A crucial role for TNF-α in mediating neutrophil influx induced by endogenously generated or exogenous chemokines,KC/CXCL1 and LIX/CXCL5

Background and purpose:

Chemokines orchestrate neutrophil recruitment to inflammatory foci. In the present study, we evaluated the participation of three chemokines, KC/CXCL1, MIP-2/CXCL2 and LIX/CXCL5, which are ligands for chemokine receptor 2 (CXCR2), in mediating neutrophil recruitment in immune inflammation induced by antigen in immunized mice.

Experimental approach:

Neutrophil recruitment was assessed in immunized mice challenged with methylated bovine serum albumin, KC/CXCL1, LIX/CXCL5 or tumour necrosis factor (TNF)-α. Cytokine and chemokine levels were determined in peritoneal exudates and in supernatants of macrophages and mast cells by elisa. CXCR2 and intercellular adhesion molecule 1 (ICAM-1) expression was determined using immunohistochemistry and confocal microscopy.

Key results:

Antigen challenge induced dose- and time-dependent neutrophil recruitment and production of KC/CXCL1, LIX/CXCL5 and TNF-α, but not MIP-2/CXCL2, in peritoneal exudates. Neutrophil recruitment was inhibited by treatment with reparixin (CXCR1/2 antagonist), anti-KC/CXCL1, anti-LIX/CXCL5 or anti-TNF-α antibodies and in tumour necrosis factor receptor 1-deficient mice. Intraperitoneal injection of KC/CXCL1 and LIX/CXCL5 induced dose- and time-dependent neutrophil recruitment and TNF-α production, which were inhibited by reparixin or anti-TNF-α treatment. Macrophages and mast cells expressed CXCR2 receptors. Increased macrophage numbers enhanced, while cromolyn sodium (mast cell stabilizer) diminished, LIX/CXCL5-induced neutrophil recruitment. Macrophages and mast cells from immunized mice produced TNF-α upon LIX/CXCL5 stimulation. Methylated bovine serum albumin induced expression of ICAM-1 on mesenteric vascular endothelium, which was inhibited by anti-TNF-α or anti-LIX/CXCL5.

Conclusion and implications:

Following antigen challenge, CXCR2 ligands are produced and act on macrophages and mast cells triggering the production of TNF-α, which synergistically contribute to neutrophil recruitment through induction of the expression of ICAM-1.     

Prevention of type 2 diabetes in adults with impaired glucose tolerance: the European Diabetes Prevention RCT in Newcastle upon Tyne, UK

Background  

Diabetes prevalence is increasing. The Finnish Diabetes Prevention Study (DPS) showed a 58% reduction in Type 2 Diabetes (T2D) incidence in adults with impaired glucose tolerance (IGT). The European Diabetes Prevention Study (EDIPS) extends the DPS to different European populations, using the same study design. In the Newcastle arm of this study (EDIPS-Newcastle), we tested the hypothesis that T2D can be prevented by lifestyle intervention and explored secondary outcomes in relation to diabetes incidence.     

Clinical correlates of low-risk variants in FGFR2, TNRC9, MAP3K1, LSP1 and 8q24 in a Dutch cohort of incident breast cancer cases

Introduction

Seven SNPs in five genomic loci were recently found to confer a mildly increased risk of breast cancer.

Methods

We have investigated the correlations between disease characteristics and the patient genotypes of these SNPs in an unselected prospective cohort of 1,267 consecutive patients with primary breast cancer.

Results

Heterozygote carriers and minor allele homozygote carriers for SNP rs889312 in the MAP3K1 gene were less likely to be lymph node positive at breast cancer diagnosis (P = 0.044) relative to major allele homozygote carriers. Heterozygote carriers and minor allele homozygote carriers for SNP rs3803662 near the TNCR9 gene were more likely to be diagnosed before the age of 60 years (P = 0.025) relative to major allele homozygote carriers. We also noted a correlation between the number of minor alleles of rs2981582 in FGFR2 and the average number of first-degree and second-degree relatives with breast cancer and/or ovarian cancer (P = 0.05). All other disease characteristics, including tumour size and grade, and oestrogen or progesterone receptor status, were not significantly associated with any of these variants.

Conclusion

Some recently discovered genomic variants associated with a mildly increased risk of breast cancer are also associated with breast cancer characteristics or family history of breast cancer and ovarian cancer. These findings provide interesting new clues for further research on these low-risk susceptibility alleles.     

The role of adiponectin for immune cell function in metabolic diseases

Adiponectin, as an indispensable regulator of the immune system, is the most abundant adipokine and is mainly produced by white adipose tissue. Adiponectin mediates the positive effects on systemic metabolism by regulating associated downstream signalling pathways; however, accumulating evidence shows that adiponectin plays an important role in regulating the function of innate and adaptive immune cells in the development of obesity and its related diseases. In this review, we focus on the biological function of adiponectin in regulating innate and adaptive immunity and outline the key role of adiponectin in various metabolic diseases, which will highlight a potential direction for adiponectin-based therapeutic interventions for metabolic diseases.     

Gut microbiota changes in patients with hypertension: A systematic review and meta-analysis

Hypertension is a major public health issue worldwide. The imbalance of gut microbiota is thought to play an important role in the pathogenesis of hypertension. The authors conducted the systematic review and meta-analysis to clarify the relationship between gut microbiota and hypertension through conducting an electronic search in six databases. Our meta-analysis included 19 studies and the results showed that compared with healthy controls, Shannon significantly decreased in hypertension [SMD = −0.13, 95%CI (−0.22, −0.04), p = .007]; however, Simpson [SMD = −0.01, 95%CI (−0.14, 0.12), p = .87], ACE [SMD = 0.18, 95%CI (−0.06, 0.43), p = .14], and Chao1 [SMD = 0.11, 95%CI (−0.01, 0.23), p = .08] did not differ significantly between hypertension and healthy controls. The F/B ratio significantly increased in hypertension [SMD = 0.84, 95%CI (0.10, 1.58), p = .03]. In addition, Shannon index was negatively correlated with hypertension [r = −0.12, 95%CI (−0.19, −0.05)], but had no significant correlation with SBP [r = 0.10, 95%CI (−0.19, 0.37)] and DBP [r = −0.39, 95%CI (−0.73, 0.12)]. At the phylum level, the relative abundance of Firmicutes [SMD = −0.01, 95%CI (−0.37, 0.34), p = .94], Bacteroidetes [SMD = −0.15, 95%CI (−0.44, 0.14), p = .30], Proteobacteria [SMD = 0.25, 95%CI (−0.01, 0.51), p = .06], and Actinobacteria [SMD = 0.21, 95%CI (−0.11, 0.53), p = .21] did not differ significantly between hypertension and healthy controls. At the genus level, compared with healthy controls, the relative abundance of Faecalibacterium decreased significantly [SMD = −0.16, 95%CI (−0.28, −0.04), p = .01], while the Streptococcus [SMD = 0.20, 95%CI (0.08, 0.32), p = .001] and Enterococcus [SMD = 0.20, 95%CI (0.08, 0.33), p = .002] significantly increased in hypertension. Available evidence suggests that hypertensive patients may have an imbalance of gut microbiota. However, it still needs further validation by large sample size studies of high quality.     

Association of an inter-arm systolic blood pressure difference with all-cause and cardiovascular mortality: A meta-analysis of cohort studies

This meta-analysis evaluated the potential association of a simultaneously measured inter-arm systolic blood pressure difference (IASBPD) and all-cause mortality and cardiovascular mortality. The Medline, Cochrane Library, Embase, and PubMed databases were searched through to April 14, 2023 for relevant literature. The outcomes were the associations of IASBPD with all-cause and cardiovascular mortality. Finally, 10 cohort studies that included 15 320 individuals were included. An IASBPD of ≥15 mm Hg was associated with increased all-cause mortality (pooled hazard ratio [HR] 1.28, 95% confidence interval [CI] 1.02–1.61) but an IASBPD of ≥10 mm Hg was not (pooled HR 1.28, 95% CI 0.89–1.85). The pooled HR for cardiovascular mortality was 1.88 (95% CI 1.31–2.71) for an IASBPD of ≥10 mm Hg and 1.93 (95% CI 1.24–2.99) for an IASBPD of ≥15 mm Hg. Subgroup analysis showed that younger patients (HR 9.03, 95% CI 2.00–40.82, p = .004) with an IASBPD ≥15 mm Hg were at higher risk of cardiovascular mortality than older patients (HR 1.67, 95% CI 1.06–2.64, p = .03); the difference between groups was statistically significant (p = .04). In conclusions, our findings show that a simultaneously measured IASBPD ≥15 mm Hg predicts increased all-cause mortality and an IASBPD of ≥15 mm Hg or ≥10 mm Hg predicts increased cardiovascular mortality. An IASBPD ≥15 mm Hg appears to be more correlated with cardiovascular mortality in younger patients than in older patients.     

A rare case of cardiogenic shock caused by takotsubo syndrome associated with SARS-CoV-2 infection: The value of echocardiography in the diagnosis and monitoring of the efficacy of extracorporeal membrane oxygenation

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) mainly invades the respiratory system, but may also cause various cardiovascular complications. We report a rare case of myocarditis associated with SARS-CoV-2 infection. A 61-year-old man was admitted to the hospital with a positive nucleic acid test for SARS-CoV-2. A sudden increase in troponin level (up to .144 ng/mL) was observed on the 8th day after admission. He developed symptoms of heart failure and progressed rapidly to cardiogenic shock. Echocardiography on the same day showed reduced left ventricular ejection fraction, reduced cardiac output, and segmental ventricular wall motion abnormalities. Takotsubo cardiomyopathy associated with SARS-CoV-2 infection was considered based on the typical echocardiography findings. We immediately started veno-arterial extracorporeal membrane oxygenation (VA-ECMO) treatment. The patient was successfully withdrawn from VA-ECMO after 8 days following recovery of ejection fraction to 65% and all indicators qualifying the withdrawal criteria. Echocardiography plays an important role in dynamic monitoring of cardiac changes in such cases and can help determine the timing of extracorporeal membrane oxygenation treatment and withdrawal.