The breakthrough discovery of cardiac natriuretic peptides provided the first direct demonstration of the connection between the heart and the kidneys for the maintenance of sodium and volume homeostasis in health and disease. Yet, little is still known about how the heart and other organs cross-talk. Here, we review three physiological mechanisms of communication linking the heart to other organs through: i) cardiac natriuretic peptides, ii) the microRNA-208a/mediator complex subunit-13 axis and iii) the matrix metalloproteinase-2 (MMP-2)/C-C motif chemokine ligand-7/cardiac secreted phospholipase A2 (sPLA2) axis – a pathway which likely applies to the many cytokines, which are cleaved and regulated by MMP-2. We also suggest experimental strategies to answer still open questions on the latter pathway. In short, we review evidence showing how the cardiac secretome influences the metabolic and inflammatory status of non-cardiac organs as well as the heart.
Caspase-8 (CASP8) is one key regulator of apoptosis of T lymphocytes and is encoded by the CASP8 gene. It has been reported that the six-nucleotide deletion polymorphism (-652 6N del) of the CASP8 gene had effect on some cancer risk. Few studies explored the association between CASP8 gene polymorphism and digestive tract cancer risk. To evaluate the association between the CASP8 -652 6N del polymorphism and the risk of digestive tract cancer, we conducted this meta-analysis. We found that CASP8-652 6N del polymorphism was associated with a significantly reduced risk of digestive tract cancer in the co-dominant model (del/del vs. ins/ins: OR= 0.82, 95%CI= 0.72–0.95; del/ins vs. ins/ins: OR= 0.92, 95%CI= 0.87–0.97; dominant model (del/ins+ del/del vs. ins/ins: OR= 0.91, 95%CI= 0.87–0.96, recessive model: del/del vs. del/ins+ ins/ins: OR= 0.85, 95%CI= 0.75–0.97). In the stratified analysis by cancer types, we found that all genetic models had protective effect on gastric cancer. Similar results were observed for colorectal cancer under heterozygote comparison and dominant model, but not under homozygote comparison or recessive model. In addition, a significantly decreased risk was found on esophageal cancer for most genetic models, except heterozygote comparison. When stratified by ethnicity and source of control, an evidently decreased risk was identified in the Asian populations and population-based studies. In conclusion, there exists an association between the CASP8 -652 6N del polymorphism and reduced digestive cancer risk, especially among Asians and population-based studies.
Over the recent years, it has been found that microglia pseudopodia contact synapses, detect sick ones and prune them, even in adult animals. Myelinated nerves also carry out plasticity in which microglia remove myelin debris by phagocytosis. However, it remains unknown whether microglia explore structures on nerve fibers, such as Ranvier’s node (RN) or myelin sheath, before they become debris. By double or triple staining RNs or myelin sheathes and microglia in healthy rat corpus callosum, this study unveiled direct contacts of microglia pseudopodia with RNs and with para- and inter-nodal myelin sheathes, which was then verified by electron microscopic observations. Our data indicated that microglia also explore unmyelinated nerve fibers. Furthermore, we used the animals with matured white matter; therefore, microglia may be actively involved in plasticity of matured white matter tracts as it does for synapse pruning, instead of only passively phagocytize myelin debris.
Nephrotic syndrome is one of the most common childhood kidney diseases. It is mostly found in the age group of 2 to 8 years. Around 10%–15% of nephrotic syndrome cases are non-responders of steroid treatment (SRNS). Angiotensin converting enzyme (ACE) (I/D) gene association studies are important for detecting kidney disease and herein we assessed the association of ACE (I/D) polymorphism with nephrotic syndrome in South Indian children. We recruited 260 nephrotic syndrome (162 boys and 98 girls) and 218 (140 boys and 78 girls) control subjects. ACE I/D polymorphism was analyzed by PCR using genotype allele specific primers. In ACE (I/D), we did not find significant association for the ungrouped data of nephrotic syndrome children and the control subjects. Kidney biopsies were done in 86 nephrotic syndrome cases (minimal change disease, n=51; focal segmental glomerulosclerosis, n=27; diffuse mesangial proliferation, n=8). We segregated them into the minimal change disease / focal segmental glomerulosclerosis groups and observed that the ACE‘D’ allele was identified with borderline significance in cases of focal segmental glomerulosclerosis and the ‘I’ allele was assessed as having very weak association in cases of minimal change disease. ‘II’ genotype was weakly associated with minimal change disease. Gender specific analysis revealed weak association of ‘ID’ genotype with female nephrotic syndrome in females. Dominant expression of DD genotype was observed in males with nephrotic syndrome. Our finding indicated that ACE (I/D) has moderate association with focal segmental glomerulosclerosis. However, due to the limited number of biopsy proven focal segmental glomerulosclerosis subjects enrolled, further studies are required to confirm these results.
In this study, we sought to assess the safety and accuracy of sacropelvic fixation performed with image-guided sacroiliac screw placement using postoperative computed tomography and X-rays. The sacroiliac screws were placed with navigation in five patients. Intact specimens were mounted onto a six-degrees-of-freedom spine motion simulator. Long lumbosacral constructs using bilateral sacroiliac screws and bilateral S1 pedicle and iliac screws were tested in seven cadaveric spines. Nine sacroiliac screws were well-placed under an image guidance system (IGS); one was placed poorly without IGS with no symptoms. Both fixation techniques significantly reduced range of motion (P<0.05) at L5–S1. The research concluded that rigid lumbosacral fixation can be achieved with sacroiliac screws, and image guidance improves its safety and accuracy. This new technique of image-guided sacroiliac screw insertion should prove useful in many types of fusion to the sacrum, particularly for patients with poor bone quality, complicated anatomy, infection, previous failed fusion and iliac harvesting.
Fasudil, a selective rho kinase (ROCK) inhibitor, has been reported to play a beneficial role in systemic inflammation in acute lung injury, but its mechanism for ameliorating pulmonary edema and inflammation remains unclear. Using hematoxylin-and-eosin (H&E) staining, immunohistochemistry, enzyme-linked immunosorbent assay, quantitative real time PCR and Western blotting, we found that fasudil attenuated LPS-induced lung injury, decreased lung edema, and suppressed inflammatory responses including leukocyte infiltration and IL-6 production. Further, fasudil upregulated LPS-induced aquaporin 5 reduction and inhibited NF-kB activation in the lungs of mice. Our results suggest that fasudil could restore the expression of aquaporin 5 to eliminate LPS-induced lung edema and prevent LPS-induced pulmonary inflammation by blocking the inflammatory pathway. Collectively, blockade of the ROCK pathway by fasudil may be a potential strategy for the treatment of acute lung injury.
Tumor necrosis factor alpha (TNF-α) is a cytokine that can potently stimulate the synthesis of a range of pro-inflammatory mediators in macrophages. The underlying epigenetic mechanism, however, is underexplored. Here we report that the transcriptional modulator megakaryocytic leukemia 1 (MKL1) is associated with a histone H3K4 methyltransferase activity. Re-ChIP assay suggests that MKL1 interacts with and recruits WDR5, a component of the COMPASS complex responsible for H3K4 methylation, to the promoter regions of pro-inflammatory genes in macrophages treated with TNF-α. WDR5 enhances the ability of MKL1 to stimulate the promoter activities of pro-inflammatory genes. In contrast, silencing of WDR5 attenuates TNF-α induced production of pro-inflammatory mediators and erases the H3K4 methylation from the gene promoters. Of interest, the chromatin remodeling protein BRG1 also plays an essential role in maintaining H3K4 methylation on MKL1 target promoters by interacting with WDR5. MKL1 knockdown disrupts the interaction between BRG1 and WDR5. Together, our data illustrate a role for MKL1 in moderating the crosstalk between BRG1 and WDR5 to activate TNF-α induced pro-inflammatory transcription in macrophages.
Acrylamide, a potential carcinogen, exists in carbohydrate-rich foods cooked at a high temperature. It has been reported that acrylamide can cause DNA damage and cytotoxicity. The present study aimed to investigate the potential mechanism of human hepatocarcinoma HepG2 cell proliferation induced by acrylamide and to explore the antagonistic effects of a natural polyphenol curcumin against acrylamide via miR-21. The results indicated that acrylamide (≤100 μmol/L) significantly increased HepG2 cell proliferation and miR-21 expression. In addition, acrylamide reduced the PTEN expression in protein level, while induced the expressions of p-AKT, EGFR and cyclin D1. The PI3K/AKT inhibitor decreased p-AKT protein expression and inhibited the proliferation of HepG2 cells. In addition, curcumin effectively reduced acrylamide-induced HepG2 cell proliferation and induced apoptosis through the expression of miR-21. In conclusion, the results showed that acrylamide increased HepG2 cell proliferation via upregulating miR-21 expression, which may be a new target for the treatment and prevention of cancer.