Aim To observe the influence of hydrogen sulfide on L-arginine/nitric oxide synthase(NOS)/NO pathway,explore the interaction between H_2S and NO as cardiovascular regulatory gasotransmitters.Methods Aortic thin slices in vitro were administrated with NaHS(10~(-7) mol?L~(-1)～10~(-4) mol?L~(-1)),a donor of H_2S,and incubated for 4 hours,or 50 ?mol?L~(-1) NaHS and incubated for 2 h,4 h and 6 h,respectively.The nitrite production Was measured with greiss assay;NOS activity and L-arginine transportation,with isotope tracer method;the eNOS and CAT1-A gene expression,with RT-PCR.Results After being given with NaHS(50 ?mol?L~(-1)) one time,and incubating for 2 h,the nitrite production decreased by 62%,NOS activity reduced by 48% and L-arginine transport decreased by 50%.After incubation for 6 h,the nitrite production further was inhibited by 19%(P0.05).NaHS(10~(-7) mol?L~(-1)～10~(-4) mol?L~(-1)) inhibited the L-arginine/NOS/NO pathway in a dose-dependent manner,and IC_(50) was 0.499,3.198 and 3.927 ?mol?L~(-1)(P

AIM: To observe the changes of cystathionine-lyase/hydrogen sulfide(CSE/H_2S) in vivo in vascular calcification and to explore the role of CSE/H_2S in vascular calcification.METHODS: Vascular calcification model in rats was induced by administration of vitamin D_3 plus nicotine.The extent of calcification was estimated by assaying calcium content.[~(45)Ca~(2+)] deposition and alkaline phosphatase(ALP) activity were detected.CSE mRNA amount was determined by using competitive quantitative RT-PCR.The content of H_2S and activity of CSE in the plasma and cardiovascular tissues were also determined with biochemical methods.RESULTS: Calcium content in myocardium increased by 3.8 folds in a calcification model.Compared to control,calcium content,[~(45)Ca~(2+)] accumulation and ALP activity in calcified arteries increased by 6.8,1.4,and 1.9 folds,respectively(P

AIM: To explore the effects of angiotensin II on aortic calcification in the rat. METHODS: Arterial calcification of Sprague-Dawley rats was induced by vitamin D_3 plus nicotine. Calcification was confirmed by Von Kossa staining, measurement of calcium content, [~(45)Ca~(2+)] accumulation and alkaline phosphatase (ALP) activity of vascular tissue. RESULTS: The results showed that calcium content, [~(45)Ca~(2+)] accumulation and ALP activity in calcified arteries increased significantly compared with those of control. Ang Ⅱ levels in plasma and aortic tissues and the amount of angiotensinogen mRNA in calcified aorta were also increased as compared with control. Captopril (inhibitor of ACE) and losartan (Ang Ⅱ receptor inhibitor) decreased significantly the content of calcium, [~(45)Ca~(2+)] uptake and ALP activity in calcified aorta. Ang Ⅱ levels in plasma and aortic tissues and the amount of angiotensinogen mRNA in aortic tissue were down-regulated by captopril. The amount of angiotensinogen mRNA and the content of Ang Ⅱ in the calcified aorta were also decreased by losartan. CONCLUSION: The captopril and losartan significantly alleviate the vascular calcification. [

AIM: The activity and expression of neutral endopeptidase (NEP) and the adrenomedullin (ADM) contents in various tissues were observed in septic shock and control rats to study the possible role of NEP in the change of ADM contents in tissues during septic shock. METHODS: The septic shock model of rats were established by cecal ligation and puncture (CLP). ADM contents, NEP activities, level of NEP mRNA and NEP protein were measured. RESULTS: (1) In early septic shock (ES), the ADM contents were generally higher in detected tissues, the NEP activity in left ventricle and small intestine were lower and was higher in blood than those in controls, and in lung, kidney and aorta were similar with the controls. NEP immunoreactive staining were less in lung, left ventricle, endothelium and media of aorta, but more in adventitia of aorta and kidney than those of the controls; (2) In late septic shock (LS), the ADM contents in small intestine was less but in plasma and other tissues were higher, and the NEP activity were less in plasma and other tissues than those in ES. The NEP immunoreactive staining were less in heart, endothelium and media of aorta, lung and kidney than those in ES, and was no significant change in adventitia of aorta compared with those of ES. RT-PCR found that NEP gene expression were significantly less in left ventricle, aortas, lung and small intestine than those in the controls. CONCLUSIONS: In septic shock rats, the NEP activity changes heterogeneously but the ADM contents elevate in most tissues. These results indicate that during the septic shock, the local concentrations and actions of ADM in various tissues may be regulated differently by the NEP. [

] AIM: Lysophosphatidic acid (LPA) is a bioactive phospholipid known to have growth factor-like activity on fibroblasts, and is involved in cardiovascular diseases. Besides direct effects, usually, LPA can work together with other bioactive factors to regulate cardiovascular homeostasis by induction of their expression and production, or increase in their activity. Among variety of bioactive factors, adrenomedullin (ADM) is a multifunctional peptide with an important cytoprotective effect against cardiovascular damage, but the interaction between ADM and LPA on adventitia remains unknown. METHODS: The experiment was performed on the bath of isolated rat aortic adventitia, ADM produced and secreted from adventitia stimulated by LPA was detected by using radioimmunoassay, proliferation in adventitia cells was evaluated by the level of [3H]-thymine incorporation, and prepro ADM gene expression was measured by semi-quantitative reverse transcriptase polymerase chain reaction. RESULTS: It was found that LPA stimulated aortic adventitia to secrete ADM and express its mRNA in a concentration-dependent manner. ADM inhibited LPA-induced proliferation in adventitial cells, and attenuated the activity of mitogen activated protein kinase (MAPK) stimulated by LPA. In contrast, the treatment with specific antagonists of ADM receptor potentiated the LPA-induced proliferation in adventitial cells. CONCLUSION: LPA stimulates adventitia to produce and secrete ADM, and in turn, ADM produced by adventitia regulates the vascular biological effects of LPA. [

Objective To examine whether the two vascular paracrine/autocrine factors, angiotensin Ⅱ (Ang Ⅱ) and endothelin, participate in the pathogenesis of arterial calcification. Methods Nicotine and vitamin D3 treated rats were studied. Vascular calcification was confirmed by using Von Kossa staining, measurement of calcium content,45Ca2+ uptake assay and alkaline phosphatase (ALP) activity. The plasma and vascular Ang Ⅱ and endothelin levels were measured by using radioimmunoassay. Angiotensinogen and endothelin mRNA levels were determined by RTPCR. Results The arterial calcium content, 45Ca2+ uptake and ALP activity were increased in calcification groups compared with control ( P ＜ 0.01 ). Administration of the angiotensin receptor antagonist losartan, the endothelin receptor antagonist bosentan, and the angiotensin-converting enzyme inhibitor captopril reduced significantly the arterial calcium content, 45Ca2+ uptake and ALP activity. In addition, the plasma and aortic Ang Ⅱ and endothelin contents, and vascular angiotensinogen and endothelin mRNA expression were significantly up-regulated ( P ＜0.05).Conclusions These findings suggest that functional renin-angiotensin system and endothelin pathway are involved in vascular calcification, and that activation of these systems could potentiate pathogenesis of arterial calcification. ( J Geriatr Cardiol 2004;1(2) :108-113. )

Objective:To retrospectively analyze the treatment status of tyrosine kinase inhibitors (TKI) in newly diagnosed patients with chronic myeloid leukemia (CML) in China.Methods:Data of chronic phase (CP) and accelerated phase (AP) CML patients diagnosed from January 2006 to December 2022 from 77 centers, ≥18 years old, and receiving initial imatinib, nilotinib, dasatinib or flumatinib-therapy within 6 months after diagnosis in China with complete data were retrospectively interrogated. The choice of initial TKI, current TKI medications, treatment switch and reasons, treatment responses and outcomes as well as the variables associated with them were analyzed.Results:6 893 patients in CP ( n=6 453, 93.6%) or AP ( n=440, 6.4%) receiving initial imatinib ( n=4 906, 71.2%), nilotinib ( n=1 157, 16.8%), dasatinib ( n=298, 4.3%) or flumatinib ( n=532, 7.2%) -therapy. With the median follow-up of 43 ( IQR 22-75) months, 1 581 (22.9%) patients switched TKI due to resistance ( n=1 055, 15.3%), intolerance ( n=248, 3.6%), pursuit of better efficacy ( n=168, 2.4%), economic or other reasons ( n=110, 1.6%). The frequency of switching TKI in AP patients was significantly-higher than that in CP patients (44.1% vs 21.5%, P<0.001), and more AP patients switched TKI due to resistance than CP patients (75.3% vs 66.1%, P=0.011). Multi-variable analyses showed that male, lower HGB concentration and ELTS intermediate/high-risk cohort were associated with lower cytogenetic and molecular responses rate and poor outcomes in CP patients; higher WBC count and initial the second-generation TKI treatment, the higher response rates; Ph + ACA at diagnosis, poor PFS. However, Sokal intermediate/high-risk cohort was only significantly-associated with lower CCyR and MMR rates and the poor PFS. Lower HGB concentration and larger spleen size were significantly-associated with the lower cytogenetic and molecular response rates in AP patients; initial the second-generation TKI treatment, the higher treatment response rates; lower PLT count, higher blasts and Ph + ACA, poorer TFS; Ph + ACA, poorer OS. Conclusion:At present, the vast majority of newly-diagnosed CML-CP or AP patients could benefit from TKI treatment in the long term with the good treatment responses and survival outcomes.

Alzheimer's disease (AD) is associated with the impairment of white matter (WM) tracts. The current study aimed to verify the utility of WM as the neuroimaging marker of AD with multisite diffusion tensor imaging datasets [321 patients with AD, 265 patients with mild cognitive impairment (MCI), 279 normal controls (NC)], a unified pipeline, and independent site cross-validation. Automated fiber quantification was used to extract diffusion profiles along tracts. Random-effects meta-analyses showed a reproducible degeneration pattern in which fractional anisotropy significantly decreased in the AD and MCI groups compared with NC. Machine learning models using tract-based features showed good generalizability among independent site cross-validation. The diffusion metrics of the altered regions and the AD probability predicted by the models were highly correlated with cognitive ability in the AD and MCI groups. We highlighted the reproducibility and generalizability of the degeneration pattern of WM tracts in AD.
Humans ; White Matter/diagnostic imaging* ; Diffusion Tensor Imaging/methods* ; Alzheimer Disease/complications* ; Reproducibility of Results ; Cognition ; Cognitive Dysfunction/complications* ; Brain/diagnostic imaging*