Tumour-selective activity of RAS-GTP inhibition in pancreatic cancer.

Broad-spectrum RAS inhibition has the potential to benefit roughly a quarter of human patients with cancer whose tumours are driven by RAS mutations1,2. RMC-7977 is a highly selective inhibitor of the active GTP-bound forms of KRAS, HRAS and NRAS, with affinity for both mutant and wild-type variants3. More than 90% of cases of human pancreatic ductal adenocarcinoma (PDAC) are driven by activating mutations in KRAS4. Here we assessed the therapeutic potential of RMC-7977 in a comprehensive range of PDAC models. We observed broad and pronounced anti-tumour activity across models following direct RAS inhibition at exposures that were well-tolerated in vivo. Pharmacological analyses revealed divergent responses to RMC-7977 in tumour versus normal tissues. Treated tumours exhibited waves of apoptosis along with sustained proliferative arrest, whereas normal tissues underwent only transient decreases in proliferation, with no evidence of apoptosis. In the autochthonous KPC mouse model, RMC-7977 treatment resulted in a profound extension of survival followed by on-treatment relapse. Analysis of relapsed tumours identified Myc copy number gain as a prevalent candidate resistance mechanism, which could be overcome by combinatorial TEAD inhibition in vitro. Together, these data establish a strong preclinical rationale for the use of broad-spectrum RAS-GTP inhibition in the setting of PDAC and identify a promising candidate combination therapeutic regimen to overcome monotherapy resistance.

Fruquintinib-induced renal-limited thrombotic microangiopathy: a case report.

BACKGROUND: Fruquintinib is a highly selective inhibitor of vascular endothelial growth factor receptor (VEGFR). Currently, there are no reported cases of fruquintinib causing kidney-restrictive thrombotic microangiopathy (TMA) in the available Chinese and foreign literature. CASE PRESENTATION: In this case report, we presented a 73-year-old patient receiving fruquintinib for metastatic colon cancer, manifesting abundant proteinuria, in which kidney-restrictive TMA was also diagnosed through renal biopsy. As far as we were concerned, this was the frst reported in terms of fruquintinib-induced kidney-restrictive TMA confrmed by renal biopsy. CONCLUSION: This case indicates that fruquintinib may result in kidney-restrictive TMA, which is a rare but life-threatening complication of cancer treatment drug. Therefore, regular monitoring of proteinuria and blood pressure is imperative for all patients undergoing anti-VEGF drug therapy. And renal biopsy should be promptly conducted to facilitate early detection of thrombotic microangiopathy.

The ß subunit of soluble guanylyl cyclase GUCY1B3 exerts cardioprotective effects against ischemic injury via the PKCε/Akt pathway.

The soluble form of guanylyl cyclase (sGC) is the main receptor for the signaling agent nitric oxide (NO), which regulates cardiomyocyte contractile function and attenuates cardiomyocyte hypertrophy. sGC catalyzes the formation of cyclic guanosine monophosphate (cGMP), a regulator of vascular tone, and cardiac NO-sGC-cGMP signaling modulates cardiac stress responses, including ischemia and reperfusion (IR) injury. Here, we investigated the role of GUCY1B3 (the ß subunit of sGC) in cardiomyocyte IR injury and myocardial infarction (MI) in vitro and in vivo. GUCY1B3 was upregulated in neonatal rat ventricular myocytes in response to IR injury, and GUCY1B3 overexpression restored IR-induced cell death and apoptosis. Treatment with specific inhibitors of PKCδ, PKCε, and Akt suggested that the protective effects of GUCY1B3 were mediated by PKCε/Akt signaling. In a mouse model of coronary artery ligation-induced MI, GUCY1B3 silencing aggravated MI-induced cardiac dysfunction and increased infarct size and exacerbated cardiomyocyte apoptosis in association with the inactivation of PKCε and Akt. Our results suggest that GUCY1B3 exerts cardioprotective effects through the modulation of the PKCε/Akt activity and identify a potential mechanism involved in NO-sGC-cGMP signaling in the heart.

Satisfaction of family members with inpatient psychiatric care and its correlates: a national survey in China.

BACKGROUND: Measuring family members' satisfaction with inpatient psychiatric care may help improve the quality of healthcare in psychiatric hospitals. This survey aimed to investigate the satisfaction of family members with inpatient psychiatric care and to explore its associated factors, using a newly-developed 5-item questionnaire. METHODS: This study included 1598 family members of psychiatric inpatients in 32 tertiary public psychiatric hospitals in 29 provinces of China. Satisfaction and demographic data were collected by research staff while patient and hospital data were retrieved separately. RESULTS: We found that the overall satisfaction level was 93.84% (23.46/25). The total satisfaction score in Northeast China was the highest, followed by the East, Middle and West regions (p < 0.001). There was no significant sex difference in total family satisfaction scores. Family members with a lower educational background (elementary school or less) had significantly lower satisfaction. Family members of patients who were diagnosed with schizophrenia were significantly less satisfied with doctor-family communication. In different treatment response subgroups, the marked improvement subgroup had significantly higher total satisfaction scores and subscores. Meanwhile, lower self-payment expenses and a higher number of psychologic treatments offered per day were significantly associated with higher total satisfaction scores and all subscores. Logistic regression showed a higher educational background, more psychologic treatments offered per day, adequacy of professional staffing (higher doctor/bed, nurse/bed and psychologist/bed ratio) were all significantly associated with higher family satisfaction. CONCLUSIONS: We suggest government and hospital managers recruit more mental health professions to improve family satisfaction. If feasible, providing more psychologic treatments to inpatients may also improve families' satisfaction and involvement.

Gremlin2 Regulates the Differentiation and Function of Cardiac Progenitor Cells via the Notch Signaling Pathway.

BACKGROUND/AIMS: The transplantation of cardiac progenitor cells (CPCs) improves neovascularization and left ventricular function after myocardial infarction (MI). The bone morphogenetic protein antagonist Gremlin 2 (Grem2) is required for early cardiac development and cardiomyocyte differentiation. The present study examined the role of Grem2 in CPC differentiation and cardiac repair. METHODS: To determine the role of Grem 2 during CPC differentiation, c-Kit+ CPCs were cultured in differentiation medium for different times, and Grem2, Notch1 and Jagged1 expression was determined by RT-PCR and western blotting. Short hairpin RNA was used to silence Grem2 expression, and the expression of cardiomyocyte surface markers was assessed by RT-PCR and immunofluorescence staining. In vivo experiments were performed in a mouse model of left anterior descending coronary artery ligation-induced MI. RESULTS: CPC differentiation upregulated Grem2 expression and activated the Notch1 pathway. Grem2 knockdown inhibited cardiomyocyte differentiation, and this effect was similar to that of Notch1 pathway inhibition in vitro. Jagged1 overexpression rescued the effects of Grem2 silencing. In vivo, Grem2 silencing abolished the protective effects of CPC injection on cardiac fibrosis and function. CONCLUSIONS: Grem2 regulates CPC cardiac differentiation by modulating Notch1 signaling. Grem2 enhances the protective effect of CPCs on heart function in a mouse model of MI, suggesting its potential as the rapeutic protein for cardiac repair.

Effect of remote ischemic preconditioning on left atrial remodeling and prothrombotic response after radiofrequency catheter ablation for atrial fibrillation.

BACKGROUND: Radiofrequency catheter ablation (RFCA) of atrial fibrillation (AF) is known to induce left atrial remodeling and prothrombotic response. AIMS: This study aimed to evaluate the effect of remote ischemic preconditioning (RIPC) on left atrial remodeling and prothrombotic response induced by RFCA of AF. METHODS: Forty-four patients with drug-refractory paroxysmal AF undergoing RFCA were randomized into RIPC (four short episodes of forearm ischemia) and control groups before the procedure. Blood samples were collected before RIPC/sham RIPC, and 24 and 72 hours later after the procedure. The atrial remodeling marker matrix metalloproteinase-9 (MMP-9) and endothelial damage marker von Willebrand factor (vWF) were measured using enzyme-linked immunosorbent assay. Platelet activation was evaluated by flow cytometric measurements of the expression of platelet P-selectin (CD62P) and active glycoprotein IIb/IIIa receptor (PAC-1). The early recurrence of atrial fibrillation (ERAF) in the two groups was observed over the subsequent 3 months. RESULTS: RFCA resulted in a significant increase in MMP-9 and vWF in both the groups, which persisted for 72 hours. However, the expression of CD62P and PAC-1 showed less increase during RFCA in either group. The RIPC group showed a lower increase in MMP-9 and vWF compared with the control group. In contrast, no significant differences were found in the trend of expression of CD62P and PAC-1 during RFCA between the two groups. The AF recurrence in the 3 months after the ablation was significantly lower in the RIPC group than in the control group. CONCLUSIONS: RIPC before RFCA for paroxysmal AF significantly reduces the increase in markers of left atrial remodeling and endothelial damage associated with the procedure, and results in a lower ERAF.

Sensitive detection of Campylobacter jejuni using one-step strategy based on functional nanospheres of immunomagnetic capture and quantum dots.

Campylobacter jejuni has emerged as the most common bacterial foodborne illness in the developed world. Here, we demonstrate a convenient one-step strategy for detecting C. jejuni. Immunomagnetic nanospheres (IMNS) and immunofluorescent nanospheres (IFNS, quantum dots) were used for the simultaneous, sensitive capture and recognition of C. jejuni. After magnetic separation with the IMNS, detection of C. jejuni was achieved with fluorescence measurement of the IFNS in the sandwich complexes (IMNS-bacteria-IFNS). The limit of detection of this assay was 103 CFU/mL, and the linear range was from 105 to 107 CFU/mL (R2 = 0.9994). When compared with a conventional two-step detection strategy, in which C. jejuni was first captured with the IMNS and then detected using the IFNS, this one-step detection strategy enhance sensitivity and save time. This suggested that the developed method has the potential for use as an alternative to the standard method for food quality assurance, as it provides rapid detection of C. jejuni in foodstuffs and the environment.

Epigallocatechin Gallate Attenuates ß-Amyloid Generation and Oxidative Stress Involvement of PPARγ in N2a/APP695 Cells.

The accumulation of ß-amyloid (Aß) peptide plaques is a major pathogenic event in Alzheimer's disease (AD). Aß is a cleaved fragment of APP via BACE1, which is the rate-limiting enzyme in APP processing and Aß generation. Nuclear receptor peroxisome proliferator-activated receptor gamma (PPARγ) is considered to be a potential target for AD treatment, because of its potent antioxidant and inhibitory effects on Aß production by negatively regulating BACE1. Epigallocatechin gallate (EGCG), a highly active catechin found in green tea, is known to enhance metabolic activity and cognitive ability in the mice model of AD. To investigate whether the therapeutic effect of EGCG is related to the PPARγ pathway, we analysed the alterations in the intracellular molecular expression of PPARγ after EGCG treatment in the N2a/APP695 cell line. In this study, we observed that EGCG attenuated Aß generation in N2a/APP695 cells, such as the PPARγ agonist, pioglitazone, by suppressing the transcription and translation of BACE1 and that its effect was attenuated by the PPARγ inhibitor, GW9662. Intriguingly, EGCG significantly reinforced the activity of PPARγ by promoting its mRNA and protein expressions in N2a/APP695 cells. Moreover, EGCG also decreased the expression of pro-apoptotic proteins (Bax, caspase-3), reduced the activity of the anti-inflammatory agent NF-κB and inhibited the oxidative stress by decreasing the levels of ROS and MDA and increasing the expression of MnSOD. Co-administration of GW9662 also significantly decreased the EGCG-mediated neuroprotective effect evidenced by the increase in oxidative stress and inflammatory markers. The therapeutic efficacy of EGCG in AD may be derived from the up-regulation of PPARγ mRNA and protein expressions.

Fuzhisan Ameliorates the Memory Deficits in Aged SAMP8 Mice via Decreasing Aß Production and Tau Hyperphosphorylation of the Hippocampus.

The pathological features of Alzheimer's disease (AD) include extracellular neuritic plaques containing ß-amyloid (Aß) peptide, a cleaved fragment of amyloid precursor protein (APP) via ß-site amyloid precursor protein-cleaving enzyme 1 (BACE1) and intracellular neurofibrillary tangles (NFTs) composed of hyperphosphorylated tau. Cyclin-dependent kinase 5 (Cdk5) is increasingly thought to play a pivotal role in the pathogenesis of AD, both as a regulator of the production of Aß and through its well-established role as a tau kinase. Fuzhisan (FZS), a Chinese herbal complex prescription, has been used for the treatment AD for over 20 years, and is known to enhance the cognitive ability in AD patients as well as in AD model rats. To investigate mechanisms of AD and the potential therapy of FZS in AD, we treated senescence-accelerated mouse SAMP8 mice, a useful model of AD-related memory impairment, with FZS by intragastrical administration for 8 weeks and Donepizel was used as a positive control. The results showed that FZS (0.3, 0.6, and 1.2 g/kg/day) improved impaired cognitive ability of aged SAMP8 mice in a dose-dependent manner. FZS robustly decreased Aß level and phosphorylation of tau. This was accompanied by a significant decrease in the BACE1 level and phosphorylated APP (Thr668). Futhermore, The p25/Cdk5 pathway was markedly down-regulated by FZS treatment. These results indicated that the memory ameliorating effect of FZS may be, in part, by regulation the p25/Cdk5 pathway which may contribute to down-regulation of Aß and tau hyperphosphorylation.

Efficacy and Safety of Fixed-Dose Perindopril Arginine/Amlodipine in Hypertensive Patients Not Adequately Controlled with Amlodipine 5 mg or Perindopril tert-Butylamine 4 mg Monotherapy.

OBJECTIVES: To assess the blood pressure-lowering efficacy and tolerability of perindopril/amlodipine fixed-dose combinations in Chinese patients with mild-to-moderate essential hypertension not adequately controlled with monotherapy alone. METHODS: In 2 separate double-blind studies, patients received a 4-week run-in monotherapy of amlodipine 5 mg or perindopril 4 mg, respectively. Those whose blood pressure was uncontrolled were then randomized to receive the fixed-dose combination of perindopril 5 mg/amlodipine 5 mg (Per/Amlo group) or remain on the monotherapy for 8 weeks. Patients who were uncontrolled at the week 8 (W8) visit were up-titrated for the Per/Amlo combination, or received additional treatment if on monotherapy, for a further 4 weeks. The main efficacy assessment was at 8 weeks. RESULTS: After 8 weeks, systolic blood pressure (SBP; primary criterion) was statistically significantly lower in the Per/Amlo group (vs. Amlo 5 mg, p = 0.0095; vs. Per 4 mg, p < 0.0001). Uncontrolled patients at W8 who received an up-titration of the Per/Amlo combination showed a further SBP reduction. These changes were mirrored by reassuring reductions in diastolic blood pressure. The fixed-dose combinations were well tolerated. CONCLUSIONS: Single-pill combinations of perindopril and amlodipine provide hypertensive patients with a convenient and effective method of reducing blood pressure.

CCR2 antagonist CCX140-B provides renal and glycemic benefits in diabetic transgenic human CCR2 knockin mice.

Chemokine (C-C motif) receptor 2 (CCR2) is central for the migration of monocytes into inflamed tissues. The novel CCR2 antagonist CCX140-B, which is currently in two separate phase 2 clinical trials in diabetic nephropathy, has recently been shown to reduce hemoglobin A1c and fasting blood glucose levels in type 2 diabetics. In this report, we describe the effects of this compound on glycemic and renal function parameters in diabetic mice. Since CCX140-B has a low affinity for mouse CCR2, transgenic human CCR2 knockin mice were generated and rendered diabetic with either a high-fat diet (diet-induced obesity) or by deletion of the leptin receptor gene (db/db). CCX140-B treatment in both models resulted in decreased albuminuria, which was associated with decreased glomerular hypertrophy and increased podocyte density. Moreover, treatment of diet-induced obese mice with CCX140-B resulted in decreased levels of fasting blood glucose and insulin, normalization of homeostatic model assessment of insulin resistance values, and decreased numbers of adipose tissue inflammatory macrophages. Unlike other CCR2 antagonists, CCX140-B had no effect on plasma levels of the CCR2 ligand CCL2 or on the numbers of blood monocytes. These results support the ongoing evaluation of this molecule in diabetic subjects with impaired renal function.

Feasibility and Diagnostic Accuracy for Assessment of Coronary Artery Stenosis of Prospectively Electrocardiogram-gated High-pitch Spiral Acquisition Mode Dual-source CT Coronary Angiography in Patients with Relatively Higher Heart Rates: in Comparison with Catheter Coronary Angiography.

Objective To prospectively investigate the diagnostic accuracy for coronary artery stenosis of prospectively electrocardiogram-triggered spiral acquisition mode (high pitch mode) dual-source computed tomography coronary angiography (CTCA) in patients with relatively higher heart rates (HR) compared with catheter coronary angiography (CCA). Methods Forty-seven consecutive patients with relatively higher HR (>65 and <100 bpm) (20 male, 27 female; age 55±10 years) who both underwent dual-source CTCA and CCA were prospectively included in this study. All patients were performed CTCA using high pitch mode setting at 20%-30% of the R-R interval for the image acquisition. All coronary segments were evaluated by two blinded and independent observers with regard to image quality on a three-point scale (1: excellent to 3: non-diagnostic) and for the presence of significant coronary stenoses (defined as diameter narrowing exceeding 50%). Considered CCA as the standard of reference, the sensitivity, specificity, positive predictive value and negative predictive value were calculated. Radiation dose values were calculated using the dose-length product. Results Image quality was rated as being score 1 in 92.4% of segments, score 2 in 6.1% of segmentsand score 3 in 1.5% of segments. The average image quality score per segment was 1.064±0.306. The HR variability of patients with image score 1, 2 and 3 were 2.29±1.06 bpm, 5.17±1.37 bpm, 8.88±1.53 bpm, respectively. The average HR variability of patients with different image scores were significantly different (F=170.402, P=0.001). The sensitivity, specificity, positive and negative predictive values were 92.6%, 97.0%, 87.6%, 98.3%, respectively, per segment and 90.0%, 95.2%, 85.3%, 96.9%, respectively, per vessel and 100%, 63.6%, 90.0%, 100%, respectively, per patient. The effective radiation dose was on average 0.86±0.16 mSv. Conclusion In patients with HR more than 65 bpm and below 100 bpm without cardiac arrhythmia, the prospectively electrocardiogram-gated high-pitch spiral acquisition mode with image acquired timing set at 20%-30% of the R-R interval provides a high diagnostic accuracy for the assessment of coronary stenoses combined with a 1.5% of non-diagnostic coronary segments and a radiation dose below 1 mSv.

Tumor-selective effects of active RAS inhibition in pancreatic ductal adenocarcinoma.

Broad-spectrum RAS inhibition holds the potential to benefit roughly a quarter of human cancer patients whose tumors are driven by RAS mutations. However, the impact of inhibiting RAS functions in normal tissues is not known. RMC-7977 is a highly selective inhibitor of the active (GTP-bound) forms of KRAS, HRAS, and NRAS, with affinity for both mutant and wild type (WT) variants. As >90% of human pancreatic ductal adenocarcinoma (PDAC) cases are driven by activating mutations in KRAS, we assessed the therapeutic potential of RMC-7977 in a comprehensive range of PDAC models, including human and murine cell lines, human patient-derived organoids, human PDAC explants, subcutaneous and orthotopic cell-line or patient derived xenografts, syngeneic allografts, and genetically engineered mouse models. We observed broad and pronounced anti-tumor activity across these models following direct RAS inhibition at doses and concentrations that were well-tolerated in vivo. Pharmacological analyses revealed divergent responses to RMC-7977 in tumor versus normal tissues. Treated tumors exhibited waves of apoptosis along with sustained proliferative arrest whereas normal tissues underwent only transient decreases in proliferation, with no evidence of apoptosis. Together, these data establish a strong preclinical rationale for the use of broad-spectrum RAS inhibition in the setting of PDAC.

Efficacy and safety of aranidipine enteric-coated tablets compared with amlodipine in Chinese patients with mild to moderate essential hypertension: a multicenter, randomized, double-blind, parallel-controlled clinical trial.

This is a multicenter, randomized, double-blind, parallel-controlled study, conducted in Chinese patients with mild to moderate essential hypertension. After a 2-week washout period, 236 eligible patients were randomly to receive aranidipine 5-10 mg/d (n = 118) or amlodipine 5-10 mg/d (n = 118) for 10 weeks. The blood pressure and heart rate were evaluated in outpatient clinics, and ambulatory blood pressure monitoring was performed in 24 patients in each group. The blood pressure was significantly decreased in both groups. Compared with amlodipine, the patients who received aranidipine had less response in blood pressure (P < 0.01). The trough/peak ratios of diastolic blood pressure in aranidipine and amlodipine groups were 0.57 ± 0.20 and 0.68 ± 0.19, respectively (P = 0.119). Adverse events occurred at 11.86% and 7.63% in the aranidipine and amlodipine groups, respectively (P = 0.348). Headache was observed at an incidence of >3.0% in both groups, and the serum glucose and lipid profile had no significant change in the amlodipine group. In conclusion, once-daily administration of aranidipine (5-10 mg) effectively controlled blood pressure, and the short-term treatment might result in it being less effective than amlodipine. It had a stable action over 24-hour period, and the mechanism of that is not yet clear. Aranidipine had a good safety similar to that of amlodipine.

Machine learning-based integration develops biomarkers initial the crosstalk between inflammation and immune in acute myocardial infarction patients.

Great strides have been made in past years toward revealing the pathogenesis of acute myocardial infarction (AMI). However, the prognosis did not meet satisfactory expectations. Considering the importance of early diagnosis in AMI, biomarkers with high sensitivity and accuracy are urgently needed. On the other hand, the prevalence of AMI worldwide has rapidly increased over the last few years, especially after the outbreak of COVID-19. Thus, in addition to the classical risk factors for AMI, such as overwork, agitation, overeating, cold irritation, constipation, smoking, and alcohol addiction, viral infections triggers have been considered. Immune cells play pivotal roles in the innate immunosurveillance of viral infections. So, immunotherapies might serve as a potential preventive or therapeutic approach, sparking new hope for patients with AMI. An era of artificial intelligence has led to the development of numerous machine learning algorithms. In this study, we integrated multiple machine learning algorithms for the identification of novel diagnostic biomarkers for AMI. Then, the possible association between critical genes and immune cell infiltration status was characterized for improving the diagnosis and treatment of AMI patients.

Therapeutic efficacy of dapagliflozin on diabetic kidney disease in rats.

AIM: Diabetic kidney disease (DKD) is one of the severe microvascular complications of type 2 diabetes mellitus (T2DM), which eventually leads to irreversible renal damage and develops into end-stage renal disease (ESRD). Sodium-glucose cotransporter-2 (SGLT2) inhibitors are a new class of antidiabetic drugs that act on the kidney to reduce glucose reabsorption. Increasing evidence confirms that dapagliflozin exerts a protective effect on DKD, but the mechanisms have not been reported. The aims of this study were to observe the therapeutic efficacy of dapagliflozin on DKD and investigate the possible immunological mechanism. MATERIALS AND METHODS: T2DM was modeled by a high-sugar and high-fat diet combined with STZ. Then, rats were treated with 10 mg/kg dapagliflozin for 8 weeks. The protective efficacy of dapagliflozin was evaluated by observing body weight, blood glucose, blood serum creatinine, blood urea nitrogen, 24-h urine protein, renal histology and ultrastructure, and oxidative stress levels. The immunological mechanisms were monitored by measuring the levels of TLR2/Myd88/NF-κB by immunohistochemical staining, RT-qPCR and Western blotting. RESULTS: After treatment with dapagliflozin, renal damage was greatly improved. The levels of blood glucose, renal function and proteinuria were significantly decreased, and renal pathological and ultrastructural damage was obviously extenuated, possibly due to the reduction in inflammation and the levels of oxidative stress. CONCLUSIONS: Dapagliflozin has therapeutic potential for DKD. This effect was possibly mediated by inhibiting inflammation and oxidative stress levels.

Inhibition of glycogen synthase kinase-3ß by Angelica sinensis extract decreases ß-amyloid-induced neurotoxicity and tau phosphorylation in cultured cortical neurons.

Increasing evidence has shown that ß-amyloid (Aß) induces hyperphosphorylation of tau and contributes to Aß toxicity. Recently, tau hyperphosphorylation by glycogen synthase kinase-3ß (GSK-3ß) activation has been emphasized as one of the pathogenic mechanisms of Alzheimer's disease (AD). The phosphoinositide 3 kinase (PI3K)/Akt pathway is known as an upstream element of GSK-3ß. The inhibitory control of GSK-3ß, via the PI3K/Akt pathway, is an important mechanism of cell survival. In the present study, we investigated the neuroprotective effects of Angelica sinensis (AS), a traditional Chinese herbal medicine, against Aß(1-42) toxicity in cultured cortical neurons and also the potential involvement of PI3K/Akt/GSK-3ß signal pathway. We revealed that AS extract significantly attenuated Aß(1-42) -induced neurotoxicity and tau hyperphosphorylation at multiple AD-related sites in a dose-dependent manner. Simultaneously, it increased the levels of phospho-Ser(473) -Akt and down-regulated GSK-3ß activity by PI3K activation. The neuroprotective effects of AS extract against Aß(1-42) -induced neurotoxicity and tau hyperphosphorylation were blocked by LY294002 (10 µM), a PI3K inhibitor. In addition, AS extract reversed the Aß(1-42) -induced decrease in phosphorylation cyclic AMP response element binding protein (CREB), which could be blocked by the PI3K inhibitor. These results suggest that AS-mediated neuroprotection against Aß toxicity is likely mediated by the PI3K/Akt/GSK-3ß signal pathway.

Fuzhisan, a Chinese herbal medicine, inhibits beta-amyloid-induced neurotoxicity and tau phosphorylation through calpain/Cdk5 pathway in cultured cortical neurons.

It has been shown that ß-amyloid (Aß) induced hyperphosphorylation of tau is implicated in the pathogenesis of Alzheimer's disease (AD), and deregulation of cyclin-dependent kinase 5 (Cdk5) activity is involved in the abnormal tau phosphorylation. The cleavage of neuron-specific Cdk5 activator, p35, to p25, mediated by calpain and calcium, deregulates Cdk5 activity and promotes neurodegeneration. Fuzhisan (FZS), a Chinese herbal complex prescription that has been used for the treatment of AD for over 15 years, is known to enhance the cognitive ability in AD patients. In this study, we investigated the neuroprotective effects and potential molecular mechanisms of FZS against Aß(25-35)-induced toxicity in cultured cortical neurons. We revealed that FZS attenuated Aß(25-35)-induced neurotoxicity in a dose-dependent manner. FZS inhibited Aß(25-35)-induced activation of Cdk5 and decreased tau hyperphosphorylation although it did not directly inhibit Cdk5. In addition, FZS also blocked Aß(25-35)-induced calcium influx, calpain activation and decreased cleavage of p35 to p25.

Effect of high-voltage electrostatic field pretreatment on the antioxidant system in stored green mature tomatoes.

BACKGROUND: High-voltage electrostatic field (HVEF), as a feasible and non-chemical technique, applied to food preservation is a new area of study. Our previous research suggested HVEF could maintain the quality of tomato in storage. The present article intensively investigated the effect of HVEF pretreatment on antioxidant system of green mature tomato in storage. RESULTS: Green mature tomatoes were exposed to negative (or positive) HVEF for 2 h at 20 °C and then stored for 24 days at 13 ± 1 °C, 85-90% relative humidity. The results indicated HVEF significantly reduced contents of O(2)(-) and H(2)O(2) of tomato fruits during storage compared to the control. HVEF treatment also enhanced the activities of antioxidant enzymes including catalase, superoxide dismutase, ascorbate peroxidase and peroxidase. The contents of non-enzyme antioxidant components including reduced glutathione, phenols and ascorbic acid also were increased by HVEF treatment. However, HVEF treatment did not increase the content of lycopene in tomato fruit. CONCLUSION: HVEF treatment could promote the antioxidant capacity of tomato fruits in storage. Further research is be highly recommended to understand the mechanisms improving the antioxidant capacity of tomato fruits by HVEF.

C-C chemokine receptor 5 signaling contributes to cardiac remodeling and dysfunction under pressure overload.

Aortic stenosis (AS) leads to chronic pressure overload, cardiac remodeling and eventually heart failure. Chemokines and their receptors have been implicated in pressure overload­induced cardiac remodeling and dysfunction. In the present study, the role of C­C chemokine receptor 5 (CCR5) in pressure overload­induced cardiac remodeling and dysfunction was investigated in mice subjected to transverse aortic constriction (TAC). Cardiac levels of CCR5 and C­C motif chemokine ligands (CCLs)3, 4 and 5 were determined by western blotting and reverse transcription­quantitative PCR, respectively. Cardiac functional parameters were evaluated by echocardiographic and hemodynamic measurements. Myocardial fibrosis was assessed by Masson's trichrome staining and α­smooth muscle actin immunostaining. Myocardial hypertrophy and inflammatory cell infiltration were evaluated by hematoxylin and eosin staining. Angiotensin II (Ang II)­induced hypertrophy of H9c2 cardiomyocytes was assessed by F­actin immunostaining. ERK1/2 and P38 phosphorylation was examined by western blotting. TAC mice exhibited higher myocardial CCL3, CCL4, CCL5 and CCR5 levels compared with sham mice. Compared with sham mice, TAC mice also exhibited impaired cardiac function along with myocardial hypertrophy, fibrosis and inflammatory cell infiltration. TAC­induced cardiac remodeling and dysfunction were effectively ameliorated by administration of anti­CCR5 but not by IgG control antibody. Mechanistically, increased ERK1/2 and P38 phosphorylation was detected in TAC hearts and Ang II­stimulated H9c2 cardiomyocytes. Treatment with anti­CCR5 antibody decreased ERK1/2 and P38 phosphorylation and attenuated Ang II­induced H9c2 cell hypertrophy. CCR5 inhibition protected against pressure overload­induced cardiac abnormality. The findings of the present study indicate that ERK1/2 and P38 signaling pathways may be involved in the cardioprotective effects of CCR5 inhibition.