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Biomedical subjects

S Kang

Publications and source records attributed to S Kang.

At least 73 records · Page 4Linked to original sources
PubMed2000

Cholesterol and hepatic lipoprotein assembly and secretion.

The assembly and secretion of apo B100 containing lipoproteins (i.e., VLDL) by the liver and cholesterol metabolism are interrelated on several different levels and for several different physiologic reasons. Firstly, hepatic VLDL is the major precursor for LDL, which in the human is the major vehicle responsible for transporting cholesterol to peripheral tissues. Secondly, cholesterol is supplied to many tissues by a specific uptake of LDL via LDL receptor, which is expressed in a regulated manner by most mammalian tissues. Thirdly, the rate of hepatic cholesterol biosynthesis and metabolism to bile acids correlates with production of VLDL. This apparent coordinate expression of cholesterol biosynthetic/catabolic enzymes and hepatic VLDL assembly/secretion are mediated at least in part through the sterol response element binding protein (SREBP) transcription factor family. Their gene targets include a plethora of enzymes that regulate glycolysis, energy production, lipogenesis and cholesterol catabolism. Studies of hepatoma cells overexpressing CYP7A1, the rate-limiting enzyme controlling bile acid synthesis, show that as a result of increased mature SREBP1, there is a coordinate induction of lipogenesis and the assembly and secretion of VLDL. These and additional studies show that the bile acid synthetic pathway and the VLDL assembly/secretion pathway are coordinately linked through SREBP-dependent transcription. Based on studies showing that within the liver acinus, the expression of CYP7A1 is mainly in the pericentral region while HMG-CoA reductase is mainly periportal, we propose that a 'metabolic zonal segregation' plays an important role in coordinate regulation of cholesterol and VLDL metabolism. This putative 'metabolic zonal segregation' may provide segregation of metabolic functions which may be mutually antagonistic. For example, there may be physiologic states in which the bile acid synthetic pathway may compete with the VLDL assembly/secretion pathway for a limited amount of cholesterol. Metabolic antagonism (e.g., competition for cholesterol) may be avoided via inducing SREBP-mediated transcription. Adaptation of catabolic hepatocytes to accommodate the expression of VLDL assembly/secretion may occur in response to activation of SREBP-mediated transcription. Support for these is discussed.

Animals↗
PubMed2000

Phospholipase Cdelta1 is a guanine nucleotide exchanging factor for transglutaminase II (Galpha h) and promotes alpha 1B-adrenoreceptor-mediated GTP binding and intracellular calcium release.

Effectors involved in G protein-coupled receptor signaling modulate activity of GTPases through GTPase-activating protein or guanine nucleotide exchanging factor (GEF). Phospholipase Cdelta1 (PLCdelta1) is an effector in tissue transglutaminase (TGII)-mediated alpha1B-adrenoreceptor (alpha(1B)AR) signaling. We investigated whether PLCdelta1 modulates TGII activity. PLCdelta1 stimulated GDP release from TGII in a concentration-dependent manner, resulting in an increase in GTPgammaS binding to TGII. PLCdelta1 also inhibited GTP hydrolysis by TGII that was independent from the alpha(1B)AR. These results indicate that PLCdelta1 is GEF for TGII and stabilizes the GTP.TGII complex. When GEF function of PLCdelta1 was compared with that of the alpha(1B)AR, the alpha(1B)AR-mediated GTPgammaS binding to TGII was greater than PLCdelta1-mediated binding and was accelerated in the presence of PLCdelta1. Thus, the alpha(1B)AR is the prime GEF for TGII, and GEF activity of PLCdelta1 promotes coupling efficacy of this signaling system. Overexpression of TGII and its mutants with and without PLCdelta1 resulted in an increase in alpha(1B)AR-stimulated Ca2+ release from intracellular stores in a TGII-specific manner. We conclude that PLCdelta1 assists the alpha(1B)AR function through its GEF action and is primarily activated by the coupling of TGII to the cognate receptors.

Calcium Signaling↗
PubMed2000

PCD1, a novel gene containing PDZ and LIM domains, is overexpressed in several human cancers.

In an effort to discover novel genes differentially expressed in human pancreatic cancer, we have identified a gene named PCD1 (pancreatic cancer derived) that is up-regulated in pancreatic dysplasia and cancer relative to normal pancreatic ductal epithelium. We cloned the full length (4572 bp) of this gene, which encodes a novel protein of 1064 amino acids containing a PDZ domain and a LIM domain. An alternatively spliced form with a deletion of 30 bp in the coding region was also found. In situ hybridization results showed that PCD1 is highly expressed in a significant percentage of colon, breast, liver, lung, pancreas, stomach, and prostate tumor tissues but is expressed in very few normal tissues. Northern blot hybridization confirmed the overexpression of PCD1 in colon and breast tumor tissues and also showed strong expression of PCD1 in the heart as well as in HeLa cells. Real-time quantitative reverse transcription-PCR verified the overexpression of PCD1 in primary colon tumors or in liver metastases relative to normal colon tissues in five of eight patients. The PCD1 gene maps to human chromosome 13q21.33. Because of its high levels of expression in neoplastic tissues and the presence of both PDZ and LIM domains, we suggest that PCD1 may play an important role in cytoskeletal reorganization during carcinogenesis.

Amino Acid Sequence↗
PubMed2000

Blockade of T lymphocyte costimulation with cytotoxic T lymphocyte-associated antigen 4-immunoglobulin (CTLA4Ig) reverses the cellular pathology of psoriatic plaques, including the activation of keratinocytes, dendritic cells, and endothelial cells.

Efficient T cell activation is dependent on the intimate contact between antigen-presenting cells (APCs) and T cells. The engagement of the B7 family of molecules on APCs with CD28 and CD152 (cytotoxic T lymphocyte-associated antigen 4 [CTLA-4]) receptors on T cells delivers costimulatory signal(s) important in T cell activation. We investigated the dependence of pathologic cellular activation in psoriatic plaques on B7-mediated T cell costimulation. Patients with psoriasis vulgaris received four intravenous infusions of the soluble chimeric protein CTLA4Ig (BMS-188667) in a 26-wk, phase I, open label dose escalation study. Clinical improvement was associated with reduced cellular activation of lesional T cells, keratinocytes, dendritic cells (DCs), and vascular endothelium. Expression of CD40, CD54, and major histocompatibility complex (MHC) class II HLA-DR antigens by lesional keratinocytes was markedly reduced in serial biopsy specimens. Concurrent reductions in B7-1 (CD80), B7-2 (CD86), CD40, MHC class II, CD83, DC-lysosomal-associated membrane glycoprotein (DC-LAMP), and CD11c expression were detected on lesional DCs, which also decreased in number within lesional biopsies. Skin explant experiments suggested that these alterations in activated or mature DCs were not the result of direct toxicity of CTLA4Ig for DCs. Decreased lesional vascular ectasia and tortuosity were also observed and were accompanied by reduced presence of E-selectin, P-selectin, and CD54 on vascular endothelium. This study highlights the critical and proximal role of T cell activation through the B7-CD28/CD152 costimulatory pathway in maintaining the pathology of psoriasis, including the newly recognized accumulation of mature DCs in the epidermis.

Abatacept↗
PubMed2000

Modified partial hyperfractionation in radiotherapy for bulky uterine cervical cancer: reduction of overall treatment time.

PURPOSE: The purpose of this study was to assess the feasibility and toxicity of modified fractionation of external beam radiation with the intention of reducing the overall treatment time (OT) by 1 week in cervical cancer. METHODS AND MATERIALS: Thirty-one patients (Group 1, n = 31) with bulky cervical cancer (>/= 4 cm with Stage II and III, >/= 5 cm with Stage IB2) were entered into the twice a day (b.i. d.) protocol (18 Gy/10 fx in 2 weeks followed by 18 Gy/12 fx, b.i.d. in 6 days, then midline block at 36 Gy with 45 Gy to the whole pelvis and 51-59 Gy to the parametrium). These patients underwent high-dose-rate brachytherapy with 4 Gy/fx x 7 to point A, biweekly. During the same period, patients with non-bulky tumors (Group 2, n = 31) received conventional treatment and similar brachytherapy. RESULTS: The OT of Group 1 was 7 weeks or less in 61.3%, 7.1-8 weeks in 29%, and more than 8 weeks in 9.7% (19.4%, 51.6%, and 29% in Group 2, respectively, p = 0.003). Incidences of acute complications and treatment breaks were similar in both groups. Late complication (rectal bleeding) occurred only in Group 1 (13%, 4/31), but was self-limited. Locoregional failures occurred within 2 years after completion of radiation therapy in both groups (16% and 13% in Group 1 and 2, respectively, with minimum and median follow-ups of 2 years and 34 months). CONCLUSION: Partial hyperfractionation on the third week of radiation permitted patients to finish their treatment with shorter OT without excessive acute complications and with acceptable grade 2 late rectal bleeding complications. This treatment scheme may be an effective method for the improvement of local control of bulky cervical cancer.

Adult↗
PubMed2000

Intracellular modulation of NMDA receptor function by antipsychotic drugs.

The present study deals with the functional interaction of antipsychotic drugs and NMDA receptors. We show that both the conventional antipsychotic drug haloperidol and the atypical antipsychotic drug clozapine mediate gene expression via intracellular regulation of NMDA receptors, albeit to different extents. Data obtained in primary striatal culture demonstrate that the intraneuronal signal transduction pathway activated by haloperidol, the cAMP pathway, leads to phosphorylation of the NR1 subtype of the NMDA receptor at (897)Ser. Haloperidol treatment is likewise shown to increase (897)Ser-NR1 phosphorylation in rats in vivo. Mutation of (896)Ser and (897)Ser to alanine, which prevents phosphorylation at both sites, inhibits cAMP-mediated gene expression. We conclude that antipsychotic drugs have the ability to modulate NMDA receptor function by an intraneuronal signal transduction mechanism. This facilitation of NMDA activity is necessary for antipsychotic drug-mediated gene expression and may contribute to the therapeutic benefits as well as side effects of antipsychotic drug treatment.

Animals↗
PubMed2000

4-1BB: still in the midst of darkness.

4-1BB is a member of the tumor necrosis factor receptor superfamily. The receptor functions mainly as a costimulatory molecule in T lymphocytes. In addition, several lines of evidence have shown that interactions between 4-1BB and its ligand are involved in the antigen presentation process and the generation of cytotoxic T cells. Recent studies, however, have demonstrated that 4-1BB plays more diverse roles: Signals through 4-1BB are important for long-term survival of CD8+ T cells and the induction of helper T cell anergy. Clinically, there is great interest in 4-1BB, because T-cell activation induced by anti-4-1BB monoclonal antibodies is highly efficient in the eradication of established tumor cells in mice. Now, since mice deficient in 4-1BB or the 4-1BB ligand are available, subtle roles played by 4-1BB may be revealed in the near future.

4-1BB Ligand↗
PubMed2000

Tumor necrosis factor genetic polymorphisms correlate with infections after renal transplantation.

BACKGROUND: Nonimmunosuppressed individuals possessing a NcoI restriction enzyme site in the tumor necrosis factor (TNF) gene locus produce less TNF-alpha in vitro and in vivo than do individuals lacking this site. We have previously shown that this NcoI+/low TNF-alpha genotype is independently associated with increased rates of infection for liver transplant recipients. METHODS: In this study, we performed polymerase chain reaction amplification and restriction fragment length polymorphism analysis of the TNF locus from 45 renal transplant recipients to determine whether the presence of the NcoI site is associated with the frequency of rejection, infection, time to rejection or infection, and patient or graft survival. RESULTS: Twenty-six recipients were typed with the NcoI+/low TNF-alpha genotype, whereas 19 recipients had the NcoI-/high TNF-alpha genotype. Age, sex, donor type, secondary immunosuppression, use of anti-lymphocyte preparations, graft ischemia time, and year of transplant were evenly distributed in the two groups. There was no difference between the genotype groups in the rate of, or time to, rejection. In contrast, significantly more patients with the NcoI+/low TNF-alpha site developed infections (46% vs. 10% P=0.01). In bivari able models, each controlling for donor type, ischemia time, recipient age, use of antilymphocyte agents, and secondary immunosuppression, the NcoI+/low TNF-alpha genotype was still independently associated with increased numbers of infections (relative risk, 5.38; confidence interval, 1.20-23.8). Conclusion. We conclude that in individuals genetically predetermined to be low TNF-alpha producers, the additional inhibition of TNF-alpha production by routine immunosuppression may be excessive, rendering these individuals less able to respond to infectious stimuli. These patients may benefit from lower doses or withdrawal of corticosteroids, which are known inhibitors of TNF-alpha transcription.

Adult↗
PubMed2000

Efficacy of lumbo-peritoneal versus ventriculo-peritoneal shunting for management of chronic hydrocephalus following aneurysmal subarachnoid haemorrhage.

BACKGROUND: The clinical usefulness of lumboperitoneal (LP) shunts in selecting patients with communicating hydrocephalus after aneurysmal subarachnoid haemorrhage (SAH) was compared with that of ventriculoperitoneal (VP) shunts. METHOD: Chronic hydrocephalus was defined as clinically and radiographically demonstrated hydrocephalus which lasted 3 weeks or longer after the original haemorrhage and which required shunting. Indications for a CSF shunt were assessed on the basis of neurological symptoms and signs, CT findings, and isotope cisternogram findings. The patients were treated with either LP or VP shunts. A significant response to shunting was defined as an improvement of function to a higher grade. The functioning of the shunt was evaluated by the location of the catheter on x-ray studies, CT features, and isotope cisternograms. The operation groups were checked for comparability of demographic and clinical variables including age, Fisher grade, hypertension, vasospasm, shunt interval, preshunt functional grade, and CT findings. A comparative analysis of the outcome was carried out between the two operation groups. FINDINGS: Fifty-six patients underwent shunt placements (LP shunts: 22, VP shunts with medium pressure valve: 2, VP shunts with high pressure valve: 32). There was no statistically significant difference in patient demographics and clinical characteristics between the patients with LP shunts and those with VP shunts. A follow-up time of 3 months to 8 years revealed clinical improvement in 11 cases (50.0%) of patients with LP shunts and 31 cases (91.1%) in VP shunts was seen (Fisher's exact test, P<0.005). INTERPRETATION: These findings suggest that VP shunts are a better choice of treatment than LP shunts in treating chronic hydrocephalus after aneurysmal SAH.

Adult↗
PubMed2000

Effects of administration of a single dose of a humanized monoclonal antibody to CD11a on the immunobiology and clinical activity of psoriasis.

BACKGROUND: CD11a/CD18 comprise subunits of leukocyte function associated antigen (LFA-1), a T-cell surface molecule important in T-cell activation, T-cell emigration into skin, and cytotoxic T-cell function. OBJECTIVE: We explored the immunobiologic and clinical effects of treating moderate to severe psoriasis vulgaris with a single dose of humanized monoclonal antibody against CD11a (hu1124). METHODS: This was an open label study with a single dose of hu1124 at doses of 0.03 to 10 mg/kg. Clinical (Psoriasis Area and Severity Index [PASI]) and immunohistologic parameters (epidermal thickness, epidermal and dermal T-cell numbers, and keratinocyte intercellular adhesion molecule 1 [ICAM-1] expression) were followed. RESULTS: Treatment with hu1124, at doses higher than 1.0 mg/kg (group III), completely blocks CD11a staining for at least 14 days in both blood and psoriatic plaques. At 0.3 to 1.0 mg/kg, T-cell CD11a staining was completely blocked; however, blockade lasted less than 2 weeks (group II). Only partial saturation of either blood or plaque cellular CD11a was observed at doses of hu1124 between 0.01 and 0.1 mg/kg (group I). This pharmacodynamic response was accompanied by decreased numbers of epidermal and dermal CD3(+) T cells, decreased keratinocyte and blood vessel expression of ICAM-1, and epidermal thinning. Statistically significant drops in PASI compared with baseline were observed in group II patients at weeks 3 and 4 and in group III patients at weeks 2 through 10. No significant drop in PASI score was observed in group 1. Adverse events were mild at doses of 0.3 mg/kg or less and included mild chills, abdominal discomfort, headache, and fever. At a single dose of 0.6 mg/kg or higher, headache was the most common dose-limiting toxicity observed. CONCLUSION: Targeting CD11a may improve psoriasis by inhibiting T-cell activation, T-cell emigration into the skin, and cytotoxic T-cell function.

Antibodies, Monoclonal↗
PubMed2000

Relationship between the tertiary structures of mastoparan B and its analogs and their lytic activities studied by NMR spectroscopy.

Mastoparan B (MP-B), an antimicrobial cationic tetradecapeptide amide isolated from the venom of the hornet Vespa basalis, is an amphiphilic alpha-helical peptide. MP-B possesses a variety of biological activities, such as mast cells degradation histamine release, erythrocyte lysis and inhibition of the growth of gram-positive and gram-negative bacteria. In order to study the relationship between the structure and the biological activity of MP-B, we used four analogs by replacing amino acids with alanine. Tertiary structures of MP-B and its analogs in 2,2,2-trifluoroethanol (TFE)-containing aqueous solution have been determined by NMR spectroscopy and molecular modeling. The results indicate that [Ala4]MP-B and [Ala12]MP-B with higher hydrophobicity adopt a higher content of amphiphilic helical structures, and have better antimicrobial and hemolytic activities than MP-B. However, [Ala3]MP-B and [Ala9]MP-B with lower hydrophobicity have disordered structures. [Ala3]MP-B and [Ala9]MP-B have low antimicrobial activity and much less hemolytic activity relative to MP-B. It is likely that tryptophan residue in MP-B and appropriate hydrophobicity of MP-B to induce alpha-helical structure is essential for the antibacterial and hemolytic activity of MP-B. This study can aid understanding of the structure-activity relationship of MP-B and to design peptides to possess lytic activity.

Alanine↗
PubMed2000

Decreased extracellular-signal-regulated kinase and increased stress-activated MAP kinase activities in aged human skin in vivo.

The ability of human skin to rejuvenate itself diminishes with the passage of time, resulting in increased fragility. This increased fragility reflects both reduced growth of skin cells and loss of collagenous connective tissue. Oxidative damage plays a central role in cellular aging. Cellular responses to growth signals and oxidative stress are mediated, in part, by growth-factor-activated and stress-activated MAP kinases. We report here that the extracellular-signal-regulated MAP kinase pathway is reduced and the stress-activated MAP kinase pathway is increased in old, compared with young, human skin in vivo. Extracellular-signal-regulated kinase activity was 45% lower in old skin (mean age 84.3 y) relative to young skin (mean age 23.8 y). This lower extracellular- signal-regulated kinase activity resulted from reduced activation, since total extracellular-signal-regulated kinase protein levels did not differ between young and old skin, whereas phosphorylated (i.e., activated) extracellular-signal-regulated kinase protein was reduced 60% in old skin. Cyclin D2, which is regulated by extracellular-signal-regulated kinase and functions to promote cell cycle progression, was reduced 50% in old skin compared with young skin. In contrast, stress-activated MAP kinase activity was elevated 3.4-fold in old skin compared with young skin. This increased activity resulted from enhanced activation, since total stress-activated MAP kinase protein levels were similar in old and young skin. Transcription factor c-Jun, which is activated by stress-activated MAP kinases and promotes expression of connective-tissue-degrading matrix metalloproteinases, was elevated 2-fold in old skin compared with young skin. Treatment of old skin with vitamin A (retinol) for 7 d stimulated extracellular-signal-regulated kinase activity, consistent with its demonstrated ability to stimulate cell growth in old human skin. Taken together, these data indicate that alterations in MAP kinase activities play a key role in the pathophysiology of human skin aging.

Adolescent↗
PubMed2000

Vitamin A antagonizes decreased cell growth and elevated collagen-degrading matrix metalloproteinases and stimulates collagen accumulation in naturally aged human skin.

Damage to human skin due to ultraviolet light from the sun (photoaging) and damage occurring as a consequence of the passage of time (chronologic or natural aging) are considered to be distinct entities. Photoaging is caused in part by damage to skin connective tissue by increased elaboration of collagen-degrading matrix metalloproteinases, and by reduced collagen synthesis. As matrix metalloproteinase levels are known to rise in fibroblasts as a function of age, and as oxidant stress is believed to underlie changes associated with both photoaging and natural aging, we determined whether natural skin aging, like photoaging, gives rise to increased matrix metalloproteinases and reduced collagen synthesis. In addition, we determined whether topical vitamin A (retinol) could stimulate new collagen deposition in sun-protected aged skin, as it does in photoaged skin. Sun-protected skin samples were obtained from 72 individuals in four age groups: 18-29 y, 30-59 y, 60-79 y, and 80+ y. Histologic and cellular markers of connective tissue abnormalities were significantly elevated in the 60-79 y and 80+ y groups, compared with the two younger age groups. Increased matrix metalloproteinase levels and decreased collagen synthesis/expression were associated with this connective tissue damage. In a separate group of 53 individuals (80+ y of age), topical application of 1% vitamin A for 7 d increased fibroblast growth and collagen synthesis, and concomitantly reduced the levels of matrix-degrading matrix metalloproteinases. Our findings indicate that naturally aged, sun-protected skin and photoaged skin share important molecular features including connective tissue damage, elevated matrix metalloproteinase levels, and reduced collagen production. In addition, vitamin A treatment reduces matrix metalloproteinase expression and stimulates collagen synthesis in naturally aged, sun-protected skin, as it does in photoaged skin.

Adolescent↗
PubMed2000

Down-regulation of cell surface receptors is modulated by polar residues within the transmembrane domain.

How recycling receptors are segregated from down-regulated receptors in the endosome is unknown. In previous studies, we demonstrated that substitutions in the transferrin receptor (TR) transmembrane domain (TM) convert the protein from an efficiently recycling receptor to one that is rapidly down regulated. In this study, we demonstrate that the "signal" within the TM necessary and sufficient for down-regulation is Thr(11)Gln(17)Thr(19) (numbering in TM). Transplantation of these polar residues into the wild-type TR promotes receptor down-regulation that can be demonstrated by changes in protein half-life and in receptor recycling. Surprisingly, this modification dramatically increases the TR internalization rate as well ( approximately 79% increase). Sucrose gradient centrifugation and cross-linking studies reveal that propensity of the receptors to self-associate correlates with down-regulation. Interestingly, a number of cell surface proteins that contain TM polar residues are known to be efficiently down-regulated, whereas recycling receptors for low-density lipoprotein and transferrin conspicuously lack these residues. Our data, therefore, suggest a simple model in which specific residues within the TM sequences dramatically influence the fate of membrane proteins after endocytosis, providing an alternative signal for down-regulation of receptor complexes to the well-characterized cytoplasmic tail targeting signals.

Amino Acid Sequence↗
PubMed2000

Structural and functional dissection of human cytomegalovirus US3 in binding major histocompatibility complex class I molecules.

The human cytomegalovirus US3, an endoplasmic reticulum (ER)-resident transmembrane glycoprotein, forms a complex with major histocompatibility complex (MHC) class I molecules and retains them in the ER, thereby preventing cytolysis by cytotoxic T lymphocytes. To identify which parts of US3 confine the protein to the ER and which parts are responsible for the association with MHC class I molecules, we constructed truncated mutant and chimeric forms in which US3 domains were exchanged with corresponding domains of CD4 and analyzed them for their intracellular localization and the ability to associate with MHC class I molecules. All of the truncated mutant and chimeric proteins containing the luminal domain of US3 were retained in the ER, while replacement of the US3 luminal domain with that of CD4 led to cell surface expression of the chimera. Thus, the luminal domain of US3 was sufficient for ER retention. Immunolocalization of the US3 glycoprotein after nocodazole treatment and the observation that the carbohydrate moiety of the US3 glycoprotein was not modified by Golgi enzymes indicated that the ER localization of US3 involved true retention, without recycling through the Golgi. Unlike the ER retention signal, the ability to associate with MHC class I molecules required the transmembrane domain in addition to the luminal domain of US3. Direct interaction between US3 and MHC class I molecules could be demonstrated after in vitro translation by coimmunoprecipitation. Together, the present data indicate that the properties that allow US3 to be localized in the ER and bind MHC class I molecules are located in different parts of the molecule.

Endoplasmic Reticulum↗
PubMed2000

c-Jun-dependent inhibition of cutaneous procollagen transcription following ultraviolet irradiation is reversed by all-trans retinoic acid.

The aged appearance of skin following repeated exposure to solar ultraviolet (UV) irradiation stems largely from damage to cutaneous connective tissue, which is composed primarily of type I and type III collagens. We report here that a single exposure to UV irradiation causes significant loss of procollagen synthesis in human skin. Expression of type I and type III procollagens is substantially reduced within 24 hours after a single UV exposure, even at UV doses that cause only minimal skin reddening. Daily UV exposures over 4 days result in sustained reductions of both type I and type III procollagen protein levels for at least 24 hours after the final UV exposure. UV inhibition of type I procollagen synthesis is mediated in part by c-Jun, which is induced by UV irradiation and interferes with procollagen transcription. Pretreatment of human skin in vivo with all-trans retinoic acid inhibits UV induction of c-Jun and protects skin against loss of procollagen synthesis. We have reported previously that UV irradiation induces matrix-degrading metalloproteinases in human skin and that pretreatment of skin with all-trans retinoic acid inhibits this induction. UV irradiation, therefore, damages human skin connective tissue by simultaneously inhibiting procollagen synthesis and stimulating collagen breakdown. All-trans retinoic acid protects against both of these deleterious effects and may thereby retard premature skin aging.

Dose-Response Relationship, Radiation↗
PubMed2000

3'UTR polymorphisms in the NRAMP1 gene are associated with susceptibility to tuberculosis in Koreans.

SETTING: Korea University and the Korean Institute of Tuberculosis, Seoul, Korea. OBJECTIVE: To determine whether polymorphisms in the 3' untranslated region (UTR) of the NRAMP1 gene are associated with susceptibility to tuberculosis in Koreans. DESIGN: A case-control study design was used to compare the frequency of 3'UTR of NRAMP1 among 192 tuberculosis patients and 192 healthy individuals. All of the samples were diagnosed by X-ray, smear and culture tests between 1998 and 1999 in the Cross of Lorraine Clinic at the Korean Institute of Tuberculosis. RESULTS: A significant association was found between the Korean tuberculosis patients and polymorphisms in the 3'UTR of the NRAMP1 gene (odds ratio [OR] 1.845; 95% confidence interval [CI] 1.097-3.104; chi2 = 5.424; P = 0.020). CONCLUSION: This study showed that genetic variations in the human NRAMP1 gene are associated with susceptibility to smear-positive tuberculosis in Korean patients. The 3'UTR variant allele associated with susceptibility to tuberculosis is very uncommon in Caucasians, but is present in Koreans and West Africans. These observations may explain in part why African Americans and Koreans have greater susceptibility to tuberculosis than Caucasians.

Alleles↗