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Amaryllidaceae alkaloids (AAs) are a structurally diverse family of alkaloids recognized for their many therapeutic properties, such as antiviral, anti-cholinesterase, and anticancer properties. Norbelladine and its derivatives, whose biological properties are poorly studied, are key intermediates required for the biosynthesis of all ~650 reported AAs. To gain insight into their therapeutic potential, we synthesized a series of O-methylated norbelladine-type alkaloids and evaluated their cytotoxic effects on two types of cancer cell lines, their antiviral effects against the dengue virus (DENV) and the human immunodeficiency virus 1 (HIV-1), and their anti-Alzheimer’s disease (anti-cholinesterase and -prolyl oligopeptidase) properties. In monocytic leukemia cells, norcraugsodine was highly cytotoxic (CC50 = 27.0 μM), while norbelladine was the most cytotoxic to hepatocarcinoma cells (CC50 = 72.6 μM). HIV-1 infection was impaired only at cytotoxic concentrations of the compounds. The 3,4-dihydroxybenzaldehyde (selectivity index (SI) = 7.2), 3′,4′-O-dimethylnorbelladine (SI = 4.8), 4′-O-methylnorbelladine (SI > 4.9), 3′-O-methylnorbelladine (SI > 4.5), and norcraugsodine (SI = 3.2) reduced the number of DENV-infected cells with EC50 values ranging from 24.1 to 44.9 μM. The O-methylation of norcraugsodine abolished its anti-DENV potential. Norbelladine and its O-methylated forms also displayed butyrylcholinesterase-inhibition properties (IC50 values ranging from 26.1 to 91.6 μM). Altogether, the results provided hints of the structure−activity relationship of norbelladine-type alkaloids, which is important knowledge for the development of new inhibitors of DENV and butyrylcholinesterase.

Ten Amaryllidaceae alkaloids (AAs) were isolated for the first time from Pancratium maritimum collected in Calabria region, Italy. They belong to different subgroups of this family and were identified as lycorine, which is the main alkaloid, 9-O-demethyllycorine, haemanthidine, haemanthamine, 11-hydroxyvittatine, homolycorine, pancracine, obliquine, tazettine and vittatine. Haemanthidine was isolated as a scalar mixture of two 6-epimers, as already known also for other 6-hydroxycrinine alkaloids, but for the first time they were separated as 6,11-O,O′-di-p-bromobenzoyl esters. The evaluation of the cytotoxic and antiviral potentials of all isolated compounds was undertaken. Lycorine and haemanthidine showed cytotoxic activity on Hacat cells and A431 and AGS cancer cells while, pancracine exhibited selective cytotoxicity against A431 cells. We uncovered that in addition to lycorine and haemanthidine, haemanthamine and pancracine also possess antiretroviral abilities, inhibiting pseudotyped human immunodeficiency virus (HIV)−1 with EC50 of 25.3 µM and 18.5 µM respectively. Strikingly, all the AAs isolated from P. maritimum were able to impede dengue virus (DENV) replication (EC50 ranged from 0.34−73.59 µM) at low to non-cytotoxic concentrations (CC50 ranged from 6.25 µM to >100 µM). Haemanthamine (EC50 = 337 nM), pancracine (EC50 = 357 nM) and haemanthidine (EC50 = 476 nM) were the most potent anti-DENV inhibitors. Thus, this study uncovered new antiviral properties of P. maritimum isolated alkaloids, a significant finding that could lead to the development of new therapeutic strategies to fight viral infectious diseases.

Background: Standing on a foam surface is used to investigate how aging affect the ability to keep balance when somatosensory inputs from feet soles become unreliable. However, since standing on foam also affects the efficacy of postural adjustments, the respective contributions of sensory and motor components are impossible to separate. This study tested the hypothesis that these components can be untangled by comparing changes of center of pressure (CoP) parameters induced by standing on a foam pad vs. a novel vibration (VIB) platform developed by our team and targeting feet soles' mechanoreceptors. Methods: Bipedal postural control of young ( n = 20) and healthy elders ( n = 20) was assessed while standing barefoot on a force platform through 3 randomized conditions: (1) Baseline (BL); (2) VIB; and (3) Foam. CoP Amplitude and Velocity in the antero-posterior/medio-lateral (AP/ML) directions and COP Surface were compared between conditions and groups. Findings: Both VIB and Foam increased CoP parameters compared to BL, but Foam had a significantly greater impact than VIB for both groups. Young and Old participants significantly differed for all three Conditions. However, when correcting for BL levels of postural performance, VIB-related increase of COP parameters was no longer different between groups, conversely to Foam. Interpretation: Although both VIB and Foam highlighted age-related differences of postural control, their combined use revealed that "motor" and "sensory" components are differently affected by aging, the latter being relatively unaltered, at least in healthy/active elders. The combined used of these methods could provide relevant knowledge to better understand and manage postural impairments in the aging population., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Lauzier, Kadri, Bouchard, Bouchard, Gaboury, Gagnon, Girard, Larouche, Robert, Lapointe, da Silva and Beaulieu.)

Aim: To further the understanding of the pathophysiological mechanisms underlying tension-type headache (TTH) by comparing the endurance and strength of neck extensor muscles under acute muscle fatigue in participants with TTH and asymptomatic participants., Methods: We conducted a cross-sectional analysis of neck extensor muscle performance. Asymptomatic participants and participants with TTH were recruited via social media platforms and from the Université du Québec à Trois-Rivières community and employees. A total of 44 participants with TTH and 40 asymptomatic participants took part in an isometric neck extensor endurance task performed at 60% of their maximum voluntary contraction. Inclusion criteria for the headache group were to be older than 18 years old and to fulfil the International Headache Society classification's criteria for either frequent episodic or chronic TTH. Clinical (self-efficacy, anxiety, neck disability and kinesiophobia) and physical parameters (neck extensors maximum voluntary contraction, endurance time, muscle fatigue) as well as characteristics of headache episodes (intensity, frequency and associated disability) were collected for all participants. Surface electromyography was used to document upper trapezius, splenius capitis and sternocleidomastoids muscle activity and muscle fatigue., Results: Both groups displayed similar neck extensor muscle endurance capacity with a mean difference of 6.2 s (p>0.05) in favour of the control group (control=68.1±32.3; TTH=61.9±20.1). Similarly, participants in the headache group showed comparable neck extensor muscle strength (95.9±30.4 N) to the control group (111.3±38.7 N). Among participants with TTH, those scoring as severely incapacitated by headaches were the ones with higher neck-related disability (F[1,44]=10.77; p=0.002), the more frequent headache episodes (F[1,44]=6.70; p=0.01) and higher maximum headache intensity (F[1,44]=10.81; p=0.002)., Conclusion: A fatigue task consisting of isometric neck extension cannot efficiently differentiate participants with TTH from asymptomatic participants., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

At least 49 phase I trials of candidate vaccines for HIV/AIDS, together with two phase II trials and two phase III trials have been completed since the mid 1980s, involving more than 35 different vaccine formulations, 14 different adjuvants and more than 12000 volunteers. Although several neutralizing epitopes have been identified on the surface of the virus glycoprotein spikes, the goal of an HIV envelope-based vaccine capable of eliciting broadly reactive neutralizing antibodies is elusive. A gp120-based vaccine, which was tested in two phase III trials (one in the USA and the other in Thailand), was found to have no protective efficacy when injected every 6 months. The observation that, in the monkey model, both viremia (virus load) and clinical outcome are controlled by the CD8+ T cell response, prompted the development of an array of candidate vaccines capable of inducing HIV-specific T cell responses. A series of HIV vaccines based on live virus vectors are already undergoing clinical studies, including a live recombinant canarypox virus vaccine (ALVAC), which is in phase III trials in Thailand, a non-replicative adenovirus type 5 (Ad5) vaccine, which is entering a phase II trial in the USA and the Caribbean, and live recombinant vaccines based on the attenuated vaccinia virus MVA vector, which have already completed several phase I studies, used either alone or combined with DNA vaccine priming. A whole array of other vaccines based on live vectors, DNA, peptides and other designs, are being tested in nonhuman primates. None of these vaccines has been able to prevent infection following experimental challenge, but all were found to control viral load and to prevent CD4 cell loss. T cell-stimulating vaccines are thus unable to prevent infection but prevent or slow disease progression by controlling virus replication. Their efficacy in humans remains to be determined.