Brasilicardin A (BraA) is a natural diterpene glycoside isolated from the pathogenic actinomycete Nocardia brasiliensis IFM 0406 with highly potent immunosuppressive activity (IC₅₀=0.057 μg/mL). BraA potently inhibits the uptake of amino acids that are substrates for amino acid transport system L of T cells, which is different from the existing clinical immunosuppressants. BraA is more potent in a mouse mixed lymphocyte reaction and less toxic against various human cell lines compared with the known clinical immunosuppressants, such as cyclosporin A, ascomycin and tacrolimus. Therefore, BraA attracted more attention as a new promising immunosuppressant. However, the development of this promising immunosuppressant as drug for medical use is so far hindered because BraA has the unusual and synthetically challenging skeleton and shows the low-yield production in the natural pathogenic producer. This review introduces the molecular structure of BraA, its activity, mechanism of action, chemical synthesis of BraA analogs, heterologous expression of gene cluster, and an application of combining microbial and chemical synthesis for production of BraA, with the aim to facilitate the efficient production of BraA and its analogs.
Animals ; Mice ; Humans ; Immunosuppressive Agents/chemistry* ; Aminoglycosides/pharmacology* ; Cyclosporine/pharmacology* ; Diterpenes

BackgroundImmunosuppressive agents are still inefficient in preventing biopsy-proven acute rejection (BPAR) after expanded criteria donor (ECD) kidney transplantation. The aim of this study was to investigate the relationships between early immunosuppressive exposure and the development of BPAR.

MethodsWe performed a retrospective study of 58 recipients of ECD kidney transplantation treated with enteric-coated-mycophenolate sodium, tacrolimus (Tac), and prednisone. The levels of mycophenolic acid-area under the curve (MPA-AUC) and Tac Cwere measured at the 1 week and the 1 month posttransplant, respectively. The correlation was assessed by multivariate logistic regression.

ResultsThe occurrence rates of BPAR and antibody-mediated rejection were 24.1% and 10.3%, respectively. A low level of MPA-AUC at the 1 week posttransplant was found in BPAR recipients (38.42 ± 8.37 vs. 50.64 ± 13.22, P < 0.01). In addition, the incidence of BPAR was significantly high (P < 0.05) when the MPA-AUClevel was <30 mg·h·L at the 1 week (15.0% vs. 44.4%) or the Tac Cwas <4 ng/ml at the 1 month posttransplant (33.3% vs. 21.6%). Multivariable logistic regression analysis showed that the MPA-AUC at the 1 week (OR: 0.842, 95% CI: 0.784-0.903) and the Tac Cat the 1 month (OR: 0.904, 95% CI: 0.822-0.986) had significant inverse correlation with BPAR (P < 0.05).

ConclusionsLow-level exposure of MPA and Tac Cin the early weeks posttransplant reflects an increased acute rejection risk, which suggested that MPA-AUC <30 mg·h·L and Tac C <4 ng/ml should be avoided in the first few weeks after transplantation.

Adult ; Female ; Graft Rejection ; immunology ; prevention & control ; Humans ; Immunosuppressive Agents ; chemistry ; therapeutic use ; Kidney Transplantation ; adverse effects ; methods ; Male ; Middle Aged ; Mycophenolic Acid ; chemistry ; therapeutic use ; Retrospective Studies ; Tacrolimus ; chemistry ; therapeutic use ; Time Factors

Hedyotis hedyotidea has been traditionally used for the treatment of arthritis, cold, cough, gastro-enteritis, headstroke, etc. But few studies have screened the active compounds from extracts of H. hedyotidea. In this study, the structure of the chemical constituents from stems of H. hedyotidea were determined and the immunosuppressive activity of the compounds was evaluated. The compounds were separated and purified with silica gel, gel column chromatographies and preparative HPLC, and their structures were identified by spectral methods such as MS and NMR. Eleven compounds were obtained and identified as(6S,9S) -vomifoliol (1), betulonic acid (2), betulinic acid (3), betulin(4), 3-epi-betulinic acid (5), ursolic acid (6), β-sitosterol (7), stigmast-4-en-3-one (8), 7β-hydroxysitosterol (9), (3β,7β) -7-methoxystigmast-5-en-3-ol (10) and morindacin (11). This is the first report of compounds 1, 2, 4, 8, 9, 10 and 11 from H. hedyotidea. Compounds 1, 2 and 8-11 were firstly isolated from the genus Hedyotis, and compounds 9 and 10 were isolated from the family Rubiaceae for the first time. The immunosuppressive activity of these compounds was tested using the lymphocyte transsormationtest. Compounds 4, 6 and 9 showed significant immunosuppressive activity.
Animals ; Drugs, Chinese Herbal ; chemistry ; isolation & purification ; pharmacology ; Hedyotis ; chemistry ; Immunosuppressive Agents ; chemistry ; isolation & purification ; pharmacology ; Lymphocytes ; drug effects ; immunology ; Male ; Mass Spectrometry ; Mice ; Mice, Inbred C57BL ; Molecular Structure ; Plant Stems ; chemistry

To investigate me material basis of Mahuang Fuzi Xixin decoction (MFXD) for anti-inflammation and immune-suppression based on the combined method of serum chemical and serum pharmacological. The LC-MS/MS fingerprints of MFXD, drug-containing serum and blank serum were compared to define the components in plasma. Histamine, β-hexosaminidase released from RBL-2H3 cell infulenced by drug-containing serum at different time points were measured by ELISA. The effect of drug-containing serum on lipopolysaccharide-induced splenocyte proliferation at different time points were determined by MTT. A correlation analysis was made on components of MFXD and pharmacological indexes based the stepwise regression method. After the intragastrical administration with MFXD, 32 components were discovered in rat serum, including 27 prototype components (10 from Mahuang, 13 from Fuzi and four from Xixin) and five unknown components. Compared with blank serum, drug-containing serum could reduce the release of histamine from RBL-2H3 induced by antigen at different time points (P < 0.05); except the 4-hour drug-containing serum, all of the remaining drug-containing serums could inhibit the RBL-2H3 mastocyte degranulation induced by antigen at different time points (P < 0.05). Drug-containing serum could significantly lipopolysaccharide-induced mouse splenocyte proliferation at 15 and 30 min (P < 0.05). A regression analysis was made on the chemical data of components absorbed into blood and pharmacological indexes, i. e. release rate of histamine, release rate of β-hexosaminidase and inhibition rate of splenocyte. This suggested the close correlations among methyl pseudo-ephedrine, pseudoephedrine and histamine released from RBL-2H3 induced by antigen; pseudoephedrine, hypaconine, methyl pseudoephedrine and β-hexosaminidase released from RBL-2H3 induced by antigen; as well as benzoyl hypaconine, benzoylaconine, 14-benzoyl-10-OH-mesaconine, mesaconine and lipopolysaccharide-induced mouse splenocyte proliferation. Methylpseudoephedrine, pseudoephedrine, benzoyl hypaconine, benzoylaconine and mesaconine may be part of material basis of MFXD on anti-inflammation and immune suppression.
Animals ; Anti-Inflammatory Agents ; chemistry ; pharmacology ; Cell Degranulation ; drug effects ; Drugs, Chinese Herbal ; chemistry ; pharmacology ; Female ; Histamine ; immunology ; Immunosuppressive Agents ; chemistry ; pharmacology ; Male ; Mass Spectrometry ; Mast Cells ; drug effects ; immunology ; Mice ; Rats ; Rats, Wistar ; Serum ; chemistry

A novel series of fingolimod analogues containing diphenyl ether moiety were designed and synthesized based on the modification of immunosuppressive agent fingolimod used in the treatment of multiple sclerosis. Compounds were evaluated in vivo for lymphopenic activity and heart rate affection. Most compounds showed moderate lymphopenic activity. It is worth noting that compounds 6c, 6d and 14c-14e showed considerable immunosuppressive activities comparable to fingolimod. And compound 14e had no effect on heart rate.
Animals ; Fingolimod Hydrochloride ; chemical synthesis ; pharmacology ; Heart Rate ; drug effects ; Immunosuppressive Agents ; chemistry ; Lymphopenia ; pathology ; Phenyl Ethers ; chemistry ; Structure-Activity Relationship

No abstract available.
Adolescent ; Adult ; Aged ; Aged, 80 and over ; Anti-Bacterial Agents/pharmacology/therapeutic use ; Ceftriaxone/pharmacology/therapeutic use ; Echocardiography ; Endocarditis, Bacterial/*diagnosis/drug therapy/microbiology ; Female ; Humans ; Immunosuppressive Agents/therapeutic use ; Infant, Newborn ; Male ; Microbial Sensitivity Tests ; Micrococcaceae/drug effects/*isolation & purification ; Middle Aged ; RNA, Ribosomal, 16S/chemistry/metabolism ; Republic of Korea

BACKGROUND/AIMS: Azathioprine (AZA) has been widely used in the therapy of inflammatory bowel disease (IBD) and autoimmune hepatitis (AIH). However, studies evaluating the adverse effects of AZA in these two diseases are lacking. The aim of this study was to compare the adverse effects of AZA in Korean IBD and AIH patients. METHODS: Patients with IBD or AIH who were treated with AZA at Keimyung University Dongsan Medical Center (Daegu, Korea) between January 2002 and March 2011 were enrolled. Their medical records were reviewed retrospectively in terms of clinical characteristics and adverse effects of AZA. RESULTS: A total of 139 IBD patients and 55 AIH patients were finally enrolled. Thirty IBD patients (21.6%) and eight AIH patients (14.5%) experienced adverse effects of AZA. In particular, the prevalence of leukopenia was significantly higher in the IBD group than in the AIH group (p=0.026). T474C mutation was observed in three of 10 patients who were assessed for thiopurine methyltransferase (TPMT) genotype. CONCLUSIONS: IBD patients are at increased risk for the adverse effects of AZA compared with AIH patients, of which leukopenia was the most commonly observed. Therefore, IBD patients receiving AZA therapy should be carefully monitored.
Adolescent ; Adult ; Aged ; Azathioprine/adverse effects/*therapeutic use ; Base Sequence ; Female ; Genotype ; Hepatitis, Autoimmune/*drug therapy ; Humans ; Immunosuppressive Agents/adverse effects/*therapeutic use ; Inflammatory Bowel Diseases/*drug therapy ; Leukopenia/epidemiology/etiology ; Male ; Methyltransferases/chemistry/genetics ; Middle Aged ; Polymorphism, Single Nucleotide ; Republic of Korea ; Retrospective Studies ; Young Adult

A series of phthalazine ketone compounds were synthesized and the structures were confirmed by H NMR and HR-MS spectrum. All target compounds were obtained through 7 steps, including selective reduction, nitration, bromination, ring enlargement, reduction, Knoevenagel and acylated reaction. The compounds were evaluated for their immunosuppressive effects of T-cell proliferation and inhibitory activity of IMPDH type II in vitro, as well as their structure-activity relationship were assessed. Several compounds exhibited strong immunosuppressive properties, especially compounds 7f and 7h, with IC50 values of 0.093 micromol x L(-1) and 0.14 micromol x L(-1) respectively, which were superior to mycophenolic acid. The information obtained from the studies may be useful for further research on the immunosuppressive agents.
Animals ; Cell Proliferation ; drug effects ; Female ; IMP Dehydrogenase ; metabolism ; Immunosuppressive Agents ; chemical synthesis ; chemistry ; pharmacology ; Inhibitory Concentration 50 ; Mice ; Mice, Inbred BALB C ; Phthalazines ; chemical synthesis ; chemistry ; pharmacology ; Spleen ; cytology ; Structure-Activity Relationship ; T-Lymphocytes ; drug effects

This paper is aimed to study the bioavailability and bioequivalence of Cyclosporin Soft Capsules (test preparation and reference preparation) in Chinese healthy volunteers. A high performance liquid chromatography-ultraviolet (HPLC-UV) method for determining the concentration of Cyclosporin A in human whole blood was developed and methodological validated. In accordance with the randomized two-period self crossover study, 24 volunteers received a single oral dose of 400 mg of test preparation or reference preparation. Multiple blood samples were collected post dose and then the concentration of Cyclosporin A in human whole blood samples was determined using the validated assay. The pharmacokinetic parameters including AUC0-t, Cmax, Tmax, and T1/2 were calculated using the non-compartmental method. The bioequivalence of the two preparations was evaluated. After receiving single dose of 400 mg of Cyclosporine A, the pharmacokinetic parameters of T1/2, Cmax, Tmax, and AUC0-t, of Cyclosporin A were (10.114 +/- 6.329) h and (9.717 +/- 4.076) h, (2021.235 +/- 298.581) ng x ml(-1) and (1992.192 +/- 1286.923) ng x ml(-1) (1.729 +/- 0.361) h and (1.813 +/- 0.323) h, (9824.811 +/- 1633.026) ng x h x ml(-1) and (10316.514 +/- 1395.955) ng x h x ml(-1) for test preparation and reference preparation, respectively. The statistical results suggested that these parameters were comparable between the two preparations. The results showed that the test preparation was bioequivalent with the reference preparation in healthy volunteers.
Area Under Curve ; Biological Availability ; Capsules ; Chemistry, Pharmaceutical ; Chromatography, High Pressure Liquid ; methods ; Cross-Over Studies ; Cyclosporine ; administration & dosage ; blood ; pharmacokinetics ; Humans ; Immunosuppressive Agents ; administration & dosage ; blood ; pharmacokinetics ; Therapeutic Equivalency

This study is to elucidate the immunoregulation mechanisms of artesunate (AST) on allergic contact dermatitis (ACD). Pharmacodynamics analyses, HE staining, semi-quantitative RT-PCR and Western blotting were used to explore the effects of AST on the related cytokines, transcription factor and signaling molecule of ACD respectively. The results indicated that topical administration of AST not only reduced the increase of ear swelling, spleen index and inflammatory cells infiltration in ACD mice, but also inhibited remarkably the expression of IFN-gamma, T-bet and NF-kappaB p65. It's suggested that AST could exhibit suppressive effects on inflammatory response and immune function of ACD, which indicates the possibility of developing AST as a novel immunoregulatory agent in the treatment of ACD and other immune-related diseases.
Administration, Topical ; Animals ; Artemisinins ; administration & dosage ; chemistry ; pharmacology ; Dermatitis, Allergic Contact ; immunology ; metabolism ; pathology ; Ear ; pathology ; Female ; GATA3 Transcription Factor ; genetics ; metabolism ; Hypersensitivity, Delayed ; drug therapy ; Immunosuppressive Agents ; administration & dosage ; chemistry ; pharmacology ; Interferon-gamma ; genetics ; metabolism ; Interleukin-4 ; genetics ; metabolism ; Mice ; Mice, Inbred ICR ; Molecular Structure ; NF-kappa B ; metabolism ; RNA, Messenger ; metabolism ; T-Box Domain Proteins ; genetics ; metabolism