Comparative clinical outcomes and predictive biomarkers of sintilimab combinations vs. single therapy in cancer: a systematic review and meta-analysis of randomized controlled trials.

OBJECTIVE: This study aimed to compare the efficacy and safety between sintilimab combinations and single treatment in cancer patients, as well as identify biomarkers for selection of patients who might benefit from the combination treatments. MATERIALS AND METHODS: A search of randomized clinical trials (RCTs) comparing sintilimab combinations vs. single treatment in different tumors according to the PRISMA guidelines was performed. Selected endpoints included completion response rate (CR), objective response rate (ORR), disease control rate (DCR), overall survival (OS), progression-free survival (PFS), major adverse effects (AEs), immune-related adverse events (irAEs). Subgroup analyses based on different combination regimens, tumor type and basic biomarkers were included. RESULTS: Results reported from 11 RCTs involving 2,248 patients were included in this analysis. Pooled results indicated that both sintilimab plus chemotherapy and sintilimab plus targeted therapy significantly improved CR [RR=2.44, 95% CI (1.14, 5.20), p=0.021; RR=2.91, 95% CI (1.29, 6.57), p=0.010], ORR [RR=1.34, 95% CI (1.13, 1.59), p=0.001; RR=1.70, 95% CI (1.13, 2.56), p=0.011], PFS [HR=0.56, 95% CI (0.43, 0.69), p<0.001; HR=0.56, 95% CI (0.49, 0.64), p<0.001] and OS [HR=0.59, 95% CI (0.48, 0.70), p<0.001]. Subgroup analyses suggested that the sintilimab-chemotherapy group exhibited a superior PFS benefit than the chemotherapy alone group regardless of age, gender, EGOS PS, PD-L1 expression, smoking status, and clinical stage. There were no significant statistical differences in the incidence of any grade and grade 3 or worse AEs between the two groups [RR=1.00, 95% CI (0.91, 1.10), p=0.991; RR=1.06, 95% CI (0.94, 1.20), p=0.352]. While the incidence of any grade irAEs was higher with sintilimab plus chemotherapy as compared to chemotherapy alone (RR=1.24, 95% CI (1.01, 1.54), p=0.044), but no significant difference was found for grade 3 or worse irAEs (RR=1.11, 95% CI (0.60, 2.03), p=0.741). CONCLUSIONS: Sintilimab combinations brought benefits to a greater number of patients at the cost of a mild increase of irAEs. PD-L1 expression may not be used as a predictive biomarker, composite biomarkers consisting of PD-L1 and MHC class II expression are worth to be explored to enlarge the patient population that benefits from sintilimab combinations.

[A deep learning segmentation model for detecting caries in molar teeth].

This study aimed to build a home use deep learning segmentation model to identify the scope of caries lesions. A total of 494 caries photographs of molars and premolars collected via endoscopy were selected. Subsequently, these photographs were labeled by physicians and underwent segmentation training by using DeepLabv3+, and then verification and evaluation were performed. The mean accuracy was 0.993, the sensitivity was 0.661, the specificity was 0.997, the Dice coefficient was 0.685, and the intersection over union (IoU) was 0.529. Therefore, the present deep learning segmentation model can identify and segment the scope of caries.

Structural difference analysis of adult's intestinal flora basing on the 16S rDNA gene sequencing technology.

OBJECTIVE: Through 16S rDNA technology, we aimed at separating adults aging 20-50 years old into a few groups and processing the high-throughput sequencing analysis, in order to explore the features and differences of intestinal flora in each age group in a microcosmic perspective. PATIENTS AND METHODS: 120 stool specimens were collected strictly in accordance with acceptance criteria and exclusion criteria. 49 subjects aging 20-29 years old (Group AGE1), 51 subjects aging 30-39 years old (Group AGE2), and 20 subjects aging 40-49 years old (Group AGE3) were divided into 3 groups. Bacteria DNA from fresh stool specimens of 3 groups were abstracted. Illumina MiSeq high-throughput sequencing platform was applied to process 16S rDNA sequencing in Area 338F_806R for intestinal flora detection. I-Sanger Bio-cloud platform was applied for the analysis of intestinal flora structure changes in phylum level and genus level. RESULTS: Among the age of 20-50, with older age, the abundance of intestinal flora decreased among healthy adults more than 40 years old. In addition, the diversity and sample dispersion of intestinal flora is significantly different from people among 20-40 years old. The decrease ratio of Firmicutes/Bacteroidetes indicated that as the age grows, glucose tolerance might decrease. Comparing with people among 20-40 years old, the amount of Bifidobacterium and Eubacterium in people over 40 years old have significantly decreased. The decrease of Bifidobacterium and Eubacterium may increase the risks of cognitive impairment and lower the anti-inflammation and anti-cancer efficacy in human body, respectively. Subdoligranulum relates to poor metabolism and chronic inflammation and it happens more in people aged over 40 than young people who are among 20-40 years old. CONCLUSIONS: There are differences in the intestinal flora of healthy adults aged 20-50. Effective intervention of the intestinal flora may play a role in delaying aging and preventing diseases.

[A case of colchicine poisoning complicated with extra pontine myelinolysis].

To analyze the clinical presentation and the treatment process of one case of colchicine poisoning complicated with extra pontine myelinolysis and discuss its pathogenesis. Increasing the attention of hyponatremia caused by colchicine poisoning is of great significance for improving the prognosis and quality of life of patients.

Laser-engineered heavy hydrocarbons: Old materials with new opportunities.

Polycyclic heavy hydrocarbons (HHs) such as coal, tar, and pitch are a family of materials with extremely rich and complex chemistry, representing a massive opportunity for their use in a range of potential applications. The present work shows that optimal selection of initial HHs based on molecular constituents is essential in tuning the material for a particular and targeted electronic application. Combining the selection of feedstock chemistry (H:C and aromatic content) and controlling variable laser treatment parameters (laser power, speed, and focus) lead to full control over the H:C ratio, sp2 concentration, and degree of graphitic stacking order of the products. The broad intertunability of these factors results from a wide distribution of carbon material crystallinity from amorphous to highly graphitic and a broad distribution of electrical conductivity up to 103 S/m.

LncRNA TUG1 inhibits the proliferation and fibrosis of mesangial cells in diabetic nephropathy via inhibiting the PI3K/AKT pathway.

OBJECTIVE: To elucidate the potential function of long non-coding RNA (lncRNA) TUG1 in the progression of diabetic nephropathy (DN) and the underlying mechanism. MATERIALS AND METHODS: Rat diabetes mellitus (DM) model was established by streptozocin (STZ) administration. In vivo levels of TUG1 and relative genes in the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT) pathway in DM rats and control rats were determined by the quantitative Real Time-Polymerase Chain Reaction (qRT-PCR). Moreover, levels of kidney weight, 24 h-urine protein, blood urea nitrogen and serum creatinine in DM rats and controls were detected. Mesangial cells were subjected to induction of high-level glucose. Relative levels of TUG1 and relative genes in the PI3K/AKT pathway in mesangial cells were determined as well. Through Cell Counting Kit-8 (CCK-8) and 5-Ethynyl-2'-deoxyuridine (EdU) assay, the regulatory effect of TUG1 on the proliferative ability of mesangial cells induced with high-level glucose was evaluated. Finally, expression changes in the PI3K/AKT pathway and extracellular matrix (ECM)-related genes in mesangial cells were determined. RESULTS: TUG1 was downregulated in DM rats and mesangial cells induced with high-level glucose. Compared with controls, DM rats presented higher levels of kidney weight, 24 h-urine protein, blood urea nitrogen and serum creatinine, which were markedly reduced after TUG1 overexpression in vivo. Moreover, overexpression of TUG1 downregulated TGF-ß1, FN, and COL-IV, and inhibited the activation of the PI3K/AKT pathway. CONCLUSIONS: TUG1 is downregulated in DN. The overexpression of TUG1 could suppress the proliferation and ECM accumulation of mesangial cells via inhibiting the PI3K/AKT pathway.

Urgent-start peritoneal dialysis and patient outcomes: a systematic review and meta-analysis.

OBJECTIVE: The present study was aimed at illustrating short- or long-term patient outcome among individuals with urgent-start peritoneal dialysis (PD) compared with those with conventional PD. MATERIALS AND METHODS: We searched the PubMed, EMBASE, Cochrane Controlled Trials Register and China National Knowledge Infrastructure databases. Cohort studies were investigated comparing the effects of urgent start of PD (<14 days after catheter insertion) to those of conventional start of PD (≥14 days after catheter insertion). Risks of bias across studies were evaluated using Newcastle-Ottawa Quality Assessment Scale. We calculated the pooled risk ratios and mean differences with 95% confidence intervals for dichotomous data and continuous data, respectively. RESULTS: Six studies involving 1,242 patients were identified. Compared with conventional PD, urgent-start PD was not associated with a high mortality (RR: 1.25, 95% CI: 0.92 to 1.69; I2=0%, p=0.99) and a higher prevalence of overall mechanical complications (RR: 1.79, 95% CI: 0.85 to 3.78; p=0.12; I2=64%, p=0.02). However, urgent-start PD was associated with a higher prevalence of leakage (RR: 6.72, 95% CI: 2.11 to 21.32; I2=0%, p=0.60). In terms of infectious complications, data analysis of the fixed-effects model showed no difference between the two groups. (RR: 1.36, 95% CI: 0.90 to 2.05, p=0.14), regardless of peritonitis (RR: 1.36, 95% CI: 0.90 to 2.05, p=0.14; I2=0%, p=0.70) or other infections (RR: 1.15, 95% CI: 0.49 to 2.69, p=0.99; I2=0%, p=0.75). CONCLUSIONS: Urgent-start PD was not associated with a higher risk of mortality and dialysis-related complications. However, compared with conventional PD, an urgent start of PD may increase the risk of a leak.

Pharmacokinetics and pharmacodynamics of the novel monobactam LYS228 in a neutropenic murine thigh model of infection.

Objectives: The neutropenic murine thigh infection model and a dose-fractionation approach were used to determine the pharmacokinetic/pharmacodynamic (PK/PD) relationship of LYS228, a novel monobactam antibiotic with activity against Enterobacteriaceae including carbapenem-resistant strains. Methods: Mice (n = 4 per group) were inoculated with Enterobacteriaceae strains via intramuscular injection. Two hours post-bacterial inoculation, treatment with LYS228 was initiated. Animals were euthanized with CO2 24 h after the start of therapy and bacterial counts (log10 cfu) per thigh were determined. PK parameters were calculated using free (f) plasma drug levels. Results: Following a dose-fractionation study, non-linear regression analysis determined that the predominant PK/PD parameter associated with antibacterial efficacy of LYS228 was the percentage of the dosing interval that free drug concentrations remained above the MIC (%fT>MIC). In a dose-dependent manner, LYS228 reduced the thigh bacterial burden in models established with Enterobacteriaceae producing ß-lactamase enzymes of all classes (e.g. ESBLs, NDM-1, KPC, CMY-2 and OXA-48). The range of the calculated static dose was 86-649 mg/kg/day for the isolates tested, and the magnitude of the driver of efficacy was 37-83 %fT>MIC. %fT>MIC was confirmed as the parameter predominantly driving efficacy as evidenced by a strong coefficient of determination (r2 = 0.68). Neutrophils had minimal impact on the effect of LYS228 in the murine thigh infection model. Conclusions: LYS228 is efficacious in murine thigh infection models using ß-lactamase-producing strains of Enterobacteriaceae, including those expressing metallo-ß-lactamases, ESBLs and serine carbapenemases, with the PK/PD driver of efficacy identified as %T>MIC.

Targeting enhancer of zeste homolog 2 protects against acute kidney injury.

Despite the established oncogenic and profibrotic functions of enhancer of zeste homolog 2 (EZH2), a methyltransferase that induces histone H3 lysine 27 trimethylation (H3K27me3), its role in acute kidney injury (AKI) remains unclear. In this study, we demonstrated that EZH2 and H3K27me3 were upregulated in the murine kidney with AKI induced by either ischemia-reperfusion (I/R) or folic acid (FA). Pharmacologic inhibition of EZH2 with 3-deazaneplanocin A (3-DZNeP) prevented tubular injury in both models as demonstrated by reduced renal dysfunction, diminished neutrophil gelatinase-associated lipocalin expression and decreased renal tubular cell death. Injury to the kidney resulted in reduced expression of E-cadherin and ZO-1, whereas EZH2 inhibition largely preserved their expression. Moreover, 3-DZNep was effective in counteracting the increased expression of matrix metalloproteinase (MMP)-2 and MMP-9, as well as the phosphorylation of Raf-1 and ERK1/2 in the injured kidney. Conversely, blocking EZH2 reversed the decrease of tissue inhibitor of metalloproteinase (TIMP)-2 and metalloproteinase (TIMP)-3, and Raf kinase inhibitor protein (RKIP) in the kidney after acute injury. Similarly, oxidant injury to cultured kidney proximal tubular epithelial cells caused a decrease in the expression of E-cadherin, ZO-1, TIMP-2/-3, and RKIP, as well as an increase in the expression of MMP-2/9 and phosphorylation of Raf-1 ERK1/2. Blocking EZH2 with 3-DZNep or SiRNA hindered these responses. Thus, these results suggest that targeting EZH2 protects against AKI through a mechanism associated with the preservation of adhesion/junctions, reduction of matrix metalloproteinases and attenuation of the Raf-1/ERK1/2 pathway.

Impact of knee varus and valgus deformity on alignment in lower extremities after total knee arthroplasty (TKA).

OBJECTIVE: To investigate the impact of knee varus and valgus in varying degrees on the alignment in lower extremities of patients who received the total knee arthroplasty (TKA). PATIENTS AND METHODS: We retrospectively analyzed the condition of varus and valgus deformity in full-length X-ray films of double lower extremities in weight-bearing position of 120 patients before and after they firstly received the TKA between March 2012 and May 2014 to discover the impact of knee varus and valgus in varying degrees on the alignment in lower extremities of patients who received the total knee arthroplasty (TKA). 120 patients were divided into three groups by the pre-operative hip-knee-ankle angle (HKA), the HKAs of three groups were compared after operation, and linear regression analysis was conducted to identify the correlation between pre- and post-operative HKAs. In addition, comparison between the pre- and post-operative lean of arms and legs (LMAL) was carried out to explore the variations before and after operation as well as the differences in the average variations among three groups. RESULTS: The differences were statistically significant in comparison of the pre- and post-operative HKAs and medial proximal tibia angles (MPTA) of all affected extremities (p<0.05), but no statistically significant difference was shown in comparison between the pre- and post-operative knee physical valgus angles (KPVA) (p>0.05). The post-operative lengths of 86.57% of affected extremities (116/134) were longer than those before operation with statistically significant differences (p<0.05). However, no statistically significant difference was identified in comparison between the pre- and post-operative lengths of extremities that did not receive any operation (p>0.05). The ratios of HKAs between -3° and 3° in normal group, mild-deformity group and severe-deformity group were respectively 90.48%, 81.25%, and 34.69% with a statistically significant difference (p<0.05). Besides, the scatter plot revealed that there was a linear regression relation between pre- and post-operative HKAs (F=51.197, p<0.05). There were statistically significant differences in comparisons of the pre-operative KPVA and MPTAs among three groups (p<0.05). CONCLUSIONS: Severe knee varus and valgus deformity can increase the deviation of alignment in lower extremities after TKA, and most of LMALs after TKA are longer than those before TKA, and the most significant extension is identified in severe varus and valgus deformity.

The expression of B7-H3 and B7-H4 in human gallbladder carcinoma and their clinical implications.

OBJECTIVE: To investigate the expression of B7-H3 and B7-H4 and their clinical implications in human gallbladder carcinoma. PATIENTS AND METHODS: The expression of B7-H3 and B7-H4 in the 252 samples (126 cases of chronic cholecystitis and 126 cases of gallbladder cancer) was detected by the streptavidin-peroxidase immunohistochemical method, and their associations with tumor classification, clinical grade, and recurrence were assessed. RESULTS: In chronic cholecystitis tissue, B7-H3 and B7-H4 were not detected. In 126 cases of gallbladder carcinoma, the positive rates of B7-H3 and B7-H4 expression were 66.67% and 69.05% respectively (p < 0.05). The positive rate of B7-H3 in the primary-onset group was 53.57%, and that in recurrence group was 92.86% (p < 0.05). The positive rate of B7-H4 in the primary-onset group was 85.19%, and that in recurrence group was 40.00% (p < 0.05). Expression of B7-H3 was consistent with B7-H4 expression in gallbladder carcinoma. CONCLUSIONS: B7-H3 and B7-H4 were up-regulated in gallbladder cancer; the high expression of B7-H3 may contribute to the early diagnosis of gallbladder carcinoma and the assessment of postoperative survival and recurrence. B7-H4 may play an important role in the incidence of gallbladder cancer. B7-H3 and B7-H4 may play a synergetic role in gallbladder carcinoma. Combined tests were available for the diagnosis, degree assessment and prognosis of gallbladder carcinoma, which may be a new target for molecular targeted therapy of gallbladder carcinoma.

Proteome analysis of the liver in the Chinese fire-bellied newt Cynops orientalis.

The Chinese fire-bellied newt, Cynops orientalis, belonging to Amphibia, Caudata, Salamandridae is a species endemic to China. The liver, which is an important digestive gland and the largest amphibian organ, has various functions, including detoxification, glycogen storage, protein synthesis, and hormone production. However, the newt liver has rarely been studied at the molecular level. We performed histomorphology and high-throughput proteomic analysis of the Chinese fire-bellied newt liver, using hematoxylin and eosin (H&E) staining and two-dimensional electrophoresis coupled with mass spectrometry. The H&E staining showed that the newt liver nuclei are large and round, are located in the lateral cytoplasm, and contain a large quantity of lipid droplets. Melanins were abundantly present throughout the hepatic parenchyma. The proteome analysis showed a total of 545 proteins detected in the newt liver. Furthermore, a gene ontology analysis suggested that these proteins were associated with metabolism, immune response, cellular homeostasis, etc. Among these, proteins with metabolic functions were found to be the most abundant and highly expressed. This supports the role of the liver as the metabolic center. The proteomic results provide new insights into the aspects of the liver proteomes of the Chinese fire-bellied newt. The identification of a more global liver proteome in the newt may provide a basis for characterizing and comparing the liver proteomes from other amphibian species.

New strategies of DLI in the management of relapse of hematological malignancies after allogeneic hematopoietic SCT.

DLI is an effective strategy for patients with recurrent hematological malignancies after allogeneic hematopoietic SCT (allo-HSCT). DLI has been widely applied to boost the graft vs tumor (GVT) or GVL effects. However, given the potentially severe complications associated with conventional DLI and transient GVL effect, new strategies for DLI are emerging. In this review, we have discussed the recent important studies on DLI as a prophylactic or therapeutic modality for relapsed hematological disorders after allo-HSCT. The strategies to separate GVL from GVHD have also been discussed. Leukemia-targeting therapy and lymphodepletion combined with DLI, and prophylactic DLI after allo-HSCT are often employed for patients with high risk of relapse, which has been reviewed as well. In addition, we have also discussed the issues on DLI to be further addressed, such as the doses, timing and frequency of DLI in different clinical settings, leukemic antigen-specific DLI as well as how to augment GVL effect while attenuating GVHD.

A study on knowledge, attitudes and health behaviours regarding Alzheimer's disease among community residents in Tianjin, China.

ACCESSIBLE SUMMARY: What is known on the subject? Several studies have measured the general public's knowledge and attitudes towards Alzheimer's disease; however, much of this work is based on western samples. Due to cultural differences, the western findings may be difficult to generalize to the Chinese general public. In addition, the few studies conducted in China were often restricted to a relatively narrow range of knowledge and attitudes. What this paper adds to existing knowledge? The general public had little knowledge of Alzheimer's disease, especially on the causes, symptoms and risk factors. In terms of attitudes, although the general public held positive attitudes towards persons with Alzheimer's disease, most of them were not sure whether or not to share a diagnosis of Alzheimer's disease with the patient. In daily life, only a low proportion of people kept mentally active. What are the implications for practice? A popularization of a wide range of knowledge about Alzheimer's disease needs to be undertaken, especially focusing on persons with low educational level and emphasizing the causes, symptoms and risk factors. Besides, there is a significant need to draw up evidence-based dietary and lifestyle guidelines for Alzheimer's disease risk reduction. Moreover, health promotion agencies should identify priority groups for Alzheimer's disease risk reduction initiatives, especially those with lower income, a lower level of knowledge on Alzheimer's disease and with chronic diseases. AIM: The purpose of this descriptive correlational cross-sectional study was to assess the current level of knowledge, attitudes and health behaviours regarding Alzheimer's disease among community residents in Tianjin, China and to identify factors related to these attributes. METHOD: A convenience sample of 140 community-dwelling adults aged 20-75 years was selected to complete a researcher-designed questionnaire about Alzheimer's disease-related knowledge, attitudes and health behaviours. RESULTS: The findings revealed that 15.7% of the participants knew the risk factors for Alzheimer's disease. With regard to attitude, 138 participants (98.6%) believed that people with Alzheimer's disease should not be discriminated against, and 55.7% were not sure whether to share a diagnosis of Alzheimer's disease with the patient. In daily life, 28.6% of the participants pursued their interests and hobbies. A lower level of health behaviours was associated with lower income, presence of chronic diseases and a lower level of knowledge about Alzheimer's disease. DISCUSSION: These findings provide a strong case for population-level risk reduction initiatives to be undertaken, especially among people with lower income, a lower level of knowledge on Alzheimer's disease and with chronic diseases.

Expression and activity of V-H+ -ATPase in gill and kidney of marbled eel Anguilla marmorata in response to salinity challenge.

The full-length complementary (c)DNA of vacuolar-type-H(+) -ATPase B1 gene (vhab1) in marbled eel Anguilla marmorata with 1741 base pairs (bp) was identified. It contained a 1512 bp open reading frame encoding a polypeptide with 503 amino acids (55·9 kDa), an 83 bp 5'-untranslated region (UTR) and a 146 bp 3'-UTR. The expression levels of A. marmorata vhab1 in gill and kidney of A. marmorata were evaluated at different intervals during the exposure to various salinities (0, 10 and 25). The results indicated that the expression levels of A. marmorata vhab1 messenger (m)RNA in gill and kidney had a significant increase and reached the highest level at 1 h in brackish water (BW, salinity 10) group and 6 h in seawater (SW, salinity 25) group. Therefore, salinity did affect the relative expression level of A. marmorata vhab1 mRNA in gills, which exhibited the enhancement by c. 44 times in SW group when compared with that in fresh water. No remarkable difference in the expression of A. marmorata vhab1 mRNA was observed after 15 days of SW exposure (P > 0·05). V-H(+) -ATPase activity exhibited an increase by two- to three-fold when compared with that in gill and kidney from the control group. The consequence primarily suggested that A. marmorata vhab1 gene product in elvers from A. marmorata plays an important role in adaptation response to SW.

B7x/B7-H4 modulates the adaptive immune response and ameliorates renal injury in antibody-mediated nephritis.

Kidney disease is one of the leading causes of death in patients with lupus and other autoimmune diseases affecting the kidney, and is associated with deposition of antibodies as well as infiltration of T lymphocytes and macrophages, which are responsible for initiation and/or exacerbation of inflammation and tissue injury. Current treatment options have relatively limited efficacy; therefore, novel targets need to be explored. The co-inhibitory molecule, B7x, a new member of the B7 family expressed predominantly by non-lymphoid tissues, has been shown to inhibit the proliferation, activation and functional responses of CD4 and CD8 T cells. In this study, we found that B7x was expressed by intrinsic renal cells, and was up-regulated upon stimulation with inflammatory triggers. After passive administration of antibodies against glomerular antigens, B7x(-/-) mice developed severe renal injury accompanied by a robust adaptive immune response and kidney up-regulation of inflammatory mediators, as well as local infiltration of T cells and macrophages. Furthermore, macrophages in the spleen of B7x(-/-) mice were polarized to an inflammatory phenotype. Finally, treatment with B7x-immunoglobulin (Ig) in this nephritis model decreased kidney damage and reduced local inflammation. We propose that B7x can modulate kidney damage in autoimmune diseases including lupus nephritis and anti-glomerular basement membrane disease. Thus, B7x mimetics may be a novel therapeutic option for treatment of immune-mediated kidney disease.

In vivo mechanism study of NGAL in rat renal ischemia-reperfusion injury.

This study aimed to determine the protective effect and mechanism of neutrophil gelatinase-associated lipocalin (NGAL) in rat kidney on ischemia/reperfusion injury (I/R). The rat I/R model was set up by cutting one kidney and clamping the contralateral renal pedicle for 45 min. Male SD rats were randomly divided into sham-operation, I/R and NGAL groups. Hematoxylin-eosin staining was performed to observe the renal pathological changes in the 3 groups; serum creatinine (Scr) and blood urea nitrogen (BUN) determined in blood samples taken from the inferior vena cava 24 h after the reperfusion were measured; TUNEL was used to observe the apoptosis of renal tubular epithelial cells; immunohistochemistry was performed to evaluate the expressions of Bax and activated caspase-3; Western blotting was used to determine the expression changes in apoptotic proteins Fas and Bcl-2. Compared with the I/R group, Scr and BUN of the NGAL group were 63.400 ± 11.908 vs 121.857 ± 17.151 µM and 14.840 ± 2.868 vs 28.557 ± 6.434 mM, respectively. The number of apoptotic tubular epithelial cells was reduced (7.800 ± 1.924 vs 15.400 ± 3.049); the expression of renal tissue Fas mRNA of the NGAL group was decreased (2.34 ± 0.51 vs 6.84 ± 2.34); the expression of the Bax protein was lower (7.440 ± 1.640 vs 15.456 ± 1.955%); the expression of the CC3 protein was decreased (3.171 ± 0.321 vs 7.291 ± 1.059%), while the expression of the Bcl-2 protein increased (6.91 ± 1.64 vs 5.30 ± 1.48), P < 0.05. NGAL had a protective effect towards the renal tubular epithelial cells in I/R, and the effect might have been associated with the reduction in apoptosis and the altered expression of apoptotic proteins, which would thereby reduce tissue damage and protect the kidney.

Paraquat increases connective tissue growth factor expression and impairs lung fibroblast proliferation and viscoelasticity.

This in vitro study was designed to investigate the molecular mechanisms of paraquat-induced damage using cultured human fetal lung fibroblasts (MRC-5 cells), in order to promote the development of improved therapies for paraquat poisoning. Paraquat's effects on proliferation were examined by flow cytometry, on viscoelasticity by the micropipette aspiration technique, and on connective tissue growth factor (CTGF) expression by real-time polymerase chain reaction and enzyme-linked immunosorbent assay. Paraquat was found to significantly reduce the proliferation index of MRC-5 cells in a concentration-dependent manner (p < 0.05) and to significantly impair the viscoelastic properties in a time-independent manner (p < 0.05). Exposure to paraquat led to a significant and time-dependent increase in CTGF expression (p < 0.05) and induced changes in the morphology and biomechanical characteristics of the MRC-5 cells. These findings not only provide novel insights into the mechanisms of paraquat-induced lung fibrosis but may represent useful targets of improved molecular-based therapies for paraquat poisoning.

Icariin promotes histone acetylation and attenuates post-stroke cognitive impairment in the central cholinergic circuits of mice.

Post-stroke dementia (PSD) is a common clinical disease and the central cholinergic circuits are important to cognitive function. Icariin (ICA), a flavonoid isolated from Herba Epimedii, was reported to improve cognitive function through modulating the cholinergic system. But there were no studies exploring the role of ICA in PSD animal models. In this study, we used transient middle cerebral artery occlusion mice with cognitive dysfunction in the PSD model. PSD mice were then randomly divided into six groups: Sham-operated+placebo group, Sham-operated+ICA group (60mg/kg), PSD model+placebo group, PSD model+ICA group (30, 60, or 120mg/kg). We observed spatial learning ability and memory by Morris water maze test. The levels of acetylcholine (ACH) and choline acetyltransferase (ChAT), the degree of histone acetylation and the cAMP response element-binding protein (CREB) phosphorylation in the central cholinergic circuits were investigated by Western blot and immunofluorescence. After the administration of various doses of ICA, the escape latency and searching distance of the PSD mice were reduced significantly compared with those without ICA treatment. While the levels of ACH and ChAT declined, the degree of histone acetylation and the CREB phosphorylation was improved in a dose-dependent manner in central cholinergic circuits. In conclusion, ICA can improve post-stroke dementia, and the mechanism is likely to enhance CREB phosphorylation in the central cholinergic circuits, thus improving the damage in cholinergic circuits histone acetylation homeostasis.