Mitochondrial transplantation as a promising therapy for mitochondrial diseases

Mitochondrial diseases are a group of inherited or acquired metabolic disorders caused by mitochondrial dysfunction which may affect almost all the organs in the body and present at any age. However, no satisfactory therapeutic strategies have been available for mitochondrial diseases so far. Mitochondrial transplantation is a burgeoning approach for treatment of mitochondrial diseases by recovery of dysfunctional mitochondria in defective cells using isolated functional mitochondria. Many models of mitochondrial transplantation in cells, animals, and patients have proved effective via various routes of mitochondrial delivery. This review presents different techniques used in mitochondrial isolation and delivery, mechanisms of mitochondrial internalization and consequences of mitochondrial transplantation, along with challenges for clinical application. Despite some unknowns and challenges, mitochondrial transplantation would provide an innovative approach for mitochondrial medicine.

Histamine H / 中国药理学通报

Pitolisant is an orally active histamine H

NAD replenishment with nicotinamide mononucleotide protects blood-brain barrier integrity and attenuates delayed tissue plasminogen activator-induced haemorrhagic transformation after cerebral ischaemia / 中国药理学与毒理学杂志

OBJECTIVE Tissue plasminogen activator (tPA) is the only approved pharmaco-logical therapy for acute brain ischaemia;however,a major limitation of tPA is the haemorrhagic trans-formation that follows tPA treatment. Here, we determined whether nicotinamide mononucleotide (NMN), a key intermediate of nicotinamide adenine dinucleotide biosynthesis, affects tPA-induced haemorrhagic transformation. METHODS Middle cerebral artery occlusion (MCAO) was achieved in CD1 mice by introducing a filament to the left MCA for 5 h.When the filament was removed for reperfusion, tPA was infused via the tail vein.A single dose of NMN was injected i.p.(300 mg·kg-1).Mice were killed at 24 h post ischaemia, and their brains were evaluated for brain infarction, oedema, haemoglobin content, apoptosis, neuroinflammation, blood-brain barrier (BBB) permeability, the expression of tight junction proteins(TJPs)and the activity/expression of MMPs. RESULTS In the mice infused with tPA at 5 h post ischaemia, there were significant increases in mortality, brain infarction, brain oedema, brain haemoglobin level, neural apoptosis, Iba-1 staining (microglia activation) and myeloperoxidase staining (neutrophil infiltration). All these tPA-induced alterations were significantly prevented by NMN administration. Mechanistically, the delayed tPA treatment increased BBB permeability by down-regulating TJPs, including claudin-1, occludin and zonula occludens-1,and enhancing the activities and protein expression of MMP9 and MMP2. Similarly, NMN administration partly blocked these tPA-induced molecular changes. CONCLUSION Our results demonstrate that NMN ameliorates tPA-induced haemorrhagic transformation in brain ischaemia by maintaining the integrity of the BBB.

Arterial baroreflex function and left ventricular hypertrophy / 第二军医大学学报

It is well known that the arterial baroreflex(ABR)plays a key role in the regulation of heart rate and stabilization of blood pressure.Currently,it appears that ABR dysfunction is involved in the pathophysiology of cardiovascular disease states.Since the mid-1990s,a number of studies have been carried out in our laboratory to explore the pathological significance of ABR function in cardiovascular damage.This minireview summarizes our research work on the topic of ABR and left ventricular hypertrophy(LVH).On the basis of discussion concerning the importance of ABR dysfunction in hypertensive LVH and sinoaortic denervation-induced LVH,we advance a new strategy for reversal of LVH,that is,restoration of impaired ABR function.We tested this hypothesis in animal models with ABR deficiency.It was found that improvement of impaird ABR function with long-term treatment of ketanserin or candesartan was accompanied by reversal of LVH.The preliminary results indicate that it is feasible to target ABR for treatment of LVH.

Effects of glucose-insulin-potassium on baroreflex sensitivity, left ventricular function and ventricular arrhythmia in the subacute phase of myocardial infarction in rats / 第二军医大学学报

Objective:Glucose-insulin-potassium(GIK) is clinically used for reducing mortality in acute myocardial infarction(MI). It is known that ventricular arrhythmia, left ventricular dysfunction and impaired baroreflex sensitivity(BRS) are the three major determinants for predicting the mortality after acute MI. The present work was designed to study the effects of GIK on BRS, ventricular arrhythmia, and left ventricular function in rats with coronary artery ligature. Sprague-Dawley rats were used and the myocardial infarction was produced by ligature of the left anterior descending artery. Five weeks after coronary artery ligation, BRS was measured in conscious state with a computerized blood pressure monitoring system and left ventricular function and electrocardiogram were determined in the anaesthetized state in the subacute phase of myocardial infarction. It was found that GIK did not affect the blood pressure and heart period in both conscious and anaesthetized rats. GIK did not enhance BRS, but reduced ventricular arrhythmia and improved left ventricular function by reducing left ventricular end diastolic pressure in anaesthetized rats with MI. It is proposed that reducing ventricular arrhythmia and improving left ventricular function contribute to the effect of GIK on reducing the mortality after MI.

Contribution of blood pressure variability to the effect of nitrendipine on end-organ damage in spontaneously hypertensive rats / 第二军医大学学报

Objective:It has been proposed that blood pressure variability(BPV) is positively related to end-organ damage(EOD) in hypertension.The present work was designed to observe the effects of long-term treatment with nitrendipine and hydralazine on BPV and EOD in spontaneously hypertensive rats(SHR),to examine the hypothesis that lowering BPV with an antihypertensive drug is an important factor in organ protection.Design and methods:Drugs were mixed in rat chow.After 4 months of drug administration,blood pressure was recorded continuously in conscious freely moving rats for 24 h.The heart,kidneys,and brain were then isolated and examined.Results:It was found that nitrendipine significantly decreased blood pressure and BPV,and significantly decreased EOD score in SHR.Hydralazine decreased blood pressure,but did not lower BPV.No effect on EOD was found in hydralazine-treated rats.In control rat(n=38),EOD score was weakly related to systolic blood pressure(r=0.331,P<0.05) and closely related to long-term systolic BPV(r=0.551,P<0.01).In nitrendipine-treated rats,EOD score was closely related to long-term systolic BPV(r=0.602,P<0.01),but not to blood pressure level(r=0.174,P>0.05).Conclusion:BPV plays an important role in the organ-protecting effects of nitrendipine.

Arterial baroreflex function and left ventricular hypertrophy / 第二军医大学学报

It is well known that the arterial baroreflex(ABR)plays a key role in the regulation of heart rate and stabilization of blood pressure.Currently,it appears that ABR dysfunction is involved in the pathophysiology of cardiovascular disease states.Since the mid-1990s,a number of studies have been carried out in our laboratory to explore the pathological significance of ABR function in cardiovascular damage.This minireview summarizes our research work on the topic of ABR and left ventricular hypertrophy(LVH).On the basis of discussion concerning the importance of ABR dysfunction in hypertensive LVH and sinoaortic denervation-induced LVH,we advance a new strategy for reversal of LVH,that is,restoration of impaired ABR function.We tested this hypothesis in animal models with ABR deficiency.It was found that improvement of impaird ABR function with long-term treatment of ketanserin or candesartan was accompanied by reversal of LVH.The preliminary results indicate that it is feasible to target ABR for treatment of LVH.

Effects of glucose-insulin-potassium on baroreflex sensitivity, left ventricular function and ventricular arrhythmia in the subacute phase of myocardial infarction in rats / 第二军医大学学报

Objective:Glucose-insulin-potassium(GIK) is clinically used for reducing mortality in acute myocardial infarction(MI). It is known that ventricular arrhythmia, left ventricular dysfunction and impaired baroreflex sensitivity(BRS) are the three major determinants for predicting the mortality after acute MI. The present work was designed to study the effects of GIK on BRS, ventricular arrhythmia, and left ventricular function in rats with coronary artery ligature. Sprague-Dawley rats were used and the myocardial infarction was produced by ligature of the left anterior descending artery. Five weeks after coronary artery ligation, BRS was measured in conscious state with a computerized blood pressure monitoring system and left ventricular function and electrocardiogram were determined in the anaesthetized state in the subacute phase of myocardial infarction. It was found that GIK did not affect the blood pressure and heart period in both conscious and anaesthetized rats. GIK did not enhance BRS, but reduced ventricular arrhythmia and improved left ventricular function by reducing left ventricular end diastolic pressure in anaesthetized rats with MI. It is proposed that reducing ventricular arrhythmia and improving left ventricular function contribute to the effect of GIK on reducing the mortality after MI.

Contribution of blood pressure variability to the effect of nitrendipine on end-organ damage in spontaneously hypertensive rats / 第二军医大学学报

Objective:It has been proposed that blood pressure variability(BPV) is positively related to end-organ damage(EOD) in hypertension.The present work was designed to observe the effects of long-term treatment with nitrendipine and hydralazine on BPV and EOD in spontaneously hypertensive rats(SHR),to examine the hypothesis that lowering BPV with an antihypertensive drug is an important factor in organ protection.Design and methods:Drugs were mixed in rat chow.After 4 months of drug administration,blood pressure was recorded continuously in conscious freely moving rats for 24 h.The heart,kidneys,and brain were then isolated and examined.Results:It was found that nitrendipine significantly decreased blood pressure and BPV,and significantly decreased EOD score in SHR.Hydralazine decreased blood pressure,but did not lower BPV.No effect on EOD was found in hydralazine-treated rats.In control rat(n=38),EOD score was weakly related to systolic blood pressure(r=0.331,P<0.05) and closely related to long-term systolic BPV(r=0.551,P<0.01).In nitrendipine-treated rats,EOD score was closely related to long-term systolic BPV(r=0.602,P<0.01),but not to blood pressure level(r=0.174,P>0.05).Conclusion:BPV plays an important role in the organ-protecting effects of nitrendipine.