bluuebunny/crossref_metadata_2025 huggingface dataset:
Three-Month vs. One-Year Detraining Effects after Multicomponent Exercise Program in Hypertensive Older Women
Authors: Leitão Luis , Marocolo Moacir , de Souza Hiago L. R. , Arriel Rhai André , Campos Yuri , Mazini Mauro , Junior Ricardo Pace , Figueiredo Teresa , Louro Hugo , Pereira Ana
Published: March 2022

Background: Chronic diseases are the leading causes of death and disability in older women. Physical exercise training programs promote beneficial effects for health and quality of life. However, exercise interruption periods may be detrimental for the hemodynamic and lipidic profiles of hypertensive older women with dyslipidemia. Methods: Nineteen hypertensive older women with dyslipidemia (exercise group: 67.5 ± 5.4 years, 1.53 ± 3.42 m, 71.84 ± 7.45 kg) performed a supervised multicomponent exercise training program (METP) during nine months, followed by a one-year detraining period (DT), while fourteen hypertensive older women (control group: 66.4 ± 5.2 years, 1.56 ± 3.10 m, 69.38 ± 5.24 kg) with dyslipidemia kept their continued daily routine without exercise. For both groups, hemodynamic and lipidic profiles and functional capacities (FCs) were assessed four times: before and after the METP and after 3 and 12 months of DT (no exercise was carried out). Results: The METP improved hemodynamic and lipidic profiles (p < 0.05), while three months of DT decreased all (p < 0.05) parameters, with the exception of diastolic blood pressure (DBP). One year of DT significantly (p < 0.01) decreased systolic blood pressure (7.85%), DBP (2.29%), resting heart rate (7.95%), blood glucose (19.14%), total cholesterol (10.27%), triglycerides (6.92%) and FC—agility (4.24%), lower- (−12.75%) and upper-body strength (−12.17%), cardiorespiratory capacity (−4.81%) and lower- (−16.16%) and upper-body flexibility (−11.11%). Conclusion: Nine months of the exercise program significantly improved the hemodynamic and lipid profiles as well as the functional capacities of hypertensive older women with dyslipidemia. Although a detraining period is detrimental to these benefits, it seems that the first three months are more prominent in these alterations.
Maritime Environment Assessment and Management Using through Balanced Scorecard by Using DEMATEL and ANP Technique
Authors: Lin Wen Cheng
Published: March 2022

Previous studies have found that the occurrence of maritime accidents often lacks a sound environment management mechanism. The reason is that maritime safety needs management functions to promote each other. This study aims to assess the risk analysis of maritime accidents, applying balanced scorecard (BSC) concepts integrating decision-making trial and evaluation laboratory (DEMATEL) with analytic network process (ANP). The empirical results are that the balanced scorecard could be applied as a maritime procedure management method in maritime risk analysis. A total of 30 questionnaires were collected via scholar questionnaire, and five criteria or key factors for strengthening risk assessment of marine accidents were determined. According to the application of BSC, the risk analysis criteria constructed can assist maritime authorities to reduce the maritime accidents.
A Cybercartographic Atlas of the Sky: Cybercartography, Interdisciplinary and Collaborative Work among the Pa Ipai Indigenous Families from Baja California, Mexico
Authors: Domínguez Núñez Martín Cuitzeo
Published: March 2022

In this article, I discuss how sky mapping was carried out among the Pa Ipai peoples from Baja California in Mexico. This mapping was elaborated through an interdisciplinary study that combined cybercartography, ethnography, cultural astronomy, semiotics, and collaborative work. The central argument of the article focuses on how the cybercartographic sky atlas of the Pa Ipai people responded to the situation and social problems of these communities. Some of these problems are extreme poverty, violence, and conflicts with the Mexican state and the academic world. In this context, the atlas and the collaborative work became tools that created links with indigenous families, especially with the young people. The mapping process also helped to resolve the tensions mentioned above. The article also addresses how the economic and political situation in Mexico has an effect on the preservation of the atlas. Some of the results of this work are that the Pai Ipai atlas allows, conserves, and renews songs, stories, and experiences around heaven. Another remarkable result is that the teenagers have positively received the atlas and the collaborative experience derived from it.
Bone Reconstruction Using Two-Layer Porcine-Derived Bone Scaffold Composed of Cortical and Cancellous Bones in a Rabbit Calvarial Defect Model
Authors: Seo Yong-Ho , Hwang Su-Hyun , Kim Yu-Na , Kim Hyung-Joon , Bae Eun-Bin , Huh Jung-Bo
Published: March 2022

In this study, we aimed to investigate the bone regeneration efficiency of two-layer porcine-derived bone scaffolds composed of cancellous and cortical bones in a rabbit calvarial defect model. Four circular calvaria defects were formed on cranium of rabbit and were filled with block bone scaffolds of each group: cortical bone block (Cortical group), cancellous bone block (Cancellous group), and two-layer bone block (2layer group). After 8 weeks, new bones were primarily observed in cancellous parts of the Cancellous and 2layer groups, while the Cortical group exhibited few new bones. In the results of new bone volume and area analyses, the Cancellous group showed the highest value, followed by the 2layer group, and were significantly higher than the Cortical group. Within the limitations of this study, the cancellous and two-layer porcine-derived bone scaffolds showed satisfactory bone regeneration efficiency; further studies on regulating the ratio of cortical and cancellous bones in two-layer bones are needed.
Functional Conversion of Acetyl-Coenzyme a Synthase to a Nickel Superoxide Dismutase via Rational Design of Coordination Microenvironment for the Nid-Site
Authors: Wei Yaozhu , Zhou Yajun , Yuan Hong , Liu Yi , Lin Ying-Wu , Su Jihu , Tan Xiangshi
Published: March 2022

The Nid site coordination microenvironment of a truncated acetyl-coenzyme A synthase has been designed systematically for functional conversion to a Ni-SOD-like enzyme. To this end, the first strategy is to introduce an axial histidine ligand, using mutations F598H, S594H and S594H-GP individually. The resulting three mutants obtained Ni-SOD-like activity successfully, although the catalytic activity was about 10-fold lower than in native Ni-SOD. The second strategy is to mimic the H-bond network in the second sphere coordination microenvironment of the native Ni-SOD. Two mutations based on F598H (EFG-F598H and YGP-F598H) were designed. The successful EFG-F598H exhibited ~3-fold Ni-SOD-like activity of F598H. These designed Ni-SOD-like metalloproteins were characterized by UV/Vis, EPR and Cyclic voltammetry while F598H was also characterized by X-ray protein crystallography. The pH titrations were performed to reveal the source of the two protons required for forming H2O2 in the SOD catalytic reaction. Based on all of the results, a proposed catalytic mechanism for the Ni-SOD-like metalloproteins is presented.
CabZIP23 Integrates in CabZIP63–CaWRKY40 Cascade and Turns CabZIP63 on Mounting Pepper Immunity against Ralstonia solanacearum via Physical Interaction
Authors: Lu Qiaoling , Huang Yu , Wang Hui , Wan Meiyun , Lv Jingang , Cheng Xingge , Chen Yuanhui , Cai Weiwei , Yang Sheng , Shen Lei , Guan Deyi , He Shuilin
Published: March 2022

CabZIP63 and CaWRKY40 were previously found to be shared in the pepper defense response to high temperature stress (HTS) and to Ralstonia solanacearum inoculation (RSI), forming a transcriptional cascade. However, how they activate the two distinct defense responses is not fully understood. Herein, using a revised genetic approach, we functionally characterized CabZIP23 in the CabZIP63–CaWRKY40 cascade and its context specific pepper immunity activation against RSI by interaction with CabZIP63. CabZIP23 was originally found by immunoprecipitation-mass spectrometry to be an interacting protein of CabZIP63-GFP; it was upregulated by RSI and acted positively in pepper immunity against RSI by virus induced gene silencing in pepper plants, and transient overexpression in Nicotiana benthamiana plants. By chromatin immunoprecipitation (ChIP)-qPCR and electrophoresis mobility shift assay (EMSA), CabZIP23 was found to be directly regulated by CaWRKY40, and CabZIP63 was directly regulated by CabZIP23, forming a positive feedback loop. CabZIP23–CabZIP63 interaction was confirmed by co-immunoprecipitation (CoIP) and bimolecular fluorescent complimentary (BiFC) assays, which promoted CabZIP63 binding immunity related target genes, including CaPR1, CaNPR1 and CaWRKY40, thereby enhancing pepper immunity against RSI, but not affecting the expression of thermotolerance related CaHSP24. All these data appear to show that CabZIP23 integrates in the CabZIP63–CaWRKY40 cascade and the context specifically turns it on mounting pepper immunity against RSI.
Molecular Imaging and Nanotechnology—Emerging Tools in Diagnostics and Therapy
Authors: Woźniak Marcin , Płoska Agata , Siekierzycka Anna , Dobrucki Lawrence W. , Kalinowski Leszek , Dobrucki Iwona T.
Published: March 2022

Personalized medicine is emerging as a new goal in the diagnosis and treatment of diseases. This approach aims to establish differences between patients suffering from the same disease, which allows to choose the most effective treatment. Molecular imaging (MI) enables advanced insight into molecule interactions and disease pathology, improving the process of diagnosis and therapy and, for that reason, plays a crucial role in personalized medicine. Nanoparticles are widely used in MI techniques due to their size, high surface area to volume ratio, and multifunctional properties. After conjugation to specific ligands and drugs, nanoparticles can transport therapeutic compounds directly to their area of action and therefore may be used in theranostics—the simultaneous implementation of treatment and diagnostics. This review summarizes different MI techniques, including optical imaging, ultrasound imaging, magnetic resonance imaging, nuclear imaging, and computed tomography imaging with theranostics nanoparticles. Furthermore, it explores the potential use of constructs that enables multimodal imaging and track diseases in real time.
Evidence of a Gastro-Duodenal Effect on Adipose Tissue and Brain Metabolism, Potentially Mediated by Gut–Liver Inflammation: A Study with Positron Emission Tomography and Oral 18FDG in Mice
Authors: Guzzardi Maria Angela , La Rosa Federica , Campani Daniela , Cacciato Insilla Andrea , Nannipieri Monica , Brunetto Maurizia Rossana , Bonino Ferruccio , Iozzo Patricia
Published: March 2022

Interventions affecting gastrointestinal (GI) physiology suggest that the GI tract plays an important role in modulating the uptake of ingested glucose by body tissues. We aimed at validating the use of positron emission tomography (PET) with oral 18FDG administration in mice, and to examine GI effects on glucose metabolism in adipose tissues, brain, heart, muscle, and liver, and interfering actions of oral lipid co-administration. We performed sequential whole-body PET studies in 3 groups of 10 mice, receiving i.p. glucose and 18FDG or oral glucose and 18FDG ± lipids, to measure tissue glucose uptake (GU) and GI transit, and compute the absorption lumped constant (LCa) as ratio of oral 18FDG-to-glucose incremental blood levels. GI and liver histology and circulating hormones were tested to generate explanatory hypothesis. Median LCa was 1.18, constant over time and not significantly affected by lipid co-ingestion. Compared to the i.p. route, the oral route (GI effect) resulted in lower GU rates in adipose tissues and brain, and a greater steatohepatitis score (+17%, p = 0.03). Lipid co-administration accelerated GI transit, in relation to the suppression in GIP, GLP1, glucagon, PP, and PYY (GI motility regulators), abolishing GI effects on subcutaneous fat GU. Duodenal crypt size, gastric wall 18FDG uptake, and macro-vesicular steatosis were inversely related to adipose tissue GU, and positively associated with liver GU. We conclude that 18FDG-PET is a suitable tool to examine the role of the GI tract on glucose transit, absorption, and bio-distribution. The GI effect consists in the suppression of glucose metabolism selectively in organs responsible for energy intake and storage, and is blunted by lipid ingestion. Modulation of gut and liver inflammation, as reflected by high GU, may be involved in the acute signalling of the energy status.
The Role of Endothelial Progenitor Cells in Atherosclerosis and Impact of Anti-Lipemic Treatments on Endothelial Repair
Authors: Altabas Velimir , Biloš Lora Stanka Kirigin
Published: March 2022

Cardiovascular complications are associated with advanced atherosclerosis. Although atherosclerosis is still regarded as an incurable disease, at least in its more advanced stages, the discovery of endothelial progenitor cells (EPCs), with their ability to replace old and injured cells and differentiate into healthy and functional mature endothelial cells, has shifted our view of atherosclerosis as an incurable disease, and merged traditional theories of atherosclerosis pathogenesis with evolving concepts of vascular biology. EPC alterations are involved in the pathogenesis of vascular abnormalities in atherosclerosis, but many questions remain unanswered. Many currently available drugs that impact cardiovascular morbidity and mortality have shown a positive effect on EPC biology. This review examines the role of endothelial progenitor cells in atherosclerosis development, and the impact standard antilipemic drugs, including statins, fibrates, and ezetimibe, as well as more novel treatments such as proprotein convertase subtilisin/kexin type 9 (PCSK9) modulating agents and angiopoietin-like proteins (Angtpl3) inhibitors have on EPC biology.
Tamoxifen Exerts Anticancer Effects on Pituitary Adenoma Progression via Inducing Cell Apoptosis and Inhibiting Cell Migration
Authors: Lv Tingting , Zhang Zirui , Yu Haoying , Ren Shuyue , Wang Jingrong , Li Shang , Sun Lan
Published: March 2022

Although pituitary adenomas are histologically benign, they are often accompanied by multiple complications, such as cardiovascular disease and metabolic dysfunction. In the present study, we repositioned the Food and Drug Administration -approved immune regulator tamoxifen to target STAT6 based on the genomics analysis of PAs. Tamoxifen inhibited the proliferation of GH3 and AtT-20 cells with respective IC50 values of 9.15 and 7.52 μM and increased their apoptotic rates in a dose-dependent manner. At the molecular level, tamoxifen downregulated phosphorylated PI3K, phosphorylated AKT and the anti-apoptotic protein Bcl-2 and increased the expression of pro-apoptotic proteins p53 and Bax in GH3 and AtT-20 cells. Furthermore, tamoxifen also inhibited the migration of both cell lines by reprogramming tumor-associated macrophages to the M1 phenotype through STAT6 inactivation and inhibition of the macrophage-specific immune checkpoint SHP1/SHP. Finally, administration of tamoxifen (20, 50, 100 mg·kg−1·d−1, for 21 days) inhibited the growth of pituitary adenomas xenografts in nude mice in a dose-dependent manner. Taken together, tamoxifen is likely to be a promising combination therapy for pituitary adenomas and should be investigated further.
Kupffer Cells and Blood Monocytes Orchestrate the Clearance of Iron–Carbohydrate Nanoparticles from Serum
Authors: Arsiwala Tasneem , Vogt Anne-Cathrine S. , Barton Amy E. , Manolova Vania , Funk Felix , Flühmann Beat , Bachmann Martin F.
Published: March 2022

Intravenous (IV) iron nanoparticle preparations are widely used to treat iron deficiency. The mechanism of mononuclear phagocyte system-mediated clearance of IV iron nanoparticles is unknown. The early uptake and homeostasis of iron after injection of ferric carboxymaltose (FCM) in mice was studied. An increase in serum iron was observed at 2.5 h followed by a return to baseline by 24 h. An increase in circulating monocytes was observed, particularly Ly6Chi and Ly6Clow. FCM was also associated with a time-dependent decrease in liver Kupffer cells (KCs) and increase in liver monocytes. The increase in liver monocytes suggests an influx of iron-rich blood monocytes, while some KCs underwent apoptosis. Adoptive transfer experiments demonstrated that following liver infiltration, blood monocytes differentiated to KCs. KCs were also critical for IV iron uptake and biodegradation. Indeed, anti-Colony Stimulating Factor 1 Receptor (CSF1R)-mediated depletion of KCs resulted in elevated serum iron levels and impaired iron uptake by the liver. Gene expression profiling indicated that C-C chemokine receptor type 5 (CCR5) might be involved in monocyte recruitment to the liver, confirmed by pharmaceutical inhibition of CCR5. Liver KCs play a pivotal role in the clearance and storage of IV iron and KCs appear to be supported by the expanded blood monocyte population.
New Perspectives to Improve Mesenchymal Stem Cell Therapies for Drug-Induced Liver Injury
Authors: Ezquer Fernando , Huang Ya-Lin , Ezquer Marcelo
Published: March 2022

Drug-induced liver injury (DILI) is one of the leading causes of acute liver injury. Many factors may contribute to the susceptibility of patients to this condition, making DILI a global medical problem that has an impact on public health and the pharmaceutical industry. The use of mesenchymal stem cells (MSCs) has been at the forefront of regenerative medicine therapies for many years, including MSCs for the treatment of liver diseases. However, there is currently a huge gap between these experimental approaches and their application in clinical practice. In this concise review, we focus on the pathophysiology of DILI and highlight new experimental approaches conceived to improve cell-based therapy by the in vitro preconditioning of MSCs and/or the use of cell-free products as treatment for this liver condition. Finally, we discuss the advantages of new approaches, but also the current challenges that must be addressed in order to develop safer and more effective procedures that will allow cell-based therapies to reach clinical practice, enhancing the quality of life and prolonging the survival time of patients with DILI.
MISF2 Encodes an Essential Mitochondrial Splicing Cofactor Required for nad2 mRNA Processing and Embryo Development in Arabidopsis thaliana
Authors: Nguyen Tan-Trung , Best Corinne , Shevtsov Sofia , Zmudjak Michal , Quadrado Martine , Mizrahi Ron , Zer Hagit , Mireau Hakim , Ostersetzer-Biran Oren
Published: March 2022

Mitochondria play key roles in cellular energy metabolism in eukaryotes. Mitochondria of most organisms contain their own genome and specific transcription and translation machineries. The expression of angiosperm mtDNA involves extensive RNA-processing steps, such as RNA trimming, editing, and the splicing of numerous group II-type introns. Pentatricopeptide repeat (PPR) proteins are key players in plant organelle gene expression and RNA metabolism. In the present analysis, we reveal the function of the MITOCHONDRIAL SPLICING FACTOR 2 gene (MISF2, AT3G22670) and show that it encodes a mitochondria-localized PPR protein that is crucial for early embryo development in Arabidopsis. Molecular characterization of embryo-rescued misf2 plantlets indicates that the splicing of nad2 intron 1, and thus respiratory complex I biogenesis, are strongly compromised. Moreover, the molecular function seems conserved between MISF2 protein in Arabidopsis and its orthologous gene (EMP10) in maize, suggesting that the ancestor of MISF2/EMP10 was recruited to function in nad2 processing before the monocot–dicot divergence ~200 million years ago. These data provide new insights into the function of nuclear-encoded factors in mitochondrial gene expression and respiratory chain biogenesis during plant embryo development.
Identification and DNA Marker Development for a Wheat-Leymus mollis 2Ns (2D) Disomic Chromosome Substitution
Authors: Feng Xianbo , Du Xin , Wang Siwen , Deng Pingchuan , Wang Yongfu , Shang Lihui , Tian Zengrong , Wang Changyou , Chen Chunhuan , Zhao Jixin , Ji Wanquan
Published: March 2022

Leymus mollis (2n = 4x = 28, NsNsXmXm), a wild relative of common wheat (Triticum aestivum L.), carries numerous loci which could potentially be used in wheat improvement. In this study, line 17DM48 was isolated from the progeny of a wheat and L. mollis hybrid. This line has 42 chromosomes forming 21 bivalents at meiotic metaphase I. Genomic in situ hybridization (GISH) demonstrated the presence of a pair chromosomes from the Ns genome of L. mollis. This pair substituted for wheat chromosome 2D, as shown by fluorescence in situ hybridization (FISH), DNA marker analysis, and hybridization to wheat 55K SNP array. Therefore, 17DM48 is a wheat-L. mollis 2Ns (2D) disomic substitution line. It shows longer spike and a high level of stripe rust resistance. Using specific-locus amplified fragment sequencing (SLAF-seq), 13 DNA markers were developed to identify and trace chromosome 2Ns of L. mollis in wheat background. This line provides a potential bridge germplasm for genetic improvement of wheat stripe rust resistance.
Zebrafish Mutant Lines Reveal the Interplay between nr3c1 and nr3c2 in the GC-Dependent Regulation of Gene Transcription
Authors: Dinarello Alberto , Tesoriere Annachiara , Martini Paolo , Fontana Camilla Maria , Volpato Davide , Badenetti Lorenzo , Terrin Francesca , Facchinello Nicola , Romualdi Chiara , Carnevali Oliana , Dalla Valle Luisa , Argenton Francesco
Published: March 2022

Glucocorticoids mainly exert their biological functions through their cognate receptor, encoded by the nr3c1 gene. Here, we analysed the glucocorticoids mechanism of action taking advantage of the availability of different zebrafish mutant lines for their receptor. The differences in gene expression patterns between the zebrafish gr knock-out and the grs357 mutant line, in which a point mutation prevents binding of the receptor to the hormone-responsive elements, reveal an intricate network of GC-dependent transcription. Particularly, we show that Stat3 transcriptional activity mainly relies on glucocorticoid receptor GR tethering activity: several Stat3 target genes are induced upon glucocorticoid GC exposure both in wild type and in grs357/s357 larvae, but not in gr knock-out zebrafish. To understand the interplay between GC, their receptor, and the mineralocorticoid receptor, which is evolutionarily and structurally related to the GR, we generated an mr knock-out line and observed that several GC-target genes also need a functional mineralocorticoid receptor MR to be correctly transcribed. All in all, zebrafish mutants and transgenic models allow in vivo analysis of GR transcriptional activities and interactions with other transcription factors such as MR and Stat3 in an in-depth and rapid way.
Genome-Wide Identification and Expression Analysis of Pseudouridine Synthase Family in Arabidopsis and Maize
Authors: Xie Yuting , Gu Yeting , Shi Guangping , He Jianliang , Hu Wenjing , Zhang Zhonghui
Published: March 2022

Pseudouridine (Ψ), the isomer of uridine (U), is the most abundant type of RNA modification, which is crucial for gene regulation in various cellular processes. Pseudouridine synthases (PUSs) are the key enzymes for the U-to-Ψ conversion. However, little is known about the genome-wide features and biological function of plant PUSs. In this study, we identified 20 AtPUSs and 22 ZmPUSs from Arabidopsis and maize (Zea mays), respectively. Our phylogenetic analysis indicated that both AtPUSs and ZmPUSs could be clustered into six known subfamilies: RluA, RsuA, TruA, TruB, PUS10, and TruD. RluA subfamily is the largest subfamily in both Arabidopsis and maize. It’s noteworthy that except the canonical XXHRLD-type RluAs, another three conserved RluA variants, including XXNRLD-, XXHQID-, and XXHRLG-type were also identified in those key nodes of vascular plants. Subcellular localization analysis of representative AtPUSs and ZmPUSs in each subfamily revealed that PUS proteins were localized in different organelles including nucleus, cytoplasm and chloroplasts. Transcriptional expression analysis indicated that AtPUSs and ZmPUSs were differentially expressed in various tissues and diversely responsive to abiotic stresses, especially suggesting their potential roles in response to heat and salt stresses. All these results would facilitate the functional identification of these pseudouridylation in the future.
Potential of a Novel Chemical Compound Targeting Matrix Metalloprotease-13 for Early Osteoarthritis: An In Vitro Study
Authors: Inagaki Junko , Nakano Airi , Hatipoglu Omer Faruk , Ooka Yuka , Tani Yurina , Miki Akane , Ikemura Kentaro , Opoku Gabriel , Ando Ryosuke , Kodama Shintaro , Ohtsuki Takashi , Yamaji Hirosuke , Yamamoto Shusei , Katsuyama Eri , Watanabe Shogo , Hirohata Satoshi
Published: March 2022

Osteoarthritis is a progressive disease characterized by cartilage destruction in the joints. Matrix metalloproteinases (MMPs) and a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTSs) play key roles in osteoarthritis progression. In this study, we screened a chemical compound library to identify new drug candidates that target MMP and ADAMTS using a cytokine-stimulated OUMS-27 chondrosarcoma cells. By screening PCR-based mRNA expression, we selected 2-(8-methoxy-2-methyl-4-oxoquinolin-1(4H)-yl)-N-(3-methoxyphenyl) acetamide as a potential candidate. We found that 2-(8-methoxy-2-methyl-4-oxoquinolin-1(4H)-yl)-N-(3-methoxyphenyl) acetamide attenuated IL-1β-induced MMP13 mRNA expression in a dose-dependent manner, without causing serious cytotoxicity. Signaling pathway analysis revealed that 2-(8-methoxy-2-methyl-4-oxoquinolin-1(4H)-yl)-N-(3-methoxyphenyl) acetamide attenuated ERK- and p-38-phosphorylation as well as JNK phosphorylation. We then examined the additive effect of 2-(8-methoxy-2-methyl-4-oxoquinolin-1(4H)-yl)-N-(3-methoxyphenyl) acetamide in combination with low-dose betamethasone on IL-1β-stimulated cells. Combined treatment with 2-(8-methoxy-2-methyl-4-oxoquinolin-1(4H)-yl)-N-(3-methoxyphenyl) acetamide and betamethasone significantly attenuated MMP13 and ADAMTS9 mRNA expression. In conclusion, we identified a potential compound of interest that may help attenuate matrix-degrading enzymes in the early osteoarthritis-affected joints.
Multiple Roles for Cytokines in Atopic Dermatitis: From Pathogenic Mediators to Endotype-Specific Biomarkers to Therapeutic Targets
Authors: Fania Luca , Moretta Gaia , Antonelli Flaminia , Scala Enrico , Abeni Damiano , Albanesi Cristina , Madonna Stefania
Published: March 2022

Atopic dermatitis (AD) is one of the most common chronic inflammatory skin diseases, which generally presents with intense itching and recurrent eczematous lesions. AD affects up to 20% of children and 10% of adults in high-income countries. The prevalence and incidence of AD have increased in recent years. The onset of AD mostly occurs in childhood, although in some cases AD may persist in adult life or even manifest in middle age (adult-onset AD). AD pathophysiology is made of a complex net, in which genetic background, skin barrier dysfunction, innate and adaptive immune responses, as well as itch contribute to disease development, progression, and chronicization. One of the most important features of AD is skin dehydration, which is mainly caused by filaggrin mutations that determine trans-epidermal water loss, pH alterations, and antigen penetration. In accordance with the “outside-inside” theory of AD pathogenesis, in a context of an altered epidermal barrier, antigens encounter epidermal antigen presentation cells (APCs), such as epidermal Langerhans cells and inflammatory epidermal dendritic cells, leading to their maturation and Th-2 cell-mediated inflammation. APCs also bear trimeric high-affinity receptors for immunoglobulin E (IgE), which induce IgE-mediated sensitizations as part of pathogenic mechanisms leading to AD. In this review, we discuss the role of cytokines in the pathogenesis of AD, considering patients with various clinical AD phenotypes. Moreover, we describe the cytokine patterns in patients with AD at different phases of the disease evolution, as well as in relation to different phenotypes/endotypes, including age, race, and intrinsic/extrinsic subtypes. We also discuss the outcomes of current biologics for AD, which corroborate the presence of multiple cytokine axes involved in the background of AD. A deep insight into the correlation between cytokine patterns and the related clinical forms of AD is a crucial step towards increasingly personalized, and therefore more efficient therapy.
Alzheimer’s Disease as Type 3 Diabetes: Common Pathophysiological Mechanisms between Alzheimer’s Disease and Type 2 Diabetes
Authors: Michailidis Michalis , Moraitou Despina , Tata Despina A. , Kalinderi Kallirhoe , Papamitsou Theodora , Papaliagkas Vasileios
Published: March 2022

Globally, the incidence of type 2 diabetes mellitus (T2DM) and Alzheimer’s disease (AD) epidemics is increasing rapidly and has huge financial and emotional costs. The purpose of the current review article is to discuss the shared pathophysiological connections between AD and T2DM. Research findings are presented to underline the vital role that insulin plays in the brain’s neurotransmitters, homeostasis of energy, as well as memory capacity. The findings of this review indicate the existence of a mechanistic interplay between AD pathogenesis with T2DM and, especially, disrupted insulin signaling. AD and T2DM are interlinked with insulin resistance, neuroinflammation, oxidative stress, advanced glycosylation end products (AGEs), mitochondrial dysfunction and metabolic syndrome. Beta-amyloid, tau protein and amylin can accumulate in T2DM and AD brains. Given that the T2DM patients are not routinely evaluated in terms of their cognitive status, they are rarely treated for cognitive impairment. Similarly, AD patients are not routinely evaluated for high levels of insulin or for T2DM. Studies suggesting AD as a metabolic disease caused by insulin resistance in the brain also offer strong support for the hypothesis that AD is a type 3 diabetes.
CFTR, Cell Junctions and the Cytoskeleton
Authors: Pankonien Ines , Quaresma Margarida C. , Rodrigues Cláudia S. , Amaral Margarida D.
Published: March 2022

The multi-organ disease cystic fibrosis (CF) is caused by mutations in the gene encoding the CF transmembrane conductance regulator (CFTR) protein, a cAMP regulated chloride (Cl−) and bicarbonate (HCO3−) ion channel expressed at the apical plasma membrane (PM) of epithelial cells. Reduced CFTR protein results in decreased Cl− secretion and excessive sodium reabsorption in epithelial cells, which consequently leads to epithelial dehydration and the accumulation of thick mucus within the affected organs, such as the lungs, pancreas, gastrointestinal (GI) tract, reproductive system and sweat glands. However, CFTR has been implicated in other functions besides transporting ions across epithelia. The rising number of references concerning its association to actin cytoskeleton organization, epithelial cell junctions and extracellular matrix (ECM) proteins suggests a role in the formation and maintenance of epithelial apical basolateral polarity. This review will focus on recent literature (the last 10 years) substantiating the role of CFTR in cell junction formation and actin cytoskeleton organization with its connection to the ECM.
Diesel Particulate Extract Accelerates Premature Skin Aging in Human Fibroblasts via Ceramide-1-Phosphate-Mediated Signaling Pathway
Authors: Shin Kyong-Oh , Uchida Yoshikazu , Park Kyungho
Published: March 2022

Both intrinsic (i.e., an individual’s body clock) and extrinsic factors (i.e., air pollutants and ultraviolet irradiation) accelerate premature aging. Epidemiological studies have shown a correlation between pollutant levels and aging skin symptoms. Diesel particle matter in particular leads to some diseases, including in the skin. Our recent study demonstrates that diesel particulate extract (DPE) increases apoptosis via increases in an anti-mitogenic/pro-apoptotic lipid mediator, ceramide in epidermal keratinocytes. Here, we investigated whether and how DPE accelerates premature skin aging using cultured normal human dermal fibroblasts (HDF). We first demonstrated that DPE increases cell senescence marker β-galactosidase activity in HDF. We then found increases in mRNA and protein levels, along with activity of matrix metalloprotease (MMP)-1 and MMP-3, which are associated with skin aging following DPE exposure. We confirmed increases in collagen degradation in HDF treated with DPE. Nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (NOX) is activated by DPE and results in increased ceramide production by sphingomyelinase activation in HDF. We identified that ceramide-1-phosphate (C1P) (produced from ceramide by ceramide kinase activation) activates MMP-1 and MMP-3 through activation of arachidonate cascade, followed by STAT 1- and STAT 3-dependent transcriptional activation.
β–Lactam TRPM8 Antagonist RGM8-51 Displays Antinociceptive Activity in Different Animal Models
Authors: Martín-Escura Cristina , Medina-Peris Alicia , Spear Luke A. , de la Torre Martínez Roberto , Olivos-Oré Luis A. , Barahona María Victoria , González-Rodríguez Sara , Fernández-Ballester Gregorio , Fernández-Carvajal Asia , Artalejo Antonio R. , Ferrer-Montiel Antonio , González-Muñiz Rosario
Published: March 2022

Transient receptor potential melastatin subtype 8 (TRPM8) is a cation channel extensively expressed in sensory neurons and implicated in different painful states. However, the effectiveness of TRPM8 modulators for pain relief is still a matter of discussion, since structurally diverse modulators lead to different results, depending on the animal pain model. In this work, we described the antinociceptive activity of a β–lactam derivative, RGM8-51, showing good TRPM8 antagonist activity, and selectivity against related thermoTRP channels and other pain-mediating receptors. In primary cultures of rat dorsal root ganglion (DRG) neurons, RGM8-51 potently reduced menthol-evoked neuronal firing without affecting the major ion conductances responsible for action potential generation. This compound has in vivo antinociceptive activity in response to cold, in a mouse model of oxaliplatin-induced peripheral neuropathy. In addition, it reduces cold, mechanical and heat hypersensitivity in a rat model of neuropathic pain arising after chronic constriction of the sciatic nerve. Furthermore, RGM8-51 exhibits mechanical hypersensitivity-relieving activity, in a mouse model of NTG-induced hyperesthesia. Taken together, these preclinical results substantiate that this TRPM8 antagonist is a promising pharmacological tool to study TRPM8-related diseases.
Thidiazuron Promotes Leaf Abscission by Regulating the Crosstalk Complexities between Ethylene, Auxin, and Cytokinin in Cotton
Authors: Li Fangjun , Wu Qian , Liao Baopeng , Yu Keke , Huo Yini , Meng Lu , Wang Songman , Wang Baomin , Du Mingwei , Tian Xiaoli , Li Zhaohu
Published: March 2022

Thidiazuron (TDZ) is widely used as a defoliant to induce leaf abscission in cotton. However, the underlying molecular mechanism is still unclear. In this study, RNA-seq and enzyme-linked immunosorbent assays (ELISA) were performed to reveal the dynamic transcriptome profiling and the change of endogenous phytohormones upon TDZ treatment in leaf, petiole, and abscission zone (AZ). We found that TDZ induced the gene expression of ethylene biosynthesis and signal, and promoted ethylene accumulation earlier in leaf than that in AZ. While TDZ down-regulated indole-3-acetic acid (IAA) biosynthesis genes mainly in leaf and IAA signal and transport genes. Furthermore, the IAA content reduced more sharply in the leaf than that in AZ to change the auxin gradient for abscission. TDZ suppressed CTK biosynthesis genes and induced CTK metabolic genes to reduce the IPA accumulation for the reduction of ethylene sensitivity. Furthermore, TDZ regulated the gene expression of abscisic acid (ABA) biosynthesis and signal and induced ABA accumulation between 12–48 h, which could up-regulate ABA response factor genes and inhibit IAA transporter genes. Our data suggest that TDZ orchestrates metabolism and signal of ethylene, auxin, and cytokinin, and also the transport of auxin in leaf, petiole, and AZ, to control leaf abscission.
Circadian Regulation of Retinal Pigment Epithelium Function
Authors: Baba Kenkichi , Goyal Varunika , Tosini Gianluca
Published: March 2022

The retinal pigment epithelium (RPE) is a single layer of cells located between the choriocapillaris vessels and the light-sensitive photoreceptors in the outer retina. The RPE performs physiological processes necessary for the maintenance and support of photoreceptors and visual function. Among the many functions performed by the RPE, the timing of the peak in phagocytic activity by the RPE of the photoreceptor outer segments that occurs 1–2 h. after the onset of light has captured the interest of many investigators and has thus been intensively studied. Several studies have shown that this burst in phagocytic activity by the RPE is under circadian control and is present in nocturnal and diurnal species and rod and cone photoreceptors. Previous investigations have demonstrated that a functional circadian clock exists within multiple retinal cell types and RPE cells. However, the anatomical location of the circadian controlling this activity is not clear. Experimental evidence indicates that the circadian clock, melatonin, dopamine, and integrin signaling play a key role in controlling this rhythm. A series of very recent studies report that the circadian clock in the RPE controls the daily peak in phagocytic activity. However, the loss of the burst in phagocytic activity after light onset does not result in photoreceptor or RPE deterioration during aging. In the current review, we summarized the current knowledge on the mechanism controlling this phenomenon and the physiological role of this peak.
Replication-Deficient Lymphocytic Choriomeningitis Virus-Vectored Vaccine Candidate for the Induction of T Cell Immunity against Mycobacterium tuberculosis
Authors: Belnoue Elodie , Vogelzang Alexis , Nieuwenhuizen Natalie E. , Krzyzaniak Magdalena A. , Darbre Stephanie , Kreutzfeldt Mario , Wagner Ingrid , Merkler Doron , Lambert Paul-Henri , Kaufmann Stefan H. E. , Siegrist Claire-Anne , Pinschewer Daniel D.
Published: March 2022

Mycobacterium tuberculosis (Mtb) represents a major burden to global health, and refined vaccines are needed. Replication-deficient lymphocytic choriomeningitis virus (rLCMV)-based vaccine vectors against cytomegalovirus have proven safe for human use and elicited robust T cell responses in a large proportion of vaccine recipients. Here, we developed an rLCMV vaccine expressing the Mtb antigens TB10.4 and Ag85B. In mice, rLCMV elicited high frequencies of polyfunctional Mtb-specific CD8 and CD4 T cell responses. CD8 but not CD4 T cells were efficiently boosted upon vector re-vaccination. High-frequency responses were also observed in neonatally vaccinated mice, and co-administration of rLCMV with Expanded Program of Immunization (EPI) vaccines did not result in substantial reciprocal interference. Importantly, rLCMV immunization significantly reduced the lung Mtb burden upon aerosol challenge, resulting in improved lung ventilation. Protection was associated with increased CD8 T cell recruitment but reduced CD4 T cell infiltration upon Mtb challenge. When combining rLCMV with BCG vaccination in a heterologous prime-boost regimen, responses to the rLCMV-encoded Mtb antigens were further augmented, but protection was not significantly different from rLCMV or BCG vaccination alone. This work suggests that rLCMV may show utility for neonatal and/or adult vaccination efforts against pulmonary tuberculosis.
NADPH Oxidase 4 (NOX4) in Cancer: Linking Redox Signals to Oncogenic Metabolic Adaptation
Authors: Szanto Ildiko
Published: March 2022

Cancer cells can survive and maintain their high proliferation rate in spite of their hypoxic environment by deploying a variety of adaptative mechanisms, one of them being the reorientation of cellular metabolism. A key aspect of this metabolic rewiring is the promotion of the synthesis of antioxidant molecules in order to counter-balance the hypoxia-related elevation of reactive oxygen species (ROS) production and thus combat the onset of cellular oxidative stress. However, opposite to their negative role in the inception of oxidative stress, ROS are also key modulatory components of physiological cellular metabolism. One of the major physiological cellular ROS sources is the NADPH oxidase enzymes (NOX-es). Indeed, NOX-es produce ROS in a tightly regulated manner and control a variety of cellular processes. By contrast, pathologically elevated and unbridled NOX-derived ROS production is linked to diverse cancerogenic processes. In this respect, NOX4, one of the members of the NOX family enzymes, is of particular interest. In fact, NOX4 is closely linked to hypoxia-related signaling and is a regulator of diverse metabolic processes. Furthermore, NOX4 expression and function are altered in a variety of malignancies. The aim of this review is to provide a synopsis of our current knowledge concerning NOX4-related processes in the oncogenic metabolic adaptation of cancer cells.
Cartilage Formation In Vivo Using High Concentration Collagen-Based Bioink with MSC and Decellularized ECM Granules
Authors: Isaeva Elena V. , Beketov Evgeny E. , Demyashkin Grigory A. , Yakovleva Nina D. , Arguchinskaya Nadezhda V. , Kisel Anastas A. , Lagoda Tatiana S. , Malakhov Egor P. , Smirnova Anna N. , Petriev Vasiliy M. , Eremin Petr S. , Osidak Egor O. , Domogatsky Sergey P. , Ivanov Sergey A. , Shegay Petr V. , Kaprin Andrey D.
Published: March 2022

The aim of this study was to verify the applicability of high-concentration collagen-based bioink with MSC (ADSC) and decellularized ECM granules for the formation of cartilage tissue de novo after subcutaneous implantation of the scaffolds in rats. The printability of the bioink (4% collagen, 2.5% decellularized ECM granules, derived via 280 μm sieve) was shown. Three collagen-based compositions were studied: (1) with ECM; (2) with MSC; (3) with ECM and MSC. It has been established that decellularized ECM granules are able to stimulate chondrogenesis both in cell-free and MSC-laden scaffolds. Undesirable effects have been identified: bone formation as well as cartilage formation outside of the scaffold area. The key perspectives and limitations of ECM granules (powder) application have been discussed.
Metformin and Breast Cancer: Where Are We Now?
Authors: Cejuela Mónica , Martin-Castillo Begoña , Menendez Javier A. , Pernas Sonia
Published: March 2022

Breast cancer is the most prevalent cancer and the leading cause of cancer-related death among women worldwide. Type 2 diabetes–associated metabolic traits such as hyperglycemia, hyperinsulinemia, inflammation, oxidative stress, and obesity are well-known risk factors for breast cancer. The insulin sensitizer metformin, one of the most prescribed oral antidiabetic drugs, has been suggested to function as an antitumoral agent, based on epidemiological and retrospective clinical data as well as preclinical studies showing an antiproliferative effect in cultured breast cancer cells and animal models. These benefits provided a strong rationale to study the effects of metformin in routine clinical care of breast cancer patients. However, the initial enthusiasm was tempered after disappointing results in randomized controlled trials, particularly in the metastatic setting. Here, we revisit the current state of the art of metformin mechanisms of action, critically review past and current metformin-based clinical trials, and briefly discuss future perspectives on how to incorporate metformin into the oncologist’s armamentarium for the prevention and treatment of breast cancer.
LC-MS Analysis Revealed the Significantly Different Metabolic Profiles in Spent Culture Media of Human Embryos with Distinct Morphology, Karyotype and Implantation Outcomes
Authors: Eldarov Chupalav , Gamisonia Alina , Chagovets Vitaliy , Ibragimova Luiza , Yarigina Svetlana , Smolnikova Veronika , Kalinina Elena , Makarova Nataliya , Zgoda Victor , Sukhikh Gennady , Bobrov Mikhail
Published: March 2022

In this study we evaluated possible differences in metabolomic profiles of spent embryo culture media (SECM) of human embryos with distinct morphology, karyotype, and implantation outcomes. A total of 153 samples from embryos of patients undergoing in vitro fertilization (IVF) programs were collected and analyzed by HPLC-MS. Metabolomic profiling and statistical analysis revealed clear clustering of day five SECM from embryos with different morphological classes and karyotype. Profiling of day five SECM from embryos with different implantation outcomes showed 241 significantly changed molecular ions in SECM of successfully implanted embryos. Separate analysis of paired SECM samples on days three and five revealed 46 and 29 molecular signatures respectively, significantly differing in culture media of embryos with a successful outcome. Pathway enrichment analysis suggests certain amino acids, vitamins, and lipid metabolic pathways to be crucial for embryo implantation. Differences between embryos with distinct implantation potential are detectable on the third and fifth day of cultivation that may allow the application of culture medium analysis in different transfer protocols for both fresh and cryopreserved embryos. A combination of traditional morphological criteria with metabolic profiling of SECM may increase implantation rates in assisted reproductive technology programs as well as improve our knowledge of the human embryo metabolism in the early stages of development.
A New Perspective on Thyroid Hormones: Crosstalk with Reproductive Hormones in Females
Authors: Ren Bingtao , Zhu Yan
Published: March 2022

Accumulating evidence has shown that thyroid hormones (THs) are vital for female reproductive system homeostasis. THs regulate the reproductive functions through thyroid hormone receptors (THRs)-mediated genomic- and integrin-receptor-associated nongenomic mechanisms, depending on TH ligand status and DNA level, as well as transcription and extra-nuclear signaling transduction activities. These processes involve the binding of THs to intracellular THRs and steroid hormone receptors or membrane receptors and the recruitment of hormone-response elements. In addition, THs and other reproductive hormones can activate common signaling pathways due to their structural similarity and shared DNA consensus sequences among thyroid, peptide, and protein hormones and their receptors, thus constituting a complex and reciprocal interaction network. Moreover, THs not only indirectly affect the synthesis, secretion, and action of reproductive hormones, but are also regulated by these hormones at the same time. This crosstalk may be one of the pivotal factors regulating female reproductive behavior and hormone-related diseases, including tumors. Elucidating the interaction mechanism among the aforementioned hormones will contribute to apprehending the etiology of female reproductive diseases, shedding new light on the treatment of gynecological disorders.