Lack of Myosin X Enhances Osteoclastogenesis and Increases Cell Surface Unc5b in Osteoclast-Lineage Cells.

Normal bone mass is maintained by balanced bone formation and resorption. Myosin X (Myo10), an unconventional "myosin tail homology 4-band 4.1, ezrin, radixin, moesin" (MyTH4-FERM) domain containing myosin, is implicated in regulating osteoclast (OC) adhesion, podosome positioning, and differentiation in vitro. However, evidence is lacking for Myo10 in vivo function. Here we show that mice with Myo10 loss of function, Myo10m/m , exhibit osteoporotic deficits, which are likely due to the increased OC genesis and bone resorption because bone formation is unchanged. Similar deficits are detected in OC-selective Myo10 conditional knockout (cko) mice, indicating a cell autonomous function of Myo10. Further mechanistic studies suggest that Unc-5 Netrin receptor B (Unc5b) protein levels, in particular its cell surface level, are higher in the mutant OCs, but lower in RAW264.7 cells or HEK293 cells expressing Myo10. Suppressing Unc5b expression in bone marrow macrophages (BMMs) from Myo10m/m mice by infection with lentivirus of Unc5b shRNA markedly impaired RANKL-induced OC genesis. Netrin-1, a ligand of Unc5b, increased RANKL-induced OC formation in BMMs from both wild-type and Myo10m/m mice. Taken together, these results suggest that Myo10 plays a negative role in OC formation, likely by inhibiting Unc5b cell-surface targeting, and suppressing Netrin-1 promoted OC genesis. © 2019 American Society for Bone and Mineral Research.

Acebutolol, a Cardioselective Beta Blocker, Promotes Glucose Uptake in Diabetic Model Cells by Inhibiting JNK-JIP1 Interaction

The phosphorylation of JNK is known to induce insulin resistance in insulin target tissues. The inhibition of JNK-JIP1 interaction, which interferes JNK phosphorylation, becomes a potential target for drug development of type 2 diabetes. To discover the inhibitors of JNK-JIP1 interaction, we screened out 30 candidates from 4320 compound library with In Cell Interaction Trap method. The candidates were further confirmed and narrowed down to five compounds using the FRET method in a model cell. Among those five compounds, Acebutolol showed notable inhibition of JNK phosphorylation and elevation of glucose uptake in diabetic models of adipocyte and liver cell. Structural computation showed that the binding affinity of Acebutolol on the JNK-JIP1 interaction site was comparable to the known inhibitor, BI-78D3. Our results suggest that Acebutolol, an FDA-approved beta blocker for hypertension therapy, could have a new repurposed effect on type 2 diabetes elevating glucose uptake process by inhibiting JNK-JIP1 interaction.

BLIND: a set of semantic feature norms from the congenitally blind.

Feature-based descriptions of concepts produced by subjects in a property generation task are widely used in cognitive science to develop empirically grounded concept representations and to study systematic trends in such representations. This article introduces BLIND, a collection of parallel semantic norms collected from a group of congenitally blind Italian subjects and comparable sighted subjects. The BLIND norms comprise descriptions of 50 nouns and 20 verbs. All the materials have been semantically annotated and translated into English, to make them easily accessible to the scientific community. The article also presents a preliminary analysis of the BLIND data that highlights both the large degree of overlap between the groups and interesting differences. The complete BLIND norms are freely available and can be downloaded from http://sesia.humnet.unipi.it/blind_data .

Mammalian selenocysteine lyase is involved in selenoprotein biosynthesis.

Selenocysteine lyase (SCL) catalyzes the decomposition of L-selenocysteine to yield L-alanine and selenium by acting exclusively on l-selenocysteine. The X-ray structural analysis of rat SCL has demonstrated how SCL discriminates L-selenocysteine from L-cysteine on the molecular basis. SCL has been proposed to function in the recycling of the micronutrient selenium from degraded selenoproteins containing selenocysteine residues, but the role of SCL in selenium metabolism in vivo remains unclear. We here demonstrate that the (75)Se-labeling efficiency of selenoproteins with (75)Se-labeled selenoprotein P (Sepp1) as a selenium source was decreased in HeLa cells transfected with SCL siRNA as compared to the cells transfected with control siRNA. Immunocytochemical analyses showed high SCL expression in kidney and liver cells, where selenocysteine is recovered from selenoproteins. Mature testes of mice exhibited a specific staining pattern of SCL in spermatids that actively produce selenoproteins. However, SCL was weakly expressed in Sertoli cells, which receive Sepp1 and supply selenium to germ cells. These demonstrate that SCL occurs in the cells requiring selenoproteins, probably to recycle selenium derived from selenoproteins such as Sepp1.

Smith-Magenis syndrome: a case report of improved sleep after treatment with beta1-adrenergic antagonists and melatonin.

This report describes the case of a 4-year-old boy diagnosed with Smith-Magenis syndrome in whom treatment with a beta(1)-adrenergic antagonist in the morning (to suppress the diurnal melatonin secretion) and melatonin in the evening (to generate a nocturnal peak of melatonin) improved his sleep quality, evaluated by polysomnographic studies.

Effects of antihypertensive agents on circadian blood pressure in hypertensive patients with previous brain infarction.

To evaluate the effects of antihypertensive agents on the circadian blood pressure (BP) of patients with previous brain infarction, the ambulatory BP was measured non-invasively for 24 h before and after administration of antihypertensive agents. One hundred milligrams of acebutolol twice daily (n = 15) is effective in lowering the BP during the daytime, but has little effect during the night and the morning. Twenty milligrams of slow-release nifedipine twice daily (n = 14) produced a consistent reduction in the BP over the entire 24-h period and effectively blunted the rise in BP in the morning. Captopril (12.5 mg) twice daily (n = 15) produced a mild reduction in BP with little change in the circadian pattern. The slow-release nifedipine group had the greatest decrease in mean systolic and diastolic BP. The heart rate significantly increased after administration of slow-release nifedipine and decreased after administration of acebutolol. To reduce stroke recurrence, we should consider the effects of antihypertensive agents on circadian BP in hypertensive patients with previous brain infarction.

Effects of long-term antihypertensive therapy on physical fitness of men with mild hypertension.

This study was conducted to investigate the effects of long-term administration of a calcium-channel antagonist (nifedipine) and a beta-blocker (acebutolol) on physical fitness in men with mild hypertension. All subjects underwent symptom-limited treadmill stress testing and routine echocardiographic studies. Twenty-two subjects who had either a causal diastolic blood pressure of more than 105 mmHg or a left ventricular mass index (LVMI) of 125 g/m2 or more during follow-up were assigned to receive medical therapy. The other 31 men who did not meet either criterion were continuously followed-up without medication. Among the 22 treated men, the age-adjusted treadmill time (normalized treadmill time, TMTn) significantly decreased before the initiation of medication, while 31 untreated men showed no change in TMTn throughout the study. The 22 treated subjects were subsequently divided into two groups; 13 were given nifedipine and 9 were given acebutolol. All treated subjects were followed-up for more than 3 years. After treatment, the two groups showed similar reductions in blood pressure and LVMI, but a different outcome for TMTn: TMTn increased from 104 +/- 8% to 115 +/- 16% in subjects given nifedipine (p < 0.05) and decreased from 106 +/- 12% to 99 +/- 10% (p < 0.01) in those given acebutolol. Thus, the physical fitness of subjects who required medication significantly deteriorated without medication; their physical fitness improved after treatment with a calcium-channel antagonist and deteriorated after treatment with a beta-blocker.

Long-term effects on sexual function of five antihypertensive drugs and nutritional hygienic treatment in hypertensive men and women. Treatment of Mild Hypertension Study (TOMHS)

Problems with sexual function have been a long-standing concern in the treatment of hypertension and may influence the choice of treatment regimens and decisions to discontinue drugs. The Treatment of Mild Hypertension Study (TOMHS) provides an excellent opportunity for examination of sexual function and effects of treatment on sexual function in men and women with stage I diastolic hypertension because of the number of drug classes studied, the double-blind study design, and the long-term follow-up. TOMHS was a double-blind, randomized controlled trial of 902 hypertensive individuals (557 men, 345 women), aged 45 to 69 years, treated with placebo or one of five active drugs (acebutolol, amlodipine maleate, chlorthalidone, doxazosin maleate, or enalapril maleate). All participants received intensive lifestyle counseling regarding weight loss, dietary sodium reduction, alcohol reduction (for current drinkers), and increased physical activity. Sexual function was ascertained by physician interviews at baseline and annually during follow-up. At baseline, 14.4% of men and 4.9% of women reported a problems with sexual function. In men, 12.2% had problems obtaining and/or maintaining an erection; 2.0% of women reported a problem having an orgasm. Erection problems in men at baseline were positively related to age, systolic pressure, and previous antihypertensive drug use. The incidences of erection dysfunction during follow-up in men were 9.5% and 14.7% through 24 and 48 months, respectively, and were related to type of antihypertensive therapy. Participants randomized to chlorthalidone reported a significantly higher incidence of erection problems through 24 months than participants randomized to placebo (17.1% versus 8.1%, P = .025). Incidence rates through 48 months were more similar among treatment groups than at 24 months, with nonsignificant differences between the chlorthalidone and placebo groups. Incidence was lowest in the doxazosin group but was not significantly different from the placebo group. Incidence for acebutolol, amlodipine, and enalapril groups was similar to that in the placebo group. In many cases, erection dysfunction did not require withdrawal of medication. Disappearance of erection problems among men with problems at baseline was common in all groups but greatest in the doxazosin group. Incidence of reported sexual problems in women was low in all treatment groups. In conclusion, long-term incidence of erection problems in treated hypertensive men is relatively low but is higher with chlorthalidone treatment. Effects of erection dysfunction with chlorthalidone appear relatively early and are often tolerable, and new occurrences after 2 years are unlikely. The rate of reported sexual problems in hypertensive women is low and does not appear to differ by type of drug. Similar incidence rates of erection dysfunction in placebo and most active drug groups caution against routine attribution of erection problems to antihypertensive medication.

Effects of turpentine oil pretreatment on beta-blocker pharmacokinetic parameters in rats.

Turpentine oil treatment (0.2 mL kg-1, s.c.) was used to increase the plasma concentration of alpha 1-acid glycoprotein (0.13 mg mL-1 in control rats) to 1.72 mg mL-1 after 2 days, and allow assessment of its effects on the pharmacokinetics and stereoselective binding of three beta-blockers. Racemates (5 mg kg-1) were administered intravenously to control and turpentine oil-pretreated rats and the plasma concentrations were determined up to 90 min. Stereoselective analysis showed the apparent distribution volume and the area under plasma concentration-time curves (AUC) of R-(+)-propranolol to be, respectively, one-quarter and twice those of the S-(-)-enantiomer and differences in pharmacokinetic parameters between the two were magnified by turpentine oil pretreatment. Pharmacokinetic parameters of oxprenolol enantiomers were essentially similar for the controls but after turpentine oil pretreatment, a higher affinity of the R-(+)-enantiomer for plasma was observed. Acebutolol enantiomers behaved non-stereospecifically throughout. These results were consistent with predictions from the in-vitro stereospecific binding properties of these agents to purified rat alpha 1-acid glycoprotein.

[Evaluation of the efficacy and tolerance of three antihypertensive agents used as single-drug therapy, nifedipine, prazosin and acebutolol in severe, idiopathic hypertension in adolescents]. / Evaluation de l'efficacité et de la tolérance de trois antihypertenseurs utilisés en monothérapie, nifédipine, prazosin et acébutolol dans l'hypertension idiopathique grave de l'adolescent.

The antihypertensive efficacy of single-drug therapy with nifedipine (N), prazosin (P), or acebutolol (A) and the influence of these agents on coronary risk factors including hypoglycemia, hyperuricemia, and hyperlipidemia, were studied in adolescents with hypertension. Ninety patients (73 girls and 17 boys) aged 14 to 18 years with idiopathic hypertension (IH) were randomized into three groups. Each group received N, P, or A as single-drug therapy for six months. Systolic and diastolic blood pressures fell in all three groups, from 152/90 mmHg to 127/70 mmHg* with N, from 150/90 mmHg to 121/70 mmHg* with P, and from 148/92 mmHg to 122/74 mmHg* mmHg with A. In 17% of cases, N failed to reduce blood pressures below the 90th centiles. Heart rate was not influenced by N or P but decreased from 84 to 75 bpm with A. Although none of the drugs modified serum uric acid levels, fractional uric acid secretion rose with P and A (from 4.1% to 6% with P; and from 4.4% to 6% with A). The lipid profile remained unchanged under N and P, whereas a decrease in serum LDL-cholesterol from 99.6 to 88.8% mg* was seen with A. Fasting serum glucose levels increased from 86.4 to 92.7 mg %* in the group given A. N, P, and A are suitable for single-drug therapy of IH in adolescents; the most appropriate drug should be selected on the basis of medical history.

[Electrocardiographic and echocardiographic changes during antihypertensive therapy]. / Modificazioni elettrocardiografiche ed ecocardiografiche durante terapia antipertensiva.

To investigate the changes of electrocardiographic and echocardiographic indexes of left ventricular hypertrophy (LVH) during antihypertensive therapy, 100 hypertensive patients, mean age 46 years, were studied in pretreatment condition and during 12 months of antihypertensive therapy. In pretreatment condition, 83 patients showed LVH by echocardiography (echo; left ventricular mass index greater than 130 g/m2) and 30 patients had LVH by electrocardiography (ECG) (Sokolow index greater than 35 mm). In comparison to echo index of LVH, Sokolow index showed a sensibility of 34% and a specificity of 88%. Both LV mass echo index and ECG index significantly decreased after 3 months but in different way. LV mass index mainly decreased after 12 months, whereas Sokolow index particularly decreased after 6 months, with no further changes in the subsequent months. After 12 months of therapy, the LV mass echo index normalized in 19% of the patients (16/83) and Sokolow index normalized in 57% (17/30). ECG sensibility and specificity, in comparison to LV mass echo, was 20% and 100%, respectively. Thus, ECG appears less sensitive than echo in the detection of LVH. During antihypertensive therapy ECG index of LVH normalized more precociously and to a greater extent than the echo index. However, the normalization of LVH by ECG does not necessarily mean that a complete anatomic regression of LVH has occurred.

[Therapy of moderate hypertension with the calcium antagonist nitrendipine in combination with beta receptor blocker or diuretic]. / Therapie der mittelschweren Hypertonie mit dem Calciumantagonisten Nitrendipin in Kombination mit Betarezeptorenblocker oder Diuretikum.

The efficacy of the calcium channel blocker nitrendipine alone and in combination with the beta blocking agent acebutolol or hydrochlorothiazide was tested in 34 patients with moderate essential hypertension. After a wash out period of three to four weeks, all patients received placebo for two weeks, thereafter 20 mg of nitrendipine per day for four weeks. When diastolic blood pressure remained above 95 mmHg with nitrendipine, acebutolol (200 mg/d) or the thiazide (25 mg/d) was added in a randomised double-blind fashion. With nitrendipine alone, blood pressure could be normalized in nine patients with a drop in pressure from 168/108 to 152/89 mmHg. The other patients showed a fall in blood pressure from 164/110 to 152/102 mmHg. In these patients, the addition of acebutolol or thiazide was followed by a further fall in blood pressure which was similar with both drugs. With acebutolol blood pressure decreased from 154/102 to 146/94 mmHg and with the thiazide from 152/102 to 147/95 mmHg, respectively. Minor and mostly transient side effects were predominantly seen during therapy with nitrendipine alone. The fall in diastolic but not systolic blood pressure with nitrendipine was correlated with age. The blood pressure lowering effect of nitrendipine was independent of plasma renin activity and intracellular electrolyte concentrations. In the therapy of moderate hypertension, nitrendipine given in combination with a betablocker or a thiazide diuretic is effective and well tolerated.

[Regression of left ventricular hypertrophy in hypertensive patients under long-term therapy with antihypertensive agents]. / Rückbildung der Linksherzhypertrophie bei Hochdruckkranken durch antihypertensive Langzeittherapie.

The effect of long-term therapy of hypertension with antihypertensive drugs was investigated in 117 previously untreated patients (15 women, 102 men; mean age 46.4 +/- 9 years) with echocardiographically proven left-ventricular hypertrophy. 22 patients (group 1) received 100 mg/d Gallopamil, 25 (group 2) received 200 mg/d Metoprolol, 35 daily received both 50 mg Atenolol and 20 mg Nifedipine (group 3), 14 received daily 200 mg Acebutolol plus 20 mg Nifedipine (group 4), and 21 (group 5) 50 mg Atenolol plus 10 mg Enalapril daily. The treatment period lasted a mean of 38 (36.2-42.3) months. Left-ventricular muscle mass index (LVMI) as well as septal and posterior-wall thickness decreased significantly after 12.8 and 38.5 months (P less than 0.001). After a mean of 38.5 months LVMI had decreased by 36.7% in group 1, 35.1% in group 2, 42.3% in group 3, 45% in group 4 and 39.6% in group 5. LVMI was within normal range (less than or equal to 95 g/m2) in 81 of the 117 patients (69.2%) at the end of the treatment period. There was, however, no significant increase of the end-diastolic dimension of the left ventricle, but a significant increase of "fractional shortening" as a measure of myocardial contractility.

Regression of left ventricular hypertrophy by acebutolol and nifedipine.

Fourteen patients with previously untreated essential hypertension and left ventricular hypertrophy were treated with a fixed-dose combination of acebutolol 200 mg and nifedipine 20 mg once daily for a followup of 25.6 +/- 1.8 months. Echocardiography showed a significant decrease after a mean period of 6.6 months in interventricular septal thickness (14.8%, p less than 0.001), posterior wall thickness (14.8%, p less than 0.001), and left ventricular mass index (21.3%). After 25.6 months, the reductions were 29% (p less than 0.001), 28.1% (p less than 0.001), and 38.7% (p less than 0.001), respectively. Left wall thickness was significantly reduced, but left ventricular end-systolic and end-diastolic dimensions and fractional shortening remained unchanged. Treatment reduced resting blood pressure from 161/102 mmHg to 132/87 mmHg (p less than 0.001) and reduced exercise blood pressure at 100 W from 208/113 mmHg to 170/94 mmHg (p less than 0.001). Thus, nifedipine in combination with acebutolol produces significant blood-pressure reduction accompanied by regression of left ventricular hypertrophy without noticeable changes in left ventricular function.

Comparison of beta 1- and beta 2-adrenoceptor effects on gastric emptying of a fat meal in mice.

The effects of intraperitoneal administration of isoproterenol (a mixed beta 1- and beta 2-agonist), dobutamine (a selective beta 1-agonist) and clenbuterol (a selective beta 2-agonist) on gastric emptying were investigated in mice killed 30 min after gavage with a 51Cr radiolabeled milk meal. Administered 30 min prior to the meal, isoproterenol (2 mg/kg) and dobutamine (1 and 2 mg/kg) accelerated gastric emptying and clenbuterol (0.05 and 0.1 mg/kg) slowed it. The stimulation of gastric emptying by isoproterenol (2 mg/kg) and dobutamine (2 mg/kg) was blocked by the previous administration of either mixed beta 1- and beta 2-antagonist, propranolol (1 mg/kg), or a specific beta 1-antagonist, acebutolol (1 mg/kg). Only propranolol (1 mg/kg) antagonized the decrease of gastric emptying induced by clenbuterol. A high dose of propranolol (10 mg/kg), injected alone, reduced gastric emptying. It is concluded that the increase in gastric emptying caused by beta-adrenergic drugs is mediated through beta 1-adrenoceptors, while beta 2-receptors are involved in the inhibition of this function. The lack of effects of propranolol at doses able to block the action of beta 1- and beta 2-adrenoceptor agonists suggests that beta-adrenoceptors are not physiologically involved in the control of gastric emptying.

[Regression of left heart hypertrophy in hypertensive patients as a result of antihypertensive therapy]. / Regression der Linksherzhypertrophie Hochdruckkranker durch antihypertensive Therapie.

In a previous study (1) we could show a significantly more pronounced reversal of LVH with metoprolol than with gallopamil, whereas the combined therapy with atenolol and nifedipine was even more effective. We now report in 121 previously untreated hypertensive patients the longterm effect of the beta-blocker metoprolol (200 mg/die); 25 patients, mean age 43.6 yrs., follow-up 32.1 +/- 3.5 months, group A); the calcium antagonist gallopamil, 26 patients, mean age 49.7 yrs., follow-up 36.2 +/- 2.6 months, group B); the combined therapy with 50 mg atenolol and 20 mg nifedipine, 35 patients, mean age 44.5 yrs., follow-up 31.7 +/- 1.1 months, group C); 200 mg acebutolol and 20 mg nifedipine, mean age 52.1 yrs., follow-up 31.8 +/- 1.8 months, group D); 50 mg atenolol and 10 mg enalapril, mean age 43.3 yrs., follow-up 31.9 +/- 1.3 months, group E). Similar results were obtained for intraventricular septal and posterior wall thickness. Left ventricular enddiastolic dimensions remained unchanged but fractional shortenings were significantly (p less than 0.05-p less than 0.01) increased after 32 months of treatment.

Efficacy and tolerance of nifedipine retard vs acebutolol in patients with essential hypertension treated for 26 weeks.

Patients with essential hypertension were given calcium channel antagonist, Nifedipine Retard or Acebutolol for 26 weeks in a single blind, randomised trial. Both drugs reduced mean systolic and diastolic blood pressure, but side effects were less frequent and caused less drop-outs in Nifedipine than in Acebutolol group of patients. We conclude that both Nifedipine Retard and Acebutolol were equally effective in essential hypertension but side effects were considerably milder in patients treated with Nifedipine Retard.

Long-term treatment of essential arterial hypertension with nitrendipine.

The efficacy and safety of long-term treatment with oral nitrendipine were evaluated in 34 patients with essential arterial hypertension. Nitrendipine alone significantly lowered systolic and diastolic blood pressure levels in 28 patients who completed the preliminary four-week dose-setting phase. Twenty-one patients completed the one-year treatment. Blood pressure control was maintained by nitrendipine alone in 11 patients. Ten patients not adequately controlled at the end of the dose-setting phase were successfully treated with nitrendipine combined with acebutolol or muzolimine. It is concluded that nitrendipine is a promising calcium antagonist for the treatment of arterial hypertension.