Brazilian Amazon Red Propolis: Leishmanicidal Activity and Chemical Composition of a New Variety of Red Propolis.

Leishmaniasis is caused by protozoans of the genus Leishmania, and its treatment is highly toxic, leading to treatment discontinuation and the emergence of resistant strains. In this study, we assessed the leishmanicidal activity and chemical composition of red propolis collected from the Amazon-dominated region of northern Tocantins State, Brazil. The MTT assay was employed to determine the samples' activity against Leishmania amazonensis promastigotes and their cytotoxicity against RAW macrophages. Spectrophotometric assays were utilised to measure the concentrations of total phenolics and flavonoids, while high-performance liquid chromatography coupled to a mass spectrometer (LC-MS/MS) was used to determine the chemical composition. An in silico study was conducted to evaluate which compounds from Brazilian Amazon red propolis may correlate with this biological activity. Brazilian Amazon red propolis exhibited a high concentration of phenolic compounds and an inhibitory activity against L. amazonensis, with an IC50 ranging from 23.37 to 36.10 µg/mL. Moreover, fractionation of the propolis yielded a fraction with enhanced bioactivity (16.11 µg/mL). Interestingly, neither the propolis nor its most active fraction showed cytotoxicity towards macrophages at concentrations up to 200 µg/mL. The red colour and the presence of isoflavonoid components (isoflavones, isoflavans, and pterocarpans) confirm that the substance is Brazilian red propolis. However, the absence of polyprenylated benzophenones suggests that this is a new variety of Brazilian red propolis. The in silico study performed with two of the main leishmanicidal drug targets using all compounds identified in Amazon red propolis reported that liquiritigenin was the compound that exhibited the best electronic interaction parameters, which was confirmed in an assay with promastigotes using a standard. The findings indicate that Amazon red propolis possesses leishmanicidal activity, low toxicity, and significant biotechnological potential.

Molecular mechanisms of action and chemosensitization of tumor cells in ovarian cancer by phytochemicals: A narrative review on pre-clinical and clinical studies.

Ovarian cancer is the second-leading cause of death among women with cancer of the genital tract. Currently, drugs derived from platinum and taxanes constitute the majority of ovarian cancer treatments. Patients undergoing this chemotherapy are susceptible to cumulative toxic effects and resistance to chemotherapy. Therefore, it is crucial to identify treatment options that are both more effective and better tolerated by patients. Phytochemicals in this context are plant-derived chemicals with antitumor activity that can be used as therapeutic or adjuvant agents in the treatment of ovarian cancer. Consequently, the purpose of this literature review is to demonstrate through existing pre-clinical and clinical trials the potential of phytochemicals in the treatment of ovarian cancer, the mechanisms of action involved, and to contribute to the development of new therapeutic options for ovarian cancer. For this review, the databases PubMed, Scopus, Science Direct, and ClinicalTrials.gov were queried between 2010 and 2022 using terms such as "ovarian cancer," "phytochemicals," "phenolic compounds," "terpenes," and "alkaloids." The present review summarized the possible molecular mechanisms of action by which phytochemicals, such as phenolic acids, flavonoids, diterpenes, triterpenes, saponins, and alkaloids, inhibit this type of cancer, specifically the ability of phytochemicals to induce cell growth regulation, apoptosis, oxidative stress reduction, anti-angiogenesis, and chemosensitization of tumors in ovarian cancer. As their action and cellular mechanism have already been demonstrated in several pre-clinical trials, the phytochemicals identified in our study have the potential to be investigated for the treatment of ovarian cancer. Through pre-clinical and clinical trials, our study demonstrates the potential of phytochemicals in the treatment of ovarian cancer, contributing to the development of novel therapeutic options for ovarian cancer.

Cuminaldehyde Effects in a MIA-Induced Experimental Model Osteoarthritis in Rat Knees.

Osteoarthritis (OA) is a chronic degenerative disease that has a significant global impact. It is associated with aging and characterized by widespread joint destruction. Cuminaldehyde is a biologically active component of essential oils that has shown promise in the treatment of nociceptive and inflammatory diseases. This study investigated the effects of cuminaldehyde on an experimental model of osteoarthritis induced in rat knees. Cuminaldehyde was found to be as effective as indomethacin in reducing pain in all evaluated tests, including forced walking, functional disability of weight distribution on the legs, and spontaneous pain in animals with osteoarthritis. The knees of animals treated with cuminaldehyde had significantly higher radiographic and histopathological scores than those of animals that did not receive the treatment. Cuminaldehyde also modulated the production of pro-inflammatory cytokines. In vitro assays showed that cuminaldehyde preferentially inhibits COX-2 enzyme activity. In silico studies demonstrated that cuminaldehyde has satisfactory energy affinity parameters with opioid receptors and COX-2. These findings suggest that cuminaldehyde's anti-inflammatory activity is multifactorial, acting through multiple pathways. Its nociceptive activity occurs via central and peripheral mechanisms. Cuminaldehyde modulates the immune response of the inflammatory process and may be considered a leading compound for the development of new anti-inflammatory and analgesic drugs.

Anti-Candida albicans Activity of Ononin and Other Secondary Metabolites from Platonia Insignis MART.

Candida albicans is a human pathogen that is part of the healthy microbiome. However, it is often associated with opportunistic fungal infections. The treatment of these infections is challenging because prolonged exposure to antifungal drugs can culminate in fungal resistance during therapy, and there is a limited number of available drugs. Therefore, this study investigated the antifungal activity of ononin by in silico and in vitro assays, and in Tenebrio molitor as an alternative in vivo model of infection caused by C. albicans. Ononin is an isoflavone glycoside derived from formononetin that has various biological activities. According in silico evaluation, ononin showed the best electron affinity in molecular docking with CaCYP51, with a binding free energy of -10.89 kcal/mol, superior to that of the antifungal drugs fluconazole and posaconazole. The ononin + CaCYP51 complex formed hydrogen bonds with Tyr132, Ser378, Phe380, and Met508, as well as hydrophobic connections with Tyr118, Leu121, Phe126, Leu131, Ile304, and Leu309, and interactions with the heme group. Ononin exerted anti-Candida albicans activity, with MIC between 3.9 and 7.8 µg/mL, and inhibited young and mature biofilms, with a reduction in cell density and metabolic activity of 50 to 80%. The compound was not cytotoxic to sheep red blood cells at concentrations up to 1000 µg/mL. Larvae of the mealworm T. molitor were used as an alternative in vivo model of C. albicans infection. Ononin was able to prolong larval survival at concentrations of 0.5, 1, and 5 mg/kg, and was not toxic up to a concentration of 20 mg/kg. Moreover, ononin reduced the fungal charge in treated animals. In conclusion, our results suggest that ononin has anti-Candida albicans activity and is a potential candidate for the development of new therapeutic alternatives.

Plant Metabolites as SARS-CoV-2 Inhibitors Candidates: In Silico and In Vitro Studies.

Since it acquired pandemic status, SARS-CoV-2 has been causing all kinds of damage all over the world. More than 6.3 million people have died, and many cases of sequelae are in survivors. Currently, the only products available to most of the world's population to fight the pandemic are vaccines, which still need improvement since the number of new cases, admissions into intensive care units, and deaths are again reaching worrying rates, which makes it essential to compounds that can be used during infection, reducing the impacts of the disease. Plant metabolites are recognized sources of diverse biological activities and are the safest way to research anti-SARS-CoV-2 compounds. The present study computationally evaluated 55 plant compounds in five SARS-CoV-2 targets such Main Protease (Mpro or 3CL or MainPro), RNA-dependent RNA polymerase (RdRp), Papain-Like Protease (PLpro), NSP15 Endoribonuclease, Spike Protein (Protein S or Spro) and human Angiotensin-converting enzyme 2 (ACE-2) followed by in vitro evaluation of their potential for the inhibition of the interaction of the SARS-CoV-2 Spro with human ACE-2. The in silico results indicated that, in general, amentoflavone, 7-O-galloylquercetin, kaempferitrin, and gallagic acid were the compounds with the strongest electronic interaction parameters with the selected targets. Through the data obtained, we can demonstrate that although the indication of individual interaction of plant metabolites with both Spro and ACE-2, the metabolites evaluated were not able to inhibit the interaction between these two structures in the in vitro test. Despite this, these molecules still must be considered in the research of therapeutic agents for treatment of patients affected by COVID-19 since the activity on other targets and influence on the dynamics of viral infection during the interaction Spro x ACE-2 should be investigated.

Use of Stingless Bee Propolis and Geopropolis against Cancer-A Literature Review of Preclinical Studies.

Cancer is one of the major maladies affecting humankind and remains one of the leading causes of death worldwide. The investigation of the biological activities of stingless bee products, especially propolis and geopropolis, has revealed promising therapeutic properties, especially in the research on new antineoplastic agents. This literature review of preclinical trials, involving biological assays of antitumor activity and identification of the chemical composition of propolis and geopropolis of stingless bee species, describes the cytotoxicity in tumor lineages (breast, lung, ovarian, liver, mouth, pharynx, larynx, colon, stomach, colorectal, cervix, kidney, prostate, melanoma, human glioblastoma, canine osteosarcoma, erythroleukemia, human chronic myelocytic leukemia, and human promyelocytic leukemia) of propolis and geopropolis of 33 species of stingless bees. The chemical composition of propolis and geopropolis was identified, indicating that these belong to the chemical classes of phenolic acids, flavonoids, coumarins, benzophenones, anthraquinones, alkaloids, terpenes, steroids, saponins, fatty acids, and carbohydrates and are possibly responsible for the cytotoxicity in tumor cells. Apoptosis was one of the main mechanisms of cytotoxicity of extracts and substances isolated from stingless bee products. Although the results found are encouraging, other preclinical studies and clinical trials are essential for the discovery of new anticancer agents.

Arrabidaea chica Verlot fractions reduce MIA-induced osteoarthritis progression in rat knees.

This study aims to investigate the activity of n-hexane, ethyl acetate and butanol fractions obtained from Arrabidaea chica Verlot against MIA-induced osteoarthritis (OA). The antinociceptive potentials of each fraction were evaluated through a cyclooxygenase (COX) 1 and 2 inhibition test and an in vivo OA-model. In addition, toxicity assessments in the liver, spleen and kidney, as well as radiographic and histopathological knee analyses, were performed. The chemical composition of the n-hexane fraction was elucidated, and a molecular docking protocol was carried out to identify which compounds are associated with the detected bioactivity. The n-hexane A. chica fraction preferentially inhibits COX-2, with 90% inhibition observed at 10 µg/mL. The fractions also produced significant improvements in OA incapacity, motor activity and hyperalgesia parameters and in radiological knee conditions. However, concerning the histopathological evaluations, these improvements were only significant in the hexane and ethyl acetate fraction treatments, which resulted in better average scores, suggesting that these fractions slow OA-promoted joint injury progression. Histopathological organ analyses indicate that the fractions are not toxic to animals. Twenty compounds were identified in the n-hexane fraction, comprising fatty acids, terpenes and phytosterols. In silico analyses indicate the presence of favourable interactions between some of the identified compounds and the COX-2 enzyme, mainly concerning alpha-tocopherol (Vitamin E), squalene and beta-sitosterol. The findings indicate that A. chica fractions display analgesic, anti-inflammatory properties, are non-toxic and are able to slow OA progression, and may, therefore, be prioritized as natural products in OA human clinical trials.

Cytotoxicity and Pro-Apoptotic, Antioxidant and Anti-Inflammatory Activities of Geopropolis Produced by the Stingless Bee Melipona fasciculata Smith.

Geopropolis is produced by some stingless bee species, such as Melipona fasciculata Smith, a native species from Brazil. This study aims to investigate the antioxidant and anti-inflammatory activities and cytotoxicity effects of geopropolis hydroethanolic extracts against lung (H460 and A549) and ovarian (A2780 and ES2) cancer cell lines and non-tumor (HUVEC) cell lines using chemical identification by LC/MS/MS analysis and in silico assays to determine which compounds are associated with bioactivity. The antioxidant activity of extracts and inhibitory activity against COX enzymes were assessed by in vitro assays; cytotoxicity effect was evaluated by the MTT assay; cell cycle was assessed by flow cytometry and apoptosis by Western blotting. The geopropolis extracts showed great radical scavenging potential, preferential inhibition of COX-2, decreased cancer cell viability, non-cytotoxic effects against the non-tumoral cell line, besides modulating the cell cycle and inducing cancer cell apoptosis through the activation of caspase-3 and PARP protein cleavage. The in silico study suggests that corilagin, typhaneoside, taraxerone and marsformosanone, identified by LC/MS/MS, can be associated with anti-inflammatory activity and cytotoxic effects. Thus, the current study suggests the potential of geopropolis concerning the research field of new pharmacological alternatives regarding cancer therapy.

Anti-Inflammatory and Antioxidant Activity of Pollen Extract Collected by Scaptotrigona affinis postica: in silico, in vitro, and in vivo Studies.

Bees are of great importance for plant diversity for being an important pollinating agents. Stingless bees such as Scaptotrigona affinis postica, is cultivated largely due to the products offered by it. Pollen is one of these products, which has been highlighted for exhibit various therapeutic properties. Considering the bioactivity of this natural product, this study investigated the antioxidant, anti-inflammatory, antinociceptive activities, and elucidated the chemical composition of pollen collected extract by Scaptotrigona affinis postica. Using in vitro assays, the antioxidant potential and inhibitory activity against the COX enzyme from pollen extract was evaluated. Additionally, tests were performed to measure the anti-inflammatory and antinociceptive activities in animal models. In our results, we found that pollen extract showed antioxidant effects and inhibitory activity against the COX enzyme. The in vivo assays showed that the extract acts on the nervous system in local and systemic levels and that the anti-inflammatory activity is due the prostanoids reducing. Chemical analyses recognize 10 molecules in the extract belonging to the polyphenol and flavonoids classes and the computational study suggests that is responsible for the observed results. Thus, it is reported for the first time the biological potential of S. aff. postica pollen extract and we conclude that this bee product can be considered as one source of potential new drugs.

Anti-Inflammatory and Antinociceptive Activity of Pollen Extract Collected by Stingless Bee Melipona fasciculata.

The stingless bee, Melipona fasciculata Smith (Apidae, Meliponini), is a native species from Brazil. Their products have high biotechnological potential, however there are no studies about the biological activities of pollen collected by M. fasciculata. In this context, the present study investigated the chemical composition, anti-oxidant, anti-inflammatory, and analgesic activities of hydroethanolic pollen extracts collected by M. fasciculata in three cities in Maranhão State, Brazil. We verified the antioxidant activity of the extracts and inhibitory activity against the cyclooxygenase enzyme using in vitro assays and in allowed to select the extract with higher efficiency to be used on in vivo assays. In these trials, the selected extract showed high anti-inflammatory activity as well as nociceptive effects at central and peripheral level, suggesting that this extract acts on inhibition of histamine release and decreased synthesis of prostaglandins and the in-silico study suggested that polyphenols and acids fatty acids in the extract may be associated with these activities. The results of the present study report the high biological potential of pollen extract and we conclude that the pollen collected by M. fasciculata can be considered as the object of research for new pharmacological alternatives.

Effects of Extract of Arrabidaea chica Verlot on an Experimental Model of Osteoarthritis.

The aim of this study was to analyze the analgesic potential of Arrabidaea chica extract (EHA) as an alternative to osteoarthritis (OA) treatment. Thus, the extract was initially evaluated by the cyclooxygenase inhibition test. The analgesic effect of the extract, in vivo, was also verified in a model of OA induced by sodium monoiodoacetate (2 mg). EHA was administered to rats at doses of 50, 150, and 450 mg/kg between 3 and 25 days after OA induction. The animals were clinically evaluated every 7 days, euthanized at 29 days, and the liver, spleen, kidney and knee collected for histopathological analysis. The chemical composition of EHA was identified by HPLC-MS and the identified compounds submitted to molecular docking study. The results showed that the extract promoted cyclooxygenase inhibition and produced significant improvements in disability, motor activity, hyperalgesia, and OA-induced allodynia parameters, in addition to improvements in the radiological condition of the knees (but not observed in the histopathological study). Chemically the extract is rich in flavonoids. Among them, we evidence that amentoflavone showed very favorable interactions with the enzyme COX-2 in the in silico analysis. Thus, it is concluded that A. chica has important analgesic properties for the treatment of OA.

Therapeutic Use of Scoparia dulcis Reduces the Progression of Experimental Osteoarthritis.

Pain is recognized as one of the main symptoms in knee osteoarthritis and is the main reason why patients seek medical attention. Scoparia dulcis has been popularly used to relieve discomfort caused by various painful conditions. The objective of the study is to evaluate the analgesic and anti-inflammatory effect of the crude extract of S. dulcis, in an experimental model of osteoarthritis. The experiment was performed with Wistar rats divided into 4 groups with 5 animals each: healthy, saline, crude extract, and meloxicam groups. Knee osteoarthritis was induced by intra-articular injection of sodium mono-iodoacetate. First, clinical parameters of pain were assessed at days 0, 5, 10, 15, and 20 after induction. Second, the potential cyclooxygenase inhibition was evaluated, and the cytokines of the synovial fluid were quantified. An in silico test and Molecular Docking tests were performed. A histopathological evaluation was made on articular cartilage with safranin O staining. The results showed that a 15-day treatment with crude extract reduced edema, spontaneous pain, peripheral nociceptive activity, and proinflammatory cytokines in the synovial fluid. The highest inhibition of cyclooxygenase 2 in the crude extract occurred at 50 µg/mL. The crude extract of S. dulcis presents therapeutic potential for the treatment of osteoarthritis due to its anti-inflammatory and anti-nociceptive action.