Fibrosis ; drug therapy ; metabolism ; Humans ; Immunosuppressive Agents ; therapeutic use ; Models, Biological ; Sirolimus ; therapeutic use

BACKGROUNDAccording to the renal phospholipase A2 receptor (PLA2R) immunohistochemistry, idiopathic membranous nephropathy (iMN) could be categorized into PLA2R-associated and non-PLA2R-associated iMN. This study aimed to examine whether the non-PLA2R-associated iMN had any difference in clinical features compared with PLA2R-associated iMN.

METHODSA total of 231 adult patients diagnosed as iMN were recruited to this retrospective study. Renal PLA2R expression was examined by immunofluorescence. Among these patients, 186 (80.5%) with complete baseline clinical data were used for further study. Urinary protein excretion, serum albumin, and creatinine were analyzed. For those patients with follow-up longer than 1 year, the relationship between PLA2R and response to immunosuppressants were analyzed. The t-test was used for parametric analysis and the Mann-Whitney U-test was used for nonparametric analysis. Categorical variables were described as frequencies or percentages, and the data were analyzed with Pearson's Chi-square test or Fisher's exact test.

RESULTSOf the 231 iMN patients, 189 showed renal detectable PLA2R expression (81.8%). The baseline serum creatinine, serum albumin, and urine protein excretion were not significantly different between PLA2R-associated (n = 145) and non-PLA2R-associated iMN patients (n = 41). However, about 1/3 of the non-PLA2R-associated iMN had abnormal serological tests, significantly more common than PLA2R-associated iMN (31.7% vs. 8.3%, P = 0.000). The non-PLA2R-associated iMN had lower C4 levels compared with PLA2R-associated iMN (P = 0.004). The non-PLA2R-associated iMN patients also showed a better response to immunosuppressants (complete remission [CR] 42.9%; partial remission [PR] 14.3%) compared with PLA2R-associated iMN (CR 3.2%; PR 48.4%, P = 0.004) at the 3rd month.

CONCLUSIONSThere were no significant differences in serum creatinine, albumin, and urine protein excretion between PLA2R-associated and non-PLA2R-associated iMN, while the non-PLA2R-associated iMN patients showed more abnormal serological tests. The non-PLA2R-associated iMN seemed to respond more quickly to the immunosuppressive therapy compared with PLA2R-associated iMN.

Adult ; Autoantibodies ; metabolism ; Female ; Glomerulonephritis, Membranous ; drug therapy ; metabolism ; pathology ; urine ; Humans ; Immunosuppressive Agents ; therapeutic use ; Kidney ; metabolism ; pathology ; Male ; Middle Aged ; Receptors, Phospholipase A2 ; metabolism ; Retrospective Studies

M1-type macrophages are capable of inducing lysis in various types of cancer cells, but the mechanism of action is unclear. It has been noted that an "unknown protein" produced together with protease by activated macrophages is responsible for this action. Activated M1 macrophages have been recently reported to produce family 18 chitinases, all of which have been named chitotriosidase. Our experiments have demonstrated that family 18 chitinases work together with proteases and can damage various cancer cells both in vitro and in vivo. Thus, in this article, we suggest that the 50-kDa chitotriosidase is the reported "unknown protein". In addition, we discuss how to properly stimulate activated M1 macrophages to produce 50-kDa chitotriosidases and proteases for destroying cancer cells. Because family 19 chitinase has recently been reported to kill cancer cells, we also discuss the possibility of directly using human family 18 chitotriosidase and the humanized plant family 19 chitinase for cancer treatment.
Animals ; Antineoplastic Agents, Alkylating ; pharmacology ; Chitinases ; metabolism ; Cyclophosphamide ; pharmacology ; Hexosaminidases ; metabolism ; Humans ; Immunosuppressive Agents ; pharmacology ; Macrophage Activation ; immunology ; Macrophages ; classification ; enzymology ; immunology ; pathology ; Neoplasms ; immunology ; pathology ; Peptide Hydrolases ; metabolism ; T-Lymphocytes, Regulatory ; metabolism ; Th1 Cells ; metabolism ; Th2 Cells ; metabolism

This study is to investigate the effect of FK506 on expression of hepatocyte growth factor (HGF) in rats' spinal cord following peripheral nerve injury and to elucidate the mechanisms for neuroprotective property of FK506. Fifty male rats were randomly divided into normal group, injury group and treatment group. Models of peripheral nerve injury were established by bilateral transection of sciatic nerve 0.5 cm distal to piriform muscle. Then the treatment group received subcutaneous injection of FK506 (1 mg/kg) at the back of neck, while the injury group was given 0.9% saline. The L(4-6) spinal cords were harvested at various time points after the surgery. Western blotting and immunofluorescent staining were used to detect the level and position of HGF in spinal cord. Immunofluorescent staining showed that HGF-positive neurons were located in anterior horn, intermediate zone and posterior horn of gray matter in normal spinal cord. Western blotting revealed that there was no significant difference in the expressions of HGF between the injury group and the normal group, while the expression of HGF was significantly higher in the treatment group than in the injury group 7 and 14 days after surgery. It is suggested that peripheral nerve injury does not result in up-regulation of the expression of HGF in spinal cord, while FK506 may induce high expression of endogenous HGF after injury thereby protecting neurons and promoting axonal outgrowth.
Cells, Cultured ; Gene Expression Regulation ; Hepatocyte Growth Factor/metabolism ; Immunosuppressive Agents/metabolism ; Immunosuppressive Agents/*pharmacology ; Microscopy, Fluorescence/methods ; Neurons/metabolism ; Peripheral Nervous System/*metabolism ; Sciatic Nerve/metabolism ; Spinal Cord/*cytology ; Spinal Cord/metabolism ; Spinal Cord Injuries/*drug therapy ; Tacrolimus/metabolism ; Tacrolimus/*pharmacology

OBJECTIVETo test the immunosuppressive effect of cyclosporine (Cs) in a polymer placed in the anterior chamber of corneal allograft recipients.

METHODSWistar inbred rats with vascularized corneas were recipients of corneal allografts from Sprague-Dawley donor rats. Rats underwent penetrating keratoplasty and were divided randomly into four groups: untreated control animals (UCA); Cs-polymer anterior chamber recipients (CPA); co-polymer subconjunctival recipients (CPS); and Cs-olive oil drop recipients (COO). Grafts were examined by slit lamp every 3 days and clinical conditions were scored. Cs concentration in the aqueous humor was assayed at 1, 2, and 4 weeks. At 1, 2 and 4 weeks after transplantation, the operated eyes were collected for histopathological evaluation of the grafts.

RESULTSThe median survival time of the allografts was 8.2 +/- 1.48 days for the UCA group, 11.4 +/- 2.50 days for the CPS group, and 17.0 +/- 2.00 days for the CPA group. There was a statistically significant difference (P < 0.05) between survival time of the allografts in the animals of the CPA group compared to the other groups of graft recipients. Significantly higher concentrations of Cs were found in the eyes given an anterior chamber implant of Cs-polymer, compared to other treatment groups or untreated rats. A transient inflammatory response in the anterior chamber was observed in the CPA group.

CONCLUSIONSCs-polymer placed in the anterior chamber significantly prolongs corneal allograft survival time in a high risk corneal graft rejection model. This intraocular delivery system may be a valuable adjunct for the suppression of immune graft rejection.

Animals ; Aqueous Humor ; metabolism ; Corneal Transplantation ; Cyclosporine ; administration & dosage ; metabolism ; Drug Delivery Systems ; Graft Survival ; Immunosuppressive Agents ; administration & dosage ; Male ; Rats ; Rats, Wistar ; Transplantation, Homologous

OBJECTIVETo establish a new rat model of chronic cyclosporine A nephrotoxicity and explore its features.

METHODSTotally 24 male SD rats were equally randomized divided into 3 groups: sham-adrenalectomized (sham-ADX) group, ADX group and ADX plus cyclosporine A (CsA) group. Rats in ADX and CsA group first underwent adrenalectomy, followed by the administration of placebo or dexamethasone, respectively. Rats in sham-ADX group received sham adrenalectomy and distilled water as control. Six weeks later, all rats were sacrificed and the following indicators were evaluated: urine protein excretion, creatinine clearance, aldosterone level in serum and urine, aldosterone level and its synthase CYP11B2 gene expression in kidney, serum natrium and potassium, urine natrium and potassium excretion, and tubulointerstitial fibrosis by masson trichrome stain.

RESULTSIn ADX and CsA group, serum and urine aldosterone were undetectable on the second post-operative day, with other observations including natriuresis, hyponatremia, decreased urine potassium excretion, and hyperpotassemia, suggesting that adrenals were removed intact and the adrenalectomy was successful. Rats in CsA group showed increased urine protein, decreased creatinine clearance and tubulointerstitial fibrosis, suggesting that a model of chronic CsA nephrotoxicity was successfully established. At the endpoint, serum potassium, serum aldosterone, urine potassium and urine aldosterone excretion partially retrieved. Natrium in serum and urine was not significant different between ADX group/CsA group and sham-ADX group. Local renal aldosterone and its gene expression were remarkably upregulated.

CONCLUSIONSWe successfully established a new rat model of chronic CsA nephrotoxicity by adrenalectomy without low sodium diet. After adrenalectomy, local renal aldosterone in kidney may compensate for circulatory aldosterone deficit to maintain electrolyte balance.

Acute Kidney Injury ; chemically induced ; Adrenalectomy ; Aldosterone ; metabolism ; Animals ; Cyclosporine ; toxicity ; Disease Models, Animal ; Immunosuppressive Agents ; toxicity ; Kidney ; drug effects ; metabolism ; pathology ; Male ; Rats ; Rats, Sprague-Dawley

OBJECTIVE: To detect the correlation between survivin and rheumatoid arthritis (RA) to determine the possible mechanism of RA and multidrug resistance in refractory rheumatoid arthritis (RRA). METHODS: We collected 15 normal controls, 35 early untreated RA patients, 20 effectively treated RA patients and 25 RRA patients according to selection standard. The expression of survivin in the peripheral blood lymphocytes was detected by immunocytochemical method. RESULTS: There was significant difference in the survivin expression in the peripheral blood lymphocytes between the early untreated and normal control group (χ(2)=29.59, P<0.01). The survivin expression in the peripheral blood lymphocytes of effectively treated RA group slightly elevated, but had no significant difference with the normal control group (χ(2)=1.591, P>0.05). The survivin expression in the peripheral blood lymphocytes of the RRA group was significantly stronger than in the effectively treated RA group (χ(2)=24.35, P<0.01), and normal control group (χ(2)=26.53, P<0.01), with no significant difference compared with early untreated group (χ(2)=0.014,P>0.05). CONCLUSION Survivin has an influential role in the occurrence and development of rheumatism arthritis. Survivin might be involved in refractory multidrug resistance of RA and be one of the multidrug resistance mechanism of RRA.
Adult ; Antirheumatic Agents ; therapeutic use ; Arthritis, Rheumatoid ; drug therapy ; metabolism ; Case-Control Studies ; Drug Resistance, Multiple ; Female ; Humans ; Immunosuppressive Agents ; therapeutic use ; Inhibitor of Apoptosis Proteins ; metabolism ; Lymphocytes ; metabolism ; Male ; Middle Aged ; Survivin ; Young Adult

Even though uroplakins (UPs) are believed to serve a strong protective barrier against toxic materials, cyclophosphamide (CP) causes extensive cystitis. We investigated the expression of UPs in the urothelium in CP induced mouse cystitis. A total of 27 ICR female mice received a single intraperitoneal injection of 200 mg CP/kg. Nine CP-treated mice and 6 controls were sequentially killed at 12, 24, and 72 hr post injection. Extensive cystitis and an increased vesical weight were seen. These all peaked within 12 hr post injection and they tended to decrease thereafter. The level of all the UPs mRNA, the protein expressions of UP II and III on immunoblotting study, and the expression of UP III on immunolocalization study were maximally suppressed within 12 hr; this partially recovered at 24 hr, and this completely recovered at 72 hr post CP injection. In conclusion, CP reduced the expression of UPs. The reduction of the UPs mRNA and protein was time dependent, and this peaked within 12 hr after CP injection. However, the damage was rapidly repaired within 24 hr. This study demonstrates a dynamic process, an extensive reduction and rapid recovery, for the UPs expression of the mouse urinary bladder after CP injection.
Animals ; Cyclophosphamide/*toxicity ; Cystitis/chemically induced/*metabolism/pathology ; Female ; Immunosuppressive Agents/*toxicity ; Membrane Glycoproteins/*metabolism ; Membrane Proteins/*metabolism ; Mice ; Mice, Inbred ICR ; RNA, Messenger/metabolism ; Time Factors ; Urinary Bladder/*metabolism

OBJECTIVETo investigate the change in telomere length and TERC and TERT mutations in peripheral blood leukocytes of children with chronic aplastic anemia (CAA).

METHODSSixty-nine children with CAA were divided into untreated group (n=24) who did not receive immunosuppressive therapy (IST), response group (n=36) who showed response to IST, and non-response group (n=9) who showed no response to IST; another 35 healthy children matched for age and sex were selected as the control group. The telomere-to-single copy gene (T/S) ratio in peripheral blood leukocytes was measured by real-time PCR in all groups. PCR was performed to detect TERC and TERT mutations in all children with CAA.

RESULTSThe untreated and non-response groups had significantly lower T/S ratios than the control and response groups (P<0.01), whereas there was no significant difference in T/S ratio between the response and control groups (P>0.05). TERC and TERT mutations were not found in all children with CAA.

CONCLUSIONSThe change in telomere length in children with CAA may be related to the development and progression of disease. Telomere length measurement may be used as a prognostic indicator in children with CAA.

Adolescent ; Anemia, Aplastic ; drug therapy ; genetics ; Child ; Child, Preschool ; Chronic Disease ; Humans ; Immunosuppressive Agents ; therapeutic use ; Infant ; Leukocytes ; metabolism ; Male ; Mutation ; Telomerase ; genetics ; Telomere

OBJECTIVETo explore the therapeutic effect of Jiawu Mufangji Decoction (JMD) in treating rats with adjuvant arthritis (AA) and its mechanism.

METHODSAA model rats induced by Freund's complete adjuvant were treated with JMD by gastrogavage starting from 18 days after modeling. On the 39th day, body weight, spleen and thymus index, and swelling degree of paw of the AA rats were measured, pathological changes of the ankle joint tissue were observed using HE staining, and serum levels of interleukin-1beta (IL-1beta) and tumor necrosis factor a (TNF-alpha) were determined by enzyme-linked immunosorbent assay (ELISA).

RESULTSJMD could relieve the symptoms of AA rats, decrease the paw swelling, improve the weight and spleen and thymus index, reduce the dropsy of joints and lymphocytes infiltration, inhibit the proliferation of synovium, and obviously lower the serum levels of interleukin-1beta and TNF-alpha.

CONCLUSIONThe therapeutic effect of JMD might be related to its action in down-regulating the serum levels of IL-1beta and tumor necrosis factor alpha.

Animals ; Arthritis, Experimental ; drug therapy ; Drugs, Chinese Herbal ; therapeutic use ; Immunosuppressive Agents ; therapeutic use ; Interleukin-1 ; blood ; Male ; Phytotherapy ; Rats ; Rats, Wistar ; Tumor Necrosis Factor-alpha ; metabolism