JournalTOCs

Inflammation Research
Journal Prestige (SJR): 1.062

Citation Impact (citeScore): 3
Number of Followers: 4

Hybrid journal (It can contain Open Access articles)
ISSN (Print) 1420-908X - ISSN (Online) 1023-3830
Published by Springer-Verlag

[2469 journals]

Post-genomic platform for development of oligonucleotide vaccines against
RNA viruses: diamond cuts diamond
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  Abstract: Abstract The coronavirus pandemic has starkly demonstrated the need to create highly effective vaccines against various viral diseases. The emerging new platforms for vaccine creation (adenovirus vectors and mRNA vaccines) have shown their worth in the fight against the prevention of coronavirus infection. However, adenovirus vectors and mRNA vaccines have a serious disadvantage: as a rule, only the S protein of the coronavirus is presented as an antigen. This tactic for preventing infection allows the ever-mutating virus to escape quickly from the immunity protection provided by such vaccines. Today, viral genomic databases are well-developed, which makes it possible to create new vaccines on a fundamentally new post-genomic platform. In addition, the technology for the synthesis of nucleic acids is currently experiencing an upsurge in demand in various fields of molecular biology. The accumulated experience suggests that the unique genomic sequences of viruses can act as antigens that trigger powerful humoral and cellular immunity. To achieve this effect, the following conditions must be created: the structure of the nucleic acid must be single-stranded, have a permanent 3D nanostructure, and have a unique sequence absent in the vaccinated organism. Oligonucleotide vaccines are able to resist the rapidly changing genomic sequences of RNA viruses by using conserved regions of their genomes to generate a long-term immune response, acting according to the adage that a diamond cuts a diamond. In addition, oligonucleotide vaccines will not contribute to antibody-dependent enhanced infection, since the nucleic acid of the coronavirus is inside the viral particle. It is obvious that new epidemics and pandemics caused by RNA viruses will continue to arise periodically in the human population. The creation of new, safe, and effective platforms for the production of vaccines that can flexibly change and adapt to new subtypes of viruses is very urgent and at this moment should be considered as a strategically necessary task.
  PubDate: 2022-05-06
“Novel insights into the roles of mast cells and basophils”: Joint
Webinar of the Japanese and the European Histamine Research Societies
(JHRS/EHRS)
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  Abstract: Abstract The joint webinar of the Japanese (JHRS) and the European (EHRS) Histamine Research Society focusing on “Novel insights into the roles of mast cells and basophils” was organized in hybrid format on January 7, 2022 during the 23rd meeting of the JHRS held in Kyoto, Japan. Tissue mast cells and circulating basophils are the primary sources of histamine, and they are considered to be pivotal components shaping inflammatory and immune-related processes. The webinar comprised four lectures delivered by experts in the field from Japan and the European Mast Cell and Basophil Research Network (EMBRN) that exposed novel insights into the contribution of basophils and mast cells in inflammatory and (auto)immune diseases, including allergies, asthma, and urticaria. Several targets were also highlighted in terms of developing novel and improved treatments for these pathologies.
  PubDate: 2022-05-04
SRY-related high-mobility group box 9 (SOX9) alleviates cigarette smoke
extract (CSE)-induced inflammatory injury in human bronchial epithelial
cells by suppressing stromal interaction molecule 1 (STIM1) expression
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  Abstract: Background and objective Chronic obstructive pulmonary disease (COPD) is a chronic airway disease with airflow limitation and abnormal inflammatory response. It has been verified that SOX9 plays a key role in lung function of various lung diseases and SOX9 is closely associated with COPD. Additionally, literature has reported that STIM1 is involved in lung injury and is highly expressed in neutrophils from COPD patients. This study aimed to characterize the biological roles of SOX9 and STIM1 in the pathogenesis of COPD and to elucidate the regulatory mechanism. Methods Human bronchial epithelial cells (BEAS-2B) were treated with CSE to construct in vitro COPD model. The levels of SOX9 and STIM1 in CSE-treated BEAS-2B cells were detected by western blot and RT-qPCR assay. Then, JASPAR datasets were utilized to analyze SOX9 binding sites in the promoter region of STIM1. Besides, luciferase reporter assay and ChIP assay were employed to validate the binding sites in STIM1 promoter region to SOX9. In addition, viability and apoptosis of BEAS-2B cells were assessed by utilizing MTT assay and TUNEL staining. ELISA kits and corresponding commercial kits were applied to measure the levels of TNF-α, IL-6, IL-1β, SOD, GSH-Px and MDA. Results CSE treatment dose- and time-dependently reduced SOX9 expression in BEAS-2B cells. SOX9 overexpression enhanced the viability and suppressed the apoptosis of CSE-treated BEAS-2B cells as well as attenuated CSE-induced inflammation and oxidative stress. Then, it was validated that SOX9 bound to the promoter region of STIM1. Moreover, SOX9 overexpression-mediated impacts on cell viability, cell apoptosis, inflammation and oxidative stress in CSE-treated BEAS-2B cells were partially abolished by upregulation of STIM1. Conclusion To sum up, results here suggested that overexpression of SOX9 could mitigate inflammatory injury in CSE-treated bronchial epithelial cells by suppressing STIM1.
  PubDate: 2022-04-30
Inflammatory biomarkers in staging of chronic kidney disease: elevated
TNFR2 levels accompanies renal function decline
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  Abstract: Background Inflammation is a common feature in the pathogenesis of chronic kidney disease (CKD), regardless of the disease cause. Our aim was to evaluate the potential of several inflammatory biomarkers in CKD diagnosis and staging. Methods A total of 24 healthy controls and 92 pre-dialysis CKD patients with diverse etiologies, were enrolled in this study and grouped according to their CKD stage. We analysed the circulating levels of inflammatory molecules, C-reactive protein (CRP), interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α), tumor necrosis factor receptor 2 (TNFR2), pentraxin 3 (PTX3) and leptin, as well as the hemogram. We studied their association with parameters of kidney function and kidney injury, to evaluate their potential as early markers of the disease and/or of its worsening, as well as their interplay. Results Compared to controls, patients in CKD stages 1–2 presented significantly higher IL-6 and TNFR2 levels, and higher neutrophil-to-lymphocyte ratio. All inflammatory cytokines and acute-phase proteins showed a trend to increase up to stage 3, stabilizing or declining thereafter, save for TNFR2, which steadily increased from stage to stage. All inflammatory molecules, apart from PTX3, were negatively and significantly correlated with eGFR, with a remarkable value for TNFR2 (r = − 0.732, p < 0.001). Conclusion TNFR2 might be useful for an early detection of CKD, as well as for disease staging/worsening. Still, the potential value of this biomarker in disease progression warrants further investigation.
  PubDate: 2022-04-26
Pregnancy tailors endotoxin-induced monocyte and neutrophil responses in
the maternal circulation
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  Abstract: Objective To comprehensively characterize monocyte and neutrophil responses to E. coli and its product [lipopolysaccharide (LPS) or endotoxin] in vitro during pregnancy. Material or subjects Peripheral blood was collected from pregnant women during the third trimester (n = 20) and from non-pregnant women (n = 20). Methods The number, phagocytic activity, and reactive oxygen species (ROS) production of peripheral monocytes and neutrophils were investigated using flow cytometry. The phenotypes of peripheral monocytes and neutrophils after acute or chronic LPS stimulation were also determined using flow cytometry. Cytokine profiles were quantified for LPS-stimulated peripheral blood mononuclear cells (PBMCs) and a whole blood TruCulture® system using a multiplex immunoassay. Results Increased number, phagocytic activity, and ROS production capacity of monocytes and neutrophils were found in pregnant compared to non-pregnant women. Additionally, specific subsets of pro-inflammatory monocytes (IL-6+CD14+ or MIP-1α+CD14+ cells) and neutrophils (IL-1β+CD15+ or MIP-1β+CD15+ cells) were increased in pregnant women in response to acute LPS stimulation. Moreover, distinct subsets of intermediate-activated monocytes expressing CD142, IL-6, and IL-1RA were increased in pregnant women upon chronic LPS stimulation. Last, pregnant women displayed a different cytokine profile than non-pregnant women in LPS-stimulated PBMCs and in whole blood. Conclusions Pregnancy tailors the immune responses of circulating monocytes and neutrophils to endotoxin, a Gram-negative bacterial product.
  PubDate: 2022-04-21
Bioinformatics analysis for identifying micro-RNAs, long noncoding RNAs,
transcription factors, and immune genes regulatory networks in diabetic
cardiomyopathy using an integrated bioinformatics analysis
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  Abstract: Objectives We identified functional genes and studied the underlying molecular mechanisms of diabetic cardiomyopathy (DCM) using bioinformatics tools. Methods Original gene expression profiles were obtained from the GSE21610 and GSE112556 data sets. We used GEO2R to screen the differentially expressed genes (DEGs). Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses were performed on DEGs. Protein–protein interaction (PPI) networks of DEGs were constructed using STRING and hub genes of signaling pathways were identified using Cytoscape. Aberrant hub gene expression was verified using The Cancer Genome Atlas data set. Results The DEGs in DCM were mainly enriched in the nuclei and cytoplasm and involved in DCM and chemokine-related signaling pathways. In the PPI network, 32 nodes were chosen as hub nodes and an RNA interaction network was constructed with 517 interactions. The expression of key genes (JPIK3R1, CCR9, XIST, WDFY3.AS2, hsa-miR-144-5p, and hsa-miR-146b-5p) was significantly different between DCM and normal tissues. Conclusions The identified hub genes could be associated with DCM pathogenesis and could be used for treating DCM.
  PubDate: 2022-04-19
A new mouse unilateral model of diffuse alveolar damage of the lung
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  Abstract: Objective and design The existing biological models of diffuse alveolar damage (DAD) in mice have many shortcomings. To offset these shortcomings, we have proposed a simple, nonsurgical, and reproducible method of unilateral total damage of the left lung in ICR mice. This model is based on the intrabronchial administration of a mixture of bacterial lipopolysaccharide (LPS) from the cell wall of S. enterica and α-galactosylceramide (inducing substances) to the left lung. Methods Using computer tomography of the lungs with endobronchial administration of contrast material, we have been able to perform an operative intravital verification of the targeted delivery of the inducer. The model presented is characterized by more serious and homogeneous damage of the affected lung compared to the existing models of focal pneumonia; at the same time, our model is characterized by longer animal survival since the right lung remains intact. Results The model is also characterized by diffuse alveolar damage of the left lung, animal survival of 100%, abrupt increases in plasma levels of TNFa, INFg, and IL-6, and significant myocardial overload in the right heart. It can be used to assess the efficacy of innovative drugs for the treatment of DAD and ARDS as the clinical manifestations that are developed in patients infected with SARS-CoV-2. Morphological patterns of lungs in the noninfectious (“sterile”) model of DAD induced by LPS simultaneously with α-galactosylceramide (presented here) and in the infectious model of DAD induced by SARS-CoV-2 have been compared. Conclusion The DAD model we have proposed can be widely used for studying the efficacy of candidate molecules for the treatment of infectious respiratory diseases, such as viral pneumonias of different etiology, including SARS-CoV-2.
  PubDate: 2022-04-17
A20 attenuates pyroptosis and apoptosis in nucleus pulposus cells via
promoting mitophagy and stabilizing mitochondrial dynamics
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  Abstract: Background A20 is an anti-inflammatory molecule in nucleus pulposus (NP) cells. The anti-inflammatory properties of A20 are mainly attributed to its ability to suppress the NF-κB pathway. However, A20 can protect cells from death independently of NF-κB regulation. This study aimed to investigate the effects of A20 on pyroptosis and apoptosis of NP cells induced by lipopolysaccharide (LPS). Methods NP cells induced by LPS were used as an in vitro model of the inflammatory environment of the intervertebral disc. Pyroptosis, apoptosis, and mitophagy marker proteins were detected. Then, NP cells were transfected with A20 overexpressed lentivirus or A20-siRNA. Annexin V FITC/PI, Western blotting, and immunofluorescence assays were used to detect the apoptosis, pyroptosis, and mitophagy of NP cells. Furthermore, the expressions of A20, related proteins, and related inflammatory cytokines were detected by western blotting, and ELISA. Results Apoptosis and pyroptosis of NP cells increased gradually treated with LPS for 12 h, 24 h, and 48 h. Differently, the level of mitophagy increased first and then decreased, and was the highest at LPS treatment for 12 h. Overexpression or knockdown of A20 in NP cells revealed that A20 attenuated the pyroptosis, apoptosis, and production of inflammatory cytokines of NP cells induced by LPS, while A20 sponsored mitophagy, reduced ROS production and collapse of mitochondrial membrane potential (ΔΨm). Moreover, A20 also promoted mitochondrial dynamic homeostasis and attenuated LPS-induced excessive mitochondrial fission. Excitingly, inhibition of mitophagy attenuated the effect of A20 on the negative regulation of pyroptosis of NP cells induced by LPS. Pyroptosis was accompanied by a large release of inflammatory cytokines. Inhibition of pyroptosis also significantly reduced apoptosis of NP cells. Finally, The mitochondria-targeted active peptide SS-31 inhibited LPS-induced pyroptosis and ROS production in NP cells. Conclusions To sum up, A20 attenuates pyroptosis and apoptosis of NP cells via promoting mitophagy and stabilizing mitochondrial dynamics. Besides, A20 reduces LPS-induced NP cell apoptosis by inhibiting NLRP3 inflammasome-mediated pyroptosis. It provides theoretical support for the reduction of functional NP cell loss in the intervertebral disc through the gene-targeted intervention of A20.
  PubDate: 2022-04-15
TMS member news
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  PubDate: 2022-04-13
Inhibition of endoplasmic reticulum stress by 4-phenylbutyrate alleviates
retinal inflammation and the apoptosis of retinal ganglion cells after
ocular alkali burn in mice
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  Abstract: Objective Retinal ganglion cell (RGC) apoptosis is one of the most severe complications that causes permanent visual impairment following ocular alkali burn (OAB). Currently, very few treatment options exist for this condition. This study was conducted to determine the effect of 4-phenylbutyric acid (4-PBA) on endoplasmic reticulum (ER) stress after OAB using a well-established OAB mouse model. Methods Ocular alkali burn was induced in C57BL/6 mouse corneas using 1 M NaOH. 4-PBA (10 mg/kg; 250 μL per injection) or saline (250 μL per injection) was injected intraperitoneally once per day for 3 days before the establishment of the OAB model. The apoptosis of retinal ganglion cells (RGCs) was assessed by terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) assay, and the histological damage was examined by hematoxylin and eosin and immunofluorescence assay on retinal flat mounts. The key inflammatory response and the expression of ER stress-related markers in the retinal tissues were assessed by real-time PCR, western blotting and histologic analyses. Results 4-PBA significantly alleviated the apoptosis of RGCs and prevented the structural damage of the retina, as determined by the evaluation of RGC density and retinal thickness. Inhibition of ER stress by 4-PBA decreased the expression of vital proinflammatory cytokines, tumor necrosis factor alpha, and interleukin-1 beta; and suppressed the activation of retinal microglial cells and nuclear factor-kappa B (NF-κB). 4-PBA reduced the expression of the ER stress molecules, glucose-regulated protein 78, activated transcription factor 6, inositol-requiring enzyme-1 (IRE1), X-box-binding protein 1 splicing, and CCAAT/enhancer-binding protein homologous protein, in the retinal tissues and RGCs of OAB mice. Conclusions The present study demonstrated that the inhibition of ER stress by 4-PBA alleviates the inflammatory response via the IRE1/NF-κB signaling pathway and protects the retina and RGCs from injury in an OAB mouse model. Such findings further suggest that 4-PBA might have potential therapeutic implications for OAB treatment.
  PubDate: 2022-04-12
Monocytes augment inflammatory responses in human aortic valve
interstitial cells via β2-integrin/ICAM-1-mediated signaling
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  Abstract: Objective Inflammatory infiltration in aortic valves promotes calcific aortic valve disease (CAVD) progression. While soluble extracellular matrix (ECM) proteins induce inflammatory responses in aortic valve interstitial cells (AVICs), the impact of monocytes on AVIC inflammatory responses is unknown. We tested the hypothesis that monocytes enhance AVIC inflammatory responses to soluble ECM protein in this study. Methods Human AVICs isolated from normal aortic valves were cocultured with monocytes and stimulated with soluble ECM protein (matrilin-2). ICAM-1 and IL-6 productions were assessed. YAP and NF-κB phosphorylation were analyzed. Recombinant CD18, neutralizing antibodies against β2-integrin or ICAM-1, and inhibitor of YAP or NF-κB were applied. Results AVIC expression of ICAM-1 and IL-6 was markedly enhanced by the presence of monocytes, although matrilin-2 did not affect monocyte production of ICAM-1 or IL-6. Matrilin-2 up-regulated the expression of monocyte β2-integrin and AVIC ICAM-1, leading to monocyte-AVIC adhesion. Neutralizing β2-integrin or ICAM-1 in coculture suppressed monocyte adhesion to AVICs and the expression of ICAM-1 and IL-6. Recombinant CD18 enhanced the matrilin-2-induced ICAM-1 and IL-6 expression in AVIC monoculture. Further, stimulation of coculture with matrilin-2 induced greater YAP and NF-κB phosphorylation. Inhibiting either YAP or NF-κB markedly suppressed the inflammatory response to matrilin-2 in coculture. Conclusion Monocyte β2-integrin interacts with AVIC ICAM-1 to augment AVIC inflammatory responses to soluble matrilin-2 through enhancing the activation of YAP and NF-κB signaling pathways. Infiltrated monocytes may promote valvular inflammation through cell–cell interaction with AVICs to enhance their sensitivity to damage-associated molecular patterns.
  PubDate: 2022-04-11
Anti-coronavirus vaccines will not accelerate the transition of humanity
to a non-pandemic period, but the pandemic will take fewer victims
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  Abstract: Abstract The vaccination rate worldwide has reached enormous proportions, and it is likely that at least 75% of the world's population will be vaccinated. The controversy is that, while people aged 65 and older suffer a significantly higher mortality rate from COVID-19, plans are being made to vaccinate young people under the age of 20. Equally thorny is the question of vaccinating people who already have antibodies to SARS-CoV-2, as well as B and T memory cells, because they contracted and survived the virus. The possible consequences of large-scale vaccination are difficult to predict, when some people do not have access to the vaccine at all and others have already received 3 doses of the vaccine. SARS-CoV-2 will circulate through the human population forever and continue to mutate, as viruses do. Therefore, in the coming years, the need to develop and use effective vaccines and medicines for the prevention and treatment of COVID-19 will remain urgent in view of the high mortality rate from this disease. To date, three vaccine platforms have been most used: adenoviral vector, inactivated, and mRNA. There is some concern about the side effects that occur after vaccination. Whether modern anti-coronavirus vaccines can raise the safety threshold, only time will answer. It is obvious that the pandemic will end, but the virus will remain in the human population, leaving behind invaluable experience and tens of millions of victims. This article is based on search retrieves in research articles devoted to COVID-19 mainly published in 2020–2021 and examines the possible consequences of the worldwide vaccination against SARS-CoV-2 and suggests that, while anti-coronavirus vaccines will not magically transport humanity to a non-pandemic world, they may greatly reduce the number of victims of the pandemic and help us learn how to live with COVID-19.
  PubDate: 2022-04-10
Inflammatory profile in cervical cancer: influence of purinergic signaling
and possible therapeutic targets
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  Abstract: Introduction and objective Cervical cancer is the fourth most prevalent type of cancer in the world. The tumor microenvironment of this disease is associated with the production of several cytokines, pro and anti-inflammatory, and with the purinergic signaling system so that changes in these components are observed throughout the pathological process. The aim of this review is to understand the pathophysiology of cervical cancer based on immunological processes and purinergic signaling pathways, in addition to suggesting possibilities of therapeutic targets. Materials and methods To make up this review, studies covering topics of cervical cancer, inflammation and purinergic system were selected from the Pubmed. Results The main pro-inflammatory cytokines involved are IL-17, IL-1β, IL-6, and IL-18, and among the anti-inflammatory ones, IL-10 and TGF-β stand out. As new therapeutic targets, P2X7 and A2A receptors have been suggested, since blocking P2X7 would lead to reduced release of pro-inflammatory cytokines, and blocking A2A would increase activation of cytotoxic T lymphocytes in the context of tumor combat. The association between the immune system and the purinergic system, already known in other types of disease, also presents possibilities for a better understanding of biomolecular processes and therapeutic possibilities in the context of cervical cancer.
  PubDate: 2022-04-04
Supraphysiological testosterone supplementation improves granulation
tissue maturation through angiogenesis in the early phase of a cutaneous
wound healing model in rats
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  Abstract: Objective The aim of this study was to evaluate the effects of both testosterone depletion and supraphysiological testosterone supplementation in the early phase of an animal cutaneous wound healing model in comparison with the physiological hormonal condition. Material and Methods Forty rats were distributed into the following four groups: Control, Orchiectomy (OCX), Durateston (Dura) and OCX+Dura. On day 1, the testicles were removed (OCX group) and the rats (Dura group) received a supraphysiological dose (250 mg/kg) of exogenous testosterone weekly. After 15 days a full-thickness excisional skin wound was created in all animals, which was healed by the second intention for 7 days. On day 22, the rats were euthanatized and the wounds were harvested for histopathological evaluation, immunohistochemistry analyses and multiplex immunoassay. One-way ANOVA and post-hoc Tukey tests were performed. Results It was found that the supraphysiological testosterone level increased extracellular matrix deposition, promoted higher blood vessel formation and reduced wound contraction (p < 0.05). Additionally, it also stimulated PCNA-positive fibroblasts and KGF-positive cells (p < 0.05), while orchiectomy reduced the expression of IL-6 and TNF-α and increased VEGF and PDGF (p < 0.05) . Conclusion In conclusion, the results provide evidence that supraphysiological testosterone supplementation plays a positive role in the early phase of cutaneous wound healing, thus improving granulation tissue maturation through the enhancement of angiogenesis.
  PubDate: 2022-03-30
The RNA-binding protein SND1 promotes the degradation of GPX4 by
destabilizing the HSPA5 mRNA and suppressing HSPA5 expression, promoting
ferroptosis in osteoarthritis chondrocytes
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  Abstract: Background Heat shock protein family A member 5 (HSPA5), a recently identified suppressor of ferroptosis, was reported to potentially regulating osteoarthritis. However, the exact role of HSPA5 and how its expression was regulated in osteoarthritis are largely unclear. Methods Rat primary chondrocytes were treated with 10 ng/mL IL-1β for 24 h and incubated with ferrostatin-1 (a ferroptosis inhibitor). Cell viability, production of TNF-α, ROS and MDA, expression levels of collagen II, MMP13, GPX4, and SND1, and Fe2+ concentration were detected. Gain- and loss-of-function manipulations were performed to investigate the effect of HSPA5 on chondrocyte functions, and SND1 shRNA (sh-SND1) was transfected into IL-1β-treated primary chondrocytes alone or together with sh-HSPA5. Furthermore, the interaction between HSPA5 and GPX4 and the regulation of HSPA5 on GPX4 were explored. Finally, SND1 was knocked down in the rats with osteoarthritis, and the histopathology, expression of HSPA5-GPX4 axis, and levels of oxidative stress markers were evaluated. Results IL-1β treatment could enhance extracellular matrix (ECM) degradation (collagen II reduced and MMP13 increased), promote ferroptosis, manifested by decreased cell viability, increased levels of TNF-α, ROS, MDA, and Fe2+ concentrations, and decreased level of GPX4 protein, and increase SND1 expression in chondrocytes, which could be reversed by ferrostatin-1. Knockdown of SND1 enhanced ECM degradation and suppressed ferroptosis IL-1β-treated chondrocytes, which could be eliminated by knockdown of HSPA5. SND1 bound with HSPA5 at the 3’UTR and destabilized the HSPA5 mRNA. HSPA5 protein directly bound with GPX4 protein and positively regulate its expression. HSPA5 overexpression suppressed IL-1β-induced chondrocyte ferroptosis, while this effect was counteracted by GPX4 silencing. Knockdown of SND1 upregulated HSPA5 and GPX4 in rat cartilage, inhibited inflammatory damage and ferroptosis, and alleviated OA progression. Conclusion The RNA-binding protein SND1 promotes the degradation of GPX4 by destabilizing the HSPA5 mRNA and suppressing HSPA5 expression, promoting ferroptosis in osteoarthritis chondrocytes.
  PubDate: 2022-03-23
Diamine oxidase knockout mice are not hypersensitive to orally or
subcutaneously administered histamine
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  Abstract: Objective To evaluate the contribution of endogenous diamine oxidase (DAO) in the inactivation of exogenous histamine, to find a mouse strain with increased histamine sensitivity and to test the efficacy of rhDAO in a histamine challenge model. Methods Diamine oxidase knockout (KO) mice were challenged with orally and subcutaneously administered histamine in combination with the β-adrenergic blocker propranolol, with the two histamine-N-methyltransferase (HNMT) inhibitors metoprine and tacrine, with folic acid to mimic acute kidney injury and treated with recombinant human DAO. Core body temperature was measured using a subcutaneously implanted microchip and histamine plasma levels were quantified using a homogeneous time resolved fluorescence assay. Results Core body temperature and plasma histamine levels were not significantly different between wild type (WT) and DAO KO mice after oral and subcutaneous histamine challenge with and without acute kidney injury or administration of HNMT inhibitors. Treatment with recombinant human DAO reduced the mean area under the curve (AUC) for core body temperature loss by 63% (p = 0.002) and the clinical score by 88% (p < 0.001). The AUC of the histamine concentration was reduced by 81%. Conclusions Inactivation of exogenous histamine is not driven by enzymatic degradation and kidney filtration. Treatment with recombinant human DAO strongly reduced histamine-induced core body temperature loss, histamine concentrations and prevented the development of severe clinical symptoms.
  PubDate: 2022-03-18
Regulation of TRPV1 channel in monosodium urate-induced gouty arthritis in
mice
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  Abstract: Objective The transient receptor potential vanilloid subtype 1 (TRPV1) channel is considered to play an important regulatory role in the process of pain. The purpose of this study is to observe the change characteristics of TRPV1 channel in MSU-induced gouty arthritis and to find a new target for clinical treatment of gout pain. Methods Acute gouty arthritis was induced by injection of monosodium urate (MSU) crystals into the ankle joint of mice. The swelling degree was evaluated by measuring the circumference of the ankle joint. Mechanical hyperalgesia was conducted using the electronic von Frey. Calcium fluorescence and TRPV1 current were recorded by applying laser scanning confocal microscope and patch clamp in dorsal root ganglion (DRG) neurons, respectively. Results MSU treatment resulted in significant inflammatory response and mechanical hyperalgesia. The peak swelling degree appeared at 12 h, and the minimum pain threshold appeared at 8 h after MSU treatment. The fluorescence intensity of capsaicin-induced calcium response and TRPV1 current were increased in DRG cells from MSU-treated mice. The number of cells that increased calcium response after MSU treatment was mainly distributed in small-diameter DRG cells. However, the action potential was not significantly changed in small-diameter DRG cells after MSU treatment. Conclusions These findings identified an important role of TRPV1 in mediating mechanical hyperalgesia in MSU-induced gouty arthritis and further suggest that TRPV1 can be regarded as a potential new target for the clinical treatment of gouty arthritis.
  PubDate: 2022-03-17
Dihydroartemisinin ameliorates chronic nonbacterial prostatitis and
epithelial cellular inflammation by blocking the E2F7/HIF1α pathway
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  Abstract: Objective Chronic nonbacterial prostatitis (CNP) has remained one of the most prevalent urological diseases, particularly in older men. Dihydroartemisinin (DHA) has been identified as a semi-synthetic derivative of artemisinin that exhibits broad protective effects. However, the role of DHA in inhibiting CNP inflammation and prostatic epithelial cell proliferation remains largely unknown. Materials and methods CNP animal model was induced by carrageenan in C57BL/6 mouse. Enzyme linked immunosorbent assay (ELISA), Real-time quantitative polymerase chain reaction (RT-qPCR) and Western blot were used to examine inflammatory cytokines and proliferation genes expression. Immunofluorescence and immunochemistry staining were used to detect and E2F7 expression. Human prostatic epithelial cells (HPECs) and RWPE-1 was induced by lipopolysaccharide (LPS) to mimic CNP model in vitro. Cell proliferation was determined using MTS assay. Results DHA significantly alleviated the rough epithelium and inhibited multilamellar cell formation in the prostatic gland cavity and prostatic index induced by carrageenan. In addition, DHA decreased the expression of TNF-α and IL-6 inflammatory factors in prostatitis tissues and in LPS-induced epithelial cells. Upregulation of transcription factor E2F7, which expression was inhibited by DHA, was found in CNP tissues, human BPH tissues and LPS-induced epithelial cells inflammatory response. Mechanically, we found that depletion of E2F7 by shRNA inhibited epithelial cell proliferation and LPS-induced inflammation while DHA further enhance these effects. Furthermore, HIF1α was transcriptional regulated by E2F7 and involved in E2F7-inhibited CNP and cellular inflammatory response. Interestingly, we found that inhibition of HIF1α blocks E2F7-induced cell inflammatory response but does not obstruct E2F7-promoted cell growth. Conclusion The results revealed that DHA inhibits the CNP and inflammation by blocking the E2F7/HIF1α pathway. Our findings provide new evidence for the mechanism of DHA and its key role in CNP, which may provide an alternative solution for the prevention and treatment of CNP.
  PubDate: 2022-03-13
Protease-activated receptor 2 enhances innate and inflammatory mechanisms
induced by lipopolysaccharide in macrophages from C57BL/6 mice
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  Abstract: Objective This study was conducted to investigate the effects of the synthetic PAR2 agonist peptide (PAR2-AP) SLIGRL-NH2 on LPS-induced inflammatory mechanisms in peritoneal macrophages. Methods Peritoneal macrophages obtained from C57BL/6 mice were incubated with PAR2-AP and/or LPS, and the phagocytosis of zymosan fluorescein isothiocyanate (FITC) particles; nitric oxide (NO), reactive oxygen species (ROS), and cytokine production; and inducible NO synthase (iNOS) expression in macrophages co-cultured with PAR-2-AP/LPS were evaluated. Results Co-incubation of macrophages with PAR2AP (30 µM)/LPS (100 ng/mL) enhanced LPS-induced phagocytosis; production of NO, ROS, and the pro-inflammatory cytokines interleukin (IL)-1β, tumour necrosis factor (TNF)-α, IL-6, and C–C motif chemokine ligand (CCL)2; and iNOS expression and impaired the release of the anti-inflammatory cytokine IL-10 after 4 h of co-stimulation. In addition, PAR2AP increased the LPS-induced translocation of the p65 subunit of the pro-inflammatory transcription factor nuclear factor kappa B (NF-κB) and reduced the expression of inhibitor of NF-κB. Conclusion This study provides evidence of a role for PAR2 in macrophage response triggered by LPS enhancing the phagocytic activity and NO, ROS, and cytokine production, resulting in the initial and adequate macrophage response required for their innate response mechanisms.
  PubDate: 2022-03-11
Standardized fraction of Xylocarpus moluccensis inhibits inflammation by
modulating MAPK-NFκB and ROS-HIF1α-PKM2 activation
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  Abstract: Objective Present study investigates the effect of Xylocarpus moluccensis (Lamk.) M. Roem fruit fraction (CDR) on endotoxemia and explores the underlying mechanisms. Materials and methods The effect of CDR (1–100 µg/ml) was assessed on cytokines, MAPKs, ROS, and metabolic reprogramming in LPS-induced cells (J774.2 and THP-1) by the conventional methodology of ELISA, PCR, and Western blotting. The effect of CDR (1–50 mg/kg, p.o.) was also evaluated in the mice model of endotoxemia and sepsis. Results CDR prevents LPS-induced cytokine production from murine and human whole blood and cell lines. CDR suppressed total cellular and mitochondrial superoxide generation and preserved mitochondrial function in LPS-stimulated phagocytes. Additionally, CDR abrogated LPS-induced MAPK’s phosphorylation and IκBα degradation in J774.2 cells. Moreover, CDR suppressed LPS-induced glycolytic flux as indicated from PKM2, HK-2, PDK-2, and HIF-1α expression in J774.2 cells. In vivo, CDR pre-treatment inhibited pro-inflammatory cytokines release, metabolic reprogramming from oxidative phosphorylation to glycolysis in both LPS-induced endotoxemia and cecal slurry-induced sepsis mice model. Conclusion Present study demonstrates the protective effect of CDR on LPS-induced inflammation and sepsis and identifies MAPK-NFκB and ROS-HIF1α-PKM2 as the putative target axis.
  PubDate: 2022-03-10