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Biomedical subjects

M Heinrich

Publications and source records attributed to M Heinrich.

At least 55 records · Page 3Linked to original sources
PubMed2001

Inhibition of TNF-alpha synthesis in LPS-stimulated primary human monocytes by Harpagophytum extract SteiHap 69.

Harpagophytum procumbens (Devil's Claw) is often used in the supportive treatment of inflammatory and degenerative diseases of the skeletal system. Here we studied the anti-inflammatory properties of the Harpagophytum extract SteiHap 69 (Steiner Harpagophytum procumbens extract 69) on primary human monocytes, a useful model of peripheral inflammation. After eliminating lipopolysaccharides of bacterial origin, SteiHap 69 prevented the LPS-induced synthesis of tumour necrosis factor alpha (TNFalpha) in stimulated primary human monocytes in a dose-dependent manner. Harpagide and harpagoside had no effect on LPS-induced TNFalpha-release. Our data provides evidence that the Harpagophytum extract SteiHap 69 has anti-inflammatory properties. Further studies are required in order to elucidate the molecular mechanism of Devil's claw anti-inflammatory effects.

Anti-Inflammatory Agents↗
PubMed2001

Ethnopharmacology in drug discovery: an analysis of its role and potential contribution.

In this paper we discuss some examples of ethnopharmacological research as it has been conducted during the last two centuries and look at the current role of this discipline in drug discovery (especially with respect to the American and European markets) and the further development of these phytotherapeutical resources for local use in the countries of origin (ethnopharmacology). Examples from 19th century research on curare (Humboldt and Bernard), from the 20th century on hallucinogenic mushrooms (Wasson), on Mexican Indian indigenous plants (our own research) and of current industry based research are used to illustrate the development of this discipline and to highlight the challenges for the future.

Agaricales↗
PubMed2001

Ethnopharmacology of the Popoluca, Mexico: an evaluation.

Medicinal plants are an essential part of indigenous pharmaceutical systems. We studied the medicinal plants used by the Popoluca of the Sierra Santa Marta (Eastern Mexico). This study is part of a series on the ethnopharmacology of various Macro-Mayan groups. During 16 months of ethnobotanical fieldwork, 614 taxa used medicinally and 4488 individual use-reports were documented. The data are analysed using the concept of the "healers' consensus" in order to identify culturally important medicinal plants. The medicinal uses of the plants were grouped into 13 illness categories. The responses for each species were summarized for each of the categories and were ordered by frequency of mention. The most frequently recorded medicinal plants of the Popoluca are Hamelia patens, used to stop bleeding from wounds, and Byrsonima crassifolia, used against diarrhoea. The high-ranked medicinal species were assessed pharmacognostically using published phytochemical and pharmacological data. Popoluca medicinal uses were fairly consistent with published data on active ingredients for those plants for which such data exist. However, data is still lacking for many other species. Toxicological studies are particularly scarce. This study will be used as a basis for subsequent studies on the pharmacology and phytochemistry of medicinal plant species.

Animals↗
PubMed2000

The non-competitive antagonists 2-methyl-6-(phenylethynyl)pyridine and 7-hydroxyiminocyclopropan[b]chromen-1a-carboxylic acid ethyl ester interact with overlapping binding pockets in the transmembrane region of group I metabotropic glutamate receptors.

We have investigated the mechanism of inhibition and site of action of the novel human metabotropic glutamate receptor 5 (hmGluR5) antagonist 2-methyl-6-(phenylethynyl)pyridine (MPEP), which is structurally unrelated to classical metabotropic glutamate receptor (mGluR) ligands. Schild analysis indicated that MPEP acts in a non-competitive manner. MPEP also inhibited to a large extent constitutive receptor activity in cells transiently overexpressing rat mGluR5, suggesting that MPEP acts as an inverse agonist. To investigate the molecular determinants that govern selective ligand binding, a mutagenesis study was performed using chimeras and single amino acid substitutions of hmGluR1 and hmGluR5. The mutants were tested for binding of the novel mGluR5 radioligand [(3)H]2-methyl-6-(3-methoxyphenyl)ethynyl pyridine (M-MPEP), a close analog of MPEP. Replacement of Ala-810 in transmembrane (TM) VII or Pro-655 and Ser-658 in TMIII with the homologous residues of hmGluR1 abolished radioligand binding. In contrast, the reciprocal hmGluR1 mutant bearing these three residues of hmGluR5 showed high affinity for [(3)H]M-MPEP. Radioligand binding to these mutants was also inhibited by 7-hydroxyiminocyclopropan[b]chromen-1a-carboxylic acid ethyl ester (CPCCOEt), a structurally unrelated non-competitive mGluR1 antagonist previously shown to interact with residues Thr-815 and Ala-818 in TMVII of hmGluR1. These results indicate that MPEP and CPCCOEt bind to overlapping binding pockets in the TM region of group I mGluRs but interact with different non-conserved residues.

Amino Acid Sequence↗
PubMed2000

Production of ceramides causes apoptosis during early neural differentiation in vitro.

To investigate signal transduction pathways leading to apoptosis during the early phase of neurogenesis, we employed PCC7-Mz1 cells, which cease to proliferate and begin to differentiate into a stable pattern of neurons, astroglial cells, and fibroblasts upon incubation with retinoic acid (RA). As part of lineage determination, a sizable fraction of RA-treated cultures die by apoptosis. Applying natural long-chain C(16)-ceramides as well as membrane-permeable C(2)/C(6)-ceramide analogs caused apoptosis, whereas the biologically nonactive C(2)-dihydroceramide did not. Treating PCC7-Mz1 stem cells with a neutral sphingomyelinase or with the ceramidase inhibitor N-oleoylethanolamine elevated the endogenous ceramide levels and concomitantly induced apoptosis. Addition of RA caused an increase in ceramide levels within 3-5 h, which reached a maximum (up to 3.5-fold of control) between days 1 and 3 of differentiation. Differentiated PCC7-Mz1 cells did not respond with ceramide formation and apoptosis to RA treatment. The acidic sphingomyelinase contributed only weakly and the neutral Mg(2+)-dependent and Mg(2+)-independent sphingomyelinases not at all to the RA-mediated production of ceramides. However, ceramide increase was sensitive to the ceramide synthase inhibitor fumonisin B(1), suggesting a crucial role for the de novo synthesis pathway. Enzymatic assays revealed that ceramide synthase activity remained unaltered, whereas serine palmitoyltransferase (SPT), a key enzyme in ceramide synthesis, was activated approximately 2.5-fold by RA treatment. Activation of SPT seemed to be mediated via a post-translational mechanism because levels of the mRNAs coding for the two SPT subunits were unaffected. Expression of marker proteins shows that ceramide regulates apoptosis, rather than differentiation, during early neural differentiation.

Acyltransferases↗
PubMed2000

Ethnobotany and its role in drug development.

The botanical collections of early explorers and the later ethnobotany have played important roles in the development of new drugs for many centuries. In the middle of the last century interest in this approach had declined dramatically, but has risen again during its last decade, and new foci have developed. The systematic evaluation of indigenous pharmacopoeias in order to contribute to improved health care in marginalized regions has been placed on the agenda of international and national organizations and of NGOs. In this paper the results of various projects on Mexican Indian ethnobotany and some of the subsequent pharmacological and phytochemical studies are summarized. Medicinal plants are an important element of indigenous medical systems in Mexico. This study uses the medicinal plants in four indigenous groups of Mexican Indians-Maya, Nahua, Zapotec and Mixe-as an example. The relative importance of a medicinal plant within a culture is documented using a quantitative method and the data are compared intra- and interculturally. While the species used by the indigenous groups vary, the data indicate that there exist well-defined criteria specific for each culture, which lead to the selection of a plant as a medicine. For example, a large number of species are used for gastrointestinal illnesses by two or more of the indigenous groups. At least in this case, the multiple transfers of species and their uses within -Mexico seems to be an important reason for the widespread use of a species. Some of the data we gathered in order to evaluate the indigenous claims are also discussed, focusing on the transcription factor NF-kappaB as a molecular target. This led to the identification of sesquiterpene lactones such as parthenolide as potent and relatively specific inhibitors of this transcription factor.

Drugs, Investigational↗
PubMed2000

Ceramide as an activator lipid of cathepsin D.

We have identified the aspartic protease cathepsin D as a novel intracellular target protein for the lipid second messenger ceramide. Ceramide specifically binds to and induces CTSD proteolytic activity. A-SMase deficient cells derived from Niemann-Pick patients show decreased CTSD activity that was reconstituted by transfection with A-SMase cDNA. Ceramide accumulation in cells derived from A-ceramidase defective Farber patients correlates with enhanced CTSD activity. These findings suggest that A-SMase-derived ceramide targets endolysosomal CTSD.

Amidohydrolases↗
PubMed2000

Cytotoxic cardenolides and antibacterial terpenoids from Crossopetalum gaumeri.

From the methanol extract of the roots of (Crossopetalum gaumeri, four new highly cytotoxic cardenolides, securigenin-3beta-O-beta-6-deoxyguloside (2), 19-hydroxy-sarmentogenin-3beta-O-beta-6-deoxyguloside (4), sarmentogenin-3beta-O-[alpha-allosyl-(1-->4)-beta-6-deoxy alloside] (5), and securigenin-3beta-O-[alpha-allosyl-(1-->4)-beta-6-deoxyal loside] (6) were isolated. The dichloromethane extract afforded the new diterpene 3,15-dihydroxy-18-norabieta-3,8,11,13-tetraene (7) as well as the new triterpene 2,3,7-trihydroxy-6-oxo-1,3,5(10),7-tetraene-24-nor-friedelane-29-o ic acid methylester (11). The new terpenoids lack cytotoxicity and the antibacterial activity is moderate to low.

Anti-Bacterial Agents↗
PubMed1999

Cathepsin D targeted by acid sphingomyelinase-derived ceramide.

Ceramide has been recognized as a common intracellular second messenger for various cytokines, growth factors and other stimuli, such as CD95, chemotherapeutic drugs and stress factors. To understand the role of ceramide during apoptosis and other cellular responses, it is critically important to characterize direct targets of ceramide action. In this paper, we show that ceramide specifically binds to and activates the endosomal acidic aspartate protease cathepsin D. Direct interaction of ceramide with cathepsin D results in autocatalytic proteolysis of the 52 kDa pre-pro cathepsin D to form the enzymatically active 48/32 kDa isoforms of cathepsin D. Acid sphingomyelinase (A-SMase)-deficient cells show decreased cathepsin D activity, which could be reconstituted by transfection with A-SMase cDNA. The results of our study identify cathepsin D as the first endosomal ceramide target that colocalizes with and may mediate downstream signaling effects of A-SMase.

Animals↗
PubMed1999

Inhibition of receptor internalization by monodansylcadaverine selectively blocks p55 tumor necrosis factor receptor death domain signaling.

The 55-kDa receptor for tumor necrosis factor (TR55) triggers multiple signaling cascades initiated by adapter proteins like TRADD and FAN. By use of the primary amine monodansylcadaverine (MDC), we addressed the functional role of tumor necrosis factor (TNF) receptor internalization for intracellular signal distribution. We show that MDC does not prevent the interaction of the p55 TNF receptor (TR55) with FAN and TRADD. Furthermore, the activation of plasmamembrane-associated neutral sphingomyelinase activation as well as the stimulation of proline-directed protein kinases were not affected in MDC-treated cells. In contrast, activation of signaling enzymes that are linked to the "death domain" of TR55, like acid sphingomyelinase and c-Jun-N-terminal protein kinase as well as TNF signaling of apoptosis in U937 and L929 cells, are blocked in the presence of MDC. The results of our study suggest a role of TR55 internalization for the activation of select TR55 death domain signaling pathways including those leading to apoptosis.

Antigens, CD↗
PubMed1999

2-Methyl-6-(phenylethynyl)-pyridine (MPEP), a potent, selective and systemically active mGlu5 receptor antagonist.

In the present paper we describe 2-methyl-6-(phenylethynyl)-pyridine (MPEP) as a potent, selective and systemically active antagonist for the metabotropic glutamate receptor subtype 5 (mGlu5). At the human mGlu5a receptor expressed in recombinant cells, MPEP completely inhibited quisqualate-stimulated phosphoinositide (PI) hydrolysis with an IC50 value of 36 nM while having no agonist or antagonist activities at cells expressing the human mGlu1b receptor at concentrations up to 30 microM. When tested at group II and III receptors, MPEP did not show agonist or antagonist activity at 100 microM on human mGlu2, -3, -4a, -7b, and -8a receptors nor at 10 microM on the human mGlu6 receptor. Electrophysiological recordings in Xenopus laevis oocytes demonstrated no significant effect at 100 microM on human NMDA (NMDA1A/2A), rat AMPA (Glu3-(flop)) and human kainate (Glu6-(IYQ)) receptor subtypes nor at 10 microM on the human NMDA1A/2B receptor. In rat neonatal brain slices, MPEP inhibited DHPG-stimulated PI hydrolysis with a potency and selectivity similar to that observed on human mGlu receptors. Furthermore, in extracellular recordings in the CA1 area of the hippocampus in anesthetized rats, the microiontophoretic application of DHPG induced neuronal firing that was blocked when MPEP was administered by iontophoretic or intravenous routes. Excitations induced by microiontophoretic application of AMPA were not affected.

Animals↗
PubMed1999

Hypericin as a non-antioxidant inhibitor of NF-kappa B.

NF-kappa B is a transcription factor involved in immune and inflammatory responses. Here we show that micromolar concentrations of hypericin inhibited the PMA- and TNF-alpha-induced activation of NF-kappa B in HeLa and TC10 cells, respectively. In contrast, NF-kappa B activated by H2O2 was not influenced by hypericin, indicating a pathway-specificity of hypericin. Hyperforin and a Hypericum perforatum extract standardised on 0.15% hypericin and 5% hyperforin were not active at pharmacologically relevant concentrations. The PMA/TNF-alpha-induced transcription of a reporter gene, which is under the control of the NF-kappa B-dependent IL-6 promoter, was strongly reduced by preincubation with hypericin.

Animals↗
PubMed1999

Neurotrophin-3 (NT-3) modulates early differentiation of oligodendrocytes in rat brain cortical cultures.

Multiple extracellular signals are required for oligodendroglia survival, proliferation and differentiation, and increasing evidence has accumulated that also neurotrophins regulate glial cell development in the central nervous system (CNS). In the present study we have investigated the influence of neurotrophin-3 (NT-3) on the in vitro differentiation and proliferation of oligodendrocytes prepared from the brains of newborn rats. Cells were grown in chemically defined growth medium, in the absence of fetal calf serum (FCS). RT-PCR analysis confirmed the expression of mRNA encoding the NT-3 receptor trkC in oligodendrocytes throughout in vitro development. Cell morphology was observed by phase contrast microscopy and indirect immunofluorescence staining using anti-galactocerebroside (GalC) antibodies. An increase in process formation and arborization was observed 8-24 h after the treatment with NT-3 (5-50 ng/ml). Concomitantly, NT-3 caused an increase in the appearance of GalC-positive cells. Long-term treatment with NT-3 (up to seven days) did not yield any further improvement of process formation. To elucidate the molecular mechanisms and signal transduction pathways underlying the effect of NT-3 in oligodendrocytes, the time- and concentration-dependent effect of NT-3 on c-Fos protein expression was studied by Western blot analysis. The data show that NT-3 stimulated the appearance of two c-Fos immunoreactive polypeptides with apparent molecular weights of 62 and 55 kDa, respectively. This effect was maximal at a concentration of 50 ng/ml of NT-3 after 8-24 h. NT-3-modulated morphological differentiation and c-Fos protein expression was regulated by protein kinases. Whereas the protein kinase C (PKC) inhibitors staurosporine and chelerythrine chloride had a stimulatory effect on NT-3-promoted process formation, the tyrosine kinase inhibitor genistein had an inhibitory effect and mainly cells with a bipolar and immature morphology were observable. The inhibition of tyrosine kinase activity prevented NT-3-promoted induction of c-Fos protein. Thus, in addition to its mitogenic effects, NT-3 during early time points influences the in vitro differentiation of oligodendrocytes. This process involves the induction of c-Fos protein and is mediated by PKC and trosine kinase activities.

Animals↗
PubMed1999

Enhancing the quality of home health care.

A strong partnership between clinical practice and nursing education is essential to innovative home health care services. Nevertheless, these two components have not always worked in close association for mutual benefit--bringing the two together has been a continuing challenge. Recently, such an alliance was achieved in Edmonton, Alberta, brought on by necessity and triggered by rapid and substantial changes in both home health care and nursing educational environments.

Alberta↗
PubMed1998

Sesquiterpene lactones specifically inhibit activation of NF-kappa B by preventing the degradation of I kappa B-alpha and I kappa B-beta.

Extracts from certain Mexican Indian medicinal plants used in traditional indigenous medicine for the treatment of inflammations contain sequiterpene lactones (SLs), which specifically inhibit the transcription factor NF-kappa B (Bork, P. M., Schmitz, M. L., Kuhnt, M., Escher, C., and Heinrich, M. (1997) FEBS Lett. 402, 85-90). Here we show that SLs prevented the activation of NF-kappa B by different stimuli such as phorbol esters, tumor necrosis factor-alpha, ligation of the T-cell receptor, and hydrogen peroxide in various cell types. Treatment of cells with SLs prevented the induced degradation of I kappa B-alpha and I kappa B-beta by all these stimuli, suggesting that they interfere with a rather common step in the activation of NF-kappa B. SLs did neither interfere with DNA binding activity of activated NF-kappa B nor with the activity of the protein tyrosine kinases p59fyn and p60arc. Micromolar amounts of SLs prevented the induced expression of the NF-kappa B target gene intracellular adhesion molecule 1. Inhibition of NF-kappa B by SLs resulted in an enhanced cell killing of murine fibroblast cells by tumor necrosis factor-alpha. SLs lacking an exomethylene group in conjugation with the lactone function displayed no inhibitory activity on NF-kappa B. The analysis of the cellular redox state by fluorescence-activated cell sorter showed that the SLs had no direct or indirect anti-oxidant properties.

Animals↗