The inhibitory effect of
Andrographis paniculata extract (APE) and andrographolide (AND), the most medicinally active phytochemical in the extract, on hepatic cytochrome P450s (CYPs) activities was ...examined using rat and human liver microsomes. For this purpose, CYP1A2-dependent ethoxyresorufin-
O-deethylation, CYP2B1-dependent benzyloxyresorufin-
O-dealkylation, CYP2B6-dependent bupropion hydroxylation, CYP2C-dependent tolbutamide hydroxylation, CYP2E1-dependent
p-nitrophenol hydroxylation and CYP3A-dependent testosterone 6β-hydroxylation activities, were determined in the presence and absence of APE or AND (0–200
μM). APE inhibited ethoxyresorufin-
O-deethylation activity in rat and human liver microsomes, with apparent
K
i
values of 8.85 and 24.46
μM, respectively. In each case, the mode of inhibition was noncompetitive. APE also inhibited tolbutamide hydroxylation both in rat and human microsomes with apparent
K
i
values of 8.21 and 7.51
μM, respectively and the mode of inhibition was mixed type. In addition, APE showed a competitive inhibition only on CYP3A4 in human microsomes with
K
i
of 25.43
μM. AND was found to be a weak inhibitor of rat CYP2E1 with a
K
i
of 61.1
μM but did not affect human CYP2E1. In conclusion, it cannot be excluded from the present study that APE could cause drug–drug interactions in humans through CYP3A and 2C9 inhibition.
Summary
Cardiofaciocutaneous syndrome (CFC) is one of a group of rare genetic disorders called the RASopathies because they are caused by mutations in the genes related to HRAS, KRAS or NRAS. The ...other RASopathies are Noonan (NS) and Costello (CS) syndromes. These conditions can affect the heart, nervous system, bony skeleton and muscles; there is sometimes an unusual facial appearance and occasionally a tendency to develop tumours. CFC patients often have skin problems but dermatologists have difficulty recognising the syndrome because it is very rare and the skin symptoms are not particularly unusual. Also there is a lot of overlap between the different RASopathies. In this study from France, geneticists and dermatologists reviewed 45 patients with CFC caused by mutations in the genes BRAF, MAP2K1 or MAP2K2 and compared the findings with published data. They noted a lack of precise dermatological descriptions in the RASopathy literature. They observed certain skin conditions more frequently in CFC patients than is reported in the general population. These included common disorders such as prominent follicles (keratosis pilaris), multiple moles, and curly hair, and unusual but rather non‐specific features such as lax skin, thickened palms and soles, sparse eyebrows and excessive sweating. The thickened palms and soles responded well to treatment with a drug called acitretin in two patients. As the accompanying commentary points out, most people with these skin features do not have a RASopathy, but that diagnosis is worth considering if the skin condition is unusually marked, is absent in close family members, or associated with other abnormalities.
Linked Article: Bessis et al. Br J Dermatol 2019; 180:172–180
Dispersal processes of fungal plant pathogens can be inferred from analysis of spatial genetic structures resulting from recent range expansion. The relative importance of long-distance dispersal ...(LDD) events vs. gradual dispersal in shaping population structures depends on the geographical scale considered. The fungus Mycosphaerella fijiensis, pathogenic on banana, is an example of a recent worldwide epidemic. Founder effects in this species were detected at both global and continental scale, suggesting stochastic spread of the disease through LDD events. In this study, we analysed the structure of M. fijiensis populations in two recently (~1979-1980) colonized areas in Costa Rica and Cameroon. Isolates collected in 10-15 sites distributed along a ~250- to 300- km-long transect in each country were analysed using 19 microsatellite markers. We detected low-to-moderate genetic differentiation among populations in both countries and isolation by distance in Cameroon. Combined with historical data, these observations suggest continuous range expansion at the scale of banana-production area through gradual dispersal of spores. However, both countries displayed specific additional signatures of colonization: a sharp discontinuity in gene frequencies was observed along the Cameroon transect, while the Costa Rican populations seemed not yet to have reached genetic equilibrium. These differences in the genetic characteristics of M. fijiensis populations in two recently colonized areas are discussed in the light of historical data on disease spread and ecological data on landscape features.
Retrospective long-term study to evaluate the efficacy of botulinum neurotoxin A (BoNT/A) therapy for epiphora due to non-surgical nasolacrimal duct obstruction.
BoNT/A has been used successfully ...since 2000 in axillary hyperhidrosis to reduce secretory disorders. Some isolated cases of hyperlacrimation or crocodile tear syndrome have been treated on this basis. We used BoNT/A to decrease lacrimal secretion in cases of epiphora.
We reviewed the qualitative and quantitative degree of improvement of epiphora after botulinum neurotoxin injections in the palpebral lobe of the lacrimal gland, carried out in an ophthalmic centre between 2009 and 2016. Epiphora was graded using a questionnaire, Munk scores and Schirmer tests before and after injections. Severity of side effects was recorded.
Twenty-seven palpebral lacrimal glands of twenty patients with epiphora, mean age 65±13, were treated with BoNT/A (Botox
or Xeomin
) from April 2009 to April 2016. The epiphora was induced by persistent nasolacrimal duct stenosis after surgical treatment. No conventional medical nor surgical treatment was effective at this time. The technique of injection, dilution and dosage were specific. We re-injected 14/27 cases on an as-needed basis, 7/27 cases three times, 3/27 cases four times, and 2/27 cases (same patient both glands) five times. The Schirmer test measured a decrease of lacrimal secretion in 24/27 (89%) lacrimal glands after neurotoxin injection. Side effects were ptosis in 4 cases and transient esotropia in 2 cases. The authors describe the injection techniques, the dosage, the volume and concentration of BoNT/A.
Patients with epiphora can be treated effectively with BoNT/A to reduce lacrimal secretion of the principal lacrimal gland in its palpebral portion. Ninety percent of the patients were very satisfied, with few side effects (ptosis or mild diplopia lasting from 3 days to 3 weeks). More studies are needed to delineate which types of epiphora can be treated with BoNT/A.
Large monitoring programs exist in many countries and are necessary to assess present and past biodiversity status and to evaluate the consequences of habitat degradation or destruction. Using such ...an extensive data set of the floristic richness in the Paris Ile-de-France region (France), we compared different sampling efforts and protocols in different habitat units to highlight the best methods for assessing the actual plant biodiversity. Our results indicate that existing data can be used for a general understanding of site differences, but analysts should be aware of the limitations of the data due to non-random selection of sites, inconsistent observer knowledge, and inconsistent sampling period. The average species diversity recorded in a specific habitat does not necessarily reflect its actual diversity, unless the monitoring effort was very strong. Overall, increasing the sampling effort in a given region allows improvement of the (1) number of habitats visited, (2) the total sampled area for a given habitat type, (3) the number of seasons investigated. Our results indicate that the sampling effort should be planned with respect to these functional, spatial and temporal heterogeneities, and to the question examined. While the effort should be applied to as many habitats as possible for the purpose of capturing a large proportion of regional diversity, or comparing different regions, inventories should be conducted in different seasons for the purpose of comparing species richness in different habitats.
Banana fruit are typically harvested at a green preclimacteric stage prior to sale. The green life (GL), which is defined as the number of days between harvesting and initiation of the natural ...ripening process, is important for harvesting, shipping and marketing. Sigatoka disease (SD) has previously been shown to influence the postharvest quality of banana fruit. The present study was conducted to determine (1) whether there is a relationship between the level of SD severity and the banana quality as characterized by several pomological traits and fruit green life, and (2) whether there is a level of SD severity that is acceptable for fruit exporting. In an experiment conducted with fruit harvested at a constant physiological age, our results showed that the disease decreases fruit GL. Based on the relationship established between SD severity and GL, it is possible to define an acceptable disease level threshold corresponding to a specified GL. Additionally, we found that high SD infections caused a reduction in fruit weight but did not affect fruit size. Possible explanations are discussed.
•SD might affect the weight of banana fruit, in the higher disease levels.•GL of banana fruit is reduced by SD infestation as hard as infestation level.•The nature of the relationship between SD and GL does not present a critical level of disease, from which the GL is affected.•There is a disease level maximum which leads to a GL available for fruit exportation.
It is important to investigate the induction of cytochrome
P450 (CYP) enzymes by drugs. The most relevant end point is enzyme activity; however, this requires many cells and is low throughput. We ...have compared the CYP1A, CYP2B and CYP3A induction response to eight inducers in rat and human hepatocytes using enzyme activities (CYP1A2 (ethoxyresorufin), 2B (benzoxyresorufin for rat and bupropion for human) and CYP3A (testosterone)) and Taqman™ Low Density Array (TLDA) analysis. There was a good correlation between the induction of CYP1A2, CYP2B6 and CYP3A4 enzyme activities and mRNA expression in human hepatocytes. In contrast, BROD activities and mRNA expression in rat hepatocytes correlated poorly. However, bupropion hydroxylation correlated well with Cyp2b1 expression in rat hepatocytes. TLDA analysis of a panel of mRNAs encoding for CYPs, phase 2 enzymes, nuclear receptors and transporters revealed that the main genes induced by the 8 compounds tested were the CYPs. AhR ligands also induced UDP-glucuronosyltransferases and glutathione S-transferases in rat and human hepatocytes. The transporters,
MDR1,
MDR3 and
OATPA were the only transporter genes significantly up-regulated in human hepatocytes. In rat hepatocytes Bsep, Mdr2, Mrp2, Mrp3 and Oatp2 were up-regulated. We could then show a good
in vivo:
in vitro correlation in the induction response of isolated rat hepatocytes and ex-vivo hepatic microsomes for the drug development candidate, EMD392949. In conclusion, application of TLDA methodology to investigate the potential of compounds to induce enzymes in rat and human hepatocytes increases the throughput and information gained from one assay, without reducing the predictive capacity.
We evaluated the antioxidant status, namely cellular lipid peroxidation, by measuring thiobarbituric acid reactive substances (TBARS), cellular reduced glutathione (GSH) content, glutathione ...reductase (GSSG-R), glutathione transferase (GST), glutathione peroxidase (GSH-Px) and catalase activities in rat liver, hepatocytes immediately after isolation and in two-dimensional (2D) culture (on non-coated or collagen-coated dishes, as collagen–collagen or collagen–Matrigel sandwich cultures) or three-dimensional (3D) culture on Matrigel-coated dishes. Microsomal cytochrome P450 (CYP)- and UDP-glucuronosyl transferase (UGT)- dependent activities were also assessed in rat livers and hepatocyte cultures. The overall antioxidant status of rat hepatocytes immediately after isolation was not significantly different from that of rat livers. During culture, GSH was increased in 2D but not in 3D cultures in accordance with morphological observations; that is that matrix–cell interactions involving GSH, important in 2D, are minimal in 3D cultures. While UGT- and GST-dependent activities were equivalent in cultured hepatocytes and in rat livers, both catalase and GSH-Px activities decreased with time in all culture configurations. Constitutive CYP-dependent activities were drastically decreased in hepatocytes after isolation and attachment and did not recover in any culture configuration tested. Our results highlight that, although 2D sandwich cultures and 3D cultures on Matrigel allow longevity of rat hepatocyte cultures and optimal induction of CYPs, an imbalance in phase I/phase II detoxication processes in cultured rat hepatocytes occurs, whatever the culture configuration.
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