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174 inflammation Preprints

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Please note: These are preprints and have not been peer reviewed. Data may be preliminary. Preprints should not be relied on to guide medical practice or health-related decisions. News media reporting on preprints should stress that the research should not yet be considered conclusive.
Therapeutic strategies to fight COVID-19: which is the status artis?
Cristina Scavone
Annamaria Mascolo

Cristina Scavone

and 12 more

January 18, 2021
COVID-19 is a complex disease and many difficulties are faced today especially in the proper choice of pharmacological treatments. The role of antiviral agents for COVID-19 is still being investigated. The evidence for immunomodulatory and anti-inflammatory drugs is quite conflicting, while the use of corticosteroids is supported by robust evidence. The use of heparins in hospitalized critically ill patients is preferred over other anticoagulants. Lastly, conflicting data were found regarding to the use of convalescent plasma and vitamin D. According to data shared by the WHO, many vaccines are under phase 3 clinical trials and some of them already received the marketing approval in EU countries and in the US. In conclusion, drugs repurposing has represented the main approach recently used in the treatment of patients with COVID-19. At this moment, the analysis of efficacy and safety data of drugs and vaccines used in real life context is strongly needed.
COVID-19 and intestinal dysbiosis: the proposed mechanism of short-chain fatty acids...
Manon Jardou
Roland Lawson

Manon Jardou

and 1 more

January 08, 2021
The world is currently facing the COVID-19 pandemic that is taking a heavy toll on several countries. While many infected patients have a good prognosis, in some cases the progression can be serious and even lead to death. The commonly seen complications are a cytokine storm and multi-organ failure that require intensive care. The mortality of critically ill patients depends on age (> 65 years), sex (male) or co-morbidities. There is an urgent need to discover a biomarker to identify early on patients at risk of developing serious complications, and to find an effective treatment that could prevent disease progression and critical states. Recent investigations have pointed to the possible contribution of intestinal dysbiosis to the pathophysiology of COVID-19. Herein, we hypothesize that butyrate, a short-chain fatty acid produced by the gut microbiota, can prevent immune system activation and disease progression.
Time-dependent dual effect of NLRP3 inflammasome in brain ischemia
Alejandra Palomino-Antolin
Paloma Narros-Fernández

Alejandra Palomino-Antolin

and 10 more

December 31, 2020
Background: Post-ischemic inflammation contributes to worsening of ischemic brain injury and in this process, the inflammasomes play a key role. Inflammasomes are cytosolic multiprotein complexes which upon assembly activate the maturation and secretion of the inflammatory cytokines IL-1β and IL-18. However, participation of the NLRP3 inflammasome in ischemic stroke remains controversial. Our aims were to determine the role of NLRP3 in ischemia and to explore the mechanism involved in the potential protective effect of the neurovascular unit. Methods: WT and NLRP3 knock-out mice were subjected to ischemia by middle cerebral artery occlusion (60 minutes) with or without treatment with MCC950 at different time points post-stroke. Brain injury was measured histologically with 2,3,5-triphenyltetrazolium chloride (TTC) staining. Results: We identified a time-dependent dual effect of NLRP3. While neither the pre-treatment with MCC950 nor the genetic approach (NLRP3 KO) proved to be neuroprotective, post-reperfusion treatment with MCC950 significantly reduced the infarct volume in a dose-dependent manner. Importantly, MCC950 improved the neuro-motor function and reduced the expression of different pro-inflammatory cytokines (IL-1β, TNF-α), NLRP3 inflammasome components (NLRP3, pro-caspase-1), protease expression (MMP9) and endothelial adhesion molecules (ICAM, VCAM). We observed a marked protection of the blood-brain barrier (BBB), which was also reflected in the recovery of the tight junctions proteins (ZO-1, Claudin-5). Additionally, MCC950 produced a reduction of the CCL2 chemokine in blood serum and in brain tissue, which lead to a reduction in the immune cell infiltration. Conclusions: These findings suggest that post-reperfusion NLRP3 inhibition may be an effective acute therapy for protecting the blood-brain barrier in cerebral ischemia with potential clinical translation.
ACE2 receptor, TRL-4 and SARS CoV-2: Do long acting opioids and opioid antagonists ha...
Marie Eagleton
Siobhan Stokes

Marie Eagleton

and 3 more

December 28, 2020
Despite the advent of a vaccine, broadening the arsenal of drugs effective in the treatment and prevention of COVID-19 disease remains critical in the global effort to control the SARSCoV2 pandemic. Opioids and opioid antagonists may have a role in treating and in the prevention of this disease based on a number of observations: an unexpectedly low incidence of COVID-19 has been observed in patients treated for opioid dependency with long acting opioid drugs such as methadone; opioids bind to the ACE2 transmembrane protein, a molecule that is widely considered to be main host cell receptor for SARS CoV2 cell entry; opioids have systemic immunomodulatory effects which may influence the response to the virus; studies aimed at repurposing drugs for treatment of COVID-19 have identified that opioids have therapeutic potential and finally there are ongoing trials of some of these drugs. The interaction of long acting opioids or opioid antagonists with the ACE2 receptor and the possible effects on TLR4 function in SARS CoV2 infection should be given serious consideration when developing effective therapies.
The relationship of the immature platelet fraction with the diagnosis and severity of...
MURAT DOĞAN
MEHMET KOSE

MURAT DOĞAN

and 4 more

December 20, 2020
Objective: Acute bronchiolitis is one of the most common causes of hospitalization for children younger than 1 year. Although the prognosis for these children is generally good, the condition involves a risk of mortality. Here, we evaluate the immature platelet fraction (IPF) as a biomarker for the severity of acute bronchiolitis. Material and Methods: In total, 179 children who had been diagnosed with acute bronchiolitis were classified into three groups: mild, moderate, and severe bronchiolitis, and 80 healthy children were included as a control group. The diagnostic capacity of the IPF, mean platelet volume (MPV), platelet distribution width (PDW), white blood cell count (WBC), and platelet count (PLT) values to predict bronchiolitis was evaluated using receiver operating characteristic (ROC) curves and their respective areas under the curves (AUCs) calculated with 95% confidence intervals. Results: Patients with acute bronchiolitis had a larger IPF than their healthy counterparts (p < 0.001). Additionally, a positive correlation was observed between the clinical severity of the disease and the IPF. The ROC curve analysis indicated that the IPF cut-off point for predicting acute bronchiolitis was >3.2%, with a sensitivity of 84% and specificity of 97%. Our results clearly demonstrate that the AUCs for IPF, MPV, PDW, WBC, and PLT were statistically significant for the bronchiolitis versus the control group. The AUC was greatest for the IPF. Conclusion: The IPF is a new marker for diagnosing and evaluating the clinical severity of acute bronchiolitis.
Impaired endothelial function irrespective of systemic inflammation or atherosclerosi...
Nida Oztop
Pelin Karaca Ozer

Nida Oztop

and 12 more

December 15, 2020
Background: Knowledge on endothelial dysfunction and its relation to atherosclerosis in mastocytosis is limited. Aim: To investigate the endothelial function in mastocytosis by flow mediated dilatation (FMD) and biomarkers related to vascular endothelia, the presence of subclinical atherosclerosis by carotid intima media thickness (CIMT). Method: Forty-nine patients with mastocytosis and 25 healthy controls (HCs) were included. FMD and CIMT during transthoracic echocardiography, biomarkers including endocan, endothelin-1 (ET-1), vascular endothelial growth factor (VEGF) were measured in sera of participants. Tumor necrosis factor-alpha (TNF-α), interleukine-6 (IL-6) and high sensitive c-reactive protein (hsCRP) were determined as inflammatory biomarkers. Result: The mean FMD% was lower in the patients than HCs (11.26±5.85% vs 17.84±5.27% p<0.001) and was the lowest in the advSM and SSM group among the patients (p=0.03). The median value of VEGF was significantly higher in patients than HCs. [73.30 pg/mL; min-max (32.46-295.29) pg/mL vs (46.64 pg/mL; min-max 11.09-99.86 pg/mL; p:0.001] and it was the highest in the advSM and SSM group (p:0.01). FMD was inversely correlated with endocan (r:-.390, p:0.006), ET-1 (r:-.363, p:0.01) and VEGF (r:-.402, p:0.004) but there were no correlations between FMD and TNF-α, IL-6, and hsCRP. No differences in CIMT values between patients and HCs and no correlation between CIMT and the biomarkers were observed. Conclusion: Endothelial dysfunction in mastocytosis becomes evident with decreased FMD and elevated serum VEGF, in the absence of atherosclerosis or systemic inflammation and is related to disease severity. Keywords: CIMT, Endocan, Endothelial function, Endothelin-1, FMD, VEGF
The Janus face of Ouabain in Na+, K+-ATPase and calcium signalling in neurons
Paula Kinoshita
Ana  Orellana

Paula Kinoshita

and 6 more

December 10, 2020
Na+,K+ATPase (NKA), a transmembrane protein essential for maintaining the electrochemical gradient across the plasma membrane, acts as a receptor for cardiotonic steroids (CTS) such as ouabain. CTS binding to NKA, triggers signalling pathways or inhibits NKA activity in a concentration-dependent manner, resulting in a modulation of Ca2+ levels, which are essential for homeostasis in neurons. However, most of the pharmacological strategies for avoiding neuronal death do not target NKA activity, due to its complexity and poor comprehension of the mechanisms involved in NKA modulation. The present review aims to discuss two points regarding the interplay between NKA and Ca2+ signalling in the brain: NKA impairment causing illness as well as neuronal death due to Ca2+ signalling and benefits to the brain by modulating NKA activity. These interactions play an essential role in neuronal cell fate determination and are relevant to finding new targets for the treatment of neurodegenerative diseases.
Celastrol alleviates comorbid obesity and depression by directly binding amygdala hnR...
Chunyan Zhu
Jun Yang

Chunyan Zhu

and 9 more

December 01, 2020
Background and Purpose: Obesity and depression are highly comorbid and far from effective treating. Celastrol was reported useful for obesity, but its role in the obesity-depression comorbidity remains unknown. This study aims to investigate the efficacy and associated mechanism of celastrol in this comorbidity. Experimental Approach: A comorbidity mice model of obesity and depression were constructed. Bodyweight, adipose tissue rate, blood glucose, and blood lipids were used to assess obesity. Forced swimming test and tail suspension test were investigated to evaluate depression. In microglial cells, direct targets of celastrol were screened and determined by chemical proteomics, pull-down experiment, and competitive binding assay. In the mice model, the target gene’s mediating effect was investigated by stereotactic injection of AAV9 virus. The expression level of target molecules was detected by immunofluorescence. Key Results: Celastrol relieved the comorbid symptoms, inhibited the mal-activated Neuropeptide Y, and activated the mal-inhibited 5-HT neurons in the amygdala. The efficacy was associated with the inhibition of the mal-activated microglia. Chemical proteomics, pull-down experiment, and competitive binding assay results indicated celastrol’s directly binding hnRNPA1. In the animal model, downregulation of hnRNPA1 in the amygdala relived symptoms and NPY and 5-HT neurons’ changes. Meanwhile, overexpression of hnRNPA1 aggravated the comorbidity and antagonized the effect of celastrol. Conclusion and Implications: Celastrol alleviated comorbid obesity and depression in a mouse model by directly binding hnRNPA1 in the amygdala. Celastrol may become a potential drug, and hnRNPA1 in the amygdala could be a useful target to combat the comorbidity.
Canthin-6-one ameliorates TNBS-induced colitis in rats by modulating inflammation and...
Domingos Tabajara Martins
Karuppusamy Arunachalam

Domingos Tabajara Martins

and 10 more

December 01, 2020
Background and Purpose: Canthin-6-one (Cant) is an indole alkaloid found in different medicinal plants, reported to be gastroprotective, anti-inflammatory, anti-microbial, anti-diarrheal and anti-proliferative. We aimed to explore Cant in the management of ulcerative colitis (UC) using a trinitrobenzenesulfonic acid (TNBS)-induced rat model. Experimental Approach: Cant (1, 5 and 25 mg/kg) was administered by oral gavage to Wistar rats followed by induction of colitis with TNBS. Macroscopic and histopathological scores, myeloperoxidase (MPO), malondialdehyde (MDA) and reduced glutathione (GSH) were assessed in colon tissues. Pro- (TNF-α, IL-1β and IL-12p70) and anti-inflammatory (IL-10) cytokines, and vascular endothelial growth factor (VEGF) were also quantified. Mitogen-activated protein kinase 14 (MAPK14) and Toll-like receptor-8 (TLR8), as putative targets, were considered through in silico analysis. Key Results: Cant (5 and 25 mg/kg) reduced macroscopic and histological colon damage scores in TNBS-treated rats. MPO and MDA were reduced by up to 61.69% and 92.45%, respectively, compared to TNBS-treated rats alone. Glutathione concentration was reduced in rats administered with TNBS alone (50.00% of sham group), being restored to 72.73% (of sham group) under Cant treatment. TNF-α, IL-1β, IL-12p70 and VEGF were reduced, and anti-inflammatory IL-10 was increased following Cant administration compared to rats administered TNBS alone. Docking ligation results for MAPK14 (p38α) and TLR8 with Cant, confirmed that these proteins are feasible putative targets. Conclusions and Implications: Cant has an anti-inflammatory effect in the intestine by down-regulating immune molecular mediators and decreasing oxidative stress. Therefore, Cant could have therapeutic potential for the treatment of inflammatory bowel disease and related syndromes.
Astragaloside IV Protects Against Diabetic Nephropathy by Inhibiting Pyroptosis Based...
Yudi Zhang
Chunhe Tao

Yudi Zhang

and 4 more

December 01, 2020
Background and Purpose: Diabetic nephropathy (DN) is a common and severe chronic complication in diabetes mellitus. The purpose of this study was to explore the effect and mechanism of Astragaloside IV (AS-IV) on renal pyroptosis in DN. Experimental Approach: High-fat diet and a small dose of streptozotocin were used to establish the DN model. Rats were treated with vehicle or AS-IV (20-, 40- and 80-mg/kg/day) or valsartan (30mg/kg/day) by gavage. After 12 weeks, animals were euthanized; samples of urine and blood were collected to examine biochemical indicators, advanced glycation end products (AGEs), inflammatory cytokines; kidney tissues were collected for histological observation, TUNEL staining, AGEs, inflammatory cytokines, redox indicators, western blot, and immunohistochemistry. Key Results: Biochemical results showed that AS-IV could significantly alleviate the degree of clinical symptoms and the levels of blood glucose, HbA1C, TG, MDA, AGEs, Interleukin (IL)-1β, and IL-18 while improving the activity of SOD and the secretion and sensitivity of insulin. Histological examination and TUNEL staining indicated that AS-IV attenuated the damage of tissues and cells in the kidney from DN rats. Western blot results revealed that AS-IV relieved the activation of NOX4/TXNIP/NLRP3 pathway and the expression of collagen IV and fibronectin in DN rats. Immunohistochemistry results showed that AS-IV attenuated collagen IV and fibronectin in the kidney from DN rats. Conclusion and Implications: The NOX4/TXNIP/NLRP3 pathway mediated renal pyroptosis could play a crucial role in kidney damage and DN development in rats. Restoration of renal pyroptosis by AS-IV be a potential therapeutic strategy against DN.
Development and Validation of an Interleukin-6 Nomogram to Predict Primary Non-respon...
Yueying Chen
Hanyang Li

Yueying Chen

and 3 more

December 01, 2020
Background: The primary nonresponse (PNR) rate of Infliximab (IFX) varies from 20% to 46% for the treatment of Crohn’s disease (CD). Detected PNR reduces the improper use of specific treatments. To date, there is hardly any knowledge regarding early markers of PNR. The aim of this study was to evaluate the role of Interleukin-6 (IL-6) as an early predictor of PNR of IFX for the treatment of CD. Methods: We enrolled 322 bio-naïve patients diagnosed with CD from January 2016 to May 2020. Primary response was determined at week 14. Multivariable logistic regression was used to construct prediction models. The discrimination, calibration and clinical validity of the models in the validation cohort were assessed by area under the curve (AUC), calibration and decision curves analyses. GEO data were analyzed to identify potential mechanisms of IL-6 in IFX therapy for CD. Results: PNR occurred in 31.06% (100 of 322) patients who were assessable at week 14. IL-6 levels significantly decreased after IFX therapy (P < 0.001). The validation model containing IL-6 presented enhanced discrimination with an AUC of 0.908 and high calibration. Decision curve analysis (DCA) indicated that the model added extra predictive value. GEO data confirmed the IL-6 levels were increased in the PNR group and IL-6-related differently expressed genes (DEGs) were enriched in the inflammatory response. Conclusion: We concluded that IL-6 may be used as a predictive factor to assess the risk of PNR to IFX therapy.
Botanical Drugs and Supplements Affecting the Immune Response in the Time of COVID-19...
Thomas Brendler
Ahmed Al-Harrasi

Thomas Brendler

and 12 more

November 28, 2020
In times of health crisis, including the current COVID-19 pandemic, the potential benefit of botanical drugs and supplements emerges as a focus of attention, although controversial efficacy claims are rightly a concern. Phytotherapy has an established role in everyday selfcare and health care, and since botanical preparations contain many chemical constituents rather than single compounds, challenges arise in demonstrating efficacy and safety. However, there is ample traditional, empirical and clinical evidence that botanicals can offer some protection and alleviation of disease symptoms as well as promoting general well-being. Newly emerging viral infections, specifically COVID-19, represent a unique challenge in their novelty and absence of established antiviral treatment or immunization. We discuss here the roles and limitations of phytotherapy in helping to prevent and address viral infections, and specifically regarding their effects on immune response. Botanicals with a documented immunomodulatory, immunostimulatory, and anti-inflammatory effect include adaptogens, Boswellia spp., Curcuma longa, Echinacea spp., Glycyrrhiza spp., medicinal fungi, Pelargonium sidoides, salicylate-yielding herbs, and Sambucus spp. We further provide a clinical perspective on applications and safety of these herbs in prevention, onset, progression, and convalescence from respiratory viral infections.
Interleukin-31: The ‘itchy’ cytokine in inflammation and therapy
Angeliki Datsi
Majid Alam

Angeliki Datsi

and 4 more

November 27, 2020
Interleukin-31 has been implicated in the pathophysiology of multiple atopic disorders such as atopic dermatitis (AD), rhinitis and airway hyperreactivity. In AD, IL-31 has been identified as one of the main ‘drivers’ of its cardinal symptom pruritus. Here, we aim to summarize the mechanisms by which IL-31 modulates inflammatory and allergic diseases. TH2 cells play a central role in AD and release high levels of TH2-produced cytokines including IL-31, thereby mediating inflammatory responses, initiating immunoregulatory circuits, and stimulating itch and neuronal outgrowth through activation of the heterodimer receptor IL-31 receptor alpha (IL31RA)/Oncostatin M receptor β. IL31RA expression is found on human and murine dorsal root ganglia neurons, epithelial cells including keratinocytes as well as various innate immune cells. IL-31 is a critical cytokine involved in neuro-immune communication, which opens new avenues for cytokine modulation in neuroinflammatory diseases including AD/pruritus, as validated by recent clinical trials using an anti-IL-31 antibody. Accordingly, inhibition of IL-31 downstream signaling may be a beneficial approach for various inflammatory diseases including prurigo nodularis. For example, whether downstream JAK inhibitors directly block IL-31-mediated-signaling needs to be clarified. Targeting the IL-31/IL31RA/OSMRβ axis appears to be a promising approach for inflammatory, neuroinflammatory and pruritic disorders in the future.
Cell death as part of Innate Immunity: cause or consequence?
Mario Riera-Romo

Mario Riera-Romo

November 26, 2020
Regulated or programmed cell death play a critical role in development and tissue organization and function. In addition, it is intrinsically connected with immunity and host defense. Increasing cellular and molecular findings are changing the concept of cell death, revealing an expanding network of regulated cell death modalities and their biochemical programs. Likewise, recent evidences are demonstrating the interconnection between cell death pathways and how they are involved in different immune mechanisms. This work provides an overview of the main cell death programs and their implication in innate immunity not only as an immunogenic/inflammatory process, but also as an active defense strategy during immune response and at the same time, as a regulatory mechanism.
Ouabain induces the extinction of contextual fear memory in rats subjected to chronic...
Cristoforo Scavone (GUEST EDITOR)
Jacqueline  Leite

Cristoforo Scavone (GUEST EDITOR)

and 8 more

November 24, 2020
Ouabain (OUA) is an inhibitor of Na+, K+ -ATPase that has been identified as an endogenous substance present in human plasma, and it has been shown to be associated with the response to acute stress in both animals and humans. Chronic stress is a major aggravating factor of psychiatric disorders, including depression and anxiety. The present work investigates the effects of OUA intermittent administration during chronic unpredictable stress (CUS) protocol in the rat’s central nervous system (CNS). Adult male Wistar rats were pretreated intraperitoneally with ouabain (1.8 μg/kg), followed by CUS protocol for 14 days. The levels of serum corticosterone, ACTH, and CRH serum were evaluated through ELISA and the expression of CRH, CRHR1, and CRHR2 genes in the hypothalamus and hippocampus of the animals through RT-PCR. Inflammatory parameters were also investigated, as well as the behavioral CUS effects on memory, that were assayed through the object recognition task, contextual fear conditioning, and memory extinction paradigms. The results suggest that intermittent OUA treatment reversed CUS-induced HPA axis hyperactivity through the reduction of (i) glucocorticoids levels, (ii) CRH-CRHR1 expression, and by decreasing neuroinflammation with the reduction of iNOS activity, without interfering with the expression of antioxidant enzymes. These changes in both the hypothalamus and hippocampus may reflect in the rapid extinction of aversive memory. The present data demonstrate, for the first time, the ability of OUA to modulate the HPA axis as well as the disappearance of aversive memory in rats.
De-escalation Antibiotic Therapy Alleviates Organ Injury through Modulation of NET Fo...
Tian Xie
Chengnan Chu

Tian Xie

and 6 more

November 19, 2020
Empiric broad-spectrum antimicrobials therapy is suggested to be started immediately for sepsis patients. Empiric antimicrobial therapy should be narrowed once pathogen identification and sensitivities are established. However, the detail mechanisms of de-escalation strategy are still unclear. Here we hypothesized neutrophil extracellular trap (NETs) played an essential role and de-escalation strategy might alleviate organs injury through regulation of NETs formation in sepsis. We evaluated the effect of imipenem and ceftriaxone on NETs formation in vitro and examined the role of reactive oxygen species (ROS). Next, we designed de-escalation and escalation strategy based on their effects on NETs formation in CLP model. Organ injury, inflammatory cytokines, NETs levels were compared and evaluated. The in vitro study showed that imipenem and ceftriaxone had opposite effects on NETs formation in activated neutrophils. De-escalation therapy resulted in an evaluated MPO-DNA during early stage and decreased MPO-DNA during late stage, which exerted the reverse effects in escalation therapy sepsis animal model. Inflammatory response and organ injury exacerbated when eliminated NETs with DNAseI during early stage of sepsis (p<0.01). Histopathological analysis showed decreased injury in lung, liver and intestine in de-escalation therapy compared with escalation therapy (p<0.01). De-escalation therapy results in the highest 6-day survival rate compared with the control group (p<0.01), however, no significant difference was found between de-escalation and escalation group (p=0.051). We demonstrate that de-escalation, not escalation, therapy reduces organ injury, decreases inflammatory response by promoting NETs formation in the early stage and inhibiting NETs formation in the late stage of sepsis.
Standardized Study of Atorvastatin Possible Osteoarthritis Disease-Modifying Effect i...
Ali Gaballah
Doaa Genedy

Ali Gaballah

and 4 more

November 12, 2020
Background and purpose: Osteoarthritis (OA) is a chronic and progressive joint disorder characterized by structural damage to one or more joints. However, drugs that could cure or at least stop the progression of this disease are still given no satisfactory outcome. The purpose of this work is to study the potential OA disease-modifying effects of atorvastatin in an experimental model of osteoarthritis and the possible underlining mechanisms if any. Experimental Approach: Seventy-six adult male Sprague-Dawley rats (250-300gms) were used throughout this study. Forty rats were used to assess the effect of atorvastatin in surgically induced OA. While 36 rats were used to assess its anti-inflammatory effect in carrageenan-induced paw edema. In the model of OA; the degree of joint stiffness was assessed by measuring the angle of knee extension besides, the histopathological changes of the OA knee joints and measurement of serum Interleukin-1beta (IL-1β), Matrix metalloproteinase-13 (MMP13), and reduced glutathione (GSH) concentration were biochemically assessed. In the carrageenan-induced paw edema, the paw thickness and pain threshold were assessed in different groups. Key Results: Atorvastatin was found to produce significant improvement of joint stiffness, the histopathological changes, a significant correction in the increased MMP13 and IL1-β, and the decreased GTH in OA rats. Also, atorvastatin showed a significant improvement in both paw thickness and pain threshold. Conclusion and Implications These results present atorvastatin as OA disease-modifying drug worse clinical trials.
NEUROLOGICAL RISKS AND BENEFITS OF CYTOKINE-BASED TREATMENTS IN COVID-19: A JOURNEY F...
GIUSEPPE PIGNATARO
Mauro Cataldi

GIUSEPPE PIGNATARO

and 2 more

November 05, 2020
IImmunodeficiency and hyperinflammation characterize COVID-19 associated states; thus, repurposing of multiple cytokine and/or anti-cytokine drugs currently being used in other therapeutic areas has been suggested as a potential therapeutic strategy in COVID-19 patients. Clinical trials involving these drugs target the most frequent and life-threatening peripheral consequences of the disease, mainly focusing on lung, heart, and coagulation functions; however, a growing number of reports describe a wide range of COVID-associated neurological manifestations (altogether defined as neuro-COVID) including anosmia, seizures, confusion, stroke, encephalopathy, and paralysis. Notably, the underlying pathophysiological mechanisms for neuro-COVID may also include dysregulation of cytokines/chemokines, deficiencies in the innate immune response, and autoimmunity. This suggests that therapeutic attempts with drugs targeting cytokine-mediated inflammation in peripheral organs could also positively affect neuro-COVID manifestations. As a matter of fact, some of these drugs have also been scrutinized for their potential efficacy in treating neuroinflammatory diseases such as optic neuromyelitis, epilepsy, stroke, and traumatic brain injury, among others. On the other hand, anti-cytokine drugs, by impairing relevant physiological activities exerted by these mediators in the CNS, may also be endowed with significant neurological risk. Therefore, the primary aim of the present manuscript is to review the available preclinical and clinical data regarding the neurological effects of the drugs targeting cytokine-mediated inflammation, in order to raise awareness about their potentially beneficial or detrimental neurological consequences when used to treat COVID-19 patients.
K-7174 protects against OA pathogenesis through blockade of the Zmiz1-GATA axis.
Jiho Nam
Li-Jung Kang

Jiho Nam

and 6 more

November 05, 2020
Background and Purpose Osteoarthritis (OA) is a leading cause of disability and bears a large socioeconomic cost, but we lack an effective disease-modifying therapy. There is great need to identify novel target molecules in OA pathogenesis. Here, by asking why old cartilage appears to be more sensitive to OA pathogenic factors, we identified the importance and underlying mechanism of K-7174 as a blocker of the Zmiz1-GATA axis in age-related OA pathogenesis. Experimental Approach As a novel transcriptional regulator in OA pathogenesis, Zmiz1 was isolated as an up-regulated gene from aged cartilage, using microarray and Ingenuity Pathway Analysis (IPA). Infection and intra-articular injection of Ad-Zmiz1 were performed in vitro and in vivo. Cartilage-specific Col2a1-Zmiz1 TG mice with or without DMM (destabilization of the medial meniscus) surgery were evaluated by measurement of OA manifestations. To identify a specific Zmiz1-related transcription factor and a potential inhibitor, we performed transcription factor, in silico binding, and inhibition assays. Key Results The transcriptional regulator, Zmiz1, is up-regulated in old mouse cartilage and highly expressed in damaged cartilage of OA patients and DMM mice. Col2a1-Zmiz1 TG mice and DMM-induced Col2a1-Zmiz1 TG mice showed more severe cartilage destruction. Overexpression of Zmiz1 induced cartilage destruction by up-regulating Mmps and Cox2 through activation of the Zmiz1-GATA axis. Finally, we demonstrate that K-7174 interfered with the activation of the Zmiz1-GATA axis to crucially protect against OA pathogenesis and promote ECM synthesis. Conclusion and Implications The K-7174-mediated blockade of the Zmiz1-GATA axis could be a useful therapeutic strategy for blocking OA pathogenesis.
Prognostic and pathogenic role of CXC Motif Ligand 16 in sepsis
Jiaxi Li
Lili Huang

Jiaxi Li

and 4 more

November 04, 2020
Chemokine CXC motif ligand 16 (CXCL16) is a multifaceted chemokine that has been shown to participate in a variety of inflammatory diseases. The role of CXCL16 in the immunopathology of sepsis remains unidentified. In this study, human patients with sepsis and healthy controls were used to obtain blood for in vitro studies, and female C57BL/6J mice were taken for in vivo studies. The effects of recombinant CXCL16 protein or anti-CXCL16 monoclonal antibody on sepsis were evaluated in a murine model of cecal ligation and puncture (CLP)–induced polymicrobial sepsis. On admission, human patients with sepsis had significantly higher soluble levels of serum CXCL16 than healthy controls. Soluble CXCL16 remained significantly elevated in septic patients from day 0 to 7. Admission levels of soluble CXCL16 were positively correlated disease severity and the serum levels of other inflammatory cytokines and chemokines. Furthermore, nonsurvivors displayed significantly higher admission levels of soluble CXCL16 compared with survivors of septic patients. Soluble CXCL16 levels revealed significant prognostic value for 28-day mortality, and CXCL16 was found to be an independent predictor of 28-day mortality in septic patients. In CLP-induced nonsevere sepsis, administration with recombinant CXCL16 increased mortality and tissue injury. Conversely, neutralizing CXCL16 by anti-CXCL16 monoclonal antibody decreased mortality and tissue injury in CLP-induced severe sepsis. However, CXCL16 did not affect the ability of these mice to clear bacteria in CLP. Taken together, CXCL16 could be linked to sepsis not only as a new marker of prognosis, but also as a potential target for therapeutic intervention.
Potential pharmacological mechanism of Colitis treatment by diosmetin
hailong Li
Yiying Wei

hailong Li

and 11 more

November 01, 2020
BACKGROUND AND PURPOSE Diosmetin exhibits a series of therapeutic efficacy but little is known of its effects on colitis. EXPERIMENTAL APPROACH In this study, two mouse models of DSS (the concentration of 3% and 5%)-induced colitis and Caco2 and IEC-6 cells were employed. The 16S amplicon sequencing was used to assess Gut microbiota changes by diosmetin. Various physical signs of mice (body weight, colon length and DAI score), proinflammatory cytokines and antioxidant enzymes were tested. KEY RESULTS The results showed that diosmetin can markedly decrease the disease activity index and microscopic colon tissue damage, increase the expression of tight junction protein (Occludin, Claudin-1 and Zo-1) and reduce the secretion of proinflammatory cytokines. And diosmetin also significantly inhibited colon oxidative damage through adjusting the levels of intracellular ROS, mitochondrial ROS, GSH-Px, SOD, MDA and GSH in vitro and in vivo. Furthermore, it was found that diosmetin can modulate the abundance of Bacteroidetes, Actinobacteria, Cyanobacteria and Firmicutes, which were reported to be the crucial bacteria related to inflammatory bowel disease (IBD). Also, diosmetin significantly increased the expression of Nrf2 and HO-1 and reduced the ratio of acetylated NF-κB and NF-κB by activating the circ-Sirt1/Sirt1 axis, thereby inhibiting oxidative stress and inflammation. CONCLUSIONS AND IMPLICATIONS Our results have linked colitis to the circ-Sirt1/Sirt1 signaling pathway, which is regulated by diosmetin. It implies that diosmetin may be a novel candidate to alleviate DSS-induced colitis or a lead compound for future optimization and modification.
Ex-Situ Normothermic Split Liver Machine Perfusion: Protocol for Robust Comparative C...
Joseph  Attard
Yuri Boteon

Joseph Attard

and 10 more

October 30, 2020
Background: Ex-situ donor liver machine perfusion is a promising tool to assess organ viability prior to transplantation and a platform to investigate novel therapeutic interventions. However, the wide variability in donor and graft characteristics between individual donor livers limits the comparability of results. We investigated the hypothesis that the development of a split liver ex-situ machine perfusion protocol provides the ideal comparative controls in the investigation of machine perfusion techniques and therapeutic interventions, thus leading to more comparable results. Methods: Four discarded human donor livers were surgically split following identification and separation of right and left inflow and outflow vessels. Each lobe, on separate perfusion machines, was subjected to normothermic perfusion using an artificial haemoglobin-based oxygen carrier solution for six hours. Metabolic parameters as well as hepatic artery and portal vein perfusion parameters monitored. Results: Trends in hepatic and portal vein flows showed a general increase in both lobes throughout each perfusion experiment, even when normalised for tissue weight. Progressive decreases in perfusate lactate and glucose levels exhibited comparable trends in between lobes. Conclusion: Our results demonstrate comparability between right and left lobes when simultaneously subjected to normothermic machine perfusion. In the pre-clinical setting, this model provides the ideal comparative controls in the investigation of therapeutic interventions for GMP cellular therapies.
The CXCL13 chemokine serves as a potential biomarker to diagnose systemic lupus eryth...
yanli zeng
Yan Zhang

yanli zeng

and 8 more

October 30, 2020
Objectives: Our study purpose was to assess the regulatory response of the chemokine CXCL13 in the serum of patients with systemic lupus erythaematosus (SLE) and to evaluate its influence on the inflammatory process in SLE. Methods: Serum samples from 97 SLE patients, 49 non-SLE patients (23 patients with other autoimmune diseases and 26 patients with rheumatoid arthritis ) and 50 healthy controls were analysed for the concentration of CXCL13 using ELISA. Results: The results indicated that the serum levels of CXCL13 were significantly higher in SLE patients than in non-SLE patients and healthy controls (p<0.001). Moreover, the level of CXCL13 decreased as the level of anti-dsDNA IgG decreased after treatment between the anti-dsDNA-positive SLE patients and the anti-dsDNA-negative SLE patients. In addition, serum CXCL13 levels were correlated with SLEDAI in different activities of SLE, renal involvement and active LN. Furthermore, the level of CXCL13 was positively related to the SLEDAI,level of anti-dsDNA IgG , level of ESR and RAI of high-avidity IgG ANAs (HA IgG ANAs). Additionally, ROC curve analysis revealed that the serum CXCL13 levels were robust in discriminating patients with active SLE from patients with inactive SLE and SLE patients with high-avidity IgG ANAs from SLE patients with low-avidity IgG ANAs. Conclusions: First, we demonstrated that CXCL13 was elevated in SLE patients regardless of the presence or absence of anti-dsDNA IgG ANAs. Furthermore, HA IgG ANAs might affect the circulation of CXCL13. Therefore, the chemokine CXCL13 might be a risk factor influencing the inflammatory process in SLE.
The Ingenious Mast Cell: Contemporary insights into mast cell behavior and function
Joakim Dahlin
Marcus Maurer

Joakim Dahlin

and 5 more

October 28, 2020
Mast cells are (in)famous for their role in allergic diseases, but the physiological and pathophysiological roles of this ingenious cell are still not fully understood. Mast cells are important for homeostasis and surveillance of the human system, recognizing both endogenous and exogenous agents, which induce release of a variety of mediators acting on both immune and non-immune cells, including nerve cells, fibroblasts, endothelial cells, smooth muscle cells and epithelial cells. During recent years, clinical and experimental studies on human mast cells as well as experiments using animal models have resulted in many discoveries that help decipher the function of mast cells in health and disease. In this review we focus particularly on new insights into mast cell biology, with a focus on mast cell development, recruitment, heterogeneity and reactivity. We also highlight the development in our understanding of mast cell driven-diseases and discuss the development of novel strategies to treat such conditions.
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