Drugs and natural products for the treatment of COVID-19 during 2020, the first year of the pandemic.

This work aimed to show which treatments showed efficacy against coronavirus disease 2019 (COVID-19); therefore, the results of 37 clinical trials started in 2020 and completed in 2021 are reviewed and discussed here. These were selected from databases, excluding vaccines, computational studies, in silico, in vitro, and those with hyperimmune sera from recovered patients. We found 34 drugs, one vitamin, and one herbal remedy with pharmacological activity against symptomatic COVID-19. They reduced mortality, disease progression, or recovery time. For each treatment, the identifier and type of trial, the severity of the disease, the sponsor, the country where the trial was conducted, and the trial results are presented. The drugs were classified according to their mechanism of action. Several drugs that reduced mortality also reduced inflammation in the most severe cases. These include some that are not considered anti-inflammatory, such as Aviptadil, pyridostigmine bromide, anakinra, imatinib, baricitinib, and bevacizumab, as well as the combination of ivermectin, aspirin, dexamethasone, and enoxaparin. Nigella sativa seeds with honey have also been reported to have therapeutic activity. On the other hand, tofacitinib, novaferon with ritonavir, and lopinavir were also effective, as well as in combination with antiviral therapies such as danoprevir with ritonavir. The natural products colchicine and Vitamin D3 were only effective in patients with mild-to-moderate COVID-19, as was hydroxychloroquine. Drug repositioning has been the main tool in the search for effective therapies by expanding the pharmacological options available to patients.

El objetivo del presente trabajo fue conocer qué tratamientos mostraron efectividad contra COVID-19, para lo cual se revisan y discuten los resultados de 37 estudios clínicos iniciados durante 2020 y concluidos en 2021. Estos fueron seleccionados de bases de datos, excluyendo vacunas, estudios computacionales, in silico, in vitro y con sueros hiperinmunes de pacientes recuperados. Se documentaron 34 fármacos, una vitamina y un remedio herbolario, con actividad farmacológica ante COVID-19 sintomático. Estos redujeron la mortalidad, el progreso de la enfermedad, o el tiempo de recuperación. Para cada tratamiento se presenta identificador y tipo de estudio, la gravedad de la enfermedad, patrocinador, país donde se realizó, así como sus resultados. Los fármacos se clasificaron de acuerdo con su mecanismo de acción. Varios fármacos que redujeron la mortalidad también disminuyeron la inflamación en los casos más graves. Esto incluyendo algunos no considerados antiinflamatorios, como el aviptadil, el bromuro de piridostigmina, el anakinra, el imatinib, el baricitinib y el bevacizumab, así como la combinación de ivermectina, aspirina, dexametasona y enoxaparina. También se reportaron con actividad terapéutica las semillas de Nigella sativa con miel. Además, resultaron efectivos el tofacitinib, el novaferón con ritonavir y lopinavir, así como los antivirales en terapias combinadas como el danoprevir con ritonavir. Los productos naturales colchicina y vitamina D3, solo tuvieron actividad en los pacientes en estado leve a moderado de la COVID-19, así como la hidroxicloroquina. El reposicionamiento de fármacos fue la principal herramienta para buscar terapias efectivas ampliando las opciones farmacológicas accesibles a los pacientes.

Drugs and natural products for the treatment of COVID-19 during 2020, the first year of the pandemic / Fármacos y productos naturales para el tratamiento de la COVID-19 durante 2020, el primer año de la pandemia

Abstract This work aimed to show which treatments showed efficacy against coronavirus disease 2019 (COVID-19); therefore, the results of 37 clinical trials started in 2020 and completed in 2021 are reviewed and discussed here. These were selected from databases, excluding vaccines, computational studies, in silico, in vitro, and those with hyperimmune sera from recovered patients. We found 34 drugs, one vitamin, and one herbal remedy with pharmacological activity against symptomatic COVID-19. They reduced mortality, disease progression, or recovery time. For each treatment, the identifier and type of trial, the severity of the disease, the sponsor, the country where the trial was conducted, and the trial results are presented. The drugs were classified according to their mechanism of action. Several drugs that reduced mortality also reduced inflammation in the most severe cases. These include some that are not considered anti-inflammatory, such as Aviptadil, pyridostigmine bromide, anakinra, imatinib, baricitinib, and bevacizumab, as well as the combination of ivermectin, aspirin, dexamethasone, and enoxaparin. Nigella sativa seeds with honey have also been reported to have therapeutic activity. On the other hand, tofacitinib, novaferon with ritonavir, and lopinavir were also effective, as well as in combination with antiviral therapies such as danoprevir with ritonavir. The natural products colchicine and Vitamin D3 were only effective in patients with mild-to-moderate COVID-19, as was hydroxychloroquine. Drug repositioning has been the main tool in the search for effective therapies by expanding the pharmacological options available to patients.

Resumen El objetivo del presente trabajo fue conocer qué tratamientos mostraron efectividad contra COVID-19, para lo cual se revisan y discuten los resultados de 37 estudios clínicos iniciados durante 2020 y concluidos en 2021. Estos fueron seleccionados de bases de datos, excluyendo vacunas, estudios computacionales, in silico, in vitro y con sueros hiperinmunes de pacientes recuperados. Se documentaron 34 fármacos, una vitamina y un remedio herbolario, con actividad farmacológica ante COVID-19 sintomático. Estos redujeron la mortalidad, el progreso de la enfermedad, o el tiempo de recuperación. Para cada tratamiento se presenta identificador y tipo de estudio, la gravedad de la enfermedad, patrocinador, país donde se realizó, así como sus resultados. Los fármacos se clasificaron de acuerdo con su mecanismo de acción. Varios fármacos que redujeron la mortalidad también disminuyeron la inflamación en los casos más graves. Esto incluyendo algunos no considerados antiinflamatorios, como el aviptadil, el bromuro de piridostigmina, el anakinra, el imatinib, el baricitinib y el bevacizumab, así como la combinación de ivermectina, aspirina, dexametasona y enoxaparina. También se reportaron con actividad terapéutica las semillas de Nigella sativa con miel. Además, resultaron efectivos el tofacitinib, el novaferón con ritonavir y lopinavir, así como los antivirales en terapias combinadas como el danoprevir con ritonavir. Los productos naturales colchicina y vitamina D3, solo tuvieron actividad en los pacientes en estado leve a moderado de la COVID-19, así como la hidroxicloroquina. El reposicionamiento de fármacos fue la principal herramienta para buscar terapias efectivas ampliando las opciones farmacológicas accesibles a los pacientes.

Alternatives for mushroom poisoning timely care in Mexico and Central America.

BACKGROUND: In countries where the consumption of mushrooms is common, hundreds of mushroom poisonings occur every year, which represents a public health problem. In Mexico, mushroom poisoning is classified as a non-bacterial gastrointestinal poisoning, which prevents timely care. OBJECTIVE: To create a free-access platform that synthesizes and standardizes the information on mycetism cases and offers tools for diagnosis and timely treatment. MATERIAL AND METHODS: In locations where cases of mycetism have occurred, information was obtained on the fungi involved, the poisonings that occurred, care protocols, and sample processing. RESULTS: Records were generated that synthesize and describe the types of mycetism with the highest probability of occurrence in Mexico. Therein, the biological characteristics of fungi, the symptoms they cause and their treatment are described. A protocol proposal for patient care and for the processing of biological samples is presented. Finally, a form is included to collect information on cases of poisoning. CONCLUSIONS: Systematized and analyzed information on mycetism allows to simplify its diagnosis, attention and treatment. The protocols for clinical care and sample processing are the basis for generating strategies that prevent deaths due to mycetism.

ANTECEDENTES: En países donde el consumo de hongos es frecuente ocurren cientos de casos de micetismos al año, por lo que representan un problema de salud pública. En México, los micetismos son clasificados como una intoxicación gastrointestinal de tipo no bacteriano, lo que impide su atención oportuna. OBJETIVO: Crear una plataforma de libre acceso que sintetice y estandarice la información de los casos de micetismos y ofrezca herramientas para su diagnóstico y tratamiento oportuno. MATERIAL Y MÉTODOS: En localidades donde han ocurrido casos de micetismos se obtuvo información sobre los hongos involucrados, las intoxicaciones ocurridas, protocolos de atención y procesamiento de muestras. RESULTADOS: Se generaron cédulas que sintetizan y describen las intoxicaciones por hongos con mayor probabilidad de ocurrencia en México. En ellas se describen las características biológicas de los hongos, síntomas que provocan y su tratamiento. Se presenta una propuesta de protocolo para la atención del paciente y para el procesamiento de muestras biológicas. Por último, se incluye un formulario para recopilar información sobre los casos de intoxicaciones. CONCLUSIONES: La información sistematizada y analizada sobre los micetismos permite simplificar su diagnóstico, atención y tratamiento. Los protocolos para la atención clínica y el procesamiento de muestras son la base para generar estrategias que eviten decesos por micetismo.

Alternativas para la atención oportuna de las intoxicaciones por consumo de hongos en México y Centroamérica / Alternatives for mushroom poisoning timely care in Mexico and Central America

Resumen Antecedentes: En países donde el consumo de hongos es frecuente ocurren cientos de casos de micetismos al año, por lo que representan un problema de salud pública. En México, los micetismos son clasificados como una intoxicación gastrointestinal de tipo no bacteriano, lo que impide su atención oportuna. Objetivo: Crear una plataforma de libre acceso que sintetice y estandarice la información de los casos de micetismos y ofrezca herramientas para su diagnóstico y tratamiento oportuno. Material y métodos: En localidades donde han ocurrido casos de micetismos se obtuvo información sobre los hongos involucrados, las intoxicaciones ocurridas, protocolos de atención y procesamiento de muestras. Resultados: Se generaron cédulas que sintetizan y describen las intoxicaciones por hongos con mayor probabilidad de ocurrencia en México. En ellas se describen las características biológicas de los hongos, síntomas que provocan y su tratamiento. Se presenta una propuesta de protocolo para la atención del paciente y para el procesamiento de muestras biológicas. Por último, se incluye un formulario para recopilar información sobre los casos de intoxicaciones. Conclusiones: La información sistematizada y analizada sobre los micetismos permite simplificar su diagnóstico, atención y tratamiento. Los protocolos para la atención clínica y el procesamiento de muestras son la base para generar estrategias que eviten decesos por micetismo.

Abstract Background: In countries where the consumption of mushrooms is common, hundreds of mushroom poisonings occur every year, which represents a public health problem. In Mexico, mushroom poisoning is classified as a non-bacterial gastrointestinal poisoning, which prevents timely care. Objective: To create a free-access platform that synthesizes and standardizes the information on mycetism cases and offers tools for diagnosis and timely treatment. Material and methods: In locations where cases of mycetism have occurred, information was obtained on the fungi involved, the poisonings that occurred, care protocols, and sample processing. Results: Infographics were generated that synthesize and describe the types of mycetism with the highest probability of occurrence in Mexico. Therein, the biological characteristics of fungi, the symptoms they cause and their treatment are described. A protocol proposal for patient care and for the processing of biological samples is presented. Finally, a form is included to collect information on cases of poisoning. Conclusions: Systematized and analyzed information on mycetism allows to simplify its diagnosis, attention and treatment. The protocols for clinical care and sample processing are the basis for generating strategies that prevent deaths due to mycetism.

Synergy of Plant Essential Oils in Antibiotic Therapy to Combat Klebsiella pneumoniae Infections.

Increased antibiotic resistance presents a health problem worldwide. The World Health Organization published a list of pathogens considered a priority for designing new treatments. Klebsiella pneumoniae (Kp) is a top-priority microorganism, highlighting the strains that produce carbapenemases. Developing new efficient therapies or complementing existing treatments is a priority, and essential oils (EOs) provide an alternative. EOs could act as antibiotic adjuvants and enhance antibiotic activity. Employing standard methodologies, the antibacterial activity of the EOs and their synergic effect with antibiotics were detected. A string test was used to identify the impact of the EOs over the hypermucoviscosity phenotype presented by Kp strains, and Gas Chromatography-Mass Spectrometry analysis identified EOs and the composition of EOs. The potential of EOs for designing synergistic therapies with antibiotics to combat the infection of KPC diseases was demonstrated. In addition, the alteration of the hypermucoviscosity phenotype was shown as the principal mechanism of a synergic action between EOs and antibiotics. The differential composition of the EOs lets us identify some molecules that will be analyzed. Synergic activity of EOs and antibiotics can provide a solid platform for combating multiresistant pathogens that represent a severe health sector problem, such as Kp infections.

Potent Anti-amoebic Effects of Ibogaine, Voacangine and the Root Bark Alkaloid Fraction of Tabernaemontana arborea.

Plants of Tabernaemontana species have several pharmacological activities including antimicrobial effects. Amoebiasis continues to be a public health problem, with increasing evidence of resistance to metronidazole. In this study, we assessed the effect of the alkaloid fraction of T. arborea root bark and the alkaloids ibogaine and voacangine on the viability and infectivity of Entamoeba histolytica trophozoites. Cultures were exposed to 0.1 - 10 µg/mL for 24, 48 and 72 h, and viability was then determined using a tetrazolium dye reduction assay and type of cellular death analyzed by flow cytometry. Results showed that the alkaloid fraction, but mainly ibogaine and voacangine alkaloids, exhibited potent dose-dependent anti-amoebic activity at 24 h post-exposure (IC50 4.5 and 8.1 µM, respectively), comparable to metronidazole (IC50 6.8 µM). However, the effect decreased after 48 and 72 h of exposure to concentrations below 10 µg/mL, suggesting that the alkaloids probably were catabolized to less active derivatives by the trophozoites. The treatment of trophozoites with the IC50 s for 24 h induced significant morphological changes in the trophozoites, slight increase in granularity, and death by apoptonecrosis. The capacity of T. arborea alkaloids to inhibit the development of amoebic liver abscesses in hamsters was evaluated. Results showed that even when the treatments reduced the number of amoebic trophozoites in tissue sections of livers, they were unable to limit the formation of abscesses, suggesting their rapid processing to inactive metabolites. This work leaves open the possibility of using Tabernaemontana alkaloids as a new alternative for amoebiasis control.

Five centuries of Cirsium ehrenbergii Sch. Bip. (Asteraceae) in Mexico, from Huitzquilitl to Cardo Santo: History, ethnomedicine, pharmacology and chemistry.

ETHNOPHARMACOLOGICAL RELEVANCE: Several medicinal plants, including the endemic herb Cirsum ehrenbergii (Asteraceae), have been documented in manuscripts, medical and botanical books written in Mexico since the XVI century until the present. This unique circumstance is a real window in the time that allows to investigate historical and contemporary ethnopharmacological knowledge. AIM OF THE STUDY: To examine the persistence, disappearance, and transformation of ethnomedicinal knowledge of C. ehrenbergii along time. Also, to investigate the chemistry and pharmacology of this species in relation to its historical and present day main ethnomedical applications related to Central Nervous System and inflammation. MATERIALS AND METHODS: A thorough review was performed of written sources of medicinal plants from XVI and onwards. For the pharmacological studies, the organic extracts were tested in mice models to assess its antidepressant and anti-inflammatory properties. The active extracts were studied chemically. The isolated compounds were identified by 1H, 13C NMR, or characterized by GC-MS. RESULTS: Cirsum ehrenbergii was illustrated for the first time (1552) in the Libellus de Medicinalibus Indorum Herbis (Booklet of Medicinal Plants of the Indians) and named in the Nahuatl native language as huitzquilitl (edible thistle). It was there recommended as nigris sanguinis remedium (remedy for black blood), and for the treatment of illnesses with an inflammatory component. Nigris sanguinis was well known in the European medicine of that time and currently it has been interpreted as "depression". At the present time, peasants and native population in Mexico mainly name C. ehrenbergii in Spanish as cardo Santo (holy thistle). Its original Nahuatl name has been almost forgotten. However, these communities use this species, among other maladies, to heal "nervios" (anxiety and/or depression) and for anti-inflammatory purposes. These ailments and treatments resemble those recorded in the Libellus and in several medicinal plant books along centuries. The ethanol extract of C. ehrenbergii roots showed antidepressant-like activity in mice administered at 300 mg/kg, as indicated by the forced swim test (FST). The glycosylated flavonoid linarin was identified as antidepressant principle and was active at the doses of 30 and 60 mg/kg in the FST. Regarding to anti-inflammatory activity, the most active was the methylene chloride extract of the aerial parts, which contains taraxasterol, pseudotaraxasterol, ß-sitosterol and stigmasterol. CONCLUSIONS: Cirsium ehrenbergii extracts possess antidepressant-like (roots, EtOH) and anti-inflammatory (aerial parts, CH2Cl2) properties, containing active compounds. Our results sustain historical and present day ethnomedical applications of this species documented along five centuries.

Jacareubin inhibits TLR4-induced lung inflammatory response caused by the RBD domain of SARS-CoV-2 Spike protein.

BACKGROUND: COVID-19, the disease caused by SARS-CoV-2 virus infection, has been a major public health problem worldwide in the last 2 years. SARS-CoV-2-dependent activation of innate immune receptors contributes to the strong local and systemic inflammatory reaction associated with rapid disease evolution. The receptor-binding domain (RBD) of Spike (S) viral protein (S-RBD) is essential for virus infection and its interacting molecules in target cells are still under identification. On the other hand, the search for accessible natural molecules with potential therapeutic use has been intense and remains an active field of investigation. METHODS: C57BL6/J (control) and Toll-like receptor (TLR) 4-deficient (Lps del) mice were nebulized with recombinant S-RBD. Tumor Necrosis Factor-alpha (TNF-α) and Interleukin (IL)-6 production in bronchoalveolar lavages (BALs) was determined by enzyme-linked immunosorbent assay (ELISA). Lung-infiltrating cells recovered in BALs were quantified by hematoxylin-eosin (H&E) stain. In selected groups of animals, the natural compound Jacareubin or dexamethasone were intraperitoneally (ip) administered 2 hours before nebulization. RESULTS: A rapid lung production of TNF-α and IL-6 and cell infiltration was induced by S-RBD nebulization in control but not in Lps del mice. Pre-treatment with Jacareubin or dexamethasone prevented S-RBD-induced TNF-α and IL-6 secretion in BALs from control animals. CONCLUSIONS: S-RBD domain promotes lung TNF-α and IL-6 production in a TLR4-dependent fashion in C57BL6/J mice. Xanthone Jacareubin possesses potential anti-COVID-19 properties that, together with the previously tested anti-inflammatory activity, safety, and tolerance, make it a valuable drug to be further investigated for the treatment of cytokine production caused by SARS-CoV-2 infection.

Tabernaemontana arborea and ibogaine induce paroxysmal EEG activity in freely moving mice: Involvement of serotonin 5-HT1A receptors.

Several Apocynaceae species, most notably Tabernanthe iboga, Voacanga africana and many Tabernaemontana species, produce ibogan-type alkaloids. Although a large amount of information exists about the Tabernaemontana genus, knowledge concerning chemistry and biological activity remains lacking for several species, especially related to their effects on the central nervous system (CNS). The aim of this study was to evaluate the effect of Tabernaemontana arborea Rose ex J.D.Sm. (T. arborea) hydroalcoholic extract (30, 56.2 and 100 mg/kg, i.p.) and two of its main alkaloids (ibogaine and voacangine, 30 mg/kg, i.p.) on electroencephalographic (EEG) activity alone and in the presence of the chemical convulsant agent pentylenetetrazole (PTZ, 85 mg/kg, i.p.) in mice. EEG spectral power analysis showed that T. arborea extract (56.2 and 100 mg/kg) and ibogaine (30 mg/kg, i.p.) promoted a significant increase in the relative power of the delta band and a significant reduction in alpha band values, denoting a CNS depressant effect. Voacangine (30 mg/kg, i.p.) provoked an EEG flattening pattern. The PTZ-induced seizures were not modified in the presence of T. arborea, ibogaine, or voacangine. However, sudden death was observed in mice treated with T. arborea extract at 100 mg/kg, i.p., combined with PTZ. Because T. arborea extract (100 mg/kg, i.p.) and ibogaine (30 mg/kg, i.p.), but not voacangine (30 mg/kg, i.p.), induced paroxysmal activity in the EEG, both were explored in the presence of a serotonin 5-HT1A receptor antagonist (WAY100635, 1 mg/kg, i.p.). The antagonist abolished the paroxysmal activity provoked by T. arborea (100 mg/kg, i.p.) but not that observed with ibogaine, corroborating the participation of serotonin neurotransmission in the T. arborea effects. In conclusion, high doses of the T. arborea extract induced abnormal EEG activity due in part to the presence of ibogaine and involving serotonin 5-HT1A receptor participation. Nevertheless, other possible constituents and mechanisms might participate in this complex excitatory activity that would be interesting to explore in future studies.

Antimycobacterial Activity of Alkaloids and Extracts from Tabernaemontana alba and T. arborea.

Tuberculosis is the main cause of death from a single infectious agent. Globally, according to the World Health Organization, in 2018, there were an estimated 1.2 million tuberculosis deaths. Moreover, there is a continuous appearance of drug-resistant strains. Thus, development of new antituberculosis medicines should receive high priority. Plant-derived natural products are promising candidates for this purpose. We therefore screened alkaloid extracts obtained from the root and stem barks of the Mexican Apocynaceae species Tabernaemontana alba and Tabernaemontana arborea, as well as the pure alkaloids ibogaine, voacangine, and voacamine, tested for activity against Mycobacterium tuberculosis H37Rv and cytotoxicity to mammalian Vero cells using the resazurin microtiter and the MTT assays, respectively. The extracts were analyzed by GC-MS and HPLC-UV. T. arborea root bark alkaloid extract showed the highest activity against M. tuberculosis (MIC100 = 7.8 µg/mL) of the four extracts tested. HPLC suggested that voacangine and voacamine were the major components. The latter was isolated by column chromatography, and its chemical structure was elucidated by 1H and 13C NMR, and MS. Unambiguous assignation was performed by HSQC, HMBC, and NOESY experiments. Voacamine is a dimeric bis-indole-type alkaloid and is 15 times more potent than the monomeric ibogan-type alkaloids ibogaine and voacangine (MIC100 = 15.6, 250.0, and 250.0 µg/mL, respectively). However, all of these compounds showed cytotoxicity to Vero cells, with a poor selectivity index of 1.00, 0.16, and 1.42, respectively. This is the first report of voacamine activity against M. tuberculosis.

Plants of the 'Libellus de Medicinalibus Indorum Herbis' from Mexico, 1552. Zephyranthes fosteri (Amaryllidaceae) Alkaloids.

The Libellus de Medicinalibus Indorum Herbis (Booklet of Indian Medicinal Plants) is the first book of medicinal plants written in the American continent. It was first published in 1939 as 'An Aztec Herbal'. One of the depicted plants is Huetzcanixochitl (laughing flower) interpreted as Zephyranthes fosteri (Amaryllidaceae). No chemical or pharmacological studies are reported for this species; so, we decide to investigate it. The GC/MS of the bulbs and aerial parts extracts indicated that they contain Amaryllidaceae alkaloids, among them: lycorine, 3-O-acetylpowelline, and norlycoramine. An unknown major alkaloid was isolated and identified by 1 H, 13 C-NMR and MS, as 3'-demethoxy-6-epimesembranol (1). The methanolic extract, the alkaloid fraction, and compound 1 inhibited acetylcholinesterase in vitro. Mesembrine alkaloids are found in Sceletium species (Aizoaceae). Several are known as serotonin recapture inhibitors and have been proposed as potential antidepressant drugs. The presence of 1 suggests that Z. fosteri was probably used in pre-Columbian times in Mexico as a 'stimulant and euphoriant', alike Sceletium tortuosum by several ethnic groups in South Africa.

Sobre el primer libro de plantas medicinales escrito en el Continente Americano: El Libellus Medicinalibus Indorum Herbis de México, 1552. Una revisión / On the first book of medicinal plants written in the American Continent: The Libellus Medicinalibus Indorum Herbis from Mexico, 1552. A review

Resumen: El "Libellus de Medicinalibus Indorum Herbis" (Librito de las Hierbas Medicinales de los Indios) fue elaborado por los sabios indígenas Martín De la Cruz y Juan Badiano, 31 años después de la caída del imperio azteca. El primero es su autor, el segundo tradujo el manuscrito del Náhuatl al latín. Contiene numerosas recetas para tratar enfermedades humanas y 185 dibujos a color de las plantas utilizadas. En 1939 se publicó por primera vez como "Un Herbario Azteca". Empero, también contiene enfermedades y prácticas médicas europeas del siglo XVI. Presentamos una revisión actualizada de este hermoso códice, su historia, concepción, creadores y botánica; además, la química y farmacología de cinco plantas ahí citadas. El Libellus es una ventana en el tiempo que permite la investigación científica del antiguo conocimiento etnofarmacológico en Mesoamérica y documentar su persistencia, desaparición o transformación. Sin embargo, esto requiere superar desafíos lingüísticos, pero también derivados de su contexto histórico, antropológico, cultural, botánico y médico.

Abstract: The "Libellus de Medicinalibus Indorum Herbis" (Little Book of Indian Medicinal Plants) was composed by the indigenous sages Martín De la Cruz and Juan Badiano, 31 years after the Aztec Empire fall. The former was the author, and the latter translated the manuscript from the Nahuatl language to Latin. It contains numerous recipes for treating human diseases and 185 colored drawings of the prescribed plants. In 1939 it was first published as "An Aztec Herbarium". However, it also contains XVI century European diseases and medical practices. We present an updated review of this beautiful codex, its history, conception, creators, and botany; as well as, the chemistry and pharmacology of five plants therein cited. The Libellus is a window in the time that allows the scientific research of ancient ethnopharmacological knowledge in Mesoamerica and document its persistence, disappearance, or transformation. However, this requires overcoming linguistic defies, but also derived from its historical, anthropological, cultural, botanical, and medical context.

Effects of seed priming on germination and seedling growth of desiccation-sensitive seeds from Mexican tropical rainforest.

Seed priming increases the vigor of seeds and seedlings through metabolic and biochemical processes occurring during controlled hydration, followed by dehydration. In the field, seeds are exposed to hydration-dehydration events in and on the soil after dispersal, as in seed priming. Nevertheless, seed priming has been sparsely tested on desiccation-sensitive seeds, which are vulnerable to climate change effects. We evaluated the effect of two priming methods on seeds from two tropical rainforest species: Cupania glabra and Cymbopetalum baillonii. For hydropriming, the seeds were fully hydrated and then dehydrated to three dehydration levels. For natural priming, the seeds were buried for 12 days in either closed forest or forest gap. Primed seeds were sown in 1% agar medium and placed in an environmental chamber. The growth of the seedlings from the highest germination priming treatments was evaluated for 1 year in the field. Our results showed that for C. glabra and C. baillonii, hydroprimed seeds varied in their germination response, depending on the degree of their dehydration. However, for C. baillonii, hydropriming seems to invigorate seeds, compared to non-imbibed seeds of the same dehydration level. Natural priming increased germination speed in both species without any difference between closed forest and forest gap. Moreover, seeds with natural priming had a higher final germination percentage than seeds with hydropriming. Seedlings from seeds with natural priming showed a higher growth rate than the controls in both species, whereas hydropriming produced a similar effect in C. glabra. Both priming methods could be used for restoration practices with the studied species, natural priming being a novel method. The ecological implications of priming in desiccation sensitive seeds are discussed in this study.

Mammea type coumarins isolated from Calophyllum brasiliense induced apoptotic cell death of Trypanosoma cruzi through mitochondrial dysfunction, ROS production and cell cycle alterations.

Chagas Disease is a neglected tropical disease caused by the protozoan parasite Trypanosoma cruzi which affects 6-8 million people, mostly in Latin America. The medical treatment is based on two nitroimidazole compounds, which have limited effectiveness in the chronic phase of the disease and produce several adverse effects; consequently, there is an urgent need to develop new, safe, and effective drugs. Previous reports had shown that natural coumarins, especially mammea A/BA isolated from the tropical tree Calophyllum brasiliense, is a promissory molecule for developing new drugs, due to its potent activity, higher than benznidazole, selectivity, and its low toxicity in mice. However, its mode of action is still unknown. In the present work, we evaluated the mechanism of action of the coumarin mammea A/BA (93.6%), isolated from the tropical tree C. brasiliense on Querétaro strain (Tc1) of T. cruzi. This compound was tested in vitro on epimastigotes and trypomastigotes of T. cruzi for intracellular esterase activity, plasma membrane integrity, phosphatidylserine exposure, ROS production, mitochondrial membrane potential, caspase-like activity, DNA integrity, cell cycle and autophagy. Mammea A/BA showed a 50% lethal concentration (LC50) of 85.8 and 36.9 µM for epimastigotes and trypomastigotes respectively. It affected intracellular esterase activity, produced important plasma membrane damage and induced phosphatidylserine exposure. An increase in reactive oxygen species (ROS) and decrease in mitochondrial membrane potential were detected. Caspase-like activity was present in both parasite forms producing DNA integrity damage. This compound also induced a cell cycle arrest in the G1 phase and the presence of autophagy vacuoles. The above data suggest that mammea A/BA induce cell death of T. cruzi by autophagy and apoptosis-like phenomena and support our suggestion that mammea A/BA could be a promising molecule for the development of new drugs to treat Chagas Disease.

Quantitative Evaluation of a Mexican and a Ghanaian Tabernaemontana Species as Alternatives to Voacanga africana for the Production of Antiaddictive Ibogan Type Alkaloids.

In continuation of our efforts to provide quantitative information on antiaddictive ibogan type alkaloid-producing Tabernaemontana species, we used gas chromatography-mass spectrometry (GC/MS) to compare the alkaloid profiles of the barks and/or leaves of one Mexican and one African species - T. arborea and T. crassa, respectively, with the primary sources of commercially available semisynthetic ibogaine, Voacanga africana root and stem bark. The qualitative and quantitative similarities between T. arborea and V. africana barks consolidate previous reports regarding the potential of the former as a promising alternative source of voacangine and ibogaine. The results also suggest that T. crassa could be used to produce conopharyngine and ibogaline, two compounds with the same basic skeletal structure and possibly similar antiaddictive properties as ibogaine.

Extraction and Conversion Studies of the Antiaddictive Alkaloids Coronaridine, Ibogamine, Voacangine, and Ibogaine from Two Mexican Tabernaemontana Species (Apocynaceae).

Several species from the Apocynaceae family, such as Tabernanthe iboga, Voacanga africana, and many Tabernaemontana species, produce ibogan type alkaloids, some of which present antiaddictive properties. In this study, we used gas chromatography/mass spectrometry (GC/MS) to examine the efficiency of methanol, acetone, ethyl acetate, dichloromethane, chloroform, and hydrochloric acid in extracting the antiaddictive compounds coronaridine, ibogamine, voacangine, and ibogaine (altogether the CIVI-complex) from the root barks of Tabernaemontana alba and Tabernaemontana arborea. These Mexican species have recently shown great potential as alternative natural sources of the aforementioned substances. Methanol proved to be the most suitable solvent. Furthermore, the crude methanolic extracts could be engaged in a one-step demethoxycarbonylation process that converted coronaridine and voacangine directly into its non-carboxylic counterparts ibogamine and ibogaine, respectively, without the intermediacy of their carboxylic acids. The established protocol straightforwardly simplifies the alkaloid mixture from four to two majority compounds. In summary, our findings facilitate and improve both the qualitative and quantitative analysis of CIVI-complex-containing plant material, as well as outlining a viable method for the bulk production of these scientifically and pharmaceutically important substances from Mexican Tabernaemontana species.

Coumarins isolated from Calophyllum brasiliense produce ultrastructural alterations and affect in vitro infectivity of Trypanosoma cruzi.

BACKGROUND: The current drugs for Chagas Disease caused by the protozoan Trypanosoma cruzi have limited therapeutic potential and are associated with serious side effects. Natural products can aid to develop new chemotherapeutic agents. Several natural coumarins, especially Mammea A/BA, have shown significant activity against T. cruzi and low toxicity on human lymphocytes, but its effectivity on a wide range of strains need to be tested, as well as to deepen in their mode of action and safety. HYPOTHESIS/PURPOSE: To discern the effects and explore the action mechanisms of mammea A/BA and a mixture of mammea coumarins isolated from Calophyllum brasiliense on Mexican strains of T. cruzi belonging to different genotypes and compare its effectivity with the drug benznidazole. STUDY DESIGN: We evaluated the trypanocidal activity in vitro of mammea A/BA (93.6%), and a mixture of coumarins, mammea A/BA + A/BB + A/BD (86:10:1%) on Mexican T. cruzi strains belonging to different genotypes Ninoa, Querétaro (TcI) and Ver6 (TcVI). MATERIAL AND METHODS: Mammea A/BA and the mixture of coumarins, were isolated from Calophyllum brasiliense, identified by proton NMR and purity determined by HPLC. The in vitro trypanocidal activity was evaluated on mobility, growth recovery, morphology and infectivity of T. cruzi. The cytotoxicity on mammalian cells was compared with benznidazole. The ultrastructure of the treated epimastigotes was analyzed by transmission electron microscopy (TEM). RESULTS: Mammea A/BA and the mixture of coumarins showed high trypanocidal activity, affecting the mobility, growth recovery, morphology, ultrastructure of epimastigotes, and drastically reduce trypomastigotes infectivity on Vero cells. These substances were four times more potent than benznidazole and showed low cytotoxicity and high selectivity index. The TEM showed severe alterations on the plasmatic membrane, nuclear envelope, as well as, mitochondrial swelling, that leads to the death of parasites. CONCLUSION: Mammea A/BA (93.6%) and a mixture of mammea A/BA + A/BB and A/BD (86: 10: 1%) isolated from the tropical tree C. brasiliense showed higher trypanocidal activity than the current drug benznidazole on three Mexican strains of T. cruzi. These compounds induced severe physiological and morphological alterations. These results suggest their possible use in preclinical studies.

Metabolite Profiling of Anti-Addictive Alkaloids from Four Mexican Tabernaemontana Species and the Entheogenic African Shrub Tabernanthe iboga (Apocynaceae).

Ibogaine and other ibogan type alkaloids present anti-addictive effects against several drugs of abuse and occur in different species of the Apocynaceae family. In this work, we used gas chromatography-mass spectrometry (GC/MS) and principal component analysis (PCA) in order to compare the alkaloid profiles of the root and stem barks of four Mexican Tabernaemontana species with the root bark of the entheogenic African shrub Tabernanthe iboga. PCA demonstrated that separation between species could be attributed to quantitative differences of the major alkaloids, coronaridine, ibogamine, voacangine, and ibogaine. While T. iboga mainly presented high concentrations of ibogaine, Tabernaemontana samples either showed a predominance of voacangine and ibogaine, or coronaridine and ibogamine, respectively. The results illustrate the phytochemical proximity between both genera and confirm previous suggestions that Mexican Tabernaemontana species are viable sources of anti-addictive compounds.

Network Pharmacology Uncovers Anticancer Activity of Mammea-Type Coumarins from Calophyllum brasiliense.

Mammea-type coumarins are a particular type of secondary metabolites biosynthesized by the tropical rainforest tree Calophyllum Brasiliense, which is distributed from South America to Mexico. Particularly, mammea A/BA and A/BB (alone or as a mixture) possess biological properties such as cytotoxic and antitumoral activities, however, most of its molecular targets remain unknown. In this context, novel bioinformatic approaches, such as network pharmacology analysis, have been successfully used in herbal medicine to accelerate research in this field, and the support of experimental validations has been shown to be quite robust. In the present study, we performed a network pharmacology analysis to assess the possible molecular biological networks that interact with mammea A/BA and A/BB. Moreover, we validated the most relevant networks experimentally in vitro on K562 cancer cells. The results of the network pharmacology analysis indicate that mammea A/BA and A/BB interacts with cell death, PI3K/AKT, MAPK, Ras, and cancer pathways. The in vitro model shows that mammea A/BA and A/BB induce apoptosis through the overexpression of the proapoptotic proteins Bax and Bak, disrupt the autophagic flux as seen by the cytosolic accumulation of LC3-II and p62, disrupting the mitochondria ultrastructure and concomitantly increase the intracellular calcium concentration. Additionally, docking analysis predicted a possible interaction with a rapamycin-binding domain of mTOR. In conclusion, we validated network pharmacology analysis and report, for the first time, that mammea A/BA and A/BB coumarins induce apoptosis through the inhibition of the autophagic flux, possibly interacting with mTOR.