Transmembrane heparan sulfate proteoglycans regulate multiple aspects of cell behavior, but the molecular basis of their signaling is unresolved. The major family of transmembrane proteoglycans is ...the syndecans, present in virtually all nucleated cells, but with mostly unknown functions. Here, we show that syndecans regulate transient receptor potential canonical (TRPCs) channels to control cytosolic calcium equilibria and consequent cell behavior. In fibroblasts, ligand interactions with heparan sulfate of syndecan-4 recruit cytoplasmic protein kinase C to target serine714 of TRPC7 with subsequent control of the cytoskeleton and the myofibroblast phenotype. In epidermal keratinocytes a syndecan-TRPC4 complex controls adhesion, adherens junction composition, and early differentiation in vivo and in vitro. In Caenorhabditis elegans, the TRPC orthologues TRP-1 and -2 genetically complement the loss of syndecan by suppressing neuronal guidance and locomotory defects related to increases in neuronal calcium levels. The widespread and conserved syndecan-TRPC axis therefore fine tunes cytoskeletal organization and cell behavior.
The majority of the population in South Africa use traditional health care to treat various mental conditions. In this review, we present ethnobotanical information on plants used by the traditional ...healers in South Africa to treat mental illnesses, specifically epilepsy, depression, age-related dementia and debilitative mental disorders. Details of the recent scientific studies conducted on some of these plants are reviewed.
Extracts of
Searsia chirindensis,
Cotelydon orbiculata and
Leonotis leonurus have shown
in vivo anticonvulsant activity. Extracts from
Searsia dentata and
Searsia pyroides showed spontaneous epileptiform discharge in mouse cortical slices, and acted as NMDA-receptor antagonists. Apigenin, amentoflavone and agathisflavone with affinity to the benzodiazepine site on the GABA
A-receptor were isolated from
Searsia pyroides. Naringenin with affinity to the GABA
A-benzodiazepine receptor was isolated from
Mentha aquatica.
Agapanthus campanulatus,
Boophone disticha,
Mondia whitei and
Xysmalobium undulatum exhibited antidepressant-like activity in three
in vivo models for depression. Amaryllidaceae alkaloids with activity to the serotonin transporter were isolated from
Boophone disticha. The alkaloid mesembrine, which act as a serotonin reuptake inhibitor, was isolated from
Sceletium tortuosum.
Investigations of plants used to treat age-related dementia and debilitative mental disorders lead to the isolation of a number of Amaryllidaceae alkaloids with acetylcholinesterase inhibitory activity from
Boophone disticha and
Crinum species. Extracts of
Mentha aquatica,
Gasteria croucheri,
Ruta graveolens and
Scotia brachypetala inhibited MAO-B. Naringenin was isolated from
Mentha aquatica as a MAO inhibitor.
Only a small number of the more than 300 southern African plant species reported to treat or affect the CNS have been scientifically evaluated. Very few of the active compounds have been isolated and identified.
Piper capense L.f. (Piperaceae) is used traditionally in South Africa as a sleep inducing remedy. Bioassay-guided fractionation of the roots of P. capense led to the isolation of piperine (1) and ...4,5-dihydropiperine (2), which showed moderate affinity for the benzodiazepine site on the GABA(A) receptor (IC(50) values of 1.2 mM and 1.0 mM, respectively). The present study suggests that strict structural properties of the amides are essential for affinity. Taken together, these observations suggest that the carbon chain must contain not less than four carbons, and that a conjugated double bond, adjacent to the amide group, is necessary for binding to the receptor and that the amine part should be bulky.
The four South African medicinal plants
Agapanthus campanulatus (AC),
Boophone distica (BD),
Mondia whitei (MW) and
Xysmalobium undulatum (XU) are used in traditional medicine to treat depression.
To ...evaluate the effect of ethanolic extracts of the plants in models for depression.
The extracts were screened for affinity for the serotonin transporter (SERT) in the
3H-citalopram-binding assay. The inhibitory potency of the extracts towards the SERT, the noradrenalin transporter (NAT) and the dopamine transporter (DAT) were determined in a functional uptake inhibition assay. Antidepressant-like effects of the extracts were investigated using the tail suspension test (TST) and the forced swim test in both rats (rFST) and mice (mFST).
All four plants showed affinity for SERT in the binding assay. AC and BD showed functional inhibition of SERT, NAT and DAT, MW affected SERT while XU showed no effect. BD showed significant effect in the TST and in the mFST/rFST, AC showed significant effect in mFST, MW showed significant effect in the rFST and XU showed significant effect in the mFST.
In this study we have demonstrated the antidepressant activity of four South African medicinal plants
in vitro and
in vivo, supporting their rational use in traditional medicine.
Several medicinal plants are used in Mali to treat epilepsy and convulsions. So far, no studies have investigated the pharmacological effect of these plants.
The aim of this study was to investigate ...the
in vitro and
in vivo antiepileptic potential of the ethanolic extracts of 11 Malian medicinal plants.
The extracts were screened for antiepileptic properties in the mouse cortical wedge preparation and in the
3H-flumazenil binding assay. Two of the plant extracts were investigated for anticonvulsive properties in the pentylenetetrazol (PTZ) kindling model in mice. Possible side effects on motor impairment were evaluated using the rota-rod test.
Extracts of 10 of the 11 medicinal plants showed affinity to the benzodiazepine binding site on the GABA
A receptor. Seven of the 11 extracts inhibited the spontaneous discharges (SEDs) in the mouse cortical wedge preparation, with the extracts of
Flueggea virosa and
Psorospermum senegalense being the most potent. However, when tested for
in vivo anticonvulsive properties these two extracts failed to show any effect on PTZ-induced seizures in mice.
The pharmacological screening of the ethanolic extracts of 11 Malian medicinal plants
in vitro lead to the identification of several extracts with potential anticonvulsant properties.
The cortical wedge is a commonly applied model for in vitro screening of new antiepileptic drugs (AEDs) and has been extensively used in characterization of well-known AEDs. However, the predictive ...validity of this model as a screening model has been questioned as, e.g., carbamazepine has been reported to lack effect in this model. The neuroplastic changes induced in acute and chronic animal models of epilepsy are known to affect the pharmacological profile of AEDs in vivo. Hence, we investigated whether brain slices from pentylenetetrazole (PTZ)-kindled animals could provide a more predictive screening model for AEDs. To this end, we compared the in vitro and in vivo pharmacological profile of several selected AEDs (phenobarbital, phenytoin, tiagabine, fosphenytoin, valproate, and carbamazepine) along with citalopram using the PTZ-kindled model and brain slices from naïve, saline-injected and PTZ-kindled mice. Our data suggest that the use of slices from PTZ-kindled mice in the cortical wedge does not increase the predictive validity of the model as an in vitro screening model for AEDs. Traditionally, the incidence of certain seizure types is widely used as a measure to characterize drug action in animal models of epilepsy. In our study, the anticonvulsant effect of the AEDs was investigated in vivo using several observational parameters (i.e., incidence and duration of convulsions, latency to clonic convulsions, and severity of convulsions). We found that including the observational parameter “severity” offered important additional information about the drug profile that would otherwise be lost if only a single parameter as “incidence” was used.
Ethnopharmacological relevance Several medicinal plants are used in Mali to treat epilepsy and convulsions. So far, no studies have investigated the pharmacological effect of these plants. Aims The ...aim of this study was to investigate the in vitro and in vivo antiepileptic potential of the ethanolic extracts of 11 Malian medicinal plants. Materials and methods The extracts were screened for antiepileptic properties in the mouse cortical wedge preparation and in the 3H-flumazenil binding assay. Two of the plant extracts were investigated for anticonvulsive properties in the pentylenetetrazol (PTZ) kindling model in mice. Possible side effects on motor impairment were evaluated using the rota-rod test. Results Extracts of 10 of the 11 medicinal plants showed affinity to the benzodiazepine binding site on the GABAA receptor. Seven of the 11 extracts inhibited the spontaneous discharges (SEDs) in the mouse cortical wedge preparation, with the extracts of Flueggea virosa and Psorospermum senegalense being the most potent. However, when tested for in vivo anticonvulsive properties these two extracts failed to show any effect on PTZ-induced seizures in mice. Conclusions The pharmacological screening of the ethanolic extracts of 11 Malian medicinal plants in vitro lead to the identification of several extracts with potential anticonvulsant properties.
Summary
In recent decades, the prognosis of Mantle Cell Lymphoma (MCL) has been significantly improved by intensified first‐line regimens containing cytarabine, rituximab and consolidation with ...high‐dose‐therapy and autologous stem cell transplantation. One such strategy is the Nordic MCL2 regimen, developed by the Nordic Lymphoma Group. We here present the 15‐year updated results of the Nordic MCL2 study after a median follow‐up of 11·4 years: For all patients on an intent‐to‐treat basis, the median overall and progression‐free survival was 12·7 and 8·5 years, respectively. The MCL International Prognostic Index (MIPI), biological MIPI, including Ki67 expression (MIPI‐B) and the MIPI‐B including mIR‐18b expression (MIPI‐B‐miR), in particular, significantly divided patients into distinct risk groups. Despite very long response durations of the low and intermediate risk groups, we observed a continuous pattern of relapse and the survival curves never reached a plateau. In conclusion, despite half of the patients being still alive and 40% in first remission after more than 12 years, we still see an excess disease‐related mortality, even among patients experiencing long remissions. Even though we consider the Nordic regimen as a very good choice of regimen, we recommend inclusion in prospective studies to explore the benefit of novel agents in the frontline treatment of MCL.
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