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关键词： Actinobacillus pleuropneumoniae   CpxAR   Lipopolysaccharide   Amyloid precursor protein   beta-Amyloid   IL-1 beta   Porcine alveolar macrophage  

摘要： Actinobacillus pleuropneumoniae (A. pleuropneumoniae), a porcine respiratory tract pathogen, causes porcine pleuropneumonia. Porcine alveolar macrophages (PAMs) play a crucial role during A. pleuropneumoniae infection. Amyloid precursor protein (APP) can be cleaved by beta- and gamma-secretase to produce beta-amyloid (A beta). APP and A beta are associated with the inflammatory response. They activate microglia and astrocytes to secrete IL-1 beta, IL-6, and other cytokines. In this study, we found that during the interaction between A. pleuropneumoniae and PAMs, the two-component system CpxAR upregulates wecA expression, increasing lipopolysaccharide (LPS) production. LPS promotes APP production and cleavage to generate A beta. The A beta activates NF-kappa B, leading to increased IL-1 beta expression. We hypothesize that A. pleuropneumoniae infection of PAMs regulates APP production and cleavage to control A beta levels. Different quantities of A beta induce PAMs to produce varying amounts of cytokines, leading to different pathological processes in porcine pleuropneumonia.

关键词： Immunomodulatory activity   Lycopodium complanatum ssp. chamaecyparissus   TNF-alpha   IL-6   Lycopodine  

摘要： In the current work, the results of in vivo bioactivities of the petroleum ether (PE), chloroform (CHL), and methanol (MET) extracts of Lycopodium complanatum L. ssp. chamaecyparissus (***.) Doll (LCC, Lycopodiaceae) were assessed in a dose-dependent manner on tumor necrosis factor (TNF-a), and interleukin-6 (IL-6) in specific pathogen-free (6-8 weeks SPF) mice. The levels of proinflammatory cytokines, e.g. TNF-a and IL-6 secreted from murine peritoneal macrophages, were assayed and determined following exposure to varying doses (50 and 100 mg kg-1) of LCC-PE, LCC--CHL, and LCC-MET using anti-mouse ELISA kits. The samples with or without control lipopolysaccharide (LPS, Escherichia coli 026: B6) were collected from SPF mice on the treatment days. The cytopathogenic effect was not observed in the samples at the tested doses times. According to our data, at 100 mg kg-1 dose of PE, CHL, and MET extracts of LCC, moderate activities were observed, where significant differences were found between the doses of the samples (p < 0.05). The antimicrobial and antiviral data we obtained from our previous research and the current data obtained have been consistent with the immunomodulatory activity of LCC-PE in particular. The immunomodulatory activity of the extracts might be due to their alkaloidal content such as lycopodine as the major alkaloid, along with dihydrolycopodine and lycodine. (c) 2025 SAAB. Published by Elsevier B.V. All rights are reserved, including those for text and data mining, AI training, and similar technologies.

关键词： Coenzyme Q 10   FCA-Salt rat   Cardiac fibrosis   Renal fibrosis   Inflammation  

摘要： Hypertension is one of the most common factors contributing to cardiac remodeling that links to changes in both heart and kidney functions. Several studies have reported the beneficial effects of Coenzyme Q10 (CoQ10) in reducing oxidative stress due to its antioxidant properties. However, the cardioprotective and nephroprotective roles of CoQ10 against the toxicity induced by fludrocortisone acetate (FCA) have yet to be investigated. Therefore, we evaluated the CoQ10 effects on FCA-induced cardiotoxicity and nephrotoxicity in a rat model (FCASalt). We analyzed various oxidative stress parameters and antioxidant enzyme activities using biochemical assays. In addition, we examined inflammatory and fibrosis via histological staining of heart and kidney tissues. CoQ10 significantly reduced lipid peroxidation product-malondialdehyde (MDA) while increased nitric oxide (NO) in the FCA-Salt rats. Antioxidant enzyme activities were also enhanced by CoQ10 in these rats. Histopathological examination detected tissue damage and fibrosis in the FCA-Salt group, which was significantly reduced by CoQ10. Furthermore, enzyme-linked immunosorbent assay (ELISA) indicated the activation of Transforming growth factor-(31/Tumor necrosis factor-alpha (TGF-(31/TNF-alpha) by CoQ10. Consequently, our study suggests that CoQ10 can effectively protect heart and kidney health against cardiotoxicity and nephrotoxicity in FCA-Salt hypertensive rats via TGF-(31/TNF-alpha pathway.

关键词： cytokines   fever   heat shock proteins   innate immunity   tuberculosis  

摘要： Fever is a common clinical symptom in patients with tuberculosis (TB). During fever, heat-shock proteins (HSPs), such as HSP70, are expressed, which are molecular chaperones regulating protein folding and may also have immunomodulatory properties. How fever modulates immune responses during TB and by which mechanisms is unknown. In this study, we investigated the effects of fever, and specifically the role of HSP70, on Mycobacterium tuberculosis (Mtb)-induced macrophage inflammatory responses. Human monocyte-derived macrophages (MDM) were infected with Mtb at 37 degrees C or 40 degrees C to mimic febrile conditions. Fever suppresses Mtb-induced IL-1 beta and IL-10 gene expression and secretion from MDM, but enhances Mtb-induced HSP70 secretion and intracellular accumulation in MDM. Extracellular HSP70 and HSP70-expressing macrophages are abundant in granulomas in TB patient biopsies. HSP70 antagonism decreases Mtb-induced IL-1 beta secretion during febrile conditions but has no significant effect on IL-10 secretion. Pretreatment of MDM with recombinant HSP70 significantly increases Mtb-induced IL-1 beta at 37 degrees C. Finally, extracellular HSP70 negatively regulates further HSP70 secretion from MDM during Mtb infection. Overall, fever and subsequent HSP70 expression modulates proinflammatory innate immune response in TB, which may have implications for the development of host-directed therapies.

关键词： Cytokines   Leishmaniasis   Variant genotypes   Parasitic diseases   Lesions   Leishmania   Medical risk factors   Phylogeography  

摘要： Background The long non-coding RNA interferon gamma antisense-1 (IFNGAS-1) is essential for Th1 lineage specific expression of IFNG. IFN-gamma is a key component cytokine in host immune response against intracellular pathogens like Leishmania. We investigated the association of two genetic variants of IFNGAS-1, rs4913269 and rs7134599, with susceptibility or protection to Leishmania guyanensis- induced cutaneous leishmaniasis (Lg-CL).Methods A case-control study involving 1,714 individuals (855 Lg-CL and 859 healthy controls) was conducted in the state of Amazonas, Brazil. Genotyping of rs4913269 and rs7134599 were performed using direct nucleotide sequencing and polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP), respectively. Plasma cytokines concentrations (IL-10, IL-12p70, IL-4, IL-1 beta and TNF-alpha) were quantified using multiplex Luminex platform. Logistic regression, linkage disequilibrium (LD), and haplotype analyses were applied to assess genetic associations and cytokine *** Individuals with the rs4913269 G/G genotype had a 46% reduced risk of developing Lg-CL, (OR adjusted for age and sex [ORadj] = 0.54;95% CI 0.39-0.75;Pvadj = 0.0001). Carriers of the rs7134599 A/A genotype had a 130% increased risk of progression to Lg- CL (ORadj = 2.3;95% CI, 1.6-3.4;P = 0.0001). The rs7134599 A/G genotype also showed a 52% increased risk compared to GG genotype (ORadj = 1.52, 95%CI 1.22-1.89;Pvadj = 0.0002). The rs4913269 G/G genotype was associated with lower levels of IL-10 (P = 0.05) and IL-12p70 (P = 0.009) compared to the C/C genotype. Conversely, the rs7134599 AA genotypes were correlated with higher levels of TNF-alpha, IL-4, IL-10 and IL-1 beta in comparison to the GG genotype. LD revealed independent segregation of the *** The IFNG-AS1 variants rs4913269 and rs7134599 exert opposing effects on Lg-CL risk and modulate key cytokines involved in disease pathogenesis. These findings underscore the re

关键词： AKI   IL-6   NAMPT   renal stromal cell   sepsis  

摘要： Background Activated macrophages, pivotal for driving the immune response in sepsis, express high levels of CD38. Although the circulating levels of its ligand, CD31, increase in sepsis, the functions of CD38 and its ligation remain elusive. This study aimed to elucidate the impact of CD38 ligation on sepsis using single-cell and single-nucleus RNA sequencing (scRNA-seq and snRNA-seq, respectively) to identify a novel therapeutic target for severe *** We performed scRNA-seq analysis of mouse peritoneal immune cells to precisely identify cell types exhibiting increased CD38 expression upon exposure to lipopolysaccharide (LPS). Subsequently we induced CD38 ligation using a well-established agonistic anti-CD38 antibody in a mouse model of LPS-induced sepsis. We analysed its pathophysiological effects using kidney snRNA-seq. Finally, we performed histological analysis of septic tissues collected from patients to ensure consistency of our findings between mice and *** LPS stimulation upregulated CD38 expression in peritoneal macrophages. CD38 ligation significantly exacerbated LPS-induced inflammation in vivo, particularly in the kidneys. Kidney snRNA-seq analysis revealed that CD38 ligation induced interleukin (IL)-6 production in renal stromal cells via nicotinamide phosphoribosyltransferase (NAMPT) signalling originating from CD38-positive macrophages. NAMPT inhibition significantly ameliorated LPS-induced IL-6 production and kidney injury. Histological analysis of human septic tissues demonstrated upregulation of IL6 messenger RNA and NAMPT in renal stromal cells and CD38-positive macrophages, *** Our findings elucidate the implications of CD38 ligation in an LPS-induced sepsis model and uncover shared signalling pathways between mice and human sepsis. NAMPT signalling identified in this study may be a novel therapeutic target for mitigating systemic inflammation and kidney injury associated with severe sepsis.

关键词： Asthma   Ma-Xing-Shi-Gan decoction   Gut microbiota   Treg cells   histone deacetylation  

摘要： Background: Gut microbiota imbalance is well-known as one important trigger of allergic asthma. Ma-Xing-ShiGan decoction (MXSG) is a traditional Chinese medicine prescription with ideal clinical efficacy on asthma. However, whether and how MXSG exerts its efficacy on asthma through gut microbiota remains unclear. Purpose: To investigate the underlying mechanism of MXSG against asthma using multi-omics technologies. Methods: An asthma model was established using 8-week-old C57BL/6 J mice, after which they were daily administrated with high-, medium- and low-dose MXSG for 7 days. Histopathological examinations and flow cytometry were performed to evaluate the effects of MXSG on lung immune injury. Key regulatory pathways were predicted via network pharmacology and verified using 16S rRNA sequencing, metagenomics, metabolomics, and in vivo experiments including the knockout of the targeting gene. Results: MXSG alleviated asthma symptoms, elevated intestinal microbial diversities, and enriched potential beneficial microbes such as Lactococcus, Lactobacillus, and Limosilactobacillus. Network pharmacology and experimental validation highlighted the IL-17/Treg signaling as crucial for asthma treatment. IL-17 knockout experiments revealed its necessity for Treg differentiation during asthma. Moreover, IL-17-deficient asthmatic mice exhibited lower levels of Lactobacillus and significant changes in microbial genes involving histone deacetylases (HDAC) and short-chain fatty acids (SCFAs). Finally, MXSG significantly boosted SCFA production and reduced HDAC9 expression, which were correlated with Treg cell ratios. Conclusion: Our study delineates a novel mechanism where MXSG synergizes with the IL-17 family to enrich intestinal beneficial microbes (e.g. Lactobacillus) and SCFAs. This inhibits the expression of SCFA-downstream HDAC9 to promote Treg differentiation, and thus potentially alleviates asthma.

关键词： Inflammation   Immune epilepsy   Cytokines   Ghrelin  

摘要： Purpose: This study aimed to investigate the relationship between ghrelin levels and severity of inflammation in children with epilepsy by evaluating the differences in total ghrelin, High Mobility Group Box 1 (HMGB1), Interleukin-1 Receptor Type 1 (IL1R1), and Interleukin-1 Beta (IL1-beta) levels in patients with drug-resistant and non-drug-resistant epilepsy and comparing these parameters with those of healthy controls. Methods: We measured total ghrelin, HMGB1, IL1R1, and IL1-beta levels-known to play roles in epileptogenesis-in patients with severe (n: 28), mild (n:29) epilepsy, and 31 healthy controls. The severe epilepsy group included patients with treatment-resistant epilepsy, while the mild epilepsy group consisted of patients whose seizures could be controlled with monotherapy. Results: Total ghrelin levels, along with HMGB1, IL1R1, and IL1-beta, were significantly elevated in children with epilepsy compared to healthy controls. This increase was more pronounced in the drug-resistant epilepsy group, suggesting a potential role for ghrelin in drug-resistant epilepsy. While no direct correlation was found between ghrelin and the inflammatory markers, we observed that ghrelin levels rose significantly when levels of IL1R1, IL1-beta, and HMGB1 surpassed their respective cut-off values in epilepsy patients. The biomarkers IL1R1 and IL1-beta had the strongest discriminative potential in distinguishing patients with severe epilepsy from healthy controls. Although ghrelin was not as powerful a diagnostic marker as IL1R1 or IL1-beta, it still showed moderate diagnostic value. Conclusion: Ghrelin could serve as a biomarker reflecting both inflammation and drug resistance in epilepsy. It may be associated with inflammatory responses in epilepsy and could play a potential role in the pathophysiology of the disease.