Induction Of Inflammatory Response Research Articles

TP73 Isoform-specific disruption reveals a critical role of TAp73beta in growth suppression and inflammatory response

TP73 is expressed as multiple N- and C-terminal isoforms through two separate promoters or alternative splicing. While N-terminal p73 isoforms have been well studied, very little is known about p73 C-terminal isoforms. Thus, CRISPR was used to delete TP73 Exon13 (E13-KO) to induce p73α to p73β isoform switch. We showed that E13-KO led to decreased cell proliferation and migration and sensitized cells to ferroptosis, which can be reverted by knockdown of TAp73β in E13-KO cells. To understand the biological function of p73β in vivo, we generated a mouse model in that the Trp73 E13 was deleted by CRISPR. We showed that p73α to p73β isoform switch led to increased cellular senescence in mouse embryonic fibroblasts. We also showed that E13-deficient mice exhibited shorter life span and were prone to spontaneous tumors, chronic inflammation and liver steatosis as compared to WT mice. Additionally, we found that the incidence of chronic inflammation and liver steatosis was higher in E13-deficient mice than that in Trp73-deficient mice, suggesting that p73β is a strong inducer of inflammatory response. Mechanistically, we showed that TAp73β was able to induce cysteine dioxygenase 1 (CDO-1), leading to cysteine depletion and subsequently, enhanced ferroptosis and growth suppression. Conversely, knockdown of CDO-1 was able to alleviate the growth suppression and ferroptosis in E13-KO cells. Together, our data suggest that at a physiologically relevant level, TAp73β is a strong inducer of growth suppression but insufficient to compensate for loss of TAp73α in tumor suppression due to aberrant induction of inflammatory response and liver steatosis.

BACTERIOPHAGE M13 MODULATES THE SEPSIS-RELATED INFLAMMATORY RESPONSES AND ORGAN DAMAGE IN A CLP MODEL.

Background: Sepsis is a life-threatening disorder that leads to the induction of inflammatory responses and organ failure. Phage therapy is a new approach to controlling infections resistant to common treatments, including sepsis. Several studies have shown the effect of lytic bacteriophages on infection control by reducing the bacterial load. The present study deals with lysogenic bacteriophage M13 on the inflammatory responses caused by cecal ligation and puncture (CLP)-induced sepsis in a mouse model. Methods Bacteriophage M13 harvested from ER2738, titrated, and confirmed by transmission electron microscopy analysis. In vitro toxicity and immunomodulatory effect of bacteriophage M13 were assessed on splenocytes by measurement of cell viability and the production level of cytokines, nitric oxide, and reactive oxygen species. For in vivo experiments, 8-weeks-old male C57BL/6 mice were randomly divided into the following three groups: CLP + NS (treated with normal saline), CLP + M13 (treated with an intraperitoneal injection of 10 9 PFU/mL of bacteriophage M13), and sham + NS (induced surgery but without ligation and puncture, treated with NS). The mice were killed at different time points after surgery (6, 24, 48, and 72, n = 10 for each time point of each group). The kidney, liver, and lungs were harvested for histopathological analysis, and blood was obtained for cytokine and liver enzyme assay. The spleen was used to assess the bacterial load using colony-forming unit assay. The rectal temperature and survival were evaluated during the study. Results According to the in vitro results, 10 9 PFU/mL of bacteriophage M13 was not toxic and did not affect the level of cytokine, nitric oxide, and reactive oxygen species production by splenocytes, but it reduced the inflammatory response of splenocytes in responses to LPS. In vivo studies indicated that the amount of proinflammatory cytokines, liver enzymes, bacterial load, and organ failure were decreased in the CLP + M13 group compared with CLP + NS, whereas the survival rate was increased. Conclusions These experiments demonstrated that bacteriophage M13 could lessen the consequences related to sepsis in CLP mice and can be considered a therapeutic approach in sepsis.

LncRNA RNA XIST binding to GATA1 contributes to rheumatoid arthritis through its effects on proliferation of synovial fibroblasts and angiogenesis via regulation of CCN6

This study explored the role of the long non-coding RNA (lncRNA) XIST (X-inactive specific transcript) as a driver of RA pathogenesis, with a particular focus on the ability of this lncRNA to interact with GATA1 and CCN6. The GSE83147and GSE181614 datasets were downloaded for analysis. XIST and CCN6 expression were assessed in synovial fibroblasts (SFs) and in both normal cartilage samples and those from RA patients, with the relationship between XIST and CCN6 additionally being examined. XIST and CCN6 were respectively knocked down or overexpressed in SFs to establish their regulatory roles in these cells in the context of RA. Further studies of the regulatory interplay between XIST, GATA1, and CCN6 were then performed through RNA immunoprecipitation, RNA pull-down, gain-of-function, loss-of-function, and luciferase reporter assays. In addition, RA model rats were established and used to measure the production of TNF-α, IL-6, and IL-8 and to subject tissues from these animals to histopathological examination. RA patient synovial tissues and SFs exhibited XIST and CCN6 upregulation. The knockdown of XIST suppressed SF migratory, proliferative, invasive, and angiogenic activity, while CCN6 knockdown partially reversed the ability of XIST to influence these phenotypic outcomes in vitro and in vivo. XIST bound to GATA1 within SFs, thus promoting enhanced CCN6 transcription. Knocking down XIST alleviated RA-related pathological damage, synovial injury, and inflammatory response induction in rats. The binding of XIST to GATA1 leads to CCN6 upregulation, driving RA pathogenesis by altering SF proliferation and angiogenic activity, suggesting that this pathway may represent a viable target for therapeutic intervention.

Herbo-mineral formulation, Divya-Swasari-Vati averts SARS-CoV-2 pseudovirus entry into human alveolar epithelial cells by interfering with spike protein-ACE 2 interaction and IL-6/TNF-α /NF-κB signaling.

The herbo-mineral formulation, Divya-Swasari-Vati (DSV), is a well-known Ayurvedic medication for respiratory ailments. In a recent pre-clinical study, DSV rescued humanized zebrafish from SARS-CoV-2 S-protein-induced pathologies. This merited for an independent evaluation of DSV as a SARS-CoV-2 entry inhibitor in the human host cell and its effectiveness in ameliorating associated cytokine production. The ELISA-based protein-protein interaction study showed that DSV inhibited the interactions of recombinant human ACE 2 with three different variants of S proteins, namely, Smut 1 (the first reported variant), Smut 2 (W436R variant) and Smut 3 (D614G variant). Entry of recombinant vesicular stomatitis SARS-CoV-2 (VSVppSARS-2S) pseudovirus, having firefly luciferase and EGFP reporters, was assessed through luciferase assay and fluorescent microscopy. DSV exhibited dose-dependent inhibition of VSVppSARS-2S pseudovirus entry into human lung epithelial A549 cells and also suppressed elevated levels of secreted pro-inflammatory cytokines such as interleukin-6 (IL-6), interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α) induced by viral infection mimicking Poly I:C-, S-protein- and VSVppSARS-2S pseudovirus. In human immune cells, DSV also moderated TNF-α-mediated NF-κB induction, in a dose-dependent manner. The observed anti-viral effect of DSV against SARS-CoV-2 is attributable to the presence of different metabolites Summarily, the observations from this study biochemically demonstrated that DSV interfered with the interaction between SARS-CoV-2 S-protein and human ACE 2 receptor which consequently, inhibited viral entry into the host cells and concomitant induction of inflammatory response.

NGF regulates sertoli cell growth and prevents LPS-induced junction protein damage via PI3K/AKT/NFκB signaling

Damage to Sertoli cell junction proteins caused by inflammation can lead to male infertility. Nerve growth factor (NGF) plays an important role in reproductive and inflammatory disease; however, whether and how NGF regulates Sertoli cell function remains unclear. Here, we aimed to assess the effect of NGF on the growth of Sertoli cells isolated from the testes of dairy goats and evaluate if NGF has a protective effect on these cells. We confirmed that Sertoli cell viability, proliferation, and ATP content increased following NGF treatment. In addition, qPCR results suggested that Sertoli cell apoptosis was inhibited after NGF treatment. To investigate the protective effect of NGF on Sertoli cells under pathological inflammatory conditions, LPS was used to induce inflammatory response in Sertoli cells. Post-treatment, the entangled filamentous pseudopodia of the cells loosened and no longer spanned adjacent cells. The expression of several junction proteins (ZO-1, occludin, CX-43, β-catenin, and N-cadherin), which was down-regulated after inflammatory response induction, was restored following NGF treatment. LPS-induced changes in cytotoxicity and transepithelial electrical resistance were reversed and the intercellular connections became tighter after NGF treatment. We further demonstrated that NGF prevented the inflammatory response of Sertoli cells via the PI3K/AKT/NFκB signaling pathway, similar to the effect of the PI3K-inhibitor, LY294002, which is modified by the PI3K activator, 740Y–P. These results provide insights for devising strategies for protecting the male reproductive system and curing or preventing associated pathological conditions.

Annexin A2 regulates Mycoplasma bovis adhesion and invasion to embryo bovine lung cells affecting molecular expression essential to inflammatory response.

Mycoplasma bovis (M. bovis) is an important pathogen of the bovine respiratory disease complex, invading lower respiratory tracts and causing severe pneumonia. However, its molecular mechanism largely remains unknown. Host annexin A2 (ANXA2) is a calcium-dependent phospholipid-binding protein. The current study sought to determine whether ANXA2 could mediate M. bovis adhesion and invasion thereby affecting its induction of inflammatory response. ANXA2 expression was upregulated in M. bovis-infected bovine lung epithelial cells (EBL), and blocking ANXA2 with an anti-ANXA2 antibody reduced M. bovis adhesion to EBL. Compared with uninfected cells, more ANXA2 was translocated from the cytoplasm to the cell surface after M. bovis infection. Furthermore, RNA interference knockdown of ANXA2 expression in EBL cells resulted in a significant decrease in M. bovis invasion and F-actin polymerization. Next, the transcriptomic study of M. bovis-infected EBL cells with and without ANXA2 knockdown were performed. The data exhibited that ANXA2 knockdown EBL cells had 2487 differentially expressed genes (DEGs), with 1175 upregulated and 1312 downregulated compared to control. According to GO and KEGG analyses, 50 genes potentially linked to inflammatory responses, 23 involved in extracellular matrix (ECM) receptor interaction, and 48 associated with PI3K-AKT signal pathways were upregulated, while 38 mRNA binding genes, 16 mRNA 3′-UTR binding genes, and 34 RNA transport genes were downregulated. Furthermore, 19 genes with various change-folds were selected for qPCR verification, and the results agreed with the RNA-seq findings. Above all, the transcription of two chemokines (IL-8 and CXCL5) and a key bovine β-defensin TAP in IL-17 signaling pathway were significantly increased in ANXA2 knockdown cells. Moreover, ANXA2 knockdown or knockout could increase NF-κB and MAPK phosphorylation activity in response to M. bovis infection. Additionally, ANXA2 knockdown also significantly decreased the CD44 transcripts via exon V3 and V7 skipping after M. bovis infection. We concluded that M. bovis borrowed host ANXA2 to mediate its adhesion and invasion thereby negatively regulating molecular expression essential to IL-17 signal pathway. Furthermore, CD44 V3 and V7 isoforms might contribute to this ANXA2 meditated processes in M. bovis infected EBL cells. These findings revealed a new understanding of pathogenesis for M. bovis infection.

STAT4 Play A Critical Role in Aging and High Fat Diet‐Associated Decline in Long‐Term, Activity‐Dependent Potentiation of Synaptic Transmission

Aging and Alzheimer’s disease (AD) both exhibit declines in the magnitude of long‐term, activity‐dependent synaptic potentiation in humans and animals that correlate with declines in cognitive function and long‐term memory in a range of behavioral tasks. Signal Transducer and Activator of Transcription 4 (STAT4) is a transcription factor that is essential for mediating T helper 1 cell differentiation and induction of inflammatory responses to IL‐12. STAT4 plays a vital role in signaling in a range of inflammatory diseases, including cardiovascular inflammation in diabetes, systemic lupus erythematosus and rheumatoid arthritis. It is, however, unknown what role STAT4 plays in central nervous system diseases such as AD, which also have significant inflammatory components to the progression of neurodegeneration. The present study examined the effects of elimination of STAT4 signaling in transgenic mice lacking myeloid cell‐specific STAT4 expression on the expression of long‐term potentiation (LTP) of synaptic transmission, and learning and memory, in mice fed normal versus high‐fat diets. Electrophysiological recordings from Schaffer collateral‐CA1 synapses in hippocampal slices from 3 or 24 week old LysMcreStat4fl/flLdlr‐/‐ mice showed no differences in baseline synaptic transmission, paired‐pulse facilitation (PPF, a measure of presynaptic function), or LTP compared to age‐matched Stat4fl/flLdlr‐/‐ control littermates. Feeding mice a high cholesterol, high carbohydrate diet (DDC) diet from 8‐24 weeks of age resulted in marked, significant impairments in LTP compared to age‐matched mice fed a chow diet, without differences in basal transmission or PPF. In contrast to Stat4fl/flLdlr‐/‐ control mice, LysMcreStat4fl/flLdlr‐/‐ mice receiving the same DDC diet were completely protected from DDC‐associated reductions in LTP. Our current behavioral data support the idea that DDC fed Ldlr‐/‐ mice may experience cognitive and memory declines associated with early AD in comparison with LysMcreStat4fl/flLdlr‐/‐ mice. Taken together, our data support an essential role for the transcription factor STAT4 in the sensitivity of the central nervous system to DDC ‐induced impairments in synaptic plasticity and potentially cognitive function, and suggest that STAT4 pathways are a promising new target for interventions to treat neurodegenerative diseases such as Alzheimer’s, where chronic neuroinflammation is a critical disease mediator.

Construction of a prognostic classifier and prediction of the immune landscape and immunosuppressive molecules in gliomas based on combination of inflammatory response-related genes and angiogenesis-associated genes

Objective:We aimed to combine inflammatory response-related genes (IRRGs) and angiogenesis-associated genes (AAGs) to build a prognostic classifier and to predict immune landscapes and immunosuppressive molecules in gliomas. Introduction: Gliomas, the commonest primary brain tumors, account for about 80% of cancerous tumors in the central nervous system (CNS), featuring rapid progression, high malignancy, and extremely poor prognosis. The induction of inflammatory responses and angiogenesis have been considered to be closely related to tumors. However, there are little publications systematically elaborating on their impacts on gliomas. Methods: We downloaded the data of IRRGs and AAGs from The Cancer Genome Atlas (TCGA) and Chinese Glioma Genome Atlas (CGGA) databases, and retrieved 68 differentially expressed genes (DEGs), of which 13 DEGs pertained to the prognosis of glioma cases. Next, 9 DEGs were screened from the 13 major DEGs with predictive significance and utilized to build a 9-gene signature as a prognostic risk score model (PRSM) with the aid of univariate Cox regression analyses (CRA) and least absolute shrinkage and selection operator (LASSO)-CRA. On this basis, glioma patients fell into high-risk (HR) group and low-risk (LR) group. Later, we implemented Gene Set Enrichment Analysis (GSEA, Gene Set: WP_ANGIOGENESIS) and calculate the scores of cell infiltration and immune-associated function by harnessing single-sample GSEA (ssGSEA). Results: The prognosis was compared between the two groups by introducing Kaplan-Meier (KM) analysis, which yielded that HR group exhibited poorer prognosis. Additionally, the predictive capacity and independent characteristics were proven by the receiver operating characteristic curve (ROC) and multivariate CRA. Further, We took an evaluation of immune profiles, which unraveled that immunosuppressive cell count was distinctively larger in HS group. Finally, a protein-protein interaction (PPI) network of DEGs was built, and 10 hub genes were obtained, of which epidermal growth factor receptor (EGFR) was closely related to poor prognosis. Conclusion: A 9-gene signature was established on the strength of IRRGs and AAGs for predicting glioma prognosis, tumor microenvironment (TME), immune landscapes and immunosuppressive molecules. However, the molecular mechanism developed by this signature to function in tumor immunity needs further experimental research in the future and is expected to be a research target for glioma immunotherapy strategies.

<i>Helicobacter pylori</i>-associated comorbidity

Helicobacter pylori (H. pylori) infection is known to lead to various diseases such as gastric and duodenal ulcers, chronic gastritis and malignant diseases, including MALT lymphoma and stomach cancer. To date, various factors of pathogenicity and virulence of the H. pylori bacterium have been studied. The interaction of infection with host cells leads to the induction of inflammatory responses through the release of cytokines, activation of apoptosis or proliferation, which leads to inflammation and dysfunction of the epithelial barrier. This process can facilitate the movement of H. pylori virulence factors and inflammatory mediators into the bloodstream and promote or enhance the development of a systemic inflammatory response and the possible clinical effects of H. pylori infections outside the stomach. The purpose of this review is to clarify the available data on H. pylori-associated comorbidity with diseases of the cardiovascular, nervous, endocrine systems, autoimmune diseases and some other pathologies outside the digestive system.

Dynamic changes in macrophage metabolism modulate induction and suppression of Type I inflammatory responses.

During microbial infection, macrophages link recognition of microbial stimuli to the induction of Type I inflammatory responses. Such inflammatory responses coordinate host defense and pathogen elimination but induce significant tissue damage if sustained, so macrophages are initially activated to induce inflammatory responses but then shift to a tolerant state to suppress inflammatory responses. Macrophage tolerance is regulated by induction of negative regulators of TLR signaling, but its metabolic basis was not known. Here, we review recent studies that indicate that macrophage metabolism changes dynamically over the course of microbial exposure to influence a shift in the inflammatory response. In particular, an initial increase in oxidative metabolism boosts the induction of inflammatory responses, but is followed by a shutdown of oxidative metabolism that contributes to suppression of inflammatory responses. We propose a unifying model for how dynamic changes to oxidative metabolism influences regulation of macrophage inflammatory responses during microbial exposure.

Autocrine S100B in astrocytes promotes VEGF-dependent inflammation and oxidative stress and causes impaired neuroprotection.

Minimal hepatic encephalopathy (MHE) is strongly associated with neuroinflammation. Nevertheless, the underlying mechanism of the induction of inflammatory response in MHE astrocytes remains not fully understood. In the present study, we investigated the effect and mechanism of S100B, a predominant isoform expressed and released from mature astrocytes, on MHE-like neuropathology in the MHE rat model. We discovered that S100B expressions and autocrine were significantly increased in MHE rat brains and MHE rat brain-derived astrocytes. Furthermore, S100B stimulates VEGF expression via the interaction between TLR2 and RAGE in an autocrine manner. S100B-facilitated VEGF autocrine expression further led to a VEGFR2 and COX-2 interaction, which in turn induced the activation of NFƙB, eventually resulting in inflammation and oxidative stress in MHE astrocytes. MHE astrocytes supported impairment of neuronal survival and growth in a co-culture system. To sum up, a comprehensive understanding of the role of S100B-overexpressed MHE astrocyte in MHE pathogenesis may provide insights into the etiology of MHE.

NLRP3‐mediated dysfunction of mitochondria leads to cell death in CFT073‐stimulated macrophages

AbstractUrinary tract infections (UTIs) are commonly caused by uropathogenic E coli (UPEC), which uses different mechanisms to invade and damage hosts. NLRP3 inflammasome activation is a double‐edged sword, although beneficial in the clearance of dysfunctional cells or pathogens but results in severe pathologies, if unchecked. NLRP3 inflammasome plays a critical role in UPEC‐mediated inflammatory cell death during UPEC infection, though the effects of its activation are not clearly understood yet. Inflammatory response usually involves Signal‐I (MyD88, TRIF and NF‐κB signalling) and Signal‐II (Inflammasome oligomerization) which is induced by the pathogen‐associated molecular patterns during infection. We observed that proIL‐1β and mature IL‐1β remained unchanged on inhibition of MyD88 and TRIF‐dependent signalling in CFT073‐insulted THP‐1m. However, inhibition of NF‐κB pathway resulted in concomitant reduction in both pro‐ and cleaved forms of IL‐1β in cellular extracts but there was no change in IL‐1 β secretion. Interestingly, inhibition of NLRP3 completely abolished the maturation and release of cleaved form of IL‐1β. Additionally, NLRP3‐mediated mitochondrial dysfunction (increased mito‐ROS and mitochondrial hyperpolarization) resulting in cell death was induced in CFT073‐insulted THP‐1m, which was rescued upon inhibition of NLRP3 activation. Therefore, we have concluded that UPEC uses a different signal‐I pathway (other than MyD88 and TRIF), while NLRP3 inflammasome is the major signal‐II for the induction of inflammatory response. Further, this study signifies the importance of NLRP3‐mediated mitochondrial dysfunction in CFT073‐induced inflammatory cell death of macrophages, which could be rescued through inhibition of NLRP3 activation.

Parabens disrupt non-canonical inflammasome activation

Parabens are synthetic chemicals widely used as preservatives in cosmetics, pharmaceuticals, and foods. Although parabens, i.e., ethyl- and methyl-parabens, are considered relatively safe, study of possible health hazards has been undertaken due to the frequent exposure to parabens and their accumulation in the body. In this study, we elucidated the effect of parabens on inflammasome induction of inflammatory responses in innate immunity, such as interleukin (IL)-1β maturation and gasdermin D (GSDMD)-mediating pyroptosis. Parabens attenuated the inflammatory responses to intracellular lipopolysaccharide (LPS) triggering of non-canonical (NC) inflammasome activation, but did not alter canonical inflammasome (i.e., NLRP3, NLRC4 and AIM2) responses. The NC inflammasome is assembled by the interaction of murine caspase (Casp)-11 (Casp4/5 in human) with cytosolic LPS, inducing endotoxin sepsis. Parabens selectively inhibited NC inflammasome activation in both human and murine macrophages and diminished the peritoneal IL-1β production in LPS-injected mice. Parabens blocked the cleavage of GSDMD, Casp1, and Casp4, but did not change the expression of Casp11 or the activity of Casp1. Taken together, the results indicate that parabens could disrupt Gram-negative pathogen infection through the inhibition of NC inflammasome activation.

Galangin mitigates iron overload-triggered liver injury: Up-regulation of PPARγ and Nrf2 signaling, and abrogation of the inflammatory responses

AimHepatotoxicity is a critical consequence of the iron overload conditions such as hemochromatosis and blood transfusion-requiring anemia. Iron induces hepatotoxicity largely through disruption of cellular redox homeostasis and induction of inflammatory responses. The present work explored the hepatoprotective activity of the bio-active flavone galangin against iron-evoked hepatotoxicity. Main methodsIron overload model was established in male Wistar rats via intraperitoneal injection of 150 mg/kg iron-dextran subdivided over a ten-day experimental period. Galangin was administered in a daily oral dose of 15 mg/kg throughout the experimental period. Blood and liver tissue samples were collected on day eleven and subjected to biochemical and molecular investigations. Key findingsGalangin significantly reduced liver iron content and serum ferritin level, and alleviated the iron-evoked oxidative stress. It enhanced the liver cell integrity as reflected by decreased serum activity of the liver enzymes. Mechanistically, galangin up-regulated the redox-regulating transcription factor Nrf2 and its responsive proteins HO-1 and NQO1. Interestingly, galangin up-regulated the antioxidant and anti-inflammatory protein PPARγ and serum hepcidin levels under the iron overload conditions. Equally important, it diminished the nuclear shift of the inflammatory transcription factor NF-κB p65 and down-regulated the levels of the pro-inflammatory cytokines TNF-α and IL-1β. SignificanceThe results of the present study highlight the mitigating activity of galangin against iron-induced hepatotoxicity. The study accentuated targeting of Nrf2, PPARγ, and NF-κB signaling as potential contributing mechanisms. While clinical studies are still required, the current study supports the possible implementation of galangin in controlling iron overload-associated hepatotoxicity.

Early whole blood transcriptional responses to radiation-attenuated Plasmodium falciparum sporozoite vaccination in malaria na\xefve and malaria pre-exposed adult volunteers

BackgroundVaccination with radiation-attenuated Plasmodium falciparum sporozoites is known to induce protective immunity. However, the mechanisms underlying this protection remain unclear. In this work, two recent radiation-attenuated sporozoite vaccination studies were used to identify potential transcriptional correlates of vaccination-induced protection.MethodsLongitudinal whole blood RNAseq transcriptome responses to immunization with radiation-attenuated P. falciparum sporozoites were analysed and compared across malaria-naïve adult participants (IMRAS) and malaria-experienced adult participants (BSPZV1). Parasite dose and method of delivery differed between trials, and immunization regimens were designed to achieve incomplete protective efficacy. Observed protective efficacy was 55% in IMRAS and 20% in BSPZV1. Study vaccine dosings were chosen to elicit both protected and non-protected subjects, so that protection-associated responses could be identified.ResultsAnalysis of comparable time points up to 1 week after the first vaccination revealed a shared cross-study transcriptional response programme, despite large differences in number and magnitude of differentially expressed genes between trials. A time-dependent regulatory programme of coherent blood transcriptional modular responses was observed, involving induction of inflammatory responses 1–3 days post-vaccination, with cell cycle responses apparent by day 7 in protected individuals from both trials. Additionally, strongly increased induction of inflammation and interferon-associated responses was seen in non-protected IMRAS participants. All individuals, except for non-protected BSPZV1 participants, showed robust upregulation of cell-cycle associated transcriptional responses post vaccination.ConclusionsIn summary, despite stark differences between the two studies, including route of vaccination and status of malaria exposure, responses were identified that were associated with protection after PfRAS vaccination. These comprised a moderate early interferon response peaking 2 days post vaccination, followed by a later proliferative cell cycle response steadily increasing over the first 7 days post vaccination. Non-protection is associated with deviations from this model, observed in this study with over-induction of early interferon responses in IMRAS and failure to mount a cell cycle response in BSPZV1.

Biochemical investigation of human exposure to aflatoxin M1 and its association with risk factors of diabetes mellitus.

Recently, aflatoxin M1 (AFM1) has emerged as a major health concern owing to its exposure to human being via consumption of milk, dairy products, and food commodities, and this has a strong association with risk factors that may lead to the onset of type 2 diabetes mellitus (T2DM) and various other associated metabolic disorders. This study was conducted to investigate the exposure to AFM1 and its association with sociodemographic features and risk factors of T2DM. Urine and blood samples from 672 participants were collected to investigate the concentration of AFM1 in urine and glucose, glycosylated hemoglobin (HbA1c), insulin, α-amylase, dipeptidyl peptidase-IV (DPP-IV), free fatty acids (FFAs), triglycerides (TGs), high-density lipoprotein cholesterol (HDL-chol), interleukine-6 (IL-6), tumor necrosis factor-α (TNF-α), malondialdehyde (MDA), glutathione (GSH), superoxide dismutase (SOD), creatinine, uric acid, blood urea nitrogen (BUN), aspartate aminotransferase (AST), and alanine transaminase (ALT) from the blood of study participants. Association of exposure to AFM1 with sociodemographic features and risk factors of T2DM was determined using person correlation coefficient (r), coefficient of determination (R2), and 95% confidence interval, and the level of significance (P<0.05) was measured by Student's unpaired t-test. Among the participants in which AFM1 was detected, 62.91% of participants were found to be diabetic and 37.09% of participants were found to be non-diabetic. Further to this, it was also found that concentration of AFM1 in the urine of diabetic participants was found to be higher (P<0.05) as compared to that in non-diabetic participants. Association of AFM1 exposure with risk factors of T2MD exhibits that exposure to AFM1 was responsible for the induction of inflammatory responses and oxidative stress that may lead to the onset of impaired insulin secretion and metabolism of carbohydrates and ultimately the onset of T2DM and associated metabolic disorders. Hence, it can be summarized that exposure to AFM1 is one of the causative factors that may lead to potentiate the several risk factors notably inflammatory responses and oxidative stress that ultimately induce the pathogenesis of T2DM and associated metabolic disorders. The key findings of this study suggest that human population who are at greater risk of AFM1 exposure can develop T2DM and other associated metabolic risk factors.

Cancer-Related Venous Thromboembolism: From Pathogenesis to Risk Assessment.

Cancer-related venous thromboembolism (VTE) remains a major health problem, accounting for at least 18% of all cases of VTE. Cancer patients with VTE have worse prognosis than those without VTE. Prophylaxis reduces VTE risk, but it is not feasible for all outpatients with cancer due to an increased bleeding risk. The factors involved in the pathogenesis of cancer-related VTE are direct coagulation activation, platelet activation, induction of inflammatory responses, and inhibition of fibrinolysis. Direct coagulation activation can be due to cancer procoagulant (a cysteine protease), microvesicles, or other prothrombotic abnormalities. Risk factors for developing VTE in cancer patients can be divided into four groups: tumor-related risk factors, patient-related risk factors, treatment-related risk factors, and biomarkers. Cancers of the pancreas, kidney, ovary, lung, and stomach have the highest rates of VTE. Patient-related risk factors such as age, obesity, or the presence of medical comorbidities can contribute to VTE. Platinum-based chemotherapies and antiangiogenesis treatments have also been associated with VTE. Biomarkers identified as risk factors include high platelet count, high leukocyte count, P-selectin, prothrombin fragments, D-dimer, and C-reactive protein. Based on the known risk factors, risk assessment models were developed to stratify patients who would benefit from thromboprophylaxis. The Khorana model was the first and is still the most widely used model. Because of its low sensitivity for certain tumor types, four new models have been developed in recent years. In this review, we describe the current knowledge about the pathogenesis and risk factors for cancer-related VTE, hoping to contribute to further research on the still many obscure aspects of this topic.

Physiological and Pathological Inflammation Induced by Antibodies and Pentraxins.

Macrophages play a key role in induction of inflammatory responses. These inflammatory responses are mostly considered to be instigated by activation of pattern recognition receptors (PRRs) or cytokine receptors. However, recently it has become clear that also antibodies and pentraxins, which can both activate Fc receptors (FcRs), induce very powerful inflammatory responses by macrophages that can even be an order of magnitude greater than PRRs. While the physiological function of this antibody-dependent inflammation (ADI) is to counteract infections, undesired activation or over-activation of this mechanism will lead to pathology, as observed in a variety of disorders, including viral infections such as COVID-19, chronic inflammatory disorders such as Crohn’s disease, and autoimmune diseases such as rheumatoid arthritis. In this review we discuss how physiological ADI provides host defense by inducing pathogen-specific immunity, and how erroneous activation of this mechanism leads to pathology. Moreover, we will provide an overview of the currently known signaling and metabolic pathways that underlie ADI, and how these can be targeted to counteract pathological inflammation.

Three functional variants in the NLRP3 gene are associated with susceptibility and clinical characteristics of systemic lupus erythematosus.

Nod-like receptor pyrin domain containing 3 (NLRP3) gene encodes an intracellular receptor whose dysregulation in systemic lupus erythematosus (SLE) has been reported in multiple studies. Activation of NLRP3 inflammasome leads to the induction of inflammatory response via cleaving and producing of specific cytokines. In the present study, we assessed the possible association between three functional polymorphisms in this gene and SLE risk in the Iranian population. These variants include two gain of function (rs4612666 and rs10754558) and one loss of function (rs6672995) which are correlated with modulation of expression of NLRP3. A case-control study involving 110 SLE patients and 116 control subjects was undertaken to estimate the frequency of rs4612666, rs10754558, and rs6672995 genotypes using real-time PCR high resolution melting method (HRM). Our findings revealed significant associations between GG genotype and G allele of rs10754558 with increased risk of SLE (OR for GG genotype= 2.82; 95%CI [1.45-5.46]/OR for G allele= 1.97; 95%CI [1.36-2.87]). Although, no significant associations were recognized between allele and genotype frequencies of rs4612666 and rs6672995 polymorphisms with SLE risk (P > 0.05). Also, our analysis revealed that the C allele in rs4612666 and G allele in rs10754558 was correlated with the severity of disease activity (P < 0.001). Moreover, these common variants were associated with lower age of onset and some clinical symptoms in the patient group, such as skin manifestation, neurological symptom and, renal involvement (P < 0.05). This study demonstrates a substantial association between NLRP3 polymorphisms with increased risk, clinical symptoms, and the severity of disease activity of SLE.

Neuroimmune disruptions from naturally occurring levels of mycotoxins.

Substantial pieces of evidence support the potential of exogenous toxins in disrupting neuroimmune homeostasis. It appears that mycotoxins are one of the noticeable sources of naturally occurring substances dysregulating the immune system, which involves the physiology of many organs, such as the central nervous system (CNS). The induction of inflammatory responses in microglial cells and astrocytes, the CNS resident cells with immunological characteristics, could interrupt the hemostasis upon even with low-level exposure to mycotoxins. The inevitable widespread occurrence of a low level of mycotoxins in foods and feed is likely increasing worldwide, predisposing individuals to potential neuroimmunological dysregulations. This paper reviews the current understanding of mycotoxins' neuro-immunotoxic features under low-dose exposure and the possible ways for detoxification and clearance as a perspective.