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Biomedical subjects

R Park

Publications and source records attributed to R Park.

At least 37 records · Page 2Linked to original sources
PubMed2000

Hwansodan protects PC12 cells against serum-deprivation-induced apoptosis via a mechanism involving Ras and mitogen-activated protein (MAP) kinase pathway.

Hwansodan has been used as a prescription for senile and vascular dementia in Oriental medicine. We investigated the neuroprotective effects of Hwansodan water extract on the apoptotic death of PC12 cells by serum deprivation. Hwansodan significantly rescued PC12 cells from apoptotic death by serum deprivation in a dose-dependent manner. The nuclear staining of PC12 cells clearly showed that Hwansodan attenuated nuclear condensation and fragmentation, which represents typical neuronal apoptotic characteristics. Hwansodan also prevents DNA fragmentation and caspase-3-like protease activation in serum-deprived PC12 cells and induces the tyrosine phosphorylation of proteins around 44 kDa, which was identified as ERK1 with electrophoretic gel mobility shift by Western blot. In addition, MEK inhibitor PD98059 and Ras inactivator, alpha-hydroxyfarnesylphosphonic acid and mevastatin, attenuated the neuroprotective effects of Hwansodan in serum-deprived PC12 cells. These results indicate that Ras/MEK/ERK signaling pathway plays a role in neuroprotective effects of Hwansodan in serum-deprived PC12 cells.

Animals↗
PubMed2000

The water extract of Samultang protects the lipopolysaccharide (LPS)/phorbol 12-myristate 13-acetate (PMA)-induced damage and nitric oxide production of C6 glial cells via down-regulation of NF-kappaB.

Samultang has been traditionally used for treatment of ischemic heart and brain diseases in oriental medicine. However, little is known about the mechanism by which Samultang rescues the myocardial and neuronal cells from ischemic damage. This study was designed to evaluate whether the water extract of Samultang may modulate the production of nitric oxide (NO) in LPS and PMA treated-C6 glial cells to protect the cells from NO-induced cytotoxicity. C6 glial cells treated with both LPS and PMA significantly produced a large amount of NO compared to untreated, PMA, or LPS-treated cells. In parallel with NO production, cotreatment of LPS and PMA induced the severe apoptotic death of C6 glial cells. However, Samultang significantly reduced both cell death and NO production by LPS/PMA in a dose-dependent manner. In addition, the modulatory effects of Samultang on LPS/PMA-induced cytotoxicity and NO production could be mimicked by exogenous treatments of N(G)MMA, a nitric oxide synthase (NOS) inhibitor, and pyrrolidine dithiocarbamate (PDTC), a strong NF-kappaB inhibitor. Treatment of C6-glial cells with LPS/PMA induced the transcriptional activation of NF-kappaB, which was markedly inhibited by Samultang. Taken together, we suggest that the protective effects of Samultang against LPS/PMA-induced cytotoxicity may be mediated by the suppression of NO synthesis via down-regulation of NF-kappaB activation.

Cell Survival↗
PubMed2000

Activation of caspase cascades in Korean mistletoe (Viscum album var. coloratum) lectin-II-induced apoptosis of human myeloleukemic U937 cells.

Mistletoe lectins are of high biological activity and exert cytotoxic effects. We have previously shown that Korean mistletoe, Viscum album var. coloratum, lectin-II specifically induces apoptotic cell death in cancer cells, not normal lymphocytes. The destructive mechanism by mistletoe lectins on tumor cells was mediated by activation of c-JUN N-terminal kinase (JNK)/stress-activated protein kinase. Herein, we investigated the involvement of caspase cascade and its proteolytic cleavage effects on biosubstrates of human myeloleukemic U937 cells by D-galactoside and N-acetyl-galactosamine-specific Korean mistletoe lectin-II. Mistletoe lectin-II induced ladder pattern DNA fragmentation and activation of caspase-3, -8, and -9 of U937 cells, but not caspase-1 protease, in a time- and dose-dependent manner. Consistent with catalytic activation of protease, both poly(ADP-ribose) polymerase (PARP) and protein kinase C-delta (PKC-delta) are also cleaved in mistletoe lectin-II-treated U937 cells. An inhibitor of caspase-3-like protease, DEVD-CHO peptide, significantly inhibited mistletoe lectin-II-induced apoptosis, PARP cleavage, and fragmentation of DNA. These results provide the evidence that Korean mistletoe lectin-II induces apoptotic death of U937 cells via activation of caspase cascades.

Adjuvants, Immunologic↗
PubMed2000

Cyclic adenosine monophosphate inhibits ursolic acid-induced apoptosis via activation of protein kinase A in human leukaemic HL-60 cells.

This study was designed to investigate the effect of cAMP on ursolic acid-induced apoptosis of HL-60 cells. Ursolic acid decreased the viability of the cells in a dose-dependent manner, which was revealed as an apototic process characterized by ladder-pattern DNA fragmentation in agarose gel electrophoresis and segmented nuclei in DAPI-sulpharhodamin 101 staining. Ursolic acid-induced apoptosis of the cells was markedly inhibited by the addition of cAMP-elevating agents including DB-cAMP, CPT-cAMP, 8-Br-cAMP and forskolin. These results were further evidenced by the fact that inhibitors of cAMP-dependent protein kinase including H89 and KT5720 completely inhibited the cAMP-mediated rescue of HL-60 cells from ursolic acid-induced apoptosis. In addition, differentiating agents of the cells such as dimethyl sulfoxide and retinoic acid did not affect the ursolic acid-induced apoptosis of HL-60 cells. These results suggest that signaling pathway of cAMP-dependent activation of protein kinase A may affect the responsiveness of tumor cells upon ursolic acid.

Antineoplastic Agents, Phytogenic↗
PubMed2000

The water extract of Jagamchotang protects the ischemia/reperfusion-induced cytotoxicity of rat neonatal myocardial cells via generation of nitric oxide.

Jagamchotang has been used for treatment of ischemic myocardial diseases in Chinese traditional medicine. However, little is known about the mechanism by which Jagamchotang rescues myocardial cells from ischemic damages. To elucidate the protective mechanisms, the effects of Jagamchotang on ischemia/reperfusion-induced cytotoxicity and generation of nitric oxide (NO) are investigated in primary neonatal myocardial cells. Ischemia/reperfusion itself induces severe myocardial cell death in vitro. However, treatment of the cells with Jagamchotang significantly reduces both ischemia/reperfusion-induced myocardial cell death and LDH release. In addition, pretreatment of Jagamchotang before reperfusion recovers the lose of beating rates after ischemia/reperfusion. For a while, the water extract of Jagamchotang stimulates myocardial cells in ischemic condition to produce nitric oxide (NO) in a dose dependent manner and it protects the damage of myocardial cells. Furthermore, the protective effects of the water extract of Jagamchotang is mimicked by treatment of sodium nitroprusside, an exogenous NO donor. NG-monomethyi-L-argine (NGMMA), a specific inhibitor of nitric oxide synthase (NOS), significantly blocks the protective effects of Jagamchotang on the cells after ischemia/reperfusion. Taken together, we suggest that the protective effects of Jagamchotang against ischemia/reperfusion-induced myocardial damages may be mediated by NO production during ischemic condition.

Animals↗
PubMed2000

LPS induces direct death of IFN-gamma primed murine embryonic hepatocyte, BNL CL2 cells in a TNF-alpha independent manner.

Although it has been well known that the role of LPS on liver damage is mediated through TNF-alpha, the mechanism by which LPS modulates the cytotoxicity of IFN-gamma on hepatocytes has not yet been clearly demonstrated. Here, we demonstrate that IFN-gamma mediated apoptosis in murine embryonic hepatocyte BNL CL2 cells is potentiated by the addition of LPS (0.5 microg/ml). Consistently, LPS markedly increases the catalytic activity of caspase 3-like protease but not caspase 1-like protease in IFN-gamma treated cells. In addition, TNF-alpha alone does not affect cell viability but rather it potentiates the cytotoxic effect of IFN-gamma on BNL CL2 cells. However, the cell viability of IFN-gamma/LPS treated cells is affected by the addition of polymyxin B but not by TNF binding protein I (TNF-BPI). These data suggest that the lipid moiety of LPS may mediate direct cytotoxicity of BNL CL2 cells in a TNF-alpha independent manner.

Animals↗
PubMed1999

The methanol extract of Spiraea prunifolia var. simpliciflora root inhibits the generation of nitric oxide and superoxide in RAW 264.7 cells.

It is well established that nitric oxide (NO) and superoxide radicals play pivotal roles in the pathogenesis of inflammatory diseases and fever. This study is undertaken to address whether the methanol extract of Spiraea prunifolia var. simpliciflora root, a traditional medicine as an antipyretic, modulates the generation of NO and superoxide in IFN-gamma primed or polymyristic acetate (PMA) stimulated RAW 264.7 cells, respectively. The generation of NO as well as the expression of inducible nitric oxide synthase (iNOS) protein from IFN-gamma primed RAW 264.7 cells is markedly decreased by the methanol extract in a dose dependent manner. However, the methanol extract does not affect the viability of RAW 264.7 cells, as assessed by methylthiazol-2-yl-2,5-diphenyl tetrazolium bromide (MTT) assay. In addition, the methanol extract suppresses the generation of superoxide in PMA-stimulated RAW 264.7 cells in a dose and a time dependent manner. Taken together, anti-pyretic effects of Spiraea prunifolia var. simpliciflora root extract could result from direct suppression of NO and decreased superoxide generation.

Analgesics, Non-Narcotic↗
PubMed1999

Enhancement of nitric oxide synthesis by the aqueous extract of Spiraea prunifolia var. simpliciflora's root in RAW 264.7 cells.

The effects of aqueous extract of Spiraea prunifolia var. simpliciflora's root, a traditional medicine for the treatment of malaria in Chinese medicine, on the generation of nitric oxide (NO) are investigated in RAW 264.7 cells. NO generation from IFN-gamma primed RAW 264.7 cells is markedly increased by the addition of aqueous extract in a dose-dependent manner. The enhancement of NO generation by the aqueous extract is accompanied by a significantly increased expression of inducible nitric oxide synthase (iNOS). However, the aqueous extract of Spiraea prunifolia var. simpliciflora's root does not affect the viability of RAW 264.7 cells, as assessed by MTT assay. Polymyxin B does not inhibit NO generation by the aqueous extract in IFN-gamma primed RAW 264.7 cells. However, polymyxin B significantly decreases NO generation by lipopolysaccharide (LPS) in IFN-gamma primed RAW 264.7 cells. These data indicate that the signaling pathway of the aqueous extract-induced NO generation is not dependent on PKC. These results strongly support the mechanism by which the aqueous extract may exert anti-malarial effect via direct cytotoxicity of NO as well as NO-mediated modulation of immune functions.

Animals↗
PubMed1998

Association of Shc, Cbl, Grb2, and Sos following treatment with 2,3,7,8-tetrachlorodibenzo-p-dioxin in primary rat hepatocytes.

c-Src kinases and p21 Ras are known to be implicated in 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-mediated signal transduction. However, the effects of TCDD on the molecular interaction of adaptor complex in the protein tyrosine kinase signaling cascade have not been reported. The present study is designed to clarify whether TCDD modulates the molecular interactions of Shc, Cbl, Grb2, and Sos in primary rat hepatocytes. TCDD causes an electrophoretic mobility shift of Sos and increases Sos/Grb2 association. Tyrosine phosphorylated Shc, mainly p52, unloads to the Grb2/Sos complex upon TCDD stimulation. Interestingly, TCDD decreases the tyrosine phosphorylation level of Cbl, although Cbl recruits more Grb2 and Shc proteins by TCDD. These results indicate that TCDD modulates the molecular interaction of adaptor complex proteins including Shc, Grb2, Sos, and Cbl. Furthermore, tyrosine phosphorylation of Cbl may not be critical for interaction of the protein with Grb2 and Shc in the TCDD signaling pathway in primary rat hepatocytes.

Adaptor Proteins, Signal Transducing↗
PubMed1998

Antiviral activities of methylated nordihydroguaiaretic acids. 2. Targeting herpes simplex virus replication by the mutation insensitive transcription inhibitor tetra-O-methyl-NDGA.

We had previously reported that tetramethyl-O-NGDA (M4N), a synthetic derivative of the naturally occurring nordihydroguaiaretic acid (NDGA), is able to inhibit HIV Tat transactivation by blocking host Sp1 protein at the Sp1 cognate binding site on the HIV LTR promoter. The present studies were undertaken to examine whether M4N is able to inhibit the replication of herpes simplex virus (HSV), another Sp1-regulated virus. The results showed that in Vero cells, M4N inhibits at micromolar levels (IC50 = 43.5 microM) the expression of the herpes immediate early gene (alpha-ICP4), which is essential for HSV replication. An electrophoretic mobility shift assay, examining Sp1 binding to the alpha-ICP4 promoter, showed a significant inhibition of the control bands: 88% inhibition of the fast moving band (FMB) and 45% of the slow moving band (SMB), at 100 microM of drug concentration. Comparative studies between M4N and acycloguanosine (acyclovir, ACV) in cultured Vero cells revealed an interesting pattern in the drug sensitivity (IC50) and cytotoxicity (TC50) parameters. For M4N, the IC50 varied between 11.7 and 4 microM in 10 passages of HSV-1 and 4 passages of HSV-2 with no indication for a requirement of higher drug concentration. In contrast, for acyclovir, the IC50 increased from 7 microM in the first passage to 444 microM in the tenth passage of HSV-1, and >88 microM for the fourth passage of HSV-2, indicating a rapid build-up of drug resistance against acyclovir. While the selective index (SI), defined as the ratio: TC50/IC50, remained relatively constant for M4N; it dropped 60-fold for acyclovir in the endpoints of viral passages. Drug sensitivity for M4N toward the acyclovir-sensitive strain (sm44) and the acyclovir-resistant strain (ACV-10) of HSV-1 was similar, indicating no cross-resistance between M4N and acyclovir in their anti-HSV effects. These results may have an important clinical relevance since HSV has been shown to be a factor for spreading of HIV.

Acyclovir↗
PubMed1997

Audit of a pre-employment risk identification form.

A risk identification form was introduced as part of Southmead Health Services NHS Trust's pre-employment procedure. Its purpose was to allow occupational health nurses to identify employees with specific occupational health needs. One hundred employees' risk identification forms were studied and a comparison made between the manager's assessment and that of an independent occupational health nurse's assessment based on job title alone. The actual risks involved in the post were identified by the employee after 1 month employment, together with an occupational health nurse from Southmead NHS Trust. There was a greater agreement between the managers' assessments and the actual risks identified (range 83-100%), than between the independent nurse's assessments and the actual risks identified (range 59-100%), in all categories other than driving. The sensitivity of the managers' risk assessments were higher than that of the independent nurse in all categories and the positive predictive value of the managers' risk assessments were higher than that of the independent nurse in all but two categories.

England↗
PubMed1996

Neuronal isoform of nitric oxide synthase is expressed at low levels in human retina.

1. The expression of neuronal isoform of nitric oxide synthase (nNOS) was studied in human retinal tissues. The cDNA sequence was cloned in human retinal poly (A)+ RNA by the RT-PCR method and encompassed an open-reading frame of 4,302 bp encoding 1,434 amino acids. This sequence showed a possibility of genetic polymorphism in comparison to human brain form. 2. Restriction fragment length polymorphism (RFLP) patterns of a partial cDNA fragment suggest that there is genetic polymorphism in the neuronal form of NOS. Important differences were observed in a certain region between human retinal and brain froms. This region is a result of frame shift by the addition of three cytidines. In this study, regions from human brain (cerebellum) and skeletal muscle as well as retina were sequenced to confirm the difference in this region. The sequences from these tissues were completely identical. This indicated that genetic polymorphism of nNOS gene was due to single base substitution and not frame shift phenomenon by addition or deletion of bases. 3. The nNOS mRNA of approximately 12 kb was detected by northern blot analysis. The lower level of the expression was distinguished in comparison to those of human brain and skeletal muscle. The cDNA transiently transfected into CHO-K1 cells expressed a protein which contained a significant level of NOS activity. The size of the nNOS was found to be approximately 160 kDa by both in vitro and in vivo translation systems. This NOS was calcium dependent and the K(m) for arginine was 4.4 microM. 4. The Ca+2, L-arginine and NADPH dependency along with the inhibitory effect of N-nitro-L-arginine on NOS activity were evaluated. The finding of a constitutive from of NOS in human retina, which is calcium-NADPH dependent, gives further credence to the possible role of nitric oxide in retinal function and neuronal diseases.

Adolescent↗
PubMed1996

Constitutive expression and structural diversity of inducible isoform of nitric oxide synthase in human tissues.

Nitric oxide (NO) produced by inducible nitric oxide synthase (iNOS) plays a major role in immune responses to bacteria and tumors, and the gene is induced by endotoxin and cytokines. However, we have detected iNOS cDNA sequences expressed constitutively at low level from human retinal, cerebellar and skeletal muscle tissues using northern-blot and RT-PCR analyses. In northern-blot analysis, two types (4.5 kb and 4.2 kb) of iNOS mRNA have been observed in retinal tissue, whereas only one type of mRNA was observed in cerebellum (4.5 kb) and skeletal muscle (4.2 kb). This result indicates that the presence of differential expression and/or structural diversity of the iNOS gene in various tissues, and some cells can express iNOS gene constitutively. We have also demonstrated a structural diversity formed by alternative splicing in the open reading frame sequence of the iNOS cDNA cloned from retinal tissue, which may reflect functional differences of iNOS gene.

Amino Acid Sequence↗
PubMed1996

Ifosfamide treatment of recurrent or metastatic endometrial stromal sarcomas previously unexposed to chemotherapy: a study of the Gynecologic Oncology Group.

OBJECTIVE: To determine the effectiveness and toxicity of ifosfamide chemotherapy in women with metastatic or recurrent endometrial stromal sarcomas unexposed to other chemotherapy. METHODS: In a prospective, multi-institutional phase II study conducted by the Gynecology Oncology Group, the starting dose of ifosfamide was 1.5 g/m2 given daily intravenously (i.v.) for 5 days (reduced to 1.2 g/m2 daily in patients who had previously received radiotherapy). Mesna (2 mercaptoethane sodium sulfonate) was given i.v. immediately and at 4 and 8 hours after the administration of ifosfamide. Each dose of mesna was 20% of the total daily dose of ifosfamide. Patients were treated every 3 weeks if blood counts permitted. Therapy was discontinued if there was progression of the cancer or unacceptable toxicity. RESULTS: Twenty-two patients were entered into this study. One was excluded from analysis because of the wrong histologic type, leaving 21 evaluable for response and toxicity. Gynecologic Oncology Group grade 3 or 4 granulocytopenia occurred in four patients (19%), and one patient each experienced Gynecologic Oncology Group grade 4 anemia and genitourinary toxicity. Three patients experienced complete tumor responses and four had partial responses, for an overall response rate of 33.3%. CONCLUSION: Ifosfamide is active in the therapy of women with chemotherapy-naive metastatic or recurrent endometrial stromal sarcomas.

Antineoplastic Agents, Alkylating↗
PubMed1995

Percutaneous balloon aortic valvuloplasty in high-risk elderly patients.

From 1987 to mid-1994 we performed 16 percutaneous balloon aortic valvuloplasties. All patients (mean age 80 years; 53% female, 47% male) had significant congestive heart failure from aortic valve stenosis; the majority were categorized as New York Heart Association Class IV (shortness of breath at rest). Twelve patients were not surgical candidates; four patients refused surgery. After valvuloplasty, all patients became asymptomatic (NYHA Class I & II), the average preprocedure valvular gradient of 59 mm Hg decreased to 31 mm Hg, and valve area increased from 0.8 cm2 (0.3 cm2-0.98 cm2) to 1.3 cm2 (0.6 cm2-1.44 cm2). The only complications were two minor groin hematomas (2 patients). Within 6 months, 50% of the patients were symptomatic again; the overall survival rate was 23 months. We conclude that in the proper environment this procedure can be effective and safe--even in high-risk elderly patients. Although symptom improvement is transient, valvuloplasty provides a valuable opportunity to treat intercurrent medical conditions and possibly follow up with surgery.

Age Factors↗
PubMed1995

Developing intervention/prevention strategies for individuals at high risk of developing hereditary ovarian cancer.

In 1994, an estimated 24,000 new cases of ovarian cancer will be diagnosed in the United States. Most of these patients will have disease spread beyond the ovary at the time of diagnosis; despite tumor debulking and aggressive platinum-based chemotherapy, their long-term prognosis is poor. In view of the advanced stage of disease at the time of diagnosis and the poor results of conventional therapy, advances in early detection and/or prevention are desperately needed. The recent recognition that a family history of the disease is perhaps the strongest risk factor for the development of ovarian cancer offers a unique opportunity to identify women at high risk for ovarian cancer and to develop effective screening methods and prevention/intervention strategies for these high-risk women. The results of the breakout session "Developing Strategies for Intervention/Prevention Trials for Individuals at Risk of Hereditary Ovarian Cancer" are summarized here. The majority of the discussion in this session focused on three major issues: 1) identification of moderate- and high-risk individuals who would potentially benefit from screening, prevention, and intervention efforts; 2) assessment of the effectiveness of current screening modalities and the usefulness of current intervention/prevention strategies; and 3) recommendations for clinical trial design.

Clinical Trials as Topic↗
PubMed1994

A dominant Stargardt's macular dystrophy locus maps to chromosome 13q34.

OBJECTIVE: To identify the chromosomal location of a mutated gene that causes an autosomal dominant Stargardt's macular dystrophy. METHODS: Ocular examinations were performed on 67 members of a large kindred to identify those with macular dystrophy. DNA analyses defined the genotype of all family members at 49 polymorphic loci. Linkage between the gene defect responsible for this macular dystrophy and each polymorphic locus was assessed by lodscore calculations. RESULTS: Diminished visual acuity and funduscopic abnormalities were found in 29 family members, which was diagnostic of macular dystrophy. Genetic analyses demonstrated that polymorphic loci from chromosome 13 band q34 were linked to the gene defect in this family. Haplotype analyses localized the disease locus to an 8-centimorgan interval between loci D13S159 and D13S158/D13S174. CONCLUSION: A disease locus responsible for an autosomal dominant Stargardt's macular dystrophy is located on chromosome 13 band q34. Identification of the mutated gene at this locus will lead to a better understanding of macular degeneration.

Adolescent↗