Caffeic acid phenethyl ester restores mitochondrial homeostasis against peritoneal fibrosis induced by peritoneal dialysis through the AMPK/SIRT1 pathway.

Increasing evidence suggests that peritoneal fibrosis induced by peritoneal dialysis (PD) is linked to oxidative stress. However, there are currently no effective interventions for peritoneal fibrosis. In the present study, we explored whether adding caffeic acid phenethyl ester (CAPE) to peritoneal dialysis fluid (PDF) improved peritoneal fibrosis caused by PD and explored the molecular mechanism. We established a peritoneal fibrosis model in Sprague-Dawley rats through intraperitoneal injection of PDF and lipopolysaccharide (LPS). Rats in the PD group showed increased peritoneal thickness, submesothelial collagen deposition, and the expression of TGFß1 and α-SMA. Adding CAPE to PDF significantly inhibited PD-induced submesothelial thickening, reduced TGFß1 and α-SMA expression, alleviated peritoneal fibrosis, and improved the peritoneal ultrafiltration function. In vitro, peritoneal mesothelial cells (PMCs) treated with PDF showed inhibition of the AMPK/SIRT1 pathway, mitochondrial membrane potential depolarization, overproduction of mitochondrial reactive oxygen species (ROS), decreased ATP synthesis, and induction of mesothelial-mesenchymal transition (MMT). CAPE activated the AMPK/SIRT1 pathway, thereby inhibiting mitochondrial membrane potential depolarization, reducing mitochondrial ROS generation, and maintaining ATP synthesis. However, the beneficial effects of CAPE were counteracted by an AMPK inhibitor and siSIRT1. Our results suggest that CAPE maintains mitochondrial homeostasis by upregulating the AMPK/SIRT1 pathway, which alleviates oxidative stress and MMT, thereby mitigating the damage to the peritoneal structure and function caused by PD. These findings suggest that adding CAPE to PDF may prevent and treat peritoneal fibrosis.

Outcomes of elderly peritoneal dialysis patients: 65-74 years old versus ≥ 75 years old.

OBJECTIVE: To analyze the clinical data of elderly patients with peritoneal dialysis (PD) and compare patient and technique survival rates between Group 1 (65-74 years old) and Group 2 (≥75 years old). METHODS: This retrospective study enrolled 296 elderly patients (≥65 years old) on maintenance PD who were admitted to the Peritoneal Dialysis Center of the Second Hospital of Soochow University. The patients were categorized by outcome into ongoing PD, changed to hemodialysis, renal recovery dialysis stopped, or death groups. The patients were divided into Group 1 (65-74 years old) and Group 2 (≥75 years old). Patient survival and technique survival rates were calculated by the Kaplan-Meier method. Factors associated with patient survival were analyzed using the Cox regression model. RESULTS: There were 176 (59.5%) subjects in Group 1 and 120 (40.5%) subjects in Group 2. The primary causes of death were cardiovascular events, peritonitis, and other infections. The patient survival rates at 1, 3, and 5 years were 91.2%, 68.0%, and 51.3% in Group 1 and 76.8%, 37.5%, and 17.6% in Group 2 (p < 0.001, HR 0.387, 95% CI 0.282-0.530). There was no statistically significant difference in the technique survival rate between the two groups (p = 0.54). CONCLUSION: The elderly PD patients in this cohort mostly died from cardiovascular events, with a higher patient survival rate in Group 1 and similar technique survival in both groups. Older age, lower prealbumin, higher creatinine, not being on activated vitamin D, and high Charlson's comorbidity index (CCI) score were independent risk factors for death.

Activated cathepsin L is associated with the switch from autophagy to apoptotic death of SH-SY5Y cells exposed to 6-hydroxydopamine.

Autophagy and apoptosis are common responses to pathological damage in the process of Parkinson's disease (PD), and lysosome dysfunction may contribute to the etiology of PD's neurodegenerative process. In this study, we demonstrated that the neurotoxin 6-hydroxydopamine (6-OHDA) increased autophagy in SH-SY5Y cells, as determined by detection of the lysosome marker lysosomal-associated membrane protein1, the autophagy protein light chain 3 (LC3)-II and the autophagy substrate P62 protein. Meanwhile, autophagy repression with 3-methyladenine accelerated the activation of caspase-3 and PARP and aggravated the cell apoptotic death induced by 6-OHDA. Furthermore, we found that 6-OHDA treatment resulted in a transient increase in the intracellular and nuclear expression of cathepsin L (CTSL). The CTSL inhibitor, Z-FY-CHO, could promote autophagy, decrease accumulation of P62, and block activation of caspase-3 and PARP. Taken together, these results suggest that activation of autophagy may primarily be a protective process in SH-SY5Y cell death induced by 6-OHDA, and the nuclear translocation of CTSL could enhance the cell apoptotic cascade via disturbing autophagy-apoptotic systems in SH-SY5Y cells. Our findings highlight the potential role of CTSL in the cross talk between autophagy and apoptosis, which might be considered a therapeutic strategy for treatment of pathologic conditions associated with neurodegeneration.

Parkinson's Disease rs117896735 Variant Regulates INPP5F Expression in Brain Tissues and Increases Risk of Alzheimer's Disease.

BACKGROUND: Both INPP5D and INPP5F are members of INPP5 family. INPP5F rs117896735 variant was associated with Parkinson's disease (PD) risk, and INPP5D was an Alzheimer's disease (AD) risk gene. However, it remains unclear about the roles of INPP5F rs117896735 variant in AD. OBJECTIVE: We aim to investigate the roles of rs117896735 in AD. METHODS: First, we conducted a candidate variant study to evaluate the association of rs117896735 variant with AD risk using the large-scale AD GWAS dataset. Second, we conducted a gene expression analysis of INPP5F to investigate the expression difference of INPP5F in different human tissues using two large-scale gene expression datasets. Third, we conducted an expression quantitative trait loci analysis to evaluate whether rs117896735 variant regulate the expression of INPP5F. Fourth, we explore the potentially differential expression of INPP5F in AD and control using multiple AD-control gene expression datasets in human brain tissues and whole blood. RESULTS: We found that 1) rs117896735 A allele was associated with the increased risk of AD with OR = 1.15, 95% CI 1.005-1.315, p = 0.042; 2) rs117896735 A allele could increase INPP5F expression in multiple human tissues; 3) INPP5F showed different expression in different human tissues, especially in brain tissues; 4) INPP5F showed significant expression dysregulation in AD compared with controls in human brain tissues. CONCLUSION: Conclusion: We demonstrate that PD rs117896735 variant could regulate INPP5F expression in brain tissues and increase the risk of AD. These finding may provide important information about the role of rs117896735 in AD.

Educational Attainment and Ischemic Stroke: A Mendelian Randomization Study.

Observational studies have evaluated the potential association of socioeconomic factors such as higher education with the risk of stroke but reported controversial findings. The objective of our study was to evaluate the potential causal association between higher education and the risk of stroke. Here, we performed a Mendelian randomization analysis to evaluate the potential association of educational attainment with ischemic stroke (IS) using large-scale GWAS datasets from the Social Science Genetic Association Consortium (SSGAC, 293,723 individuals), UK Biobank (111,349 individuals), and METASTROKE consortium (74,393 individuals). We selected three Mendelian randomization methods including inverse-variance-weighted meta-analysis (IVW), weighted median regression, and MR-Egger regression. IVW showed that each additional 3.6-year increase in years of schooling was significantly associated with a reduced IS risk (OR = 0.54, 95% CI: 0.41-0.71, and p = 1.16 × 10-5). Importantly, the estimates from weighted median (OR = 0.49, 95% CI: 0.33-0.73, and p = 1.00 × 10-3) and MR-Egger estimate (OR = 0.18, 95% CI: 0.06-0.60, and p = 5.00 × 10-3) were consistent with the IVW estimate in terms of direction and magnitude. In summary, we provide genetic evidence that high education could reduce IS risk.

Pharmacological Modulation of Nrf2/HO-1 Signaling Pathway as a Therapeutic Target of Parkinson's Disease.

Parkinson's disease (PD) is a complex neurodegenerative disorder featuring both motor and nonmotor symptoms associated with a progressive loss of dopaminergic neurons in the substantia nigra pars compacta. Oxidative stress (OS) has been implicated in the pathogenesis of PD. Genetic and environmental factors can produce OS, which has been implicated as a core contributor to the initiation and progression of PD through the degeneration of dopaminergic neurons. The transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2) orchestrates activation of multiple protective genes, including heme oxygenase-1 (HO-1), which protects cells from OS. Nrf2 has also been shown to exert anti-inflammatory effects and modulate both mitochondrial function and biogenesis. Recently, a series of studies have reported that different bioactive compounds were shown to be able to activate Nrf2/antioxidant response element (ARE) and can ameliorate PD-associated neurotoxin, both in animal models and in tissue culture. In this review, we briefly overview the sources of OS and the association between OS and the pathogenesis of PD. Then, we provided a concise overview of Nrf2/ARE pathway and delineated the role played by activation of Nrf2/HO-1 in PD. At last, we expand our discussion to the neuroprotective effects of pharmacological modulation of Nrf2/HO-1 by bioactive compounds and the potential application of Nrf2 activators for the treatment of PD. This review suggests that pharmacological modulation of Nrf2/HO-1 signaling pathway by bioactive compounds is a therapeutic target of PD.

Serum Calcium Levels and Parkinson's Disease: A Mendelian Randomization Study.

BACKGROUND: Though increasing epidemiological studies have evaluated the correlation between serum calcium contents and Parkinson's disease (PD), the results are inconsistent. At present, whether there is a causal association between serum calcium content and PD remains undetermined. OBJECTIVE AND METHODS: This study was designed to explore the relationship between increased serum calcium contents and PD risk. In this present study, a Mendelian randomization trial was carried out using a large-scale serum calcium genome-wide association study (GWAS) dataset (N = 61,079, Europeans) and a large-scale PD GWAS dataset (N = 8,477, Europeans including 4,238 PD patients and 4,239 controls). Here, a total of four Mendelian randomization methods comprising weighted median, inverse-variance weighted meta-analysis (IVW), MR-Egger, and MR-PRESSO were used. RESULTS: Our data concluded that genetically higher serum calcium contents were not significantly related to PD. CONCLUSION: In conclusion, we provided genetic evidence that there was no direct causal relationship between serum calcium contents and PD. Hence, calcium supplementation may not result in reduced PD risk.

[Image identification for microscopic structures of Mongolian herbal flowers with invariant moments].

Microscopic characteristics of several Mongolian Herbal flowers were extracted by improved Pseudo-Jacobi (p = 4, q = 2)-Fourier Moments (PJFM's), and 368 different versions of 28 microscopic characteristics of these herbs were identified by using the minimum-mean-distance rule. The experimental results showed that the average identification rate reaches as high as 98.1%. Therefore, this study can provide new techniques for digitalization and visualization of microscopic characteristics of Mongolian Herbs.

Hydrogen sulfide inhibits epithelial-mesenchymal transition in peritoneal mesothelial cells.

Peritoneal fibrosis (PS) determines the long-term outcome of peritoneal dialysis (PD). We previous confirmed that hydrogen sulfide (H2S) inhibited PS, but its cellular mechanism was not fully elucidated. Epithelial-mesenchymal transition (EMT) of mesothelial cells (MCs) is an important cellular event of PS, we therefore investigated whether EMT can be affected by H2S in MCs. Rats were treated with 4.25% -glucose PD fluids plus lipopolysaccharide for 28 days to produce PS, and NaHS (56 µg/kg.d) was given simultaneously. NaHS (56 µg/kg.d) reduced the deposition of collagen in the submesothelial zone compared with the PS group. In primarily cultured rat MCs, 4.25% -glucose PD fluid induced EMT in MCs featured as loss of ZO-1 and Cytokeratin, and increase of α-SMA, plasminogen activator inhibitor 1, fibronectin and TGF-ß1 proteins. PD fluid also increased IL-6 and monocyte chemotactic protein-1 mRNA expressions as well as the phosphorylation of Smad2/3 and Smad3. NaHS (50-300 µmol/L) reversed the above alterations with the optimal dose at 100 µmol/L. Thus, exogenous H2S improves PS by inhibiting EMT in MCs. The anti-EMT effect of H2S is associated with the inhibition of inflammation and TGF-ß1-Smad signal pathway.

The protective effect of hydrogen sulfide on systemic sclerosis associated skin and lung fibrosis in mice model.

BACKGROUD: Systemic sclerosis (SSc) caused fibrosis can be fatal and it still lack of effective treatment. Hydrogen sulfide (H2S) appears to be an attractive therapeutic candidates. This study aimed to investigate the protective effect of H2S on SSc-associated skin and lung fibrosis. METHODS: We developed a model of SSc by subcutaneous injecting BLM to female C3H mice. The mice received daily subcutaneous injections of NaHS (56 and 112 µg/kg), an H2S donor. On days 7, 28, and 42, the mice were killed and blood samples were collected to measure the plasma H2S concentration, the skin and lung tissues was harvested for microscopic examination, immunohistochemistry and quantify biological parameters (hydroxyproline content, RT-qPCR and Western blot). RESULTS: In model group, the dermis of skin tissues at different time points gradually thickened, collagen deposition increased. The lung tissues presented pathological changes such as obvious inflammatory cell infiltration, increased collagen deposition and the plasma H2S concentrations points significantly decreased. Administration of NaHS markedly decreased the biomarkers of fibrosis such as α-smooth muscle actin, collagen-I, collagen-III, fibronectin, transforming growth factor-ß1, Smad2/3 phosphorylation and inflammation including the marker protein of monocyte/macrophage and monocyte chemoattractant protein-1 in the lung. Compared to the low dose group, the expression in the high dose group have decreased trend, but the difference was not significant. CONCLUSION: We demonstrate the beneficial effects of H2S on SSc-associated skin and lung fibrosis. H2S may be a potential therapy against this intractable disease.

Hydrogen Sulfide Alleviates Peritoneal Fibrosis via Attenuating Inflammation and TGF-ß1 Synthesis.

BACKGROUND/AIMS: Peritoneal fibrosis is one of the long-term complications in peritoneal dialysis (PD) patients. Recent evidences have suggested that hydrogen sulfide (H2S) is beneficial in treating various fibrotic diseases, including pulmonary fibrosis, cirrhosis, kidney fibrosis and cardiac hypertrophy. However, no information is known about the effect of H2S on peritoneal fibrosis. In the present study, we investigated the effect of H2S on peritoneal fibrosis and explored its potential mechanisms. METHODS: We developed a model of peritoneal fibrosis by intraperitoneally injecting 4.25%-glucose PD fluids and lipopolysaccharide to Sprague-Dawley rats. The rats received daily intraperitoneal injections of NaHS (56 µg/kg), an H2S donor. After 28 days, the peritoneal equilibration test (PET) was used to assess peritoneal function. At the end of dialysis, the rats were killed and parietal peritoneum was harvested for microscopic examination and immunohistochemistry. RESULTS: On the 28th day, the parietal peritoneum of the PD rats markedly thickened as a result of increased depositions of type III collagen and fibronectin. Moreover, the number of ED-1-positive cells and the expressions of monocyte chemoattractant protein-1, transforming growth factor-ß1 (TGF-ß1), α-smooth muscle actin and CD31 were significantly increased in the fibrotic peritoneum. Administration of NaHS markedly decreased the biomarkers of inflammation, fibrosis and angiogenesis in the peritoneum. NaHS also improved peritoneal function assessed by PET. CONCLUSION: Exogenous H2S ameliorates the pathologic process of peritonitis via attenuating inflammatory events and TGF-ß1 synthesis. These results suggest that H2S may be a potential therapy against peritoneal fibrosis during chronic PD. In the future, compounds releasing H2S at controlled rate will be assessed as potential candidates to treat peritoneal fibrosis.

The effect of renin-angiotensin system inhibitors on intact parathyroid hormone levels in peritoneal dialysis patients.

HYPOTHESIS/INTRODUCTION: The objective of this article is to investigate the effect of renin-angiotensin system inhibitors (RASIs) on intact parathyroid hormone (iPTH) levels in continuous ambulatory peritoneal dialysis (CAPD) patients. MATERIALS AND METHODS: All patients were divided into RASI-treated and non-treated groups. The relationships between the iPTH levels in CAPD patients and the clinical parameters and medication use were analyzed via linear regression. RESULTS: A total of 149 CAPD patients were included in this study. The average iPTH level of the entire group was 189.4 pg/ml (range, 102.8-373.4 pg/ml). There were 79 (53.0%) and 70 (47.0%) cases in the RASI-treated and non-treated groups, respectively, with average iPTH levels of 139.0 pg/ml (range, 91.6-258.4 pg/ml) and 253.0 pg/ml (range, 134.3-467.2 pg/ml), respectively; this difference was statistically significant (p = 0.001). Multilinear regression analysis showed that age, dialysis vintage, serum phosphatemia, ALP, Hb and RASI use were independent factors that were associated with iPTH level. CONCLUSION: RASI use may be associated with a lower iPTH level in CAPD patients, although the underlying mechanism requires further study.

Anti-inflammatory effects of vinpocetine on the functional expression of nuclear factor-kappa B and tumor necrosis factor-alpha in a rat model of cerebral ischemia-reperfusion injury.

OBJECTIVE: The restoration of blood flow to the brain after ischemic stroke prevents further, extensive damage but can result in reperfusion injury. The inflammation response is one of many factors involved in cerebral ischemia-reperfusion injury. This study investigated the use of vinpocetine, a drug used to treat cognitive impairment, to explore its effects on inflammation in a rat model of cerebral ischemia-reperfusion. METHODS: Wistar rats were randomly assigned to a control group, (n=40) a cerebral ischemia-reperfusion group (n=52) and a vinpocetine cerebral ischemia-reperfusion group (n=52). A model of middle cerebral artery occlusion was induced for 2h followed by reperfusion and the infarct size was determined by 2,3,5-triphenyltetrazolium chloride (TTC) staining 6h, 24h, 3 days, and 7 days after reperfusion. The dry-wet weight method was used to measure brain water content and evaluate the extent of brain edema. Immunohistochemistry and in-situ hybridization were used to detect the expression of NF-κB and TNF-α. RESULTS: The NF-κB levels in ischemic brain tissue increased 6h after reperfusion and the TNF-α levels increased at 24h, both reached their peaks at day 3 then decreased gradually, but remained above the controls at day 7. Vinpocetine decreased the levels of NF-κB and TNF-α 24h and 3 days after reperfusion. CONCLUSION: NF-κB and TNF-α is associated with changes in brain edema and infarct volume. Vinpocetine decreases the expression of NF-κB and TNF-α and inhibits the inflammatory response after cerebral ischemia-reperfusion.