Melatonin prevents Drp1‐mediated mitochondrial fission in diabetic hearts through SIRT1‐PGC1α pathway

Myocardial contractile dysfunction is associated with an increase in mitochondrial fission in patients with diabetes. However, whether mitochondrial fission directly promotes diabetes‐induced cardiac dysfunction is still unknown. Melatonin exerts a substantial influence on the regulation of mitochondrial fission/fusion. This study investigated whether melatonin protects against diabetes‐induced cardiac dysfunction via regulation of mitochondrial fission/fusion and explored its underlying mechanisms. Here, we show that melatonin prevented diabetes‐induced cardiac dysfunction by inhibiting dynamin‐related protein 1 (Drp1)‐mediated mitochondrial fission. Melatonin treatment decreased Drp1 expression, inhibited mitochondrial fragmentation, suppressed oxidative stress, reduced cardiomyocyte apoptosis, improved mitochondrial function and cardiac function in streptozotocin (STZ )‐induced diabetic mice, but not in SIRT 1^?/? diabetic mice. In high glucose‐exposed H9c2 cells, melatonin treatment increased the expression of SIRT 1 and PGC ‐1α and inhibited Drp1‐mediated mitochondrial fission and mitochondria‐derived superoxide production. In contrast, SIRT 1 or PGC ‐1α siRNA knockdown blunted the inhibitory effects of melatonin on Drp1 expression and mitochondrial fission. These data indicated that melatonin exerted its cardioprotective effects by reducing Drp1‐mediated mitochondrial fission in a SIRT 1/PGC ‐1α‐dependent manner. Moreover, chromatin immunoprecipitation analysis revealed that PGC ‐1α directly regulated the expression of Drp1 by binding to its promoter. Inhibition of mitochondrial fission with Drp1 inhibitor mdivi‐1 suppressed oxidative stress, alleviated mitochondrial dysfunction and cardiac dysfunction in diabetic mice. These findings show that melatonin attenuates the development of diabetes‐induced cardiac dysfunction by preventing mitochondrial fission through SIRT 1‐PGC 1α pathway, which negatively regulates the expression of Drp1 directly. Inhibition of mitochondrial fission may be a potential target for delaying cardiac complications in patients with diabetes.     

An association between Type 2 diabetes and α1‐antitrypsin deficiency

Aims α₁‐Antitrypsin (AAT) is a serine protease inhibitor which recently has been shown to prevent Type 1 diabetes development, to prolong islet allograft survival and to inhibit pancreatic B‐cell apoptosis in vivo. It has also been reported that Type 1 diabetic patients have significantly lower plasma concentrations of AAT, suggesting the potential role of AAT in the pathogenesis of Type 1 diabetes. We have investigated whether plasma AAT levels are altered in Type 2 diabetes. Methods The study included patients with Type 2 diabetes (n = 163) and non‐diabetic control subjects matched for age, sex and smoking habits (n = 158) derived from the population‐based Malmö Diet and Cancer study. Plasma samples were analysed for AAT concentration and phenotype and serum glucose, insulin, C‐reactive protein and lipid levels were measured. Glycated haemoglobin was also measured. Results In the diabetic group, the women had higher mean plasma AAT levels than men (P < 0.05). The mean plasma AAT levels did not differ between diabetic and control subjects. However, the number of individuals with low AAT levels (< 1.0 mg/ml) was 50% higher in the diabetic group (P < 0.05) and the frequency of AAT deficiency genotypes was 50% higher (NS) in diabetic compared with control subjects. In the group of diabetic patients with AAT < 1 mg/ml, AAT directly correlated with systolic blood pressure (P = 0.048) and inversely correlated with waist–hip ratio (P = 0.031). Conclusions Our results provide evidence that deficiency of AAT may be associated with an increased risk of developing Type 2 diabetes.     

Molecular characterization of a new family with α-Thalassemia-1 (——MA mutation)

A Spanish family with α-thalassemia-1 (α-Thal-1), deletion (—^MA), is described. In addition to the loss of 22 kb of DNA with a deletion of the α₁, α₂, α₁, α₂, and Ψζ₁ genes, a triplication of the ζ gene cluster in “cis” is produced. The structure of this triplication is formed by the Ψα₁, gene, the interzeta region, and, possibly, the insertion of the Ψα₂ fragment. © 1995 Wiley-Liss, Inc.     

Familial α1-Antichymotrypsin Deficiency

ABSTRACT We studied patients and their relatives with partial deficiency, approximately 50% of normal plasma levels, of α₁-antichymotrypsin (ACT), an acute phase reactant with anti-cathepsin G activity. Six of eight ACT deficient individuals, over 25 years of age, had liver and three of eight lung manifestations, varying from severe disease to subtle laboratory abnormalities. The ACT of deficient individuals (who are heterozygotes for a rare gene, q=0.003) had normal crossed immunoelectrophoretic properties. The abnormal gene is inherited in an autosomal, dominant way. The results suggest that deficiency of this antiprotease, which also has immune response modulating properties, may predispose to liver and lung disease.     

α-thalassemia-1 (— −-CAL mutation) in a Spanish family

We have detected a second family (five members affected) with a large (32 kb) deletion involving the α₁, α₂, ψα₁, ψα₂,ψζ₁, and ζ-globin genes. This mutation has been previously described in Calabria, Italy, in a child and his mother and has been named α-thalassemia ?- ?-^CAL . © 1994 Wiley-Liss, Inc.     

Recent topics on α‐fetoprotein

Zinc‐fingers and homeoboxes 2 (ZHX2) and zinc‐finger and BTB domain containing 20 (ZBTB20) repress the postnatal expression of α‐fetoprotein (AFP) by interacting with the AFP gene promoter regions. ZHX2 inhibits the expression of AFP and cyclins A and E. ZBTB20 is negatively regulated by CUX1, which promotes cell‐cycle progression, suggesting that AFP reactivation is closely linked to hepatocyte proliferation. A slight elevation in the serum AFP level often occurs in patients with chronic hepatitis C in the absence of hepatocellular carcinoma (HCC) and is an independent risk factor for HCC development to complement the fibrosis stage. In addition, the sustained elevation of AFP after interferon therapy is a risk factor of HCC development. AFP levels are clinically useful in predicting the outcomes of liver transplantation and sorafenib therapy for HCC patients. A low preoperative AFP level is a predictor of long‐term survival and is associated with a low recurrence rate of HCC after liver transplantation. AFP response (≥20% decrease in AFP during 6–8 weeks of treatment) rather than radiological outcomes is a significant prognostic factor for survival in sorafenib‐treated HCC patients. Highly sensitive Lens culinaris agglutinin‐reactive AFP (AFP‐L3) is 5–10 times more sensitive than conventional AFP‐L3, and useful for early detection of HCC in patients with total AFP below 20 ng/mL.     

Role of α1‐blockers in the current management of hypertension

There is emerging evidence that α1‐blockers can be safely used in the treatment of hypertension. These drugs can be used in almost all hypertensive patients for blood pressure control. However, there are several special indications. Benign prostatic hyperplasia is a compelling indication of α1‐blockers, because of the dual treatment effect on both high blood pressure and lower urinary tract symptoms. Many patients with resistant hypertension would require α1‐blockers as add‐on therapy. Primary aldosteronism screen is a rapidly increasing clinical demand in the management of hypertension, where α1‐blockers are useful for blood pressure control in the preparation for the measurement of plasma aldosterone and renin. Nonetheless, α1‐blockers have to be used under several considerations. Among the currently available agents, only long‐acting α1‐blockers, such as doxazosin gastrointestinal therapeutic system 4–8 mg daily and terazosin 2–4 mg daily, should be chosen. Orthostatic hypotension is a concern with the use of α1‐blockers especially in the elderly, and requires careful initial bedtime dosing and avoiding overdosing. Fluid retention is potentially also a concern, which may be overcome by combining an α1‐blocker with a diuretic.     

Analysis of N1‐acetyl‐N2‐formyl‐5‐methoxykynuramine/N1‐acetyl‐5‐methoxy‐kynuramine formation from melatonin in mice

Abstract: The interactions of melatonin, a potent endogenous antioxidant, with reactive oxygen species generate several products that include N¹‐acetyl‐N²‐formyl‐5‐methoxykynuramine (AFMK) and N¹‐acetyl‐5‐methoxy‐kynuramine (AMK). The physiological or pathological significance of AFMK/AMK formation during the process of melatonin metabolism in mammals has not been clarified. Using a metabolomic approach in the current study, the AFMK/AMK pathway was thoroughly investigated both in mice and humans. Unexpectedly, AFMK and AMK were not identified in the urine of humans nor in the urine, feces or tissues (including liver, brain, and eyes) in mice under the current experimental conditions. Metabolomic analysis did identify novel metabolites of AMK, i.e. hydroxy‐AMK and glucuronide‐conjugated hydroxy‐AMK. These two newly identified metabolites were, however, not found in the urine of humans. In addition, oxidative stress induced by acetaminophen in the mouse model did not boost AFMK/AMK formation. These data suggest that AFMK/AMK formation is not a significant pathway of melatonin disposition in mice, even under conditions of oxidative stress.     

Endobronchial valve deployment in severe α‐1 antitrypsin deficiency emphysema: a case series

Introduction: Patients with end‐stage emphysema because of α‐1 antitrypsin (AAT) deficiency represent a challenging clinical management problem, and studies of volume reduction therapy to date have largely excluded these patients. We report the outcome of bronchoscopic volume reduction with the insertion of Emphasys endobronchial valves (Emphasys Medical, Redwood City, CA, USA) in six patients with end‐stage emphysema because of AAT deficiency. Case Series: Of 51 patients with end stage emphysema referred for transplantation, we studied six patients with AAT deficiency and utilized the BODE index and lung allocation score for survival estimation. Measurements and Main Results: The forced expiratory volume in 1 s improved from a median of 0.575 L to 0.905 L (P = 0.028). There was a median reduction in total lung capacity (TLC) of 0.61 L. The residual volume /TLC fell from 74.0% to 58.4%. Before treatment, four patients had a BODE index of greater than eight units, which correlates with a 4‐year survival of 18%. After treatment, two patients improved their BODE index to below seven units, which correlates with an estimated 4‐year survival of over 50%. Conclusions: The data from this case series suggest that this intervention may provide bridging therapy to subsequent transplantation for younger AAT patients with end‐stage emphysema. Please cite this paper as: Tuohy MM, Remund KF, Hilfiker R, Murphy DT, Murray JG and Egan JJ. Endobronchial valve deployment in severe α‐1 antitrypsin deficiency emphysema: a case series. Clin Respir J 2013; 7: 45–52.     

Nondeletional α-thalassemia: First description of αHphα and αNcoα mutations in a Spanish population

Several different deletions underlie the molecular basis of α-thalassemia. The most common α-thalassemia determinant in Spain is the rightward deletion (−α^3.7). To our knowledge, however, no cases of α-thalassemia due to nondeletional mutations have so far been described in this particular Mediterranean area. Here, we report the existence of nondeletional forms of α-thalassemia in ten Spanish families. The α₂-globin gene was characterized in ten unrelated patients and their relatives only when the presence of deletional α-thalassemia was ruled out. The α₂-globin gene analysis was performed using the polymerase chain reaction (PCR) followed by restriction enzyme analysis or by allele-specific priming. This allowed the identification of a 5-base pair (bp) deletion at the donor site of IVS I (α^Hphα) in 9 cases and the α₂ initiation codon mutation (α^Ncoα) in one case. Although these α₂-globin gene mutations are found in other Mediterranean areas, our results demonstrate their presence in the Spanish population and suggest that the α^Hphα/αα genotype is probably the most common nondeletional form of α-thalassemia in Spain. © 1996 Wiley-Liss, Inc.     

Conversion to Silodosin in Men on Conventional α1‐Blockers for Symptomatic Benign Prostatic Hyperplasia

Objectives: α₁‐blockers have commonly been used as first‐line medical therapy for symptomatic benign prostatic hyperplasia (BPH). Recently, a highly selective α_1A‐adrenoceptor antagonist, silodosin, was developed in Japan. We examined the efficacy and safety of conversion from conventional α₁‐blockers to silodosin in men with BPH. Methods: Conversion to silodosin was proposed to consecutive patients on conventional α₁‐blockers for symptomatic BPH for at least 6 months. The effects of conversion were examined by the International Prostate Symptom Score, quality of life index, overactive bladder symptom score, peak flow rate, residual urine volume, and adverse events at 12 weeks. The efficacy of silodosin was also evaluated by patients' impression. Results: Eighty‐one men underwent conversion, for the most part because of dissatisfaction with the efficacy of their current treatment in improving nocturia or weak stream. The International Prostate Symptom Score total score significantly improved from 12.7 ± 5.9 at baseline to 10.6 ± 5.4 at 4 weeks (P < 0.001) and 10.9 ± 5.8 at 12 weeks (P < 0.01). The progress was mostly due to improvement in voiding symptoms, although reduction of storage symptoms was also significant. The quality of life index also significantly decreased with conversion to silodosin. Efficacy as judged by patients' impression was 76% (37/49) at 12 weeks of treatment. None of the overactive bladder symptom score, peak flow rate, and residual urine volume exhibited significant change. No serious adverse events were observed during the study period. Conclusion: Conversion to silodosin may be beneficial in men who are dissatisfied with conventional α₁‐blockers for BPH, and be particularly useful in improving voiding symptoms.