bluuebunny/crossref_metadata_2025 huggingface dataset:
Different Flavors of Astrocytes: Revising the Origins of Astrocyte Diversity and Epigenetic Signatures to Understand Heterogeneity after Injury
Authors: Villarreal Alejandro , Vogel Tanja
Published: June 2021

Astrocytes are a specific type of neuroglial cells that confer metabolic and structural support to neurons. Astrocytes populate all regions of the nervous system and adopt a variety of phenotypes depending on their location and their respective functions, which are also pleiotropic in nature. For example, astrocytes adapt to pathological conditions with a specific cellular response known as reactive astrogliosis, which includes extensive phenotypic and transcriptional changes. Reactive astrocytes may lose some of their homeostatic functions and gain protective or detrimental properties with great impact on damage propagation. Different astrocyte subpopulations seemingly coexist in reactive astrogliosis, however, the source of such heterogeneity is not completely understood. Altered cellular signaling in pathological compared to healthy conditions might be one source fueling astrocyte heterogeneity. Moreover, diversity might also be encoded cell-autonomously, for example as a result of astrocyte subtype specification during development. We hypothesize and propose here that elucidating the epigenetic signature underlying the phenotype of each astrocyte subtype is of high relevance to understand another regulative layer of astrocyte heterogeneity, in general as well as after injury or as a result of other pathological conditions. High resolution methods should allow enlightening diverse cell states and subtypes of astrocyte, their adaptation to pathological conditions and ultimately allow controlling and manipulating astrocyte functions in disease states. Here, we review novel literature reporting on astrocyte diversity from a developmental perspective and we focus on epigenetic signatures that might account for cell type specification.
Bisphosphonate-Based Conjugates and Derivatives as Potential Therapeutic Agents in Osteoporosis, Bone Cancer and Metastatic Bone Cancer
Authors: Mbese Zintle , Aderibigbe Blessing A.
Published: June 2021

Metastatic bone cancer occurs in every type of cancer but is prevalent in lung, breast, and prostate cancers. These metastases can cause extensive morbidity, including a range of skeletal-related events, often painful and linked with substantial hospital resource usage. The treatment used is a combination of chemotherapy and surgery. However, anticancer drugs are still limited due to severe side effects, drug resistance, poor blood supply, and non-specific drug uptake, necessitating high toxic doses. Bisphosphonates are the main class of drugs utilized to inhibit metastatic bone cancer. It is also used for the treatment of osteoporosis and other bone diseases. However, bisphosphonate also suffers from serious side effects. Thus, there is a serious need to develop bisphosphonate conjugates with promising therapeutic outcomes for treating metastatic bone cancer and osteoporosis. This review article focuses on the biological outcomes of designed bisphosphonate-based conjugates for the treatment of metastatic bone cancer and osteoporosis.
Efficacy of a Chitin-Based Water-Soluble Derivative in Inducing Purpureocillium lilacinum against Nematode Disease (Meloidogyne incognita)
Authors: Zhan Jiang , Qin Yukun , Gao Kun , Fan Zhaoqian , Wang Linsong , Xing Ronge , Liu Song , Li Pengcheng
Published: June 2021

Plant-parasitic nematodes cause severe economic losses annually which has been a persistent problem worldwide. As current nematicides are highly toxic, prone to drug resistance, and have poor stability, there is an urgent need to develop safe, efficient, and green strategies. Natural active polysaccharides such as chitin and chitosan with good biocompatibility and biodegradability and inducing plant disease resistance have attracted much attention, but their application is limited due to their poor solubility. Here, we prepared 6-oxychitin with good water solubility by introducing carboxylic acid groups based on retaining the original skeleton of chitin and evaluated its potential for nematode control. The results showed that 6-oxychitin is a better promoter of the nematicidal potential of Purpureocillium lilacinum than other water-soluble chitin derivatives. After treatment, the movement of J2s and egg hatching were obviously inhibited. Further plant experiments found that it can destroy the accumulation and invasion of nematodes, and has a growth-promoting effect. Therefore, 6-oxychitin has great application potential in the nematode control area.
Betulinic Acid Ameliorates the Severity of Acute Pancreatitis via Inhibition of the NF-κB Signaling Pathway in Mice
Authors: Zhou Ziqi , Choi Ji-Won , Shin Joon Yeon , Kim Dong-Uk , Kweon Bitna , Oh Hyuncheol , Kim Youn-Chul , Song Ho-Joon , Bae Gi-Sang , Park Sung-Joo
Published: June 2021

Acute pancreatitis (AP) is an inflammatory disorder, involving acinar cell death and the release of inflammatory cytokines. Currently, there are limited effective therapeutic agents for AP. Betulinic acid (BA) is a pentacyclic triterpenoid extracted from Betula platyphylla that has been shown to have anti-inflammatory effects. In this study, we aimed to investigate the effects of BA on AP and elucidate the potential underlying mechanisms. AP was induced in mice through six intraperitoneal injections of cerulein. After the last cerulein injection, the mice were sacrificed. Our results revealed that pre- and post-treatment with BA significantly reduced the severity of pancreatitis, as evidenced by a decrease in histological damage in the pancreas and lung, serum amylase and lipase activity and pancreatic myeloperoxidase activity. Furthermore, BA pretreatment reduced proinflammatory cytokine production, augmentation of chemokines, and infiltration of macrophages and neutrophils in the pancreas of AP mice. In addition, mice that were pretreated with BA showed a reduction in Iκ-Bα degradation and nuclear factor-kappa B (NF-κB) binding activity in the pancreas. Moreover, BA reduced the production of proinflammatory cytokines and NF-κB activation in pancreatic acinar cells (PACs). These findings suggest that BA may have prophylactic and therapeutic effects on AP via inhibition of the NF-κB signaling pathway.
Sympathetic Denervation Alters the Inflammatory Response of Resident Muscularis Macrophages upon Surgical Trauma and Ameliorates Postoperative Ileus in Mice
Authors: Mallesh Shilpashree , Schneider Reiner , Schneiker Bianca , Lysson Mariola , Efferz Patrik , Lin Eugene , de Jonge Wouter J , Wehner Sven
Published: June 2021

Interactions between the peripheral nervous system and resident macrophages (MMs) modulate intestinal homeostatic functions. Activation of β2-adrenergic receptors on MMs has been shown to reduce bacterial challenges. These MMs are also crucial for the development of bowel inflammation in postoperative ileus (POI), an iatrogenic, noninfectious inflammation-based motility disorder. However, the role of the sympathetic nervous system (SNS) in the immune modulation of these MMs during POI or other noninfectious diseases is largely unknown. By employing 6-OHDA-induced denervation, we investigated the changes in the muscularis externa by RNA-seq, quantitative PCR, and flow cytometry. Further, we performed transcriptional phenotyping of sorted CX3CR1+ MMs and ex vivo LPS/M-CSF stimulation on these MMs. By combining denervation with a mouse POI model, we explored distinct changes on CX3CR1+ MMs as well as in the muscularis externa and their functional outcome during POI. Our results identify SNS as an important mediator in noninfectious postoperative inflammation. Upon denervation, MMs anti-inflammatory genes were reduced, and the muscularis externa profile is shaped toward a proinflammatory status. Further, denervation reduced MMs anti-inflammatory genes also in the early phase of POI. Finally, reduced leukocyte infiltration into the muscularis led to a quicker recovery of bowel motility in the late phase of POI.
De novo ssRNA Aptamers against the SARS-CoV-2 Main Protease: In Silico Design and Molecular Dynamics Simulation
Authors: Morena Francesco , Argentati Chiara , Tortorella Ilaria , Emiliani Carla , Martino Sabata
Published: June 2021

Herein, we have generated ssRNA aptamers to inhibit SARS-CoV-2 Mpro, a protease necessary for the SARS-CoV-2 coronavirus replication. Because there is no aptamer 3D structure currently available in the databanks for this protein, first, we modeled an ssRNA aptamer using an entropic fragment-based strategy. We refined the initial sequence and 3D structure by using two sequential approaches, consisting of an elitist genetic algorithm and an RNA inverse process. We identified three specific aptamers against SARS-CoV-2 Mpro, called MAptapro, MAptapro-IR1, and MAptapro-IR2, with similar 3D conformations and that fall in the dimerization region of the SARS-CoV-2 Mpro necessary for the enzymatic activity. Through the molecular dynamic simulation and binding free energy calculation, the interaction between the MAptapro-IR1 aptamer and the SARS-CoV-2 Mpro enzyme resulted in the strongest and the highest stable complex; therefore, the ssRNA MAptapro-IR1 aptamer was selected as the best potential candidate for the inhibition of SARS-CoV-2 Mpro and a perspective therapeutic drug for the COVID-19 disease.
Lanthionine, a Novel Uremic Toxin, in the Vascular Calcification of Chronic Kidney Disease: The Role of Proinflammatory Cytokines
Authors: Perna Alessandra Fortunata , Russo Luigi , D’Esposito Vittoria , Formisano Pietro , Bruzzese Dario , Vigorito Carmela , Coppola Annapaola , Lombari Patrizia , Russo Domenico , Ingrosso Diego
Published: June 2021

Vascular calcification (VC) is a risk factor for cardiovascular events and mortality in chronic kidney disease (CKD). Several components influence the occurrence of VC, among which inflammation. A novel uremic toxin, lanthionine, was shown to increase intracellular calcium in endothelial cells and may have a role in VC. A group of CKD patients was selected and divided into patients with a glomerular filtration rate (GFR) of <45 mL/min/1.73 m2 and ≥45 mL/min/1.73 m2. Total Calcium Score (TCS), based on the Agatston score, was assessed as circulating lanthionine and a panel of different cytokines. A hemodialysis patient group was also considered. Lanthionine was elevated in CKD patients, and levels increased significantly in hemodialysis patients with respect to the two CKD groups; in addition, lanthionine increased along with the increase in TCS, starting from one up to three. Interleukin IL-6, IL-8, and Eotaxin were significantly increased in patients with GFR < 45 mL/min/1.73 m2 with respect to those with GFR ≥ 45 mL/min/1.73 m2. IL-1b, IL-7, IL-8, IL-12, Eotaxin, and VEGF increased in calcified patients with respect to the non-calcified. IL-8 and Eotaxin were elevated both in the low GFR group and in the calcified group. We propose that lanthionine, but also IL-8 and Eotaxin, in particular, are a key feature of VC of CKD, with possible marker significance.
Effect of the Nucleophile’s Nature on Chloroacetanilide Herbicides Cleavage Reaction Mechanism. A DFT Study
Authors: Cuesta Sebastián A. , Torres F. Javier , Rincón Luis , Paz José Luis , Márquez Edgar A. , Mora José R.
Published: June 2021

In this study, the degradation mechanism of chloroacetanilide herbicides in the presence of four different nucleophiles, namely: Br−, I−, HS−, and S2O3−2, was theoretically evaluated using the dispersion-corrected hybrid functional wB97XD and the DGDZVP as a basis set. The comparison of computed activation energies with experimental data shows an excellent correlation (R2 = 0.98 for alachlor and 0.97 for propachlor). The results suggest that the best nucleophiles are those where a sulfur atom performs the nucleophilic attack, whereas the other species are less reactive. Furthermore, it was observed that the different R groups of chloroacetanilide herbicides have a negligible effect on the activation energy of the process. Further insights into the mechanism show that geometrical changes and electronic rearrangements contribute 60% and 40% of the activation energy, respectively. A deeper analysis of the reaction coordinate was conducted, employing the evolution chemical potential, hardness, and electrophilicity index, as well as the electronic flux. The charge analysis shows that the electron density of chlorine increases as the nucleophilic attack occurs. Finally, NBO analysis indicates that the nucleophilic substitution in chloroacetanilides is an asynchronous process with a late transition state for all models except for the case of the iodide attack, which occurs through an early transition state in the reaction.
Epigallocatechin-3-Gallate Modulates Postoperative Pain by Regulating Biochemical and Molecular Pathways
Authors: Siracusa Rosalba , Monaco Francesco , D’Amico Ramona , Genovese Tiziana , Cordaro Marika , Interdonato Livia , Gugliandolo Enrico , Peritore Alessio Filippo , Crupi Rosalia , Cuzzocrea Salvatore , Impellizzeri Daniela , Fusco Roberta , Di Paola Rosanna
Published: June 2021

Treating postoperative (PO) pain is a clinical challenge. Inadequate PO pain management can lead to worse outcomes, for example chronic post-surgical pain. Therefore, acquiring new information on the PO pain mechanism would increase the therapeutic options available. In this paper, we evaluated the role of a natural substance, epigallocatechin-3-gallate (EGCG), on pain and neuroinflammation induced by a surgical procedure in an animal model of PO pain. We performed an incision of the hind paw and EGCG was administered for five days. Mechanical allodynia, thermal hyperalgesia, and motor dysfunction were assessed 24 h, and three and five days after surgery. At the same time points, animals were sacrificed, and sera and lumbar spinal cord tissues were harvested for molecular analysis. EGCG administration significantly alleviated hyperalgesia and allodynia, and reduced motor disfunction. From the molecular point of view, EGCG reduced the activation of the WNT pathway, reducing WNT3a, cysteine-rich domain frizzled (FZ)1 and FZ8 expressions, and both cytosolic and nuclear β-catenin expression, and the noncanonical β-catenin–independent signaling pathways, reducing the activation of the NMDA receptor subtype NR2B (pNR2B), pPKC and cAMP response element-binding protein (pCREB) expressions at all time points. Additionally, EGCG reduced spinal astrocytes and microglia activation, cytokines overexpression and nuclear factor kappa-light-chain-enhancer of activated B cells (NFkB) pathway, downregulating inducible nitric oxide synthase (iNOS) activation, cyclooxygenase 2 (COX-2) expression, and prostaglandin E2 (PGE2) levels. Thus, EGCG administration managing the WNT/β-catenin signaling pathways modulates PO pain related neurochemical and inflammatory alterations.
Strain-Relief Patterns and Kagome Lattice in Self-Assembled C60 Thin Films Grown on Cd(0001)
Authors: Wang Zilong , Tao Minlong , Yang Daxiao , Li Zuo , Shi Mingxia , Sun Kai , Yang Jiyong , Wang Junzhong
Published: June 2021

We report an ultra-high vacuum low-temperature scanning tunneling microscopy (STM) study of the C60 monolayer grown on Cd(0001). Individual C60 molecules adsorbed on Cd(0001) may exhibit a bright or dim contrast in STM images. When deposited at low temperatures close to 100 K, C60 thin films present a curved structure to release strain due to dominant molecule–substrate interactions. Moreover, edge dislocation appears when two different wavy structures encounter each other, which has seldomly been observed in molecular self-assembly. When growth temperature rose, we found two forms of symmetric kagome lattice superstructures, 2 × 2 and 4 × 4, at room temperature (RT) and 310 K, respectively. The results provide new insight into the growth behavior of C60 films.
Shared Biological Pathways between Antipsychotics and Omega-3 Fatty Acids: A Key Feature for Schizophrenia Preventive Treatment?
Authors: Frajerman Ariel , Scoriels Linda , Kebir Oussama , Chaumette Boris
Published: June 2021

Schizophrenia typically emerges during adolescence, with progression from an ultra-high risk state (UHR) to the first episode of psychosis (FEP) followed by a chronic phase. The detailed pathophysiology of schizophrenia and the factors leading to progression across these stages remain relatively unknown. The current treatment relies on antipsychotics, which are effective for FEP and chronic schizophrenia but ineffective for UHR patients. Antipsychotics modulate dopaminergic and glutamatergic neurotransmission, inflammation, oxidative stress, and membrane lipids pathways. Many of these biological pathways intercommunicate and play a role in schizophrenia pathophysiology. In this context, research of preventive treatment in early stages has explored the antipsychotic effects of omega-3 supplementation in UHR and FEP patients. This review summarizes the action of omega-3 in various biological systems involved in schizophrenia. Similar to antipsychotics, omega-3 supplementation reduces inflammation and oxidative stress, improves myelination, modifies the properties of cell membranes, and influences dopamine and glutamate pathways. Omega-3 supplementation also modulates one-carbon metabolism, the endocannabinoid system, and appears to present neuroprotective properties. Omega-3 has little side effects compared to antipsychotics and may be safely prescribed for UHR patients and as an add-on for FEP patients. This could to lead to more efficacious individualised treatments, thus contributing to precision medicine in psychiatry.
Metabolomic Reprogramming of C57BL/6-Macrophages during Early Infection with L. amazonensis
Authors: Mamani-Huanca Maricruz , Muxel Sandra Marcia , Acuña Stephanie Maia , Floeter-Winter Lucile Maria , Barbas Coral , López-Gonzálvez Ángeles
Published: June 2021

Leishmania survival inside macrophages depends on factors that lead to the immune response evasion during the infection. In this context, the metabolic scenario of the host cell–parasite relationship can be crucial to understanding how this parasite can survive inside host cells due to the host’s metabolic pathways reprogramming. In this work, we aimed to analyze metabolic networks of bone marrow-derived macrophages from C57BL/6 mice infected with Leishmania amazonensis wild type (La-WT) or arginase knocked out (La-arg−), using the untargeted Capillary Electrophoresis-Mass Spectrometry (CE-MS) approach to assess metabolomic profile. Macrophages showed specific changes in metabolite abundance upon Leishmania infection, as well as in the absence of parasite-arginase. The absence of L. amazonensis-arginase promoted the regulation of both host and parasite urea cycle, glycine and serine metabolism, ammonia recycling, metabolism of arginine, proline, aspartate, glutamate, spermidine, spermine, methylhistidine, and glutathione metabolism. The increased L-arginine, L-citrulline, L-glutamine, oxidized glutathione, S-adenosylmethionine, N-acetylspermidine, trypanothione disulfide, and trypanothione levels were observed in La-WT-infected C57BL/6-macrophage compared to uninfected. The absence of parasite arginase increased L-arginine, argininic acid, and citrulline levels and reduced ornithine, putrescine, S-adenosylmethionine, glutamic acid, proline, N-glutamyl-alanine, glutamyl-arginine, trypanothione disulfide, and trypanothione when compared to La-WT infected macrophage. Moreover, the absence of parasite arginase leads to an increase in NO production levels and a higher infectivity rate at 4 h of infection. The data presented here show a host-dependent regulation of metabolomic profiles of C57BL/6 macrophages compared to the previously observed BALB/c macrophages infected with L. amazonensis, an important fact due to the dual and contrasting macrophage phenotypes of those mice. In addition, the Leishmania-arginase showed interference with the urea cycle, glycine, and glutathione metabolism during host–pathogen interactions.
Microbial Conjugation Studies of Licochalcones and Xanthohumol
Authors: Han Fubo , Xiao Yina , Lee Ik-Soo
Published: June 2021

Microbial conjugation studies of licochalcones (1–4) and xanthohumol (5) were performed by using the fungi Mucor hiemalis and Absidia coerulea. As a result, one new glucosylated metabolite was produced by M. hiemalis whereas four new and three known sulfated metabolites were obtained by transformation with A. coerulea. Chemical structures of all the metabolites were elucidated on the basis of 1D-, 2D-NMR and mass spectroscopic data analyses. These results could contribute to a better understanding of the metabolic fates of licochalcones and xanthohumol in mammalian systems. Although licochalcone A 4′-sulfate (7) showed less cytotoxic activity against human cancer cell lines compared to its substrate licochalcone A, its activity was fairly retained with the IC50 values in the range of 27.35–43.07 μM.
Protective Effect of Membrane-Free Stem Cells against Lipopolysaccharide and Interferon-Gamma-Stimulated Inflammatory Responses in RAW 264.7 Macrophages
Authors: He Mei Tong , Park Hye Sook , Kim Young Sil , Lee Ah Young , Cho Eun Ju
Published: June 2021

Recently, adipose-derived stem cells (ADSCs) are considered to be ideal for application in cell therapy or tissue regeneration, mainly due to their wide availability and easy access. In this study, we examined the anti-inflammatory effects of membrane-free stem cell extract (MFSC-Ex) derived from ADSCs against lipopolysaccharide (LPS)/interferon-gamma (IFN-γ) on RAW 264.7 macrophage cells. Exposure of RAW macrophages to LPS and IFN-γ stimuli induced high levels of nitric oxide (NO), cyclooxygenase-2 (COX-2), and prostaglandin E2 (PGE2) production. However, pretreatment with MFSC-Ex inhibited LPS/IFN-γ-induced these pro-inflammatory mediators. To clarify the molecular mechanisms underlying the anti-inflammatory property of MFSC-Ex, we analyzed nuclear factor-kappa B (NF-κB) and mitogen-activated protein kinases (MAPKs) protein expressions by Western blotting. Our study showed that treatment of MFSC-Ex significantly down-regulated inducible nitric oxide synthase (iNOS) and COX-2 protein expressions. Furthermore, phosphorylation of extracellular signal-regulated kinase (ERK) and p38 was also blocked by treatment with MFSC-Ex, indicating that inhibitory effect of MFSC-Ex on MAPK signaling cascade may attribute to inactivation of NF-κB. From these findings, we suggest that MFSC-Ex exert anti-inflammatory activities, which suppressed LPS/IFN-γ-induced production of NO, COX-2 and PGE2 by regulation of NF-κB and MAPK signaling pathway in RAW 264.7 macrophages. In conclusion, MFSC-Ex might provide a new therapeutic opportunity to treatment of inflammatory-related diseases.
Neuroprotective Effects of Guanosine in Ischemic Stroke—Small Steps towards Effective Therapy
Authors: Chojnowski Karol , Opielka Mikolaj , Nazar Wojciech , Kowianski Przemyslaw , Smolenski Ryszard T.
Published: June 2021

Guanosine (Guo) is a nucleotide metabolite that acts as a potent neuromodulator with neurotrophic and regenerative properties in neurological disorders. Under brain ischemia or trauma, Guo is released to the extracellular milieu and its concentration substantially raises. In vitro studies on brain tissue slices or cell lines subjected to ischemic conditions demonstrated that Guo counteracts destructive events that occur during ischemic conditions, e.g., glutaminergic excitotoxicity, reactive oxygen and nitrogen species production. Moreover, Guo mitigates neuroinflammation and regulates post-translational processing. Guo asserts its neuroprotective effects via interplay with adenosine receptors, potassium channels, and excitatory amino acid transporters. Subsequently, guanosine activates several prosurvival molecular pathways including PI3K/Akt (PI3K) and MEK/ERK. Due to systemic degradation, the half-life of exogenous Guo is relatively low, thus creating difficulty regarding adequate exogenous Guo distribution. Nevertheless, in vivo studies performed on ischemic stroke rodent models provide promising results presenting a sustained decrease in infarct volume, improved neurological outcome, decrease in proinflammatory events, and stimulation of neuroregeneration through the release of neurotrophic factors. In this comprehensive review, we discuss molecular signaling related to Guo protection against brain ischemia. We present recent advances, limitations, and prospects in exogenous guanosine therapy in the context of ischemic stroke.
Biological Mechanisms of Paeonoside in the Differentiation of Pre-Osteoblasts and the Formation of Mineralized Nodules
Authors: Park Kyung-Ran , Lee Joon Yeop , Cho Myounglae , Hong Jin Tae , Yun Hyung-Mun
Published: June 2021

Paeonia suffruticosa is a magnificent and long-lived woody plant that has traditionally been used to treat various diseases including inflammatory, neurological, cancer, and cardiovascular diseases. In the present study, we demonstrated the biological mechanisms of paeonoside (PASI) isolated from the dried roots of P. suffruticosa in pre-osteoblasts. Herein, we found that PASI has no cytotoxic effects on pre-osteoblasts. Migration assay showed that PASI promoted wound healing and transmigration in osteoblast differentiation. PASI increased early osteoblast differentiation and mineralized nodule formation. In addition, PASI enhanced the expression of Wnt3a and bone morphogenetic protein 2 (BMP2) and activated their downstream molecules, Smad1/5/8 and β-catenin, leading to increases in runt-related transcription factor 2 (RUNX2) expression during osteoblast differentiation. Furthermore, PASI-mediated osteoblast differentiation was attenuated by inhibiting the BMP2 and Wnt3a pathways, which was accompanied by reduction in the expression of RUNX2 in the nucleus. Taken together, our findings provide evidence that PASI enhances osteoblast differentiation and mineralized nodules by regulating RUNX2 expression through the BMP2 and Wnt3a pathways, suggesting a potential role for PASI targeting osteoblasts to treat bone diseases including osteoporosis and periodontitis.
Predictive Ability of Procalcitonin for Acute Kidney Injury: A Narrative Review Focusing on the Interference of Infection
Authors: Kan Wei-Chih , Huang Ya-Ting , Wu Vin-Cent , Shiao Chih-Chung
Published: June 2021

Acute kidney injury (AKI) is a common yet complicated clinical entity with high morbidity and mortality. An essential strategy to improve AKI patients’ prognoses is finding optimal biomarkers to identify AKI in a timely manner. Procalcitonin (PCT), a well-recognized biomarker for diagnosing infection and guiding antibiotics therapy, has been proposed to predict AKI development and recovery in many clinical settings. The current review provides comprehensive and updated information from relevant studies to evaluate PCT’s AKI-predictive ability and the influence of infection on this predictive ability. PCT has demonstrated optimal predictive ability for AKI in various populations irrespective of infection. However, the predictive ability seems to be blunted by infection since infection and inflammation have a more potent influence than AKI on PCT elevation. We furthermore explain the complicated association between elevated PCT levels and AKI in infection and inflammation situations and recommend directions for further investigations to clarify the essential issue. In conclusion, although conflicting data exist, serum PCT level is a potential biomarker for predicting AKI in many clinical settings regardless of infection. Nevertheless, further studies are warranted to clarify the association between PCT, infection, and AKI and to confirm the utilization of PCT for AKI prediction.
Genome-Wide Characterization and Identification of Long Non-Coding RNAs during the Molting Process of a Spider Mite, Panonychus citri
Authors: Li Gang , Liu Xunyan , Smagghe Guy , Niu Jinzhi , Wang Jinjun
Published: June 2021

Molting is essential for arthropods to grow. As one of the important arthropod pests in agriculture, key spider mite species (Tetranychus and Panonychus) can normally molt three times from the larva to adult stage within a week. This physiological strategy results in the short lifecycle of spider mites and difficulties in their control in the field. Long non-coding RNAs (lncRNAs) regulate transcriptional editing, cellular function, and biological processes. Thus, analysis of the lncRNAs in the spider mite molting process may provide new insights into their roles in the molting mechanism. For this purpose, we used high-throughput RNA-seq to examine the expression dynamics of lncRNAs and mRNAs in the molting process of different development stages in Panonychus citri. We identified 9199 lncRNAs from 18 transcriptomes. Analysis of the lncRNAs suggested that they were shorter and had fewer exons and transcripts than mRNAs. Among these, 356 lncRNAs were differentially expressed during three molting processes: late larva to early protonymph, late protonymph to early deutonymph, and late deutonymph to early adult. A time series profile analysis of differentially expressed lncRNAs showed that 77 lncRNAs were clustered into two dynamic expression profiles (Pattern a and Pattern c), implying that lncRNAs were involved in the molting process of spider mites. Furthermore, the lncRNA–mRNA co-expression networks showed that several differentially expressed hub lncRNAs were predicted to be functionally associated with typical molting-related proteins, such as cuticle protein and chitin biosynthesis. These data reveal the potential regulatory function of lncRNAs in the molting process and provide datasets for further analysis of lncRNAs and mRNAs in spider mites.
Mutagenic Analysis of the Putative ABCC6 Substrate-Binding Cavity Using a New Homology Model
Authors: Szeri Flora , Corradi Valentina , Niaziorimi Fatemeh , Donnelly Sylvia , Conseil Gwenaëlle , Cole Susan , Tieleman D. , van de Wetering Koen
Published: June 2021

Inactivating mutations in ABCC6 underlie the rare hereditary mineralization disorder pseudoxanthoma elasticum. ABCC6 is an ATP-binding cassette (ABC) integral membrane protein that mediates the release of ATP from hepatocytes into the bloodstream. The released ATP is extracellularly converted into pyrophosphate, a key mineralization inhibitor. Although ABCC6 is firmly linked to cellular ATP release, the molecular details of ABCC6-mediated ATP release remain elusive. Most of the currently available data support the hypothesis that ABCC6 is an ATP-dependent ATP efflux pump, an un-precedented function for an ABC transporter. This hypothesis implies the presence of an ATP-binding site in the substrate-binding cavity of ABCC6. We performed an extensive mutagenesis study using a new homology model based on recently published structures of its close homolog, bovine Abcc1, to characterize the substrate-binding cavity of ABCC6. Leukotriene C4 (LTC4), is a high-affinity substrate of ABCC1. We mutagenized fourteen amino acid residues in the rat ortholog of ABCC6, rAbcc6, that corresponded to the residues in ABCC1 found in the LTC4 binding cavity. Our functional characterization revealed that most of the amino acids in rAbcc6 corresponding to those found in the LTC4 binding pocket in bovine Abcc1 are not critical for ATP efflux. We conclude that the putative ATP binding site in the substrate-binding cavity of ABCC6/rAbcc6 is distinct from the bovine Abcc1 LTC4-binding site.
Bisphenol a Interferes with Uterine Artery Features and Impairs Rat Feto-Placental Growth
Authors: Barberio Laura , Paulesu Luana , Canesi Laura , Grasselli Elena , Mandalà Maurizio
Published: June 2021

Bisphenol A (BPA) is a widespread environmental contaminant, found in human fluids and tissues. Maternal BPA exposure is associated with alterations in pregnancy outcomes. Because maternal uterine circulation plays a crucial role in normal placenta and fetal growth, we hypothesized that BPA compromises the function of uterine arteries (UAs) and fetoplacental development. Female rats were orally administered with BPA (2.5, 25 and 250 µg/kg/day) or with its vehicle (ethanol) for 30 days before pregnancy and during the first 20 days of pregnancy. To compare the effect of BPA in the reproductive vs. systemic circulation, it was tested on UAs and mesenteric arteries (MAs). Arteries were isolated and examined by pressure myography. Moreover, fetuses and placentas were weighed to provide an index of reproductive performance. In UAs of BPA-treated rats, lumen diameter, acetylcholine-relaxation and expressions of endothelial nitric oxide synthase 3 (NOS3), estrogen receptor α (ERα) and peroxisome proliferator-activated receptor ɣ (PPARɣ) were reduced. Conversely, no changes were observed in MAs. BPA treatment also reduced placental weights, while fetal weights were increased. For the first time, our results indicate that UAs represent a specific target of BPA during pregnancy and provide insight into the molecular mechanisms that underlie its negative effects on pregnancy outcomes.
Fibrin(ogen) as a Therapeutic Target: Opportunities and Challenges
Authors: Gaule Thembaninkosi G. , Ajjan Ramzi A.
Published: June 2021

Fibrinogen is one of the key molecular players in haemostasis. Thrombin-mediated release of fibrinopeptides from fibrinogen converts this soluble protein into a network of fibrin fibres that form a building block for blood clots. Thrombin-activated factor XIII further crosslinks the fibrin fibres and incorporates antifibrinolytic proteins into the network, thus stabilising the clot. The conversion of fibrinogen to fibrin also exposes binding sites for fibrinolytic proteins to limit clot formation and avoid unwanted extension of the fibrin fibres. Altered clot structure and/or incorporation of antifibrinolytic proteins into fibrin networks disturbs the delicate equilibrium between clot formation and lysis, resulting in either unstable clots (predisposing to bleeding events) or persistent clots that are resistant to lysis (increasing risk of thrombosis). In this review, we discuss the factors responsible for alterations in fibrin(ogen) that can modulate clot stability, in turn predisposing to abnormal haemostasis. We also explore the mechanistic pathways that may allow the use of fibrinogen as a potential therapeutic target to treat vascular thrombosis or bleeding disorders. Better understanding of fibrinogen function will help to devise future effective and safe therapies to modulate thrombosis and bleeding risk, while maintaining the fine balance between clot formation and lysis.
n-6 High Fat Diet Induces Gut Microbiome Dysbiosis and Colonic Inflammation
Authors: Selmin Ornella I. , Papoutsis Andreas J. , Hazan Sabine , Smith Christopher , Greenfield Nick , Donovan Micah G. , Wren Spencer N. , Doetschman Thomas C. , Snider Justin M. , Snider Ashley J. , Chow Sherry H.-H. , Romagnolo Donato F.
Published: June 2021

Background: Concerns are emerging that a high-fat diet rich in n-6 PUFA (n-6HFD) may alter gut microbiome and increase the risk of intestinal disorders. Research is needed to model the relationships between consumption of an n-6HFD starting at weaning and development of gut dysbiosis and colonic inflammation in adulthood. We used a C57BL/6J mouse model to compare the effects of exposure to a typical American Western diet (WD) providing 58.4%, 27.8%, and 13.7% energy (%E) from carbohydrates, fat, and protein, respectively, with those of an isocaloric and isoproteic soybean oil-rich n-6HFD providing 50%E and 35.9%E from total fat and carbohydrates, respectively on gut inflammation and microbiome profile. Methods: At weaning, male offspring were assigned to either the WD or n-6HFD through 10–16 weeks of age. The WD included fat exclusively from palm oil whereas the n-6HFD contained fat exclusively from soybean oil. We recorded changes in body weight, cyclooxygenase-2 (COX-2) expression, colon histopathology, and gut microbiome profile. Results: Compared to the WD, the n-6HFD increased plasma levels of n-6 fatty acids; colonic expression of COX-2; and the number of colonic inflammatory and hyperplastic lesions. At 16 weeks of age, the n-6HFD caused a marked reduction in the gut presence of Firmicutes, Clostridia, and Lachnospiraceae, and induced growth of Bacteroidetes and Deferribacteraceae. At the species level, the n-6HFD sustains the gut growth of proinflammatory Mucispirillum schaedleri and Lactobacillus murinus. Conclusions: An n-6HFD consumed from weaning to adulthood induces a shift in gut bacterial profile associated with colonic inflammation.
Molecular Basis for the Activation of Human Innate Immune Response by the Flagellin Derived from Plant-Pathogenic Bacterium, Acidovorax avenae
Authors: Javaid Nasir , Hirai Hiroyuki , Che Fang-Sik , Choi Sangdun
Published: June 2021

Acidovorax avenae is a flagellated, pathogenic bacterium to various plant crops that has also been found in human patients with haematological malignancy, fever, and sepsis; however, the exact mechanism for infection in humans is not known. We hypothesized that the human innate immune system could be responsive to the purified flagellin isolated from A. avenae, named FLA-AA. We observed the secretion of inflammatory cytokines such as tumor necrosis factor-alpha (TNF-α), interleukin (IL)-6, and IL-8 by treating FLA-AA to human dermal fibroblasts, as well as macrophages. This response was exclusively through TLR5, which was confirmed by using TLR5-overexpression cell line, 293/hTLR5, as well as TLR5-specific inhibitor, TH1020. We also observed the secretion of inflammatory cytokine, IL-1β, by the activation of NLRC4 with FLA-AA. Overall, our results provide a molecular basis for the inflammatory response caused by FLA-AA in cell-based assays.
The Roles of Pseudophosphatases in Disease
Authors: Mattei Andrew M. , Smailys Jonathan D. , Hepworth Emma Marie Wilber , Hinton Shantá D.
Published: June 2021

The pseudophosphatases, atypical members of the protein tyrosine phosphatase family, have emerged as bona fide signaling regulators within the past two decades. Their roles as regulators have led to a renaissance of the pseudophosphatase and pseudoenyme fields, catapulting interest from a mere curiosity to intriguing and relevant proteins to investigate. Pseudophosphatases make up approximately fourteen percent of the phosphatase family, and are conserved throughout evolution. Pseudophosphatases, along with pseudokinases, are important players in physiology and pathophysiology. These atypical members of the protein tyrosine phosphatase and protein tyrosine kinase superfamily, respectively, are rendered catalytically inactive through mutations within their catalytic active signature motif and/or other important domains required for catalysis. This new interest in the pursuit of the relevant functions of these proteins has resulted in an elucidation of their roles in signaling cascades and diseases. There is a rapid accumulation of knowledge of diseases linked to their dysregulation, such as neuropathies and various cancers. This review analyzes the involvement of pseudophosphatases in diseases, highlighting the function of various role(s) of pseudophosphatases involvement in pathologies, and thus providing a platform to strongly consider them as key therapeutic drug targets.
Oral Pathogenic Bacteria-Inducing Neurodegenerative Microgliosis in Human Neural Cell Platform
Authors: Tran Tran Thi Ai , Kang You Jung , Kim Hyun-Kyoung , Kim Hyung-Ryong , Cho Hansang
Published: June 2021

Porphyromonas gingivalis is a gram-negative bacterium found in the human oral cavity and is responsible for the development of chronic periodontitis as well as neurological diseases, including Alzheimer’s disease (AD). Given the significance of the roles of P. gingivalis in AD pathogenesis, it is critical to understand the underlying mechanisms of P. gingivalis-driven neuroinflammation and their contribution to neurodegeneration. Herein, we hypothesize that P. gingivalis produces secondary metabolites that may cause neurodegeneration through direct or indirect pathways mediated by microglia. To test our hypothesis, we treated human neural cells with bacterial conditioned media on our brain platforms and assessed microgliosis, astrogliosis and neurodegeneration. We found that bacteria-mediated microgliosis induced the production of nitric oxide, which causes neurodegeneration assessed with high pTau level. Our study demonstrated the elevation of detrimental protein mediators, CD86 and iNOS and the production of several pro-inflammatory markers from stimulated microglia. Through inhibition of LPS and succinate dehydrogenase in a bacterial conditioned medium, we showed a decrease in neurodegenerative microgliosis. In addition, we demonstrated the bidirectional effect of microgliosis and astrogliosis on each other exacerbating neurodegeneration. Overall, our study suggests that the mouth-brain axis may contribute to the pathogenesis of AD.
Altered Induction of Reactive Oxygen Species by X-rays in Hematopoietic Cells of C57BL/6-Tg (CAG-EGFP) Mice
Authors: Liu Cuihua , Hirakawa Hirokazu , Katsube Takanori , Fang Yaqun , Tanaka Kaoru , Nenoi Mitsuru , Fujimori Akira , Wang Bing
Published: June 2021

Previous work pointed to a critical role of excessive production of reactive oxygen species (ROS) in increased radiation hematopoietic death in GFP mice. Meanwhile, enhanced antioxidant capability was not demonstrated in the mouse model of radio-induced adaptive response (RAR) using rescue of radiation hematopoietic death as the endpoint. ROS induction by ex vivo X-irradiation at a dose ranging from 0.1 to 7.5 Gy in the nucleated bone marrow cells was comparatively studied using GFP and wild type (WT) mice. ROS induction was also investigated in the cells collected from mice receiving a priming dose (0.5 Gy) efficient for RAR induction in WT mice. Significantly elevated background and increased induction of ROS in the cells from GFP mice were observed compared to those from WT mice. Markedly lower background and decreased induction of ROS were observed in the cells collected from WT mice but not GFP mice, both receiving the priming dose. GFP overexpression could alter background and induction of ROS by X-irradiation in hematopoietic cells. The results provide a reasonable explanation to the previous study on the fate of cells and mice after X-irradiation and confirm enhanced antioxidant capability in RAR. Investigations involving GFP overexpression should be carefully interpreted.
Emerging Advances of Nanotechnology in Drug and Vaccine Delivery against Viral Associated Respiratory Infectious Diseases (VARID)
Authors: Seyfoori Amir , Shokrollahi Barough Mahdieh , Mokarram Pooneh , Ahmadi Mazaher , Mehrbod Parvaneh , Sheidary Alireza , Madrakian Tayyebeh , Kiumarsi Mohammad , Walsh Tavia , McAlinden Kielan D. , Ghosh Chandra C. , Sharma Pawan , Zeki Amir A. , Ghavami Saeid , Akbari Mohsen
Published: June 2021

Viral-associated respiratory infectious diseases are one of the most prominent subsets of respiratory failures, known as viral respiratory infections (VRI). VRIs are proceeded by an infection caused by viruses infecting the respiratory system. For the past 100 years, viral associated respiratory epidemics have been the most common cause of infectious disease worldwide. Due to several drawbacks of the current anti-viral treatments, such as drug resistance generation and non-targeting of viral proteins, the development of novel nanotherapeutic or nano-vaccine strategies can be considered essential. Due to their specific physical and biological properties, nanoparticles hold promising opportunities for both anti-viral treatments and vaccines against viral infections. Besides the specific physiological properties of the respiratory system, there is a significant demand for utilizing nano-designs in the production of vaccines or antiviral agents for airway-localized administration. SARS-CoV-2, as an immediate example of respiratory viruses, is an enveloped, positive-sense, single-stranded RNA virus belonging to the coronaviridae family. COVID-19 can lead to acute respiratory distress syndrome, similarly to other members of the coronaviridae. Hence, reviewing the current and past emerging nanotechnology-based medications on similar respiratory viral diseases can identify pathways towards generating novel SARS-CoV-2 nanotherapeutics and/or nano-vaccines.
Imatinib (STI571) Inhibits the Expression of Angiotensin-Converting Enzyme 2 and Cell Entry of the SARS-CoV-2-Derived Pseudotyped Viral Particles
Authors: Lin You-Zhe , Shen Yi-Chun , Wu Wan-Rong , Wang Wei-Jan , Wang Yuan-Liang , Lin Chen-Yuan , Hung Mien-Chie , Wang Shao-Chun
Published: June 2021

A group of clinically approved cancer therapeutic tyrosine kinase inhibitors was screened to test their effects on the expression of angiotensin-converting enzyme 2 (ACE2), the cell surface receptor for SARS-CoV-2. Here, we show that the receptor tyrosine kinase inhibitor imatinib (also known as STI571, Gleevec) can inhibit the expression of the endogenous ACE2 gene at both the transcript and protein levels. Treatment with imatinib resulted in inhibition of cell entry of the viral pseudoparticles (Vpps) in cell culture. In FVB mice orally fed imatinib, tissue expression of ACE2 was reduced, specifically in the lungs and renal tubules, but not in the parenchyma of other organs such as the heart and intestine. Our finding suggests that receptor tyrosine kinases play a role in COVID-19 infection and can be therapeutic targets with combined treatments of the best conventional care of COVID-19.
17β-Estradiol Exacerbated Experimental Occlusal Interference-Induced Chronic Masseter Hyperalgesia by Increasing the Neuronal Excitability and TRPV1 Function of Trigeminal Ganglion in Ovariectomized Rats
Authors: Liu Yun , Xu Xiao-Xiang , Cao Ye , Mo Si-Yi , Bai Shan-Shan , Fan Ying-Ying , Zhang Xiao-Yu , Xie Qiu-Fei
Published: June 2021

Pain symptoms in temporomandibular disorders (TMD) predominantly affect reproductive women, suggesting that estrogen regulates pain perception. However, how estrogen contributes to chronic TMD pain remains largely unclear. In the present study, we performed behavioral tests, electrophysiology, Western blot and immunofluorescence to investigate the role and underlying mechanisms of estrogen in dental experimental occlusal interference (EOI)-induced chronic masseter mechanical hyperalgesia in rats. We found that long-term 17β-estradiol (E2) replacement exacerbated EOI-induced masseter hyperalgesia in a dose-dependent manner in ovariectomized (OVX) rats. Whole-cell patch-clamp recordings demonstrated that E2 (100 nM) treatment enhanced the excitability of isolated trigeminal ganglion (TG) neurons in OVX and OVX EOI rats, and EOI increased the functional expression of transient receptor potential vanilloid-1 (TRPV1). In addition, E2 replacement upregulated the protein expression of TRPV1 in EOI-treated OVX rats. Importantly, intraganglionic administration of the TRPV1 antagonist AMG-9810 strongly attenuated the facilitatory effect of E2 on EOI-induced masseter mechanical sensitivity. These results demonstrate that E2 exacerbated EOI-induced chronic masseter mechanical hyperalgesia by increasing TG neuronal excitability and TRPV1 function. Our study helps to elucidate the E2 actions in chronic myogenic TMD pain and may provide new therapeutic targets for relieving estrogen-sensitive pain.