Sex differences in the pathogenesis of hypertension exist. While gut microbiota (GM) has been associated with hypertension, it is unclear whether there are sex-linked differences in the association ...between GM and hypertension.
We conducted a cross-sectional study to investigate the sex differences in associations between GM characterized by shotgun sequencing, GM-derived short-chain fatty acids, and 24-hour ambulatory blood pressure in 241 Hong Kong Chinese (113 men and 128 women; mean age, 54±6 years).
The hypertensive group was associated with GM alterations; however, significant differences in β-diversity and GM composition in hypertensive versus normotensive groups were only observed in women and not in men under various statistical models adjusting for the following covariates: age, sex, body mass index, sodium intake estimated by spot urine analysis, blood glucose, triglycerides, low- and high-density lipoprotein cholesterol, smoking, menopause, and fatty liver status. Specifically,
,
, and
were significantly more abundant in the hypertensive women, whereas
was more abundant in the normotensive women. No bacterial species were found to be significantly associated with hypertension in men. Furthermore, total plasma short-chain fatty acids and propionic acid were independent predictors of systolic and diastolic blood pressure in women but not men.
GM dysregulation was strongly associated with 24-hour ambulatory blood pressure in women but not men, which may be mediated through propionic acid. Our work suggests that sex differences may be an important consideration while assessing the role of GM in the development and treatment of hypertension.
Chinese rural students have been documented to have relatively delayed cognitive development. From an ecological system perspective, empirical studies have identified the significant effect of the ...proximal environment on Chinese rural students' cognitive development. Yet, little do we know the mechanism behind that. More importantly, how the mechanism differs among rural students with different left-behind characteristics remains obscure.
Drawing longitudinal data from a nationally representative survey, this study examines the interrelations between rural students' parental educational expectation perception, their own educational expectation, and cognitive ability. Two models were examined using path analysis. The first mediation model tests the mediating effect of educational expectation between the association of parental educational expectation perception and cognitive ability, while the second moderated mediation identifies the moderating effect of rural students' left-behind status on the association between their parental educational expectation perception and educational expectation.
The first mediation analysis reveals that rural students' perception of parental educational expectation is positively correlated with their educational expectation, which further positively correlated with their cognitive ability. The following moderated mediation analysis suggests that students' left-behind status significantly moderated the effect of their perceived parental educational expectations on their own educational expectation.
Chinese rural students' perception of parental educational expectation affects their cognitive ability through their own educational expectations. The number of migrant parents within a family further moderates the indirect effect of education expectation.
Negative association was found between the frontal theta/beta ratio and mind wandering in participants with high schizotypal traits, while no such association was found in participants with low ...schizotypal traits. These findings provide insights into the neural mechanism of mind wandering in individuals with high schizotypal traits.
Suicide is a major social and public health problem, but its neurobiology in major depressive disorder is poorly understood. The purpose of this study was to use magnetic resonance diffusion tensor ...imaging to characterize abnormalities of white matter integrity in major depressive disorder patients with and without a history of suicide attempts.
Participants were 52 patients with major depressive disorder, with (N=16) and without (N=36) a history of suicide attempts, and 52 healthy comparison subjects matched for age, gender, education, and ethnicity. Diffusion tensor imaging in a 3.0 Tesla magnetic resonance scanner was performed. Whole-brain voxel-based analysis was used to compare fractional anisotropy across the three groups and analyze the correlation with symptom severity. A region-of-interest analysis was applied to the bilateral hippocampus, thalamus, and lentiform nucleus
Fractional anisotropy was decreased in the left anterior limb of the internal capsule in suicide attempters relative to both nonattempters and healthy comparison subjects, in the right frontal lobe relative to comparison subjects only, and in the right lentiform nucleus relative to nonattempters only. There was no significant correlation with symptom severity.
Decreased fractional anisotropy in the left anterior limb of the internal capsule appears to characterize patients with major depressive disorder who have a history of attempting suicide. Longitudinal studies are required to validate this as a potential marker that may inform the development of strategies for reducing suicide.
Background
Pro‐inflammatory cytokines play important pathological effects in various diseases and allotransplantation; however, their pathological role in xenotransplantation remains elusive. In ...pig‐to‐human cell or organ transplantation, whether porcine cells or organs are activated by human cytokines or not as an important question needs to be investigated.
Methods
We investigated the effect of human IL‐6, IFN‐γ, IL‐17, IL‐1β, and TNF‐α in xenotransplantation using several in vitro models and porcine aortic endothelial cells (PAECs) as target cells. The downstream signaling pathways activated by these cytokines were studied with Western blotting, the regulation of the pro‐inflammatory related genes and pro‐coagulation factor were assessed using real‐time PCR or enzyme‐linked immunosorbent assay, and swine leukocyte antigen (SLA) class I and SLA class II DR were analyzed by flow cytometry.
Results
We found that NF‐κB and mitogen‐activated protein kinases (MAPKs) were activated by recombinant human IL‐17 (rhIL‐17), rhIL‐1β, and rhTNF‐α, while rhIL‐6 activated signal transducer and activator of transcription 3 (STAT3) in PAECs. The adhesion molecules (E‐selectin, VCAM‐1, and ICAM‐1), pro‐inflammatory gene (IL‐6), chemokines (IL‐8 and MCP‐1), and the pro‐coagulation factor (tissue factor) were induced by rhIL‐17, rhIL‐1β, and rhTNF‐α, while rhIL‐6 only increased the expression of MCP‐1 and tissue factor. Using flow cytometry analysis, SLA class I was upregulated in PAECs after exposure to rhIL‐1β and rhTNF‐α, but not rhIL‐6 or rhIL‐17, whereas SLA class II DR could not be induced by rhIL‐6, rhIL‐17, rhIL‐1β, or rhTNF‐α, although it could by recombinant porcine IFN‐γ (rpIFN‐γ). Although activation of PAECs by rhIL‐17 alone was not strong, rhIL‐17 combined with rhTNF‐α amplified the expression of E‐selectin, IL‐6, and IL‐8. Unexpectedly, we found that tocilizumab, a humanized anti‐human IL‐6 receptor antibody, could not block rhIL‐6‐mediated STAT3 activation in PAECs. Human IFN‐γ could not activate STAT1 or induce the downstream gene expression in PAECs, which was consistent with a previous report.
Conclusion
In conclusion, our data suggest that human IL‐6, IL‐17, IL‐1β, and TNF‐α significantly activate PAECs and are likely to promote inflammation and coagulation reaction in response to xenograft.
Advanced glycation end-products (AGEs) can induce expression of connective tissue growth factor (CTGF), which seems to promote the development of diabetic nephropathy, but the exact signaling ...mechanisms that mediate this induction are unknown. Here, AGEs induced CTGF expression in tubular epithelial cells (TECs) that either lacked the TGF-beta1 gene or expressed dominant TGF-beta receptor II, demonstrating independence of TGF-beta. Furthermore, conditional knockout of the gene encoding TGF-beta receptor II from the kidney did not prevent AGE-induced renal expression of CTGF and collagen I. More specific, AGEs induced CTGF expression via the receptor for AGEs-extracellular signal-regulated kinase (RAGE-ERK)/p38 mitogen-activated protein kinase-Smad cross-talk pathway because inhibition of this pathway by several methods (anti-RAGE antibody, specific inhibitors, or dominant negative adenovirus to ERK1/2 and p38) blocked this induction. Overexpressing Smad7 abolished AGE-induced Smad3 phosphorylation and CTGF expression, demonstrating the necessity for activation of Smad signaling in this process. More important, knockdown of either Smad3 or Smad2 demonstrated that Smad3 but not Smad2 is essential for CTGF induction in response to AGEs. In conclusion, AGEs induce tubular CTGF expression via the TGF-beta-independent RAGE-ERK/p38-Smad3 cross-talk pathway. These data suggest that overexpression of Smad7 or targeting Smad3 may have therapeutic potential for diabetic nephropathy.
Bone marrow-derived mesenchymal stem cells (BM-MSCs) have recently shown promise as a therapeutic tool in various types of chronic kidney disease (CKD) models. However, the mechanism of action is ...incompletely understood. As renal prognosis in CKD is largely determined by the degree of renal tubular injury that correlates with residual proteinuria, we hypothesized that BM-MSCs may exert modulatory effects on renal tubular inflammation and epithelial-to-mesenchymal transition (EMT) under a protein-overloaded milieu. Using a co-culture model of human proximal tubular epithelial cells (PTECs) and BM-MSCs, we showed that concomitant stimulation of BM-MSCs by albumin excess was a prerequisite for them to attenuate albumin-induced IL-6, IL-8, TNF-α, CCL-2, CCL-5 overexpression in PTECs, which was partly mediated via deactivation of tubular NF-κB signaling. In addition, albumin induced tubular EMT, as shown by E-cadherin loss and α-SMA, FN and collagen IV overexpression, was also prevented by BM-MSC co-culture. Albumin-overloaded BM-MSCs per se retained their tri-lineage differentiation capacity and overexpressed hepatocyte growth factor (HGF) and TNFα-stimulating gene (TSG)-6 via P38 and NF-κB signaling. Albumin-induced tubular CCL-2, CCL-5 and TNF-α overexpression were suppressed by recombinant HGF treatment, while the upregulation of α-SMA, FN and collagen IV was attenuated by recombinant TSG-6. Neutralizing HGF and TSG-6 abolished the anti-inflammatory and anti-EMT effects of BM-MSC co-culture in albumin-induced PTECs, respectively. In vivo, albumin-overloaded mice treated with mouse BM-MSCs had markedly reduced BUN, tubular CCL-2 and CCL-5 expression, α-SMA and collagen IV accumulation independent of changes in proteinuria. These data suggest anti-inflammatory and anti-fibrotic roles of BM-MSCs on renal tubular cells under a protein overloaded condition, probably mediated via the paracrine action of HGF and TSG-6.
Bone morphogenetic protein 7 (BMP7) has been reported to confer renoprotective effects in acute and chronic kidney disease models, but its potential role in Type 2 diabetic nephropathy remains ...unknown. In cultured human proximal tubular epithelial cells (PTECs), exposure to advanced glycation end-products (AGEs) induced overexpression of intercellular adhesion molecule 1 (ICAM1), monocyte chemoattractant protein 1 (MCP1), interleukin 8 (IL-8) and interleukin 6 (IL-6), involving activation of p44/42 and p38 mitogen-activated protein kinase (MAPK) signalling. BMP7 dose-dependently attenuated AGE-induced up-regulation of ICAM1, MCP1, IL-8 and IL-6 at both mRNA and protein levels. Moreover, BMP7 suppressed AGE-induced p38 and p44/42 MAPK phosphorylation and reactive oxygen species production in PTECs. Compared with vehicle control, uninephrectomized db/db mice treated with BMP7 for 8 weeks had significantly lower urinary albumin-to-creatinine ratio (3549±816.2 μg/mg compared with 8612±2037 μg/mg, P=0.036), blood urea nitrogen (33.26±1.09 mg/dl compared with 37.49±0.89 mg/dl, P=0.006), and renal cortical expression of ICAM1 and MCP1 at both gene and protein levels. In addition, BMP7-treated animals had significantly less severe tubular damage, interstitial inflammatory cell infiltration, renal cortical p38 and p44/42 phosphorylation and lipid peroxidation. Our results demonstrate that BMP7 attenuates tubular pro-inflammatory responses in diabetic kidney disease by suppressing oxidative stress and multiple inflammatory signalling pathways including p38 and p44/42 MAPK. Its potential application as a therapeutic molecule in diabetic nephropathy warrants further investigation.
Abstract
Switchbacks are rapid magnetic field reversals that last from seconds to hours. Current Parker Solar Probe (PSP) observations pose many open questions in regard to the nature of switchbacks. ...For example, are they stable as they propagate through the inner heliosphere, and how are they formed? In this work, we aim to investigate the structure and origin of switchbacks. In order to study the stability of switchbacks, we suppose the small-scale current sheets therein are generated by magnetic braiding, and they should work to stabilize the switchbacks. With more than 1000 switchbacks identified with PSP observations in seven encounters, we find many more current sheets inside than outside switchbacks, indicating that these microstructures should work to stabilize the S-shape structures of switchbacks. Additionally, we study the helium variations to trace the switchbacks to their origins. We find both helium-rich and helium-poor populations in switchbacks, implying that the switchbacks could originate from both closed and open magnetic field regions in the Sun. Moreover, we observe that the alpha-proton differential speeds also show complex variations as compared to the local Alfvén speed. The joint distributions of both parameters show that low helium abundance together with low differential speed is the dominant state in switchbacks. The presence of small-scale current sheets in switchbacks along with the helium features are in line with the hypothesis that switchbacks could originate from the Sun via interchange reconnection process. However, other formation mechanisms are not excluded.
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