Mechanisms responsible for reduced cardiotoxicity of mitoxantrone compared to doxorubicin examined in isolated guinea-pig heart preparations

We reported previously that doxorubicin, an anticancer agent that has an anthracycline structure, alters Ca2+ releasing and uptake mechanisms in the sarcoplasmic reticulum of myocardial cells. These effects of doxorubicin are apparently related to its cardiotoxicity. Mitoxantrone is a similar anticancer agent with an anthracenedion structure that has been shown to be significantly less cardiotoxic. In the present study, the effects of mitoxantrone on the functions of the sarcoplasmic reticulum were examined in isolated muscle preparations obtained from the guinea-pig heart. In electrically-stimulated left atrial muscle preparations, incubation in vitro for 4 hr with 30 or 100 microM mitoxantrone significantly prolonged the time to the peak of twitch tension, markedly increased the developed tension observed at lower stimulation frequencies, thereby attenuating the slope of positive force-frequency relationships, and increased the postrest contraction observed after a 60-sec quiescent period. In myocytes isolated from ventricular muscles, 30 microM mitoxantrone increased the peak and the size of intracellular Ca2+ concentrations ([Ca2+] i), and prolonged the time to peak [Ca2+]i. In skinned muscle fiber preparations obtained from the left ventricular muscle, 30 muM mitoxantrone significantly increased the caffeine-induced contraction without affecting the Ca2+ sensitivity of contractile proteins. These results suggest that mitoxantrone enhances Ca2+ release from the sarcoplasmic reticulum in isolated atrial muscle preparations obtained from the guinea-pig heart. Apparent enhancement of the sarcoplasmic reticulum functions, in contrast to anthracyclines that has been shown to suppress these functions, seems to explain the relative lack of marked cardiotoxicity of mitoxantrone.     

Brainstem Auditory Evoked Responses Elicited by Tone-Burst Stimuli in Clinically Normal Dogs

Brainstem auditory evoked responses (BAERs) to click and tone-burst stimuli (0.5, 1, 2, 4, and 8 kHz) were recorded from 32 ears in 16 adult Beagles. BAERs were used to establish a normative database and describe response thresholds and latencies (wave I-IV) for the different stimuli. The frequencies of sound used were 8, 4, 2, 1, and 0.5 kHz. Sound stimuli were delivered by a closed headphone and masking stimuli were not applied. The BAER waveforms obtained were similar to those reported previously, except for a frequency-following response evoked by 1-kHz tone-bursts. The threshold was lowest when clicks and 4-kHz tone-bursts were used. Significant differences were observed between the mean values of the peak latencies for clicks and 4-and 8-kHz tone-bursts. The tone-burst stimulation used in our experiment was shown to be an appropriate method for detecting the BAERs. Thus, for investigating the frequency-specificity of the auditory sense, BAER data obtained using tone-burst sound in dogs may be meaningful.     

Reduction in aggressiveness among hybrids between host-specific pathotypes of Magnaporthe oryzae is caused by reduced ability to overcome adult resistance at the level of penetration

A genetic cross between a Triticum isolate (pathogenic on wheat) and a Setaria isolate (pathogenic on foxtail millet) of Magnaporthe oryzae yielded several F₁ cultures that were virulent on both wheat and foxtail millet at the primary leaf stage. To estimate whether these cultures survive in nature, they were sprayed onto 1-, 2-, and 3-week-old wheat and foxtail millet. As the age of the inoculated plants increased, the lesion number and size were greatly reduced. The F₁ cultures were almost nonpathogenic on both wheat and foxtail millet at the 3-week-old stage. Cytological analysis revealed that the low pathogenicity of the F₁ cultures on older plants was primarily associated with a reduced ability to penetrate the cuticle. When placed on wounded leaf surfaces, the F₁ cultures produced large lesions on 4-week-old wheat and foxtail millet. These results indicate that hybridization between species-specific pathotypes results in a reduction of aggressiveness. We therefore suggest that, even if such hybrids were produced in nature, they might not survive in the natural environment.     

Meningoventriculitis caused by Streptococcus pluranimalium in a neonatal calf of premature birth

Pathological and bacteriological examinations were carried out on a neonatal calf that had developed nervous symptoms such as opisthotonus and blindness since it was born one month prior to full term. The principal lesions were characterized by fibrinopurulent inflammation of the meninges, choroid plexuses, and ventricular walls with limited extension to the subependymal parenchyma in the spinal cord. Purulent inflammation was also found in several visceral organs and tissues. Streptococcus pluranimalium was isolated from the brain and cerebrospinal fluid. These results suggest that the animal suffered from meningoventriculitis with septicemic S. pluranimalium infection.     

Meiotic resumption of porcine immature oocytes is prevented by ooplasmic Gsalpha functions

A high cyclic adenosine monophosphate (cAMP) level in fully-grown immature oocytes prevents meiotic resumption. In Xenopus, inhibitory cAMP is synthesized within oocytes depending on a stimulatory alpha-subunit of G-protein (Gsalpha). In the present study, we examined whether ooplasmic Gsalpha is involved in meiotic arrest of porcine oocytes. First, we studied the presence of Gsalpha molecules in porcine oocytes by immunoblotting, and this suggested the presence of reported isoforms (45 and 48 kDa) not only in cumulus cells but also in porcine oocytes. Then we injected an anti-Gsalpha antibody into porcine immature oocytes and found that inhibition of ooplasmic Gsalpha functions significantly promoted germinal vesicle breakdown of the oocytes, whose spontaneous meiotic resumption was prevented by 3-isobutyl-l-methylxanthine (IBMX) treatment. Although cyclin B synthesis and M-phase promoting factor (MPF) activation were largely prevented until 30 h of culture in IBMX-treated oocytes, injection of anti-Gsalpha antibody into these oocytes partially recovered cyclin B synthesis and activated MPF activity at 30 h. These results suggest that meiotic resumption of porcine oocytes is prevented by ooplasmic Gsalpha, which may stimulate cAMP synthesis within porcine oocytes, and that synthesized cAMP prevents meiotic resumption of oocytes through the signaling pathways involved in MPF activation.     

Increased expression of NOR‐1 mRNA in the skeletal muscles of cold‐exposed neonatal chicks

Nuclear receptor subfamily 4, group A (NR4A) subgroup orphan receptors are rapidly induced by various physiological stimuli and have been suggested to regulate oxidative metabolism and muscle mass in mammalian skeletal muscle. The results showed that the NR4A subgroup orphan receptor, NOR‐1 (NR4A3), was acutely increased in skeletal muscles of neonatal chicks in response to short‐term cold exposure. The increased NOR‐1 gene expression was concomitant with cold‐induced changes in gene expression of both myostatin and proliferator‐activated receptor‐gamma coactivator‐1 (PGC‐1α), and the increase in skeletal muscle mass. These observations suggest that NOR‐1 might play a role in controlling skeletal muscle growth in cold‐exposed neonatal chicks.     

Dimethoxypyrimidines as novel herbicides. Part 4. Quantitative structure–activity relationships of dimethoxypyrimidinyl(thio)salicylic acids

The activity of a number of O-(4,6-dimethoxypyrimidin-2-yl)salicylic acids and their thio analogs inhibiting acetolactate synthase (ALS) preparation was measured. The effects of substituents on the salicylic-benzene ring on the inhibitory activity were analyzed quantitatively with physicochemical substituent parameters. For 6-substituted (thio)salicylic acids, the activity was shown to vary parabolically with the ‘intramolecular’ steric parameter ( E_s ). In addition, the higher steric dimension of substituents in terms of the STERIMOL width or length parameter lowered the activity. The field-inductive electron-withdrawing property of the 6-substituents in terms of the Swain–Lupton–Hansch F was favorable for the activity of salicylic acid series. In 5-substituted salicylic acids, the activity was increased by electron-donating substituents with smaller size. The relationships between ALS inhibitory and herbicidal activities were also analyzed with some weed species. Both pre- and post-emergence activities against barnyard grass, Echinochloa crus-galli, were linearly related to the ALS inhibitory activity after allowing for the hydrophobic factor that may contribute to the transport processes. Those against two broad-leaved weed species, Polygonum convolvulus and Abutilon theophrasti were linearly related to the in-vitro activity with no significant participation of the hydrophobic factor. © 1998 SCI     

Dimethoxypyrimidines as Novel Herbicides. Part 2. Synthesis and Herbicidal Activity of O-Pyrimidinylsalicylates and Analogues

A new series of the O-pyrimidinylsalicylates was synthesized and their herbicidal activity was examined. Some of these compounds showed very strong herbicidal activity under pre- and post-emergent treatment conditions against various kinds of grass and broadleaf weeds. Among these compounds, O-(4, 6-dimethoxypyrimidin-2-yl) salicylic acid and its methyl ester were found to exhibit the highest activity. The herbicidal symptoms observed after the treatments included early cessation of plant growth followed by chlorosis, necrosis and plant death. The symptoms were similar to those caused by sulfonylureas and imidazolinones, which inhibit branched-chain amino acid biosynthesis.     

Sodium fluoride influences calcium metabolism resulting from the suppression of osteoclasts in the scales of nibbler fish <Emphasis Type="Italic">Girella punctata</Emphasis>

The influence of sodium fluoride (NaF) on calcium metabolism was examined in nibbler fish (marine teleosts). Two days after the administration of NaF (5 μg/g of body weight) (around 10^?4 M in fish), we showed that plasma calcium levels significantly decreased in NaF-treated nibbler fish. In addition, we detected fluoride in the treated scales by use of a scanning electron microscope with an energy-dispersive X-ray microanalysis, indicating that NaF directly affects their scales. Therefore, the influence of NaF on osteoblasts and osteoclasts in the scales was examined. In the scales of NaF-injected nibbler fish, tartrate-resistant acid phosphatase (TRAP) (osteoclastic marker enzyme) decreased, although alkaline phosphatase (osteoblastic marker enzyme) was activated. To confirm the effect of NaF on osteoclasts, furthermore, the mRNA expressions of osteoclastic markers (matrix metalloproteinase-9 and TRAP) were decreased significantly 2 days after incubation. In barred knifejaws, plasma calcium levels decreased as they did in nibbler fish. Therefore, NaF functions in both osteoblasts and osteoclasts and then influences calcium metabolism in marine fish. In the marine environment, high levels of fluoride (1.2–1.5 mg F^?/l) (around 10^?5–10^?4 M) are present in seawater. It is probable that teleosts living in seawater efficiently use fluoride to regulate their blood calcium levels.