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.

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.

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.

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.

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.

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.

Protective Effect of S-Allyl Cysteine Against Neonatal Asthmatic Rats.

S-Allyl cysteine (SAC), an organic compound and a natural constituent of Allium sativum, commonly known as garlic have been consumed in routine foods are known to possess various biological activities. Nevertheless, scientific evidence on the protective effect of SAC against neonatal asthmatic rats is not available. Hence, the present study aimed at investigating the anti-asthmatic activity of SAC in neonatal asthmatic rats using Wistar rats. The study conducted in 4 groups consists of normal control rats, asthma-induced, asthma animals administered with SAC (25 mg/kg), and SAC control. At the end of the experimental period, inflammatory cells in bronchoalveolar lavage fluid (BALF), inflammatory markers, fibrinogen level, activated partial thromboplastin time, coagulation factor activity, and histopathology were elucidated. The current investigation exhibits that SAC significantly reduced the total leukocytes, with restored fibrinogen level, and activated partial thromboplastin time. In addition, the levels of inflammatory cytokines such as TNF-α (tumor necrosis factor- α), IL-6 (Interleukin 6), and IL-1ß have also attenuated in SAC treated animals. Furthermore, the mRNA expression levels of COX2 (cyclooxygenase-2), MCP-1 (monocyte chemoattractant protein-1), RANTES (regulated upon activation, normal T cell expressed and secreted), and eotaxin were reduced in SAC treated animals. Treatment of rats with SAC significantly reduced inflammation and eosinophil infiltration in the lungs. These results suggest that SAC exert protection in neonatal asthmatic rats suffering from acute or chronic inflammation by inducing anti-inflammatory and cell-protective responses.

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.

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.

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.

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.

Evaluation of dual energy computed tomography iodine mapping within the myocardial blood pool for detection of acute myocardial infarction: correlation with histopathological findings in a porcine model.

OBJECTIVE: We assessed the diagnostic value of "one-step" dual energy CT (DECT) in combination with coronary CT angiography and iodine mapping within the myocardial blood pool in detecting acute myocardial infarction (AMI). METHODS: Five minipigs were subjected to transcatheter embolization of coronary artery with a gelatin sponge to induce AMI. Arterial-phase myocardial DECT imaging was carried out 1 h before and 24 h after embolism of the coronary. Color-coded iodine maps were used to evaluate myocardial blood pool deficits in the 17-segment model. Myocardial DECT imaging 24 h after MI induction was used for final comparison with post-mortem histology. RESULTS: We found a sensitivity of 95.55% and a specificity of 95%, respectively, for AMI detection by DECT-based iodine mapping within the myocardial blood pool. The dose-length product values were 219.4 ± 60.9 mGy.cm (172-321 mGy.cm) and the effective radiation dose was 5.7 ± 1.5 mSv (4.4-8.3 mSv). CONCLUSION: This experimental study demonstrated that DECT-based iodine mapping shows a high value for the detection of myocardial perfusion defects in the first-pass myocardial perfusion. Hybrid heart images obtained by coronary CT angiography and DECT-based iodine mapping may yield valuable data and help clinicians accurately identify cases requiring further treatment after AMI. Advances in knowledge: This study demonstrated that DECT-based iodine mapping is a promising new technique for the detection of myocardial perfusion defects in the first-pass myocardial perfusion.

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.

Inflammatory biomarkers of coronary heart disease.

Coronary heart disease (CHD) is one of the leading causes of death worldwide. CHD is characterized by formation of arterial plaques which are mainly comprised of lipids, calcium and inflammatory cells. These plaques narrow the lumen of coronary arteries leading to episodic or persistent angina. Rupture of these plaques leads to the formation of thrombus, which as a result of cessation of blood flow, causes myocardial infarct and death. CHD is exacerbated by risk factors including obesity, diabetes mellitus, and hypertension. Diagnosis is established by the level of blood cholesterol, triglycerides and lipoproteins Inflammation is considered significant in the pathogenesis of CHD and for this reason, severity and prognosis of CHD is assessed by the levels of inflammatory biomarkers, including interleukin-6, C-reactive protein (CRP), complement, CD40 and myeloperoxidase (MPO).

[Triperygium wilfordii multiglucoside ameliorates kidney damage in diabetic rats by inhibiting the expressions of MBL and MASP2].

Objective To explore the effect of Triperygium wilfordii multiglucoside (TWM) on the expressions of mannose-binding lectin (MBL) and mannan-binding lectin serine peptidase 2 (MASP2) in the kidney of diabetic rats, and discuss the protective role of TWM in diabetic nephropathy and its possible mechanism. Methods Forty-five male SD rats were randomly assigned into model group (n=35) and normal control group (n=10). Rats in the normal control group were fed with regular diet, while those in the model group were fed with high-fat high-sugar diet and given an intraperitoneal injection of 40 mg/kg streptozotocin (STZ) six weeks later. The successfully induced type 2 diabetic rat models (n=33) were then randomized into DM group (n=16) and TWM treatment group (n=17) treated with TWM [10 mg/(kg.d)] for eight weeks. At the end of 14th week, the levels of blood sugar, 24-hour urine protein, serum creatinine and blood urea nitrogen were measured. Renal pathological changes were examined with PAS staining. MBL-A and MASP2 expressions were detected by immunohistochemistry in the renal tissues. The expressions of MBL1, MASP2, NF-κB and MCP-1 mRNAs were semi-quantified by real-time PCR. The expressions of MBL-A, MASP2, NF-κB and MCP-1 proteins were determined by Western blotting. Results Compared with the diabetic group, the levels of serum creatinine, blood urea nitrogen, 24-hour urine protein decreased, renal histopathology was improved, the expressions of MBL, MASP2, NF-κB and MCP-1 mRNAs and proteins were reduced in the TWM group. Correlation analysis showed that the expression of MBL was positively correlated with MASP2, NF-κB, MCP-1 and 24-hour urine protein. Conclusion MBL and MASP2 are over-expressed in the kidney of diabetic rats. TWM can ameliorate kidney damage in diabetic rats and delay the development of diabetic nephropathy by inhibiting the expressions of MBL and MASP2.

Nonalcoholic Fatty Liver Disease and Coronary Artery Calcification in a Northern Chinese Population: a Cross Sectional Study.

Nonalcoholic fatty liver disease (NAFLD) has become an emerging health issue with a high prevalence in general population. The cross-sectional study was performed to investigate the association between NAFLD and coronary artery calcification (CAC) in individuals from northern city of China. A total of 2345 participants aged ≥40 (1035 men and 1310 women) were selected from the Jidong community of Tangshan city. Liver ultrasonography was used to the diagnosis of NAFLD. A 64-slice CT scanner was used to determine coronary artery calcification score (CACS), with CACS > 0 defined to be the presence of CAC. The risk level of coronary heart disease (CHD) was graded by CACS according to the 4 commonly used thresholds in clinical practice (0, 10, 100, and 400 Agatston units). NAFLD was significantly associated with CAC (crude OR: 1.631, 95% CI: 1.295-2.053, adjusted OR: 1.348, 95% CI: 1.030-1.765). The association between NAFLD and increased risk level of CHD (Crude OR: 1.639 95% CI: 1.303-2.063; adjusted OR: 1.359 95% CI: 1.043-1.770) was observed. The associations between NAFLD and CAC or increased risk level of CHD were significant in female but not in male. Our finding further confirmed the association between NAFLD and CAC, especially in Asian population.

Diagnostic accuracy of coronary CT angiography combined with dual-energy myocardial perfusion imaging for detection of myocardial infarction.

The aim of the present study was to evaluate the diagnostic accuracy of second generation dual-energy computed tomography (DECT) myocardial perfusion imaging for the detection of myocardial infarction (MI) in patients with suspected MI. In total, 56 patients underwent DECT. Among those, 40 patients had MI that was detected by catheter coronary angiography and cardiac troponin I elevation and evolution of acute MI detected by electrocardiogram changes. The diagnostic accuracy, including the sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) for the detection of MI were evaluated, as well as the coronary image quality of coronary artery and radiation dose. The sensitivity, specificity, PPV and NPV for the detection of MI were 95.0, 97.0, 86.4 and 98.9%, respectively. Moreover, the image quality was rated excellent (score 1) in 90.2% (515/571), good (score 2) in 6.5% (37/571), adequate (score 3) in 1.9% (11/571) and non-diagnostic (score 4) in 1.4% (8/571) of the coronary segments. The effective radiation dose was on average 6.1±1.5 mSv (3.1-10.9 mSv). Therefore, combined DE iodine maps and coronary CT angiography using the DECT may provide a high diagnostic accuracy for detecting MI with lower radiation exposure in patients with suspected MI.

Cardioprotective Effects of SIRT6 in a Mouse Model of Transverse Aortic Constriction-Induced Heart Failure.

SIRT6, a member of the NAD (+)-dependent class III deacetylase sirtuin family, plays important roles in the maintenance of cardiovascular homeostasis. Telomere shortening is a risk factor for age-associated diseases, including heart disease. In the present study, we investigated the role of SIRT6 and telomerase in a mouse model of transverse aortic constriction (TAC)-induced heart failure. SIRT6, telomerase reverse transcriptase (TERT), and telomere repeat binding factor (TRF)-1 were significantly downregulated in TAC mice compared with their expression in sham-operated mice. Lentiviral vector-mediated overexpression of SIRT6 upregulated TERT and TRF1 and increased the survival of mice after TAC. Echocardiography and hemodynamic measurements as well as histological analyses indicated that SIRT6 overexpression attenuated TAC-induced heart dysfunction and decreased TAC-induced cardiac inflammatory responses, reducing cardiac fibrosis and decreasing infarct size. Taken together, our findings indicate that SIRT6 protects the myocardium against damage and this effect may be mediated by the modulation of telomeres. Our findings linking SIRT6 and telomere integrity in the heart warrant further investigation into the underlying mechanisms and support SIRT6 as a promising therapeutic target for the treatment of cardiovascular diseases.

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.

New insights into epigenetic modifications in heart failure.

Heart failure (HF) is a complex syndrome that occurs when the heart is unable to take in and/or eject sufficient blood to meet the needs. HF is generally accompanied by hypertrophic changes of cardiac myocytes, the hallmark of HF. At the molecular level, these changes in cardiomyocyte phenotypes are linked to reprogramming of gene expression. Therefore, understanding the molecular mechanisms involved in these gene expression changes in HF could allow for the development of new therapies for this pathology. One mechanism of gene expression regulation that attracts attention is epigenetic modifications, including DNA methylation, histone methylation and acetylation, microRNA, and long noncoding RNA. In this review, we will discuss diverse functions of these epigenetic modifications in HF, and highlight growing evidence for the important roles of epigenetic changes acting as biomarkers for early diagnosis and prognosis of HF, or even as therapeutic targets in HF.