Interaction of CD154 with different receptors and its role in bidirectional signals

In addition to its classical receptor, CD40, it is now well established that CD154 also binds αIIbβ3, α5β1, and αMβ2 integrins. Although these integrins are all members of the same family, they bind CD154 differently. The current investigation aims to analyze the interaction of CD154 with α5β1 and αMβ2 and investigate its role in bidirectional signals in various human cell lines. Results obtained herein indicate that the CD154 residues involved in the interaction with α5β1 are N151 and Q166, whereas those involved in αMβ2 binding are common to residues required for CD40, namely Y145 and R203. Soluble CD40/CD154 or αMβ2/CD154 complexes do not interfere with the binding of CD154 to α5β1‐positive cells, but inhibit the binding of CD154 to CD40‐ or αMβ2‐positive cells, respectively. Ligation of CD154 on CD154‐positive cells with soluble CD40, αIIbβ3, α5β1, or αMβ2 stimulates intracellular signaling, including MAPK phosphorylation. Given that CD154 exists as a trimer, our data strongly suggest that CD154 may bind concomitantly to two receptors of the same or different family, and biologically activate cells expressing both receptors. The characterization of CD154/receptor interactions helps the identification of new therapeutic targets for the prevention and/or treatment of CD154‐associated autoimmune and inflammatory diseases.     

Nature of fatty acids in high fat diets differentially delineates obesity-linked metabolic syndrome components in male and female C57BL/6J mice

Background

C-reactive protein (CRP) is positively associated with risk for cardiovascular disease and all-cause mortality. Some but not all randomized and non-randomized clinical trials found significant associations between fenofibrate therapy and CRP but the direction and magnitude of the association varied across studies. The duration of treatment, patient populations and sample sizes varied greatly, and most short-term studies (i.e., ≤ 12 weeks) had fewer than 50 patients. In this study we meta-analyzed randomized clinical trials to determine the short-term effect of fenofibrate on CRP.

Methods

Two reviewers independently searched PubMed and other online databases for short-term randomized clinical trials that reported CRP concentrations before and after fenofibrate treatment. Of the 81 studies examined, 14 studies with 540 patients were found eligible. Data for the change in CRP and corresponding measures of dispersion were extracted for use in the meta-analysis.

Results

The weighted mean CRP concentrations before and after fenofibrate therapy were 2.15 mg/L and 1.53 mg/L (-28.8% change), respectively. Inverse-variance weighted random effects meta-analysis revealed that short-term fenofibrate treatment significantly lowers CRP by 0.58 mg/L (95% CI: 0.36-0.80). There was significant heterogeneity between studies (Q statistic = 64.5, P< 0.0001, I² = 79.8%). There was no evidence of publication bias and sensitivity analysis revealed that omitting any of the 14 studies did not lead to a different conclusion from the overall meta-analysis result.

Conclusion

Short-term treatment with fenofibrate significantly lowers CRP concentration. Randomized trials that will recruit patients based with high baseline CRP concentrations and with change in CRP as a primary outcome are needed.     

The use of statins and lung function in current and former smokers

BACKGROUND: Smokers are affected by a variety of inflammatory diseases, including COPD. Statins, 3-hydroxy-3-methyl-glutaryl-coenzyme-A reductase inhibitors, are used for their lipid-lowering characteristics but also appear to have antiinflammatory and immunomodulatory activities. We assessed their ability to preserve lung function in current and former smokers. METHODS: All smokers and ex-smokers seen at the Oklahoma City VA hospital in 2005 with abnormal baseline spirometry findings and two or more pulmonary function tests done 6 months apart were classified into obstructive and restrictive groups based on the initial PFT result. Statin use, annual decline in FEV(1) and FVC, and need for respiratory-related urgent care (emergency department or inpatient) were compared. RESULTS: Approximately one half, 215 of 418 patients, were receiving a statin. Compared to the control group, statin users had a lower decline in FEV(1) (- 0.005 +/- 0.20 L/yr vs 0.085 +/- 0.17 L/yr, p < 0.0001) and FVC (- 0.046 +/- 0.45 L/yr vs 0.135 +/- 0.32 L/yr, p < 0.0001) [mean +/- SD]. This difference remained significant irrespective of whether the patient had obstructive (n = 319), or restrictive (n = 99) disease, and regardless of whether the patient continued or stopped smoking. In patients with an obstructive spirometry finding, we found a lower incidence of respiratory-related urgent care in favor of the statin group (0.12 +/- 0.29 patient-years vs 0.19 +/- 0.32/patient-years; p = 0.02). CONCLUSION: In smokers and former smokers, statins are associated with a slower decline in pulmonary function, independent of the underlying lung disease. Clinical implication: Prospective, randomized trials are needed to study the effect of statins on lung function.     

HLA-Cw7 Zygosity Affects the Size of a Subset of CD158b+ Natural Killer Cells

Individuals with certain HLA class I genotypes are highly susceptible to disease after viral infection. Natural killer (NK) cells kill virus-infected cells through a mechanism involving HLA class I receptors. These facts may be connected if an individual's HLA genotype regulates the number and function of NK cells. We have observed that subjects homozygous for the HLA-B/C region of conserved major histocompatibility complex (MHC) extended haplotypes have lower NK cell activity and a significantly lower frequency of CD16⁺CD56⁺ NK cells than heterozygotes. The proportion of CD16^–CD56⁺ NK cells was unaffected by zygosity for the HLA-B/C region. We show here that the frequency of CD16⁺CD158b⁺, but not CD16^–CD158b⁺ NK cells, was significantly lower (p <0.026) in homozygotes for HLA-Cw7 (NK1 ligand) haplotypes than in heterozygotes. The frequencies of CD16⁺CD158a⁺ and CD16^–CD158a⁺ and CD16^–CD158a⁺ or CD16⁺NKB1⁺ and CD16^–NKB1⁺ NK cells were not different in these donor groups. These findings suggest that the proportion of NK cells coexpressing CD16 and CD158b, but not CD158a nor NKB1, is influenced by zygosity for the HLA-Cw7 (NK1 ligand) haplotype. Since NK cells are involved in protection from virus infection, a reduced size of a ligand-specific NK subset in individuals homozygous for some HLA-B/C haplotypes may help explain their increased susceptibility to virus-induced diseases.     

Resilience by design: How nature,nurture, environment,and microbiome mitigate stress and allostatic load

Resilience to psychological stress is defined as adaption to challenging life experiences and not the absence of adverse life events. Determinants of resilience include personality traits, genetic/epigenetic modifications of genes involved in the stress response, cognitive and behavioral flexibility, secure attachment with a caregiver, social and community support systems, nutrition and exercise, and alignment of circadian rhythm to the natural light/dark cycle. Therefore, resilience is a dynamic and flexible process that continually evolves by the intersection of different domains in human’s life; biological, social, and psychological. The objective of this minireview is to summarize the existing knowledge about the multitude factors and molecular alterations that result from resilience to stress response. Given the multiple contributing factors in building resilience, we set out a goal to identify which factors were most supportive of a causal role by the current literature. We focused on resilience-related molecular alterations resulting from mind-body homeostasis in connection with psychosocial and environmental factors. We conclude that there is no one causal factor that differentiates a resilient person from a vulnerable one. Instead, building resilience requires an intricate network of positive experiences and a healthy lifestyle that contribute to a balanced mind-body connection. Therefore, a holistic approach must be adopted in future research on stress response to address the multiple elements that promote resilience and prevent illnesses and psychopathology related to stress allostatic load.