Assessment of mitochondrial dysfunction and implications in cardiovascular disorders.

Mitochondria play a pivotal role in cellular function, not only acting as the powerhouse of the cell, but also regulating ATP synthesis, reactive oxygen species (ROS) production, intracellular Ca2+ cycling, and apoptosis. During the past decade, extensive progress has been made in the technology to assess mitochondrial functions and accumulating evidences have shown that mitochondrial dysfunction is a key pathophysiological mechanism for many diseases including cardiovascular disorders, such as ischemic heart disease, cardiomyopathy, hypertension, atherosclerosis, and hemorrhagic shock. The advances in methodology have been accelerating our understanding of mitochondrial molecular structure and function, biogenesis and ROS and energy production, which facilitates new drug target identification and therapeutic strategy development for mitochondrial dysfunction-related disorders. This review will focus on the assessment of methodologies currently used for mitochondrial research and discuss their advantages, limitations and the implications of mitochondrial dysfunction in cardiovascular disorders.

Molecular Determinants for the High-Affinity Blockade of Human Ether-à-go-go-Related Gene K + Channel by Tolterodine.

ABSTRACT: Tolterodine is a first-line antimuscarinic drug used to treat overactive bladder. Adverse cardiac effects including tachycardia and palpitations have been observed, presumably because of its inhibition of the human ether-à-go-go-related gene (hERG) K + channel. However, the molecular mechanism of hERG channel inhibition by tolterodine is largely unclear. In this study, we performed molecular docking to identify potential binding sites of tolterodine in hERG channel, and two-microelectrode voltage-clamp to record the currents of hERG and its mutants expressed in Xenopus oocytes. The results of computational modeling demonstrated that phenylalanine at position 656 (F656) and tyrosine at position 652 (Y652) on the S6 helix of hERG channel are the most favorable binding residues of tolterodine, which was validated by electrophysiological recordings on Y652A and F656A hERG mutants. The Y652A and F656A mutations decreased inhibitory potency of tolterodine 345-fold and 126-fold, respectively. The Y652A mutation significantly altered the voltage dependence of channel inhibition by tolterodine. For both the wild-type and the mutant channels, tolterodine reduced the currents in a time-dependent manner, and the blockade occurred with the channel activated. Tolterodine did not interfere with hERG channel deactivation, whereas channel inactivation greatly impaired its blocking effect. The inhibition of hERG channel by tolterodine is independent of its action on muscarinic acetylcholine receptors. In conclusion, tolterodine is an open-state blocker of hERG K + channel with nanomolar potency. Y652 and F656, 2 aromatic residues on the inner S6 helix, are responsible for the high-affinity binding of tolterodine to hERG channel.

Using a fretsaw in treating chronic penial incarceration: A case report.

BACKGROUND: Penial incarceration (PI) is a rare situation. It is usually caused by a foreign object which strangulates at the base of the penis. PI may derive from pranks, sexual demand, mental disease, or intention to prohibit urinary disease. Generally, these situations are emergent and immediate treatments are needed. Cases of chronic PI are less reported, and their treating methods are yet to be discussed. CASE SUMMARY: We reported a case on treating a 73-year-old male who had PI with a metallic hoop for three months. After multidisciplinary consultation, the operation was performed successfully with the help of a fretsaw. Despite the chronic strangulation, the prognosis of the patient was satisfying. To the best of our knowledge, this case was rare and precious as it featured the longest strangulating time, which might enlighten the treating process of future PI cases. Also, we have reviewed and summarized major published cases to encapsulate appropriate approaches when facing diverse strangulation situations. CONCLUSION: The selection of surgical tools depends on the material of the strangulating objects, the availability of equipment, and the severity of the penial damage. The urination function may not be affected after three months of incarceration as in our case, whilst prudent preoperative measures and multidisciplinary evaluations are always essential. Although using a fretsaw is comparatively slow, it is safe and feasible to treat metallic penial incarceration.

Effect of chronic intermittent hypobaric hypoxia on heart rate variability in conscious rats.

To examine the effect of chronic intermittent hypobaric hypoxia (CIHH) on heart rate variability (HRV), male adult Sprague Dawley rats were exposed to hypoxia (oxygen 11.1%) in a hypobaric chamber for 42 days, 6 hours each day, simulating an altitude of 5000 m. The body weight and blood pressure of rats were recorded once a week, electrocardiograms were analyzed continuously using biotelemetry, before, during and after CIHH treatment each day, and HRV was evaluated using spectrum analysis. No significant difference of body weight and blood pressure was found between CIHH and control rats. After 4 weeks of CIHH treatment, total power (TP) and very low-frequency component (VLF) were lower in CIHH rats than in control rats under hypobaric hypoxia condition. During CIHH treatment, low frequency (LF) was higher in 1 week and lower in 5-6 weeks in CIHH rats than control rats under hypobaric hypoxia, but not normoxic conditions. The high-frequency component (HF) was not changed during CIHH treatment, so LF/HF increased initially, and then recovered under the hypobaric hypoxia condition following 3 weeks of CIHH treatment. In addition, the HR was increased in CIHH rats after 4 weeks of CIHH treatment compared with control rats. Furthermore, HRV was altered significantly in control rats, but not in CIHH rats exposed to acute normobaric hypoxia. These data suggest that CIHH treatment modulates cardiac autonomic activity adaptively and inhibits the acute normobaric hypoxia-induced changes in HRV.

Hyperpolarization-Activated Cyclic Nucleotide-Gated Ion (HCN) Channels Regulate PC12 Cell Differentiation Toward Sympathetic Neuron.

Hyperpolarization-activated cyclic nucleotide-gated ion channels (HCN channels) are widely expressed in the central and peripheral nervous systems and organs, while their functions are not well elucidated especially in the sympathetic nerve. The present study aimed to investigate the roles of HCN channel isoforms in the differentiation of sympathetic neurons using PC12 cell as a model. PC12 cells derived from rat pheochromocytoma were cultured and induced by nerve growth factor (NGF) (25 ng/ml) to differentiate to sympathetic neuron-like cells. Sympathetic directional differentiation of PC12 cells were evaluated by expressions of growth-associated protein 43 (GAP-43) (a growth cone marker), tyrosine hydroxylase (TH) (a sympathetic neuron marker) and neurite outgrowth. Results show that the HCN channel isoforms (HCN1-4) were all expressed in PC12 cells; blocking HCN channels with ivabradine suppressed NGF-induced GAP-43 expression and neurite outgrowth; silencing the expression of HCN2 and HCN4 using silenced using small interfering RNAs (siRNA), rather than HCN1 and HCN3, restrained GAP-43 expression and neurite outgrowth, while overexpression of HCN2 and HCN4 channels with gene transfer promoted GAP-43 expression and neurite outgrowth. Patch clamp experiments show that PC12 cells exhibited resting potentials (RP) of about -65 to -70 mV, and also presented inward HCN channel currents and outward (K+) currents, but no inward voltage-gated Na+ current was induced; NGF did not significantly affect the RP but promoted the establishment of excitability as indicated by the increased ability to depolarize and repolarize in the evoked suspicious action potentials (AP). We conclude that HCN2 and HCN4 channel isoforms, but not HCN1 and HCN3, promote the differentiation of PC12 cells toward sympathetic neurons. NGF potentiates the establishment of excitability during PC12 cell differentiation.

Celastrol attenuates renal injury in diabetic rats via MAPK/NF-κB pathway.

The purpose of this study was to investigate the renal protective effect of celastrol on diabetic rats. Furthermore, the mechanism of its action was discussed whether it was related to MAPK/NF-κB signaling pathway. There were a total of 36 rats. Six rats were randomly chosen as the control group. The remaining 30 rats were given 1% streptozotocin intraperitoneal injection (50 mg/kg) and were randomly divided into five groups: the model control group, the low-dose celastrol group, the high-dose celastrol group, the Tripterygium wilfordii polyglycosides group, and the MAPK/NF-κB inhibitor group. After 4 weeks of continuous administration, 24-hr urine volume, urinary protein, blood urea nitrogen, and serum creatinine content were observed, and hematoxylin-eosin (HE) staining of the kidney and liver were evaluated. p38MAPK was designated by immunohistochemical method, and NF-κB p65 in renal tissue was detected by western blotting. Our results showed that celastrol could not only reduce contents of creatinine and urea nitrogen in blood but also reduce excretion of urinary protein in diabetic rats, improve renal pathological injury, and down-regulate the expression of p38MAPK and NF-κB p65. In conclusion, celastrol could protect kidney of diabetic rats by regulating the signal pathway of MAPK/NF-κB, inhibiting inflammation and delaying renal injury.

The Effectiveness of Sorafenib over Other Targeted Agents in the Second-Line Treatment of Metastatic Renal Cell Carcinoma: a Meta-Analysis.

The aim of the study was to perform a meta-analysis to compare the therapeutic effects and adverse events (AEs) of sorafenib in second-line treatments of metastatic renal cell carcinoma (mRCC). We searched online electronic databases: Pubmed, Embase, Cochrane library updated on November 2017.Trials of the effectiveness of sorafenib in second-line treatments of advanced RCC were included, of which the main outcomes were objective response rate (ORR), progression-free survival (PFS), overall survival (OS) and grade 3/4 AE. Other TAs significantly reduced the risk of PFS compared to sorafenib with respect to second-line treatment (HR = 0.74; 95% CI, 0.65-0.83; p < 0.00001). No significant differences were, however, found in patients in terms of the ORR (HR = 1.82; 95% CI, 0.98-3.35; p = 0.06). Frequencies of the most common toxicities were overall similar and adverse events differed only in sensitivity analysis in rash with exclusion of other TAs (HR = 0.16; 95% CI, 0.05-0.52; p = 0.002). Overall survival was not debated between groups. In patients with mRCC, second-line sorafenib is associated with similar ORR as other target agents. While, sorafenib did not demonstrate a PFS advantage compared with other target agents, suggests sorafenib may not benefit patients with mRCC. Tolerability due to toxicities is similar compared sorafenib with other target agents. Further characterization of the RCC oncogenic pathway, and the ongoing clinical trials should help optimize the treatment option for second-line therapy of advanced renal cell carcinoma.

Anti-Inflammatory and Antioxidant Effects of Kelong-Capsule on Testosterone-Induced Benign Prostatic Hyperplasia in Rats.

Benign prostatic hyperplasia (BPH) is a common disease in the current ageing male population. This research aims to study the effects of Kelong-Capsules (KLC) on testosterone-induced BPH. Thirty rats were randomly divided into normal group, model group, and three treatment groups. Three treatment groups were given KLC (3.6 g/kg), KLC (7.2 g/kg), and finasteride (0.9 mg/kg), respectively, for 28 days after establishing the animal model. The BPH rat models were evaluated by Traditional Chinese Medicine (TCM) symptoms and prostate index (PI). Results indicated that three treatment groups all alleviated the pathological changes of prostate and kidney at different levels. Compared with the model group, the PI of the groups treated with KLC (7.2 g/kg) and finasteride decreased significantly. The expressions of NF-E2 related factor 2 (Nrf-2) and quinine oxidoreductase (NQO1) in the group treated with KLC (3.6 g/kg) increased markedly (p < 0.01). The cyclooxygenase-2 (COX-2) protein expression of the group treated with KLC (7.2 g/kg) was increased (p < 0.01). In conclusion, KLC could obviously inhibit the growth of prostate, and KLC (3.6 g/kg) could promote the expressions of Nrf2 and NQO1.

Danshen modulates Nrf2-mediated signaling pathway in cisplatin-induced renal injury.

Danshen, an efficacious agent for cardiovascular diseases, has been found to play an essential role in kidney injury. In the present study, the effect of Danshen on cisplatin-induced renal dysfunction was investigated in a mouse model. Danshen was administered to mice at a dose of 3 g/kg 4 days before and 3 days after cisplatin treatment. A single intraperitoneal injection of 20 mg/kg cisplatin was used to induce nephrotoxicity. The mice were sacrificed 72 h after cisplatin intoxication. Biochemical parameters including serum creatinine and blood urea nitrogen were analyzed. Histopathological changes of kidney tissues were detected using HE staining. Antioxidant enzymes (GSH-Px and SOD) and peroxidative product (MDA) were detected. Protein expressions of Nrf2 and its target genes including HO-1 and NQO1 were measured by Western blotting. The results showed that pretreatment with Danshen significantly reduced serum creatinine and blood urea nitrogen in the cisplatin-treated mice. Histopathological examination showed that Danshen mitigated the renal damage induced by cisplatin. Moreover, Danshen restored the activities of antioxidant enzymes (GSH-Px and SOD) and normalized the MDA contents in renal tissues. Western blotting revealed that Danshen enhanced the expressions of Nrf2 and its target genes in cisplatin-exposed mice. It was suggested that Danshen protects against the cisplatin-induced renal impairment in the mice, which is potentially associated with the upregulation of Nrf2-mediated signaling pathway.

Rosemary Extracts Upregulate Nrf2, Sestrin2, and MRP2 Protein Level in Human Hepatoma HepG2 Cells.

In the past few decades, the incidence of liver cancer has been rapidly rising across the world. Rosemary is known to possess antioxidant activity and is used as natural antioxidant food preservative. It is proposed to have anticancer activity in treating different tumor models. In this study, we try to explore the impact of rosemary extracts on upregulating the level of Nrf2 and Nrf2-regulatory proteins, Sestrin2 and MRP2 in HepG2 cells, and to speculate its potential mechanism. The anticancer activity of rosemary extract, including its polyphenolic diterpenes carnosic acid and carnosol, was evaluated to understand the potential effect on HepG2 cells. Rosemary extract, carnosic acid, and carnosol induced the expression of Sestrin2 and MRP2 associate with enhancement of Nrf2 protein level in HepG2 cells, in which carnosic acid showed most obvious effect. Although the activation pathway of Nrf2/ARE was not exactly assessed, it can be assumed that the enhancement of expression of Sestrin2 and MRP2 may result from upregulation of Nrf2.

Danshen Modulates Nrf2-mediated Signaling Pathway in Cisplatin-induced Renal Injury / 华中科技大学学报（医学）（英德文版）

Danshen,an efficacious agent for cardiovascular diseases,has been found to play an essential role in kidney injury.In the present study,the effect of Danshen on cisplatin-induced renal dysfunction was investigated in a mouse model.Danshen was administered to mice at a dose of 3 g/kg 4 days before and 3 days after cisplatin treatment.A single intraperitoneal injection of 20 mg/kg cisplatin was used to induce nephrotoxicity.The mice were sacrificed 72 h after cisplatin intoxication.Biochemical parameters including serum creatinine and blood urea nitrogen were analyzed.Histopathological changes of kidney tissues were detected using HE staining.Antioxidant enzymes (GSH-Px and SOD) and peroxidative product (MDA) were detected.Protein expressions of Nrf2 and its target genes including HO-1 and NQO1 were measured by Western blotting.The results showed that pretreatment with Danshen significantly reduced serum creatinine and blood urea nitrogen in the cisplatin-treated mice.Histopathological examination showed that Danshen mitigated the renal damage induced by cisplatin.Moreover,Danshen restored the activities of antioxidant enzymes (GSH-Px and SOD) and normalized the MDA contents in renal tissues.Western blotting revealed that Danshen enhanced the expressions of Nrf2 and its target genes in cisplatin-exposed mice.It was suggested that Danshen protects against the cisplatin-induced renal impairment in the mice,which is potentially associated with the upregulation of Nrf2-mediated signaling pathway.

Tolterodine reduces veratridine-augmented late INa, reverse-INCX and early afterdepolarizations in isolated rabbit ventricular myocytes.

AIM: The augmentation of late sodium current (INa.L) not only causes intracellular Na+ accumulation, which results in intracellular Ca2+ overload via the reverse mode of the Na+/Ca2+ exchange current (reverse-INCX), but also prolongs APD and induces early afterdepolarizations (EAD), which can lead to arrhythmia and cardiac dysfunction. Thus, the inhibition of INa.L is considered to be a potential way for therapeutic intervention in ischemia and heart failure. In this study we investigated the effects of tolterodine (Tol), a competitive muscarinic receptor antagonist, on normal and veratridine (Ver)-augmented INa.L, reverse-INCX and APD in isolated rabbit ventricular myocytes, which might contribute to its cardioprotective activity. METHODS: Rabbit ventricular myocytes were prepared. The INa.L and reverse-INCX were recorded in voltage clamp mode, whereas action potentials and Ver-induced early afterdepolarizations (EADs) were recorded in current clamp mode. Drugs were applied via superfusion. RESULTS: Tol (3-120 nmol/L) concentration-dependently inhibited the normal and Ver-augmented INa.L with IC50 values of 32.08 nmol/L and 42.47 nmol/L, respectively. Atropine (100 µmol/L) did not affect the inhibitory effects of Tol (30 nmol/L) on Ver-augmented INa.L. In contrast, much high concentrations of Tol was needed to inhibit the transient sodium current (INa.T) with an IC50 value of 183.03 µmol/L. In addition, Tol (30 nmol/L) significantly shifted the inactivation curve of INa.T toward a more depolarizing membrane potential without affecting its activation characteristics. Moreover, Tol (30 nmol/L) significantly decreased Ver-augmented reverse-INCX. Tol (30 nmol/L) increased the action potential duration (APD) by 16% under the basal conditions. Ver (20 µmol/L) considerably extended the APD and evoked EADs in 18/24 cells (75%). In the presence of Ver, Tol (30 nmol/L) markedly decreased the APD and eliminated EADs (0/24 cells). CONCLUSION: Tol inhibits normal and Ver-augmented INaL and decreases Ver-augmented reverse-INCX. In addition, Tol reverses the prolongation of the APD and eliminates the EADs induced by Ver, thus prevents Ver-induced arrhythmia.

[Exploration of the Essence of "Endogenous Turbidity" in Chinese Medicine].

The essence of endogenous turbidity in Chinese medicine (CM) is different from cream, fat, phlegm, retention, damp, toxicity, and stasis. Along with the development of modern scientific technologies and biology, researches on the essence of endogenous turbidity should keep pace with the time. Its material bases should be defined and new connotation endowed at the microscopic level. The essence of turbidity lies in abnormal functions of zang-fu organs. Sugar, fat, protein, and other nutrient substances cannot be properly decomposed, but into semi-finished products or intermediate metabolites. They are inactive and cannot participate in normal material syntheses and decomposition. They cannot be transformed to energy metabolism, but also cannot be synthesized as executive functioning of active proteins. If they cannot be degraded by autophagy-lysosome or ubiquitin-prosome into glucose, fatty acids, amino acids, and other basic nutrients to be used again, they will accumulate inside the human body and become endogenous turbidity. Therefore, endogenous turbidity is different from final metabolites such as urea, carbon dioxide, etc., which can transform vital qi. How to improve the function of zang-fu organs, enhance its degradation by autophagy-lysosome or ubiquitin-prosome is of great significance in normal operating of zang-fu organs and preventing the emergence and progress of related diseases.

Remodeling of Kv1.5 channel in right atria from Han Chinese patients with atrial fibrillation.

BACKGROUND: The incidence of atrial fibrillation (AF) in rheumatic heart diseases (RHD) is very high and increases with age. Occurrence and maintenance of AF are very complicated process accompanied by many different mechanisms. Ion-channel remodeling, including the voltage-gated potassium channel Kv1.5, plays an important role in the pathophysiology of AF. However, the changes of Kv1.5 channel expression in Han Chinese patients with RHD and AF remain poorly understood. The aim of the present study was to investigate whether the Kv1.5 channels of the right atria may be altered with RHD, age, and sex to contribute to AF. MATERIAL/METHODS: Right atrial appendages were obtained from 20 patients with normal cardiac functions who had undergone surgery, and 26 patients with AF. Subjects were picked from 4 groups: adult and aged patients in normal sinus rhythm (SR) and AF. Patients were divided into non-RHD and RHD groups or men and women groups in normal SR and AF, respectively. The expression of Kv1.5 protein and messenger RNA (mRNA) were measured using Western blotting and polymerase chain reaction (PCR) method, respectively. RESULTS: Compared with the SR group, the expression of Kv1.5 protein decreased significantly in the AF group. However, neither Kv1.5 protein nor KCNA5 mRNA had significant differences in adult and aged groups, non-RHD and RHD group, and men and women group of AF. CONCLUSIONS: The expression of Kv1.5 channel protein changes with AF but not with age, RHD, and sex in AF.

Serum CA 19-9 as a good prognostic biomarker in patients with bladder cancer.

BACKGROUND: Bladder cancer (BC) is the second leading malignant tumors of the genitourinary system. CA 19-9 has served as a diagnostic and prognostic marker for pancreatic carcinoma for years. In recent year, although a few studies have evaluated the roles of CA 19-9 in BC, the results are conflicting and the number of the patients studied is very small. AIM: To investigate the potential of serum CA 19-9 to serve as a diagnostic and prognostic marker of BC in a larger number of patients. METHODS: A total of 272 (144 BC patients and 128 healthy subjects) were enrolled. Patients were followed-up routinely at 3-month intervals for 5 years. Serum CA 19-9 level was detected by ELISA. RESULTS: CA 19-9 level was much higher than that in healthy subjects (43.69 ± 6.92 U/ml vs. 12.31 ± 4.39 U/ml, p < 0.001). However, when the value of 37 U/ml of serum CA 19-9 was used as the cut-off value for BC the sensitivity of CA 19-9 for BC was dropped to 38.8%. CA 19-9 was much higher in muscle invasive tumor subgroup than that in superficial tumor subgroup (38.09 ± 7.14 U/ml vs. 20.71 ± 4.15 U/ml, p < 0.027). CA 19-9 level was comparable in both subgroups (29.78 ± 5.07 U/ml vs. 26.13 ± 5.97 U/ml, p = 0.565). BC patients with more than 5 years survival time had lower serum CA 19-9 level than the rest (15.86 U/ml vs 46.68 U/ml, p < 0.001). Survival rate (>5 years) of patients with lower CA 19-9 levels (<29 U/ml) was significantly increased in comparison to those with elevated serum CA 19-9 levels (>29 U/ml) (p < 0.001). CONCLUSIONS: serum CA 19-9 is not a good diagnostic maker, but a very powerful prognostic marker for BC. Such a study might be helpful for urologists to manage patients with BC.

A protective mechanism of licorice (Glycyrrhiza uralensis): isoliquiritigenin stimulates detoxification system via Nrf2 activation.

ETHNOPHARMACOLOGICAL RELEVANCE: Licorice (Glycyrrhizae radix), the root of Glycyrrhiza uralensis Fisch. (Leguminosae), is mainly used to moderate the characteristics of toxic herbs in Traditional Chinese Medicine, which could be partly interpreted as detoxification. However, the underlying mechanism is still not fully elucidated. Nuclear factor erythroid 2-related factor 2 (Nrf2) plays a key role in the protection against toxic xenobiotics. In our previous research, we have identified that extracts from Glycyrrhiza uralensis induced the expression of Nrf2 nuclear protein and its downstream genes. This research aims to screen the most potent Nrf2 inducer isolated from Glycyrrhiza uralensis and examine its effect on Nrf2 signaling pathway and detoxification system. MATERIALS AND METHODS: Four compounds derived from Glycyrrhiza uralensis (glycyrrhetinic acid, liquiritigenin, isoliquiritigenin and liquiritin) were screened by ARE-luciferase reporter. The most potent ARE-luciferase inducer was chosen to further examine its effect on Nrf2 and detoxification genes in HepG2 cells. The role of Nrf2-dependent mechanism was tested by using Nrf2 knockout mice (Nrf2 KO) and Nrf2 wild-type mice (Nrf2 WT). RESULTS: ARE-luciferase reporter assay showed these four compounds were all potent Nrf2 inducers, and isoliquiritigenin was the most potent inducer. Isoliquiritigenin significantly up-regulated the expression of Nrf2 and its downstream detoxification genes UDP-glucuronosyltransferase 1A1 (UGT1A1), glutamate cysteine ligase (GCL), multidrug resistance protein 2 (MRP2) and bile salt export pump (BSEP) in vitro and in vivo. Additionally, isoliquiritigenin showed Nrf2-dependent transactivation of UGT1A1, GCLC and MRP2. CONCLUSIONS: Isoliquiritigenin, isolated from Glycyrrhiza uralensis, stimulates detoxification system via Nrf2 activation, which could be a potential protective mechanism of licorice.

Effect of licorice on the induction of phase II metabolizing enzymes and phase III transporters and its possible mechanism.

Licorice has a marked detoxifying effect that can treat drug poisoning and/or relieve adverse effects. However, the exact mechanism of this action is not entirely elucidated, but is believed to be related to the modulation of drug disposition when interacting with other drugs. Additionally, Nuclear factor erythroid 2-related factor 2 (Nrf2) plays a significant role in mediating phase II xenobiotic metabolizing enzymes (XMEs) and phase III transporters. In the present study, we showed that licorice induced the mRNA expression of phase II XMEs UDP-glucuronosyltransferases 1A1 (UGT1A1), glutamate cysteine ligase (GCL), glutathione-s-transferase (GST) and phase III transporters multidrug resistance protein 2 (MRP2), as well as a rapid increase in Nrf2 nuclear accumulation. These findings suggests that licorice may intervene in the Nrf2 signal pathway to induce UGT1A1, GCLC, GST and MRP2, which provide a novel mechanism for the use of licorice to treat drug poisoning and/or relieve adverse effects.

Blocking effect of methylflavonolamine on human Na(V)1.5 channels expressed in Xenopus laevis oocytes and on sodium currents in rabbit ventricular myocytes.

AIM: To investigate the blocking effects of methylflavonolamine (MFA) on human Na(V)1.5 channels expressed in Xenopus laevis oocytes and on sodium currents (I(Na)) in rabbit ventricular myocytes. METHODS: Human Na(V)1.5 channels were expressed in Xenopus oocytes and studied using the two-electrode voltage-clamp technique. I(Na) and action potentials in rabbit ventricular myocytes were studied using the whole-cell recording. RESULTS: MFA and lidocaine inhibited human Na(V)1.5 channels expressed in Xenopus oocytes in a positive rate-dependent and concentration-dependent manner, with IC(50) values of 72.61 micromol/L and 145.62 micromol/L, respectively. Both of them markedly shifted the steady-state activation curve of I(Na) toward more positive potentials, shifted the steady-state inactivation curve of I(Na) toward more negative potentials and postponed the recovery of the I(Na) inactivation state. In rabbit ventricular myocytes, MFA inhibited I(Na) with a shift in the steady-state inactivation curve toward more negative potentials, thereby postponing the recovery of the I(Na) inactivation state. This shift was in a positive rate-dependent manner. Under current-clamp mode, MAF significantly decreased action potential amplitude (APA) and maximal depolarization velocity (V(max)) and shortened action potential duration (APD), but did not alter the resting membrane potential (RMP). The demonstrated that the kinetics of sodium channel blockage by MFA resemble those of class I antiarrhythmic agents such as lidocaine. CONCLUSION: MFA protects the heart against arrhythmias by its blocking effect on sodium channels.

[Effects of docetaxel and prednisone for hormone-refractory prostate cancer].

OBJECTIVE: To investigate the role and side effects of docetaxel and prednisone on treating hormone-refractory prostate cancer (HRPC). METHODS: Docetaxel (75 mg/m(2)) and prednisone (5 mg, bid) were given to 14 patients, whose age range from 51 to 78 years old, of hormone-refractory prostate cancer for 3 - 8 cycles. Three-week is a chemotherapy cycle. Comparing the prostate specific antigen (PSA), alkaline phosphatase (ALP), pain score, Karnofsky performance status, bone scan, lymph node size before and after chemotherapy. RESULTS: 100 - 140 milligram docetaxel were given for each cycle, 1-8 cycles were experienced. The responses of PSA: excellence-5 cases, utility-3 cases, uselessness-6 cases, PSA response ratio was 57.1%. Among 6 N(1) cases, lymph nodes diminished in 2 cases and enlarged in 1 case after chemotherapy. Bone scan has improved in 2 cases, and no differences in other cases. Pain scores were decreased from 0 to 6, and the average Karnofsky performance status was increased by 4%. The common adverse events were myelosuppression, alopecia, fatigue, nail changes, phlebitis. CONCLUSION: Docetaxel plus prednisone for the treatment of HRPC can delay the progression of the disease, decrease the PSA value, diminish the lymph node, ease the pain, improve the quality of live, and the tolerance is quite good.

Expression and effect of adrenomedullin in pheochromocytoma.

This study investigates the expression of human adrenomedullin (ADM) and its receptor-receptor activity modifying protein 2/calcitonin receptor-like receptor (RAMP2/CRLR) mRNA in pheochromocytoma by reverse transcriptase polymerase chain reaction (RT-PCR) and its effect on the proliferation of pheochromocytoma cells by MTT. The mRNA expression of ADM and its receptor RAMP2/CRLR was present in normal adrenal medulla and pheochromocytoma tissues. The mRNA expression of ADM, RAMP2, and CRLR is markedly higher in pheochromocytomas than in normal medulla. ADM inhibits the proliferation of human pheochromocytoma cells and exerts a possible autocrine or paracrine effect in the adrenal.