The effect of oxygen in Sirt3-mediated myocardial protection: a proof-of-concept study in cultured cardiomyoblasts

Sirtuin 3 is a nicotinamide adenine dinucleotide dependent mitochondrial deacetylase that governs mitochondrial metabolism and oxidative defense. The demise in myocardial function following myocardial ischemia has been associated with mitochondrial dysfunction. Sirt3 maintains myocardial contractile function and protects from cardiac hypertrophy. The role of Sirt3 in ischemia is controversial. Our objective was to understand, under what circumstances Sirt3 is protective in different facets of ischemia, using an in vitro proof-of-concept approach based on simulated ischemia in cultured cardiomyoblasts. Cultured H9c2 cardiomyoblasts were subjected to hypoxia and/or serum deprivation, the combination of which we refer to as simulated ischemia. Apoptosis, as assessed by Annexin V staining in life-cell imaging and propidium-iodide inclusion in flow cytometry, was enhanced following simulated ischemia. Interestingly, serum deprivation was a stronger trigger of apoptosis than hypoxia. Knockdown of Sirt3 further increased apoptosis upon serum deprivation, whereas no such effect occurred upon additional hypoxia. Similarly, only upon serum deprivation but not upon simulated ischemia, silencing of Sirt3 led to a deterioration of mitochondrial function in extracellular flux analysis. In the absence of oxygen these Sirt3-dependent effects were abolished. These data indicate, that Sirt3-mediated myocardial protection is oxygen-dependent. Thus, mitochondrial respiration takes center-stage in Sirt3-dependent prevention of stress-induced myocardial damage.

     

动脉功能不全与溃疡的诊断与治疗选择

多种全身疾病可以导致下肢溃疡,其中最常见的原因是诸如周围动脉和静脉的血管疾病。周围动脉疾病是一种进展缓慢的、隐匿的疾病进程,在美国大约800万~1 200万人受累于此病,而且每年的发病率还在不断增长。有20%的65岁以上的美国人患有周围动脉疾病,其中只有25%的人接受治疗。据估计,1 050万该病患者有症状,而另外1 650万的该病患者则无症状。有研究结果报道下肢溃疡的发病率为0·12%~1·8%。由于病人及初级治疗提供者不清楚周围动脉疾病的早期表现,并且几乎没有治疗方面的知识,因此常常不能做出正确诊断。动脉溃疡的病理生理学动脉血供不足…     

Pentalinon andrieuxii Root Extract is Effective in the Topical Treatment of Cutaneous Leishmaniasis Caused by Leishmania mexicana

Cutaneous leishmaniasis (CL) manifests as localized skin lesions, which lead to significant tissue destruction and disfigurement. In the Yucatan Peninsula, Mayan traditional healers use Pentalinon andrieuxii Muell.‐Arg. (Apocynaceae) roots for the topical treatment of CL. Here, we studied the effect of P. andrieuxii root hexane extract (PARE) on the parasites and host cells in vitro and examined its efficacy in the topical treatment of CL caused by Leishmania mexicana. PARE exhibited potent antiparasitic activity in vitro against promastigotes as well as amastigotes residing in macrophages. Electron microscopy of PARE‐treated parasites revealed direct membrane damage. PARE also activated nuclear factor kappaB and enhanced interferon‐γ receptor and MHC class II expression and TNF‐α production in macrophages. In addition, PARE induced production of the Th1 promoting cytokine IL‐12 in dendritic cells as well as enhanced expression of the co‐stimulatory molecules CD40, CD80, and CD86. In vivo studies showed that L. mexicana‐infected mice treated by topical application of PARE resulted in the significant reduction in lesion size and parasite burden compared to controls. These findings indicate that PARE could be used as an alternative therapy for the topical treatment of CL. Copyright © 2013 John Wiley & Sons, Ltd.     

Dronabinol zur supportiven Therapie metastasierter maligner Melanome mit Lebermetastasen

BACKGROUND: Loss of appetite and nausea can reduce the quality of life of patients with malignant melanoma and liver metastases. Often established antiemetic drugs fail to bring relief. Tetrahydrocannabinol (THC, Marinol), which is the active agent of Indian hemp, has been used successfully in this situation for other malignant tumors. PATIENTS AND METHODS: We treated 7 patients with hematogenous metastatic melanoma and liver metastases suffering from extensive loss of appetite and nausea supportively with dronabinol (Marinol. All of these patients had previously received standard antiemetic therapy without adequate relief. Dronabinol is a synthetic Delta-tetrahydrocannabinol. The drug was administered in capsule form. We evaluated the palliative effects of dronabinol with a special patient evaluation form, which was filled out at the beginning of the therapy and again after 4 weeks. RESULTS: The majority of patients described a significant increase in appetite and decrease in nausea. These effects remained for some weeks, but then decreased as metastases progressed and the general condition worsened. All of the patients experienced slight to moderate dizziness, but it was not sufficiently troubling to cause interruption or termination of therapy. CONCLUSION: Loss of appetite and nausea due to liver metastases of malignant melanoma can be treated in individual cases supportively with Dronabinol.