental root. The RALF family members of cucumber were identified using phylogenetic analysis. The sequence of events involved in the initiation and development of lateral root primordia in cucumber was examined in detail. To elucidate the role of the small signaling peptide CsRALF34 and its receptor CsTHESEUS1 in the initial stages of lateral root formation in the parental root meristem in cucumber, we studied the expression patterns of both genes, as well as the localization and transport of the CsRALF34 peptide. CsRALF34 is expressed in all plant organs. CsRALF34 seems to differ from AtRALF34 in that its expression is not regulated by auxin. The expression of AtRALF34, as well as CsRALF34, is regulated in part by ethylene. CsTHESEUS1 is expressed constitutively in cucumber root tissues. Our data suggest that CsRALF34 acts in a non-cell-autonomous manner and is not involved in lateral root initiation in cucumber. Full article

(This article belongs to the Special Issue Meristem and Stem Cells and Stem Cell Regulation in Plants)

► Show Figures

Graphical abstract

18 pages, 3261 KiB

Open AccessArticle

Comprehensive Analysis of Rice Seedling Transcriptome during Dehydration and Rehydration

by So Young Park and Dong-Hoon Jeong

Int. J. Mol. Sci. 2023, 24(9), 8439; https://doi.org/10.3390/ijms24098439 - 08 May 2023

Cited by 1 | Viewed by 1735

Abstract

Drought is a harmful abiotic stress that threatens the growth, development, and yield of rice plants. To cope with drought stress, plants have evolved their diverse and sophisticated stress-tolerance mechanisms by regulating gene expression. Previous genome-wide studies have revealed many rice drought stress-responsive [...] Read more.

Drought is a harmful abiotic stress that threatens the growth, development, and yield of rice plants. To cope with drought stress, plants have evolved their diverse and sophisticated stress-tolerance mechanisms by regulating gene expression. Previous genome-wide studies have revealed many rice drought stress-responsive genes that are involved in various forms of metabolism, hormone biosynthesis, and signaling pathways, and transcriptional regulation. However, little is known about the regulation of drought-responsive genes during rehydration after dehydration. In this study, we examined the dynamic gene expression patterns in rice seedling shoots during dehydration and rehydration using RNA-seq analysis. To investigate the transcriptome-wide rice gene expression patterns during dehydration and rehydration, RNA-seq libraries were sequenced and analyzed to identify differentially expressed genes (DEGs). DEGs were classified into five clusters based on their gene expression patterns. The clusters included drought-responsive DEGs that were either rapidly or slowly recovered to control levels by rehydration treatment. Representative DEGs were selected and validated using qRT-PCR. In addition, we performed a detailed analysis of DEGs involved in nitrogen metabolism, phytohormone signaling, and transcriptional regulation. In this study, we revealed that drought-responsive genes were dynamically regulated during rehydration. Moreover, our data showed the potential role of nitrogen metabolism and jasmonic acid signaling during the drought stress response. The transcriptome data in this study could be a useful resource for understanding drought stress responses in rice and provide a valuable gene list for developing drought-resistant crop plants. Full article

(This article belongs to the Special Issue Plant Response to Abiotic Stress 2.0)

► Show Figures

Figure 1

11 pages, 906 KiB

Open AccessCommunication

Analysis of Circulating Tumor DNA in Synchronous Metastatic Colorectal Cancer at Diagnosis Predicts Overall Patient Survival

by José María Sayagués, Juan Carlos Montero, Andrea Jiménez-Pérez, Sofía del Carmen, Marta Rodríguez, Rosario Vidal Tocino, Enrique Montero, Julia Sanz and Mar Abad

Int. J. Mol. Sci. 2023, 24(9), 8438; https://doi.org/10.3390/ijms24098438 - 08 May 2023

Viewed by 1527

Abstract

Sporadic colorectal cancer (sCRC) initially presents as metastatic tumors in 25–30% of patients. The 5-year overall survival (OS) in patients with metastatic sCRC is 50%, falling to 10% in patients presenting with synchronous metastatic disease (stage IV). In this study, we systematically analyzed [...] Read more.

Sporadic colorectal cancer (sCRC) initially presents as metastatic tumors in 25–30% of patients. The 5-year overall survival (OS) in patients with metastatic sCRC is 50%, falling to 10% in patients presenting with synchronous metastatic disease (stage IV). In this study, we systematically analyzed the mutations of RAS, PIK3CA and BRAF genes in circulating tumor DNA (ctDNA) and tumoral tissue DNA (ttDNA) from 51 synchronous metastatic colorectal carcinoma (SMCC) patients by real-time PCR, and their relationship with the clinical, biological and histological features of disease at diagnosis. The highest frequency of mutations detected was in the KRAS gene, in tumor biopsies and plasma samples, followed by mutations of the PIK3CA, NRAS and BRAF genes. Overall, plasma systematically contained those genetic abnormalities observed in the tumor biopsy sample from the same subject, the largest discrepancies detected between the tumor biopsy and plasma from the same patient being for mutations in the KRAS and PIK3CA genes, with concordances of genotyping results between ttDNA and ctDNA at diagnosis of 75% and 84%, respectively. Of the 51 SMCC patients in the study, 25 (49%) showed mutations in at least 1 of the 4 genes analyzed in patient plasma. From the prognostic point of view, the presence and number of the most common mutations in the RAS, PIK3CA and BRAF genes in plasma from SMCC patients are independent prognostic factors for OS. Determination of the mutational status of ctDNA in SMCC could be a key tool for the clinical management of patients. Full article

(This article belongs to the Special Issue Molecular Mechanisms and Therapies of Colorectal Cancer 2.0)

► Show Figures

Figure 1

15 pages, 334 KiB

Open AccessArticle

The Relationship between Insomnia and the Pathophysiology of Major Depressive Disorder: An Evaluation of a Broad Selection of Serum and Urine Biomarkers

by Tina Drinčić, Jens H. van Dalfsen, Jeanine Kamphuis, Mike C. Jentsch, Sjoerd M. van Belkum, Marcus J. M. Meddens, Brenda W. J. H. Penninx and Robert A. Schoevers

Int. J. Mol. Sci. 2023, 24(9), 8437; https://doi.org/10.3390/ijms24098437 - 08 May 2023

Cited by 3 | Viewed by 1568

Abstract

Insomnia exhibits a clinically relevant relationship with major depressive disorder (MDD). Increasing evidence suggests that insomnia is associated with neurobiological alterations that resemble the pathophysiology of MDD. However, research in a clinical population is limited. The present study, therefore, aimed to investigate the [...] Read more.

Insomnia exhibits a clinically relevant relationship with major depressive disorder (MDD). Increasing evidence suggests that insomnia is associated with neurobiological alterations that resemble the pathophysiology of MDD. However, research in a clinical population is limited. The present study, therefore, aimed to investigate the relationship between insomnia and the main pathophysiological mechanisms of MDD in a clinical sample of individuals with MDD. Data were extracted from three cohorts (N = 227) and included an evaluation of depression severity (Quick Inventory of Depressive Symptomatology, QIDS-SR₁₆) and insomnia severity (QIDS-SR₁₆ insomnia items) as well as serum and urine assessments of 24 immunologic (e.g., tumour necrosis factor α receptor 2 and calprotectin), neurotrophic (e.g., brain-derived neurotrophic factor and epidermal growth factor), neuroendocrine (e.g., cortisol and aldosterone), neuropeptide (i.e., substance P), and metabolic (e.g., leptin and acetyl-L-carnitine) biomarkers. Linear regression analyses evaluating the association between insomnia severity and biomarker levels were conducted with and without controlling for depression severity (M = 17.32), antidepressant use (18.9%), gender (59.0% female; 40.5% male), age (M = 42.04), and the cohort of origin. The results demonstrated no significant associations between insomnia severity and biomarker levels. In conclusion, for the included biomarkers, current findings reveal no contribution of insomnia to the clinical pathophysiology of MDD. Full article

(This article belongs to the Special Issue Depression: Molecular Pathology and Modern Therapy)

19 pages, 10741 KiB

Open AccessArticle

Sex-Dependent Impairment of Endothelium-Dependent Relaxation in Aorta of Mice with Overexpression of Hyaluronan in Tunica Media

by Karen Axelgaard Lorentzen, Raquel Hernanz, Estéfano Pinilla, Jens Randel Nyengaard, Lise Wogensen and Ulf Simonsen

Int. J. Mol. Sci. 2023, 24(9), 8436; https://doi.org/10.3390/ijms24098436 - 08 May 2023

Viewed by 1620

Abstract

Diabetic macroangiopathy is characterized by increased extracellular matrix deposition, including excessive hyaluronan accumulation, vessel thickening and stiffness, and endothelial dysfunction in large arteries. We hypothesized that the overexpression of hyaluronan in the tunica media also led to endothelial cell (EC) dysfunction. To address [...] Read more.

Diabetic macroangiopathy is characterized by increased extracellular matrix deposition, including excessive hyaluronan accumulation, vessel thickening and stiffness, and endothelial dysfunction in large arteries. We hypothesized that the overexpression of hyaluronan in the tunica media also led to endothelial cell (EC) dysfunction. To address this hypothesis, we investigated the following in the aortas of mice with excessive hyaluronan accumulation in the tunica media (HAS-2) and wild-type mice: EC dysfunction via myograph studies, nitric oxide (NO) bioavailability via diaminofluorescence, superoxide formation via dihydroethidium fluorescence, and the distances between ECs via stereological methods. EC dysfunction, characterized by blunted relaxations in response to acetylcholine and decreased NO bioavailability, was found in the aortas of male HAS-2 mice, while it was unaltered in the aortas of female HAS-2 mice. Superoxide levels increased and extracellular superoxide dismutase (ecSOD) expression decreased in the aortas of male and female HAS-2 mice. The EC–EC distances and LDL receptor expression were markedly increased in the HAS-2 aortas of male mice. Our findings suggest hyaluronan increases oxidative stress in the vascular wall and that together with increased EC distance, it is associated with a sex-specific decrease in NO levels and endothelial dysfunction in the aorta of male HAS-2 transgenic mice. Full article

(This article belongs to the Special Issue Vascular Endothelial Cells 2.0)

► Show Figures

Graphical abstract

23 pages, 2512 KiB

Open AccessArticle

Redox-Cycling “Mitocans” as Effective New Developments in Anticancer Therapy

by Rumiana Bakalova, Dessislava Lazarova, Akira Sumiyoshi, Sayaka Shibata, Zhivko Zhelev, Biliana Nikolova, Severina Semkova, Tatyana Vlaykova, Ichio Aoki and Tatsuya Higashi

Int. J. Mol. Sci. 2023, 24(9), 8435; https://doi.org/10.3390/ijms24098435 - 08 May 2023

Cited by 1 | Viewed by 1908

Abstract

Our study proposes a pharmacological strategy to target cancerous mitochondria via redox-cycling “mitocans” such as quinone/ascorbate (Q/A) redox-pairs, which makes cancer cells fragile and sensitive without adverse effects on normal cells and tissues. Eleven Q/A redox-pairs were tested on cultured cells and cancer-bearing [...] Read more.

Our study proposes a pharmacological strategy to target cancerous mitochondria via redox-cycling “mitocans” such as quinone/ascorbate (Q/A) redox-pairs, which makes cancer cells fragile and sensitive without adverse effects on normal cells and tissues. Eleven Q/A redox-pairs were tested on cultured cells and cancer-bearing mice. The following parameters were analyzed: cell proliferation/viability, mitochondrial superoxide, steady-state ATP, tissue redox-state, tumor-associated NADH oxidase (tNOX) expression, tumor growth, and survival. Q/A redox-pairs containing unprenylated quinones exhibited strong dose-dependent antiproliferative and cytotoxic effects on cancer cells, accompanied by overproduction of mitochondrial superoxide and accelerated ATP depletion. In normal cells, the same redox-pairs did not significantly affect the viability and energy homeostasis, but induced mild mitochondrial oxidative stress, which is well tolerated. Benzoquinone/ascorbate redox-pairs were more effective than naphthoquinone/ascorbate, with coenzyme Q0/ascorbate exhibiting the most pronounced anticancer effects in vitro and in vivo. Targeted anticancer effects of Q/A redox-pairs and their tolerance to normal cells and tissues are attributed to: (i) downregulation of quinone prenylation in cancer, leading to increased mitochondrial production of semiquinone and, consequently, superoxide; (ii) specific and accelerated redox-cycling of unprenylated quinones and ascorbate mainly in the impaired cancerous mitochondria due to their redox imbalance; and (iii) downregulation of tNOX. Full article

(This article belongs to the Special Issue Mitochondrial Medicine: Pharmacological Targeting of Mitochondria in Disease)

► Show Figures

Figure 1

17 pages, 2795 KiB

Open AccessReview

Functions of Astrocytes under Normal Conditions and after a Brain Disease

by Soraya L. Valles, Sandeep Kumar Singh, Juan Campos-Campos, Carlos Colmena, Ignacio Campo-Palacio, Kenia Alvarez-Gamez, Oscar Caballero and Adrian Jorda

Int. J. Mol. Sci. 2023, 24(9), 8434; https://doi.org/10.3390/ijms24098434 - 08 May 2023

Cited by 7 | Viewed by 6340

Abstract

In the central nervous system (CNS) there are a greater number of glial cells than neurons (between five and ten times more). Furthermore, they have a greater number of functions (more than eight functions). Glia comprises different types of cells, those of neural [...] Read more.

In the central nervous system (CNS) there are a greater number of glial cells than neurons (between five and ten times more). Furthermore, they have a greater number of functions (more than eight functions). Glia comprises different types of cells, those of neural origin (astrocytes, radial glia, and oligodendroglia) and differentiated blood monocytes (microglia). During ontogeny, neurons develop earlier (at fetal day 15 in the rat) and astrocytes develop later (at fetal day 21 in the rat), which could indicate their important and crucial role in the CNS. Analysis of the phylogeny reveals that reptiles have a lower number of astrocytes compared to neurons and in humans this is reversed, as there have a greater number of astrocytes compared to neurons. These data perhaps imply that astrocytes are important and special cells, involved in many vital functions, including memory, and learning processes. In addition, astrocytes are involved in different mechanisms that protect the CNS through the production of antioxidant and anti-inflammatory proteins and they clean the extracellular environment and help neurons to communicate correctly with each other. The production of inflammatory mediators is important to prevent changes in brain homeostasis. On the contrary, excessive, or continued production appears as a characteristic element in many diseases, such as Alzheimer’s disease (AD), amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), and in neurodevelopmental diseases, such as bipolar disorder, schizophrenia, and autism. Furthermore, different drugs and techniques have been developed to reverse oxidative stress and/or excess of inflammation that occurs in many CNS diseases, but much remains to be investigated. This review attempts to highlight the functional relevance of astrocytes in normal and neuropathological conditions by showing the molecular and cellular mechanisms of their role in the CNS. Full article

(This article belongs to the Special Issue Changes Produced by Viruses and Bacteria on the Nervous System)

► Show Figures

Figure 1

23 pages, 2775 KiB

Open AccessReview

The Role of Plant Transcription Factors in the Fight against Plant Viruses

by Kotapati Kasi Viswanath, Song-Yi Kuo, Chin-Wei Tu, Yau-Heiu Hsu, Ying-Wen Huang and Chung-Chi Hu

Int. J. Mol. Sci. 2023, 24(9), 8433; https://doi.org/10.3390/ijms24098433 - 08 May 2023

Cited by 12 | Viewed by 3182

Abstract

Plants are vulnerable to the challenges of unstable environments and pathogen infections due to their immobility. Among various stress conditions, viral infection is a major threat that causes significant crop loss. In response to viral infection, plants undergo complex molecular and physiological changes, [...] Read more.

Plants are vulnerable to the challenges of unstable environments and pathogen infections due to their immobility. Among various stress conditions, viral infection is a major threat that causes significant crop loss. In response to viral infection, plants undergo complex molecular and physiological changes, which trigger defense and morphogenic pathways. Transcription factors (TFs), and their interactions with cofactors and cis-regulatory genomic elements, are essential for plant defense mechanisms. The transcriptional regulation by TFs is crucial in establishing plant defense and associated activities during viral infections. Therefore, identifying and characterizing the critical genes involved in the responses of plants against virus stress is essential for the development of transgenic plants that exhibit enhanced tolerance or resistance. This article reviews the current understanding of the transcriptional control of plant defenses, with a special focus on NAC, MYB, WRKY, bZIP, and AP2/ERF TFs. The review provides an update on the latest advances in understanding how plant TFs regulate defense genes expression during viral infection. Full article

(This article belongs to the Special Issue Molecular Insights into Plant-Biotic Interactions and Crop Yield)

► Show Figures

Figure 1

14 pages, 1652 KiB

Open AccessReview

Clinico-Pathogenic Similarities and Differences between Infection-Related Glomerulonephritis and C3 Glomerulopathy

by Yukihiro Wada, Mariko Kamata, Ryoma Miyasaka, Tetsuya Abe, Sayumi Kawamura, Kazuhiro Takeuchi, Togo Aoyama, Takashi Oda and Yasuo Takeuchi

Int. J. Mol. Sci. 2023, 24(9), 8432; https://doi.org/10.3390/ijms24098432 - 08 May 2023

Cited by 5 | Viewed by 3245

Abstract

Recently, the comprehensive concept of “infection-related glomerulonephritis (IRGN)” has replaced that of postinfectious glomerulonephritis (PIGN) because of the diverse infection patterns, epidemiology, clinical features, and pathogenesis. In addition to evidence of infection, hypocomplementemia particularly depresses serum complement 3 (C3), with endocapillary proliferative and [...] Read more.

Recently, the comprehensive concept of “infection-related glomerulonephritis (IRGN)” has replaced that of postinfectious glomerulonephritis (PIGN) because of the diverse infection patterns, epidemiology, clinical features, and pathogenesis. In addition to evidence of infection, hypocomplementemia particularly depresses serum complement 3 (C3), with endocapillary proliferative and exudative GN developing into membranoproliferative glomerulonephritis (MPGN); also, C3-dominant or co-dominant glomerular immunofluorescence staining is central for diagnosing IRGN. Moreover, nephritis-associated plasmin receptor (NAPlr), originally isolated from the cytoplasmic fraction of group A Streptococci, is vital as an essential inducer of C3-dominant glomerular injury and is a key diagnostic biomarker for IRGN. Meanwhile, “C3 glomerulopathy (C3G)”, also showing a histological pattern of MPGN due to acquired or genetic dysregulation of the complement alternative pathway (AP), mimics C3-dominant IRGN. Initially, C3G was characterized by intensive “isolated C3” deposition on glomeruli. However, updated definitions allow for glomerular deposition of other complement factors or immunoglobulins if C3 positivity is dominant and at least two orders of magnitude greater than any other immunoreactant, which makes it challenging to quickly distinguish pathomorphological findings between IRGN and C3G. As for NAPlr, it was demonstrated to induce complement AP activation directly in vitro, and it aggravates glomerular injury in the development of IRGN. A recent report identified anti-factor B autoantibodies as a contributing factor for complement AP activation in pediatric patients with PIGN. Moreover, C3G with glomerular NAPlr deposition without evidence of infection was reported. Taken together, the clinico-pathogenic features of IRGN overlap considerably with those of C3G. In this review, similarities and differences between the two diseases are highlighted. Full article

(This article belongs to the Special Issue Infection and the Kidney 2.0)

► Show Figures

Figure 1

3 pages, 457 KiB

Open AccessEditorial

Editorial for the IJMS Special Issue on “Infection and the Kidney”

by Takashi Oda

Int. J. Mol. Sci. 2023, 24(9), 8431; https://doi.org/10.3390/ijms24098431 - 08 May 2023

Viewed by 880

Abstract

The coronavirus disease (COVID-19) pandemic has highlighted the close relationship between infection and kidney injury [...] Full article

(This article belongs to the Special Issue Infection and the Kidney)

► Show Figures

Figure 1

13 pages, 2249 KiB

Open AccessArticle

The Functional Characterization of DzCYP72A12-4 Related to Diosgenin Biosynthesis and Drought Adaptability in Dioscorea zingiberensis

by Weipeng Wang, Lixiu Hou, Song Li and Jiaru Li

Int. J. Mol. Sci. 2023, 24(9), 8430; https://doi.org/10.3390/ijms24098430 - 08 May 2023

Cited by 2 | Viewed by 1169

Abstract

Dioscorea zingiberensis is a perennial herb famous for the production of diosgenin, which is a valuable initial material for the industrial synthesis of steroid drugs. Sterol C26-hydroxylases, such as TfCYP72A616 and PpCYP72A613, play an important role in the diosgenin biosynthesis pathway. [...] Read more.

Dioscorea zingiberensis is a perennial herb famous for the production of diosgenin, which is a valuable initial material for the industrial synthesis of steroid drugs. Sterol C26-hydroxylases, such as TfCYP72A616 and PpCYP72A613, play an important role in the diosgenin biosynthesis pathway. In the present study, a novel gene, DzCYP72A12-4, was identified as C26-hydroxylase and was found to be involved in diosgenin biosynthesis, for the first time in D. zingiberensis, using comprehensive methods. Then, the diosgenin heterogenous biosynthesis pathway starting from cholesterol was created in stable transgenic tobacco (Nicotiana tabacum L.) harboring DzCYP90B71(QPZ88854), DzCYP90G6(QPZ88855) and DzCYP72A12-4. Meanwhile, diosgenin was detected in the transgenic tobacco using an ultra-performance liquid chromatography system (Vanquish UPLC 689, Thermo Fisher Scientific, Bremen, Germany) tandem MS (Q Exactive Hybrid Quadrupole-Orbitrap Mass Spectrometer, Thermo Fisher Scientific, Bremen, Germany). Further RT-qPCR analysis showed that DzCYP72A12-4 was highly expressed in both rhizomes and leaves and was upregulated under 15% polyethylene glycol (PEG) treatment, indicating that DzCYP72A12-4 may be related to drought resistance. In addition, the germination rate of the diosgenin-producing tobacco seeds was higher than that of the negative controls under 15% PEG pressure. In addition, the concentration of malonaldehyde (MDA) was lower in the diosgenin-producing tobacco seedlings than those of the control, indicating higher drought adaptability. The results of this study provide valuable information for further research on diosgenin biosynthesis in D. zingiberensis and its functions related to drought adaptability. Full article

(This article belongs to the Special Issue Role of Steroids and Triterpenoids in Plant Growth, Development and Stress Response)

► Show Figures

Figure 1

Journal Menu

Journal Browser

Int. J. Mol. Sci., Volume 24, Issue 9 (May-1 2023) – 780 articles

Further Information

Guidelines

MDPI Initiatives

Follow MDPI