Because of their regenerative and paracrine abilities, cardiac stem cells (CSCs) are the most appropriate, optimal and promising candidates for the development of cardiac regenerative medicine strategies. However, native and exogenous CSCs in ischemic hearts are exposed to various pro-apoptotic or cytotoxic factors preventing their regenerative and paracrine abilities.
Methods and Results
We examined the effects of H2O2 on mouse CSCs (mCSCs), and observed that hydrogen peroxide (H2O2) treatment induces mCSCs apoptosis via the caspase 3 pathway, in a dose-dependent manner. We then examined the effects of Wnt1 over-expression on H2O2-induced apoptosis in mCSCs and observed that Wnt1 significantly decreased H2O2-induced apoptosis in mCSCs. On the other hand, inhibition of the canonical Wnt pathway by the secreted frizzled related protein 2 (SFRP2) or knockdown of β-catenin in mCSCs reduced cells resistance to H2O2-induced apoptosis, suggesting that Wnt1 predominantly prevents H2O2-induced apoptosis through the canonical Wnt pathway.
Our results provide the first evidences that Wnt1 plays an important role in CSCs’ defenses against H2O2-induced apoptosis through the canonical Wnt1/GSK3β/β-catenin signaling pathway.
Mesenchymal stem cells (MSCs) can suppress dendritic cells (DCs) maturation and function, mediated by soluble factors, such as indoleamine 2,3-dioxygenase (IDO), prostaglandin E2 (PGE2), and nitric oxide (NO). Interleukin-10 (IL-10) is a common immunosuppressive cytokine, and the downstream signaling of the JAK-STAT pathway has been shown to be involved with DCs differentiation and maturation in the context of cancer. Whether IL-10 and/or the JAK-STAT pathway play a role in the inhibitory effect of MSCs on DCs maturation remains controversial. In our study, we cultured MSCs and DCs derived from rat bone marrow under different culturing conditions. Using Transwell plates, we detected by ELISA that the level of IL-10 significantly increased in the supernatants of MSC-DC co-cultures at 48 hours. The cell immunofluorescence assay suggested that the MSCs secreted more IL-10 than the DCs in the co-cultures. Adding exogenous IL-10 to the DCs monoculture or MSC-DC co-cultures stimulated IL-10 and led to a decrease in IL-12, and lower expression of the DCs surface markers CD80, CD86, OX62, MHC-II and CD11b/c. Supplementing the culture with an IL-10 neutralizing antibody (IL-10NA) showed precisely the opposite effect of adding IL-10. Moreover, we demonstrated that the JAK-STAT signaling pathway is involved in inhibiting DCs maturation. Both JAK1 and STAT3 expression and IL-10 secretion decreased markedly after adding a JAK inhibitor (AG490) to the co-culture plate. We propose that there is an IL-10 positive feedback loop, which may explain our observations of elevated IL-10 and enhanced JAK1 and STAT3 expression. Overall, we demonstrated that MSCs inhibit the maturation of DCs through the stimulation of IL-10 secretion, and by activating the JAK1 and STAT3 signaling pathway.
NQO1 is an emerging and promising therapeutic target in cancer therapy. This study was to determine whether the anti-tumor effect of tanshinone IIA (TSA) is NQO1 dependent and to elucidate the underlying apoptotic cell death pathways. NQO1+ A549 cells and isogenically matched NQO1 transfected and negative H596 cells were used to test the properties and mechanisms of TSA induced cell death. The in vivo anti-tumor efficacy and the tissue distribution properties of TSA were tested in tumor xenografted nude mice. We observed that TSA induced an excessive generation of ROS, DNA damage, and dramatic apoptotic cell death in NQO1+ A549 cells and H596-NQO1 cells, but not in NQO1− H596 cells. Inhibition or silence of NQO1 as well as the antioxidant NAC markedly reversed TSA induced apoptotic effects. TSA treatment significantly retarded the tumor growth of A549 tumor xenografts, which was significantly antagonized by dicoumarol co-treatment in spite of the increased and prolonged TSA accumulations in tumor tissues. TSA activated a ROS triggered, p53 independent and caspase dependent mitochondria apoptotic cell death pathway that is characterized with increased ratio of Bax to Bcl-xl, mitochondrial membrane potential disruption, cytochrome c release, and subsequent caspase activation and PARP-1 cleavage. The results of these findings suggest that TSA is a highly specific NQO1 target agent and is promising in developing as an effective drug in the therapy of NQO1 positive NSCLC.
In this paper, we described the symptoms and treatment of a patient with diabetic nephropathy accompanied by spontaneous retroperitoneal hemorrhage after hemodialysis. An elderly female patient with diabetic nephropathy presented with severe pain, numbness, and an increasing swelling in the left hip and left thigh after six sessions of hemodialysis involving the use of an antiplatelet drug and an anticoagulant agent. Her hemoglobin decreased to 46 g/L. An abdominal ultrasound showed a hematoma in the left retroperitoneal space, and computed tomography (CT) findings revealed a 6 cm×8 cm×10 cm hematoma in the left psoas muscle. After aggressive supportive therapy [the administration of packed red blood cell transfusion, carbazochrome sodium sulfonate injection, and continuous venovenous hemofiltration (CVVH)], the patient’s vital signs stabilized and her hemoglobin increased to 86 g/L. Repeat CT showed that the hematoma had been partially absorbed after two weeks. Eventually, the patient was discharged with stable vital signs. Physicians should be aware of the possibility of spontaneous retroperitoneal hemorrhage, particularly in patients with diabetic nephropathy undergoing hemodialysis involving the use of anticoagulant agents.
Spontaneous retroperitoneal hemorrhage; Diabetic nephropathy; Hemodialysis; Nadroparin calcium
Background and Purpose
NAD(P)H: quinone oxidoreductase 1 (NQO1) mediated quinone reduction and subsequent UDP-glucuronosyltransferases (UGTs) catalyzed glucuronidation is the dominant metabolic pathway of tanshinone IIA (TSA), a promising anti-cancer agent. UGTs are positively expressed in various tumor tissues and play an important role in the metabolic elimination of TSA. This study aims to explore the role of UGT1A in determining the intracellular accumulation and the resultant apoptotic effect of TSA.
We examined TSA intracellular accumulation and glucuronidation in HT29 (UGT1A positive) and HCT116 (UGT1A negative) human colon cancer cell lines. We also examined TSA-mediated reactive oxygen species (ROS) production, cytotoxicity and apoptotic effect in HT29 and HCT116 cells to investigate whether UGT1A levels are directly associated with TSA anti-cancer effect. UGT1A siRNA or propofol, a UGT1A9 competitive inhibitor, was used to inhibit UGT1A expression or UGT1A9 activity.
Multiple UGT1A isoforms are positively expressed in HT29 but not in HCT116 cells. Cellular S9 fractions prepared from HT29 cells exhibit strong glucuronidation activity towards TSA, which can be inhibited by propofol or UGT1A siRNA interference. TSA intracellular accumulation in HT29 cells is much lower than that in HCT116 cells, which correlates with high expression levels of UGT1A in HT29 cells. Consistently, TSA induces less intracellular ROS, cytotoxicity, and apoptotic effect in HT29 cells than those in HCT116 cells. Pretreatment of HT29 cells with UGT1A siRNA or propofol can decrease TSA glucuronidation and simultaneously improve its intracellular accumulation, as well as enhance TSA anti-cancer effect.
Conclusions and Implications
UGT1A can compromise TSA cytotoxicity via reducing its intracellular exposure and switching the NQO1-triggered redox cycle to metabolic elimination. Our study may shed a light in understanding the cellular pharmacokinetic and molecular mechanism by which UGTs determine the chemotherapy effects of drugs that are UGTs’ substrates.
In this paper, we present an investigation on the use of Au-Ag alloy popcorn-shaped nanoparticles (NPs) to realise the broadband optical absorption enhancement of dye-sensitized solar cells (DSCs). Both simulation and experimental results indicate that compared with regular plasmonic NPs, such as nano-spheres, irregular popcorn-shaped alloy NPs exhibit absorption enhancement over a broad wavelength range due to the excitation of localized surface plasmons (LSPs) at different wavelengths. The power conversion efficiency (PCE) of DSCs is enhanced by 16% from 5.26% to 6.09% by incorporating 2.38 wt% Au-Ag alloy popcorn NPs. Moreover, by adding a scattering layer on the exterior of the counter electrode, the popcorn NPs demonstrate an even stronger ability to increase the PCE by 32% from 5.94% to 7.85%, which results from the more efficient excitation of the LSP mode on the popcorn NPs.
Gastric cancer is the fourth most common cancer worldwide, with a high rate of death and low 5-year survival rate. To date, there is a lack of efficient therapeutic protocols for gastric cancer. Recent studies suggest that cancer stem cells (CSCs) are responsible for tumor initiation, invasion, metastasis, and resistance to anticancer therapies. Thus, therapies that target gastric CSCs are attractive. However, CSCs in human gastric adenocarcinoma (GAC) have not been described. Here, we identify CSCs in tumor tissues and peripheral blood from GAC patients. CSCs of human GAC (GCSCs) that are isolated from tumor tissues and peripheral blood of patients carried CD44 and CD54 surface markers, generated tumors that highly resemble the original human tumors when injected into immunodeficient mice, differentiated into gastric epithelial cells in vitro, and self-renewed in vivo and in vitro. Our findings suggest that effective therapeutic protocols must target GCSCs. The capture of GCSCs from the circulation of GAC patients also shows great potential for identification of a critical cell population potentially responsible for tumor metastasis, and provides an effective protocol for early diagnosis and longitudinal monitoring of gastric cancer.
cancer stem cells; gastric adenocarcinoma; CD44; CD54; circulating tumor cells
It is of great interest to identify new neurons in the adult human brain, but the persistence of neurogenesis in the subventricular zone (SVZ) and the existence of the rostral migratory stream (RMS)-like pathway in the adult human forebrain remain highly controversial. In the present study, we have described the general configuration of the RMS in adult monkey, fetal human and adult human brains. We provide evidence that neuroblasts exist continuously in the anterior ventral SVZ and RMS of the adult human brain. The neuroblasts appear singly or in pairs without forming chains; they exhibit migratory morphologies and co-express the immature neuronal markers doublecortin, polysialylated neural cell adhesion molecule and βIII-tubulin. Few of these neuroblasts appear to be actively proliferating in the anterior ventral SVZ but none in the RMS, indicating that neuroblasts distributed along the RMS are most likely derived from the ventral SVZ. Interestingly, no neuroblasts are found in the adult human olfactory bulb. Taken together, our data suggest that the SVZ maintains the ability to produce neuroblasts in the adult human brain.
human; rhesus monkey; stem cells; neurogenesis; neuroblasts; subventricular zone; rostral migratory stream
Although blockade of Rho kinase with pharmacologic inhibitors ameliorates renal fibrosis and diabetic kidney disease (DKD), the underlined mechanisms remain largely unclear. The present study tested the hypothesis that ROCK1 may regulate the early development of albuminuria via the megalin/cubilin-dependent mechanism.
A DKD model was induced in ROCK1 knockout and wild-type mice by streptozotocin (STZ). The effect of deleted ROCK1 on urinary albumin excretion and the expression of megalin/cubilin were examined. In addition, the effect of blocking ROCK activities with an inhibitor (Y-27632) on tubular albumin reabsorption was tested in a normal rat tubular epithelial cell line (NRK52E) under high-glucose conditions. Expression of transforming growth factor (TGF)-β1, interleukin-1β and collagen-1 was also been examined.
Urinary albumin excretion was significantly increased in ROCK1 WT mice at 8 weeks after STZ injection. In contrast, mice lacking ROCK1 gene were protected against the development of albuminuria. This was associated with the protection against the loss of megalin/cubilin and an increase in TGF-β1, IL-1β, and fibrosis in the kidney. In vitro, we also found that blockade of Rho kinase with inhibitor Y-27632 prevented high-glucose-induced loss of megalin expression and an increase of TGF-β1, thereby increasing the absorption rate of FITC-labeled albumin by tubular epithelial cells.
ROCK1 may play a role in the development of albuminuria in DKD by downregulating the endocytosis receptors complex – megalin/cubilin.
Copyright © 2011 S. Karger AG, Basel
Diabetic kidney disease; Tubular cells, albuminuria; ROCK; Megalin; Cubilin
Synthetic regrowth of ZnO nanowires [NWs] under a similar chemical vapor transport and condensation [CVTC] process can produce abundant ZnO nanostructures which are not possible by a single CVTC step. In this work, we report three different regrowth modes of ZnO NWs: axial growth, radial growth, and both directions. The different growth modes seem to be determined by the properties of initial ZnO NW templates. By varying the growth parameters in the first-step CVTC process, ZnO nanostructures (e.g., nanoantenna) with drastically different morphologies can be obtained with distinct photoluminescence properties. The results have implications in guiding the rational synthesis of various ZnO NW heterostructures.
ZnO; nanoantenna; photoluminescence; second growth
Quantitative knowledge on the anatomy of the medial collateral ligament (MCL) is important for treatment of MCL injury and for MCL release during total knee arthroplasty (TKA). The objective of this study was to quantitatively determine the morphology of the MCL of human knees.
10 cadaveric human knees were dissected to investigate the MCL anatomy. The specimens were fixed in full extension and this position was maintained during the dissection and morphometric measurements. The outlines of the insertion sites of the superficial MCL (sMCL) and deep MCL (dMCL) were digitized using a 3D digitizing system.
The insertion areas of the superficial MCL (sMCL) were 348.6 ± 42.8 mm2 and 79.7 ± 17.6 mm2 on the tibia and femur, respectively. The insertion areas of the deep MCL (dMCL) were 63.6 ± 13.4 mm2 and 71.9 ± 14.8 mm2 on the tibia and femur, respectively. The distances from the centroids of the tibial and femoral insertions of the sMCL to the tibial and femoral joint line were 62.4 ± 5.5 mm and 31.1 ± 4.6 mm, respectively. The distances from the centroids of dMCL in the tibial insertion and the femoral insertion to the tibial and femoral joint line were 6.5 ± 1.3 mm and 20.5 ± 4.2 mm, respectively. The distal portion of the dMCL (meniscotibial ligament - MTL) was approximately 1.7 times wider than the proximal portion of the dMCL (meniscofemoral ligament - MFL), whereas the MFL was approximately 3 times longer than the MTL.
The morphologic data on the MCL may provide useful information for improving treatments of MCL-related pathology and performing MCL release during TKA.
A well-known observation with respect to cancer biology is that transformed cells display a disturbed cytoskeleton. The underlying mechanisms, however, remain only partly understood. In an effort to identify possible mechanisms, we compared the proteome of pancreatic cancer with matched normal pancreas and observed diminished protein levels of gelsolin—an actin filament severing and capping protein of crucial importance for maintaining cytoskeletal integrity—in pancreatic cancer. Additionally, pancreatic ductal adenocarcinomas displayed substantially decreased levels of gelsolin as judged by Western blot and immunohistochemical analyses of tissue micoarrays, when compared with cancerous and untransformed tissue from the same patients (P < 0.05). Importantly, no marked downregulation of gelsolin mRNA was observed (P > 0.05), suggesting that post-transcriptional mechanisms mediate low gelsolin protein levels. In apparent agreement, high activity ubiquitin-proteasome pathway in both patient samples and the BxPC-3 pancreatic cancer cell line was detected, and inhibition of the 26s proteasome system quickly restored gelsolin protein levels in the latter cell line. The status of ubiquitinated gelsolin is related to lymph node metastasis of pancreatic cancer. In conclusion, gelsolin levels are actively downregulated in pancreatic cancer and enhanced targeting of gelsolin to the ubiquitin-proteasome pathway is an important contributing factor for this effect.
Alpha-synuclein (αSyn) misfolding is associated with several devastating neurodegenerative disorders, including Parkinson’s disease (PD). In yeast cells and in neurons αSyn accumulation is cytotoxic, but little is known about its normal function or pathobiology. The earliest defect following αSyn expression in yeast was a block in endoplasmic reticulum (ER)–to–Golgi vesicular trafficking. In a genomewide screen, the largest class of toxicity modifiers were proteins functioning at this same step, including the Rab guanosine triphosphatase Ypt1p, which associated with cytoplasmic αSyn inclusions. Elevated expression of Rab1, the mammalian YPT1 homolog, protected against αSyn-induced dopaminergic neuron loss in animal models of PD. Thus, synucleinopathies may result from disruptions in basic cellular functions that interface with the unique biology of particular neurons to make them especially vulnerable.
The winged-helix (WH) BF-1 gene, which encodes brain factor 1 (BF-1) (also known as foxg1), is essential for the proliferation of the progenitor cells of the cerebral cortex. Here we show that BF-1-deficient telencephalic progenitor cells are more apt to leave the cell cycle in response to transforming growth factor β (TGF-β) and activin. We found that ectopic expression of BF-1 in vitro inhibits TGF-β mediated growth inhibition and transcriptional activation. Surprisingly, we found that the ability of BF-1 to function as a TGF-β antagonist does not require its DNA binding activity. Therefore, we investigated whether BF-1 can inhibit Smad-dependent transcriptional responses by interacting with Smads or Smad binding partners. We found that BF-1 does not interact with Smads. Because the identities of the Smad partners mediating growth inhibition by TGF-β are not clearly established, we examined a model reporter system which is known to be activated by activin and TGF-β through Smads and the WH factor FAST-2. We demonstrate that BF-1 associates with FAST-2. This interaction is dependent on the same region of protein which mediates its ability to interfere with the antiproliferative activity of TGF-β and with TGF-β-dependent transcriptional activation. Furthermore, the interaction of FAST-2 with BF-1 is mediated by the same domain which is required for FAST-2 to interact with Smad2. We propose a model in which BF-1 interferes with transcriptional responses to TGF-β by interacting with FAST-2 or with other DNA binding proteins which function as Smad2 partners and which have a common mode of interaction with Smad2.
Social caste determination in the honey bee is assumed to be determined by the dietary status of the young larvae and translated into physiological and epigenetic changes through nutrient-sensing pathways. We have employed Illumina/Solexa sequencing to examine the small RNA content in the bee larval food, and show that worker jelly is enriched in miRNA complexity and abundance relative to royal jelly. The miRNA levels in worker jelly were 7–215 fold higher than in royal jelly, and both jellies showed dynamic changes in miRNA content during the 4th to 6th day of larval development. Adding specific miRNAs to royal jelly elicited significant changes in queen larval mRNA expression and morphological characters of the emerging adult queen bee. We propose that miRNAs in the nurse bee secretions constitute an additional element in the regulatory control of caste determination in the honey bee.
Lymph node metastasis (LNM) in gastric cancer is a very important prognostic factor affecting long-term survival. Currently, several common imaging techniques are used to evaluate the lymph node status. However, they are incapable of achieving both high sensitivity and specificity simultaneously. In order to deal with this complex issue, a new evidential reasoning (ER) based model is proposed to support diagnosis of LNM in gastric cancer.
There are 175 consecutive patients who went through multidetector computed tomography (MDCT) consecutively before the surgery. Eight indicators, which are serosal invasion, tumor classification, tumor enhancement pattern, tumor thickness, number of lymph nodes, maximum lymph node size, lymph node station and lymph node enhancement are utilized to evaluate the tumor and lymph node through CT images. All of the above indicators reflect the biological behavior of gastric cancer. An ER based model is constructed by taking the above indicators as input index. The output index determines whether LNM occurs for the patients, which is decided by the surgery and histopathology. A technique called k-fold cross-validation is used for training and testing the new model. The diagnostic capability of LNM is evaluated by receiver operating characteristic (ROC) curves. A Radiologist classifies LNM by adopting lymph node size for comparison.
134 out of 175 cases are cases of LNM, and the remains are not. Eight indicators have statistically significant difference between the positive and negative groups. The sensitivity, specificity and AUC of the ER based model are 88.41%, 77.57% and 0.813, respectively. However, for the radiologist evaluating LNM by maximum lymph node size, the corresponding values are only 63.4%, 75.6% and 0.757. Therefore, the proposed model can obtain better performance than the radiologist. Besides, the proposed model also outperforms other machine learning methods.
According to the biological behavior information of gastric cancer, the ER based model can diagnose LNM effectively and preoperatively.
Gastric cancer; Lymph node metastasis; Evidential reasoning
Background. Cancer/testis antigens (CTAs) are ideal targets for cancer immunotherapy in virtue of their restricted expression profile in normal tissues. However, CTA-targeted immunotherapy has been rather disappointing clinical setting for CTAs are downregulated by cytosine-phosphate-guanosine (CpG) methylation in their promoter regions, so that tumor cells have low immunogenicity. Methods. We reinduced mouse CTA P1A through demethylation process and generated P1A-specific cytotoxic lymphocytes (CTLs) by immunizing BALB/c (H-2d) mice with dendritic cells pulsed with a P1A-specific peptide and CpG oligodeoxynucleotide (ODN) immune adjuvant. Results. We found that demethylation and CpG ODN immune adjuvant stimulation facilitated DC maturation and enhanced the allogenic capacity of P1A-specific CTLs against target cells both in vitro and in vivo. Conclusions. Our results suggested that CTA induction and immune adjuvant stimulation is a feasible strategy in cancer immunotherapy.
This study investigated the influencing factors of foot plantar pressure and attempted to find practical indicators to predict abnormal foot pressure in patients with type 2 diabetes mellitus (T2DM).
Subjects and Methods
Vibration perception threshold (VPT) and foot plantar pressure in 1,126 T2DM outpatients were examined. Patients were assigned to Group A (n=599), Group B (n=312), and Group C (n=215) according to VPT values and to Group I (n=555), Group II (n=436), and Group III (n=135) based on body mass index (BMI). The clinical characteristics and pressure–time integral (PTI) were compared among the three groups, and the associated factors of the total PTI in the entire foot (T-PTI) were analyzed.
PTI of Group C in heel medial and heel lateral was significantly higher than that of Group A (all P<0.01). PTI of Group B in the right fifth metatarsal and heel medial was significantly higher than that of Group A (all P<0.05). T-PTI of Group C was significantly higher than those of Groups A and B, and that of Group B was higher than that of Group A (all P<0.01). PTI of Groups II and III in the second, third, and fourth metatarsal, midfoot, heel medial, and heel lateral was significantly higher than that of Group I (all P<0.05). T-PTI of Groups II and III was significantly higher than that of Group I (all P<0.01). Pearson correlation analysis showed that T-PTI was positively associated with age, VPT, waist circumference, waist-to-hip ratio, and BMI (P<0.05). In multiple stepwise regression analysis, VPT (P=0.004) and BMI (P=0.000) were independent risk factors of T-PTI, and each 1 unit increase in BMI increased the T-PTI by 5.962 kPa•s. Receiver operator characteristic curve analysis further revealed that the optimal cutpoint of VPT and BMI to predict the abnormal PTI was 21 V (odds ratio=2.33, 95% confidence interval 1.67–3.25) and 24.9 kg/m2 (odds ratio=2.12, 95% confidence interval 1.55–2.90), respectively.
Having a VPT higher than 21 V and a BMI above 24.9 kg/m2 increases the risk of excessive foot plantar pressure in Chinese T2DM.
The aim of this study was to understand the characteristics of blood pressure (BP) variability in subjects with diabetic nephropathy (DN), and identify the probable predictors affecting BP variability. Fifty-one chronic kidney disease (CKD)-hypertensive patients without diabetes (NDN group) and sixty type 2 diabetic patients with overt DN (DN group) were enrolled in this study. The values of short-term BP variability were obtained from 24 h ambulatory BP monitoring (ABPM). Variance analysis or nonparametric analysis revealed that 24-h systolic BP variability and nighttime systolic BP variability of the DN group were significantly higher than those of the NDN group [(12.23±3.66) vs. (10.74±3.83) mmHg, P<0.05; (11.23±4.82) vs. (9.48±3.69) mmHg, P<0.05]. Then the patients of the DN group were divided into two groups according to glycated hemoglobin (HbA1c) level: Group A (HbA1c<7%) and Group B (HbA1c≥7%), and the t-test showed that patients in Group B had larger 24-h diastolic, daytime diastolic, and nighttime systolic/diastolic BP variability compared with Group A. In the DN group, partial correlation analysis revealed that HbA1c exhibited a strong association with 24-h diastolic, daytime diastolic, nighttime systolic and diastolic BP variability (P<0.001, P<0.001, P<0.05, and P<0.001, respectively). Taken together, larger short-term BP variability was detected in hypertensive type 2 diabetic patients with overt nephropathy and renal insufficiency. It may imply that the optimal BP variability level could benefit from a better glycaemic control.
Short-term blood pressure variability; Diabetic nephropathy; Glycated hemoglobin (HbA1c); Hypertension; Glycaemic control
Studies have shown that electroacupuncture (EA) ameliorates learning and memory after ischemic injury. However, there have been few studies elucidating the mechanisms of EA on learning and memory in cerebral hypoperfusion. In this study, we explored the cAMP response element-binding protein (CREB) signaling pathway-mediated antiapoptotic action involved in EA-induced improvement of learning and memory. EA at GV20 and GV14 acupoints was applied in cerebral hypoperfusion rats. A Morris water maze task was performed, and the immunoreactivities of pCREB, Bcl-2, and Bax in the hippocampal CA1 area were evaluated by the Western blotting technique. Our findings indicated that (1) EA ameliorated spatial learning and memory impairment in cerebral hypoperfusion rats; (2) EA increased the immunoreactivities of pCREB and Bcl-2 and decreased the immunoreactivity of Bax; (3) intracerebroventricular administration of H89 (the inhibitor of protein kinase A) blocked EA-induced, pCREB-mediated antiapoptotic action and improved learning and memory. These results suggest that EA can ameliorate learning and memory via activation of the CREB signaling pathway in the hippocampus to attenuate apoptosis after cerebral hypoperfusion.
Aberrant activation of Cyclin D-Cdk4/6 signaling pathway is commonly found in pancreatic ductal adenocarcinoma (PDAC). Here, we show that PD-0332991, a highly specific inhibitor for Cdk4 and Cdk6, exerted growth inhibitory effects on three human PDAC cell lines. Microarray analysis revealed that PD-0332991 down-regulated cell-cycle-related genes, but up-regulated genes implicated in extracellular matrix (ECM) remodeling and pancreatic cancer cell invasion and metastasis. Moreover, PD-0332991 enhanced invasion in transforming growth factor-beta (TGF-β)-responsive PDAC cell lines that harbor a wild-type SMAD4 gene (COLO-357, PANC-1), but not in TGF-β-resistant AsPC-1 cells that harbor a mutated SMAD4. PD-0332991 also induced epithelial-mesenchymal transition (EMT) in COLO-357 and PANC-1, but not in AsPC-1 cells. Inhibition of CDK4/6 using shRNA mimicked the effects of PD-0332991 on EMT induction. Furthermore, PD-0332991 increased Smad transcriptional activity in luciferase readout assays and activated TGF-β signaling. SB-505124, an inhibitor of the type I TGF-β receptor (TβRI) kinase, completely blocked EMT induction by PD-0332991. When combined with PD-0332991, SB-505124 inhibited the growth of COLO-357 and PANC-1 cells. Taken together, these data suggest that anti-Cdk4/6 therapy could induce EMT and enhance pancreatic cancer cell invasion by activating Smad-dependent TGF-β signaling, and that combining PD-0332991 and SB-505124 may represent a novel therapeutic strategy in PDAC.
Pancreatic cancer; Cdk4/6; PD-0332991; EMT; TGF-β
Haemophilus influenzae; NMR assignment; structural genomics
Sinomenine (SIN) is a purified alkaloid from the Chinese herb Sinomenium acutum. Previous studies demonstrated that SIN possesses anti-inflammatory and anti-apoptotic properties. We thus in the present report conducted studies to examine its impact on ischemia reperfusion (IR) induced renal injury. Precondition of mice with 200 mg/kg of SIN provided significant protection for mice against IR-induced renal injury as manifested by the attenuated serum creatinine (Cre) and blood urea nitrogen (BUN) along with less severity for histological changes and tubular cell apoptosis. In line with these results, treatment of mice with SIN suppressed IR-induced inflammatory infiltration and the expression of chemokine CXCL-10, adhesion molecule ICAM-1, and cytokines TNF-а/IL-6. Mechanistic studies revealed that SIN inhibits NF-κB transcriptional activity to suppress IR-induced inflammatory response in the kidney, while it attenuates MAP kinase signaling to prevent tubular cells undergoing apoptosis after IR insult. Altogether, our data support that SIN could be a useful therapeutic agent for prevention and treatment of IR-induced renal injury in the clinical settings.
Sinomenine; reperfusion injury; inflammation; apoptosis
People with schizophrenia have a higher prevalence of obesity than the general population. Many people with this illness struggle with weight gain, due, in part, to medications and other factors that act as obstacles to exercise and healthy eating. Several studies have shown the benefits of behavioral weight loss programs targeting eating and/or exercise in people with schizophrenia. Fewer studies have used competitive events as a goal for an exercise program. The current study tested the feasibility of preparing, using an exercise program, for a 5-kilometer (5K) event in people with schizophrenia. The exercise program was a 10-week training program consisting of three supervised walking/jogging sessions per week and a weekly educational meeting on healthy behaviors. Almost 65% (11/17) of the subjects participated in all of the training sessions, and 82% (14/17) participated in the 5K event. Participants did not gain a significant amount of weight during the exercise program (median weight change = 0.7 kg; 25th percentile 0.5, 75th percentile 3.9, p = .10). This study suggests that using an achievable goal, such as a 5K event, promotes adherence to an exercise program and is feasible in a population of people with chronic schizophrenia.
schizophrenia; weight gain; weight management; 5K; healthy behavior