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Biomedical subjects

L Golub

Publications and source records attributed to L Golub.

At least 19 recordsLinked to original sources
PubMed2001

Doxycycline dosing.

Explore the source record for details and available documents.

Anti-Bacterial Agents↗
PubMed2001

Wound healing in ovariectomized rats: effects of chemically modified tetracycline (CMT-8) and estrogen on matrix metalloproteinases -8, -13 and type I collagen expression.

Cutaneous wound healing is a complex process involving interactions of various cell types. Skin, in addition to certain other organs, is dependent on estrogen; and estrogen-deficiency is associated with impaired wound healing. Wound healing involves the action of collagenolytic matrix metalloproteinases (MMPs). We investigated the expression and localization of collagenolytic MMPs -8 and -13 by collagenase activity assay, Western immunoblot analysis, in situ hybridization and immunohistochemical staining as well as type I collagen by hydroxyproline content analysis and immunohistochemical staining in cutaneous wounds from aged Sham and ovarioectomized (OVX) rats. After wounding, OVX rats were treated with either placebo, chemically modified tetracycline-8 (CMT-8) or estrogen. We found that MMP-8 and MMP-13 mRNA were expressed in wound epithelium of all samples examined as evidenced by in situ hybridization. Type I collagen, which was abundant in all groups examined, was decreased in OVX rats, but was increased by both CMT-8 and estrogen treatments to the level of Sham group. Hydroxyproline analysis revealed similar results. Western blot data showed that all forms of MMP-8 and MMP-13 were clearly reduced in the CMT-8 treated group compared to OVX. Analysis of collagenolytic activity confirmed the decreased collagenolysis in skin wound extracts from CMT-treated rats when compared with skin wound extracts from OVX rats. Our results show for the first time that MMP-8 mRNA and protein are expressed in rat wound epithelium. We further show that CMT-8 and estrogen have a beneficial effect on skin wound healing in OVX rats by increasing the collagen content and reducing the MMP-mediated collagenolysis.

Animals↗
PubMed2001

Biologic properties of non-antibiotic, chemically modified tetracyclines (CMTs): a structured, annotated bibliography.

The first paper reporting on a potentially important medical property of a non-antimicrobial tetracycline appeared in 1987. Since then, a literature of over 75 papers has supported the therapeutic potential of this class of compounds. In this review, this literature is grouped and organized with commentary on the data which has been published to date. The biomedical applicability of these discoveries obviously covers a wide range of medical conditions and clearly justifies their continued development.

Animals↗
PubMed2000

Inter- and intrasubunit interactions during the formation of RNA polymerase assembly intermediate.

We used yeast two-hybrid and in vitro co-immobilization assays to study the interaction between the Escherichia coli RNA polymerase (RNAP) alpha and beta subunits during the formation of alpha(2)beta, a physiological RNAP assembly intermediate. We show that a 430-amino acid-long fragment containing beta conserved segments F, G, H, and a short part of segment I forms a minimal domain capable of specific interaction with alpha. The alpha-interacting domain is held together by protein-protein interactions between beta segments F and I. Residues in catalytically important beta segments H and I directly participate in alpha binding; substitutions of strictly conserved segment H Asp(1084) and segment I Gly(1215) abolish alpha(2)beta formation in vitro and are lethal in vivo. The importance of these beta amino acids in alpha binding is fully supported by the structural model of the Thermus aquaticus RNAP core enzyme. We also demonstrate that determinants of RNAP assembly are conserved, and that a homologue of beta Asp(1084) in A135, the beta-like subunit of yeast RNAP I, is responsible for interaction with AC40, the largest alpha-like subunit. However, the A135-AC40 interaction is weak compared with the E. coli alpha-beta interaction, and A135 mutation that abolishes the interaction is phenotypically silent. The results suggest that in eukaryotes additional RNAP subunits orchestrate the enzyme assembly by stabilizing weak, but specific interactions of core subunits.

Amino Acid Sequence↗
PubMed2000

Down-regulation of trypsinogen-2 expression by chemically modified tetracyclines: association with reduced cancer cell migration.

Many types of human tumor express trypsinogen-2, which may be a significant factor in the activation of pro-MMPs and the invasiveness of tumors. Prevention of trypsinogen-2 expression in cancer cells might be of benefit in cancer therapy. We describe here chemicals capable of down-regulating the expression of trypsinogen-2. Doxycycline (DOXY) and chemically modified tetracyclines (CMTs), previously known as inhibitors of the matrix metalloproteinase (MMP)-dependent proteinase cascade, down-regulated the mRNA and protein expression of trypsinogen-2 by COLO-205 human colon adenocarcinoma cells at therapeutically attainable concentrations (0. 1 to 1.0 microM). DOXY specifically inhibited the activation of pro-MMP-9 and cell migration induced by enteropeptidase, a specific activator of trypsinogen. Pro-MMP-9 activation and cell migration were also inhibited by tumor-associated trypsin inhibitor (TATI), which is a highly specific inhibitor of trypsin. CMT-3 as well as CMT-5 also inhibited cell migration, but an effect on the enteropeptidase-enhanced activation of pro-MMP-9 was not observed. Our results indicate that CMTs, DOXY and TATI inhibit cancer cell migration by down-regulating trypsinogen-2 expression or activity. Inhibition of trypsinogen-2 expression may represent a mechanism contributing to the ability of CMTs to suppress the pericellular proteolytic activity of some tumors.

Antineoplastic Agents↗
PubMed1999

TRACE and Yohkoh Observations of High-Temperature Plasma in a Two-Ribbon Limb Flare.

The ability of the Transition Region and Coronal Explorer (TRACE) to image solar plasma over a wide range of temperatures (Te approximately 104-107 K) at high spatial resolution (0&farcs;5 pixels) makes it a unique instrument for observing solar flares. We present TRACE and Yohkoh observations of an M2.4 two-ribbon flare that began on 1999 July 25 at about 13:08 UT. We observe impulsive footpoint brightenings that are followed by the formation of high-temperature plasma (Te greater, similar10 MK) in the corona. After an interval of about 1300 s, cooler loops (Te<2 MK) form below the hot plasma. Thus, the evolution of the event supports the qualitative aspects of the standard reconnection model of solar flares. The TRACE and Yohkoh data show that the bulk of the flare emission is at or below 10 MK. The TRACE data are also consistent with the Yohkoh observations of hotter plasma (Te approximately 15-20 MK) existing at the top of the arcade. The cooling time inferred from these observations is consistent with a hybrid cooling time based on thermal conduction and radiative cooling.

Journal Article↗
PubMed1998

The potential role of doxycycline in the treatment of osteoarthritis of the temporomandibular joint.

Collagenase and gelatinase are matrix metalloproteinases (MMPs) which play an important role in tissue destruction in arthritic joints. Studies have demonstrated that tetracyclines can inhibit MMPs and prevent tissue destruction independent of their antimicrobial activity. The purpose of this pilot study is to assess the potential therapeutic role of Doxycycline in patients with advanced osteoarthritis of the temporomandibular joint (TMJ). This ongoing investigation includes patients with a diagnosis of osteoarthritis of the TMJ based on clinical and diagnostic imaging findings, symptoms (localized TMJ pain, limited mobility, dysfunction) for a minimum of 36 months, and failure of previous non-surgical and surgical modalities to alleviate the symptoms. A synovial fluid sample is collected by a saline injection and aspiration technique, followed by diagnostic arthroscopy. Patients are placed on Doxycycline 50 mg BID for three months and then undergo repeat diagnostic arthroscopy and synovial fluid collection. The samples are stored at -80 degrees C. Collagenase activity is determined by a combination of SDS-polyacrylamide gel electrophoresis and fluorography and calculated based on the percentage of collagen alpha chains that are degraded into alphaA breakdown products. Three patients have completed the three-month course of Doxycycline thus far, and 5 joints with osteoarthritis have been analyzed. All patients were female (mean age = 35, mean duration of symptoms = 132 months) and had undergone previous bilateral arthroscopies. One patient had undergone unilateral arthroplasty. The mean collagenase activity showed 55% collagen lysis prior to Doxycycline treatment and 19% after three months of therapy. The mean gelatinase activity was 28% prior to Doxycycline treatment and 7% after three months of therapy. The mean interincisal opening was 33 mm initially and 41 mm after three months of Doxycycline. Subjectively, two of the three patients reported significant improvement in their overall symptoms, which they had not experienced over the previous three years. One patient did not experience any change in symptoms, in spite of a marked reduction in collagenase activity from 86.4% to 9.6%. Because of the very small numbers of patients enrolled in this pilot study so far, no statistically significant differences could be appreciated. However, the dramatic reduction in collagenase activity in these patients, with a long history of TMJ symptoms from osteoarthritis, suggests the potential promising role of Doxycycline in the management of osteoarthritis, and further investigation is warranted.

Adult↗
PubMed1990

Minocycline-treatment of diabetic rats normalizes skin collagen production and mass: possible causative mechanisms.

Daily minocycline-treatment of streptozotocin-induced diabetic rats not only prevented a diabetes-caused atrophy of skin collagen mass (10-mos old rats), but also normalized skin collagen mass to match that of growing (ca. 1%/d) non-diabetic controls (4- and 5-mos old rats). The causative mechanism by which minocycline-treatment normalizes skin collagen mass must, in part, be related to a general anabolic effect on growth (body weight) because the effect on skin collagen mass correlates strongly to that on body weight. Consequently, a minocycline-stimulated increase of a systemic factor (such as insulin-like growth factor) is not unlikely. The anabolic effect of minocycline-treatment of diabetic rats is also expressed as a normalized cellular ribosome mass (an index of total protein synthetic capacity) and a normalized absolute rate of collagen production. (Calculation of an absolute rate was justified by an apparent maximum saturation of the prolyl-tRNA pool(s) of skin, maximum saturation obtained by the pool-flooding approach). The normalized skin ribosome amount does not, however, explain a selective effect of minocycline-treatment on collagen production as opposed to that for non-collagen protein, this selective effect measured as relative collagen production. To explain such selectivity, the inhibition of diabetes-induced excess skin collagenase activity seems unlikely. (This inference is based on results from a preliminary study indicating that recently [less than 2 h] synthesized collagen is not degraded by the excess collagenase in skin of diabetic rats). Thus, the principal collagen fraction acted on by pathologically excess collagenase might be collagen at a later stage (greater than 2 h after synthesis) in its life cycle. (Another possibility for the selective effect of minocycline on collagen production, as yet untested, is reduced intracellular procollagen degradation.) Overall, this is the first study aimed at discerning the mechanism(s) by which minocycline-treatment enhances the rate of collagen production in tissues of a diabetic rat. For future studies, the extent to which the positive effect on growth, ribosome mass, and rate of collagen production contributes to the change of collagen mass must, along with the known minocycline-inhibition of collagenase activity, be quantified. Such quantification is a prerequisite for evaluating the chemotherapeutic efficacy of minocycline-treatment on collagen-degradative diseases.

Animals↗
PubMed1989

Decreased cholestasis with enteral instead of intravenous protein in the very low-birth-weight infant.

Thirty to 50% of very low-birth-weight infants have parenteral nutrition-associated cholestasis. To test the hypothesis that the incidence of cholestasis would be decreased if parenteral amino acids were avoided and protein given enterally, infants with a gestational age of less than 30 weeks were randomized to two groups. One group received amino acid-free parenteral nutrition and whey protein enterally with added premature infant formula. The control group received standard parenteral nutrition with amino acids and enteral premature formula. At the end of 3 weeks of parenteral nutrition, infants who had a direct serum bilirubin level of greater than 3 mg/dl were considered to have significant cholestasis. Twenty-nine infants required parenteral nutrition for 3 weeks, 17 in the whey group and 12 in the control group. No instances of significant cholestasis were observed in the whey group (0/17), whereas seven of 12 infants (58%) in the amino acid control group had cholestasis (p less than 0.001).

Amino Acids↗
PubMed1988

Streptozotocin-induced diabetes and the rat periodontium: decreased relative collagen production.

This is the first study concerning the extent to which relative collagen production (RCP) in rat periodontal tissues is affected by diabetes. Determination of RCP, rather than individual production rates for collagen or for non-collagen protein, was deemed necessary because saturation of all proline pools in tissues of diabetics (and non-diabetic controls) was not achieved. Such non-saturation occurred despite the injection of a pool-expanding dose of proline (400-1150 mg/rat), non-saturation indicated by the lesser specific radioactivity (S.R.) of free-[3H]proline in tissues than that of the injected solution. RCP was decreased in five periodontal tissues (incisor and molar gingiva, incisor and molar periodontal ligament, antemolar palatal mucosa) and in skin. Diabetes-decreased RCP seems to result from decreased collagen synthesis and increased intracellular degradation, although some evidence is presented for increased extracellular degradation of recently secreted collagen.

Animals↗
PubMed1985

Dietary ascorbic acid normalizes diabetes-induced underhydroxylation of nascent type I collagen molecules.

Nascent collagen alpha chains (types I and III) isolated from diabetic rat skin were shown to be underhydroxylated, an underhydroxylation normalized (type I) or partially corrected (Type III) by dietary ascorbic acid. Increased hydroxylation occurred concomitantly with reduced intracellular procollagen degradation and increased production of nascent collagen molecules, both contributing to an increased total skin collagen mass. Overall, by correcting a defect (underhydroxylation) in a posttranslational event and by increasing collagen production, dietary ascorbic acid improved the collagen status of a diabetes-perturbed connective tissue.

Animals↗
PubMed1984

Skin collagen metabolism in the streptozotocin-induced diabetic rat: free hydroxyproline, the principal in vivo degradation product of newly synthesized collagen--probably procollagen.

We characterized the degradation products of recently synthesized collagen present in skins of control and diabetic rats. Specifically, the TCA-soluble fractions of homogenized skins from control and diabetic rats (killed 1 and 4 hours after [3H]-proline injection) were fractionated by molecular sieve chromatography, and eluted fractions were analyzed for hydroxyproline and [3H]-hydroxyproline. Free [3H]-hydroxyproline was the principal (greater than 95%), low molecular weight (greater than 2000 daltons), [3H]-hydroxyproline-containing material eluted from the molecular sieve column, this amount representing approximately 80% (controls) and approximately 87% (diabetics) of [3H]-hydroxyproline-containing material in TCA-soluble fractions of skin homogenates. These observations are similar to those from the intracellular degradation of cellular and secretory proteins in that the principal--almost exclusive--degradation product was the free amino acid. The free hydroxyproline had a greater specific radioactivity than that in any other [3H]-hydroxyproline-containing fraction (soluble and insoluble, see below); furthermore, the total radioactivity of free [3H]-hydroxyproline was greater at 1 hour than 3 hours later. These two properties (identity with free amino acid; time-dependent decrease in amounts) are consistent with [3H]-hydroxyproline arising from the intracellular degradation of procollagen. The [3H]-hydroxyproline-containing material eluting before free hydroxyproline (designated peptidyl [3H]-hydroxyproline) was similar to free [3H]-hydroxyproline in terms of specific radioactivity and the time-dependent decreases of specific and total radioactivities, these similarities indicating that the peptidyl [3H]-hydroxyproline are intermediates in the degradative pathway of procollagen to free amino acids. Results for control and diabetic rats were qualitatively similar, with regard to the inter-fraction ratios of specific radioactivities and their time-dependent changes. However, the degradative process, as assessed by the release of free and peptidyl [3H]-hydroxyproline, was dramatically enhanced by the diabetic state, extending our previous results based on analyses of uncharacterized degradation products.

Animals↗