Toll-like receptor 4 and high-mobility group box 1 are critical mediators of tissue injury and survival in a mouse model for heatstroke

The molecular mechanisms that initiate the inflammatory response in heatstroke and their relation with tissue injury and lethality are not fully elucidated. We examined whether endogenous ligands released by damaged/stressed cells such as high-mobility group box 1 (HMGB1) signaling through Toll-like receptor 4 (TLR4) may play a pathogenic role in heatstroke. Mutant TLR4-defective (C3H/HeJ) and wild type (C3H/HeOuJ) mice were subjected to heat stress in an environmental chamber pre-warmed at 43.5°C until their core temperature reached 42.7°C, which was taken as the onset of heatstroke. The animals were then allowed to recover passively at ambient temperature. A sham-heated group served as a control. Mutant mice displayed more histological liver damage and higher mortality compared with wild type mice (73% vs. 27%, respectively, P<0.001). Compared to wild type mice, mutant mice exhibited earlier plasma release of markers of systemic inflammation such as HMGB1 (206±105 vs. 63±21 ng/ml; P = 0.0018 and 209±100 vs. 46±32 ng/ml; P<0.0001), IL-6 (144±40 vs. 46±20 pg/ml; P<0.001 and 184±21 vs. 84±54 pg/ml; P = 0.04), and IL-1β (27±4 vs. 1.7±2.3 pg/ml; P<0.0001 at 1 hour). Both strains of mice displayed early release of HMGB1 into the circulation upstream of IL-1β and IL-6 responses which remained elevated up to 24 h. Specific inhibition of HMGB1 activity with DNA-binding A Box (600 µg/mouse) protected the mutant mice against the lethal effect of heat stress (60% A Box vs. 18% GST protein, P = 0.04). These findings suggest a protective role for the TLR4 in the host response to severe heat stress. They also suggest that HMGB1 is an early mediator of inflammation, tissue injury and lethality in heatstroke in the presence of defective TLR4 signaling.     

Données paléoenvironnementales sur le Vraconnien/Cénomanien de la région de Tébessa (Atlas Saharien,nord-est Algérie). Caractérisation de l’OAE2

The micropalaeontological content of five sections, located in Northeastern Algeria (Saharan Atlas) was investigated by means of washing/counting of microfossils in marly levels, and microfacies analyses of calcareous levels. In these levels of Upper Cretaceous age, hundred species of foraminifera were identified but only about 15 species of ostracoda and about ten of radiolaria. This work allows, first of all, to establish a rather precise stratigraphic frame, in particular by means of studying planktonic foraminifera. Two to five biozones were defined, between the Vraconnian (Th. Appenninica biozone) and the early Turonian (Whiteinella archaeocretacea biozone, then Helvetoglobotruncana Helvetica biozone for certain sections). Secondly, the quantitative analyses led on foraminifera allowed the definition of palaeoenvironment. The ratio P/P+B, generally very high, coupled with a little diversified benthonic microfauna, indicates a calm and deep environment, of external platform or slope type. Furthermore, at numerous levels, various indications give evidence of the existence of a strong surface productivity (presence of upwellings), responsible for the proliferation of radiolaria (late Vraconnian/early Cenomanian especially) or of globular planktonic foraminifera (hedbergellids/heterohelicids); being both associated with low-oxygen deep waters. Two anoxic events were also revealed, the first one at the end of Vraconnian (OAE1d) and the second at the end of Cenomanian (OAE2). This last event in particular was characterized on all the sections, in a more or less detailed way, thanks to the identification of certain indicator: Heterohelix “bloom”, “filament” event, disappearance of rotaliporids, presence of “blackshales” strongly enriched in organic matter (Bahloul levels).     

Dendrimers bind antioxidant polyphenols and cisplatin drug

Synthetic polymers of a specific shape and size play major role in drug delivery systems. Dendrimers are unique synthetic macromolecules of nanometer dimensions with a highly branched structure and globular shape with potential applications in gene and drug delivery. We examine the interaction of several dendrimers of different compositions mPEG-PAMAM (G3), mPEG-PAMAM (G4) and PAMAM (G4) with hydrophilic and hydrophobic drugs cisplatin, resveratrol, genistein and curcumin at physiological conditions. FTIR and UV-visible spectroscopic methods as well as molecular modeling were used to analyse drug binding mode, the binding constant and the effects of drug complexation on dendrimer stability and conformation. Structural analysis showed that cisplatin binds dendrimers in hydrophilic mode via Pt cation and polymer terminal NH(2) groups, while curcumin, genistein and resveratrol are located mainly in the cavities binding through both hydrophobic and hydrophilic contacts. The overall binding constants of durg-dendrimers are ranging from 10(2) M(-1) to 10(3) M(-1). The affinity of dendrimer binding was PAMAM-G4>mPEG-PAMAM-G4>mPEG-PAMAM-G3, while the order of drug-polymer stability was curcumin>cisplatin>genistein>resveratrol. Molecular modeling showed larger stability for genisten-PAMAM-G4 (ΔG = -4.75 kcal/mol) than curcumin-PAMAM-G4 ((ΔG = -4.53 kcal/mol) and resveratrol-PAMAM-G4 ((ΔG = -4.39 kcal/mol). Dendrimers might act as carriers to transport hydrophobic and hydrophilic drugs.     

At least five polymorphic mutants account for the prevalence of glucose-6-phosphate dehydrogenase deficiency in Algeria

The electrophoretic mobility and level of enzyme activity of glucose-6-phosphate dehydrogenase (G6PD) was established in 100 unrelated Algerian males with G6PD deficiency. DNA from these subjects was analysed for the presence of certain known G6PD mutations by the appropriate restriction enzyme digestion of fragments amplified by the polymerase chain reaction. Where the mutation could not be identified in this way, the samples were subjected to single-strand conformation polymorphism analysis and abnormal fragments were sequenced. In this way, eight different mutations have been identified, of which five are polymorphic and account for 92% of the samples. The most common variants are G6PD A-(46%) and G6PD Mediterranean (23%), both of which were associated with favism. A new polymorphic variant, G6PD Aures, has been identified during the course of this study, whereas another, G6PD Santamaria, has now been established as a polymorphic variant (11%). Thus, G6PD deficiency in Algeria is heterogeneous, suggesting that there has been significant gene flow, both from sub-Saharan Africa and from other parts of the Mediterranean.     

Bioremediation potential and lead removal capacity of heavy metal-tolerant yeasts isolated from Dayet Oum Ghellaz Lake water (northwest of Algeria)

International Microbiology - Seven metal-resistant yeast strains were isolated and selected from Dayet Oum Ghellaz Lake water (northwest of Algeria) known as a highly polluted area by lead and...     

Hsp-72, a candidate prognostic indicator of heatstroke

Exposure of rats to environmental heat enhances the expression of heat shock protein-72 (Hsp-72) in most of their organs proportionally to heat stress severity. Pre-induction or over-expression of Hsp-72 prevents organ damage and lethality, suggesting that heat shock proteins (Hsps) may have a pathogenic role in this condition. We investigated the expression profile of Hsps in baboons subjected to environmental heat stress until the core temperature attained 42.5°C (moderate heatstroke) or occurrence of hypotension associated with core temperature ≥43.5°C (severe heatstroke). Western blot analysis demonstrated a differential induction of Hsp-72 among organs of heat-stressed animals with the highest induction in the liver and the lowest in lung. Hsp-60 and Hsc-70 expression was similar between control and heat-stressed animals. ELISA studies indicated a marked release of Hsp-72 into the circulation of baboons with severe heatstroke with a peak at 24 h post-heatstroke onset and remained sustained up to 72 h. Hsp-72 release was not associated with core temperature or systolic blood pressure, but correlated with markers of liver, myocardium, and skeletal muscle tissue necrosis. Non-survivors displayed significantly higher Hsp-72 levels than survivors. No Hsp-60 was detected in the circulation. These findings add further evidence that increased expression of Hsp-72 may be an important component of the host response to severe heatstroke. They also suggest that extracellular Hsp-72 is a marker of multiple organs tissue damage. Whether extracellular Hsp-72 plays a role in the host immune response to heat stress merits further studies.