Let-7g Upregulation Attenuated the KRAS-PI3K-Rac1-Akt Axis-Mediated Bioenergetic Functions.

The aberrant activation of signaling pathways contributes to cancer cells with metabolic reprogramming. Thus, targeting signaling modulators is considered a potential therapeutic strategy for cancer. Subcellular fractionation, coimmunoprecipitation, biochemical analysis, and gene manipulation experiments revealed that decreasing the interaction of kirsten rat sarcoma viral oncogene homolog (KRAS) with p110α in lipid rafts with the use of naringenin (NGN), a citrus flavonoid, causes lipid raft-associated phosphatidylinositol 3-kinase (PI3K)-GTP-ras-related C3 botulinum toxin substrate 1 (Rac1)-protein kinase B (Akt)-regulated metabolic dysfunction of glycolysis and mitochondrial oxidative phosphorylation (OXPHOS), leading to apoptosis in human nasopharyngeal carcinoma (NPC) cells. The use of lethal-7g (let-7g) mimic and let-7g inhibitor confirmed that elevated let-7g resulted in a decrease in KRAS expression, which attenuated the PI3K-Rac1-Akt-BCL-2/BCL-xL-modulated mitochondrial energy metabolic functions. Increased let-7g depends on the suppression of the RNA-specificity of monocyte chemoattractant protein-induced protein-1 (MCPIP1) ribonuclease since NGN specifically blocks the degradation of pre-let-7g by NPC cell-derived immunoprecipitated MCPIP1. Converging lines of evidence indicate that the inhibition of MCPIP1 by NGN leads to let-7g upregulation, suppressing oncogenic KRAS-modulated PI3K-Rac1-Akt signaling and thereby impeding the metabolic activities of aerobic glycolysis and mitochondrial OXPHOS.

Vitamin D and Pancreatitis: A Narrative Review of Current Evidence.

Emerging research indicates that vitamin D metabolic disorder plays a major role in both acute pancreatitis (AP) and chronic pancreatitis (CP). This has been demonstrated by studies showing that vitamin D deficiency is associated with pancreatitis and its anti-inflammatory and anti-fibrotic effects by binding with the vitamin D receptor (VDR). However, the role of vitamin D assessment and its management in pancreatitis remains poorly understood. In this narrative review, we discuss the recent advances in our understanding of the molecular mechanisms involved in vitamin D/VDR signaling in pancreatic cells; the evidence from observational studies and clinical trials that demonstrate the connection among vitamin D, pancreatitis and pancreatitis-related complications; and the route of administration of vitamin D supplementation in clinical practice. Although further research is still required to establish the protective role of vitamin D and its application in disease, evaluation of vitamin D levels and its supplementation should be important strategies for pancreatitis management according to currently available evidence.

Effectiveness of Contralaterally Controlled Functional Electrical Stimulation versus Neuromuscular Electrical Stimulation on Upper Limb Motor Functional Recovery in Subacute Stroke Patients: A Randomized Controlled Trial.

Purpose: To compare the effectiveness of contralaterally controlled functional electrical stimulation (CCFES) versus neuromuscular electrical stimulation (NMES) on motor recovery of the upper limb in subacute stroke patients. Materials and Methods: Fifty patients within six months poststroke were randomly assigned to the CCFES group (n = 25) and the NMES group (n = 25). Both groups underwent routine rehabilitation plus 20-minute stimulation on wrist extensors per day, five days a week, for 3 weeks. Fugl-Meyer Assessment of upper extremity (FMA-UE), action research arm test (ARAT), Barthel Index (BI), and surface electromyography (sEMG) were assessed at baseline and end of intervention. Results: After a 3-week intervention, FMA-UE and BI increased in both groups (p < 0.05). ARAT increased significantly only in the CCFES group (p < 0.05). The changes of FMA-UE, ARAT, and BI in the CCFES group were not greater than those in the NMES group. The improvement in sEMG response of extensor carpi radialis by CCFES was greater than that by NMES (p = 0.026). The cocontraction ratio (CCR) of flexor carpi radialis did not decrease in both groups. Conclusions: CCFES improved upper limb motor function, but did not show better treatment effect than NMES. CCFES significantly enhanced the sEMG response of paretic extensor carpi radialis compared with NMES, but did not decrease the cocontraction of antagonist.

A new central post-stroke pain rat model: autologous blood injected thalamic hemorrhage involved increased expression of P2X4 receptor.

Stroke is the leading cause of disability and death in the world. Central post-stroke pain (CPSP), a central neuropathic pain syndrome occurring after cerebral stroke, is a serious problem. But on account of the lack of reliable animal models, the mechanisms underlying CPSP remains poorly understood. To better understand of the pathophysiological basis of CPSP, we developed and characterized a new rat model of CPSP. This model is based on a hemorrhagic stroke lesion with intra-thalamic autologous blood (ITAB) injection in the ventral posterolateral nucleus of the thalamus. Behavioral analysis demonstrated that the animals displayed a significant decrease in mechanical allodynia threshold. We found a significant increase in P2 × 4 receptor expression in microglia in thalamic peri-lesion tissues post-hemorrhage. The mechanical allodynia in rats with CPSP were reversed by blocking P2 × 4 receptors. A significant alleviation of mechanical allodynia was achieved following the administration of adrenergic antidepressants and antiepileptics. Meanwhile, we found a significant decrease in P2 × 4 receptor expression after treatment with these drugs. Taken together, our results suggest that targeting P2 × 4 receptor may be effective in the treatment of CPSP.

Effect of intralipid on myocardial injury during valve replacement surgery with concomitant radiofrequency ablation: A randomized controlled trial.

BACKGROUND: This study aimed to evaluate the effect of intralipid postconditioning (ILPC) on myocardial damage in patients undergoing valve replacement surgery with concomitant radiofrequency ablation (RFA) for atrial fibrillation (AF). METHODS: Randomized patient and assessor-blind controlled trial conducted in adult patients undergoing valve replacement surgery with concomitant RFA. Sixty-nine patients were randomly assigned to ILPC group (n = 34) or control group (n = 35): ILPC group received an intravenous infusion of 20% intralipid (2 mL/kg) just 10 minutes before aortic cross-unclamping, and control group received an equivalent volume of normal saline. Serum cardiac troponin-T (cTnT) and creatine kinase-MB (CK-MB) was measured before surgery and at 4, 12, 24, 48, and 72 hours after surgery. The primary endpoints were the 72-hour area under the curve (AUC) for cTnT and CK-MB. RESULTS: The total 72-hour AUC of cTnT (P = .33) and CK-MB (P = .52) were comparable between 2 groups. The left ventricle ejection fraction at discharge (P = .011) was higher in the ILPC group than that in the control group, while the AF recurrence did not differ significantly between 2 groups. CONCLUSIONS: There was no observed beneficial effect of ILPC on myocardial injury documented by the cardiac biomarkers in patients undergoing valve replacement surgery with concomitant RFA, and the effect of intralipid against myocardial I/R injury is undetectable within the background of massive biomarker release following ablation owing to localized myocardial necrosis. Besides, there are no other published data about the cardioprotective role of intralipid in patients undergoing this procedure and benefits of this protection need further studies to validate.

Effect of intralipid postconditioning on myocardial injury in patients undergoing valve replacement surgery: a randomised controlled trial.

OBJECTIVE: This study was conducted to determine whether the administration of intralipid just before aortic cross-unclamping would reduce myocardial injury in patients undergoing valve replacement surgery. METHODS: Seventy-three adult patients, scheduled for elective aortic or mitral valve surgery without significant coronary stenosis (>70%), were randomly assigned to the intralipid postconditioning (ILPC) group (n=37) or control group (n=36): the ILPC group received an intravenous infusion of 20% intralipid (2 mL/kg) just 10 min before aortic cross-unclamping, and the control group received an equivalent volume of normal saline. Serum cardiac troponin T (cTnT) and creatine kinase-MB (CK-MB) was measured before surgery and at 4, 12, 24, 48 and 72 hours after surgery. The primary end points were the 72-hour area under the curve (AUC) for cTnT and CK-MB. RESULTS: No significant difference between the ILPC and control arm was observed, including the age, sex or number of aortic versus mitral valves or left ventricular ejection fraction at baseline. The total 72-hour AUC of cTnT and CK-MB in patients assigned to ILPC were significantly reduced by 32.3% (p=0.004) and 26.4% (p=0.0185) compared with control, respectively. None of the treated patients had abnormal blood lipid metabolism, abnormal renal or hepatic function or significant related complications. CONCLUSION: The protective effect of postischaemic administration of intralipid prior to aortic cross-unclamping on reperfusion injury was found when determined by biomarkers of myocardial injury but not by cardiac function or other clinical outcomes in patients undergoing valve replacement surgery. Hence, clinical benefits of this protection need larger clinical trials to confirm. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov ID: ChiCTR-IOR-14005318.

High-Dose Polymerized Hemoglobin Fails to Alleviate Cardiac Ischemia/Reperfusion Injury due to Induction of Oxidative Damage in Coronary Artery.

Objective. Ischemia/reperfusion (I/R) injury is an unavoidable event for patients in cardiac surgery under cardiopulmonary bypass (CPB). This study was designed to investigate whether glutaraldehyde-polymerized human placenta hemoglobin (PolyPHb), a hemoglobin-based oxygen carrier (HBOC), can protect heart against CPB-induced I/R injury or not and to elucidate the underlying mechanism. Methods and Results. A standard dog CPB model with 2-hour cardiac arrest and 2-hour reperfusion was established. The results demonstrated that a low-dose PolyPHb (0.1%, w/v) provided a significant protection on the I/R heart, whereas the high-dose PolyPHb (3%, w/v) did not exhibit cardioprotective effect, as evidenced by the impaired cardiac function, decreased myocardial oxygen utilization, and elevated enzymes release and pathological changes. Further study indicated that exposure of isolated coronary arteries or human umbilical vein endothelial cells (HUVECs) to a high-dose PolyPHb caused impaired endothelium-dependent relaxation, which was companied with increased reactive oxygen species (ROS) production, reduced superoxide dismutase (SOD) activity, and elevated malonaldehyde (MDA) formation. Consistent with the increased oxidative stress, the NAD(P)H oxidase activity and subunits expression, including gp91(phox), p47(phox), p67(phox), and Nox1, were greatly upregulated. Conclusion. The high-dose PolyPHb fails to protect heart from CPB-induced I/R injury, which was due to overproduction of NAD(P)H oxidase-induced ROS and resultant endothelial dysfunction.

Chinese Herbal Medicine in the Treatment of Chronic Heart Failure: Three-Stage Study Protocol for a Randomized Controlled Trial.

Background. Chinese herbal medicine (CHM) has been used in the treatment of chronic heart failure (CHF) for a long time. Treatment based on syndrome differentiation and the main characteristic of TCM is the fundamental principle of TCM practice. In this study protocol, we have designed a trial to assess the efficacy and safety of CHM on CHF based on syndrome differentiation. Methods/Design. This is a three-stage trial of CHM in the treatment of CHF. The first stage is a literature review aiming to explore the common syndromes of CHF. The second is a multicentral, randomized, placebo-controlled trial to evaluate the efficacy and safety of CHM for the treatment of CHF. The third is a multicentral, randomized controlled clinical trial aiming to make cost-effectiveness analysis and evaluate the feasibility, compliance, and universality of CHM on CHF. Discussion. This trial will evaluate the efficacy, safety, feasibility, compliance, and universality of CHM on CHF. The expected outcome is to provide evidence-based recommendations for CHM on CHF and develop a prescription of CHM in the treatment of CHF. This trial is registered with NCT01939236 (Stage Two of the whole trial).

[A correlation research on Chinese medical syndromes of chronic heart failure and various complications].

OBJECTIVE: To study the correlation between various complications of chronic heart failure (CHF) patients and Chinese medical syndromes, thus indicating distribution laws of Chinese medical syndromes in various complications of CHF patients. METHODS: Chinese medical syndrome typing was performed in 630 CHF patients by cross-sectional study of the demographic data, history of present diseases, related information on Chinese medical four diagnostic methods, and the distribution of complications. Logistic regression analysis was used to determine the correlation of various complications of CHF patients and Chinese medical syndromes. RESULTS: In this study, recruited were common complications such as hypertension, diabetes, arrhythmia, hyperlipemia, and cerebral vascular accident, and so on. Main syndromes were sequenced as qi deficiency syndrome, blood stasis syndrome, water retention syndrome, yin deficiency syndrome, phlegm turbid syndrome, yang deficiency syndrome. Results of Logistic regression analysis indicated that correlation existed between common complications and Chinese medical syndromes. In CHF complicated hypertension patients, Logistic regression analysis showed qi deficiency syndrome and yang deficiency syndrome were negatively correlated with hypertension (P < 0.05). In CHF complicated diabetes patients, Logistic regression analysis showed phlegm turbid syndrome and water retention syndrome were positively correlated with diabetes (P < 0.05). In CHF complicated arrhythmia patients, there was no statistical difference in the distribution of each syndrome (P > 0.05). In CHF complicated hyperlipemia patients, Logistic regression analysis showed qi deficiency syndrome and water retention syndrome were negatively correlated with hyperlipemia (P < 0.05), while blood stasis syndrome, yin deficiency syndrome, and phlegm turbid syndrome were positively correlated with hyperlipemia (P < 0.01). In CHF complicated cerebral vascular accident patients, Logistic regression analysis showed qi deficiency syndrome and yang deficiency syndrome were negatively correlated with cerebral vascular accident (P < 0.01, P < 0.05). CONCLUSIONS: There existed certain correlations between complications of CHF and the distribution of main Chinese medical syndromes. It could be used as guidance for treating CHF and its various complications by Chinese medicine and pharmacy.

[Effects of extracts of Radix Scrophulariae on blood pressure in spontaneously hypertensive rats and the underlying mechanisms].

OBJECTIVE: To explore the effects of extracts of Radix Scrophulariae (ERS) on blood pressure, vasoconstrictors and morphology of artery in spontaneously hypertensive rats (SHRs). METHODS: Fifty SHRs were randomly divided into SHR, SHR plus 40 mg/kg of captopril, SHR plus 70 mg/kg of ERS, SHR plus 140 mg/kg of ERS and SHR plus 280 mg/kg of ERS groups. Wistar-Kyoto (WKY) rats were randomly divided into two groups, namely, WKY and WKY plus 140 mg/kg of ERS groups. The rats were orally administered with the corresponding drugs or drinking water once a day for 20 weeks. The blood pressure was determined every three weeks. At the 21st week, the concentrations of noradrenaline (NA), angiotensin II (Ang II), thromboxane B(2) (TXB(2)) and 6-keto-prostaglandin F(1α) in serum and endothelin-1 (ET-1) were detected by enzyme-linked immunosorbent assay. The morphological changes in abdominal aorta were observed under an optical microscope with hematoxylin and eosin staining. The ratio of intima-media thickness/lumen radius of abdominal aorta was calculated. RESULTS: ERS significantly lowered the blood pressure of SHRs from the 3rd to the 21st week; ERS also reduced the levels of NA, Ang II, ET-1 and TXB(2), decreased the intima-media thickness of abdominal aortal wall and improved the morphological changes in abdominal aorta in SHRs. In addition, ERS did not significantly change blood pressure and vasoactive substances in WKY rats. CONCLUSION: ERS possesses beneficial effects in inhibiting hypertension and attenuating arteriosclerosis. The underlying mechanism may be associated with restraining the release of vasoconstrictors, such as NA, Ang II, ET-1 and TXB(2).

Puerarin induces mitochondria-dependent apoptosis in hypoxic human pulmonary arterial smooth muscle cells.

BACKGROUND: Pulmonary vascular medial hypertrophy in hypoxic pulmonary arterial hypertension (PAH) is caused in part by decreased apoptosis in pulmonary artery smooth muscle cells (PASMCs). Puerarin, an isoflavone purified from the Chinese medicinal herb kudzu, ameliorates chronic hypoxic PAH in animal models. Here we investigated the effects of puerarin on apoptosis of hypoxic human PASMCs (HPASMCs), and to determine the possible underlying mechanisms. METHODOLOGY/PRINCIPAL FINDINGS: HPASMCs were cultured for 24 h in normoxia or hypoxia (5% O2) conditions with and without puerarin. Cell number and viability were determined with a hemacytometer or a cell counting kit. Apoptosis was detected with a TUNEL test, rhodamine-123 (R-123) fluorescence, a colorimetric assay, western blots, immunohistochemical staining and RT-PCR. Hypoxia inhibited mitochondria-dependent apoptosis and promoted HPASMC growth. In contrast, after puerarin (50 µM or more) intervention, cell growth was inhibited and apoptosis was observed. Puerarin-induced apoptosis in hypoxic HPASMCs was accompanied by reduced mitochondrial membrane potential, cytochrome c release from the mitochondria, caspase-9 activation, and Bcl-2 down-regulation with concurrent Bax up-regulation. CONCLUSIONS/SIGNIFICANCE: Puerarin promoted apoptosis in hypoxic HPASMCs by acting on the mitochondria-dependent pathway. These results suggest a new mechanism of puerarin relevant to the management of clinical hypoxic pulmonary hypertension.

[Diagnosis and treatment rule of traditional Chinese medicine for syndrome factors of chronic congestive heart failure: a study based on Shannon entropy method].

OBJECTIVE: The primary aim of this research is to systematically sort out and analyze available clinical documents for chronic congestive heart failure in traditional Chinese medicine (TCM) and integrated traditional Chinese and Western medicine, and to explore the diagnosis and treatment rule of TCM syndrome factors with data mining method. METHODS: Based on the China National Knowledge Internet (CNKI) and Chinese Biomedical Literature Database (CBM), using "chronic heart failure" or "chronic congestive heart failure" or "chronic cardiac insufficiency" and "traditional Chinese medicine" or "syndrome" or "integrated traditional Chinese and Western medicine" as keywords for literature selection, we used Shannon entropy nonlinear complex system method for the feature extraction after data preprocessing. RESULTS: The statistics showed that yang deficiency, qi deficiency, blood stasis, water retention, yin deficiency, and turbid phlegm were principal TCM syndrome factors; herbs of qi-tonifying, blood-activating, water-draining, phlegm-dispelling, exterior-releasing, interior-warming were main drugs for clinical application. The symptoms and Chinese herbs which intimately connect with TCM syndrome factors were extracted, while their diagnostic contribution degrees were quantified by correlation coefficient. The symptoms which had high scores were general syndromes while the symptoms which had low scores were specific manifestations of a certain patient. Common Chinese herbs corresponding to each syndrome factor were picked out, indirectly reflecting their frequencies in clinical application. CONCLUSION: Based on data mining of the relationship among the four diagnostic methods of TCM, syndrome factors and herbs, this study provided references for differentiation of TCM syndrome and selection of Chinese medicine according to clinical syndrome factors.