A Natural Small Molecule Mitigates Kidney Fibrosis by Targeting Cdc42-mediated GSK-3ß/ß-catenin Signaling.

Kidney fibrosis is a common fate of chronic kidney diseases (CKDs), eventually leading to renal dysfunction. Yet, no effective treatment for this pathological process has been achieved. During the bioassay-guided chemical investigation of the medicinal plant Wikstroemia chamaedaphne, a daphne diterpenoid, daphnepedunin A (DA), is characterized as a promising anti-renal fibrotic lead. DA shows significant anti-kidney fibrosis effects in cultured renal fibroblasts and unilateral ureteral obstructed mice, being more potent than the clinical trial drug pirfenidone. Leveraging the thermal proteome profiling strategy, cell division cycle 42 (Cdc42) is identified as the direct target of DA. Mechanistically, DA targets to reduce Cdc42 activity and down-regulates its downstream phospho-protein kinase Cζ(p-PKCζ)/phospho-glycogen synthase kinase-3ß (p-GSK-3ß), thereby promoting ß-catenin Ser33/37/Thr41 phosphorylation and ubiquitin-dependent proteolysis to block classical pro-fibrotic ß-catenin signaling. These findings suggest that Cdc42 is a promising therapeutic target for kidney fibrosis, and highlight DA as a potent Cdc42 inhibitor for combating CKDs.

The Differential Diagnostic Value of Radiomics Signatures Between Single-Nodule Pulmonary Metastases and Second Primary Lung Cancer in Patients with Colorectal Cancer.

BACKGROUND: Differential diagnosis of single-nodule pulmonary metastasis (SNPM) and second primary lung cancer (SPLC) in patients with colorectal cancer (CRC) prior to lung surgery is relatively complex. Radiomics is an emerging technique for image information analysis, while it has not yet been applied to construct a differential diagnostic model between SNPM and SPLC in patients with CRC. In the present study, we aimed to extract radiomics signatures from thin-section computed tomography (CT) images of the chest. These radiomics signatures were combined with clinical features to construct a composite differential diagnostic model. METHOD: A total of 91 patients with CRC, including 66 patients with SNPM and 25 patients with SPLC, were enrolled in this study. Patients were randomly assigned to the training cohort (n = 63) and validation cohort (n = 28) at a ratio of 7 to 3. Moreover, 107 radiomics features were extracted from the chest thin-section CT images. The least absolute shrinkage and selection operator (LASSO) regression was used to filter these features, and clinical features were screened by univariate analysis. The screened radiomics and clinical features were combined to construct a multifactorial logistic regression composite model. The receiver operating characteristic (ROC) curves were adopted to evaluate the models, and the corresponding nomograms were created. RESULTS: A series of 6 radiomics characteristics was screened by LASSO. After univariate logistic regression analysis, the composite model finally included 4 radiomics features and 4 clinical features. In the training cohort, the area under the curve scores of ROC curves were 0.912 (95% confidence interval [CI]: 0.813-0.969), 0.884 (95% CI: 0.778-0.951), and 0.939 (95% CI: 0.848-0.984) for models derived from radiomics, clinical, and combined features, respectively. Similarly, these values were 0.756 (95% CI: 0.558-0.897), 0.888 (95% CI: 0.711-0.975), and 0.950 (95% CI: 0.795-0.997) in the validation cohort, respectively. CONCLUSIONS: We constructed a model for differential diagnosis of SNPM and SPLC in patients with CRC using radiomics and clinical features. Moreover, our findings provided a new assessment tool for patients with CRC in the future.

TLR7 in B cells promotes renal inflammation and Gd-IgA1 synthesis in IgA nephropathy.

TLR7 has been linked to the pathogenesis of glomerulonephritis, but its precise roles are not clear. In this study, we evaluated the roles of TLR7 in IgA nephropathy (IgAN). TLR7 proteins were abundant in CD19+ B cells infiltrated in the kidneys of patients with IgAN. The intensities of both intrarenal TLR7 and CD19 proteins were closely associated with kidney function (estimated glomerular filtration rate [eGFR] and serum creatinine concentration) and renal histopathology (tubular atrophy, leukocyte infiltration, tubulointerstitial fibrosis, and global glomerulosclerosis) in patients with IgAN. Meanwhile, TLR7 mRNA levels were significantly increased in peripheral blood B cells of patients with IgAN. TLR7+CD19+ B cells expressed inflammatory cytokines (IL-6 and IL-12) in kidneys and produced high levels of IgA1 and galactose deficient-IgA1 (Gd-IgA1) in peripheral blood of patients with IgAN. Mechanistically, TLR7 activated B cells to produce high levels of Gd-IgA1 via the TLR7-GALNT2 axis in IgAN. Protein levels of GALNT2 were increased by overexpression of TLR7, while they were reduced by TLR7 knockdown in B cells. GALNT2 overexpression augmented Gd-IgA1 production in B cells derived from patients with IgAN. Taken together, high TLR7 expression in B cells has dual roles in the development and progression of IgAN, by facilitating renal inflammation and Gd-IgA1 antibody synthesis.

Evaluation of the early response and mechanism of treatment of Parkinson's disease with L-dopa using 18F-fallypride micro-positron emission tomography scanning.

The aim of the present study was to investigate the use of 18F-fallypride micro-positron emission tomography (micro-PET) imaging in the evaluation of the early therapeutic efficacy of L-dopa in the treatment of Parkinson's disease (PD) and the underlying mechanism. 18F-fallypride was synthesized and its specific binding with dopamine (DA) receptors in normal mouse brain was studied. Following the establishment of a mouse model of PD, the animals were divided into normal control, PD model and L-dopa treatment groups. General behavior, swimming test, locomotor activity counts, transmission electron microscopy, immunohistochemical analysis, high performance liquid chromatography-electrochemical detection and 18F-fallypride micro-PET imaging were used to study intergroup differences and the correlation between the changes of striatal uptake of 18F-fallypride and the therapeutic efficacy. The general behavioral features of PD model mice were similar to the clinical symptoms of PD patients and were alleviated after treatment. The swimming time, locomotor activity and frequency of standing posture of PD model mice were lower than those of the control mice, but had no difference from those of the control mice after L-dopa treatment. The number of tyrosine hydroxylase-positive neurons and the striatal contents of glutathione peroxidase, superoxide dismutase, DA and its metabolites 3,5-dihydroxyphenylacetic acid and homovanillic acid in the PD group were lower than those in the control group, but were significantly improved following the treatment; the significant reduction in DOPAC/DA and HVA/DA ratios post treatment suggested that the rate of DA metabolism decreased significantly. The striatal malondialdehyde content in the PD group increased compared with that in the control group, but was reduced after L-dopa treatment. Micro-PET imaging indicated that the uptake of 18F-fallypride in the mouse striatum of the PD group was lower than that of the control group and was significantly increased after the treatment. The mechanism of treatment of PD with L-dopa in mice may involve increasing the number of TH-positive cells and DA receptor levels, as well as reducing the rate of DA metabolism; such changes can be noninvasively observed in vitro by 18F-fallypride imaging.

High glucose concentrations in peritoneal dialysate are associated with all-cause and cardiovascular disease mortality in continuous ambulatory peritoneal dialysis patients.

BACKGROUND: The effect of high peritoneal dialysate glucose concentration (PDGC) on all-cause and cardiovascular disease (CVD) mortality in peritoneal dialysis (PD) patients is unclear. OBJECTIVE: Our study aimed to investigate the effect of high PDGC on all-cause and CVD mortality in continuous ambulatory PD (CAPD) patients. METHODS: The study enrolled 716 patients newly initiated on CAPD therapy between January 2006 and December 2010. We allocated the patients to low (< 1.56%), medium (≥ 1.56% to < 1.74%), and high (≥ 1.74%) average PDGC groups according to the tertile of average PDGC in the first 6 months after PD initiation. Cox regression and ordinal logistic regression were used to analyze determinants of mortality and of PDGC use respectively. RESULTS: Mean follow-up in the study cohort was 31 ± 15 months. The all-cause mortality was 4.7 events per 100 patient-years, and the leading cause of death was CVD. Patients with a higher PDGC had significantly higher cumulative rates of all-cause (log-rank p < 0.001) and CVD mortality (log-rank p < 0.001). In Cox regression analysis, high PDGC independently predicted higher all-cause (hazard ratio: 2.63; p = 0.004) and CVD mortality (hazard ratio: 2.78; p = 0.01). Compared with a lower PDGC, a higher PDGC was significantly associated with older age [odds ratio (OR): 1.02; p < 0.001], low residual renal function (OR: 0.91; p < 0.001), and high dialysate-to-plasma ratio of creatinine (OR: 28.61; p < 0.001) in ordinal logistic regression. CONCLUSIONS: Higher PDGC is associated with higher allcause and CVD mortality in CAPD patients.

Prevalence and risk factors of CKD in Chinese patients with periodontal disease.

BACKGROUND: Periodontal disease is common among adults and is associated with an increasing risk of chronic kidney disease (CKD). We aimed to investigate the prevalence and risk factors of CKD in patients with periodontal disease in China. METHODS: In the current cross-sectional study, patients with periodontal disease were included from Guangdong Provincial Stomatological Hospital between March 2011 and August 2011. CKD was defined as estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m(2), the presence of albuminuria, or hematuria. All patients with periodontal disease underwent a periodontal examination, including periodontal probing pocket depth, gingival recession, and clinical attachment level by Florida Probe. They completed a questionnaire and had blood and urine samples taken. The adjusted prevalence of indicators of kidney damage was calculated and risk factors associated with CKD were analyzed. RESULTS: A total of 1392 patients with periodontal disease were invited to participate this study and 1268 completed the survey and examination. After adjusting for age and sex, the prevalence of reduced eGFR, albuminuria, and hematuria was 2.7% (95% CI 1.7-3.7), 6.7% (95% CI 5.5-8.1) and 10.9% (95% CI 9.2-12.5), respectively. The adjusted prevalence of CKD was 18.2% (95% CI 16.2-20.3). Age, male, diabetes, hypertension, history of CKD, hyperuricemia, and interleukin-6 levels (≥7.54 ng/L) were independent risk factors for reduced eGFR. Female, diabetes, hypertension, history of CKD, hyperuricemia, high level of cholesterol, and high sensitivity C-reactive protein (hsCRP) (≥ 1.03 mg/L) and TNF-α levels (≥ 1.12 ng/L) were independently associated with an increased risk of albuminuria. Female, lower education (

High prevalence and associated risk factors for impaired renal function and urinary abnormalities in a rural adult population from southern China.

BACKGROUND: The prevalence of chronic kidney disease (CKD) has increased and will continue to rise worldwide. However, data regarding the prevalence of CKD in a rural area of China are limited. We therefore investigated the prevalence and associated risk factors of impaired renal function and urinary abnormalities in an adult rural population in southern China. METHODS: Between December 2006 and January 2007, residents older than 20 years from four villages in Zhuhai city were randomly selected using a stratified, multistage sampling technique. All participants were interviewed and tested for hematuria, albuminuria and estimated glomerular filtration rate (eGFR). The associations between age, gender, diabetes mellitus, hypertension, hyperuricemia, education level and indicators of renal damage were examined. RESULTS: Overall, 1,214 subjects were enrolled in this study. After adjustment for age and gender, the prevalence of albuminuria was 7.1% (95% CI: 4.5, 8.1), reduced eGFR was 2.6% (95% CI: 1.7%, 3.3%), and hematuria was 4.6% (95% CI: 3.3%, 6.0%). Approximately 13.6% (95% CI: 12.0%, 15.1%) of the patients had at least one indicator of renal damage, but only 8.3% were previously aware. Age, diabetes, hyperlipidemia, hypertension, hyperuricemia, use of nephrotoxic medications, coronary heart disease and history of CKD were independently associated with impaired renal function and urinary abnormalities. Additionally, age, diabetes, and hypertension were independently associated with albuminuria. Age, hypertension, hyperuricemia, central obesity, and coronary heart disease were independently associated with reduced renal function. CONCLUSIONS: The high prevalence and low awareness of impaired renal function and urinary abnormalities in this population illustrates the urgent need to implement a CKD prevention program in the rural areas of southern China.

Prevalence and risk factors of chronic kidney disease in first-degree relatives of chronic kidney disease patients in Southern China.

AIM: The aim of this study was to estimate the prevalence and risk factors of chronic kidney disease (CKD) in first-degree relatives (FDRs) of CKD patients. METHODS: A cross-section study of first-degree relatives of CKD patients was conducted between November 2007 and March 2009 in southern China. A total of 1187 first-degree relatives (494 male and 693 female; mean age 41.26 years) of 419 CKD patients (194 male and 225 female; mean age 32.10 years) were reviewed and tested for haematuria, albuminuria and reduced glomerular filtration rate. CKD risk factors, including age, gender, body mass index, hypertension and the causes of index case were also investigated. CKD was diagnosed according to the criteria of the National Kidney Foundation-Kidney Disease Outcomes Quality Initiative. RESULTS: The prevalence of CKD in first-degree relatives of CKD patients was 29.7% (95% confidence interval [CI]: 27.1%-32.2%). After adjusting for all the potential confounders, older age, female gender, hypertension, hyperglycaemia, hyperuricaemia, hypertriglyceridemic, low level of high density lipoproteins, increased body mass index and nephrotoxic medications were independently associated with increased risk of CKD. Furthermore, relatives of index cases with chronic glomerulonephritis were at higher risk haematuria (ORs = 2.12, 95% CI: 1.45-3.10) compared with relatives of index cases with other kinds of renal diseases. CONCLUSION: The first-degree relatives of CKD patients are at high risk of CKD, especially those relatives of CKD patients with chronic glomerulonephritis. Screening in this high risk population might help to identify early CKD patients and make a proper intervention strategy to prevent the disease from quick progression.

Prevalence and risk factors of chronic kidney disease: a population study in the Tibetan population.

BACKGROUND: The prevalence of chronic kidney disease (CKD) at high altitude is not known. We conducted a population-based survey in Tibet to identify the prevalence and associated risk factors of CKD in subjects living at altitudes of > 3500 m. METHODS: One thousand two hundred and eighty-nine Tibetans (≥ 18 years) from four districts of Lhasa city (altitude 3658 m) and eight villages of Dangxiong County (altitude 4200 m) were interviewed and tested for haematuria, albuminuria and estimated glomerular filtration rate (eGFR). RESULTS: The adjusted prevalence of hypertension, albuminuria, haematuria and reduced eGFR were 38.8% (95% CI: 36.2-41.5%), 16.2% (95% CI: 14.1-18.2%), 3.9% (95% CI: 2.8-4.9%) and 2.1% (95% CI: 1.3-2.9%), respectively. Both the presence of hypertension and the presence of albuminuria were strongly and independently associated with hyperuricaemia and elevated haematocrit. CONCLUSIONS: This is the first population-based epidemiological study of CKD in the Tibetan population. We found a higher prevalence of CKD and associated high prevalence of albuminuria, hypertension, hyperuricaemia and high haematocrit in the Tibetan population. The present study indicates the urgent need to develop comprehensive strategies targeted at reducing the CKD burden in this area and may lead to a better understanding of CKD in high-altitude populations.

Prevalence and risk factors associated with chronic kidney disease in an adult population from southern China.

BACKGROUND: Population-based studies evaluating the prevalence of kidney damage in different communities have been limited in developing countries. We conducted a population-based screening study in the southern Chinese city of Guangzhou that aimed to identify the prevalence and associated risk factors of chronic kidney disease (CKD) in southern Chinese populations. METHODS: We interviewed 6311 residents (>20 years) from six districts of Guangzhou from July 2006 to June 2007 and tested for haematuria, albuminuria and reduced renal function. Associations between age, gender, smoking, diabetes mellitus, hypertension, hyperuricaemia and kidney damage were examined. RESULTS: There were 6311 subjects enrolled in this study. After adjustment for age and gender, the prevalence of albuminuria, haematuria and reduced estimated glomerular filtration rate (eGFR) was 6.6% [95% confidence interval (CI): 5.5-7.6%], 3.8% (95% CI: 3.4%, 4.3%) and 3.2% (95% CI: 2.4%, 3.3%), respectively. Approximately 12.1% (95% CI: 11.3%, 12.9%) of the sample population had at least one indicator of kidney damage. Age, diabetes mellitus, hypertension, central obesity, hyperlipidaemia and use of nephrotoxic medications were independently associated with albuminuria; hyperuricaemia, age, gender, hypertension and use of nephrotoxic medications were independently associated with reduced eGFR, and female gender was independently associated with haematuria. CONCLUSIONS: In the general adult population from southern China, 12.1% has either proteinuria, haematuria and/or reduced eGFR, indicating the presence of kidney damage, with an awareness of only 9.6%. The high prevalence and low awareness of CKD in this population suggest an urgent need for CKD prevention programmes in China.

[Inhibitory effect of melatonin on the expression of nuclear factor-kappaB during acute lung injury in rats].

OBJECTIVE: To investigate the protective effect of melatonin (MT) on lung tissue during acute lung injury (ALI) in rats and its possible mechanism. METHODS: Ninety-six Sprague-Dawley (SD) rats were randomly divided into four groups: control group, lipopolysaccharide (LPS) group, dexamethasone (DEX) and MT treatment group, with 24 rats in each group. Rat model of ALI was established by instilling LPS intratracheally, and DEX and MT were injected intraperitoneally. All rats in each group were sacrificed at 3, 6 and 12 hours after intratracheal instillation of LPS, and lung tissue samples were harvested. Myeloperoxidase (MPO) activity, superoxide dismutase (SOD) activity and malondialdehyde (MDA) contents in lung tissue samples were detected in each group. In addition, the expression of nuclear factor-kappaB (NF-kappaB) was assessed with immunohistochemistry staining in lung tissues. RESULTS: Compared with control group, SOD activity in LPS group decreased at different time points significantly (P<0.05 or P<0.01), but MPO activity, MDA content and the expression of NF-kappaB increased obviously (P<0.05 or P<0.01); the administration of MT and DEX could mitigate above values significantly (P<0.05 or P<0.01). The changes in above each indexes were most obvious at 6 hours, either reaching the peak or the trough, respectively. CONCLUSION: MT possesses protective effect on lung tissues during ALI through scavenging free radicals and inhibiting the activation of NF-kappaB.

[Protective effect of endogenous carbon monoxide on organs during septic shock in rat and its mechanisms].

OBJECTIVE: To study the protective effect of endogenous carbon monoxide (CO) on lung and liver during septic shock in rat and its mechanism. METHODS: Septic shock model was replicated by cecal ligation and puncture (CLP). Ninety-six rats were randomly divided into sham operation group, CLP group, CLP+ hemin (Hm) group and CLP+zinc protoporphyrin (ZnPP) group. The carboxyhemoglobin (COHb) levels of in-flowing pulmonary blood (IPB) and out-going pulmonary blood (OPB) were determined at 2, 4 and 6 hours after treatments. Malondialdehyde (MDA) contents and superoxide dismutase (SOD) activities in the lung, liver and blood were also determined. Pathological changes in lung and liver were examined with light microscope, and immunohistochemical technique was used for analysis of heme oxygenase-1 (HO-1) protein expression and distribution in lung and liver. RESULTS: Compared with sham operation group, the COHb level in OPB and IPB as well as MDA contents of lung, liver and blood significantly increased in CLP group, while the SOD activities significantly decreased at different time points (P<0.05 or P<0.01), and the pathological changes and expressions of HO-1 in two tissues were more marked. However, in CLP+Hm group the results of MDA, SOD activities and pathological changes were reversed. The content of COHb increased compared to those of CLP group. Immunohistochemical studies showed that there were more HO-1 positive deposits in CLP+Hm group than those in CLP group. CONCLUSION: Increase in endogenous CO may play a protective role in lung and liver during septic shock.

[Protective role of endogenous carbon monoxide to lung and kidney tissues during septic shock].

AIM: To study the protective role of endogenous carbon monoxide to lung and kidney tissues during septic shock and its mechanism. METHODS: A rat model of CLP was built by using the method of CLP. The malondialdehyde (MDA) content and the activity of superoxide dematase (SOD) in blood, lung and kidney were detected by immunohistochemical technique and light microscope. RESULTS: Pathological changes of lung and kidney in CLP + Hemin group were lighter than CLP group, inflammatory reaction and lipid peroxidation were also lighter. CONCLUSION: Endogenous CO can protect lung and kidney from the oxidative injury. It can suppress in flammation and the oxidative injury caused by activated inflammatory cells, it is probably an important mechanism of its protective effects.