Characteristics of Suppressor Macrophages Induced by Mycobacterial and Protozoal Infections in relation to Alternatively Activated M2 Macrophages

In the advanced stages of mycobacterial infections, host immune systems tend to change from a Th1-type to Th2-type immune response, resulting in the abrogation of Th1 cell- and macrophage-mediated antimicrobial host protective immunity. Notably, this type of immune conversion is occasionally associated with the generation of certain types of suppressor macrophage populations. During the course of Mycobacterium tuberculosis (MTB) and Mycobacterium avium-intracellulare complex (MAC) infections, the generation of macrophages which possess strong suppressor activity against host T- and B-cell functions is frequently encountered. This paper describes the immunological properties of M1- and M2-type macrophages generated in tumor-bearing animals and those generated in hosts with certain microbial infections. In addition, this paper highlights the immunological and molecular biological characteristics of suppressor macrophages generated in hosts with mycobacterial infections, especially MAC infection

Proteomic alteration in gastic adenocarcinomas from Japanese patients

BACKGROUND: Gastric adenocarcinomas comprise one of the common types of cancers in Asian countries including Japan. Comprehensive protein profiling of paired surgical specimens of primary gastric adenocarcinomas and nontumor mucosae derived from Japanese patients was carried out by means of two-dimensional gel electrophoresis (2D-EP) and liquid chromatography-electrospray ionic tandem mass spectrometry (LC-ESI-MS) to establish gastric cancer-specific proteins as putative clinical biomarkers and molecular targets for chemotherapy. RESULTS: Relatively common alterations in protein expression were revealed in the tumor tissues. Increases in manganese dismutase and nonhistone chromosomal protein HMG-1 (HMG-1) were observed, while decreases in carbonic anhydrases I and II, glutatione-S-transferase and foveolin precursor (gastrokine-1) (FOV), an 18-kDa stomach-specific protein with putative tumor suppressor activity, were detected. RT-PCR analysis also revealed significant down-regulation of FOV mRNA expression in tumor tissues. CONCLUSION: A possible pathological role for down-regulation of FOV in gastric carcinogenesis was demonstrated. Evaluation of the specific decreases in gene and protein expression of FOV in patients may be utilized as clinical biomarkers for effective diagnosis and assessment of gastric cancer

Elastogenesis in cultured dermal fibroblasts from patients with lysosomal β-galactosidase, protective protein/cathepsin A and neuraminidase-1 deficiencies

The human GLB1 gene encodes a lysosomal β-galactosidase (β-Gal) and an elastinbinding protein(EBP). Defect of the EBP as a chaperon for tropoelastin and a component of receptor complex amongneuraminidase-1 (NEU1) and protective protein/ cathepsin A(PPCA)is suggested responsible for impaired elastogenesis in autosomal recessive β-Gal, PPCA and NEU1 deficiencies. The purpose of this study is to determine effects ofGLB1, PPCA and NEU1gene mutations on elastogenesis in skin fibroblasts. Elastic fiber formation and the EBP mRNA expression were examined by immunofluorescence with an anti-tropoelastin antibody and RT-PCR selective for EBP in skin fibroblasts with these lysosomal enzyme deficiencies. Apparently normal elastogenesis and EBP mRNA expression were observed for fibroblasts from Morquio B disease cases with the GLB1 gene alleles (W273L/W273L, W273L/R482H andW273L/W509C substitutions, respectively), a galactosialidosis case with the PPCA allele (IVS7+3A/IVS7+3A) and a sialidosis case with the NEU1 allele (V217M/G243R) as well as normal subject. In this study, theW273L substitution in the EBP could impossibly cause the proposed defect of elastogenesis, and the typical PPCA splicing mutation and the V217M/G243R substitutions in the NEU1 might hardly have effects on elastic fiber formation in the dermal fibroblasts

Identification of Novel Mycobacterial Inhibitors Against Mycobacterial Protein Kinase G

Protein kinase G (PknG) is a eukaryotic-like serine/threonine kinase that is expressed by Mycobacterium tuberculosis and promotes survival of mycobacteria in host macrophages by suppressing phagosome-lysosome fusion. Thus, compounds showing inhibitory activity against PknG are promising anti-mycobacterial agents. We therefore aimed to develop anti-mycobacterial agents by identifying new PknG inhibitors. A luciferase-based PknG kinase assay was used to screen potential inhibitors of PknG. We found that four compounds, namely AZD7762, R406, R406-free base, and CYC116, inhibited PknG activities. AZD7762, R406, and R406-free base promoted transfer of mycobacteria to lysosomes. These compounds also inhibited survival of M. bovis Bacillus Calmette–Guérin (BCG) inside human macrophages. Furthermore, R406 and R406-free base showed bactericidal activity against BCG in infected human macrophages without cytotoxicity. The PknG inhibitors identified in this study by the luciferase-based PknG kinase assay may be promising leads for the development of anti-mycobacterial agents

脂質摂取の多い食習慣とたんぱく質及び甘い食べ物に対する欲求との関連

Reducing dietary calorie density (CD) is useful in body weight management. This study investigates the association between dietary habits and preferences for different CDs. We conducted a randomized crossover study of 232 healthy subjects who consumed packed lunch boxes containing a control, high-meat and low-rice, low-vegetable, medium-fat and low-vegetable, high-fat, and high-fat and low-vegetable meals over six sessions. The subjective levels of sensory properties were assessed over time using a visual analog scale and the area under the curve. Subjects were assessed for dietary habits using a brief-type self-administered diet history questionnaire (BDHQ) and were divided into two groups based on a daily fat energy ratio≥25% (high fat [HF], n=116) and <25% (normal, n=116) that was matched for age, body mass index, and sex ratio. Our findings indicate that the desire for sweetness was higher in the HF group than in the normal group, regardless of the meals consumed. Particularly, among the 500-kcal low-CD meals, a high-protein meal provided greater fullness and satisfaction and lower prospective consumption in the HF group than in the normal group. Therefore, our study demonstrates that postprandial appetite sensation is associated with dietary habits of fat intake

成長期における食餌性リンによるα-klotho発現制御

Inorganic phosphate (Pi) is an essential nutrient for maintaining various biological functions, particularly during growth periods. Excess intake of dietary Pi increases the secretion of fibroblast growth factor 23 (FGF23) and parathyroid hormone (PTH) to maintain plasma Pi levels. FGF23 is a potent phosphaturic factor that binds to the α-klotho/FGFR complex in the kidney to promote excretion of Pi into the urine. In addition, excess intake of dietary Pi decreases renal α-klotho expression. Down-regulation or lack of α-klotho induces a premature aging-like phenotype, resulting from hyperphosphatemia, and leading to conditions such as ectopic calcification and osteoporosis. However, it remains unclear what effects dietary Pi has on α-klotho expression at different life stages, especially during growth periods. To investigate this, we used C57BL/6J mice in two life stages during growing period. Weaned (3 weeks old) and periadolescent (7 weeks old) were randomly divided into seven experimental groups and fed with 0.02, 0.3, 0.6, 0.9, 1.2, 1.5, or 1.8% Pi diets for 7 days. As a result, elevated plasma Pi and FGF23 levels and decreased renal α-klotho expression were observed in weaned mice fed with a high Pi diet. In addition, a high Pi diet clearly induced renal calcification in the weaned mice. However, in the periadolescent group, renal calcification was not observed, even in the 1.8% Pi diet group. The present study indicates that a high Pi diet in weaned mice has much greater adverse effects on renal α-klotho expression and pathogenesis of renal calcification compared with periadolescent mice

Clinical and Basic Studies on Therapeutic Efficacy of Herbal Medicines against Mycobacterial Infections

The high incidence of tuberculosis (TB) in developing countries, the resurgence of TB in industrialized countries, and the worldwide increase in the prevalence of Mycobacterium avium complex infections are important global health concerns. However, the development of novel antimycobacterial drugs is currently making very slow progress. Therefore, it is considered that devising improved administration protocols for clinical treatment against intractable mycobacteriosis using existing chemotherapeutics is more practical than awaiting the development of new antimycobacterial drugs. The regulation of host immune responses using immunoadjunctive agents may increase the efficacy of antimicrobial treatment against mycobacteriosis. In particular, the mild and long-term up-regulation of host immune reactions against mycobacterial pathogens using herbal medicines may be beneficial for such immunoadjunctive therapy. This review focuses on the current status regarding basic and clinical studies on protocols using herbal medicines, including medicinal plants, useful for the clinical treatment of intractable mycobacterial infections

Properties of immunosuppressive macrophages generated by Mycobacterium intracellulare infection in M. intracellulare-susceptible and resistant mice

The world-wide increase in the incidence of mycobacterial infections, namely tuberculosis and Mycobacterium avium-intracellulare complex (MAIC) infections, associated with AIDS has resulted in serious health problems in many countries. The generation of immunosuppressive macrophages (Mfs) is frequently encountered in hosts with such mycobacterial infections, and leads to depressed cellular host immunity in the advanced stages of infectio

Hypatulins A and B, Meroterpenes from <i>Hypericum patulum</i>

Two novel prenylated benzophenone related meroterpenes, hypatulins A (<b>1</b>) and B (<b>2</b>), were isolated from the leaves of <i>Hypericum patulum</i>. The structures of <b>1</b> and <b>2</b> were assigned by spectroscopic analysis, chemical conversion, and calculations of the ECD (electron circular dichroism) spectra. Hypatulin A (<b>1</b>) had a unique densely substituted tricyclic octahydro-1,5-methanopentalene core, while hypatulin B (<b>2</b>) possessed a bicyclo­[3.2.1]­octane moiety. Hypatulin A (<b>1</b>) exhibited antimicrobacterial activity against <i>Bacillus subtilis</i>. A possible biogenetic pathway of the new meroterpenes <b>1</b> and <b>2</b> from a prenylated benzophenone was presented