bluuebunny/crossref_metadata_2025 huggingface dataset:
Homo- and Hetero-Dimers of CAD Enzymes Regulate Lignification and Abiotic Stress Response in Moso Bamboo
Authors: Vasupalli Naresh , Hou Dan , Singh Rahul Mohan , Wei Hantian , Zou Long-Hai , Yrjälä Kim , Wu Aimin , Lin Xinchun
Published: December 2021

Lignin biosynthesis enzymes form complexes for metabolic channelling during lignification and these enzymes also play an essential role in biotic and abiotic stress response. Cinnamyl alcohol dehydrogenase (CAD) is a vital enzyme that catalyses the reduction of aldehydes to alcohols, which is the final step in the lignin biosynthesis pathway. In the present study, we identified 49 CAD enzymes in five Bambusoideae species and analysed their phylogenetic relationships and conserved domains. Expression analysis of Moso bamboo PheCAD genes in several developmental tissues and stages revealed that among the PheCAD genes, PheCAD2 has the highest expression level and is expressed in many tissues and PheCAD1, PheCAD6, PheCAD8 and PheCAD12 were also expressed in most of the tissues studied. Co-expression analysis identified that the PheCAD2 positively correlates with most lignin biosynthesis enzymes, indicating that PheCAD2 might be the key enzyme involved in lignin biosynthesis. Further, more than 35% of the co-expressed genes with PheCADs were involved in biotic or abiotic stress responses. Abiotic stress transcriptomic data (SA, ABA, drought, and salt) analysis identified that PheCAD2, PheCAD3 and PheCAD5 genes were highly upregulated, confirming their involvement in abiotic stress response. Through yeast two-hybrid analysis, we found that PheCAD1, PheCAD2 and PheCAD8 form homo-dimers. Interestingly, BiFC and pull-down experiments identified that these enzymes form both homo- and hetero- dimers. These data suggest that PheCAD genes are involved in abiotic stress response and PheCAD2 might be a key lignin biosynthesis pathway enzyme. Moreover, this is the first report to show that three PheCAD enzymes form complexes and that the formation of PheCAD homo- and hetero- dimers might be tissue specific.
Derivation of Porcine Extra-Embryonic Endoderm Cell Lines Reveals Distinct Signaling Pathway and Multipotency States
Authors: Zhang Man-Ling , Jin Yong , Zhao Li-Hua , Zhang Jia , Zhou Meng , Li Mei-Shuang , Yin Zhi-Bao , Wang Zi-Xin , Zhao Li-Xia , Li Xi-He , Li Rong-Feng
Published: December 2021

The inner cell mass of the pre-implantation blastocyst consists of the epiblast and hypoblast from which embryonic stem cells (ESCs) and extra-embryonic endoderm (XEN) stem cells, respectively, can be derived. Importantly, each stem cell type retains the defining properties and lineage restriction of its in vivo tissue origin. We have developed a novel approach for deriving porcine XEN (pXEN) cells via culturing the blastocysts with a chemical cocktail culture system. The pXEN cells were positive for XEN markers, including Gata4, Gata6, Sox17, and Sall4, but not for pluripotent markers Oct4, Sox2, and Nanog. The pXEN cells also retained the ability to undergo visceral endoderm (VE) and parietal endoderm (PE) differentiation in vitro. The maintenance of pXEN required FGF/MEK+TGFβ signaling pathways. The pXEN cells showed a stable phenotype through more than 50 passages in culture and could be established repeatedly from blastocysts or converted from the naïve-like ESCs established in our lab. These cells provide a new tool for exploring the pathways of porcine embryo development and differentiation and providing further reference to the establishment of porcine ESCs with potency of germline chimerism and gamete development.
Nutraceutical Approach to Chronic Osteoarthritis: From Molecular Research to Clinical Evidence
Authors: Colletti Alessandro , Cicero Arrigo F. G.
Published: December 2021

Osteoarthritis (OA) is a degenerative inflammatory condition of the joint cartilage that currently affects approximately 58 million adults in the world. It is characterized by pain, stiffness, and a reduced range of motion with regard to the arthritic joints. These symptoms can cause in the long term a greater risk of overweight/obesity, diabetes mellitus, and falls and fractures. Although the current guidelines for the treatment of OA suggest, as the gold standard for this condition, pharmacological treatment characterized by non-steroidal anti-inflammatory drugs (NSAID), opioids, and cyclooxygenase (COX)-2-specific drugs, a great interest has been applied to nutraceutical supplements, which include a heterogeneous class of molecules with great potential to reduce inflammation, oxidative stress, pain, and joint stiffness and improve cartilage formation. The purpose of this review is to describe the potential application of nutraceuticals in OA, highlighting its molecular mechanisms of actions and data of efficacy and safety (when available).
Targeting S100A9 Reduces Neutrophil Recruitment, Inflammation and Lung Damage in Abdominal Sepsis
Authors: Ding Zhiyi , Du Feifei , Averitt V Richard Garland , Jakobsson Gabriel , Rönnow Carl-Fredrik , Rahman Milladur , Schiopu Alexandru , Thorlacius Henrik
Published: December 2021

S100A9, a pro-inflammatory alarmin, is up-regulated in inflamed tissues. However, the role of S100A9 in regulating neutrophil activation, inflammation and lung damage in sepsis is not known. Herein, we hypothesized that blocking S100A9 function may attenuate neutrophil recruitment in septic lung injury. Male C57BL/6 mice were pretreated with the S100A9 inhibitor ABR-238901 (10 mg/kg), prior to cercal ligation and puncture (CLP). Bronchoalveolar lavage fluid (BALF) and lung tissue were harvested for analysis of neutrophil infiltration as well as edema and CXC chemokine production. Blood was collected for analysis of membrane-activated complex-1 (Mac-1) expression on neutrophils as well as CXC chemokines and IL-6 in plasma. Induction of CLP markedly increased plasma levels of S100A9. ABR-238901 decreased CLP-induced neutrophil infiltration and edema formation in the lung. In addition, inhibition of S100A9 decreased the CLP-induced up-regulation of Mac-1 on neutrophils. Administration of ABR-238901 also inhibited the CLP-induced increase of CXCL-1, CXCL-2 and IL-6 in plasma and lungs. Our results suggest that S100A9 promotes neutrophil activation and pulmonary accumulation in sepsis. Targeting S100A9 function decreased formation of CXC chemokines in circulation and lungs and attenuated sepsis-induced lung damage. These novel findings suggest that S100A9 plays an important pro-inflammatory role in sepsis and could be a useful target to protect against the excessive inflammation and lung damage associated with the disease.
Human Genetic Disorders Resulting in Systemic Selenoprotein Deficiency
Authors: Schoenmakers Erik , Chatterjee Krishna
Published: December 2021

Selenium, a trace element fundamental to human health, is incorporated as the amino acid selenocysteine (Sec) into more than 25 proteins, referred to as selenoproteins. Human mutations in SECISBP2, SEPSECS and TRU-TCA1-1, three genes essential in the selenocysteine incorporation pathway, affect the expression of most if not all selenoproteins. Systemic selenoprotein deficiency results in a complex, multifactorial disorder, reflecting loss of selenoprotein function in specific tissues and/or long-term impaired selenoenzyme-mediated defence against oxidative and endoplasmic reticulum stress. SEPSECS mutations are associated with a predominantly neurological phenotype with progressive cerebello-cerebral atrophy. Selenoprotein deficiency due to SECISBP2 and TRU-TCA1-1 defects are characterized by abnormal circulating thyroid hormones due to lack of Sec-containing deiodinases, low serum selenium levels (low SELENOP, GPX3), with additional features (myopathy due to low SELENON; photosensitivity, hearing loss, increased adipose mass and function due to reduced antioxidant and endoplasmic reticulum stress defence) in SECISBP2 cases. Antioxidant therapy ameliorates oxidative damage in cells and tissues of patients, but its longer term benefits remain undefined. Ongoing surveillance of patients enables ascertainment of additional phenotypes which may provide further insights into the role of selenoproteins in human biological processes.
Baseline Stiffness Modulates the Non-Linear Response to Stretch of the Extracellular Matrix in Pulmonary Fibrosis
Authors: Júnior Constança , Narciso Maria , Marhuenda Esther , Almendros Isaac , Farré Ramon , Navajas Daniel , Otero Jorge , Gavara Núria
Published: December 2021

Pulmonary fibrosis (PF) is a progressive disease that disrupts the mechanical homeostasis of the lung extracellular matrix (ECM). These effects are particularly relevant in the lung context, given the dynamic nature of cyclic stretch that the ECM is continuously subjected to during breathing. This work uses an in vivo model of pulmonary fibrosis to characterize the macro- and micromechanical properties of lung ECM subjected to stretch. To that aim, we have compared the micromechanical properties of fibrotic ECM in baseline and under stretch conditions, using a novel combination of Atomic Force Microscopy (AFM) and a stretchable membrane-based chip. At the macroscale, fibrotic ECM displayed strain-hardening, with a stiffness one order of magnitude higher than its healthy counterpart. Conversely, at the microscale, we found a switch in the stretch-induced mechanical behaviour of the lung ECM from strain-hardening at physiological ECM stiffnesses to strain-softening at fibrotic ECM stiffnesses. Similarly, we observed solidification of healthy ECM versus fluidization of fibrotic ECM in response to stretch. Our results suggest that the mechanical behaviour of fibrotic ECM under stretch involves a potential built-in mechanotransduction mechanism that may slow down the progression of PF by steering resident fibroblasts away from a pro-fibrotic profile.
The Many Faces of Lipids in Genome Stability (and How to Unmask Them)
Authors: Moriel-Carretero María
Published: December 2021

Deep efforts have been devoted to studying the fundamental mechanisms ruling genome integrity preservation. A strong focus relies on our comprehension of nucleic acid and protein interactions. Comparatively, our exploration of whether lipids contribute to genome homeostasis and, if they do, how, is severely underdeveloped. This disequilibrium may be understood in historical terms, but also relates to the difficulty of applying classical lipid-related techniques to a territory such as a nucleus. The limited research in this domain translates into scarce and rarely gathered information, which with time further discourages new initiatives. In this review, the ways lipids have been demonstrated to, or very likely do, impact nuclear transactions, in general, and genome homeostasis, in particular, are explored. Moreover, a succinct yet exhaustive battery of available techniques is proposed to tackle the study of this topic while keeping in mind the feasibility and habits of “nucleus-centered” researchers.
Malignant and Benign T Cells Constituting Cutaneous T-Cell Lymphoma
Authors: Nakai Shuichi , Kiyohara Eiji , Watanabe Rei
Published: December 2021

Cutaneous T-cell lymphoma (CTCL) is a heterogeneous group of non-Hodgkin lymphoma, including various clinical manifestations, such as mycosis fungoides (MF) and Sézary syndrome (SS). CTCL mostly develops from CD4 T cells with the skin-tropic memory phenotype. Malignant T cells in MF lesions show the phenotype of skin resident memory T cells (TRM), which reside in the peripheral tissues for long periods and do not recirculate. On the other hand, malignant T cells in SS represent the phenotype of central memory T cells (TCM), which are characterized by recirculation to and from the blood and lymphoid tissues. The kinetics and the functional characteristics of malignant cells in CTCL are still unclear due, in part, to the fact that both the malignant cells and the T cells exerting anti-tumor activity possess the same characteristics as T cells. Capturing the features of both the malignant and the benign T cells is necessary for understanding the pathogenesis of CTCL and would lead to new therapeutic strategies specifically targeting the skin malignant T cells or benign T cells.
Proteomic Analysis of Mesenchymal Stromal Cell-Derived Extracellular Vesicles and Reconstructed Membrane Particles
Authors: Tejeda-Mora Hector , Leon Leticia G. , Demmers Jeroen , Baan Carla C. , Reinders Marlies E. J. , Bleck Bertram , Lombardo Eleuterio , Merino Ana , Hoogduijn Martin J.
Published: December 2021

Extracellular vesicles (EV) derived from mesenchymal stromal cells (MSC) are a potential therapy for immunological and degenerative diseases. However, large-scale production of EV free from contamination by soluble proteins is a major challenge. The generation of particles from isolated membranes of MSC, membrane particles (MP), may be an alternative to EV. In the present study we generated MP from the membranes of lysed MSC after removal of the nuclei. The yield of MP per MSC was 1 × 105 times higher than EV derived from the same number of MSC. To compare the proteome of MP and EV, proteomic analysis of MP and EV was performed. MP contained over 20 times more proteins than EV. The proteins present in MP evidenced a multi-organelle origin of MP. The projected function of the proteins in EV and MP was very different. Whilst proteins in EV mainly play a role in extracellular matrix organization, proteins in MP were interconnected in diverse molecular pathways, including protein synthesis and degradation pathways and demonstrated enzymatic activity. Treatment of MSC with IFNγ led to a profound effect on the protein make up of EV and MP, demonstrating the possibility to modify the phenotype of EV and MP through modification of parent MSC. These results demonstrate that MP are an attractive alternative to EV for the development of potential therapies. Functional studies will have to demonstrate therapeutic efficacy of MP in preclinical disease models.
EGFR Transgene Stimulates Spontaneous Formation of MCF7 Breast Cancer Cells Spheroids with Partly Loss of HER3 Receptor
Authors: Troitskaya Olga , Novak Diana , Nushtaeva Anna , Savinkova Maria , Varlamov Mikhail , Ermakov Mikhail , Richter Vladimir , Koval Olga
Published: December 2021

Multicellular spheroids with 3D cell–cell interactions are a useful model to simulate the growth conditions of cancer. There is evidence that in tumor spheroids, the expression of various essential molecules is changed compared to the adherent form of cell cultures. These changes include growth factor receptors and ABC transporters and result in the enhanced invasiveness of the cells and drug resistance. It is known that breast adenocarcinoma MCF7 cells can spontaneously form 3D spheroids and such spheroids are characterized by high expression of EGFR/HER2, while the natural phenotype of MCF7 cells is EGFRlow/HER2low. Therefore, it was interesting to reveal if high epidermal growth factor receptor (EGFR) expression is sufficient for the conversion of adherent MCF7 to spheroids. In this study, an MCF7 cell line with high expression of EGFR was engineered using the retroviral transduction method. These MCF7-EGFR cells assembled in spheroids very quickly and grew predominantly as a 3D suspension culture with no special plates, scaffolds, growth supplements, or exogenous matrixes. These spheroids were characterized by a rounded shape with a well-defined external border and 100 µM median diameter. The sphere-forming ability of MCF7-EGFR cells was up to 5 times stronger than in MCF7wt cells. Thus, high EGFR expression was the initiation factor of conversion of adherent MCF7wt cells to spheroids. MCF7-EGFR spheroids were enriched by the cells with a cancer stem cell (CSC) phenotype CD24−/low/CD44− in comparison with parental MCF7wt cells and MCF7-EGFR adhesive cells. We suppose that these properties of MCF7-EGFR spheroids originate from the typical features of parental MCF7 cells. We showed the decreasing of HER3 receptors in MCF7-EGFR spheroids compared to that in MCFwt and in adherent MCF7-EGFR cells, and the same decrease was observed in the MCF7wt spheroids growing under the growth factors stimulation. To summarize, the expression of EGFR transgene in MCF7 cells stimulates rapid spheroids formation; these spheroids are enriched by CSC-like CD24−/CD44− cells, they partly lose HER3 receptors, and are characterized by a lower potency in drug resistance pomp activation compared to MCF7wt. These MCF7-EGFR spheroids are a useful cancer model for the development of anticancer drugs, including EGFR-targeted therapeutics.
Functional Genomics in Health and Disease
Authors: Braicu Cornelia
Published: December 2021

Functional genomics applied in clinical disease diagnosis and prognosis allow the achievement of the progress in all aspects of biology in health and disease [...]
Prenatal Octamethylcyclotetrasiloxane Exposure Impaired Proliferation of Neuronal Progenitor, Leading to Motor, Cognition, Social and Behavioral Functions
Authors: Tran Dinh Nam , Park Seon-Mi , Jung Eui-Man , Jeung Eui-Bae
Published: December 2021

Cyclic siloxane octamethylcyclotetrasiloxane (D4) has raised concerns as an endocrine-disrupting chemical (EDC). D4 is widely used in detergent products, cosmetics, and personal care products. Recently, robust toxicological data for D4 has been reported, but the adverse effects of D4 on brain development are unknown. Here, pregnant mice on gestational day 9.5 were treated daily with D4 to postnatal day 28, and the offspring mice were studied. The prenatal D4-treated mice exhibited cognitive dysfunction, limited memory, and motor learning defect. Moreover, prenatal D4 exposure reduced the proliferation of neuronal progenitors in the offspring mouse brain. Next, the mechanisms through which D4 regulated the cell cycle were investigated. Aberrant gene expression, such as cyclin-dependent kinases CDK6 and cyclin-dependent kinase inhibitor p27, were found in the prenatal D4-treated mice. Furthermore, the estrogen receptors ERa and ERb were increased in the brain of prenatal D4-treated mice. Overall, these findings suggest that D4 exerts estrogen activity that affects the cell cycle progression of neuronal progenitor cells during neurodevelopment, which may be associated with cognitive deficits in offspring.
Early Development of the GABAergic System and the Associated Risks of Neonatal Anesthesia
Authors: Gascoigne David A. , Serdyukova Natalya A. , Aksenov Daniil P.
Published: December 2021

Human and animal studies have elucidated the apparent neurodevelopmental effects resulting from neonatal anesthesia. Observations of learning and behavioral deficits in children, who were exposed to anesthesia early in development, have instigated a flurry of studies that have predominantly utilized animal models to further interrogate the mechanisms of neonatal anesthesia-induced neurotoxicity. Specifically, while neonatal anesthesia has demonstrated its propensity to affect multiple cell types in the brain, it has shown to have a particularly detrimental effect on the gamma aminobutyric acid (GABA)ergic system, which contributes to the observed learning and behavioral deficits. The damage to GABAergic neurons, resulting from neonatal anesthesia, seems to involve structure-specific changes in excitatory-inhibitory balance and neurovascular coupling, which manifest following a significant interval after neonatal anesthesia exposure. Thus, to better understand how neonatal anesthesia affects the GABAergic system, we first review the early development of the GABAergic system in various structures that have been the focus of neonatal anesthesia research. This is followed by an explanation that, due to the prolonged developmental curve of the GABAergic system, the entirety of the negative effects of neonatal anesthesia on learning and behavior in children are not immediately evident, but instead take a substantial amount of time (years) to fully develop. In order to address these concerns going forward, we subsequently offer a variety of in vivo methods which can be used to record these delayed effects.
AXIN2 Reduces the Survival of Porcine Induced Pluripotent Stem Cells (piPSCs)
Authors: Zhang Rui , Yu Shuai , Shen Qiaoyan , Zhao Wenxu , Zhang Juqing , Wu Xiaolong , Zhu Zhenshuo , Wu Xiaojie , Li Na , Peng Sha , Hua Jinlian
Published: December 2021

The establishment of porcine pluripotent stem cells (piPSCs) is critical but remains challenging. All piPSCs are extremely sensitive to minor perturbations of culture conditions and signaling network. Inhibitors, such as CHIR99021 and XAV939 targeting the WNT signaling pathway, have been added in a culture medium to modify the cell regulatory network. However, potential side effects of inhibitors could confine the pluripotency and practicability of piPSCs. This study aimed to investigate the roles of AXIN, one component of the WNT pathway in piPSCs. Here, porcine AXIN1 and AXIN2 genes were knocked-down or overexpressed. Digital RNA-seq was performed to explore the mechanism of cell proliferation and apoptosis. We found that (1) overexpression of the porcine AXIN2 gene significantly reduced survival and negatively impacted the pluripotency of piPSCs, and (2) knockdown of AXIN2, a negative effector of the WNT signaling pathway, enhanced the expression of genes involved in cell cycle but reduced the expression of genes related to cell differentiation, death, and apoptosis.
Involvement of the ACE2/Ang-(1–7)/MasR Axis in Pulmonary Fibrosis: Implications for COVID-19
Authors: Morganstein Taylor , Haidar Zahraa , Trivlidis Joshua , Azuelos Ilan , Huang Megan Jiaxin , Eidelman David H. , Baglole Carolyn J.
Published: December 2021

Pulmonary fibrosis is a chronic, fibrotic lung disease affecting 3 million people worldwide. The ACE2/Ang-(1–7)/MasR axis is of interest in pulmonary fibrosis due to evidence of its anti-fibrotic action. Current scientific evidence supports that inhibition of ACE2 causes enhanced fibrosis. ACE2 is also the primary receptor that facilitates the entry of SARS-CoV-2, the virus responsible for the current COVID-19 pandemic. COVID-19 is associated with a myriad of symptoms ranging from asymptomatic to severe pneumonia and acute respiratory distress syndrome (ARDS) leading to respiratory failure, mechanical ventilation, and often death. One of the potential complications in people who recover from COVID-19 is pulmonary fibrosis. Cigarette smoking is a risk factor for fibrotic lung diseases, including the idiopathic form of this disease (idiopathic pulmonary fibrosis), which has a prevalence of 41% to 83%. Cigarette smoke increases the expression of pulmonary ACE2 and is thought to alter susceptibility to COVID-19. Cannabis is another popular combustible product that shares some similarities with cigarette smoke, however, cannabis contains cannabinoids that may reduce inflammation and/or ACE2 levels. The role of cannabis smoke in the pathogenesis of pulmonary fibrosis remains unknown. This review aimed to characterize the ACE2-Ang-(1–7)-MasR Axis in the context of pulmonary fibrosis with an emphasis on risk factors, including the SARS-CoV-2 virus and exposure to environmental toxicants. In the context of the pandemic, there is a dire need for an understanding of pulmonary fibrotic events. More research is needed to understand the interplay between ACE2, pulmonary fibrosis, and susceptibility to coronavirus infection.
Merging the Versatile Functionalities of Boronic Acid with Peptides
Authors: Tan Yahong , Wu Junjie , Song Lulu , Zhang Mengmeng , Hipolito Christopher John , Wu Changsheng , Wang Siyuan , Zhang Youming , Yin Yizhen
Published: December 2021

Peptides inherently feature the favorable properties of being easily synthesized, water-soluble, biocompatible, and typically non-toxic. Thus, boronic acid has been widely integrated with peptides with the goal of discovering peptide ligands with novel biological activities, and this effort has led to broad applications. Taking the integration between boronic acid and peptide as a starting point, we provide an overview of the latest research advances and highlight the versatile and robust functionalities of boronic acid. In this review, we summarize the diverse applications of peptide boronic acids in medicinal chemistry and chemical biology, including the identification of covalent reversible enzyme inhibitors, recognition, and detection of glycans on proteins or cancer cell surface, delivery of siRNAs, development of pH responsive devices, and recognition of RNA or bacterial surfaces. Additionally, we discuss boronic acid-mediated peptide cyclization and peptide modifications, as well as the facile chemical synthesis of peptide boronic acids, which paved the way for developing a growing number of peptide boronic acids.
Dityrosine Crosslinking of Collagen and Amyloid-β Peptides Is Formed by Vitamin B12 Deficiency-Generated Oxidative Stress in Caenorhabditis elegans
Authors: Koseki Kyohei , Yamamoto Aoi , Tanimoto Keisuke , Okamoto Naho , Teng Fei , Bito Tomohiro , Yabuta Yukinori , Kawano Tsuyoshi , Watanabe Fumio
Published: December 2021

(1) Background: Vitamin B12 deficiency in Caenorhabditis elegans results in severe oxidative stress and induces morphological abnormality in mutants due to disordered cuticle collagen biosynthesis. We clarified the underlying mechanism leading to such mutant worms due to vitamin B12 deficiency. (2) Results: The deficient worms exhibited decreased collagen levels of up to approximately 59% compared with the control. Although vitamin B12 deficiency did not affect the mRNA expression of prolyl 4-hydroxylase, which catalyzes the formation of 4-hydroxyproline involved in intercellular collagen biosynthesis, the level of ascorbic acid, a prolyl 4-hydroxylase coenzyme, was markedly decreased. Dityrosine crosslinking is involved in the extracellular maturation of worm collagen. The dityrosine level of collagen significantly increased in the deficient worms compared with the control. However, vitamin B12 deficiency hardly affected the mRNA expression levels of bli-3 and mlt-7, which are encoding crosslinking-related enzymes, suggesting that deficiency-induced oxidative stress leads to dityrosine crosslinking. Moreover, using GMC101 mutant worms that express the full-length human amyloid β, we found that vitamin B12 deficiency did not affect the gene and protein expressions of amyloid β but increased the formation of dityrosine crosslinking in the amyloid β protein. (3) Conclusions: Vitamin B12-deficient wild-type worms showed motility dysfunction due to decreased collagen levels and the formation of highly tyrosine-crosslinked collagen, potentially reducing their flexibility. In GMC101 mutant worms, vitamin B12 deficiency-induced oxidative stress triggers dityrosine-crosslinked amyloid β formation, which might promote its stabilization and toxic oligomerization.
Mutants of the white ABCG Transporter in Drosophila melanogaster Have Deficient Olfactory Learning and Cholesterol Homeostasis
Authors: Myers Jennifer L. , Porter Maria , Narwold Nicholas , Bhat Krishna , Dauwalder Brigitte , Roman Gregg
Published: December 2021

Drosophila’s white gene encodes an ATP-binding cassette G-subfamily (ABCG) half-transporter. White is closely related to mammalian ABCG family members that function in cholesterol efflux. Mutants of white have several behavioral phenotypes that are independent of visual defects. This study characterizes a novel defect of white mutants in the acquisition of olfactory memory using the aversive olfactory conditioning paradigm. The w1118 mutants learned slower than wildtype controls, yet with additional training, they reached wildtype levels of performance. The w1118 learning phenotype is also found in the wapricot and wcoral alleles, is dominant, and is rescued by genomic white and mini-white transgenes. Reducing dietary cholesterol strongly impaired olfactory learning for wildtype controls, while w1118 mutants were resistant to this deficit. The w1118 mutants displayed higher levels of cholesterol and cholesterol esters than wildtype under this low-cholesterol diet. Increasing levels of serotonin, dopamine, or both in the white mutants significantly improved w1118 learning. However, serotonin levels were not lower in the heads of the w1118 mutants than in wildtype controls. There were also no significant differences found in synapse numbers within the w1118 brain. We propose that the w1118 learning defect may be due to inefficient biogenic amine signaling brought about by altered cholesterol homeostasis.
Integration of Light and Brassinosteroid Signaling during Seedling Establishment
Authors: Lin Fang , Cao Jing , Yuan Jiale , Liang Yuxia , Li Jia
Published: December 2021

Light and brassinosteroid (BR) are external stimuli and internal cue respectively, that both play critical roles in a wide range of developmental and physiological process. Seedlings grown in the light exhibit photomorphogenesis, while BR promotes seedling etiolation. Light and BR oppositely control the development switch from skotomorphogenesis in the dark to photomorphogenesis in the light. Recent progress report that substantial components have been identified as hubs to integrate light and BR signals. Photomorphogenic repressors including COP1, PIFs, and AGB1 have been reported to elevate BR response, while photomorphogenesis-promoting factors such as HY5, BZS1, and NF-YCs have been proven to repress BR signal. In addition, BR components also modulate light signal. Here, we review the current research on signaling network associated with light and brassinosteroids, with a focus on the integration of light and BR signals enabling plants to thrive in the changeable environment.
Sanguiins—Promising Molecules with Broad Biological Potential
Authors: Gesek Jakub , Jakimiuk Katarzyna , Atanasov Atanas G. , Tomczyk Michał
Published: December 2021

Compounds of natural origin, an infinite treasure of bioactive chemical entities, persist as an inexhaustible resource for discovering new medicines. In this review, we summarize the naturally occurring ellagitannins, sanguiins, which are bioactive constituents of various traditional medicinal plants, especially from the Rosaceae family. In-depth studies of sanguiin H-6 as an antimicrobial, antiviral, anticancer, anti-inflammatory, and osteoclastogenesis inhibitory agent have led to potent drug candidates. In addition, recently, virtual screening studies have suggested that sanguiin H-6 might increase resistance toward SARS-CoV-2 in the early stages of infection. Further experimental investigations on ADMET (absorption, distribution, metabolism, excretion, and toxicity) supplemented with molecular docking and molecular dynamics simulation are still needed to fully understand sanguiins’ mechanism of action. In sum, sanguiins appear to be promising compounds for additional studies, especially for their application in therapies for a multitude of common and debilitating ailments.
Phosphate Metabolism and Pathophysiology in Parathyroid Disorders and Endocrine Tumors
Authors: Zavatta Guido , Altieri Paola , Vandi Giulia , Vicennati Valentina , Pagotto Uberto , Vescini Fabio
Published: December 2021

The advent of new insights into phosphate metabolism must urge the endocrinologist to rethink the pathophysiology of widespread disorders, such as primary hyperparathyroidism, and also of rarer endocrine metabolic bone diseases, such as hypoparathyroidism and tumor-induced hypophosphatemia. These rare diseases of mineral metabolism have been and will be a precious source of new information about phosphate and other minerals in the coming years. The parathyroid glands, the kidneys, and the intestine are the main organs affecting phosphate levels in the blood and urine. Parathyroid disorders, renal tubule defects, or phosphatonin-producing tumors might be unveiled from alterations of such a simple and inexpensive mineral as serum phosphate. This review will present all these disorders from a ‘phosphate perspective’.
Focal Point of Fanconi Anemia Signaling
Authors: Zhan Sudong , Siu Jolene , Wang Zhanwei , Yu Herbert , Bezabeh Tedros , Deng Youping , Du Wei , Fei Peiwen
Published: December 2021

Among human genetic diseases, Fanconi Anemia (FA) tops all with its largest number of health complications in nearly all human organ systems, suggesting the significant roles played by FA genes in the maintenance of human health. With the accumulated research on FA, the encoded protein products by FA genes have been building up to the biggest cell defense signaling network, composed of not only 22+ FA proteins but also ATM, ATR, and many other non-FA proteins. The FA D2 group protein (FANCD2) and its paralog form the focal point of FA signaling to converge the effects of its upstream players in response to a variety of cellular insults and simultaneously with downstream players to protect humans from contracting diseases, including aging and cancer. In this review, we update and discuss how the FA signaling crucially eases cellular stresses through understanding its focal point.
Microbiota Alterations and Their Association with Oncogenomic Changes in Pancreatic Cancer Patients
Authors: Sammallahti Heidelinde , Kokkola Arto , Rezasoltani Sama , Ghanbari Reza , Asadzadeh Aghdaei Hamid , Knuutila Sakari , Puolakkainen Pauli , Sarhadi Virinder Kaur
Published: December 2021

Pancreatic cancer (PC) is an aggressive disease with a high mortality and poor prognosis. The human microbiome is a key factor in many malignancies, having the ability to alter host metabolism and immune responses and participate in tumorigenesis. Gut microbes have an influence on physiological functions of the healthy pancreas and are themselves controlled by pancreatic secretions. An altered oral microbiota may colonize the pancreas and cause local inflammation by the action of its metabolites, which may lead to carcinogenesis. The mechanisms behind dysbiosis and PC development are not completely clear. Herein, we review the complex interactions between PC tumorigenesis and the microbiota, and especially the question, whether and how an altered microbiota induces oncogenomic changes, or vice versa, whether cancer mutations have an impact on microbiota composition. In addition, the role of the microbiota in drug efficacy in PC chemo- and immunotherapies is discussed. Possible future scenarios are the intentional manipulation of the gut microbiota in combination with therapy or the utilization of microbial profiles for the noninvasive screening and monitoring of PC.
Reassessment of SST4 Somatostatin Receptor Expression Using SST4-eGFP Knockin Mice and the Novel Rabbit Monoclonal Anti-Human SST4 Antibody 7H49L61
Authors: Lupp Amelie , Ehms Blanca , Stumm Ralf , Göckeritz Johannes , Mawrin Christian , Schulz Stefan
Published: December 2021

Among the five somatostatin receptors (SST1–SST5), SST4 is the least characterized, which is in part due to the lack of specific monoclonal antibodies. We generated a knockin mouse model that expresses a carboxyl-terminal SST4-eGFP fusion protein. In addition, we extensively characterized the novel rabbit monoclonal anti-human SST4 antibody 7H49L61 using transfected cells and receptor-expressing tissues. 7H49L61 was then subjected to immunohistochemical staining of a series of formalin-fixed, paraffin-embedded normal and neoplastic human tissues. Characterization of SST4-eGFP mice revealed prominent SST4 expression in cortical pyramidal cells and trigeminal ganglion cells. In the human cortex, 7H49L61 disclosed a virtually identical staining pattern. Specificity of 7H49L61 was demonstrated by detection of a broad band migrating at 50–60 kDa in immunoblots. Tissue immunostaining was abolished by preadsorption of 7H49L61 with its immunizing peptide. In the subsequent immunohistochemical study, 7H49L61 yielded a predominant plasma membrane staining in adrenal cortex, exocrine pancreas, and placenta. SST4 was also found in glioblastomas, parathyroid adenomas, gastric and pancreatic adenocarcinomas, pheochromocytomas, and lymphomas. Altogether, we provide the first unequivocal localization of SST4 in normal and neoplastic human tissues. The monoclonal antibody 7H49L61 may also prove of great value for identifying SST4-expressing tumors during routine histopathological examinations.
Multimodal Spectroscopic Imaging of Pea Root Nodules to Assess the Nitrogen Fixation in the Presence of Biofertilizer Based on Nod-Factors
Authors: Susniak Katarzyna , Krysa Mikolaj , Kidaj Dominika , Szymanska-Chargot Monika , Komaniecka Iwona , Zamlynska Katarzyna , Choma Adam , Wielbo Jerzy , Ilag Leopold L. , Sroka-Bartnicka Anna
Published: December 2021

Multimodal spectroscopic imaging methods such as Matrix Assisted Laser Desorption/Ionization Mass Spectrometry Imaging (MALDI MSI), Fourier Transform Infrared spectroscopy (FT-IR) and Raman spectroscopy were used to monitor the changes in distribution and to determine semi quantitatively selected metabolites involved in nitrogen fixation in pea root nodules. These approaches were used to evaluate the effectiveness of nitrogen fixation by pea plants treated with biofertilizer preparations containing Nod factors. To assess the effectiveness of biofertilizer, the fresh and dry masses of plants were determined. The biofertilizer was shown to be effective in enhancing the growth of the pea plants. In case of metabolic changes, the biofertilizer caused a change in the apparent distribution of the leghaemoglobin from the edges of the nodule to its centre (the active zone of nodule). Moreover, the enhanced nitrogen fixation and presumably the accelerated maturation form of the nodules were observed with the use of a biofertilizer.
Sex Bias in Differentiated Thyroid Cancer
Authors: Suteau Valentine , Munier Mathilde , Briet Claire , Rodien Patrice
Published: December 2021

Differentiated thyroid cancers are more frequent in women than in men. These different frequencies may depend on differences in patient’s behavior and in thyroid investigations. However, an impact on sexual hormones is likely, although this has been insufficiently elucidated. Estrogens may increase the production of mutagenic molecules in the thyroid cell and favor the proliferation and invasion of tumoral cells by regulating both the thyrocyte enzymatic machinery and the inflammatory process associated with tumor growth. On the other hand, the worse prognosis of thyroid cancer associated with the male gender is poorly explained.
The Communication between Ocular Surface and Nasal Epithelia in 3D Cell Culture Technology for Translational Research: A Narrative Review
Authors: Aydin Malik , Dietrich Jana , Witt Joana , Finkbeiner Maximiliane S. C. , Park Jonas J.-H. , Wirth Stefan , Engeland Christine E. , Paulsen Friedrich , Ehrhardt Anja
Published: December 2021

There is a lack of knowledge regarding the connection between the ocular and nasal epithelia. This narrative review focuses on conjunctival, corneal, ultrastructural corneal stroma, and nasal epithelia as well as an introduction into their interconnections. We describe in detail the morphology and physiology of the ocular surface, the nasolacrimal ducts, and the nasal cavity. This knowledge provides a basis for functional studies and the development of relevant cell culture models that can be used to investigate the pathogenesis of diseases related to these complex structures. Moreover, we also provide a state-of-the-art overview regarding the development of 3D culture models, which allow for addressing research questions in models resembling the in vivo situation. In particular, we give an overview of the current developments of corneal 3D and organoid models, as well as 3D cell culture models of epithelia with goblet cells (conjunctiva and nasal cavity). The benefits and shortcomings of these cell culture models are discussed. As examples for pathogens related to ocular and nasal epithelia, we discuss infections caused by adenovirus and measles virus. In addition to pathogens, also external triggers such as allergens can cause rhinoconjunctivitis. These diseases exemplify the interconnections between the ocular surface and nasal epithelia in a molecular and clinical context. With a final translational section on optical coherence tomography (OCT), we provide an overview about the applicability of this technique in basic research and clinical ophthalmology. The techniques presented herein will be instrumental in further elucidating the functional interrelations and crosstalk between ocular and nasal epithelia.
Interaction Profiles of Central Nervous System Active Drugs at Human Organic Cation Transporters 1–3 and Human Plasma Membrane Monoamine Transporter
Authors: Angenoorth Thomas J. F. , Stankovic Stevan , Niello Marco , Holy Marion , Brandt Simon D. , Sitte Harald H. , Maier Julian
Published: December 2021

Many psychoactive compounds have been shown to primarily interact with high-affinity and low-capacity solute carrier 6 (SLC6) monoamine transporters for norepinephrine (NET; norepinephrine transporter), dopamine (DAT; dopamine transporter) and serotonin (SERT; serotonin transporter). Previous studies indicate an overlap between the inhibitory capacities of substances at SLC6 and SLC22 human organic cation transporters (SLC22A1–3; hOCT1–3) and the human plasma membrane monoamine transporter (SLC29A4; hPMAT), which can be classified as high-capacity, low-affinity monoamine transporters. However, interactions between central nervous system active substances, the OCTs, and the functionally-related PMAT have largely been understudied. Herein, we report data from 17 psychoactive substances interacting with the SLC6 monoamine transporters, concerning their potential to interact with the human OCT isoforms and hPMAT by utilizing radiotracer-based in vitro uptake inhibition assays at stably expressing human embryonic kidney 293 cells (HEK293) cells. Many compounds inhibit substrate uptake by hOCT1 and hOCT2 in the low micromolar range, whereas only a few substances interact with hOCT3 and hPMAT. Interestingly, methylphenidate and ketamine selectively interact with hOCT1 or hOCT2, respectively. Additionally, 3,4-methylenedioxymethamphetamine (MDMA) is a potent inhibitor of hOCT1 and 2 and hPMAT. Enantiospecific differences of R- and S-α-pyrrolidinovalerophenone (R- and S-α-PVP) and R- and S-citalopram and the effects of aromatic substituents are explored. Our results highlight the significance of investigating drug interactions with hOCTs and hPMAT, due to their role in regulating monoamine concentrations and xenobiotic clearance.
Tau Biomarkers in Dementia: Positron Emission Tomography Radiopharmaceuticals in Tauopathy Assessment and Future Perspective
Authors: Ricci Maria , Cimini Andrea , Camedda Riccardo , Chiaravalloti Agostino , Schillaci Orazio
Published: December 2021

Abnormal accumulation of Tau protein is closely associated with neurodegeneration and cognitive impairment and it is a biomarker of neurodegeneration in the dementia field, especially in Alzheimer’s disease (AD); therefore, it is crucial to be able to assess the Tau deposits in vivo. Beyond the fluid biomarkers of tauopathy described in this review in relationship with the brain glucose metabolic patterns, this review aims to focus on tauopathy assessment by using Tau PET imaging. In recent years, several first-generation Tau PET tracers have been developed and applied in the dementia field. Common limitations of first-generation tracers include off-target binding and subcortical white-matter uptake; therefore, several institutions are working on developing second-generation Tau tracers. The increasing knowledge about the distribution of first- and second-generation Tau PET tracers in the brain may support physicians with Tau PET data interpretation, both in the research and in the clinical field, but an updated description of differences in distribution patterns among different Tau tracers, and in different clinical conditions, has not been reported yet. We provide an overview of first- and second-generation tracers used in ongoing clinical trials, also describing the differences and the properties of novel tracers, with a special focus on the distribution patterns of different Tau tracers. We also describe the distribution patterns of Tau tracers in AD, in atypical AD, and further neurodegenerative diseases in the dementia field.
Genetic Variants of the NF-κB Pathway: Unraveling the Genetic Architecture of Psoriatic Disease
Authors: Queiro Rubén , Coto Pablo , González-Lara Leire , Coto Eliecer
Published: December 2021

Psoriasis is a multifactorial genetic disease for which the genetic factors explain about 70% of disease susceptibility. Up to 30–40% of psoriasis patients develop psoriatic arthritis (PsA). However, PsA can be considered as a “disease within a disease”, since in most cases psoriasis is already present when joint complaints begin. This has made studies that attempt to unravel the genetic basis for both components of psoriatic disease enormously difficult. Psoriatic disease is also accompanied by a high burden of comorbid conditions, mainly of the cardiometabolic type. It is currently unclear whether these comorbidities and psoriatic disease have a shared genetic basis or not. The nuclear factor of kappa light chain enhancer of activated B cells (NF-κB) is a transcription factor that regulates a plethora of genes in response to infection, inflammation, and a wide variety of stimuli on several cell types. This mini-review is focused on recent findings that highlight the importance of this pathway both in the susceptibility and in the determinism of some features of psoriatic disease. We also briefly review the importance of genetic variants of this pathway as biomarkers of pharmacological response. All the above may help to better understand the etiopathogenesis of this complex entity.
Transcriptional Responses and GCMS Analysis for the Biosynthesis of Pyrethrins and Volatile Terpenes in Tanacetum coccineum
Authors: Zeng Tuo , Li Jia-Wen , Zhou Li , Xu Zhi-Zhuo , Li Jin-Jin , Hu Hao , Luo Jing , Zheng Ri-Ru , Wang Yuan-Yuan , Wang Cai-Yun
Published: December 2021

Natural pyrethrins have been widely used as natural pesticides due to their low mammalian toxicity and environmental friendliness. Previous studies have mainly focused on Tanacetumcinerariifolium, which contains high levels of pyrethrins and volatile terpenes that play significant roles in plant defense and pollination. However, there is little information on T. coccineum due to its lower pyrethrin content and low commercial value. In this study, we measured the transcriptome and metabolites of the leaves (L), flower buds (S1), and fully blossomed flowers (S4) of T. coccineum. The results show that the expression of pyrethrins and precursor terpene backbone genes was low in the leaves, and then rapidly increased in the S1 stage before decreasing again in the S4 stage. The results also show that pyrethrins primarily accumulated at the S4 stage. However, the content of volatile terpenes was consistently low. This perhaps suggests that, despite T. coccineum and T. cinerariifolium having similar gene expression patterns and accumulation of pyrethrins, T. coccineum attracts pollinators via its large and colorful flowers rather than via inefficient and metabolically expensive volatile terpenes, as in T. cinerariifolium. This is the first instance of de novo transcriptome sequencing reported for T. coccineum. The present results could provide insights into pyrethrin biosynthetic pathways and will be helpful for further understanding how plants balance the cost–benefit relationship between plant defense and pollination.