Protection of Staphylococcus aureus-infected septic mice by suppression of early acute inflammation and enhanced antimicrobial activity by ginsan

Ginsan, an acidic polysaccharide prepared from Panax ginseng, demonstrated multiple immunomodulatory effects in previous studies. This study was conducted to elucidate the antiseptic mechanism induced by ginsan in mice infected with Staphylococcus aureus. When mice were treated with ginsan before the bacterial challenge with S. aureus, they were highly protected from sepsis-induced death. The numbers of S. aureus recovered from ginsan-treated mice were considerably lower than those recovered from nontreated mice. The in vivo depletion of monocytes/macrophages caused more S. aureus to be recovered from the bacteria-infected mice. Nevertheless, mice treated with both etoposide and ginsan were able to maintain an antibacterial activity. In addition, the phagocytic activity of ginsan-treated macrophage against S. aureus was considerably enhanced. The synthesis of inflammatory cytokines, such as tumor necrosis factor-alpha interleukin (IL)-1beta, IL-6, IFN-gamma, IL-12, IL-18 and interferon gamma, was significantly downregulated at the early phase of sepsis in mice that were treated with ginsan before the bacterial challenge. Expression of Toll-like receptors (TLRs), including TLR2, TLR4, and TLR9, as well as the adaptor molecule MyD88, was considerably reduced in peritoneal macrophages that were treated with ginsan before a subsequent contact with S. aureus. These data indicated that ginsan protected mice from S. aureus-induced sepsis through the suppression of acute inflammatory responses at an early phase and the enhancement of antimicrobial activities at subsequent phases of infection.     

Low mannose-binding lectin function is associated with sepsis in adult patients

Mannose-binding lectin (MBL) is an innate immune system pattern recognition molecule that kills a wide range of pathogens via the lectin complement pathway. MBL deficiency is associated with severe infection but the best measure of this deficiency is undecided. We investigated the influence of MBL functional deficiency on the development of sepsis in 195 adult patients, 166 of whom had bloodstream infection and 35 had pneumonia. Results were compared with 236 blood donor controls. MBL function (C4b deposition) and levels were measured by enzyme-linked immunosorbent assay. Using receiver-operator characteristics of MBL function in healthy controls, we identified a level of <0.2 U microL(-1) as a highly discriminative marker of low MBL2 genotypes. Median MBL function was lower in sepsis patients (0.18 U microL(-1)) than in controls (0.48 U microL(-1), P<0.001). MBL functional deficiency was more common in sepsis patients than controls (P<0.001). MBL functional deficient patients had significantly higher sequential organ failure assessment (SOFA) scores and higher MBL function and levels were found in patients with SOFA scores predictive of good outcome. Deficiency of MBL function appears to be associated with bloodstream infection and the development of septic shock. High MBL levels may be protective against severe sepsis.     

Biglycan: A Multivalent Proteoglycan Providing Structure and Signals

Research over the past few years has provided fascinating results indicating that biglycan, besides being a ubiquitous structural component of the extracellular matrix (ECM), may act as a signaling molecule. Proteolytically released from the ECM, biglycan acts as a danger signal signifying tissue stress or injury. As a ligand of innate immunity receptors and activator of the inflammasome, biglycan stimulates multifunctional proinflammatory signaling linking the innate to the adaptive immune response. By clustering several types of receptors on the cell surface and orchestrating their downstream signaling events, biglycan is capable to autonomously trigger sterile inflammation and to potentiate the inflammatory response to microbial invasion. Besides operating in a broad biological context, biglycan also displays tissue-specific affinities to certain receptors and structural components, thereby playing a crucial role in bone formation, muscle integrity, and synapse stability at the neuromuscular junction. This review attempts to provide a concise summary of recent data regarding the involvement of biglycan in the regulation of inflammation and the musculoskeletal system, pointing out both a signaling and a structural role for this proteoglycan. The potential of biglycan as a novel therapeutic target or agent for the treatment of inflammatory diseases and skeletal muscular dystrophies is also addressed.     

Fibrinogen alpha chain O-glycopeptides as possible markers of urinary tract infection

Urinary tract infection (UTI) is the most common bacterial infection leading to substantial morbidity and considerable health care expenditures across all ages. Here we present an exploratory UPLC-MS study of human urine in the context of febrile, complicated urinary tract infection aimed to reveal and identify possible markers of a host response on infection. A UPLC-MS based workflow, taking advantage of Ultra High Resolution (UHR) Qq-ToF-MS, and multivariate data handling were applied to a carefully selected group of 39 subjects with culture-confirmed febrile Escherichia coli UTI. Using a combination of unsupervised and supervised multivariate modeling we have pinpointed a number of peptides specific for UTI. An unequivocal structural identification of these peptides, as O-glycosylated fragments of the human fibrinogen alpha 1 chain, required MS2 and MS3 experiments on two different MS platforms: ESI-UHR-Qq-ToF and ESI-ion trap, a blast search and, finally, confirmation was achieved by matching experimental tandem mass spectra with those of custom synthesized candidate-peptides.In conclusion, exploiting non-targeted UPLC-MS based approach for the investigation of UTI related changes in urine, we have identified and structurally characterized unique O-glycopeptides, which are, to our knowledge, the first demonstration of O-glycosylation of human fibrinogen alpha 1-chain.     

C1酯酶抑制剂的非蛋白酶抑制功能

C1酯酶抑制剂(C1 esterase inhibitor,C1INH)属于丝氨酸蛋白酶抑制剂家族,能够调节补体系统、激肽释放系统、纤溶系统和凝血系统。目前在临床上主要用于遗传性血管性水肿的治疗。但最近的研究表明C1INH除丝氨酸蛋白酶抑制作用外,还具有多种非蛋白酶抑制功能,如抗炎和抗凋亡作用。而且很多动物实验和临床试验显示C1INH对脓毒症(sepsis)、心肌缺血等疾病也有治疗作用。本文主要综述C1INH的非蛋白酶抑制功能的最新研究进展。     

Differences in the proportion of collagen and muscle in the canine lower urinary tract with regard to gonadal status and gender

Gonadectomy not only affects hormonal homeostasis but also alters the turnover of different components of the extracellular matrix in urogenital tissues. Collagen is an important component of the bladder and urethral walls and thus crucial for the mechanical properties of normal lower urinary tract (LUT) functions. This study aimed at investigating the possibility of differences in the proportion of collagen and muscle tissues in the LUT of intact and gonadectomised male and female dogs. Twenty clinically healthy dogs were used including 10 sexually intact dogs (5 males, 5 anoestrus females) and 10 gonadectomised dogs (4 males and 6 females). Four regions of the LUT, i.e. body and neck of the bladder as well as proximal and distal urethra were collected. The tissue sections were stained with Masson's Trichrome. Quantitative evaluation of the blue-stained area for collagen and red-counterstained area for muscle was performed using colour image analysis. The relative proportion of collagen and muscle significantly differed with the gonadal status, the gender and the region. Overall, gonadectomised dogs had a higher (P < 0.001) proportion of collagen and consequently a lower (P < 0.001) proportion of muscle than intact dogs. Regardless of gonadal statuses, females had a higher (P < 0.05) proportion of collagen and a lower (P < 0.05) proportion of muscle tissues than males. Gender differences were found in all four regions of the LUT in intact dogs but only in proximal urethra in gonadectomised dogs where spayed females had a higher (P < 0.05) proportion of collagen and less muscle (P < 0.05). Regional differences were observed in females; a higher proportion of collagen and therefore less muscle were found in the urethra compared with the bladder. Proportional differences in collagen and muscle between intact and gonadectomised animals suggest a relation of different hormonal statuses to structural changes in the canine LUT. Excessive collagen deposits and less muscular volume may impair structural and functional integrity of the LUT which may associate with the development of post-neutering urinary incontinence in the dog.     

Immunolocalization of a mammalian aquaporin 3 homolog in water-transporting epithelial cells in several organs of the clawed toad Xenopus laevis

Nucleotide sequences of cDNA were used to construct antibodies against an aquaporin (AQP) expressed in the clawed toad, Xenopus laevis, viz., Xenopus AQP3, a homolog of mammalian AQP3. Xenopus AQP3 was immunolocalized in the basolateral membrane of the principal cells of the ventral skin, the urinary bladder, the collecting duct and late distal tubule of the kidney, the absorptive epithelial cells of the large intestine, and the ciliated epithelial cells of the oviducts. Therefore, we designated this AQP as basolateral Xenopus AQP3 (AQP-x3BL). The intensity of labeling for AQP-x3BL differed between the ventral and dorsal skin, with the basolateral membrane of the principal cells in the ventral skin showing intense labeling, whereas that in the dorsal skin was lightly labeled. AQP-x3BL was also immunolocalized in the basolateral membrane of secretory cells in the small granular and mucous glands of the skin. As AQP-x5, a homolog of mammalian AQP5, is localized in the apical membrane of these same cells, this provides a pathway for fluid secretion by the glands. Although Hyla AQP-h2 is translocated from the cytoplasm to the apical membrane of the Hyla urinary bladder in response to arginine vasotocin (AVT), AQP-h2 immunoreactivity in Xenopus bladder remains in the cytoplasm and barely moves to the apical membrane, regardless of AVT stimulation. AQP-x3 is localized in the basolateral membrane, even though the AVT-stimulated AQP-h2 does not translocate to the apical membrane. These findings provide new insights into AQP function in aquatic anurans.     

Congenital asplenia and group B streptococcus sepsis in the adult: case report and review of the literature

Asplenia is associated with an increased incidence of fatal and life-threatening sepsis caused by encapsulated pathogens. Isolated congenital asplenia is a very rare condition, with only 33 cases reported in the literature. The authors report another case of this condition complicated by overwhelming Group B streptococcus sepsis secondary to paronychia that was managed successfully.     

The socio-economic effects of tropical diseases in Nigeria

Urinary schistosomiasis is the most prevalent of the endemic tropical diseases: 48% of the population is afflicted in the study area. The socio-economic, environmental and health-seeking behavioural characteristics of the population are conducive to the spread of urinary schistosomiasis. The attitudes considered include knowledge of what causes the disease and how to control it, attitude toward the disease, care of oneself, hygiene and sanitation. The effect of such social variables as stigmatisation, and environmental variables such as water source is also considered. We find that a unit increase in the hygiene/sanitation index for adult males and adult females lead to a reduction of about 7.3 and 4.0 eggs S. haematobium in 10 ml urine sample, respectively. Thus, simple hygienic activities such as keeping the immediate environment of the household free from human wastes contribute substantially to disease control. Furthermore, prevalence of the disease is higher among males. Losses from work attributed to urinary schistosomiasis are high. Average values of key socio-economic variables-labour flow for land clearing, farm size and cash income-computed for farm families with high urinary schistosomiasis intensity in the sample are 1085 h, 1.4 ha and N 1,432 (US dollars 65) respectively. The corresponding figures for farm families free from the disease are significantly higher: 1325 h, 1.9 ha and N 3,759 (US dollars 171), respectively.     

Function, structure and regulation of the vacuolar (H+)-ATPases

The vacuolar ATPases (or V-ATPases) are ATP-driven proton pumps that function to both acidify intracellular compartments and to transport protons across the plasma membrane. Intracellular V-ATPases function in such normal cellular processes as receptor-mediated endocytosis, intracellular membrane traffic, prohormone processing, protein degradation and neurotransmitter uptake, as well as in disease processes, including infection by influenza and other viruses and killing of cells by anthrax and diphtheria toxin. Plasma membrane V-ATPases are important in such physiological processes as urinary acidification, bone resorption and sperm maturation as well as in human diseases, including osteopetrosis, renal tubular acidosis and tumor metastasis. V-ATPases are large multi-subunit complexes composed of a peripheral domain (V₁) responsible for hydrolysis of ATP and an integral domain (V₀) that carries out proton transport. Proton transport is coupled to ATP hydrolysis by a rotary mechanism. V-ATPase activity is regulated in vivo using a number of mechanisms, including reversible dissociation of the V₁ and V₀ domains, changes in coupling efficiency of proton transport and ATP hydrolysis and changes in pump density through reversible fusion of V-ATPase containing vesicles. V-ATPases are emerging as potential drug targets in treating a number of human diseases including osteoporosis and cancer.