The hippo kinases MST1/2 in cardiovascular and metabolic diseases: A promising therapeutic target option for pharmacotherapy

Cardiovascular diseases (CVDs) and metabolic disorders are major components of noncommunicable diseases, causing an enormous health and economic burden worldwide. There are common risk factors and developmental mechanisms among them, indicating the far-reaching significance in exploring the corresponding therapeutic targets. MST1/2 kinases are well-established proapoptotic effectors that also bidirectionally regulate autophagic activity. Recent studies have demonstrated that MST1/2 influence the outcome of cardiovascular and metabolic diseases by regulating immune inflammation. In addition, drug development against them is in full swing. In this review, we mainly describe the roles and mechanisms of MST1/2 in apoptosis and autophagy in cardiovascular and metabolic events as well as emphasis on the existing evidence for their involvement in immune inflammation. Moreover, we summarize the latest progress of pharmacotherapy targeting MST1/2 and propose a new mode of drug combination therapy, which may be beneficial to seek more effective strategies to prevent and treat CVDs and metabolic disorders.

Aldolase B attenuates clear cell renal cell carcinoma progression by inhibiting CtBP2 / 医学前沿

Aldolase B (ALDOB), a glycolytic enzyme, is uniformly depleted in clear cell renal cell carcinoma (ccRCC) tissues. We previously showed that ALDOB inhibited proliferation through a mechanism independent of its enzymatic activity in ccRCC, but the mechanism was not unequivocally identified. We showed that the corepressor C-terminal-binding protein 2 (CtBP2) is a novel ALDOB-interacting protein in ccRCC. The CtBP2-to-ALDOB expression ratio in clinical samples was correlated with the expression of CtBP2 target genes and was associated with shorter survival. ALDOB inhibited CtBP2-mediated repression of multiple cell cycle inhibitor, proapoptotic, and epithelial marker genes. Furthermore, ALDOB overexpression decreased the proliferation and migration of ccRCC cells in an ALDOB-CtBP2 interaction-dependent manner. Mechanistically, our findings showed that ALDOB recruited acireductone dioxygenase 1, which catalyzes the synthesis of an endogenous inhibitor of CtBP2, 4-methylthio 2-oxobutyric acid. ALDOB functions as a scaffold to bring acireductone dioxygenase and CtBP2 in close proximity to potentiate acireductone dioxygenase-mediated inhibition of CtBP2, and this scaffolding effect was independent of ALDOB enzymatic activity. Moreover, increased ALDOB expression inhibited tumor growth in a xenograft model and decreased lung metastasis in vivo. Our findings reveal that ALDOB is a negative regulator of CtBP2 and inhibits tumor growth and metastasis in ccRCC.

Chinese Medicine Regulates Knee Osteoarthritis-related Signaling Pathways： A Review / 中国实验方剂学杂志

As the research of traditional Chinese medicine （TCM） on knee osteoarthritis （KOA） is progressing， researchers have discovered that a variety of Chinese medicines can delay the progress of KOA by regulating signaling pathways at the molecular level. The Chinese medicines and their active ingredients mentioned in this article are associated with the signaling pathways in KOA. They can regulate the levels of targeted molecules via different signaling pathways to inhibit cartilage inflammatory cytokine， apoptosis， and cartilage matrix degradation and promote chondrocyte autophagy， so as to reduce the synovial inflammatory edema and delay cartilage degeneration. This paper systematically reviews the studies about the TCM intervention of KOA. Baicalein can reduce the inflammatory cytokines and apoptosis and promote the autophagy of chondrocytes by blocking the phosphatidylinositol-3 kinase/protein kinase （PI3K/Akt） signaling pathway. Cornuside I can decrease the phosphorylation activity of Janus kinase 2/signal transducer and activator of transcription 3 （JAK2/STAT3） pathway to reduce synovial inflammation and delay cartilage matrix degeneration. Salvianolic acid A can reduce inflammation and cartilage matrix degradation by inhibiting the phosphorylation of the nuclear factor-κB （NF-κB） pathway. Emodin can reduce the activity of Wnt/β-catenin pathway to inhibit the decomposition of collagen and proteoglycan. Myristicoside can inhibit apoptosis by blocking the p38 mitogen-activated protein kinase （p38 MAPK） signaling pathway. Akebia saponin D can enhance the activity of nuclear factor E2-related factor 2/heme oxygenase 1（Nrf2/HO-1） pathway to inhibit oxidative stress in chondrocytes. The saponins in Achyranthis Bidentatae Radix reduce cartilage matrix degradation by enhancing the transforming growth factor-β （TGF-β）/Smad signaling pathway. Crocin inhibits the cartilage inflammation and apoptosis factor increase by stimulating the activity of hippo-Yes-associated protein （Hippo-YAP）. Ligustrazine blocks the Notch pathway to improve the morphology and abnormality of chondrocytes. Oleanolic acid reduces the destruction and degeneration of cartilage matrix via the estrogen signaling pathway. The above summary aims to provide references for future clinical and experimental research on KOA.

Analysis of chemical ingredients of modified Shenqi Dihuang decoction by UPLC-LTQ-Orbitrap-MS / 药学实践杂志

Objective To analyze the chemical compounds of Shenqi Dihuang decoction by the ultraperformance liquid chromatography coupled with linear quadrupole ion trap-orbitrap mass spectrometry (UPLC-LTQ-Orbitrap-MS). Methods Warters ACQUITY UPLC HSS T3 (2.1 mm ×100 mm, 1.8 μm) was used as chromatographic column with mobile phase: 0.1% formic acid water (A)-0.1% formic acid acetonitrile (B) with gradient elution, and flow rate was 0.3 ml/min. Electrospray ion source (ESI) and an electrostatic field orbital ion trap mass analyzer were adopted, which was used to collect mass spectrometry fragment information with positive and negative ion modes, by comparing with the relative retention time of the reference substance. In addition, the fragment information of the mass spectrum was used to identify the compounds. The accurate identification of the chemical components in Shenqi Dihuang decoction was confirmed with literature. Results The study found that UPLC-LTQ-Orbitrap-MS technology could be used to identify 62 chemical components, including 13 aromatic acids, 9 flavonoids, 8 saponins, and 5 aromatic amines, 3 keto acids, 2 phenols, 1 aromatic quinone and other ingredients in Shenqi Dihuang decoction. Conclusion The identification analysis method in this study was efficient and accurate, which could be applied to the identification and analysis of chemical components in Shenqi Dihuang decoction and provided the important experimental data for the research on the material basis and mechanism.

Effect of probucol on serum malondialdehyde and superoxide dismutase in patients with primary hypertension / 中南大学学报(医学版)

OBJECTIVE@#To observe the therapeutic effect of probucol on serum malondialdehyde (MDA) and superoxide dismutase (SOD) in patients with primary hypertension.@*METHODS@#A randomized study was performed on 40 patients with hypertension. The patients were randomly assigned to the control (levamlodipine besylate 2.5 mg/d plus benazepril 10 mg/d, n=20) or probucol group (levamlodipine besylate 2.5 mg/d plus benazepril 10 mg/d plus probucol 500 mg/d, n=20). An additional twenty healthy people were enrolled in the study (normal group). All subjects were followed up for a period of four weeks. Lipids and hepatic/renal function were measured at baseline and after 4 weeks. The levels of serum MDA and SOD activity were assayed by chemical colorimetry, and other indices, including blood pressure, lipids and hepatic/renal function, were measured at baseline and after 4 weeks.@*RESULTS@#Compared to the normal group, the levels of MDA in all of the hypertension patient groups were higher, SOD was lower. The antihypertensive treatment decreased serum MDA levels but increased SOD content, and probucol treatment exaggerated these effects, with greater reduction of serum MDA levels and greater increase of SOD content.@*CONCLUSION@#The treatment with probucol can improve oxidative stress in hypertension patients, resulting in reduced serum MDA levels and improved SOD activity, thus contributing agreater antihypertensive effect.

Urological malignancy in renal allograft recipients: report of 22 clinical cases / 中华器官移植杂志

Objective To investigate the incidence of urological malignancy in renal allograft recipients and explore the mechanism of increased incidence in China and the management. Methods A retrospective study was performed on 22 patients with urological malignancy in renal allograft recipients between 1978 and 2010. Results Twenty-two cases of urological malignancy were diagnosed by pathologic evidence, including 9 cases of transitional cell carcinoma (TCC) of bladder, 1 case of squamous cell carcinoma of bladder, 1 case of adenocarcinoma of bladder, 1 case of TCC of pelvis, 1 case of TCC of bladder and pelvis, 1 case of TCC of ureter complicated with adenocarcinoma of bladder, 2 cases of TCC of ureter, 2 cases of TCC of ureter and bladder, 3 cases of clear cell carcinoma of kidney, and 1 case of undifferentiated carcinoma of kidney. All the malignancies belonged to native organs. All the patients suffering bladder cancer had normal function of allograft. Five patients with TCC of pelvis or ureter survived and 2 cases died early after operation. All the patients suffering renal carcinoma deceased within 6 months after diagnosis. One-year survival rate was 73. 7 % after the diagnosis of urological malignancy. Conclusion Urological malignancy ranked highest in malignancy in renal allograft recipients, and rare pathological types of urological malignancy in non-renal allograft recipients are often demonstrated. The strategy of treatment should take consideration of the relationship between the usage of immunosupressive agents and the preservation of allograft function. It is critical for the therapy of malignancies to possess satisfactory allograft function. The prognosis of renal cell carcinoma is poor.

A clikical study on kidney transplantation patients with a survival time over 10 years and long-term administration of cyclosporine / 中华器官移植杂志

Objective To investigate the effect of cyclosporine blood level at first year after kidney transplantation on patients with a survival time over 10 years. Methods 380 patients with functional allograft, a survival time over 10 years and long-term administration of cyclosporine A (CsA) were studied, and received CsA-based treatments. According to the blood CsA level at the first year after kidney transplantation, patients were divided into five groups: group 1, blood CsA level was above 0. 208 μmol/L (1 μmol/L = 1201.9 μg/L), group 2, blood CsA level between 0. 166-0. 208μmol/L; group 3, blood CsA blood level between 0. 125-0. 166 μmol/L; group 4, blood CsA blood level between 0. 083-0. 125 μmol/L; group 5, blood CsA level less than 0. 083 μmol/L. Systolic blood pressure (SBP), diastolic blood pressure (DBP), serum creatinine(SCr), uric acid (UA), cholesterol (CH), triglyceride (TG), alanine aminotransferase (ALT), direct bilirubin (DBil) and total bilibubin (TBil), albumin (Alb), hemoglobin (Hb), count of white blood cells and positive rate of proteinuria in 5 groups at the 1st, 5th and 10th year after kidney transplantation were analyzed. Results At the 5th year SBP in groups 1 and 2 was higher than in groups 3, 4 and 5. UA level in group 5 was lower than other groups, and Alb level in group 5 was higher than other 4 groups. Proteinuria positive rate in groups 4 and group was lower than other groups. At the 10th year after kidney transplantation,indexes among 5 groups had no statistically significant difference, except for SBP, DBP, DBil and CH in some groups. There was also no significant difference in SCr level among 5 groups at the 5th or 10th year after transplantation. Conclusion Blood CsA levels at the first year after kidney transplantation has no significant effect on long-term allograft function. But higher level of CsA (＞0. 166μmol/L) at the first year maybe predict high rate of hypertension, high blood UA and proteinuria at the 5th and 10th year after transplantation.

Clinical experience in treatment of malignant tumors after kidney transplantation / 中华器官移植杂志

Objective To summarize the clinical experience in treatment of malignant tumors of renal allograft recipients. Methods A retrospective study was performed on renal allograft recipients who received immunosuppressive treatment at least half a year between 1978 and 2005. Results Fifty-eight cases of tumors were found in 1812 cases undergoing renal transplantation, 50 cases of them who had complete clinical data were included into analysis. Forty-four cases, that included 19 cases in rological system, 14 cases in digestive system, 5 cases in blood system, 6 cases in other systems, were diagnosed as having malignant tumors by pathological analysis. Most of them were treated with surgery. One-year survival rate was 68.0% after the diagnosis of malignant tumor. The longest survival time was 6.5 years. Most of the survivals possessed normal function of allograft. Conclusion Systemic follow-up is important for renal allograft recipients who suffered malignant tumors. Surgical operation is still the main therapy for those solid tumors. It is critical for the therapy of malignancies and quality of life to possess satisfactory allograft function. The strategy of treatment should take consideration of the relationship between the decrease dose of immunosuppressive agents and the preservation of allograft function.

Treatment of massive proteinuria in kidney transplant recipients by losartan / 中华器官移植杂志

Objective To analyze the efficacy and safety of losartan in the treatment of massive proteinuria in kidney transplant recipients.Methods All of the 82 patients were randomized in two groups:losartan group and control group(amlodipine group).Both of the groups were divided into two different subsets according to blood pressure control Twenty-four-hour proteinuria,serum creatinine,blood pressure and adverse effects were observed.Results Losartan and amlodipine had the similar effects on blood pressure control The 24-h proteinuria in losartan group at the end of the study was significantly lower than that at the baseline,and there was significant difference between the losartan blood pressure control subset and the losartan blood pressure un-control subseL The effective rate and significant effective rate in losartan group for massive proteinuria were higher than in control group.Conclusion T Losartan can be effectively and safely used for the treatment of massive proteinuria in renal transplant recipients independent of blood pressure.

Effects of PPARs agonists on the MCP-1 expression induced by Ang Ⅱ in endothelial cells / 中华老年医学杂志

Objective To study the effect of angiotensinⅡon the expression of monocyte chemoattractant protein-1 (MCP-1) in cultured human umbilical vein endothelial cells(hUVEC) , and the effect of peroxisome proliferator- activated receptors (PPARs)?and?on MCP-1. Methods MCP-1 protein level was detected by enzyme-linked immunosorbent assay (ELISA) method, and the mRNA expression level of MCP-1 was determined by RT-PCR. Results AngiotensinⅡdistinctly increased the expression of MCP-1 in a dose-dependent manner in cultured hUVECs, and valsartan inhibited the expression of MCP-1 remarkably. Both rosiglitazone (PPAR7 agonist) and fenofibrate (PPAR?agonist) concentration- dependently reduced the expression of MCP-1 in induced by AngⅡ10-6 mol/L. Conclusions AngiotensinⅡcan increase the expression of MCP-1 evidently in hUVECs, which is inhibited by valsartan. The activation of PPARa and PPAR?can decrease the expression of MCP-1 in hUVECs.