Synthesis,cytotoxicity, and haemolytic activity of chacotrioside lupane-type neosaponins and their germanicane-type rearrangement products

The concise synthesis, via a stepwise glycosylation approach, of lupeol, betulin and betulinic acid O-glycosides bearing a chacotriosyl moiety at the C-3 position is described. All neosaponins as well as their rearrangement products of the germanicane-type were evaluated in vitro for their anticancer and haemolytic activities. Although betulinic acid and betulin 3β-O-chacotriosides were neither cytotoxic nor haemolytic, their rearrangement products allobetulin and 28-oxoallobetulin 3β-O-chacotriosides (9 and 10) exhibited a cytotoxicity profile up to fourfold superior to betulinic acid against human breast (MCF7) and prostate (PC-3) adenocarcinomas cell lines (IC₅₀ = 10–18 μM). One important result was that only chacotriosides featuring non-polar functions at the C-28 position (6, 9 and 10) exerted a haemolytic activity against red blood cells.     

Circadian fluctuations in the muscular efficiency of athletes: with sleep versus sleep deprivation

The influence of time of day on muscular performance was studied. From part of the results of two different studies (EAS et EPS), the effects of sleep deprivation were appreciated. Seven times over the 24-h period, developed torque and myoelectric activity were estimated during maximal isometric voluntary contractions using an isokinetic dynamometer: elbow flexion for EAS in standardised sleep, and knee extension for EPS in complete sleep deprivation. The results showed nycthemeral changes in torque in both conditions (p < 0.005), with maximal values recorded at the beginning of night. Although during sleep deprivation (EPS) the rhythm followed neurophysiological factors, during EAS, this rhythm was accounted for by the variations in the contractile state of muscle.     

On the relationship of ultrastructural and cytochemical features to color in mammalian skeletal muscle

Summary The semitendinosus muscle of the albino rat is divided grossly into two clearly distinguishable parallel longitudinal bands, one red (anterior) and the other white (posterior). By using mitochondrial content as a criterion for distinguishing fiber types, it is demonstrated that the red portion of the muscle is composed predominantly of red (52%) and intermediate (40%) fibers, while the white portion consists primarily of white fibers (82%). Red fibers have the smallest and white fibers have the largest average diameter. Ultrastructural characteristics of the three fiber types resemble closely those previously described for the rat diaphragm. Red fibers are rich in large mitochondria with abundant cristae, and possess the widest Z lines. In red fibers, the H-band region of the sarcoplasmic reticulum consists of an elaborate network of narrow tubules. In white fibers, mitochondria are smaller, less numerous, and have fewer cristae; Z lines are about half as wide as in red fibers. In the H-band region of the sarcoplasmic reticulum there is a more compact arrangement of broad more or less parallel tubules. Intermediate fibers are similar to red fibers except that their diameters are larger; mitochondria are somewhat smaller and cristae are less abundant; the width of the Z lines is close to that of white fibers. The consistent difference in Z line width establishes this dimension as an important criterion for distinguishing fiber types and facilitates ultrastructural identification, especially of the intermediate fiber.The clear relationship between color of the semitendinosus and cytological features of its component fibers supports the use of the terms red, white, and intermediate as simple and valid designations for fiber types in mammalian skeletal muscle. Measurement of the cross-sectional area contributed by each fiber type to the total area indicates that both red and intermediate fibers may contribute to redness in mammalian skeletal muscle.An early portion of this work was carried out with MissSharon Whelan (Mrs.Bernard Weiss). The author acknowledges the important contribution of Mr.Richard Stearns through his skillful work on the photographic illustrations and the technical assistance of MissAnn Campbell and Mrs.Joan Normington. — This study was supported by Grant No. HD 01026-04 from the United States Public Health Service.     

Segmental vitiligo as the possible expression of cutaneous somatic mosaicism: implications for common non-segmental vitiligo

Clinical findings in vitiligo challenge the widely accepted organ specific autoimmune pathomechanisms. We draw the attention to the fact that the distribution of segmental vitiligo (SV) fits in at least a subset of patients a pattern usually associated with cutaneous mosaicism. The association of SV to non-segmental vitiligo (NSV) now confirmed by several observations indicates a continuum between the two subsets with shared predisposing genetic factors, including genes operating specifically in the skin. Some pedigrees associating SV and NSV further suggest a mechanism of loss of heterozygosity for a dominant gene controlling part of the cutaneous phenotype. The mosaic hypothesis applies only to SV and to the rare SV-NSV association, but suggests that predisposing genetic factors in common NSV should also be searched directly in the skin. SV would be a good candidate disease to explore as a proof of principle of a new gene discovery strategy useful for multigenic disorders with organ specificity, applicable in priority to chronic inflammatory skin disorders.     

The loss of culturability by Escherichia coli cells in seawater depends on availability of phosphate ions and phosphate transport systems

Using strains with or without the PhoE porin or different components of the phosphate regulon, we determined that maintenance of the culturability of Escherichia coli in seawater depended significantly on the presence of structures allowing access of phosphate ions to the periplasm, then to the cytoplasm of cells. Cells totally deprived of the two main phosphate transport systems (Pit, Pst) exhibited the highest loss of culturability. Most of this effect resulted from the loss of the high-affinity Pst system, and more specifically that of the periplasmic phosphate-binding protein PhoS. Survival was enhanced in seawater supplemented with phosphate (0.5 mm), whether or not these structures were present. From an ecological point of view, it is assumed that the presence of phosphate ions, even at low concentrations, can influence the behavior of E. coli cells in seawater. Offprint requests to: M.J. Gauthier     

Examination of the Combined Effects of Chondroitinase ABC,Growth Factors and Locomotor Training following Compressive Spinal Cord Injury on Neuroanatomical Plasticity and Kinematics

While several cellular and pharmacological treatments have been evaluated following spinal cord injury (SCI) in animal models, it is increasingly recognized that approaches to address the glial scar, including the use of chondroitinase ABC (ChABC), can facilitate neuroanatomical plasticity. Moreover, increasing evidence suggests that combinatorial strategies are key to unlocking the plasticity that is enabled by ChABC. Given this, we evaluated the anatomical and functional consequences of ChABC in a combinatorial approach that also included growth factor (EGF, FGF2 and PDGF-AA) treatments and daily treadmill training on the recovery of hindlimb locomotion in rats with mid thoracic clip compression SCI. Using quantitative neuroanatomical and kinematic assessments, we demonstrate that the combined therapy significantly enhanced the neuroanatomical plasticity of major descending spinal tracts such as corticospinal and serotonergic-spinal pathways. Additionally, the pharmacological treatment attenuated chronic astrogliosis and inflammation at and adjacent to the lesion with the modest synergistic effects of treadmill training. We also observed a trend for earlier recovery of locomotion accompanied by an improvement of the overall angular excursions in rats treated with ChABC and growth factors in the first 4 weeks after SCI. At the end of the 7-week recovery period, rats from all groups exhibited an impressive spontaneous recovery of the kinematic parameters during locomotion on treadmill. However, although the combinatorial treatment led to clear chronic neuroanatomical plasticity, these structural changes did not translate to an additional long-term improvement of locomotor parameters studied including hindlimb-forelimb coupling. These findings demonstrate the beneficial effects of combined ChABC, growth factors and locomotor training on the plasticity of the injured spinal cord and the potential to induce earlier neurobehavioral recovery. However, additional approaches such as stem cell therapies or a more adapted treadmill training protocol may be required to optimize this repair strategy in order to induce sustained functional locomotor improvement.     

Pioglitazone Improves Fat Distribution,the Adipokine Profile and Hepatic Insulin Sensitivity in Non-Diabetic End-Stage Renal Disease Subjects on Maintenance Dialysis: A Randomized Cross-Over Pilot Study

Background

Fat redistribution, increased inflammation and insulin resistance are prevalent in non-diabetic subjects treated with maintenance dialysis. The aim of this study was to test whether pioglitazone, a powerful insulin sensitizer, alters body fat distribution and adipokine secretion in these subjects and whether it is associated with improved insulin sensitivity.

Trial Design

This was a double blind cross-over study with 16 weeks of pioglitazone 45 mg vs placebo involving 12 subjects.

Methods

At the end of each phase, body composition (anthropometric measurements, dual energy X-ray absorptometry (DEXA), abdominal CT), hepatic and muscle insulin sensitivity (2-step hyperinsulinemic euglycemic clamp with 2H2-glucose) were measured and fasting blood adipokines and cardiometabolic risk markers were monitored.

Results

Four months treatment with pioglitazone had no effect on total body weight or total fat but decreased the visceral/sub-cutaneous adipose tissue ratio by 16% and decreased the leptin/adiponectin (L/A) ratio from 3.63×10⁻³ to 0.76×10⁻³. This was associated with a 20% increase in hepatic insulin sensitivity without changes in muscle insulin sensitivity, a 12% increase in HDL cholesterol and a 50% decrease in CRP.

Conclusions/Limitations

Pioglitazone significantly changes the visceral-subcutaneous fat distribution and plasma L/A ratio in non diabetic subjects on maintenance dialysis. This was associated with improved hepatic insulin sensitivity and a reduction of cardio-metabolic risk markers. Whether these effects may improve the outcome of non diabetic end-stage renal disease subjects on maintenance dialysis still needs further evaluation.

Trial Registration

ClinicalTrial.gov {"type":"clinical-trial","attrs":{"text":"NCT01253928","term_id":"NCT01253928"}}NCT01253928