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.

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.

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.

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.

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.

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.

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.

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.

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.

Antinociceptive, anti-inflammatory, and central nervous system (CNS) effects of the natural coumarin soulattrolide.

Soulattrolide is a natural coumarin synthesized by the leaves of species of Calophyllum (Calophyllaceae) rain forest trees, including the American C. brasiliense, and the Asian C. teysmanii. Soulattrolide is a potent inhibitor of the reverse transcriptase from HIV-1 (RT-HIV-1), and active against Mycobacterium tuberculosis. However, the effects of this coumarins on other systems, remains to be evaluated. C. brasiliense is used in traditional medicine for the treatment of pain and inflammation. Therefore, we decided to explore the antinociceptive, anti-inflammatory activity of soulattrolide in mice, as well as, some of its possible effects on the CNS. Soulattrolide showed antinociceptive effects in the writhing test (ED50 = 33.8 mg/kg), as well as, in the formalin test with an ED50 = 7.9, and 22.1 mg/kg for Phases 1 and 2, respectively. The highest dose of soulattrolide (50 mg/kg) induced 40% of antinociception in the hot plate test. Regarding to anti-inflammatory activity, in the 12-O-Tetradecanoylphorbol-13-acetate (TPA) test, soulattrolide showed an IC50 = 1.81 µmol/ear, whereas in the myeloperoxidase assay, it showed an inhibition of 87% (1 µmol/ear). Soulattrolide showed sedative effects on the pentobarbital-induced sleeping time test, and the rotarod test, but lacked antidepressant activity on the tail suspension test. In conclusion, we report for the first time, the antinociceptive effects of soulattrolide in mice, like those of naproxen; soulattrolide also showed mild anti-inflammatory activity, as well as mild sedative and anxiolytic properties, therefore, it has also activity on the CNS.

Mexican Propolis: A Source of Antioxidants and Anti-Inflammatory Compounds, and Isolation of a Novel Chalcone and ε-Caprolactone Derivative.

The propolis produced by bees are used in alternative medicine for treating inflammation, and infections, presumably due to its antioxidant properties. In this context, five propolis from México were investigated to determine their inhibitory lipid peroxidation properties. The ethyl acetate extract from a red propolis from Chiapas State (4-EAEP) was the most potent (IC50 = 1.42 ± 0.07 µg/mL) in the TBARS assay, and selected for further studies. This extract afforded two new compounds, epoxypinocembrin chalcone (6), and an ε-caprolactone derivative (10), as well as pinostrobin (1), izalpinin (2), cinnamic acid (3), pinocembrin (4), kaempherol (5), 3,3-dimethylallyl caffeate in mixture with isopent-3-enyl caffeate (7a + 7b), 3,4-dimethoxycinnamic acid (8), rhamnetin (9) and caffeic acid (11). The HPLC profile, anti-mycobacterial, and antioxidant properties of this extract was also determined. Most of the isolated compounds were also tested by inhibition of reactive oxygen species (ROS) in challenged mouse bone marrow-derived mast cells (BMMCs), and DPPH. Their anti-inflammatory activity was evaluated by TPA, and MPO (myeloperoxidase) activity by ear edema test in mice. The most potent compounds were 7a + 7b in the TBARS assay (IC50 = 0.49 ± 0.06 µM), and 2 which restored the ROS baseline (3.5 µM). Our results indicate that 4-EAEP has anti-oxidant, and anti-inflammatory properties due to its active compounds, suggesting it has anti-allergy and anti-asthma potential.

Chemoinformatic Analysis of Selected Cacalolides from Psacalium decompositum (A. Gray) H. Rob. & Brettell and Psacalium peltatum (Kunth) Cass. and Their Effects on FcεRI-Dependent Degranulation in Mast Cells.

Cacalolides are a kind of sesquiterpenoids natural compounds synthesized by Psacalium decompositum (A. Gray) H. Rob. & Brettell or Psacalium peltatum (Kunth) Cass. Antioxidant and hypoglycemic effects have been found for cacalolides such as cacalol, cacalone or maturine, however, their effects on inflammatory processes are still largely unclear. The main aim of this study was to investigate the biological activities of secondary metabolites from P. decompositum and P. peltatum through two approaches: (1) chemoinformatic and toxicoinformatic analysis based on ethnopharmacologic background; and (2) the evaluation of their potential anti-inflammatory/anti-allergic effects in bone marrow-derived mast cells by IgE/antigen complexes. The bioinformatics properties of the compounds: cacalol; cacalone; cacalol acetate and maturin acetate were evaluated through Osiris DataWarrior software and Molinspiration and PROTOX server. In vitro studies were performed to test the ability of these four compounds to inhibit antigen-dependent degranulation and intracellular calcium mobilization, as well as the production of reactive oxygen species in bone marrow-derived mast cells. Our findings showed that cacalol displayed better bioinformatics properties, also exhibited a potent inhibitory activity on IgE/antigen-dependent degranulation and significantly reduced the intracellular calcium mobilization on mast cells. These data suggested that cacalol could reduce the negative effects of the mast cell-dependent inflammatory process.

Natural Compounds from Mexican Medicinal Plants as Potential Drug Leads for Anti-Tuberculosis Drugs.

In Mexican Traditional Medicine 187 plant species are used in the treatment of respiratory conditions that may be associated with tuberculosis. In this contribution, we review the ethnobotany, chemistry and pharmacology of 63 species whose extracts have been assayed for antimycobacterial activity in vitro. Among these, the most potent is Aristolochia brevipes (MIC= 12.5 µg/mL), followed by Aristolochia taliscana, Citrus sinensis, Chrysactinia mexicana, Persea americana, and Olea europaea (MIC<64 µg/mL). Other potent extracts (inhibition > 95%, 50 µg/mL) include: Amphipterygium adstringens, Larrea divaricata, and Phoradendron robinsoni. Several active compounds have been identified, the most potent are: Licarin A (isolated from A. taliscana), and 9-amino-9-methoxy-3,4-dihydro-2H-benzo[h]-chromen-2-one (transformation product of 9-methoxytariacuripyrone isolated from Aristolochia brevipes), both with MIC= 3.125 µg/mL, that is 8-fold less potent than the reference drug Rifampicin (MIC= 0.5 µg/mL). Any of the compounds or extracts here reviewed has been studied in clinical trials or with animal models; however, these should be accomplished since several are active against strains resistant to common drugs.

Quantification of Anti-Addictive Alkaloids Ibogaine and Voacangine in In Vivo- and In Vitro-Grown Plants of Two Mexican Tabernaemontana Species.

Tabernaemontana alba and Tabernaemontana arborea are Apocynaceae species used in Mexican traditional medicine for which little phytochemical information exists. In this study, preliminary gas chromatography/mass spectrometry analyses of different organs obtained from wild plants of both species identified a total of 10 monoterpenoid indole alkaloids (MIAs) and one simple indole alkaloid, nine of which were reported for the first time in these species. Furthermore, callus cultures were established from T. alba leaf explants and regeneration of whole plants was accomplished via somatic embryogenesis. The anti-addictive MIAs ibogaine and voacangine were then quantified by gas chromatography with flame ionization detection in wild plants of both species, as well as greenhouse-grown plants, in vitro-grown plantlets and embryogenic callus of T. alba. Ibogaine and voacangine were present in most samples taken from the whole plants of both species, with stem and root barks showing the highest concentrations. No alkaloids were detected in callus samples. It was concluded that T. alba and T. arborea are potentially viable sources of ibogaine and voacangine, and that these MIAs can be produced through somatic embryogenesis and whole plant regeneration of T. alba. Approaches to increase MIA yields in whole plants and to achieve alkaloid production directly in cell cultures are discussed.

Anthraquinones from Vismia mexicana.

Vismia mexicana (Clusiaceae) is a small tropical tree found from Mexico to Honduras. The CH2Cl2/MeOH extract from the leaves has been reported to have inhibitory properties against reverse transcriptase of human immunodeficiency virus type 1 (HIV-1 RT). In order to characterize some of its chemical constituents, the EtOAc-soluble fraction of this extract was subjected to column chromatography. A new natural product was isolated and designated vismiaquinone D [1-hydroxy-6-methoxy-7,8-(3',3'-dimethyl-pyrano) anthraquinone]. In addition, vismiaquinone was obtained. The structures of vismiaquinone and vismiaquinone D were determined by 1H and 13C NMR spectroscopy, unambiguous assignments were achieved with DEPT, HSQC, and HMBC experiments, and corroborated by X-ray diffraction studies. The isolated anthraquinones were tested against HIV-1 RT. However, none showed relevant activity, suggesting that other compounds in this extract may be responsible for its HIV-1 RT inhibitory properties.

Introducing the NUATEI Consortium: A Mexican Research Program for the Identification of Natural and Synthetic Antimicrobial Compounds for Prevalent Infectious Diseases.

The need for new drugs to treat human infections is a global health concern. Diseases like tuberculosis, trypanosomiasis, amoebiasis, and AIDS remain significant problems, especially in developing countries like Mexico. Despite existing treatments, issues such as resistance and adverse effects drive the search for new alternatives. Herein, we introduce the NUATEI research consortium, made up of experts from the Institute of Biomedical Research at UNAM, who identify and obtain natural and synthetic compounds and test their effects against human pathogens using in vitro and in vivo models. The consortium has evaluated hundreds of natural extracts and compounds against the pathogens causing tuberculosis, trypanosomiasis, amoebiasis, and AIDS, rendering promising results, including a patent with potential for preclinical studies. This paper presents the rationale behind the formation of this consortium, as well as its objectives and strategies, emphasizing the importance of natural and synthetic products as sources of antimicrobial compounds and the relevance of the diseases studied. Finally, we briefly describe the methods of the evaluation of the compounds in each biological model and the main achievements. The potential of the consortium to screen numerous compounds and identify new therapeutic agents is highlighted, demonstrating its significant contribution to addressing these infectious diseases.

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.

Antioxidant properties of xanthones from Calophyllum brasiliense: prevention of oxidative damage induced by FeSO4.

BACKGROUND: Reactive oxygen species (ROS) are important mediators in a number of degenerative diseases. Oxidative stress refers to the imbalance between the production of ROS and the ability to scavenge these species through endogenous antioxidant systems. Since antioxidants can inhibit oxidative processes, it becomes relevant to describe natural compounds with antioxidant properties which may be designed as therapies to decrease oxidative damage and stimulate endogenous cytoprotective systems. The present study tested the protective effect of two xanthones isolated from the heartwood of Calophyllum brasilienses against FeSO4-induced toxicity. METHODS: Through combinatory chemistry assays, we evaluated the superoxide (O2·â»), hydroxyl radical (OH·), hydrogen peroxide (H2O2) and peroxynitrite (ONO⁻) scavenging capacity of jacareubin (xanthone III) and 2-(3,3-dimethylallyl)-1,3,5,6-tetrahydroxyxanthone (xanthone V). The effect of these xanthones on murine DNA and bovine serum albumin degradation induced by an OH· generator system was also evaluated. Additionally, we investigated the effect of these xanthones on ROS production, lipid peroxidation and glutathione reductase (GR) activity in FeSO4-exposed brain, liver and lung rat homogenates. RESULTS: Xanthone V exhibited a better scavenging capacity for O2·â», ONOO⁻ and OH· than xanthone III, although both xanthones were unable to trap H2O2. Additionally, xanthones III and V prevented the albumin and DNA degradation induced by the OH· generator system. Lipid peroxidation and ROS production evoked by FeSO4 were decreased by both xanthones in all tissues tested. Xanthones III and V also prevented the GR activity depletion induced by pro-oxidant activity only in the brain. CONCLUSIONS: Altogether, the collected evidence suggests that xanthones can play a role as potential agents to attenuate the oxidative damage produced by different pro-oxidants.