Release Of Proinflammatory Mediators Research Articles

Targeting TNF-α: The therapeutic potential of certolizumab pegol in the early period of cerebral ischemia reperfusion injury in mice

The neuroinflammatory response triggered by cerebral ischemia–reperfusion injury (CIRI) is characterized by the upsurge of pro-inflammatory cytokines, including TNF-α, IL-1β, and IL-6, which promote leukocyte infiltration and subsequent accumulation in the ischemic zone. This accumulation further intensifies inflammation and aggravates ischemic damage. Certolizumab pegol (CZP), a monoclonal antibody targeting TNF-α, is widely used in treating various inflammatory diseases. This study explored the therapeutic potential of CZP in a mouse model of CIRI, induced by middle cerebral artery occlusion (MCAO), focusing on its influence on the microglial inflammatory response. In vitro analyses revealed that CZP markedly inhibits TNF-α-stimulated inflammation in primary microglia with an EC50 of 1.743 ng/mL. In vivo, MCAO mice treated with CZP (10 μg/mouse, i.p.) for 3 days showed reduced infarct volume, partially improved neurological function, and diminished blood–brain barrierdisruption. Additionally, CZP treatment curtailed microglial activation and the release of pro-inflammatory mediators in the early stages of stroke. It also favorably modulated microglial M1/M2 polarization, rebalanced Th17/Treg cells dynamics, and inhibited Caspase-8-mediated GSDMD cleavage, preventing microglial pyroptosis. Collectively, this study described that the treatment with CZP reversed damaging process caused by CIRI, offering a promising therapeutic strategy for the treatment of ischemic stroke.

Endolysosomal transient receptor potential mucolipins and two-pore channels: implications for cancer immunity.

Past research has identified that cancer cells sustain several cancer hallmarks by impairing function of the endolysosomal system (ES). Thus, maintaining the functional integrity of endolysosomes is crucial, which heavily relies on two key protein families: soluble hydrolases and endolysosomal membrane proteins. Particularly members of the TPC (two-pore channel) and TRPML (transient receptor potential mucolipins) families have emerged as essential regulators of ES function as a potential target in cancer therapy. Targeting TPCs and TRPMLs has demonstrated significant impact on multiple cancer hallmarks, including proliferation, growth, migration, and angiogenesis both in vitro and in vivo. Notably, endosomes and lysosomes also actively participate in various immune regulatory mechanisms, such as phagocytosis, antigen presentation, and the release of proinflammatory mediators. Yet, knowledge about the role of TPCs and TRPMLs in immunity is scarce. This prompts a discussion regarding the potential role of endolysosomal ion channels in aiding cancers to evade immune surveillance and destruction. Specifically, understanding the interplay between endolysosomal ion channels and cancer immunity becomes crucial. Our review aims to comprehensively explore the current knowledge surrounding the roles of TPCs and TRPMLs in immunity, whilst emphasizing the critical need to elucidate their specific contributions to cancer immunity by pointing out current research gaps that should be addressed.

Dexamethasone-Integrated Mesenchymal Stem Cells for Systemic Lupus Erythematosus Treatment via Multiple Immunomodulatory Mechanisms.

The therapeutic application of mesenchymal stem cells (MSCs) has good potential as a treatment strategy for systemic lupus erythematosus (SLE), but traditional MSC therapy still has limitations in effectively modulating immune cells. Herein, we present a promising strategy based on dexamethasone liposome-integrated MSCs (Dexlip-MSCs) for treating SLE via multiple immunomodulatory pathways. This therapeutic strategy prolonged the circulation time of dexamethasone liposomes in vivo, restrained CD4+T-cell proliferation, and inhibited the release of proinflammatory mediators (IFN-γ and TNF-α) by CD4+T cells. In addition, Dexlip-MSCs initiated cellular reprogramming by activating the glucocorticoid receptor (GR) signaling pathway to upregulate the expression of anti-inflammatory factors such as cysteine-rich secretory protein LCCL-containing domain 2 (CRISPLD2) and downregulate the expression of proinflammatory factors. In addition, Dexlip-MSCs synergistically increased the anti-inflammatory inhibitory effect of CD4+T cells through the release of dexamethasone liposomes or Dex-integrated MSC-derived exosomes (Dex-MSC-EXOs). Based on these synergistic biological effects, we demonstrated that Dexlip-MSCs alleviated disease progression in MRL/lpr mice more effectively than Dexlip or MSCs alone. These features indicate that our stem cell delivery strategy is a promising therapeutic approach for clinical SLE treatment.

Endothelial dysfunction in neurodegenerative disease: Is endothelial inflammation an overlooked druggable target?

Neurological diseases with a neurodegenerative component have been associated with alterations in the cerebrovasculature. At the anatomical level, these are centred around changes in cerebral blood flow and vessel organisation. At the molecular level, there is extensive expression of cellular adhesion molecules and increased release of pro-inflammatory mediators. Together, these has been found to negatively impact blood-brain barrier integrity. Systemic inflammation has been found to accelerate and exacerbate endothelial dysfunction, neuroinflammation and degeneration. Here, we review the role of cerebrovasculature dysfunction in neurodegenerative disease and discuss the potential contribution of intermittent pro-inflammatory systemic disease in causing endothelial pathology, highlighting a possible mechanism that may allow broad-spectrum therapeutic targeting in the future.

ANGPTL2 knockdown induces autophagy to relieve alveolar macrophage pyroptosis by reducing LILRB2-mediated inhibition of TREM2.

Acute lung injury (ALI) is featured with a robust inflammatory response. Angiopoietin-like protein 2 (ANGPTL2), a pro-inflammatory protein, is complicated with various disorders. However, the role of ANGPTL2 in ALI remains to be further explored. The mice and MH-S cells were administrated with lipopolysaccharide (LPS) to evoke the lung injury invivo and invitro. The role and mechanism of ANGPTL was investigated by haematoxylin-eosin, measurement of wet/dry ratio, cell count, terminal deoxynucleotidyl transferase deoxyuridine triphosphate (dUTP) nick end labeling, reverse transcription quantitative polymerase chain reaction, immunofluorescence, enzyme-linked immunosorbent assay, detection of autophagic flux and western blot assays. The level of ANGPTL2 was upregulated in lung injury. Knockout of ANGPTL2 alleviated LPS-induced pathological symptoms, reduced pulmonary wet/dry weight ratio, the numbers of total cells and neutrophils in BALF, apoptosis rate and the release of pro-inflammatory mediators, and modulated polarization of alveolar macrophages in mice. Knockdown of ANGPTL2 downregulated the level of pyroptosis indicators, and elevated the level of autophagy in LPS-induced MH-S cells. Besides, downregulation of ANGPTL2 reversed the LPS-induced the expression of leukocyte immunoglobulin (Ig)-like receptor B2 (LILRB2) and triggering receptor expressed on myeloid cells 2 (TREM2), which was reversed by the overexpression of LILRB2. Importantly, knockdown of TREM2 reversed the levels of autophagy- and pyroptosis-involved proteins, and the contents of pro-inflammatory factors in LPS-induced MH-S cells transfected with si ANGPTL2, which was further inverted with the treatment of rapamycin. Therefore, ANGPTL2 silencing enhanced autophagy to alleviate alveolar macrophage pyroptosis via reducing LILRB2-mediated inhibition of TREM2.

Impact of Isolated Exercise-Induced Small Airway Dysfunction on Exercise Performance in Professional Male Cyclists.

Professional cycling puts significant demands on the respiratory system. Exercise-induced bronchoconstriction (EIB) is a common problem in professional athletes. Small airways may be affected in isolation or in combination with a reduction in forced expiratory volume at the first second (FEV1). This study aimed to investigate isolated exercise-induced small airway dysfunction (SAD) in professional cyclists and assess the impact of this phenomenon on exercise capacity in this population. This research was conducted on professional cyclists with no history of asthma or atopy. Anthropometric characteristics were recorded, the training age was determined, and spirometry and specific markers, such as fractional exhaled nitric oxide (FeNO) and immunoglobulin E (IgE), were measured for all participants. All of the cyclists underwent cardiopulmonary exercise testing (CPET) followed by spirometry. Compared with the controls, 1-FEV3/FVC (the fraction of the FVC that was not expired during the first 3 s of the FVC) was greater in athletes with EIB, but also in those with isolated exercise-induced SAD. The exercise capacity was lower in cyclists with isolated exercise-induced SAD than in the controls, but was similar to that in cyclists with EIB. This phenomenon appeared to be associated with a worse ventilatory reserve (VE/MVV%). According to our data, it appears that professional cyclists may experience no beneficial impacts on their respiratory system. Strenuous endurance exercise can induce airway injury, which is followed by a restorative process. The repeated cycle of injury and repair can trigger the release of pro-inflammatory mediators, the disruption of the airway epithelial barrier, and plasma exudation, which gradually give rise to airway hyper-responsiveness, exercise-induced bronchoconstriction, intrabronchial inflammation, peribronchial fibrosis, and respiratory symptoms. The small airways may be affected in isolation or in combination with a reduction in FEV1. Cyclists with isolated exercise-induced SAD had lower exercise capacity than those in the control group.

Hyperforin ameliorates neuroinflammation and white matter lesions by regulating microglial VEGFR2 /SRC pathway in vascular cognitive impairment mice.

To explore the neuroprotective potential of hyperforin and elucidate its underlying molecular mechanisms involved in its therapeutic effects against vascular cognitive impairment (VCI). The active compounds and possible targets of Hypericum perforatum L. that may be effective against VCI were found by network pharmacology in this research. We utilized bilateral common carotid artery occlusion (BCCAO) surgery to induce a VCI mouse model. Morris water maze (MWM) and Y-maze tests were used to assess VCI mice's cognitive abilities following treatment with hyperforin. To evaluate white matter lesions (WMLs), we utilized Luxol fast blue (LFB) stain and immunofluorescence (IF). Neuroinflammation was assessed using IF, western blot (WB), and enzyme-linked immunosorbent assay (ELISA). The effects of hyperforin on microglia were investigated by subjecting the BV2 microglial cell line to oxygen-glucose deprivation/reperfusion (OGD/R) stimulation. The expressions of VEGFR2 , p-SRC, SRC, VEGFA, and inflammatory markers including IL-10, IL-1β, TNF-α, and IL-6 were subsequently assessed. The VEGFR2 /SRC signaling pathway is essential for mediating the protective properties of hyperforin against VCI according to network pharmacology analysis. Invivo findings demonstrated that hyperforin effectively improved BCCAO-induced cognitive impairment. Furthermore, staining results showed that hyperforin attenuated WMLs and reduced microglial activation in VCI mice. The hyperforin treatment group's ELISA results revealed a substantial decrease in IL-1β, IL-6, and TNF-α levels. According to the results of invitro experiments, hyperforin decreased the release of pro-inflammatory mediators (TNF-α, IL-6, and IL-1β) and blocked microglial M1-polarization by modulating the VEGFR2 /SRC signaling pathway. Hyperforin effectively modulated microglial M1 polarization and neuroinflammation by inhibiting the VEGFR2 /SRC signaling pathways, thereby ameliorating WMLs and cognitive impairment in VCI mice.

Biological action of bleaching agents on tooth structure: A review.

The use of bleaching agents to remove stains is one of the main dental procedures to improve the aesthetics of teeth. This review presents the main agents used for tooth whitening, existing clinical protocols, and the structural changes that may occur through their use. The main bleaching agents consist of hydrogen peroxide and carbamide peroxide, which are used in bleaching techniques for vital teeth. These techniques can be performed in the office by a professional or by the individual in a home en-vironment under professional guidance. Bleaching agents come in a variety of concentrations and there are over-the-counter products available on the market with lower concentrations of hydrogen peroxide. Due to the chemical characteristics of the agents, changes in the organic and inorganic content of the tooth structure can be observed. These changes are related to morphological changes characterized by in-creased permeability and surface roughness, such changes compromise the mechanical resistance of the tooth. Furthermore, bleaching agents can promote molecular changes after reaching the dental pulp, resulting in oxidative stress of pulp cells and the release of pro-inflammatory mediators. Despite the bleaching effectiveness, tooth sensitivity is considered the main side effect of use. Therefore, among the heterogeneity of protocols, those that used the bleaching agent for a prolonged time and in lower con-centrations presented more harmful effects on the tooth structure.

Shedding light on dermographism: a narrative review.

Dermographism is a common subtype of chronic urticaria. It generally manifests as a linear wheal after scratching or friction, with or without angioedema. The pathophysiology is not clear, but currently, we believe that the stimulation of the skin by mechanical stress leads to the activation of mast cells, which provoke the release of histamine and pro-inflammatory mediators, ultimately forming wheal along the stressed area. The gold standard for diagnosis is a medical history and provocation test or dermatographic test. As one of the subtypes of chronic urticaria, the Urticaria Control Test (UCT), Chronic Urticaria Quality of Life questionnaire (CU-Q2oL), and Dermatology Life Quality Index (DLQI) are also effective tools for evaluating disease control in dermographism patients. In addition to avoiding triggers, nonsedating H1 antihistamines are the first-line medications recommended by EAACI and other guidelines; for those who do not respond to standard doses, the recommended dosage can be increased up to 4 times. When necessary, the off-label use of omalizumab can be considered, and some drugs with potential therapeutic effects are still being explored. However, there is still a lack of biomarkers for predicting disease severity, efficacy, and prognosis. Here, we review what we know about dermographism and some points that need exploration in the future.

Synthesis and Anti-Inflammatory Activity of Ferulic Acid-Sesquiterpene Lactone Hybrids.

Acute lung injury (ALI) is a respiratory failure disease associated with high mortality rates in patients. The primary pathological damage is attributed to the excessive release of pro-inflammatory mediators in pulmonary tissue. However, specific therapy for ALI has not been developed. In this study, a series of novel ferulic acid-parthenolide (FA-PTL) and ferulic acid-micheliolide (FA-MCL) hybrid derivatives were designed, synthesized, and evaluated for their anti-inflammatory activities in vitro. Compounds 2, 4, and 6 showed pronounced anti-inflammatory activity against LPS-induced expression of pro-inflammatory cytokines in vitro. Importantly, compound 6 displayed good water solubility, and treatment of mice with compound 6 (10 mg/kg) significantly prevented weight loss and ameliorated inflammatory cell infiltration and edema in lung tissue, as well as improving the alveolar structure. These results suggest that compound 6 (((1aR,7aS,8R,10aS,10bS,E)-8-((dimethylamino)methyl)-1a-methyl-9-oxo-1a,2,3,6,7,7a,8,9,10a,10b-decahydrooxireno[2',3':9,10]cyclodeca[1,2-b]furan-5-yl)methyl (E)-3-(4-hydroxy-3-methoxyphenyl)acrylate 2-hydroxypropane-1,2,3-tricarboxylate) might be considered as a lead compound for further evaluation as a potential anti-ALI agent.

Unraveling the Link between Ιnsulin Resistance and Bronchial Asthma.

Evidence from large epidemiological studies has shown that obesity may predispose to increased Th2 inflammation and increase the odds of developing asthma. On the other hand, there is growing evidence suggesting that metabolic dysregulation that occurs with obesity, and more specifically hyperglycemia and insulin resistance, may modify immune cell function and in some degree systemic inflammation. Insulin resistance seldom occurs on its own, and in most cases constitutes a clinical component of metabolic syndrome, along with central obesity and dyslipidemia. Despite that, in some cases, hyperinsulinemia associated with insulin resistance has proven to be a stronger risk factor than body mass in developing asthma. This finding has been supported by recent experimental studies showing that insulin resistance may contribute to airway remodeling, promotion of airway smooth muscle (ASM) contractility and proliferation, increase of airway hyper-responsiveness and release of pro-inflammatory mediators from adipose tissue. All these effects indicate the potential impact of hyperinsulinemia on airway structure and function, suggesting the presence of a specific asthma phenotype with insulin resistance. Epidemiologic studies have found that individuals with severe and uncontrolled asthma have a higher prevalence of glycemic dysfunction, whereas longitudinal studies have linked glycemic dysfunction to an increased risk of asthma exacerbations. Since the components of metabolic syndrome interact with one another so much, it is challenging to identify each one's specific role in asthma. This is why, over the last decade, additional studies have been conducted to determine whether treatment of type 2 diabetes mellitus affects comorbid asthma as shown by the incidence of asthma, asthma control and asthma-related exacerbations. The purpose of this review is to present the mechanism of action, and existing preclinical and clinical data, regarding the effect of insulin resistance in asthma.

PolyphyllinVI alleviates the spared nerve injury-induced neuropathic pain based on P2X3 receptor-mediated the release of inflammatory mediators

Ethnopharmacological relevancePolyphyllinVI (PPⅥ) is the main bioactive component of Chonglou which is a traditional Chinese herbal with various effects, including antitumor, anti-inflammatory, and analgesia. Aim of the studyThis study aimed to investigate the properties and mechanisms of the analgesia of PPⅥ by using neuropathic pain (NPP) mice. Materials and methodsThe potential targets and mechanisms of PPⅥ in alleviating NPP were excavated based on the network pharmacology. Subsequently, the construction of a spared nerve injury (SNI) mice model was used to evaluate the effect of PPⅥ on NPP and the expression of the P2X3 receptor. We identified the signaling pathways of PPⅥ analgesia by RNA sequencing. ResultsThe results of network pharmacology showed that BCL2, CASP3, JUN, STAT3, and TNF were the key targets of the analgesic effect of PPⅥ. PPⅥ increased the MWT and TWL of SNI mice and decreased the level of P2X3 receptors in the dorsal root ganglion (DRG) and spinal cord (SC). Additionally, PPⅥ reduced the release of pro-inflammatory mediators (TNF-α, IL-1β, and IL-6) in the DRG, SC, and serum. Based on the KEGG enrichment of differentially expressed genes (DEGs) identified by RNA-Seq, PPVI may relieve NPP by regulating the AMPK/NF-κB signaling pathway. Western blotting results showed that the AMPK signaling pathway was activated, followed by inhibition of the NF-κB signaling pathway. ConclusionPPⅥ increased the MWT and TWL of SNI mice maybe by inhibiting the expression of the P2X3 receptor and the release of inflammatory mediators. The properties of the analgesia of PPⅥ may be based on the AMPK/NF-κB pathway.

Astragalus polysaccharides ameliorate epileptogenesis, cognitive impairment, and neuroinflammation in a pentylenetetrazole-induced kindling mouse model.

Background: Epilepsy is a prevalent neurological disease where neuroinflammation plays a significant role in epileptogenesis. Recent studies have suggested that Astragalus polysaccharides (APS) have anti-inflammatory properties, which make them a potential candidate for neuroprotection against central nervous system disease. Nevertheless, the extent of their effectiveness in treating epilepsy remains enigmatic. Therefore, our study aims to investigate the potential of APS to mitigate epileptogenesis and its comorbidities by exploring its underlying mechanism. Methods: Initially, we employed pentylenetetrazol-induced seizure mice to validate APS' effectiveness. Subsequently, we employed network pharmacology analysis to probe the possible targets and signaling pathways of APS in treating epilepsy. Ultimately, we verified the key targets and signaling pathways experimentally, predicting their mechanisms of action. Results: APS have been observed to disturb the acquisition process of kindling, leading to reduced seizure scores and a lower incidence of complete kindling. Moreover, APS has been found to improve cognitive impairments and prevent hippocampal neuronal damage during the pentylenetetrazole (PTZ)-kindling process. Subsequent network pharmacology analysis revealed that APS potentially exerted their anti-epileptic effects by targeting cytokine and toll-like receptor 4/nuclear factor kappa B (TLR4/NF-κB) signaling pathways. Finally, experimental findings showed that APS efficiently inhibited the activation of astrocytes and reduced the release of pro-inflammatory mediators, such as interleukin-1β (IL-1β), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α). In addition, APS impeded the activation of the TLR4/NF-κB signaling cascade in a PTZ-induced kindling mouse model. Conclusion: The outcomes of our study suggest that APS exerts an impact on epileptogenesis and mitigates cognitive impairment by impeding neuroinflammatory processes. The mechanism underlying these observations may be attributed to the modulation of the TLR4/NF-κB signaling pathway, resulting in a reduction of the release of inflammatory mediators. These findings partially agree with the predictions derived from network pharmacology analyses. As such, APS represents a potentially innovative and encouraging adjunct therapeutic option for epileptogenesis and cognitive deficit.

Polygalacic acid attenuates cognitive impairment by regulating inflammation through PPARγ/NF-κB signaling pathway.

We aimed to explore the role and molecular mechanism of polygalacic acid (PA) extracted from traditional Chinese medicine Polygala tenuifolia in the treatment of Alzheimer's disease (AD). The network pharmacology analysis was used to predict the potential targets and pathways of PA. Molecular docking was applied to analyze the combination between PA and core targets. Aβ42 oligomer-induced AD mice model and microglia were used to detect the effect of PA on the release of pro-inflammatory mediators and its further mechanism. In addition, a co-culture system of microglia and neuronal cells was constructed to assess the effect of PA on activating microglia-mediated neuronal apoptosis. We predict that PA might regulate inflammation by targeting PPARγ-mediated pathways by using network pharmacology. Invivo study, PA could attenuate cognitive deficits and inhibit the expression levels of inflammation-related factors. Invitro study, PA can also decrease the production of activated microglia-mediated inflammatory cytokines and reduce the apoptosis of N2a neuronal cells. PPARγ inhibitor GW9662 inversed the neuroprotective effect of PA. Both invivo and invitro studies showed PA might attenuate the inflammation through the PPARγ/NF-κB pathway. PA is expected to provide a valuable candidate for new drug development for AD in the future.

Involvement of Extracellular Vesicles in the Proinflammatory Response to Clozapine: Implications for Clozapine-Induced Agranulocytosis.

Most idiosyncratic drug reactions (IDRs) appear to be immune-mediated, but mechanistic events preceding severe reaction onset remain poorly defined. Damage-associated molecular patterns (DAMPs) may contribute to both innate and adaptive immune phases of IDRs, and changes in extracellular vesicle (EV) cargo have been detected post-exposure to several IDR-associated drugs. To explore the hypothesis that EVs are also a source of DAMPs in the induction of the immune response preceding drug-induced agranulocytosis, the proteome and immunogenicity of clozapine- (agranulocytosis-associated drug) and olanzapine- (non-agranulocytosis-associated drug) exposed EVs were compared in two preclinical models: THP-1 macrophages and Sprague-Dawley rats. Compared with olanzapine, clozapine induced a greater increase in the concentration of EVs enriched from both cell culture media and rat serum. Moreover, treatment of drug-naïve THP-1 cells with clozapine-exposed EVs induced an inflammasome-dependent response, supporting a potential role for EVs in immune activation. Proteomic and bioinformatic analyses demonstrated an increased number of differentially expressed proteins with clozapine that were enriched in pathways related to inflammation, myeloid cell chemotaxis, wounding, transforming growth factor-β signaling, and negative regulation of stimuli response. These data indicate that, although clozapine and olanzapine exposure both alter the protein cargo of EVs, clozapine-exposed EVs carry mediators that exhibit significantly greater immunogenicity. Ultimately, this supports the working hypothesis that drugs associated with a risk of IDRs induce cell stress, release of proinflammatory mediators, and early immune activation that precedes severe reaction onset. Further studies characterizing EVs may elucidate biomarkers that predict IDR risk during development of drug candidates. SIGNIFICANCE STATEMENT: This work demonstrates that clozapine, an idiosyncratic drug-induced agranulocytosis (IDIAG)-associated drug, but not olanzapine, a safer structural analogue, induces an acute proinflammatory response and increases extracellular vesicle (EV) release in two preclinical models. Moreover, clozapine-exposed EVs are more immunogenic, as measured by their ability to activate inflammasomes, and contain more differentially expressed proteins, highlighting a novel role for EVs during the early immune response to clozapine and enhancing our mechanistic understanding of IDIAG and other idiosyncratic reactions.

Bystander activation of microglia by Brucella abortus-infected astrocytes induces neuronal death via IL-6 trans-signaling.

Inflammation plays a key role in the pathogenesis of neurobrucellosis where glial cell interactions are at the root of this pathological condition. In this study, we present evidence indicating that soluble factors secreted by Brucella abortus-infected astrocytes activate microglia to induce neuronal death. Culture supernatants (SN) from B. abortus-infected astrocytes induce the release of pro-inflammatory mediators and the increase of the microglial phagocytic capacity, which are two key features in the execution of live neurons by primary phagocytosis, a recently described mechanism whereby B. abortus-activated microglia kills neurons by phagocytosing them. IL-6 neutralization completely abrogates neuronal loss. IL-6 is solely involved in increasing the phagocytic capacity of activated microglia as induced by SN from B. abortus-infected astrocytes and does not participate in their inflammatory activation. Both autocrine microglia-derived and paracrine astrocyte-secreted IL-6 endow microglial cells with up-regulated phagocytic capacity that allows them to phagocytose neurons. Blocking of IL-6 signaling by soluble gp130 abrogates microglial phagocytosis and concomitant neuronal death, indicating that IL-6 activates microglia via trans-signaling. Altogether, these results demonstrate that soluble factors secreted by B. abortus-infected astrocytes activate microglia to induce, via IL-6 trans-signaling, the death of neurons. IL-6 signaling inhibition may thus be considered a strategy to control inflammation and CNS damage in neurobrucellosis.

Platelet derived exosomes disrupt endothelial cell monolayer integrity and enhance vascular inflammation in dengue patients.

Thrombocytopenia is the most notable phenomenon in dengue. Activation status of platelets and interaction of platelets with endothelium contribute towards dengue disease pathogenesis. Platelets are the major cell types known to release extracellular vesicles, especially exosomes in circulation. However, the role of platelet derived exosomes (PLT-EXOs) in endothelial dysfunction during dengue infection remains unknown. In this study, we recruited 28 healthy subjects and 69 dengue patients categorized as WS- (n=31), WS+ (n=29) and SD (n=9). Platelets were isolated from platelet rich plasma of dengue patients and their activation was assessed by flow cytometry. PLT-EXOs were isolated by ultracentrifugation method. Western blot analyses were performed to characterize the exosomes. Exosome uptake experiment was carried out to see the internalization of exosomes inside endothelial cells (HUVECs). To observe the effect of exosomes on endothelial cells, exosomes were added on HUVECs and expression of adherens and tight junctional proteins were examined by immunofluorescence assay and western blot. Expression levels of vascular injury markers were measured in the culture supernatants of Exosome-HUVEC coculture and sera of dengue patients by MSD-multiplex assay. As compared to healthy subjects, CD41/CD61 expression was significantly reduced (p<0.0001) and CD62p expression was significantly increased (p<0.0001) on platelets in dengue patients. PLT-EXOs isolated from the dengue patients showed higher expression of CD63 and CD9 proteins than the healthy subjects. With in-vitro immunofluorescence assays, we illustrated the internalization of PLT-EXOs by the HUVECs and observed disruption of endothelial cell monolayer integrity in the presence of PLT-EXOs from WS+ and SD patients. Furthermore, the significant reduction in the expressions of ZO-2, VE-Cadherin and CD31 in endothelial cells following exposure to PLT-EXOs from the dengue patients provide direct evidence of PLT-EXOs mediated vascular permeability. PLT-EXOs stimulated the release of inflammatory markers CRP, SAA, sVCAM-1 and sICAM-1 in the supernatants of HUVEC cells. Importantly, significantly higher levels of CRP, sVCAM-1 and sICAM-1 in the sera of severe than mild dengue patients (p<0.0001) suggest their role in disease severity. In summary, our data suggest that PLT-EXOs promote vascular leakage via release of proinflammatory mediators and compromise vascular barrier integrity in dengue patients.

Acquired and familial cold-induced urticaria: a review

The exposure of skin to cold results in release of histamine, leukotrienes, and pro-inflammatory mast cell mediators which leads to the appearance of pruritic wheals with or without angioedema and in turn the onset of urticaria. According to the etiology, cold urticaria can be classified into acquired cold urticaria (ACU) and familial cold urticaria (FCU). This study aimed to overview the acquired and familial cold urticaria. The articles incorporated in writing this review were obtained through searching the scientific databases and using various related keywords. All types of articles were eligible and those written in English language. The current subject was discussed in two main titles, acquired cold urticaria and familial cold urticaria. Each title overviewed the related condition, diagnosis, and management. There is confusion regarding the classification of urticaria; ACU and FCU are two forms of urticaria based on etiology. However, there is little known about FCU, especially regarding its management. Correct and prompt diagnosis is the key factor to avoid severe consequences of these two conditions.

Immunological Landscape of Retinal Ischemia-Reperfusion Injury: Insights into Resident and Peripheral Immune Cell Responses.

Retinal ischemia-reperfusion injury (RIRI) is a complex condition characterized by immune cell-mediated inflammation and consequent neuronal damage. This review delves into the immune response mechanisms in RIRI, particularly emphasizing the roles played by resident and peripheral immune cells. It highlights the pivotal role of microglia, the primary resident immune cells, in exacerbating neuroinflammation and neuronal damage through their activation and subsequent release of pro-inflammatory mediators. Additionally, the review explores the contributions of other glial cell types, such as astrocytes and Müller cells, in modulating the immune response within the retinal environment. The dual role of the complement system in RIRI is also examined, revealing its complex functions in both safeguarding and impairing retinal health. Inflammasomes, triggered by various danger signals, are discussed as crucial contributors to the inflammatory pathways in RIRI, with an emphasis on the involvement of different NOD-like receptor family proteins. The review further analyzes the infiltration and impact of peripheral immune cells like neutrophils, macrophages, and T cells, which migrate to the retina following ischemic injury. Critical to this discussion is the interplay between resident and peripheral immune cells and its implications for RIRI pathophysiology. Finally, the review outlines future research directions, focusing on basic research and the potential for clinical translation to enhance understanding and treatment of RIRI.

Development, optimization, and characterization of rhein loaded nanoemulgel for treatment of osteoarthritis

This work aimed to design a transdermal delivery of rhein loaded nanoemulgel to improve the bioavailability and efficacy of rhein in the treatment of osteoarthritis and reduce its systemic side effects. Rhein loaded nanoemulsion (Rh-NE) prepared by application of ternary phase diagram and spontaneous emulsification method. Box-Behnken design (BBD) was employed to optimize formulation and preparation process of Rh-NE. The optimal formulation was 11.09% mixed oil (rhein and caproyl 90), 22.96% mixed emulsifier (kolliphor RH 40: transcutol HP, 1:1, w/w), and the preparation process was 23.08 min ultrasonic time and 179.5 W ultrasonic power. The particle size of the optimized Rh-NE was 24.5 ± 3.2 nm, PDI was 0.15 ± 0.02, and zeta potential was −18.6 ± 1.8 mV. The Rh-NE was incorporated into hydrogel consisted of 0.85% carbomer, 0.2% poloxamer 188 and 8.0% glycerol to form rhein loaded nanoemulgel (Rh-NE/Gel). In vitro transdermal flux of Rh-NE/Gel was 91.4 ± 0.9 μg/cm2·h. It was found that the inhibition rate of swelling degree of auricle caused by xylene was (54%), inhibition rate of writhing reaction was (60%), percentage increase in pain threshold was (P < 0.01), and the inhibition rate of capillary permeability was (69%). The therapeutic effect of Rh-NE/Gel on osteoarthritis in model rats was significantly improved compared with control group; the swelling degree of joint and toe were significantly reduced by 91% and 71%, respectively, and the contents of inflammatory factors IL-1β and NO were decreased 35.7% and 52.4%, respectively. The developed Rh-NE/Gel could provide anti-osteoarthritis effect and reduce the release of proinflammatory mediators in OA model rats.