Explore the vast range of titles available.

Several novel bisbenzylisoquinoline alkaloids (BBIQAs) have recently been isolated from a Matis tribe arrow poison and shown by two-electrode voltage-clamp to inhibit mouse muscle nicotinic acetylcholine receptors (nAChR). Here, using radioligand assay with Aplysia californica AChBP and radioiodinated α-bungarotoxin ([125I]-αBgt), we show that BBIQA1, BBIQA2, and d-tubocurarine (d-TC) have similar affinities to nAChR orthosteric site. However, a competition with [125I]-αBgt for binding to the Torpedo californica muscle-type nAChR revealed that BBIQAs1, 2, and 3 are less potent (IC50s = 26.3, 8.75, and 17.0 μM) than d-TC (IC50 = 0.39 μM), while with α7 nAChR in GH4C1 cells, BBIQA1 was less potent that d-TC (IC50s = 162 μM and 7.77 μM, respectively), but BBIQA2 was similar (IC50 = 5.52 μM). In inhibiting the Ca2+ responses induced by acetylcholine in Neuro2a cells expressing the mouse adult α1β1εδ nAChR or human α7 nAChR, BBIQAs1 and 2 had similar potencies to d-TC (IC50s in the range 0.75-3.08 μM). Our data suggest that BBIQA1 and BBIQA2 can inhibit adult muscle α1β1εδ nAChR by both competitive and noncompetitive mechanisms. Further experiments on neuronal α3β2, α4β2, and α9α10 nAChRs, expressed in Xenopus laevis oocytes, showed that similar potencies for BBIQAs1, 2, and d-TC. With α3β2γ2 GABAAR currents were almost completely inhibited by d-TC at a high (100 μM) concentration, but BBIQAs1 and 2 were less potent (only 40-50% inhibition), whereas in competition with Alexa Fluor 546-α-cobratoxin for binding to α1β3γ2 GABAAR in Neuro2a cells, d-TC and these analogs had comparable affinities. Especially interesting effects of BBIQAs1 and 2 in comparison with d-TC were observed for 5-HT3AR: BBIQA1 and BBIQA2 were 5- and 87-fold less potent than d-TC (IC50 = 22.63 nM). Thus, our results reveal that these BBIQAs differ from d-TC in their potencies towards certain Cys-loop receptors, and we suggest that understanding the reasons behind this might be useful for future drug design.

Diverse ligands of the muscle nicotinic acetylcholine receptor (nAChR) are used as muscle relaxants during surgery. Although a plethora of such molecules exists in the market, there is still a need for new drugs with rapid on/off-set, increased selectivity, and so forth. We found that pyrroloiminoquinone alkaloid Makaluvamine G (MG) inhibits several subtypes of nicotinic receptors and ionotropic γ-aminobutiric acid receptors, showing a higher affinity and moderate selectivity toward muscle nAChR. The action of MG on the latter was studied by a combination of electrophysiology, radioligand assay, fluorescent microscopy, and computer modeling. MG reveals a combination of competitive and un-competitive inhibition and caused an increase in the apparent desensitization rate of the murine muscle nAChR. Modeling ion channel kinetics provided evidence for MG binding in both orthosteric and allosteric sites. We also demonstrated that theα1 (G153S) mutant of the receptor, associated with the myasthenic syndrome, is more prone to inhibition by MG. Thus, MG appears to be a perspective hit molecule for the design of allosteric drugs targeting muscle nAChR, especially for treating slow-channel congenital myasthenic syndromes.

Several novel bisbenzylisoquinoline alkaloids (BBIQAs) have recently been isolated from a Matis tribe arrow poison and shown by two-electrode voltage-clamp to inhibit mouse muscle nicotinic acetylcholine receptors (nAChR). Here, using radioligand assay with Aplysia californica AChBP and radioiodinated [alpha]-bungarotoxin ([.sup.125 I]-[alpha]Bgt), we show that BBIQA1, BBIQA2, and d-tubocurarine (d-TC) have similar affinities to nAChR orthosteric site. However, a competition with [.sup.125 I]-[alpha]Bgt for binding to the Torpedo californica muscle-type nAChR revealed that BBIQAs1, 2, and 3 are less potent (IC.sub.50 s = 26.3, 8.75, and 17.0 [mu]M) than d-TC (IC.sub.50 = 0.39 [mu]M), while with [alpha]7 nAChR in GH.sub.4 C.sub.1 cells, BBIQA1 was less potent that d-TC (IC.sub.50 s = 162 [mu]M and 7.77 [mu]M, respectively), but BBIQA2 was similar (IC.sub.50 = 5.52 [mu]M). In inhibiting the Ca.sup.2+ responses induced by acetylcholine in Neuro2a cells expressing the mouse adult [alpha]1[beta]1[epsilon][delta] nAChR or human [alpha]7 nAChR, BBIQAs1 and 2 had similar potencies to d-TC (IC.sub.50 s in the range 0.75-3.08 [mu]M). Our data suggest that BBIQA1 and BBIQA2 can inhibit adult muscle [alpha]1[beta]1[epsilon][delta] nAChR by both competitive and noncompetitive mechanisms. Further experiments on neuronal [alpha]3[beta]2, [alpha]4[beta]2, and [alpha]9[alpha]10 nAChRs, expressed in Xenopus laevis oocytes, showed that similar potencies for BBIQAs1, 2, and d-TC. With [alpha]3[beta]2[gamma]2 GABA.sub.A R currents were almost completely inhibited by d-TC at a high (100 [mu]M) concentration, but BBIQAs1 and 2 were less potent (only 40-50% inhibition), whereas in competition with Alexa Fluor 546-[alpha]-cobratoxin for binding to [alpha]1[beta]3[gamma]2 GABA.sub.A R in Neuro2a cells, d-TC and these analogs had comparable affinities. Especially interesting effects of BBIQAs1 and 2 in comparison with d-TC were observed for 5-HT.sub.3A R: BBIQA1 and BBIQA2 were 5- and 87-fold less potent than d-TC (IC.sub.50 = 22.63 nM). Thus, our results reveal that these BBIQAs differ from d-TC in their potencies towards certain Cys-loop receptors, and we suggest that understanding the reasons behind this might be useful for future drug design.

Zoonosis are not a recent problem in the history of humanity. Throughout history, humans have lived with animals and may have contracted diseases, either through direct contact with animals or through contaminated food or the environment. Zoonotic agents often cause fatal diseases, such as plague, rabies, anthrax, brucellosis and various bacterial infections. Regarding the healthiness of meat delivered for consumption in Bukavu, out of a total of 49 samples collected and analyzed, the average FMAT (Total Aerobic Mesophilic Flora or general contamination) is 155.5. 106, total coliforms are 101.106, faecal coliforms 132.106 and pathogens 133.106/g of meat sample. The meats are more contaminated by a bacterial microflora with high loads. They are therefore unfit for consumption because they can cause toxi-infections, zoonosis and other infectious diseases.