Mitophagy-Mediated Tumor Dormancy Protects Cancer Cells from Chemotherapy.

Despite obvious tumor shrinkage, relapse after chemotherapy remains a main cause of cancer-related mortality, indicating that a subpopulation of cancer cells acquires chemoresistance and lingers after treatment. However, the mechanism involved in the emergence of chemoresistant cells remains largely unknown. Here, we demonstrate that the degradation of mitochondria via autophagy leads to a dormant state in a subpopulation of cancer cells and confers on them resistance to lethal cisplatin (DDP) exposure. The surviving DDP-resistant cells (hereafter, DRCs) have a lower metabolic rate but a stronger potential malignant potential. In the absence of DDP, these DRCs exhibit an ever-increasing self-renewal ability and heightened tumorigenicity. The combination of chloroquine and DDP exerts potent tumor-suppressive effects. In summary, our findings illuminate the mechanism between mitophagy and tumor dormancy and prove that targeting mitophagy might be a promising approach for overcoming chemoresistance in head and neck squamous cell carcinoma (HNSCC).

Rapid improvement in carotid adventitial angiogenesis and plaque neovascularization after rosuvastatin therapy in statin treatment-naïve subjects.

BACKGROUND: Statin therapy can improve plaque stability. However, the time course of effects of statin on adventitial angiogenesis and plaque neovascularization has not been studied. OBJECTIVE: The objective of the study was to investigate whether statin therapy reduces plaque neovascularization, associated with adventitial angiogenesis, over 24 months as assessed by using carotid dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI). METHODS: Forty-three lipid treatment-naïve subjects with asymptomatic carotid atherosclerosis received rosuvastatin (5-20 mg/d) to lower low-density lipoprotein cholesterol to <80 mg/dL for 24 months. Carotid DCE-MRI was performed at baseline, 3, 12 and 24 months. Vascularity (Vp = fractional plasma volume) and vascular permeability (Ktrans = transfer constant) derived from kinetic modeling of DCE-MRI were measured in both adventitia and plaque. RESULTS: Adventitia Vp and adventitia Ktrans were significantly correlated with plaque Vp and plaque Ktrans at baseline. Rosuvastatin significantly reduced both adventitial and plaque Vp significantly at 3 months from 0.121 ± 0.064 to 0.085 ± 0.049 (P = .008) and from 0.096 ± 0.052 to 0.067 ± 0.043 (P = .013). Adventitial and plaque Vp continued to decrease by 43% and 34% at 12 months and by 49% and 45% at 24 months. However, the continued reductions from 3 to 12 months and from 12 to 24 months were not statistically significant. Adventitial and plaque Ktrans showed similar trends, but nonstatistically significant decreases during the 24 months of treatment. CONCLUSIONS: Rosuvastatin therapy rapidly and significantly decreased adventitial and plaque neovascularization at 3 months followed by continued, but nonstatistically significant, decreases at 12 and 24 months.

[Relationship between blood pressure variability and combined cardiovascular events in 5-10 years in hypertensive patients].

OBJECTIVE: To explore the relationship between blood pressure variability (BPV) and combined cardiovascular events in 5-10 years in patients with hypertension. METHODS: A total of 367 hypertensive patients treated in our hospital from January, 2000 to January, 2005 were analyzed, and their BPV was assessed in comparison with 145 normotensive individuals. The hypertensive patients were classified into high BPV group and low BPV group, and the general clinical data and biochemical profiles were compared. The relationship between BPV and combined cardiovascular events of the patients within 5-10 years were explored. RESULTS: Compared with the normotensive individuals, the hypertensive patients showed significantly increased standard deviation and coefficient of variation of 24-h systolic blood pressure (SBP), 24-h diastolic blood pressrue (DBP), daytime SBP, daytime DBP, night-time SBP and night-time DBP (P<0.01). The percentages of drinking, smoking, diabetes and coronary heart disease were significantly higher in patients with high BPV than those with lower BPV (P<0.01 or 0.05); uric acid, homocysteine, urinary protein/creatinine ratio and urinary microalbumin increased more significantly in patients with high BPV (P<0.01 or 0.05). In addition, the combined cardiovascular events in 5-10 years were significantly higher in the patients with higher BPV than those with lower BPV (P<0.01 or 0.05). Logistic multivariate logistic regression analysis showed that alcohol, diabetes, coronary heart disease, uric acid and homocysteine were independent risk factors for cardiovascular events in hypertensive patients (P<0.01 or 0.05). CONCLUSION: In hypertensive patients, BPV is closely correlated with the long-term combined cardiovascular events, and a high BPV is associated with a greater likeliness of combined cardiovascular events.

The neutrophil-to-lymphocyte ratio on admission is a good predictor for all-cause mortality in hypertensive patients over 80 years of age.

BACKGROUND: Immuno-inflammation plays a major role in the process of hypertension. We aimed to evaluate the association between inflammatory markers, neutrophil-to-lymphocyte ratio (NLR), red cell distribution width (RDW) and all-cause mortality in elderly patients with hypertension. METHODS: A total of 341 hypertensive patients over 80 years of age were included to this study. The NLR and RDW were measured on admission and all the selected patients were followed up for up to 90 days. Kaplan-Meier curves were plotted to evaluate the association between the NLR and the all-cause mortality at follow-up. Using Cox regression models, we investigated the prognostic value of NLR and RDW for all-cause mortality. RESULTS: Patients with higher quartile of NLR linked to high mortality in hypertensive patients at 90 day after admission (16.47%,13.25%,1.14%,1.17% respectively; χ2 = 20.581,P = 0.000). Surviving patients had lower RDW (13.61 ± 1.37 VS 14.18 ± 1.38, p = 0.041) and NLR (4.97 ± 5.72 VS 7.95 ± 6.88,p = 0.011). The receiver operating curve (ROC) of the NLR for all-cause mortality had an area under the curve (AUC) =0.714 (95%CI: 0.629-0.798, P = 0.000), with acritical value of 2.97, with sensitivity of 92.6%, and a specificity of 52.5%. The ROC of the RDW to predict all-cause mortality, had an AUC =0.654 (95%CI:0.548-0.761, P = 0.008), with acritical value of 13.2%.The Kaplan-Meier curve showed a significant difference between different NLR levels (p = 0.002). Multivariate Cox proportional hazard analysis shown 3rd quartile of NLR(RR = 9.646, 95% CI 1.302-34.457, P = 0.041) and 4th quartiles(RR = 16.451, 95% CI 2.137-66.643, P = 0.007) were found to independently predict all-cause death in hypertensive patients over 80 years of age. Higher rank of NLR was link to higher incidence of all-cause death for such patients. CONCLUSION: The findings of the present study demonstrate the potential utility of NLR in risk stratification of elderly patients with hypertension to provide information for clinical treatment strategies.

Changes in carotid plaque tissue composition in subjects who continued and discontinued statin therapy.

BACKGROUND: Changes in plaque tissue components such as lipid-rich necrotic core (LRNC) and fibrous tissue with long-term statin treatment or discontinuation have not been studied. OBJECTIVE: LRNC and fibrous tissue by magnetic resonance imaging were evaluated in subjects who continued and discontinued statin therapy for 2 years after a prospective study. METHODS: The Rosuvastatin Evaluation of Atherosclerotic Chinese Patients study in 32 lipid treatment naïve subjects showed a significant reduction in LRNC during 24 months of rosuvastatin therapy. After Rosuvastatin Evaluation of Atherosclerotic Chinese Patients was completed, 15 subjects continued taking statins and 17 discontinued despite receiving an instruction to continue statin therapy. LRNC and fibrous tissue were compared between 24 and 48 months within each group and between the 2 groups. RESULTS: At 48 months, LRNC volume and composition decreased significantly compared with that at 24 months in the statin-continued group (101 ± 76 vs 76 ± 65 mm(3); P = .001 and 17.3 ± 11.9% vs 12.6 ± 7.6%; P = .04), whereas fibrous tissue increased significantly in both volume (337 ± 160 vs 357 ± 169 mm(3); P < .001) and composition (76.3 ± 10.5% vs 83.1 ± 10.1%, P = .002). Such changes were not seen in subjects who discontinued statin. Furthermore, the changes in LRNC volume and composition and fibrous tissue composition from 24 to 48 months were significantly different between the statin-continued and -discontinued groups (-25 ± 18 vs 9 ± 14 mm(3); P < .001) and (-4.6 ± 8.2% vs 1.3 ± 2.8%; P = .009) and (6.9 ± 6.8% vs 1.3 ± 5.4%, P = .018). CONCLUSIONS: Continued statin therapy leads to continued decrease in LRNC and increase in fibrous tissue, which indicates improved plaque stability and supports long-term statin therapy.

Involvement of energy metabolism to chilling tolerance induced by hydrogen sulfide in cold-stored banana fruit.

In this study, the effect of hydrogen sulfide (H2S) on energy metabolism in postharvest banana fruit under chilling stress was investigated. Banana fruit, fumigated with optimal concentration (0.5mM) of aqueous sodium hydrosulfide (NaHS) solution for 24h, were initially stored at 7°C for 14d and 20°C for another 6d. H2S treated banana fruit showed both higher value of firmness and Hue angle, as well as lower value of electrolyte leakage, malondialdehyde (MDA) content and ethylene production. These indicated slower development of chilling injury compared with the control. Decrease in adenosine triphosphate (ATP) and energy charge was not noticeable in H2S treated banana fruit. Moreover, the activity of H(+)-ATPase, Ca(2+)-ATPase, cytochrome C oxidase (CCO) and succinate dehydrogenase (SDH), associated with energy metabolism, were significantly enhanced by H2S treatment. Therefore, it can be deduced that H2S can potentially alleviate chilling development in banana fruit by increasing enzymes activities, involved in energy metabolism, to maintain energy charge.

[The effect of rosuvastatin therapy on CCR2 expression in mononuclear cells and its upstream pathway].

OBJECTIVE: To investigate the effect of rosuvastatin therapy on C-C chemokine receptor(CCR2)expression in mononuclear cells in patients with carotid atherosclerosis and explore the possible upstream mechanism. METHODS: Twenty patients without previous statin treatment were enrolled. Rosuvastatin were given 5 to 20 mg/day for 3 months. At baseline and 12 weeks, lipid profile and plasma monocyte chemotactic protein-1 (MCP-1) levels were examined. The mRNA and protein expressions of CCR2 in the mononuclear cells were measured with RT-PCR and flow cytometry, respectively. The mRNA and protein expression of peroxidase proliferator-activated receptor(PPAR ß) were detected with RT-PCR and Western blot, respectively. RESULTS: After 3-months rosuvastatin treatment, the patients' low-density lipoprotein cholesterol (LDL-C) levels decreased significantly (P<0.01). Compared with baseline, the mRNA and protein expressions of CCR2 in the mononuclear cells showed significantly decrease, as well as plasma MCP-1 levels (P<0.05). Both mRNA and protein expressions of PPAR ß in the mononuclear cells increased (P<0.05). CONCLUSIONS: Rosuvastatin may attenuate MCP-1/CCR2 through PPARß upstream pathway.

Early decrease in carotid plaque lipid content as assessed by magnetic resonance imaging during treatment of rosuvastatin.

BACKGROUND: Statin therapy has shown to deplete atherosclerotic plaque lipid content and induce plaque regression. However, how early the plaque lipid depletion can occur with low-density lipoprotein cholesterol (LDL-C) lowering in humans in vivo has not been fully described. METHODS: We enrolled 43 lipid treatment naïve subjects with asymptomatic carotid atherosclerosis and LDL-C ≥ 100 and ≤ 250 mg/dl. Rosuvastatin 5-20 mg/day was used to lower LDL-C levels to < 80 mg/dl. Lipid profile and carotid MRI scans were obtained at baseline, 3, 12, and 24 months. Carotid plaque lipid-rich necrotic core (LRNC) and plaque burden were measured and compared between baseline and during treatment. RESULTS: Among the 32 subjects who completed the study, at 3 months, an average dose of rosuvastatin of 11 mg/day lowered LDL-C levels by 47% (125.2 ± 24.4 mg/dl vs. 66.7 ± 17.3 mg/dl, p < 0.001). There were no statistically significant changes in total wall volume, percent wall volume or lumen volume. However, LRNC volume was significantly decreased by 7.9 mm3, a reduction of 7.3% (111.5 ± 104.2 mm3 vs. 103.6 ± 95.8 mm3, p = 0.044). Similarly, % LRNC was also significantly decreased from 18.9 ± 11.9% to 17.9 ± 11.5% (p = 0.02) at 3 months. Both LRNC volume and % LRNC continued to decrease moderately at 12 and 24 months, although this trend was not significant. CONCLUSIONS: Among a small number of lipid treatment naïve subjects, rosuvastatin therapy may induce a rapid and lasting decrease in carotid plaque lipid content as assessed by MRI. TRIAL REGISTRATION: ClinicalTrials.Gov numbers NCT00885872.

Effect of nitric oxide on antioxidative response and proline metabolism in banana during cold storage.

The effect of exogenous nitric oxide (NO) on chilling injury to banana fruit was investigated. Banana fruit was treated with NO donor sodium nitroprusside of 0.05 mM at 20 °C for 10 min and then stored at 7 °C for up to 20 days. Banana fruit treated with NO sustained a lower chilling injury index and higher firmness and kept lower electrolyte leakage and malondialdehyde content than the control. Further investigation showed that NO treatment enhanced activities of guaiacol peroxidase, ascorbate peroxidase, and glutathione reductase compared to the control. It also maintained higher ascorbic acid, reduced glutathione content, and total antioxidant capacity but reduced hydrogen peroxide and superoxide anion to lower levels compared to control fruit during storage. NO treatment significantly enhanced the accumulation of total phenolics and proline, which resulted from the increased activities of phenylalanine ammonia-lyase and Δ¹-pyrroline-5-carboxylate synthetase and decreased proline dehydrogenase activity. We proposed that the enhanced chilling tolerance induced by NO treatment may result from the reduction of oxidative stress and proline accumulation.

[Effect of intensive rosuvastatin therapy on adhesion molecules and the upstream mechanism in patients with peripheral atherosclerosis].

OBJECTIVE: To investigate the effect of intensive rosuvastatin therapy on adhesion molecules in patients with peripheral atherosclerosis and explore the possible upstream mechanism. METHODS: Twenty asymptomatic patients with peripheral atherosclerosis were enrolled and given 5-20 mg/day rosuvastatin for 3 months. Before and after the treatment, the lipid profile and plasma vascular cell adhesion molecule-1 (VCAM-1) levels were examined. The expression of intercellular adhesion molecule-1 (ICAM-1) in the mononuclear cells was measured using flow cytometry, and the mRNA and protein expressions of peroxisome proliferator-activated receptor γ (PPARγ) were detected using RT-PCR and Western blotting, respectively. RESULTS: Compared with the baseline levels, ICAM-1 expression decreased and PPARγ protein expression increased in the lymphocytes. Rosuvastatin therapy did not produce obvious effects on plasma VCAM-1 level or ICAM-1 expression in the monocytes in these patients. CONCLUSION: Rosuvastatin produces anti-inflammatory effects by decreasing the expression of ICAM-1 in mononuclear cells, and its upstream mechanism may involve the PPARγ pathway.

[The pathology investigation of femoral artery atherosclerosis in the elder patients].

OBJECTIVE: To investigate the pathology characteristic of femoral atherosclerosis through the comparision among femoral, carotid and coronary atherosclerosis. METHODS: 15 elder autopsy cases were selected. Serial sections of femoral artery, carotid artery and coronary artery of all the cases were taken. Part of the tissue sections were selected for immunohistochemistry staining. Three markers against alpha-smooth muscle actin, CD68, and bax were performed respectively. RESULTS: On the whole, both femoral and coronary atherosclerosis had a similar pathology characteristic in the lesion style and the distribution of smooth muscle cells and macrophages in the plaques. In comparing with the coronary atheroma, there were more smooth muscle cells and less macrophages in the femoral atherosclerotic plaques, expression of bax in macrophages stronger, and the expression of bax in smooth muscle cell was weaker. The pathology characteristic of femoral and carotid atherosclerosis was somewhat similar. CONCLUSIONS: The pathology characteristic of atherosclerotic lesion in femoral artery was principally consistent with that of the coronary atherosclerosis except some differences presented in certain indexes.