Revealing the pharmacological mechanisms of nao-an dropping pill in preventing and treating ischemic stroke via the PI3K/Akt/eNOS and Nrf2/HO-1 pathways.

Nao-an Dropping Pill (NADP) is a Chinese patent medicine which commonly used in clinic for ischemic stroke (IS). However, the material basis and mechanism of its prevention or treatment of IS are unclear, then we carried out this study. 52 incoming blood components were resolved by UHPLC-MS/MS from rat serum, including 45 prototype components. The potential active prototype components hydroxysafflor yellow A, ginsenoside F1, quercetin, ferulic acid and caffeic acid screened by network pharmacology showed strongly binding ability with PIK3CA, AKT1, NOS3, NFE2L2 and HMOX1 by molecular docking. In vitro oxygen-glucose deprivation/reperfusion (OGD/R) experimental results showed that NADP protected HA1800 cells from OGD/R-induced apoptosis by affecting the release of LDH, production of NO, and content of SOD and MDA. Meanwhile, NADP could improve behavioral of middle cerebral artery occlusion/reperfusion (MCAO/R) rats, reduce ischemic area of cerebral cortex, decrease brain water and glutamate (Glu) content, and improve oxidative stress response. Immunohistochemical results showed that NADP significantly regulated the expression of PI3K, Akt, p-Akt, eNOS, p-eNOS, Nrf2 and HO-1 in cerebral ischemic tissues. The results suggested that NADP protects brain tissues and ameliorates oxidative stress damage to brain tissues from IS by regulating PI3K/Akt/eNOS and Nrf2/HO-1 signaling pathways.

Macrophage KLF15 prevents foam cell formation and atherosclerosis via transcriptional suppression of OLR-1.

BACKGROUND: Macrophage-derived foam cells are a hallmark of atherosclerosis. Scavenger receptors, including lectin-like oxidized low-density lipoprotein (LDL) receptor-1 (OLR-1), are the principal receptors responsible for the uptake and modification of LDL, facilitating macrophage lipid load and the uptake of oxidized LDL by arterial wall cells. Krüppel-like factor 15 (KLF15) is a transcription factor that regulates the expression of genes by binding to the promoter during transcription. Therefore, this study aimed to investigate the precise role of macrophage KLF15 in atherogenesis. METHODS: We used two murine models of atherosclerosis: mice injected with an adeno-associated virus (AAV) encoding the Asp374-to-Tyr mutant version of human PCSK9, followed by 12 weeks on a high-fat diet (HFD), and ApoE-/-- mice on a HFD. We subsequently injected mice with AAV-KLF15 and AAV-LacZ to assess the role of KLF15 in the development of atherosclerosis in vivo. Oil Red O, H&E, and Masson's trichome staining were used to evaluate atherosclerotic lesions. Western blots and RT-qPCR were used to assess protein and mRNA levels, respectively. RESULTS: We determined that KLF15 expression was downregulated during atherosclerosis formation, and KLF15 overexpression prevented atherosclerosis progression. KLF15 expression levels did not affect body weight or serum lipid levels in mice. However, KLF15 overexpression in macrophages prevented foam cell formation by reducing OLR-1-meditated lipid uptake. KLF15 directly targeted and transcriptionally downregulated OLR-1 levels. Restoration of OLR-1 reversed the beneficial effects of KLF15 in atherosclerosis. CONCLUSION: Macrophage KLF15 transcriptionally downregulated OLR-1 expression to reduce lipid uptake, thereby preventing foam cell formation and atherosclerosis. Thus, our results suggest that KLF15 is a potential therapeutic target for atherosclerosis.

Sterol metabolism and protein metabolism are differentially correlated with sarcopenia in Asian Chinese men and women.

OBJECTIVES: Our aim was to investigate the prevalence and predictive variables of sarcopenia. METHODS: We recruited participants from the Peking Union Medical College Hospital Multicenter Prospective Longitudinal Sarcopenia Study (PPLSS). Muscle mass was quantified using bioimpedance, and muscle function was quantified using grip strength and gait speed. Logistic regression revealed the relationships between sarcopenia and nutritional, lifestyle, disease, psychosocial and physical variables. RESULTS: The prevalence of sarcopenia and sarcopenic obesity was 9.2%-16.2% and 0.26%-9.1%, respectively. Old age, single status, undernourishment, higher income, smoking, low physical activity, poor appetite and low protein diets were significantly associated with sarcopenia. Multiple logistic regression analysis showed that age was a risk factor for all stages of sarcopenia, and participants above 80 years were greater than fivefold more susceptible to sarcopenia, while lower physical activity was an independent risk factor. The optimal cut-off value for age was 71 years, which departs from the commonly accepted cut-off of 60 years. Female participants were greater than twofold less susceptible to sarcopenia than male participants. The sterol derivative 25-hydroxyvitamin D was associated with fourfold lower odds of sarcopenia in male participants. Several protein intake variables were also correlated with sarcopenia. Based on these parameters, we defined a highly predictive index for sarcopenia. CONCLUSIONS: Our findings support a predictive index of sarcopenia, which agglomerates the complex influences that sterol metabolism and nutrition exert on male vs female participants.

Synthesis and evaluation of pyrimidoindole analogs in umbilical cord blood ex vivo expansion.

The scarcity of hematopoietic stem cells (HSCs) significantly hindered their clinical potentials. Umbilical cord blood (UCB) has become the leading source of HSCs for both research and clinical applications. But the low content of HSCs in a single UCB unit limited its use only to pediatric patients. Various cytokines and small molecules have demonstrated strong abilities in promoting HSC ex vivo expansion, of which UM171 is the newest and by far the most potent HSC ex vivo expansion agent. In this study, we synthesized 37 pyrimidoindole analogs and identified 6 compounds to be potent in promoting HSC ex vivo expansion. In particular, analog 11 was found to be the most effective in stimulating ex vivo expansion of UCB CD34+ cells and CD34+CD38- cells. Initial data indicated that compound 11 promoted the absolute number of long term HSCs and inhibited their differentiation. UCB HSCs expanded with 11 retained adequate multi-lineage differentiation capacity. In addition, compound 11 is not cytotoxic at its test concentrations, suggesting that it merits further investigation for potential clinical applications.

Oridonin enhances the cytotoxicity of 5-FU in renal carcinoma cells by inducting necroptotic death.

BACKGROUND: 5-fluorouracil (5-FU) is widely used for the treatment of renal carcinoma. However, drug resistance remains the reason for failure of chemotherapy. Oridonin, extracted from Chinese herb medicine, displays anti-tumor effect in several types of cancer. Whether oridonin could enhance the effect of 5-FU in renal carcinoma has not been studied. METHODS: 786-O cells were used in the current study. Cell death was measured by MTT assay or live- and dead-cell staining assay. Glutathione (GSH) level was examined by ELISA. Necroptosis was identified by protein levels of receptors interaction protein-1 (RIP-1) and RIP-3, lactate dehydrogenase (LDH) and high mobility group box-1 protein (HMGB1) release, and poly [ADP-ribose] polymerase-1 (Parp-1) activity. Using a xenograft assay in nude mice, we tested the anti-tumor effects of the oridonin combined with 5-FU. RESULTS: 5-FU only induced apoptosis in 786-O cells. Oridonin activated both apoptosis and necroptosis in 786-O cells. Oridonin-induced necroptosis was reversed by addition of GSH or its precursorN-acetylcysteine (NAC). Oridonin-induced necroptosis was associated by activated JNK, p38, and ERK in 786-O cells, which were abolished by GSH or NAC treatment. However, JNK, p38, and ERK inhibitors showed no effect on oridonin induced-cell death. GSH or NAC treatment partly abolished the synergistic effects of oridonin and 5-FU on cell death. Oridonin enhanced the cytotoxicity of 5-FU both in vitro and in vivo. CONCLUSION: Oridonin enhances the cytotoxicity of 5-FU in renal cancer cells partially through inducing necroptosis, providing evidence of using necroptosis inducers in combination with chemotherapeutic agents for cancer treatment.

Multilayer longitudinal strain at rest may help to predict significant stenosis of the left anterior descending coronary artery in patients with suspected non-ST-elevation acute coronary syndrome.

Two-dimensional speckle tracking echocardiography (2D-STE) multilayer analysis of myocardial deformation is a non-invasive method that enables discrimination of transmural differences owing to myocardial ischemia or necrosis. We wished to ascertain if multilayer longitudinal strains at rest are associated with significant (≥70 %) stenosis of the left anterior descending coronary artery (LAD) in patients with suspected non-ST-elevation acute coronary syndrome (NSTE-ACS). Our cohort comprised 113 consecutive patients with suspected NSTE-ACS and preserved ejection fraction (EF). Using coronary angiography, we diagnosed 63 patients with significant stenosis of the LAD and 50 patients without significant coronary artery disease. Echocardiography was done ≤48 h before angiography. Multilayer longitudinal strains were assessed from the endocardium, mid-myocardium and epicardium by 2D-STE. Regional longitudinal strain in LAD territory (RLSLAD) was calculated as the mean peak systolic longitudinal strain of segments subtended by the LAD for all myocardial layers. Significant differences were observed in all strain parameters between the two groups. RLSLAD and global longitudinal strain in the endocardium showed higher accuracy than that in the mid-myocardium and epicardium, wall motion score index (WMSI), WMSI in LAD territory, and EF for detection of significant LAD stenosis (all P < 0.05), with areas under the receiver operating characteristic curve of 0.87 and 0.91, respectively. An endocardial RLSLAD cutoff of -23.52 % showed optimal sensitivity and specificity (88.9/80.0 %). In patients with suspected NSTE-ACS, multilayer longitudinal strain analysis at rest might enable prediction of significant LAD stenosis, and could help to identify patients requiring reperfusion.

Early Evaluation of Relative Changes in Tumor Stiffness by Shear Wave Elastography Predicts the Response to Neoadjuvant Chemotherapy in Patients With Breast Cancer.

OBJECTIVES: Neoadjuvant chemotherapy plays an important role in comprehensive therapy for breast cancer, but response prediction is imperfect. Shear wave elastography (SWE) is a novel technique that can quantitatively evaluate tissue stiffness. In this study, we sought to investigate the application value of SWE for early prediction of the response to neoadjuvant chemotherapy in patients with breast cancer. METHODS: We prospectively evaluated tumor stiffness in 62 patients with breast cancer using SWE, which was performed at baseline and after the second cycle of neoadjuvant chemotherapy. After chemotherapy, all of the patients underwent surgery. We investigated the correlations between the relative changes in tumor stiffness (Δ stiffness) after 2 cycles of chemotherapy and the pathologic response to the therapy. RESULTS: Compared with baseline values, tumor stiffness after 2 cycles of neoadjuvant chemotherapy was significantly decreased in responders (P < .001) but not in nonresponders (P = .172). The Δstiffness was significantly higher in responders (-42.194%) than in nonresponders (-23.593%; P = .001). As determined at either the baseline or after the second cycle of chemotherapy, tumor stiffness was significantly lower in responders than in nonresponders (P = .033 and .009, respectively). The Δ stiffness threshold for distinguishing between responders and nonresponders was -36.1% (72.92% sensitivity and 85.71% specificity). Furthermore, correlating Δ stiffness with clinical and pathologic characteristics, we found that estrogen and progesterone receptor expression showed statistically significant correlations with Δ stiffness (estrogen receptor, P = .008; progesterone receptor, P = .023). CONCLUSIONS: Early evaluation of relative changes in tumor stiffness using SWE could effectively predict the response to neoadjuvant chemotherapy in patients with breast cancer and might indicate better therapeutic strategies on a timelier basis.

Ultrasound utility for predicting biological behavior of invasive ductal breast cancers.

PURPOSE: The aim of the study was to evaluate the correlation of ultrasound features with breast cancer molecular status. MATERIALS AND METHODS: A retrospective review was performed of ultrasound findings in 263 patients diagnosed with breast invasive ductal carcinoma for comparison with immunohistochemistric results were obtained from each lesion. Relationships between ultrasound findings and molecular status were investigated by using multiple regression analysis by means of stepwise logistic regression. Differences in ultrasound criteria were assessed among women with different molecular status. RESULTS: ER positivity was associated with small size, lobulate, angular or spiculated margin contours, absence of calcification, posterior tumor shadowing and low elasticity score; PR positivity was associated with small size, lobulate or angular or spiculated margin contours and absence of calcification; HER2 positivity was associated with presence of calcification and absence of any echogenic halo. The calculated models of predicted molecular status were accurate and discriminating with AUCs of 0.78, 0.74, and 0.74, respectively. CONCLUSIONS: Breast cnacer ultrasound features show some correlation with the molecular status. These models may help to expand the scope of ultrasound in predicting tumor biology.

[Mental disorder and suicide among youths in rural China: a case control study based on consecutive samples from Hunan, Liaoning and Shandong provinces].

OBJECTIVE: To study the prevalence of mental disorders among the Chinese youths aged 15 - 34 years, in rural areas and to identify risk factors related to suicide. METHODS: A consecutive sampling strategy was used for suicidal cases in 16 randomly selected counties in Hunan, Liaoning, and Shandong provinces. Between 2005 and 2008, a total of 392 suicide cases were recruited with 416 community controls at the same age range, selected from the same areas one family member together with one close friend of each suicidal case were interviewed, using the psychological autopsy (PA) method. The same method with structured instruments was performed on the two informants for each control in the same community. SCID was used for the diagnosis of mental disease. RESULTS: 48.0% of the suicides were diagnosed as having at least one mental disorder episode, in comparison with only 3.8% among the controls. It was found that mental disorder was the most important risk factor for the Chinese young suicide cases in the rural areas. CONCLUSION: As seen in the Western countries, mental disorder had also been the number one correlate on suicidal cases in China, with the difference as other social and psychological factors might have played relatively more important roles in China.