Biomedical subjects

Akira Ito

Publications and source records attributed to Akira Ito.

At least 91 records · Page 5Linked to original sources

PubMed2004

Tumor-stromal cell contact promotes invasion of human uterine cervical carcinoma cells by augmenting the expression and activation of stromal matrix metalloproteinases.

OBJECTIVE: The augmentation of the expression and activation of matrix metalloproteinases (MMPs) is associated with tumor invasion and metastasis. In addition, tumor-stromal cell contact provides a crucial signal for regulating the pericellular proteolysis for the progression of tumor invasiveness. The present study evaluates the regulation of the expression and activation of MMPs and tissue inhibitors of metalloproteinases (TIMPs) by tumor-stromal cell contact in an in vitro co-culture model of human uterine cervical carcinoma cells and human uterine cervical fibroblasts. METHODS: When human uterine cervical carcinoma SKG-II cells were co-cultured with human uterine cervical fibroblasts (HUCFs), the invasive activity of SKG-II cells was analyzed using an in vitro invasion assay using Matrigel. The production, mRNA expression and activation of MMPs and TIMPs were monitored by Western blot and Northern blot analyses and gelatin zymography. RESULTS: SKG-II cells, which constitutively produced membrane-type 1 MMP (MT1-MMP) and a trace of proMMP-2 but neither TIMP-1 nor TIMP-2, showed poor invasiveness in vitro. Upon co-culturing with HUCFs, SKG-II cells were found to transform to the invasive phenotype by enhancing the production and mRNA expression of tumoral MT1-MMP. In addition, a sequential increase in the activation of fibroblast proMMP-2 was observed along with the formation of an MT1-MMP-TIMP-2-proMMP-2 complex on the tumor cell surface. Furthermore, the production and gene expression of fibroblast proMMP-1 and proMMP-3 were augmented under co-culture conditions, whereas mRNA expression of proMMP-2, TIMP-1 and TIMP-2 was unchanged. Moreover, we demonstrated the partial involvement of tumor-cell-derived soluble factors in the augmentation of the production of proMMP-1 and proMMP-3 in HUCFs. However, anti-integrin beta1 and beta3 antibodies failed to abolish the augmentation of fibroblast proMMP-3 production and proMMP-2 activation in the co-culture. CONCLUSION: Cell-cell contact between cervical carcinoma cells and peripheral stromal fibroblasts augments the production and activation of MMPs, and therefore the subsequent imbalance between MMPs and TIMPs may result in the progression of invasiveness of cervical carcinoma cells in vivo.

Cell Communication↗

PubMed2004

Immunization of rodents against Hymenolepis infections using non-viable homologous oncospheres.

Immunity to Taiwan Taenia infection in pigs can be stimulated using homologous or heterologous non-viable Taenia oncospheres. This study was designed to determine whether homologous non-viable oncospheres could stimulate immunity to Hymenolepis infection in rodents. Hatched oncospheres were prepared from eggs of Hymenolepis diminuta, Hymenolepis nana, and Hymenolepis microstoma and kept at -70 degrees C for more than 1 month. A mixture of 500 non-viable oncospheres of each tapeworm and complete Freund's adjuvant was injected subcutaneously in four groups of Sprague-Dawley rats or ICR mice one to four times at an interval of 1 week; controls were not immunized. After immunization, each rodent was orally inoculated with three fresh active cysticercoids of H. diminuta or H. microstoma or 500 fresh eggs of H. nana. The animals were then necropsied for adult tapeworms. No rats or mice immunized with non-viable oncospheres of H. diminuta or H. nana were infected by the challenge inoculation. However, 28 of 34 mice immunized with non-viable H. microstoma oncospheres were infected after inoculation with cysticercoids. This study demonstrated complete protection against infection by homologous parasites in rats or mice immunized with non-viable oncospheres of H. diminuta and H. nana, respectively. Repeated immunization may not be required if resistance is stimulated in rodent hosts.

Animals↗

PubMed2004

A multicenter, open-label clinical study of micafungin (FK463) in the treatment of deep-seated mycosis in Japan.

The efficacy and safety of micafungin (FK463), which is a new lipopeptide antifungal agent of the echinocandin class and is active against both Aspergillus and Candida species, were investigated in patients with deep-seated mycosis in this study. 70 patients were treated with micafungin 12.5-150 mg/d intravenously for up to 56 d. The overall clinical response rates were 60% (6/10) in invasive pulmonary aspergillosis, 67% (6/9) in chronic necrotizing pulmonary aspergillosis, 55% (12/22) in pulmonary aspergilloma, 100% (6/6) in candidemia, and 71% (5/7) in esophageal candidiasis. The response rates for patients with prior antifungal treatment which was considered ineffective or toxic, were similar to rates for patients without prior treatment. Mycological eradication was observed in patients infected with Aspergillus fumigatus, Aspergillus flavus, Aspergillus terreus, Aspergillus niger, Candida albicans, Candida glabrata, or Candida krusei. Adverse events related to micafungin were reported in 21 patients (30%), and there was no dose-related occurrence of any adverse event. It is concluded that treatment with micafungin as monotherapy seems to be effective and safe in patients with deep-seated mycosis.

Adult↗

PubMed2004

Cysticercosis/taeniasis in Asia and the Pacific.

Three taeniid tapeworms infect humans in Asia and the Pacific: Taenia solim, Taenia saginata, and Taenia asiatica. Although there is continuing debate about the definition of a new species, phylogenetic analyses of these parasites have provided multiple lines of evidence that T. asiatica is an independent species and the sister species of T. saginata. Here we review briefly the morphology, pathology, molecular biology, distribution and control options of taeniasis/cysticercosis in Asia and the Pacific and comment on the potential role which dogs may play in the transmission of T. solium. Special attention is focused on Indonesia: taeniasis caused by T. asiatica in North Sumatra, taeniasis/cysticercosis of T. solium and taeniasis of T. saginata in Bali, and taeniasis/cysticercosis of T. solium in Papua (formerly Irian Jaya). Issues relating to the spread of taeniasis/cysticercosis caused by T. solium in Papua New Guinea are highlighted, since serological evidence suggests that cysticercosis occurs among the local residents. The use of modern techniques for detection of taeniasis in humans and cysticercosis in humans, pigs and dogs, with the possible adoption of new control measures will provide a better understanding of the epidemiology of taeniasis/cysticercosis in Asia and the Pacific and lead to improved control of zoonotic and simultaneously meat-borne disease transmission.

Animals↗

PubMed2004

Usefulness of fasudil, a Rho-kinase inhibitor, to treat intractable severe coronary spasm after coronary artery bypass surgery.

We have recently demonstrated that fasudil, a Rho-kinase inhibitor, is effective in suppressing coronary artery spasm in patients with vasospastic angina. Thus, blockade of Rho-kinase may provide a novel therapeutic strategy to treat ischemic coronary syndrome caused by the spasm. Severe coronary artery spasm still remains a life-threatening serious complication of coronary artery bypass grafting (CABG). In this study, we examined the inhibitory effect of fasudil in patients with intractable severe coronary spasm after CABG. Three patients who underwent CABG showed severe myocardial ischemia resistant to intensive therapy with intravenous conventional vasodilators, including isosorbide dinitrate (ISDN), diltiazem, and nicorandil. Coronary angiography revealed severe coronary spasm in native coronary arteries and/or bypass arterial grafts in all patients. Since intracoronary and/or intragraft administration of ISDN was ineffective to resolve the spasm, we then administered fasudil (1.5 mg/min for 15 minutes) into the spastic arteries. Fasudil successfully resolved the spasm and improved myocardial ischemia in all patients without any systemic adverse effects. In conclusion, the treatment with fasudil may be useful to treat intractable and otherwise fatal coronary spasm resistant to intensive conventional vasodilator therapy after CABG.

1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine↗

PubMed2004

Changing characteristics of patients with vasospastic angina in the era of new calcium channel blockers.

In the 1980s, clinical characteristics and long-term prognosis of patients with vasospastic angina (VSA) were investigated; however, they remain to be updated after the introduction of new calcium channel blockers, benidipine and amlodipine, in 1990s. Our patient cohort registered 726 patients with VSA from January 1980 to December 2002. Before and after 1990, 138 and 527 patients were respectively entered in this study with a follow-up rate of 92%. Most of the patients were treated with calcium channel blockers, while benidipine and amlodipine were used in 28% and 21% of them only after 1990. Survival without cardiovascular events (96% versus 96%) at 5 years remained good before and after 1990. The presence of significant coronary stenosis had a negative prognostic impact both before and after 1990, whereas after 1990, diabetes mellitus, smoking, and a history of myocardial infarction became more influential. Among the calcium channel blockers, benidipine showed a better prognosis. These results suggest that in the era of new calcium channel blockers, the prognosis of patients with VSA remains good with more prognostic impact of diabetes mellitus, smoking, and a history of myocardial infarction and that benidipine might have some better prognostic effects.

Administration, Sublingual↗

PubMed2004

DNA differential diagnosis of taeniasis and cysticercosis by multiplex PCR.

Multiplex PCR was established for differential diagnosis of taeniasis and cysticercosis, including their causative agents. For identification of the parasites, multiplex PCR with cytochrome c oxidase subunit 1 gene yielded evident differential products unique for Taenia saginata and Taenia asiatica and for American/African and Asian genotypes of Taenia solium with molecular sizes of 827, 269, 720, and 984 bp, respectively. In the PCR-based detection of tapeworm carriers using fecal samples, the diagnostic markers were detected from 7 of 14 and 4 of 9 T. solium carriers from Guatemala and Indonesia, respectively. Test sensitivity may have been reduced by the length of time (up to 12 years) that samples were stored and/or small sample volumes (ca. 30 to 50 mg). However, the diagnostic markers were detected by nested PCR in five worm carriers from Guatemalan cases that were found to be negative by multiplex PCR. It was noteworthy that a 720 bp-diagnostic marker was detected from a T. solium carrier who was egg-free, implying that it is possible to detect worm carriers and treat before mature gravid proglottids are discharged. In contrast to T. solium carriers, 827-bp markers were detected by multiplex PCR in all T. saginata carriers. The application of the multiplex PCR would be useful not only for surveillance of taeniasis and cysticercosis control but also for the molecular epidemiological survey of these cestode infections.

Animals↗

PubMed2004

Molecular cloning, expression, and serological evaluation of an 8-kilodalton subunit of antigen B from Echinococcus multilocularis.

Full-length cDNA and genomic DNA encoding an 8-kDa subunit of antigen B from Echinococcus multilocularis (designated EmAgB8/1) were isolated from an E. multilocularis metacestode cDNA library and a protoscolex genomic DNA library, respectively. The open reading frame of the cDNA clone encodes a polypeptide comprising 85 amino acids with a 20-amino-acid NH(2)-terminal signal sequence, which was confirmed following N-terminal sequencing of the native antigen. Reverse transcription-PCR analysis revealed that the clone encoding EmAgB8/1 is predominantly transcribed in larval E. multilocularis. The gene consists of two exons (encoding the signal sequence and mature protein) separated by a 91-bp intron. The mature form was expressed in Escherichia coli, and its antigenic reactivity was compared with that of a counterpart, an 8-kDa subunit of antigen B from Echinococcus granulosus (EgAgB8/1) by Western blotting and enzyme-linked immunosorbent assay (ELISA) with serum samples from patients confirmed to have cystic echinococcosis (CE) and alveolar echinococcosis (AE). Recombinant EmAgB8/1 showed positive reactions in Western blots with 81.3% (65 of 80) of serum samples from CE patients and 40.6% (26 of 64) of serum samples from AE patients, while recombinant EgAgB8/1 showed positive reactions with 86% (43 of 50) and 42% (19 of 45) of the serum samples from these CE and AE patients, respectively. By the ELISA, both EmAgB8/1 and EgAgB8/1 exhibited similar positive reactions with 88% (44 of 50) of serum samples from CE patients and 37.8% (17 of 45) serum samples from AE patients. Statistical analysis revealed that the sensitivity of EmAgB8/1 was comparable to that of EgAgB8/1 for the serodiagnosis of echinococcal diseases. There was no cross-reaction with sera from patients with cysticercosis, which often cross-react when native antigens are used for serodiagnosis.

Amino Acid Sequence↗

PubMed2004

Solitary neurocysticercosis case caused by Asian genotype of Taenia solium confirmed by mitochondrial DNA analysis.

A Japanese woman presenting with neurologic symptoms was presumptively diagnosed with neurocysticercosis based on imaging findings. Hooklets in the scolex of the resected lesion were not confirmed through histopathological observation. However, the illness was confirmed by mitochondrial DNA analysis to be a solitary neurocysticercosis case caused by the Asian genotype of Taenia solium.

Animals↗

PubMed2004

Monoclonal antibodies preventing invasion of Neospora caninum tachyzoites into host cells.

Twelve monoclonal antibodies (MAbs) against Neospora caninum tachyzoites were produced to specify the antigens related to the invasion of tachyzoites into host cells. In the assay to evaluate the inhibition activity, all these MAbs prevented the cultured Vero cells from the invading by the tachyzoites. These MAbs recognized approximately a 73 kDa antigen in Western blot analysis. Immunofluorescence assay and immune electron microscopy revealed that this 73 kDa antigen is a part of the surface antigens of N. caninum tachyzoite, and that the tachyzoite antigen identified plays an important role for invasion of host cells.

Animals↗

PubMed2004

Field efficacy of recombinant R7 vaccine against chicken leucocytozoonosis.

Effectiveness of vaccine that used recombinant R7 protein (rR7) as antigen that is derived from second-generation schizont (2GS) of Leucocytozoon caulleryi was verified under a field condition against chicken leucocytozoonosis. Chickens reared in a poultry farm where the chickens are attacked by leucocytozoonosis in every year were inoculated with oil-adjuvanted rR7 vaccine (O-rR7), and the immunized chickens were found to have production of antibodies against 2GS at a high level by one shot. Leucocytozoonosis was observed at post-injection. During the epidemic period of leucocytozoonosis, the unique clinical signs of the disease such as discharge of green feces and anemia, and also parasitemia were observed, however, compared to chickens in control group, those in O-rR7 vaccinated group had significantly slight symptoms (P<0.05). In addition to this, immunized chickens had better result of egg production than the unvaccinated chickens did, and the maximum difference of egg production rate, 22%, was observed at the peak of the disease. In conclusion, it is verified that O-rR7 vaccine has efficacy against leucocytozoonosis under field condition, and this vaccine can be put into practical use.

Animal Husbandry↗

PubMed2004

Possible involvement of macrophage-colony stimulating factor in the pathogenesis of cardiac dysfunction in hemodialysis patients.

In patients with end stage renal disease on hemodialysis (HD), left ventricular (LV) function is frequently impaired. However, the mechanism of the LV dysfunction is totally unknown. It has been suggested that overproduction of nitric oxide induced by inflammatory cytokines may contribute to the LV dysfunction in some diseased states. In this study, we examined whether inflammatory cytokines play a role in the altered LV function in HD patients. The plasma concentrations of 5 major inflammatory cytokines, including interleukin (IL)-1alpha, IL-1beta, IL-6, tumor necrosis factor-alpha, and macrophage-colony stimulating factor (M-CSF) were measured by enzyme immunoassay with horseradish peroxidase in 18 consecutive patients on HD and in 16 control subjects. Then, we examined the relationship between plasma concentrations of M-CSF and LV ejection fraction (EF) on echocardiography. Among the inflammatory cytokines examined, only the plasma concentrations of M-CSF were significantly elevated in patients on HD as compared to the control subjects. There was no significant change in the M-CSF concentrations before and after HD. Furthermore, there was a significant negative correlation between the plasma concentrations of M-CSF and LVEF. These results suggest that elevated levels of plasma M-CSF may exist prior to the development of LV dysfunction observed in HD patients.

Female↗

PubMed2004

Activation of protein kinase C betaII/epsilon-c-Jun NH2-terminal kinase pathway and inhibition of mitogen-activated protein/extracellular signal-regulated kinase 1/2 phosphorylation in antitumor invasive activity induced by the polymethoxy flavonoid, nobiletin.

Flavonoids from medicinal plants have been therapeutically administered for cancer therapy. We recently reported that nobiletin (5,6,7,8,3',4'-hexamethoxy flavone) exhibits novel antitumor invasive activities by suppressing the production of pro-matrix metalloproteinases (proMMPs) and augmenting the expression of tissue inhibitor of metalloproteinases-1 (TIMP-1) in vivo and in vitro. In the present study, intracellular target molecules associated with the actions of nobiletin against tumor invasion were identified. Nobiletin inhibited the phosphorylation of mitogen-activated protein/extracellular signal-regulated kinase (MEK) 1/2, but not the activity of Ras or the phosphorylation of Raf. Moreover, a MEK1/2 inhibitor, U0126, mimicked nobiletin's ability to decrease the production of proMMPs-1 and 9 in human fibrosarcoma HT-1080 cells stimulated by 12-O-tetradecanoyl phorbol-13-acetate (TPA). In addition, neither the activity of phosphatidylinositol 3-kinase (PI3K) nor the phosphorylation of Akt was influenced by nobiletin. However, nobiletin was found to augment the phosphorylation of c-Jun NH2-terminal kinase (JNK), a downstream signal factor of the PI3K-Akt pathway, in TPA-treated HT-1080 cells. A similar augmentation of JNK phosphorylation was observed on treatment with a PI3K inhibitor, LY-294002. Furthermore, nobiletin enhancement of TIMP-1 production in TPA-stimulated HT-1080 cells was found to be diminished by adding a JNK inhibitor, SP600125. Moreover, protein kinase C (PKC) inhibitor experiments showed that PKCbetaII/epsilon were associated with the nobiletin-mediated augmentation of JNK phosphorylation. Therefore, these results introduce novel evidence that the antitumor effects of nobiletin are finely regulated by the following intracellular mechanisms: (1) the inhibition of MEK1/2 activity is involved in the suppression of MMP expression and (2) the activation of the novel PKCbetaII/epsilon-JNK pathway is associated with the augmentation of TIMP-1 expression.

Anthracenes↗

PubMed2004

Cysticercosis: IgG-ELISA evaluations of peak1 antigen and <30 kDa antigen of delipidized extract of Taenia solium metacestodes.

The antigenicity of ether-delipidized Taenia solium metacestode extract (DLPAg) was investigated by IgG-ELISA. The antigen showed higher antigenicity than that of non-delipidized antigen (NDLPAg). Then the DLPAg was subjected to Sephacryl S-200 gel chromatography and a partially purified antigen (DLPP1Ag) was identified as the promised antigen by IgG-ELISA using 25 sera from cysticercosis cases, 177 cases of 24 heterologous infections, and healthy controls. Sensitivity was 52% and specificity was 91.8% at the cut-off value (X + 7SD), 0.399. Cross-reactivity occurred with 17 cases of eight diseases: cystic echinococcosis (7/11), taeniasis (1/16), gnathostomiasis (2/8), strongyloidiasis (1/12), angiostrongyliasis (1/12), paragonimiasis heterotremus (2/15), opisthorchiasis (1/9) and fascioliasis (2/7). When DLPP1Ag was fractionated through Ultra free centrifugal tube (retained 30 kDa) and Amicon (PM10), MWCOP1Ag (<30-10> kDa) was obtained; the antigen showed better results than DLPP1Ag with 88% sensitivity and 95.6% specificity at the cut-off value (X + 4SD), 0.264. Nine cases of six diseases cross-reacted with this antigen: cystic echinococcosis (2/11), gnathostomiasis (2/8), trichinellosis (2/12), toxocariasis (1/5), schistosomiasis (1/6), and fascioliasis (1/7). MWCOP1Ag gave higher sensitivity than that of DLPP1Ag but some cross-reactivity occurred.

Animals↗

PubMed2003

A novel recombinant antigen for immunodiagnosis of human cystic echinococcosis.

A pool of serum samples from mice infected with oncospheres (eggs) of Echinococcus granulosus was used to screen a cDNA library constructed with RNA extracted from protoscolex larvae from sheep hydatid cysts. One immunoreactive clone, designated EpC1, was shown to encode a protein of 76 residues. The complementary DNA (cDNA) fragment was subcloned into an expression vector, pET-41b(+), and the resulting recombinant EpC1 glutathione S-transferase (GST) fusion protein (rEpC1-GST) was expressed in Escherichia coli and was affinity purified against the GST tag. Immunoglobulin G was the dominant antibody isotypes generated against rEpC1-GST. A total of 896 human serum samples were used to evaluate the diagnostic sensitivity and specificity of the fusion protein by immunoglobulin G immunoblotting; 324 serum samples from patients with cystic echinococcosis (CE), 172 from patients with neurocysticercosis, 89 from patients with alveolar echinococcosis, and 241 from patients with other infections or clinical presentations, as well as 70 from confirmed-negative control subjects, yielded an overall sensitivity of 92.2% and an overall specificity of 95.6%. The combined levels of sensitivity and specificity achieved with the rEpC1-GST fusion protein for diagnosis of CE are unprecedented, taking into account the large panel of serum samples that were tested.

Amino Acid Sequence↗

PubMed2003

Human Taeniasis and cysticercosis in Asia.

CONTEXT: Human Taeniasis caused by the pork, Taenia solium, or beef, T saginata, tapeworm arises after eating pork or beef contaminated with metacestodes, the larval stage of these parasites. Taeniasis with T solium can lead to neurocysticercosis and threaten others by accidental ingestion of eggs released from asymptomatic Taeniasis patients. The 2003 World Health Assembly declared that T solium is of worldwide public-health importance, and that it is an eradicable parasitic disease worldwide. Adult taeniid tapeworms expelled from people in almost all Asian countries appeared to be T saginata (the so-called Asian Taenia), even though they ate pork. The organism is now named T asiatica, and has been found in Taiwan, Korea, China, Vietnam, and Indonesia. But it has been difficult to differentiate T saginata from beef and Asian Taenia from pork. STARTING POINT: Marshall Lightowlers and colleagues (Int J Parasitol 2003; 33: 1207-17) recently demonstrated that recombinant oncosphere vaccines against several taeniid cestodes, including T ovis, T saginata, T solium, and Echinococcus granulosus, are highly effective. Protection was almost 100%, in the laboratory and in the field. These researchers found several common features, including a predicted secretory signal sequence, and one or two copies of a fibronectin type III domain, each encoded by separate exons within the associated gene. WHERE NEXT? Molecular and immunological techniques, including vaccine research and development of animal models for differentiation of taeniid species in humans, have greatly advanced over the past decade. The clinical importance of infections by these taeniids, including T asiatica, in humans, and the potential for cysticercosis attributable to T asiatica in humans, needs further study.

Animals↗

PubMed2003

Antitumor effects of combined therapy of recombinant heat shock protein 70 and hyperthermia using magnetic nanoparticles in an experimental subcutaneous murine melanoma.

Heat shock proteins (HSPs) are recognized as significant participants in cancer immunity. We previously reported that HSP70 expression following hyperthermia using magnetic nanoparticles induces antitumor immunity. In the present study, we examine whether the antitumor immunity induced by hyperthermia is enhanced by administration of recombinant HSP70 protein into the tumor in situ. Hyperthermia was conducted using our original magnetite cationic liposomes (MCLs), which have a positive surface charge and generate heat in an alternating magnetic field (AMF) due to hysteresis loss. MCLs and recombinant mouse HSP70 (rmHSP70) were injected into melanoma nodules in C57BL/6 mice, which were subjected to AMF for 30 min. Temperature within the tumor reached 43 degrees C and was maintained by controlling the magnetic field intensity. The combined treatment strongly inhibited tumor growth over a 30-day period and complete regression of tumors was observed in 20% (2/10) of mice. It was also found that systemic antitumor immunity was induced in the cured mice. This study suggests that novel combined therapy using exogenous HSP70 and hyperthermia has great potential in cancer treatment.

Animals↗

PubMed2003

Novel anti-inflammatory actions of nobiletin, a citrus polymethoxy flavonoid, on human synovial fibroblasts and mouse macrophages.

We previously reported that nobiletin (5,6,7,8,3',4'-hexamethoxy flavone), a citrus polymethoxy flavonoid, effectively interferes with the production of promatrix metalloproteinase (proMMP)-9/progelatinase B in rabbit synovial fibroblasts [J. Rheumatol. 27 (2000) 20]. In this paper, we further examine the effects of nobiletin on the production of cyclooxygenases (COXs), prostaglandin (PG) E(2), and proinflammatory cytokines in human synovial fibroblasts and the mouse macrophage J774A.1 cell line. Nobiletin suppressed the interleukin (IL)-1-induced production of PGE(2) in human synovial cells in a dose-dependent manner (<64 microM). Additionally, it selectively downregulated COX-2, but not COX-1 mRNA expression. Nobiletin also interfered with the lipopolysaccharide-induced production of PGE(2) and the gene expression of proinflammatory cytokines including IL-1alpha, IL-1beta, TNF-alpha and IL-6 in mouse J774A.1 macrophages. In addition, nobiletin downregulated the IL-1-induced gene expression and production of proMMP-1/procollagenase-1 and proMMP-3/prostromelysin-1 in human synovial fibroblasts. In contrast, production of the endogenous MMP inhibitor, TIMP-1, was augmented by nobiletin. These anti-inflammatory actions of nobiletin are very similar to those of anti-inflammatory steroids such as dexamethasone, and the upregulation of TIMP-1 production is a unique action of nobiletin. Therefore, these results further support the notion that nobiletin is likely to be a candidate for characterization as a novel immunomodulatory and anti-inflammatory drug.

Animals↗