Comments on Cabrera,Fitzgerald, Roggman,and Bradley: "Modeling the Dynamics of Paternal Influences on Children Over the Life Course"

This commentary on "Modeling the Dynamics of Paternal Influences on Children over the Life Course" briefly focuses on issues of universality, idealized fatherhood, developmental understanding of fatherhood, and measurement. It is suggested that expanding on these issues will strengthen the model's scope and broad applicability.     

Physiological effects and biochemical properties of a serum protein that produces positive inotropic and chronotropic effects on isolated guinea pig atria

Isolated left and right guinea pig atria were used as a bioassay for the detection of an endogenous cardioactive substance in bovine serum. Serum, buffer exchanged to Krebs-Henseleit solution, produced positive inotropic and chronotropic effects on the isolated guinea pig atria. The cardiotonic effects were unaffected by the combined presence of propranolol and methysergide (both 10(-6)M) and were also dissimilar in time course from other known cardiotons such as catecholamines and cardiac glycosides. Following ultrafiltration (using XM100A Amicon membranes), activity was found solely in the retentate fractions and was therefore probably due to a large molecular weight (> 100 kDa) substance or a small molecule bound to a large protein. The cardioactive factor (CF) in the whole serum was heat labile, sensitive to acidification, exposure to potassium bromide and equilibration to physiological buffers of a low ionic strength. Isolation by conventional protein purification techniques was unsuccessful due to the labile nature of the active molecule(s) when exposed to non-physiological experimental conditions. Physical and biochemical properties of the CF which may help avoid inactivation are discussed for future experiments aimed at elucidating the nature and identity of the cardiotonic principle.     

Genotypes and allele frequencies of angiotensin-converting enzyme (ACE) insertion/deletion polymorphism among Bahraini population with type 2 diabetes mellitus and related diseases

Insertion/deletion (I/D) polymorphism, of a 287-bp Alu repetitive sequence in intron 16 of the angiotensin-converting enzyme (ACE) gene has been shown to be associated with different types of diseases and has been widely investigated in different populations with different ethnic origins. Various reports were published suggesting inter-ethnic variations in the frequency of allelic forms of the ACE gene. The goal of this study was to test the distribution of alleles and the different genotypes of ACE (I/D) polymorphism in Bahraini subjects and compare the results with those obtained from other population studies. The Bahraini population is an Arabic peninsula population with a high prevalence of T2DM and hypertension. A total of 560 unrelated Bahraini individuals were recruited in this study and the presence (insertion)/absence (deletion) (I/D) polymorphism of a 287-bp Alu1 element inside intron 16 of the ACE gene was done by PCR-based assays and the presence or absence of the genotypes were analyzed by the gel electrophoresis. The distribution of II, ID, and DD genotypes showed differences among Bahraini subjects, and the frequency of the D allele was significantly (P < 0.05) higher in the studied group. The results obtained for the D allele are consistent with those obtained from previous studies among Arabs, Africans, and Caucasians, but differs significantly (P < 0.05) from those in Japanese and Chinese, thus proving the ethnic variation in the distribution of the ACE alleles in different populations.     

Effects of acidosis on ventricular myocyte shortening and intracellular Ca2+ in streptozotocin-induced diabetic rats

We have investigated the effects of acute acidosis on ventricular myocyte shortening and intracellular Ca²⁺ in streptozotocin (STZ)-induced diabetic rat. Shortening and intracellular Ca²⁺ were measured in electrically stimulated myocytes superfused with either normal Tyrode solution pH adjusted to either 7.4 (control solution) or 6.4 (acid solution). Experiments were performed at 35–36°C. At 8–12 weeks after treatment, the rats that received STZ had lower body and heart weights compared to controls, and blood glucose was characteristically increased. Contractile defects in myocytes from diabetic rat were characterized by prolonged time to peak shortening. Superfusion of myocytes from control and diabetic rats with acid solution caused a significant reduction in the amplitude of shortening; however, the magnitude of the response was not altered by STZ treatment. Acid solution also caused significant and quantitatively similar reductions in the amplitude of Ca²⁺ transients in myocytes from control and diabetic rats. Effects of acute acidosis on amplitude of myocyte contraction and Ca²⁺ transient were not significantly altered by STZ treatment. Altered myofilament sensitivity to Ca²⁺ and altered mechanisms of sarcoplasmic reticulum Ca²⁺ transport might partly underlie the acidosis-evoked reduction in amplitude of shortening in myocytes from control and STZ-induced diabetic rat. (Mol Cell Biochem 261: 227–233, 2004)     

Role of calpains in diabetes mellitus: A mini review

Type 2 diabetes mellitus (T2DM) is characterized by defects in haepatic glucose production, insulin action and insulin secretion, which can also lead to a variety of secondary disorders. The disease can lead to death without treatment and it has been predicted that T2DM will affect 215 million people world-wide by 2010. T2DM is a multifactorial condition whose precise genetic causes and biochemical defects have not been fully elucidated but at both levels, calpains appear to play a role. Positional cloning studies mapped T2DM susceptibility to CAPN10, the gene encoding the intracellular cysteine protease, calpain 10. Further studies have shown a number of non-coding polymorphisms in CAPN10 to be functionally associated with T2DM whilst the identification of coding polymorphisms, suggested that mutant calpain 10 proteins may also contribute to the disease. The presence of both calpain 10 and its mRNA have been demonstrated in tissues from several mammalian species whilst calpain 10 appears to be associated with pathways involved in glucose metabolism, insulin secretion and insulin action. It appears that other calpains may also participate in these pathways and here we present an overview of recent studies on calpains and their putative role in T2DM. (Mol Cell Biochem 261: 161–167, 2004)     

Calpains: targets of cataract prevention?

There is emerging evidence to suggest that the unregulated Ca(2+)-mediated proteolysis of essential lens proteins by calpains might be a major contributor to some forms of cataract in both animals and humans. Moreover, recently solved calpain structures have revealed molecular-level details of the activation mechanism used by these proteases, enabling the structure-based design of potent calpain inhibitors with the potential to act as anti-cataract agents. These agents offer the first real hope of an urgently needed alternative to the surgical treatment of at least some forms of cataract and relief from a life-depreciating condition on a global scale.     

Phorbol ester (TPA) potentiates noradrenaline and acetylcholine-evoked amylase secretion in the rat pancreas

The effect of the phorbol ester 12-O-tetradeconyl-phorbol-13-acetate (TPA) on noradrenaline (NA) and acetylcholine (ACh)-evoked amylase secretion in isolated segments of rat pancreas was investigated. TPA alone evoked a relatively small increase in amylase output. However, when combined with either noradrenaline or ACh, the phorbol ester markedly enhanced the secretagogue-induced amylase secretion. These effects were dose related. TPA also enhanced the amylase secretion evoked by either the Ca²⁺ ionophore A23187 or dibutyryl cyclic AMP. This potentiation by TPA of noradrenaline, ACh, Ca²⁺ ionophore A23187 and dibutyryl cyclic AMP-evoked amylase output may suggest the existence of a third pathway controlling enzyme secretion in the pancreas.     

Voltage dependence of the Ca<Superscript>2+</Superscript> transient in endocardial and epicardial myocytes from the left ventricle of Goto–Kakizaki type 2 diabetic rats

There is much evidence that a combination of ibuprofen (IBU) and Aspirin (ASA) can antagonize the irreversible inhibition of platelet function. This study was designed to investigate the degree of gastric damage, bleeding time (BT) and fluctuations in the serum levels of prostaglandin E₂ (PGE₂) and thromboxane A₂ (TXA₂) after oral administration of ASA (200 mg/kg) and IBU (50 mg/kg) either alone or in combination in rats in vivo. The stomach was assessed for any damage either after 6 h, 18 h or 6 days and carboxymethylcellulose (1% CMC) served as a vehicle and control. ELISA was used to measure TXA₂ and PGE₂ in serum. Bleeding time was assessed using tail blood. The results show that ASA and IBU either alone or in combination can cause gastric ulceration in 25–100% of the rats at 6 and 18 h. In contrast, gastric ulceration was seen in 50% of rats with a combination of ASA given before IBU only after 6 days of oral administration. BT was unaffected either by ASA or IBU when administered alone except after 18 h for IBU. In contrast, BT was significantly reduced when IBU was administered before ASA after 18 h and 6 days (P < 0.001). Serum PGE₂ levels decreased significantly after ASA administered either alone or in combination with IBU for 6 h, 18 h and 6 days (P < 0.05). Serum TXA₂ levels were significantly reduced after 6 h, 18 h and 6 days following ASA and IBU administration except for IBU alone which caused a significant increase in serum TXA₂ 6 days after its administration (P < 0.01). It can be concluded that ASA and IBU administered either alone or in combination can cause gastric ulcers in the rat stomach after 6 h and 18 h, but less severe after 6 days. IBU either alone or in combination with ASA reduced BT only after 18 h and 6 days of administration. Together, the results show that gastric ulceration correlated well with the inhibition of serum PGE₂ and TXA₂ levels.     

Type 1 diabetes mellitus induces structural changes and molecular remodelling in the rat kidney

Previous studies indicated that chlorogenic acid, a compound present in many fruits and vegetables, has anti-cancer activities. We report that chlorogenic acid regulates the expression of apoptosis-related genes and self-renewal-related stem cell markers in cancer cells. The lung cancer cell line A549 was cultured with or without chlorogenic acid. The presence of chlorogenic acid decreased cell proliferation as measured by MTT activity. Polymerase chain reaction (PCR) showed that treatment of cells with chlorogenic acid reduced the expression of BCL2 but increased that of both BAX and CASP3. Chlorogenic acid enhanced annexin V expression as measured using fluorescently labeled annexin V. Chlorogenic acid also induced p38 MAPK and JNK gene expression. Meanwhile, several agents, including SB203580 (p38 MAP kinase inhibitor), N-acetylcysteine (antioxidant inhibitor), dipyridamole (phosphodiesterase inhibitor), and apocynin (NADPH-oxidase inhibitor) blocked chlorogenic acid-induced BAX gene expression. Chlorogenic acid reduced gene expression levels of stem cell-associated markers NANOG, POU5F1, and SOX2. Together these results indicate that chlorogenic acid affects the expression of apoptosis-related genes that are part of oxidative stress and p38 MAP-dependent pathways, as well as genes encoding stem cell markers. In conclusion, chlorogenic acid may contribute to the polyphenolic anti-cancer effect associated with consumption of vegetables and fruits.     

Dietary and physiological studies to investigate the relationship between calcium and magnesium signalling in the mammalian myocardium

This study employs both dietary and physiological studies to investigate the relationship between calcium (Ca²⁺) and magnesium (Mg²⁺) signalling in the mammalian myocardium. Rats maintained on a low Mg²⁺ diet (LMD; 39 mg Kg^-1 Mg²⁺ in food) consumed less food and grew more slowly than control rats fed on a control Mg²⁺ diet (CMD; 500 mg Kg^-1 Mg²⁺ in food). The Mg²⁺ contents of the heart and plasma were 85 ± 3% and 34 ± 6.5%, respectively relative to the control group. In contrast, Ca²⁺ contents in the heart and plasma were 177 ± 5% and 95 ± 3%. The levels of potassium (K⁺) was raised in the plasma (129 ± 16%) and slightly decreased in the heart (88 ± 6%) compared to CMD. Similarly, sodium (Na⁺) contents were slightly higher in the heart and lowered in the plasma of low Mg²⁺ diet rats compared to control Mg²⁺ diet rat. Perfusion of the isolated Langendorff's rat heart with a physiological salt solution containing low concentrations (0-0.6 mM) of extracellular magnesium [Mg²⁺]₀ resulted in a small transient increase in the amplitude of contraction compared to control [Mg²⁺]₀ (1.2 mM). In contrast, elevated [Mg²⁺]₀ (2-7.2 mM) caused a marked and progressive decrease in contractile force compared to control. In isolated ventricular myocytes the L-type Ca²⁺ current (I_Ca,L was significantly (p < 0.001) attenuated in cells dialysed with 7.1 mM Mg²⁺ compared to cells dialysed with 2.9 µM Mg²⁺. The results indicate that hypomagnesemia is associated with decrease levels of Mg²⁺ and elevated levels of Ca²⁺ in the heart and moreover, internal Mg²⁺ is able to modulate the Ca²⁺ current through the L-type Ca²⁺ channel which in turn may be involved with the regulation of contractile force in the heart.