Bone metastasis: mechanisms and therapeutic opportunities

The skeleton is one of the most common sites for metastatic cancer, and tumors arising from the breast or prostate possess an increased propensity to spread to this site. The growth of disseminated tumor cells in the skeleton requires tumor cells to inhabit the bone marrow, from which they stimulate local bone cell activity. Crosstalk between tumor cells and resident bone and bone marrow cells disrupts normal bone homeostasis, which leads to tumor growth in bone. The metastatic tumor cells have the ability to elicit responses that stimulate bone resorption, bone formation or both. The net result of these activities is profound skeletal destruction that can have dire consequences for patients. The molecular mechanisms that underlie these painful and often incurable consequences of tumor metastasis to bone are beginning to be recognized, and they represent promising new molecular targets for therapy.     

Molecular mechanisms of cardiac aging

Age-associated changes in cardiovascular structure/ function are implicated in the markedly increased risk for cardiovascular disease in older persons. Aging not only prolongs exposure to several other cardiovascular risks, but also leads to intrinsic cardiac changes, which reduces cardiac functional reserve, predisposes the heart to stress and contributes to increased cardiovascular mortality in the elderly. Intrinsic cardiac aging in the murine model closely recapitulates age-related cardiac changes in humans, includ- ing left ventricular hypertrophy, fibrosis and diastolic dysfunction. Cardiac aging in mice is accompanied by accumulation of mitochondrial protein oxidation, increased mitochondrial DNA mutations, increased mitochondrial biogenesis, as well as decreased cardiac SERCA2 protein. All of these age-related changes are significantly attenu- ated in mice overexpressing catalase targeted to mitochondria （mCAT）. These findings demonstrate the critical role of rnitochondrial reactive oxygen species （ROS） in cardiac ag ing and support the potential antioxidants to cardiac aging lar diseases. application of mitochondrial and age-related cardiovascular diseases.     

Molecular mechanisms of cardiac aging

Age-associated changes in cardiovascular structure/function are implicated in the markedly increased risk for cardiovascular disease in older persons. Aging not only prolongs exposure to several other cardiovascular risks, but also leads to intrinsic cardiac changes, which reduces cardiac functional reserve, predisposes the heart to stress and contributes to increased cardiovascular mortality in the elderly. Intrinsic cardiac aging in the murine model closely recapitulates age-related cardiac changes in humans, including left ventricular hypertrophy, fibrosis and diastolic dysfunction. Cardiac aging in mice is accompanied by accumulation of mitochondrial protein oxidation, increased mitochondrial DNA mutations, increased mitochondrial biogenesis, as well as decreased cardiac SERCA2 protein. All of these age-related changes are significantly attenuated in mice overexpressing catalase targeted to mitochondria (mCAT). These findings demonstrate the critical role of mitochondrial reactive oxygen species (ROS) in cardiac aging and support the potential application of mitochondrial antioxidants to cardiac aging and age-related cardiovascular diseases.     

Dyslipidaemia and cardiorenal disease: mechanisms, therapeutic opportunities and clinical trials

Dyslipidaemia is an important risk factor for the development of chronic kidney disease (CKD) and cardiovascular disease (CVD). CKD generates an atherogenic lipid profile, characterised by high triglycerides, low high-density lipoprotein (HDL) cholesterol and accumulation of small dense low-density lipoprotein (LDL) particles, comparable to that in the metabolic syndrome. These changes are due specifically to the effects of CKD on key enzymes, transfer proteins and receptors involved in lipid metabolism. Dyslipidaemia is further compounded by dialysis, immunosuppressive drugs, and concomitant diseases such as diabetes mellitus. Post hoc analyses from large intervention trials suggest the benefit of statins in patients with early CKD, but prospective clinical trials in haemodialysis (HD) and renal transplant recipients have not conclusively shown improvements in hard cardiovascular end-points. The lack of efficacy of statins in late-stage CKD could be a consequence of other disease processes, such as calcific arteriopathy and insulin resistance, which are not modified by lipid-lowering agents. Despite uncertainty and pending the results of ongoing statin trials such as Study of Heart and Renal Protection (SHARP) and AURORA (A study to evaluate the Use of Rosuvastatin in subjects On Regular haemodialysis: an Assessment of survival and cardiovascular events), major international guidelines continue to support statin therapy in CKD and renal transplant patients to reduce cardiovascular risk burden. Because of increased risk of toxicity, particularly myopathy, statins and other lipid-regulating agents should be used cautiously in CKD and renal transplant recipients.     

Cardiac myosin-binding protein C in hypertrophic cardiomyopathy: mechanisms and therapeutic opportunities

Cardiac myosin-binding protein C (cMyBP-C) is a component of the thick filaments of the sarcomere. Understanding the structural and functional role of cMyBP-C in the heart is clinically relevant since cMyBP-C gene mutations are a widely recognized cause of hypertrophic cardiomyopathy (HCM), which affects 0.2% of the general population. Nonsense and frameshift mutations are common in cMyBP-C and their expressions are regulated by three quality control systems, the nonsense-mediated mRNA decay, ubiquitin-proteasome system, and autophagy, which contribute to minimize the production of potential poison mutant proteins. This review discusses the structural and regulatory functions of cMyBP-C, the molecular mechanisms involved in cMyBP-C-related HCM, as well as potential causative therapies for HCM.     

Joint mechanisms of impaired growth-hormone pulse renewal in aging men

CONTEXT: Aging reduces the size (mass) of GH secretory bursts and thereby reduces total GH secretion. Experimental data indicate that high-amplitude GH pulses are evoked by reversible cycles of GH-induced negative feedback. Whether aging impairs autofeedback is unknown. OBJECTIVE: The objective of this study is to assess whether age attenuates and IGF-I potentiates negative feedback by a near-physiological pulse of GH. DESIGN/SETTING/SUBJECTS: In a university setting, 17 healthy men ages 19-71 yr each underwent four randomly ordered infusion studies on separate mornings fasting. INTERVENTION: Intravenous injection of a pulse of: 1) saline or 2) recombinant human (rh) GH to impose controlled negative feedback, followed in 2 h by a bolus of 3) saline or (iv) the ghrelin analog GHRP-2 to overcome feedback inhibition. OUTCOME MEASURES: The impact of age and IGF-I concentrations on GH autofeedback was assessed by regression analysis. RESULTS: Percentage feedback inhibition correlated negatively with: 1) age after consecutive rh GH/saline infusion (R(2) = 0.42, P = 0.005) at any IGF-I concentration; and 2) total IGF-I concentrations after rh GH/GHRP-2 infusion (R(2) = 0.40, P = 0.009) at any age. In contrast, sex-steroid concentrations and body mass index were unrelated to degree of autoinhibition. CONCLUSIONS: Increased age in healthy men predicts impaired GH autofeedback, which may contribute to attenuated renewal of high-amplitude GH pulses. Conversely, higher IGF-I concentrations in young men forecast accentuated GH autoinhibition, which may drive prominent GH pulses.     

Cellular mechanisms of impaired cardiac energetics in patients with dilated cardiomyopathy: decrease in mitochondrial respiration and creatine kinase expression]

The mitochondrial functional characteristics were assessed in the biopsy specimens from patients with various Functional Classes dilated cardiomyopathy (DCMP). The assessment was made by using endomyocardial biopsy specimens weighing 2-4 mg which had been taken from 39 patients aged 19-64 years during coronary ventriculography and cardiac transplantation. The status of mitochondria and the efficiency of mitochondrial creatine kinase functioning were evaluated by recording the respiration of saponin-skinned muscular fibers. The maximum mitochondrial respiration rate calculated on a dry weight basis was not substantially different in all functional classes of DCMP, while the acceptor control index (Vmax/V0) and the level of creatine-activated respiration decreased with an increase in the functional class of DCMP. The findings show a good positive correlation between ejection fraction and creatine-stimulated respiration values and a linear negative correlation between this parameter and end-diastolic pressures. Thus, the respiratory parameters of mitochondria in the endomyocardial biopsy specimens may be used to assess the severity of cardias lesions.     

Hepatitis viruses and non-Hodgkin lymphoma: epidemiology, mechanisms of tumorigenesis, and therapeutic opportunities

Over the past 2 decades considerable evidence has accumulated on the association between hepatitis C virus (HCV) and hepatitis B virus (HBV) and several hematologic malignancies, most notably B-cell non-Hodgkin lymphoma (NHL). In this review we summarize this evidence, address possible mechanisms whereby hepatitis viruses may contribute to lymphomagenesis, and discuss the therapeutic fallouts from this knowledge. Most of this evidence is on HCV, and this is the main focus of the review. Moreover, we mainly address the association with NHL, the most prevalent hematologic malignancy, and the most extensively investigated with regard to an association with hepatitis viruses. Available evidence on the association with other hematologic malignancies is also addressed briefly.     

Implication of cardiac remodeling in heart failure: mechanisms and therapeutic strategies

The concept and clinical implication of left ventricular remodeling have been gradually extended. Cardiac remodeling plays important roles in the progression of cardiovascular diseases including myocardial infarction, valvular heart diseases, myocarditis, and dilated cardiomyopathy. In addition to cardiac myocytes, fibroblasts, extracellular matrix proteins and coronary vasculature are also involved in the remodeling process. Cardiac remodeling is associated with alterations of many mediators such as neurohumoral factors, cytokines, enzymes, ion channels, oxidative stress and mechanical stress. Although remodeling is initially an adaptive response to maintain normal cardiac function, it gradually becomes maladaptive and leads to progressive decompensation. Recent research has attempted to elucidate underlying molecular mechanisms of cardiac remodeling and to develop novel therapeutic strategies for heart failure. The modulation of remodeling process is effective for preventing the progression of heart failure.     

The role of SIRT3 in mitochondrial homeostasis and cardiac adaptation to hypertrophy and aging

Although acetyl-modification of protein lysine residues has been recognized for many decades, the appreciation that this post-translational modification is highly prevalent in mitochondria and plays a pivotal regulatory role in mitochondrial function has only become apparent since 2006. The classical biological stressors that modulate mitochondrial protein acetylation include alterations in caloric levels and redox signaling and the major enzyme orchestrating deacetylation is the mitochondrial enriched sirtuin SIRT3. Overall the action of SIRT3 modulates mitochondrial homeostasis and SIRT3 target proteins include mediators of energy metabolism and mitochondrial redox stress adaptive program proteins. Given these effects, it is not surprising that the role of SIRT3 has begun to be implicated in cardiac biology. This review gives a brief overview of sirtuin biology and then focuses on the role of the SIRT3 regulatory program in the control of cardiac hypertrophy and aging. This article is part of a Special Section entitled "Post-translational Modification."     

睾酮对衰老心肌细胞的干预作用及其机制

目的探讨不同剂量睾酮对衰老心肌细胞的干预作用及其可能机制。方法将心肌细胞随机分为正常组、衰老组、1μmol/L睾酮组、100 nmol/L睾酮组、10 nmol/L睾酮组,检测各组心肌细胞周期分布,去磷酸化视网膜母细胞瘤蛋白(RB)表达,细胞内活性氧水平以及细胞线粒体DNA突变率。结果衰老组心肌细胞G_0/G_1期比例较正常组明显升高,而1μmol/L睾酮组、100 nmol/L睾酮组、10 nmol/L睾酮组G_0/G_1期比例较衰老组明显降低(P<0.05)。除10 nmol/L睾酮组对RB表达无明显影响外,睾酮干预可下调去磷酸化RB表达,降低细胞内活性氧水平,降低线粒体DNA突变率(P<0.05,P<0.01)。结论睾酮可抑制小鼠心肌细胞衰老,这一作用部分是通过下调去磷酸化RB表达,降低细胞内活性氧水平,降低线粒体DNA突变率来实现的。     

Retinal and choroidal microangiopathies: therapeutic opportunities

Pathological angiogenesis in the retina and underlying choroid is a major cause of visual impairment in all age groups. The last decade has seen an explosion in the clinical availability of antiangiogenic compounds. Emphasis has been placed on inhibitors of the VEGF signaling pathway and considerable success has been achieved with aptamers and antibodies that bind VEGF. However, regression of neovascularization is rarely permanent and the regrowth of new vessels, often within a few months, requires multiple applications of drug. A number of antiangiogenic factors such as IGFBP3, SDF-1 blockers, PEDF, gamma-secretase, Delta-like ligand 4, and integrin antagonists have been identified, which act either indirectly on the VEGF system or independent of it. The importance of other candidates such as HIF-1alpha and protein kinase CK2, which act as "master" regulators of angiogenesis, offer realistic alternative targets for pharmacological intervention. The concept of combination therapy is rapidly gaining interest in the eye field and co-administration of two angiogenic agents (e.g., a CK2 inhibitor with a somatostatin analog, octreotide) are often significantly more effective at inhibiting retinal angiogenesis than either drug alone. The following review will discuss the current therapies available for aberrant ocular angiogenesis, consider new candidate targets for development of antiangiogenic compounds and emphasize the importance of combinatorial pharmacological agents in the treatment of such a dynamic cellular event as angiogenesis.     

Polycystic kidney disease: genes, proteins, animal models, disease mechanisms and therapeutic opportunities

An increased understanding of the genetic, molecular and cellular mechanisms responsible for the development of polycystic kidney disease has laid out the foundation for the development of rational therapies. Many animal models where these therapies can be tested are currently available. This review summarizes the rationale for these treatments, the results of preclinical trials and the prospects for clinical trials, some already in early phases of implementation.     

Caloric restriction protects mitochondrial function with aging in skeletal and cardiac muscles

In skeletal muscles and heart in vitro complex IV activity is lower in young adult caloric restricted (CR) animals despite normal aerobic function in situ and in vivo. On the other hand, whereas markers of oxidative capacity decline 25% to 46% between 8 and 10 months and 35 months in ad libitum fed (AL) animals, in most muscles there is no decline in CR across the same absolute age (35 mo old) or relative age (35% survival rate) span and PGC-1alpha gene expression in gastrocnemius muscle declines more slowly with aging. The present results show that CR largely prevents the age-associated decline in mitochondrial function in heart and skeletal muscles, and suggest that this is secondary to a better-maintained drive on mitochondrial biogenesis.     

Selective mitochondrial autophagy, or mitophagy, as a targeted defense against oxidative stress, mitochondrial dysfunction, and aging

In autophagy, portions of cytoplasm are sequestered into autophagosomes and delivered to lysosomes for degradation. Long assumed to be a random process, increasing evidence suggests that autophagy of mitochondria, peroxisomes, and possibly other organelles is selective. A recent paper (Kissova et al., J. Biol. Chem. 2004;279:39068-39074) shows in yeast that a specific outer membrane protein, Uth1p, is required for efficient mitochondrial autophagy. For this selective autophagy of mitochondria, we propose the term "mitophagy" to emphasize the non-random nature of the process. Mitophagy may play a key role in retarding accumulation of somatic mutations of mtDNA with aging.