Antidiarrheal effect of Psidium guajava L. extract in acute diarrhea: a systematic review.

Acute diarrheal diseases are a leading cause of childhood mortality and morbidity worldwide. Psidium guajava has been globally used for its antidiarrheal potential. We conducted a systematic review of scientific articles published up to the year 2021, which included in vivo pre-clinical tests and clinical trials involving patients with acute infectious diarrhea to verify the antidiarrheal, antibacterial and antispasmodic effects of galenic preparations or phytopharmaceuticals from P. guajava. PRISMA and Rayyan were used as tools for the selection of studies collected in four databases (Pubmed, Scopus, Web of Science and Science Direct). The keywords used to carry out the search were: 'Psidium guajava', 'guava', 'antidiarrhe*' and 'diarrhe*', joined by Boolean operators 'OR' or 'AND'. The characteristics of studies in animal models of acute diarrhea induction, as well as in vivo and in vitro motility and microbiological tests linked with its main pathophysiological mechanisms, were collected. Twenty-three articles were included. Twenty (87%) of these reported heterogenic preclinical studies, predominating pharmacological studies of efficacy against conventional antidiarrheal agents, which utilized relevant outcomes and models of infectious diarrhea from the top pathogens in the clinic along with classical castor oil-induced diarrhea associated with motility tests. Only three articles (13%) corresponded to clinical trials investigating the efficacy, dose and safety of these preparations. Most studies reported positive results and significant mechanistic evidence from antibacterial, anti-motility, anti-secretory and protective/anti-inflammatory perspectives. However, further studies are needed to define the clinical significance and safety treatment with P. guajava extracts. © 2024 Society of Chemical Industry.

Modified pectin with anticancer activity in breast cancer: A systematic review.

Breast cancer is the most commonly diagnosed cancer among women worldwide. The current pharmacological treatments for breast cancer have numerous adverse effects and are not always effective. Recently, the anticancer activity of modified pectins (MPs) against various types of cancers, including breast cancer, has been investigated. This systematic review was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) model, including scientific articles from the last 22 years that measured the anticancer activity of MPs on breast cancer. The articles were searched in four databases with the terms: "modified pectin" and "breast cancer". Nine articles were included, five in vitro and four mixed (in vitro and in vivo). Different models and methods by which anticancer activity was measured were analyzed. All the studies reported positive results in both cell lines and in vivo murine models of breast cancer. The extracted data suggest a positive effect and provide mechanistic evidence of MPs in the treatment of breast cancer. However, as limited number of studies were included, further in vivo studies are required to obtain more conclusive preclinical evidence.

Gastroprotective Role of Fruit Extracts in Gastric Damage Induced by Non-Steroidal Anti-Inflammatory Drugs: A Systematic Review.

The aim of this study was to systematically review the scientific literature, with Preferred Reporting Items of Systematic Reviews and Meta-analyses (PRISMA) guidelines, of the articles found in the past 11 years on the gastroprotective role of fruit extracts in gastric ulcers induced by non-steroidal anti-inflammatory drugs (NSAIDs). Scientific articles published between 2010 and 2020 were included in this systematic review, including in vitro and in vivo models, to define the gastroprotective role of fruit extracts. Studies were selected by Rayyan using PubMed, Web of Science, Scopus, and Science Direct databases. The keywords for the search strategy were: "gastric injury," "gastric ulcer," "fruit," "indomethacin," and "aspirin." Twenty-two articles with animal models of gastric ulcers were included. The NSAIDs used were aspirin and indomethacin. To know the damage caused by these, the ulceration index and biomarkers, such as aggressive/defensive factors involved in the gastric ulceration process, were measured. Most studies have shown that fruit extracts have antiulcer activity, with the most abundant metabolites being flavonoids, followed by terpenes and alkaloids. Possible antiulcer activities such as antioxidant, cytoprotective, gastric acid antisecretory, anti-inflammatory, or angiogenesis stimulant were declared, manifested mainly as a reduction of lipid peroxidation products, an increase in antioxidant enzymes and prostaglandins, and by the formation of a protective film through protein precipitation in the ulcer area. This systematic review demonstrates the importance of fruit extracts as gastric protectors.

Systematic review on the anxiolytic and hypnotic effects of flower extracts in in vivo pre-clinical studies published from 2010 to 2020.

Anxiety disorders are prevalent conditions in the world population, whose standard approaches include pharmacotherapy, psychotherapy, and combinations of these interventions. Different classes of psychopharmaceuticals are recommended as the first line of drugs to treat these disorders, which can have several adverse effects, treatment resistance, dependence, and drug-drug interactions making it necessary to search for new therapeutic agents. In particular, diazepam (DZP), a prototype drug from the group of benzodiazepines, has been commonly used and evaluated for its efficacy and safety in different anxiety disorders in clinical trials. DZP is also the most widely used reference standard in in vivo pharmacological assays of natural compounds. However, translating the results obtained in different rodent species and physiological anxiety tests instead of psychopathological animal models that can be of clinical application remains challenging. A systematic review of scientific articles published between 2010 and 2020 that included in vivo pre-clinical tests to define the anxiolytic, sedative and/or hypnotic effect of flower extracts is proposed. PRISMA and Rayyan were used for the selection of studies using four databases (Pubmed, Scopus, Web of Science, and QInsight), using the keywords: "Animals," "Anxiolytic," "Diazepam," "Elevated Plus Maze," "Flower Extracts," "Insomnia," "In vivo," "Mice," "Open Field Test," "Pre clinical" and "Sedative." The characteristics of anxiety studies in animal models, other studies related to locomotor activity, and the hypnotic effect of the extracts were compiled. Twenty-four articles were included, 21 of them performed the animal model of anxiety-like behavior of the elevated plus maze, seven the open field test, and six the light-dark box test. The locomotor activity was evaluated in 10 studies after the administration of the extracts to the animals to define their sedative effect, where only one defined that the extract (Matricaria chamomilla) had a sedative effect. The plants declared with this type of activity were Achyranthes aspera, Alcea aucheri, Brassica nigra, Cananga odorata, Carthamus tinctorius, Chrysanthemum indicum, Citrus aurantium, Couroupita guianensis, Echium amoenum, Erythrina berteroana, Gardenia jasminoides, Hibiscus tilliaceus, Lavandula officinalis, Lawsonia inermis, Matricaria chamomilla, Melia azedarach, Nerium oleander, Passiflora incarnata, Plumeria rubra, Salix aegyptiaca, Syzygium aromaticum, Tagetes erecta, Tilia americana. Although this review showed that some flower extracts have an anxiolytic effect as effective as diazepam, their therapeutic utility in anxiety disorders remains to be extensively demonstrated. Hence, more reliable and predictive behavioral tests and appropriate strategies for the experimental designs are needed to obtain more conclusive evidence with clinical significance.

Cultivo versus metagenómica para la identificación bacteriana en pacientes con osteomielitis de pie diabético: una revisión sistemática / Culture and metagenomics as bacterial identification methods in patients with diabetic foot ulcers: a systematic review

BACKGROUND: Diabetic foot osteomyelitis (DFO) is a serious complication of infected ulcers in a diabetic patient. The identification of the infecting microorganisms is generally by culture, which causes a bias. Recently, metagenomics has been used for microbial identification. AIM: To systematically review the scientific literature related to DFO in the last 10 years to evaluate if culture and metagenomics are complementary. MATERIAL AND METHODS: To carry out the systematic review, PRISMA and Rayyan were used for the selection of studies, using three databases, using the keywords diabetes, osteomyelitis, culture and microbiome. Articles in English or Spanish were included, containing information related to bacterial identification in DFO. Characteristics of the technique, patients and frequency of bacterial appearance were collected. RESULTS: Twenty six articles were included, 19 used culture and 7 metagenomics. The patients were predominantly men (68%), with an average age of 61 years, 83% had type 2 diabetes and comorbidities, mainly vascular and neuropathy. The Families with the highest frequency of appearance using the culture technique were Enterobacteriaceae (29.3%) and Staphylococcaceae(28.3%) and with metagenomics Peptoniphilaceae (22.1%) and Staphylococcaceae (9.4%). Peptoniphilaceae were not identified in culture, although they were frequently identified by metagenomics. Methicillin- resistant Staphylococcus aureus, regularly identified by culture, was not identified using metagenomics. CONCLUSIONS: Comparing results, there is a certain complementarity between microbiological culture and sequencing to identify bacteria present in DFO.

[Culture and metagenomics as bacterial identification methods in patients with diabetic foot ulcers: a systematic review]. / Cultivo versus metagenómica para la identificación bacteriana en pacientes con osteomielitis de pie diabético: una revisión sistemática.

BACKGROUND: Diabetic foot osteomyelitis (DFO) is a serious complication of infected ulcers in a diabetic patient. The identification of the infecting microorganisms is generally by culture, which causes a bias. Recently, metagenomics has been used for microbial identification. AIM: To systematically review the scientific literature related to DFO in the last 10 years to evaluate if culture and metagenomics are complementary. MATERIAL AND METHODS: To carry out the systematic review, PRISMA and Rayyan were used for the selection of studies, using three databases, using the keywords diabetes, osteomyelitis, culture and microbiome. Articles in English or Spanish were included, containing information related to bacterial identification in DFO. Characteristics of the technique, patients and frequency of bacterial appearance were collected. RESULTS: Twenty six articles were included, 19 used culture and 7 metagenomics. The patients were predominantly men (68%), with an average age of 61 years, 83% had type 2 diabetes and comorbidities, mainly vascular and neuropathy. The Families with the highest frequency of appearance using the culture technique were Enterobacteriaceae (29.3%) and Staphylococcaceae(28.3%) and with metagenomics Peptoniphilaceae (22.1%) and Staphylococcaceae (9.4%). Peptoniphilaceae were not identified in culture, although they were frequently identified by metagenomics. Methicillin- resistant Staphylococcus aureus, regularly identified by culture, was not identified using metagenomics. CONCLUSIONS: Comparing results, there is a certain complementarity between microbiological culture and sequencing to identify bacteria present in DFO.

El distrés oxidativo y sus implicaciones moleculares en algunas enfermedades infecciosas: una revisión / Oxidative distress and its molecular implication for some infectious diseases: A review

Introducción: Las especies reactivas de oxígeno, nitrógeno y azufre (ERONS) se generan continuamente en la fisiología de los organismos. Como parte de la respuesta de las células inmunitarias frente a los patógenos podrían aumentar y producir distrés oxidativo, citotoxicidad y daño de los órganos. El reconocimiento de las implicaciones moleculares de las ERONS todavía es un campo de investigación en desarrollo. Objetivo: Describir los aspectos moleculares relacionados con el metabolismo oxidativo y algunos patógenos (virus, parásitos, bacterias y hongos) en relación con las infecciones. Métodos: Se identificaron 520 documentos relacionados con los criterios de búsqueda en las bases de datos LILACS, Science Direct, SciELO, EMBASE, PubMed e Infomed, con los buscadores Google y Google académico. De estos, fueron analizados 78 documentos publicados a partir de 1980 al 2021 en español o inglés y organizados en 7 subtemas. Información, análisis y síntesis: Los agentes infecciosos y el hospedero interactúan produciendo ERONS que pueden superar los sistemas de defensa antioxidantes e influyen en el distrés oxidativo. Los procesos biológicos asociados al estado redox se relacionan con los factores de transcripción Nrf2 y NF-κB. Ambos permiten una respuesta celular entre la susceptibilidad y la resistencia a los agentes infecciosos, por lo que pueden iniciar o acelerar procesos fisiopatológicos en el organismo. En general la respuesta redox en la fisiopatología infecciosa está interconectada con la reprogramación metabólica, las respuestas antimicrobianas e inflamatorias y la disfunción celular o de tejido. Conclusiones: Los eventos moleculares redox pueden participar en diversas enfermedades infecciosas, mediando diferentes respuestas o trastornos asociados.

Introduction: Reactive oxygen/nitrogen/sulfur species (RONSS) are continuously generated in the physiology of organisms. As part of the immune cell response to pathogens, they may increase and lead to oxidative stress, cytotoxicity and organ damage. Recognizing the molecular implications of RONSS is still a developing field of research. Objective: To describe the molecular aspects related to oxidative metabolism and some pathogens (viruses, parasites, bacteria and fungi) in relation to infections. Methods: Based on the search criteria, 520 documents were identified in LILACS, Science Direct, SciELO, EMBASE, PubMed and Infomed databases, using the search engines Google and Google Scholar. Of these, 78 documents published from 1980 to 2021 in Spanish or English and organized into seven subtopics were analyzed. Information, analysis and synthesis: Infectious agents and the host interact to produce RONSS that can overcome antioxidant defense systems influencing on oxidative stress. Biological processes associated with the redox state are related to the transcription factors Nrf2 and NF-κB. Both generate a cellular response between susceptibility and resistance to infectious agents, thus they can initiate or accelerate pathophysiological processes in the organism. In general, the redox response in infectious pathophysiology is interconnected with metabolic reprogramming, antimicrobial and inflammatory responses, and cellular or tissue dysfunction. Conclusions: Molecular redox events may be involved in various infectious diseases, where different associated responses or disorders mediate.

Reactogenic sleepiness after COVID-19 vaccination. A hypothesis involving orexinergic system linked to inflammatory signals.

Coronavirus disease 2019 (COVID-19) represents a global healthcare crisis that has led to morbidity and mortality on an unprecedented scale. While studies on COVID-19 vaccines are ongoing, the knowledge about the reactogenic symptoms that can occur after vaccination and its generator mechanisms can be critical for healthcare professionals to improve compliance with the future vaccination campaign. Because sleep and immunity are bidirectionally linked, sleepiness or sleep disturbance side effects reported after some of the COVID-19 vaccines advise an academic research line in the context of physiological or pathological neuroimmune interactions. On the recognized basis of inflammatory regulation of hypothalamic neurons in sickness behavior, we hypothesized that IL-1ß, INF-γ and TNF-α pro-inflammatory cytokines inhibit orexinergic neurons promoting sleepiness after peripheral activation of the innate immune system induced by the novel COVID-19 vaccines. In addition, based on knowledge of previous vaccines and disease manifestations of SARS-CoV-2 infection, it also suggests that narcolepsy must be included as potential adverse events of particular interest to consider in pharmacovigilance studies.

Prevalence of ABCB1 3435C>T polymorphism in the Cuban population.

OBJECTIVES: ABCB1 gene polymorphisms can modify P-glycoprotein function with clinical consequences. METHODS: The 3435C>T polymorphism prevalence was analyzed using oligonucleotide probes and next-generation sequencing in 421 unrelated healthy individuals living in Cuba. Data were stratified by gender, ethnic background and residence. The genotype and allelic frequencies were determined. RESULTS: The genotype distribution met the Hardy-Weinberg equilibrium assumption. The allelic frequency was 63.5% for the 3435C variant. The genotype frequencies were 41.1% for CC, 44.9% for CT and 14.0% for TT. The allele and genotype distributions differed between individuals living in La Habana and Santiago de Cuba (p<0.05) when ethnic background was analyzed. The allelic distribution was similar among Admixed and Black subjects, and they differed from Caucasians. The CC genotype was equally distributed among Admixed and Black subjects, and they differed from Caucasians. The TT genotype frequency differed between Caucasians and Admixed. The CT genotype was distributed differently among the three groups. Similar distribution was obtained in Brazilians, whereas some similarities were observed in African, Spanish and Chinese populations, consistent with the mixed Cuban ethnic origin. CONCLUSIONS: This is the first report on allele and genotype frequencies of the 3435C>T polymorphism in Cuba, which may support personalized medicine programs.

Synergistic interaction between amitriptyline and paracetamol in persistent and neuropathic pain models: An isobolografic analysis.

The current study was designed to evaluate the transient antinociceptive interaction between amitriptyline and paracetamol in the formalin test. In addition, considering other long-term neuroprotective mechanisms of these drugs, we hypothesized that this combination might exert some synergistic effects on neuropathic pain linked with its possible ability to prevent Wallerian degeneration (WD). The effects of individual and fixed-ratio of 1:1 combinations of orally administered amitriptyline and paracetamol were assayed in the two phases of the formalin test and in the chronic constriction injury (CCI) model in rats. Isobolographic analysis was employed to characterize the synergism produced by the combinations. Amitriptyline, paracetamol, and fixed-ratio amitriptyline-paracetamol combinations produced dose-dependent antinociceptive effects mainly on the inflammatory tonic phase. Repeated doses of individual drugs and their combination decreased CCI-induced mechanical allodynia in a dose-dependent manner. ED30 (formalin) and ED50 (CCI) values were estimated for the individual drugs, and isobolograms were constructed. Theoretical ED30/50 values for the combination estimated from the isobolograms were 16.5 ± 3.9 mg/kg and 26.0 ± 7.2 mg/kg for the single and repeated doses in persistent and neuropathic pain models, respectively. These values were significantly higher than the actually observed ED30/50 values, which were 0.39 ± 0.1 mg/kg and 8.2 ± 0.8 mg/kg in each model, respectively, indicating a synergistic interaction. Remarkably, CCI-induced sciatic nerve WD-related histopathological changes were prevented by this combination compared to either drug administered alone.

Interaction of Thalassia testudinum Metabolites with Cytochrome P450 Enzymes and Its Effects on Benzo(a)pyrene-Induced Mutagenicity.

The aim of the present work was to evaluate the effects of Thalassia testudinum hydroethanolic extract, its polyphenolic fraction and thalassiolin B on the activity of phase I metabolizing enzymes as well as their antimutagenic effects. Spectrofluorometric techniques were used to evaluate the effect of tested products on rat and human CYP1A and CYP2B activity. The antimutagenic effect of tested products was evaluated in benzo[a]pyrene (BP)-induced mutagenicity assay by an Ames test. Finally, the antimutagenic effect of Thalassia testudinum (100 mg/kg) was assessed in BP-induced mutagenesis in mice. The tested products significantly (p < 0.05) inhibit rat CYP1A1 activity, acting as mixed-type inhibitors of rat CYP1A1 (Ki = 54.16 ± 9.09 µg/mL, 5.96 ± 1.55 µg/mL and 3.05 ± 0.89 µg/mL, respectively). Inhibition of human CYP1A1 was also observed (Ki = 197.1 ± 63.40 µg/mL and 203.10 ± 17.29 µg/mL for the polyphenolic fraction and for thalassiolin B, respectively). In addition, the evaluated products significantly inhibit (p < 0.05) BP-induced mutagenicity in vitro. Furthermore, oral doses of Thalassia testudinum (100 mg/kg) significantly reduced (p < 0.05) the BP-induced micronuclei and oxidative damage, together with an increase of reduced glutathione, in mice. In summary, Thalassia testudinum metabolites exhibit antigenotoxic activity mediated, at least, by the inhibition of CYP1A1-mediated BP biotransformation, arresting the oxidative and mutagenic damage. Thus, the metabolites of T. testudinum may represent a potential source of chemopreventive compounds for the adjuvant therapy of cancer.

Anti-hypernociceptive and anti-inflammatory effects of JM-20: A novel hybrid neuroprotective compound.

The present study examines the possible effect of the novel hybrid molecule JM-20 (3-ethoxycarbonyl-2-methyl-4-(2-nitrophenyl)-411-dihydro-1H-pyrido[2,3-b] [1,5] benzodiazepine) on pain-related behaviours in a persistent pain model (5% formalin test) and in the neutrophil migration events during the inflammatory process. It further introduces JM-20 in a chronic constriction injury (CCI) model to clarify the possible subjacent mechanisms with its consequent clinical relevance. A single administration of JM-20 (20 or 40 mg/kg, per os [p.o.]) decreased licking/biting exclusively in the tonic phase of the formalin test in a GABA/benzodiazepine (BZD) receptor antagonist flumazenil-sensitive manner. JM-20 reduced in vivo neutrophil migration, rolling and adhesion to the endothelium induced by intraperitoneal administration of carrageenan in mice. In addition, plasma extravasation and tumour necrosis factor alpha production in the peritoneal fluid were decreased. Treatment with JM-20 (20 mg/kg, p.o.) for 7 days after CCI reduced mechanical hypersensitivity in a NG-monomethyl-l-arginine (L-NMMA)/methylene blue/glibenclamide-sensitive manner. Histopathological signs of Wallerian degeneration (WD) of the sciatic nerve were also attenuated, as well as interleukin-1 beta release in the spinal cord. The nitrate/nitrite concentration was increased centrally and did not show differences at the peripheral nerve level. The findings of this study suggest JM-20 can decrease persistent pain. A transient activity of its BDZ portion on nociceptive pathways mediated by GABA/BDZ receptors in association with its anti-inflammatory properties could be at least partially involved in this effect. JM-20 decreased CCI-induced mechanical hypersensitivity via the l-arginine/nitric oxide (NO)/cyclic GMP-sensitive ATP-sensitive potassium channel pathway. Its neuroprotective ability by preventing WD could be implicated in its anti-neuropathic mechanisms.

Polyphenolic Fraction Obtained From Thalassia testudinum Marine Plant and Thalassiolin B Exert Cytotoxic Effects in Colorectal Cancer Cells and Arrest Tumor Progression in a Xenograft Mouse Model.

Marine plants are important sources of pharmacologically active metabolites. The aim of the present work was to evaluate the cytotoxic and antitumor activity of a polyphenolic fraction obtained from Thalassia testudinum marine plant and thalassiolin B in human colorectal cancer cells. Human cancer cell lines, including HCT15, HCT116, SW260, and HT29 were treated with tested products for cytotoxicity evaluation by crystal violet assay. The potential proapoptotic effect of these natural products was assessed by flow cytometry in HCT15 cells at 48 h using Annexin V-FITC/propidium iodide. In addition, reactive oxygen species (ROS) generation was measured by fluorescence using DCFH-DA staining, and sulfhydryl concentration by spectrophotometry. The in vivo antitumor activity of the polyphenolic fraction (25 mg/kg) was evaluated in a xenograft model in nu/nu mice. In vivo proapoptotic effect was also evaluated by immunohistochemistry using anti-caspase 3 and anti-Bcl-2 antibodies. The results showed that tested products exert colorectal cancer cell cytotoxicity. Besides, the tested products induced a significant increase (p < 0.05) of intracellular ROS generation, and a depletion of sulfhydryl concentration in HCT15 cells. The polyphenolic fraction arrested tumor growth and induced apoptosis in the xenograft mice model. These results demonstrate the cytotoxic activity of T. testudinum metabolites associated, at least, with ROS overproduction and pro-apoptotic effects. Here we demonstrated for the first time the antitumor activity of a T. testudinum polar extract in a xenograft mice model. These results suggest the potential use of T. testudinum marine plant metabolites as adjuvant treatment in cancer therapy.

Mangiferin: Possible uses in the prevention and treatment of mixed osteoarthritic pain.

Osteoarthritis (OA) pain has been proposed to be a mixed pain state, because in some patients, central nervous system factors are superimposed upon the more traditional peripheral factors. In addition, a considerable amount of preclinical and clinical evidence has shown that, accompanying the central neuroplasticity changes and partially driven by a peripheral nociceptive input, a real neuropathic component occurs that are particularly linked to disease severity and progression. Hence, innovative strategies targeting neuroprotection and particularly neuroinflammation to prevent and treat OA pain could be introduced. Mangiferin (MG) is a glucosylxanthone that is broadly distributed in higher plants, such as Mangifera indica L. Previous studies have documented its analgesic, anti-inflammatory, antioxidant, neuroprotective, and immunomodulatory properties. In this paper, we propose its potential utility as a multitargeted compound for mixed OA pain, even in the context of multimodal pharmacotherapy. This hypothesis is supported by three main aspects: the cumulus of preclinical evidence around this xanthone, some preliminary clinical results using formulations containing MG in clinical musculoskeletal or neuropathic pain, and by speculations regarding its possible mechanism of action according to recent advances in OA pain knowledge.

Anti-allodynic Effect of Mangiferin in Rats With Chronic Post-ischemia Pain: A Model of Complex Regional Pain Syndrome Type I.

The present study reproduces chronic post-ischemia pain (CPIP), a model of complex regional pain syndrome type I (CRPS-I), in rats to examine the possible transient and long-term anti-allodynic effect of mangiferin (MG); as well as its potential beneficial interactions with some standard analgesic drugs and sympathetic-mediated vasoconstriction and vasodilator agents during the earlier stage of the pathology. A single dose of MG (50 and 100 mg/kg, p.o.) decreased mechanical allodynia 72 h post-ischemia-reperfusion (I/R). MG 100 mg/kg, i.p. (pre- vs. post-drug) increased von Frey thresholds in a yohimbine and naloxone-sensitive manner. Sub-effective doses of morphine, amitriptyline, prazosin, clonidine and a NO donor, SIN-1, in the presence of MG were found to be significantly anti-allodynic. A long-term anti-allodynic effect at 7 and 13 days post-I/R after repeated oral doses of MG (50 and 100 mg/kg) was also observed. Further, MG decreased spinal and muscle interleukin-1ß concentration and restored muscle redox status. These results indicate that MG has a transient and long-term anti-allodynic effect in CPIP rats that appears to be at least partially attributable to the opioid and α2 adrenergic receptors. Additionally, its anti-inflammatory and antioxidant mechanisms could also be implicated in this effect. The association of MG with sub-effective doses of these drugs enhances the anti-allodynic effect; however, an isobolographic analysis should be performed to define a functional interaction between them. These findings suggest the possible clinical use of MG in the treatment of CRPS-I in both early sympathetically maintained pain and long-term sympathetically independent pain.

Comparative study of anti-inflammatory activity and qualitative-quantitative composition of triterpenoids from ten genotypes of Ugni molinae / Estudio comparativo de la actividad antiinflamatoria y composición química cualitativa y cuantitativa de triterpenoides de diez genotipos de Ugni molinae

The aim of this study was to assess the differences in qualitative-quantitative composition of triterpenoids and total phenolic contents, together with anti-inflammatory activity of Ugni molinae leaves obtained from ten genotypes. The ethyl acetate (EAE) and ethanol extracts (ETE) were obtained and analyzed. The plant genotypes were grown under same soil and climate conditions and under same agronomic management; the leaves were also harvested under the same conditions. Anti-inflammatory activity was evaluated by mice ear edema induced by 12-O-tetradecanoylphorbol-13-acetate (TPA) at a single dose of 200 mg/kg BW of each extract. Composition of triterpenoids and total phenolic contents was determined by HPLC-DAD and Folin-Ciocalteu method, respectively. Ugni molinae leaves of different plant genotypes exhibited significant differences in regard to their anti-inflammatory activity, as well as in qualitative-quantitative composition of triterpenoids and total phenolic content.

El objetivo de este estudio fue establecer las diferencias en la composición cualitativa y cuantitativa de triterpenoides y en los contenidos totales de fenoles, junto con la actividad antiinflamatoria de las hojas de Ugni molinae provenientes de diez genotipos. Los extractos de acetato de etilo (EAE) y etanólicos (ETE) fueron obtenidos y analizados. Los genotipos fueron cultivados bajo las mismas condiciones edafo-climáticas y con el mismo manejo agronómico; las hojas fueron cosechadas bajo las mismas condiciones. La actividad antiinflamatoria fue evaluada en ratones a los que se les indujo un edema en la oreja mediante la aplicación del 12-O-tetradecanoilforbol-13 acetato (TPA) y los extractos fueron evaluados a una dosis única de 200 mg/kg de peso corporal. La composición en triterpenoides y los contenidos de fenoles totales fueron determinados por CLAE-DAD y por el método de Folin-Ciocalteu, respectivamente. Las hojas provenientes de los diferentes genotipos de U. molinae, exhibieron significativas diferencias en sus actividades antiinflamatorias, así como, en el contenido cualitativo y cuantitativo de triterpenoides y en el contenido de fenoles totales.

Anti-hypernociceptive effect of mangiferin in persistent and neuropathic pain models in rats.

The present study examines the possible effect of the glucosylxanthone mangiferin (MG) on pain-related behaviors in a tonic acute pain model (formalin test at 5%) and in a chronic constriction injury (CCI) model to clarify the underlying transient and long-term mechanisms. Acute administration of MG (10-100mg/kg, i.p.) reduced licking/biting exclusivity in the tonic phase of formalin test in a naloxone and yohimbine-sensitive manner. This effect was enhanced by a nonselective nitric oxide synthase (NOS) inhibitor (NG-monomethyl-L-arginine) and by a non-competitive N-methyl-D-aspartate (NMDA) antagonist (ketamine), but it was reversed by the NOS substrate (L-arginine). Pre-treatment with intrathecal yohimbine prevented the anti-hypernociceptive effect of systemic MG. Pre-treatment during 4 days before surgical and 3 days after CCI with MG (50mg/kg, i.p.) reduced mechanical hypernociception and decreased the signs of Wallerian degeneration (WD) of the sciatic nerve. MG improved the PC-12 cellular viability exposure to glutamate-mediated neuronal death, also involved in neuropathic pain. The findings of this study suggest that MG shows ability to decrease tonic pain in the formalin test. A transient activity of this xanthone on nociceptive pathways mediated by α2 adrenergic receptors in cooperation with the opioid system could be involved, at least in part, in this effect. Its neuroprotective effect by preventing WD in mononeuropathic rats could be implicated in the mechano-antihypernociceptive long term mechanisms.

Antihyperalgesic effects of an aqueous stem bark extract of Mangifera indica L.: role of mangiferin isolated from the extract.

This study aimed to assess the effects of a Mangifera indica stem bark extract (MSBE) and mangiferin (MG) on pain-related acute behaviors in the formalin 5% test. Rats received repeated oral MSBE (125-500 mg/kg) once daily for 7 days before formalin injection. Other four groups with the same treatments were performed in order to study the effect of MSBE on the formalin-induced long-term secondary mechano-hyperalgesia at 7 days after the injury by means of the pin-prick method. Additional groups received a single oral MSBE dose (250 mg/kg) plus ascorbic acid (1 mg/kg, i.p.). Also, repeated oral MG doses (12.5-50 mg/kg) during 7 days were administered. MSBE decreased licking/biting and flinching behaviors only in phase II and reduced the long-term formalin injury-induced secondary chronic mechano-hyperalgesia. The combination of MSBE plus ascorbic acid produced a reinforcement of this effect for flinching behavior, advising that antioxidant mechanisms are involved, at least in part, in these actions. Chronic administration of MG reproduced the effects of MSBE. For the first time, the antihyperalgesic effects of MSBE and MG in formalin 5% test, a recommended concentration for studying the antinociceptive activity of nitric oxide-related and N-methyl-d-aspartate-related compounds, were reported. These results could represent an important contribution to explain the analgesic ethnobotanical effects recognized to M. indica and other species containing MG.

Combination of Mangifera indica L. extract supplementation plus methotrexate in rheumatoid arthritis patients: a pilot study.

The purpose of the present study was to evaluate the possible therapeutic effects and the safety of Mangifera indica extract (Vimang tablets, 300 mg) combined with methotrexate (MTX) on reducing disease activity in rheumatoid arthritis (RA). Twenty patients with active RA underwent a year of treatment with MTX (12.5 mg/week) associated to non-steroidal anti-inflammatory drugs (NSAIDs) and/or prednisone (5-10 mg/day) were randomly allocated to the experimental group (n=10), that received the extract supplementation (900 mg/day) or preceding usual treatment (n=10) during 180 days. RA activity was evaluated using the tender and swollen joint counts, erythrocyte sedimentation rate, disease activity score-28 (DAS 28), visual analogue scale (VAS) and health assessment questionnaire (HAQ). Treatment's efficacy was demonstrated with ACR criteria. Only the patients of MTX-Vimang group revealed statistically significant improvement in DAS 28 parameters with respect baseline data but no differences were observed between groups. ACR improvements amounted 80% only in MTX-Vimang group at the 90 days (p<0.001). In MTX-Vimang group, 100% of patients decreased NSAIDs administration (p<0.01) and 70% of those eradicated gastrointestinal side effects (p<0.01) ensuing of the preceding treatment. Other adverse effects were not reported.

Effects of Zuccagnia punctata extracts and their flavonoids on the function and expression of ABCB1/P-glycoprotein multidrug transporter.

ETHNOPHARMACOLOGICAL RELEVANCE: Zuccagnia punctata extracts (ZpE) are used in ethnomedicine as antimicrobial and anti-inflammatory drugs. The pharmacological properties of ZpE and their polyphenolic components suggest that they may be used as potential modulators on the P-glycoprotein (P-gp) multidrug transporter. P-gp is well known for its role in the acquired drug resistance by tumors following chemotherapy, causing a low drug bioavailability by extruding them out of the cells. AIM OF STUDY: To evaluate the effects of ZpE and three of their phenolic components: 7-hydroxyflavanone (HF), 3,7-dihydroxyflavone (DHF) and 2',4'-dihydroxychalcone (DHC) on P-gp activity and expression. MATERIAL AND METHODS: The effects of natural products on ABCB1/P-gp function and expression were evaluated by R-123 accumulation assay and western blot analysis using HK-2 cells as experimental model. The ABCB1 mRNA content was determined by SQRT-PCR. RESULTS: The accumulation of R-123 in HK-2 cells was significantly increased by ZpE and DHF, and to a lesser extent by DHC, indicating their roles on the efflux transporter activity. However, HF did not show any effect. HK-2 cells maintained in the presence of ZpE or DHF for 72 h, showed an increase in P-gp expression whereas activity was unchanged or decreased. No changes were observed in ABCB1 mRNA content. Furthermore, in these assay conditions, more sensibility of HK-2 cells to the cytotoxic action of cyclosporine A (P-gp substrate) was observed. CONCLUSION: These results may suggest an impact of Zuccagnia punctata and some of its components on the pharmacokinetics of drugs that are P-gp substrates, as well as a potential role on multidrug resistance modulation.