Brazilian essential oils as source for the discovery of new anti-COVID-19 drug: a review guided by in silico study.

The emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in China and its spread worldwide has become one of the biggest health problem due to the lack of knowledge about an effective chemotherapy. Based on the current reality of the SARS-CoV-2 pandemic, this study aimed to make a review literature about potential anti-coronavirus natural compounds guided by an in silico study. In the first step, essential oils from native species found in the Brazilian herbal medicine market and Brazilian species that have already shown antiviral potential were used as source for the literature search and compounds selection. Among these compounds, 184 showed high antiviral potential against rhinovirus or picornavirus by quantitative structure-activity relationship analysis. (E)-α-atlantone; 14-hydroxy-α-muurolene; allo-aromadendrene epoxide; amorpha-4,9-dien-2-ol; aristochene; azulenol; germacrene A; guaia-6,9-diene; hedycaryol; humulene epoxide II; α-amorphene; α-cadinene; α-calacorene and α-muurolene showed by a molecular docking study the best result for four target proteins that are essential for SARS-CoV-2 lifecycle. In addition, other parameters obtained for the selected compounds indicated low toxicity and showed good probability to achieve cell permeability and be used as a drug. These results guided the second literature search which included other species in addition to native Brazilian plants. The majority presence of any of these compounds was reported for essential oils from 45 species. In view of the few studies relating essential oils and antiviral activity, this review is important for future assays against the new coronavirus. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s11101-021-09754-4.

In silico approach of secondary metabolites from Brazilian herbal medicines to search for potential drugs against SARS-CoV-2.

The new severe acute respiratory syndrome coronavirus (SARS-CoV-2) recently emerged as a worrying pandemic, with many confirmed cases and deaths globally. Therefore, there is a clear need for identifying effective therapeutic options and a review of secondary metabolites related to Brazilian herbal medicines was performed as a strategy for the discovery of new antiviral agents. To confirm this potential, an in silico screening of the identified compounds identified was also evaluated. The review was performed by the PubMed database and the selected natural compounds were subjected to in silico analysis such as QSAR, molecular docking and ADMET. 497 secondary metabolites were identified from 23 species. The in silico assays indicated 19 potential anti-SARS-CoV-2 compounds, being triterpenes and phenolic compounds. The indicated compounds showed a high affinity with proteins considered as the main molecular targets against SARS-CoV-2 and parameters indicated low toxicity. In addition to Brazilian medicinal plants, these compounds can be found in other species and they can be a base for the synthesis of other anti-COVID-19 drugs. Therefore, this review is important to conduct researches that address the emerging need for drugs in COVID-19 treatment.

Melaleuca leucadendra Essential Oil Promotes Loss of Cell Membrane and Wall Integrity and Inhibits Bacterial Growth: An In Silico and In Vitro Approach.

Essential oils are potential antimicrobial agents and can be used as active ingredients in the pharmaceutical, food and cosmetics industries. This work intends to evaluate the antibacterial activity and design a strategy for the proposition of the mechanism of action of Melaleuca leucadendra essential oil. Optimum concentration of the bacteria and the phase where they had the highest pathogenic activity were determined. Results show that for each microorganism it is necessary to use a different concentration at the time of adjusting the initial inoculum, and that the time to achieve exponential growth phase varies from one to the other. M. leucadendra essential oil demonstrated in vitro antimicrobial properties. This oil was chemically characterized and the main compounds were evaluated by their mechanism of antibacterial action based on structure-activity analysis. The mechanism is related to the increase of bacteria cell membrane permeability. This indication was confirmed by flow cytometry and transmission electronic microscopy. Thus, in silico analysis is an important tool in the search for new antimicrobial agents and these results showed that M. leucadendra essential oil may be useful on the development of new chemotherapies or food preservation systems.

Herbal medicines to the treatment of skin and soft tissue infections: advantages of the multi-targets action.

The research for new treatments of skin and soft tissue infections (SSTIs) is important due to their high prevalence and number of hospitalizations. The purpose of this review is to address the pathophysiology of SSTIs to highlight the advantages of herbal medicines to their treatment, showing examples of species and compounds with multi-targets action. SSTIs have a complex physiopathology involving the microorganism, as well as inflammation and difficult healing. Therefore, antimicrobial, anti-inflammatory, antioxidant and healing activities are an approach possible for their treatment. Herbal medicines have a wide diversity of biological compounds, mainly phenolic compounds that may act on different targets and also have synergism between them. Therefore, a single medicine may have the four key activities that allied allow eliminating the infection, control the inflammation process and accelerating the healing process, preventing complications with chronic infections.

Salt-dependent hypertension and inflammation: targeting the gut-brain axis and the immune system with Brazilian green propolis.

Systemic arterial hypertension (SAH) is a major health problem around the world and its development has been associated with exceeding salt consumption by the modern society. The mechanisms by which salt consumption increase blood pressure (BP) involve several homeostatic systems but many details have not yet been fully elucidated. Evidences accumulated over the last 60 decades raised the involvement of the immune system in the hypertension development and opened a range of possibilities for new therapeutic targets. Green propolis is a promising natural product with potent anti-inflammatory properties acting on specific targets, most of them participating in the gut-brain axis of the sodium-dependent hypertension. New anti-hypertensive products reinforce the therapeutic arsenal improving the corollary of choices, especially in those cases where patients are resistant or refractory to conventional therapy. This review sought to bring the newest advances in the field articulating evidences that show a cross-talking between inflammation and the central mechanisms involved with the sodium-dependent hypertension as well as the stablished actions of green propolis and some of its biologically active compounds on the immune cells and cytokines that would be involved with its anti-hypertensive properties.

Nanostructured Systems Improve the Antimicrobial Potential of the Essential Oil from Cymbopogon densiflorus Leaves.

The physicochemical characteristics of nanostructured suspensions are important prerequisites for the success of new drug development. This work aimed to develop nanometric systems containing Cymbopogon densiflorus leaf essential oil and to evaluate their antimicrobial activity. The essential oil was isolated by hydrodistillation from leaves and analyzed by GC-MS. The main constituents were found to be trans-p-mentha-2,8-dien-1-ol, cis-p-mentha-2,8-dien-1-ol, trans-p-mentha-1(7),8-dien-2-ol, cis-piperitol, and cis-p-mentha-1(7),8-dien-2-ol. In silico prediction analysis suggested that this oil possesses antimicrobial potential and the main mechanism of action might be the peptidoglycan glycosyltransferase inhibition. Nanoemulsions were prepared by the phase inversion method, and liposomes were made by the film hydration method. Qualitative evaluation of the antimicrobial activity was performed by the diffusion disk assay with 24 microorganisms; all of them were found to be sensitive to the essential oil. Subsequently, this property was quantified by the serial microdilution technique, where the nanoformulations demonstrated improved activity in comparison with the free oil. Bactericidal action was tested by the propidium iodide method, which revealed that free essential oil and nanoemulsion increased cytoplasmic membrane permeability, while no difference was observed between negative control and liposome. These results were confirmed by images obtained using transmission electron microscopy. This study has shown an optimization in the antimicrobial activity of C. densiflorus essential oil by a nanoemulsion and a liposomal formulation of the active substances.

Organics Exposure in Orbit (OREOcube): A next-generation space exposure platform.

The OREOcube (ORganics Exposure in Orbit cube) experiment on the International Space Station (ISS) will investigate the effects of solar and cosmic radiation on organic thin films supported on inorganic substrates. Probing the kinetics of structural changes and photomodulated organic-inorganic interactions with real-time in situ UV-visible spectroscopy, this experiment will investigate the role played by solid mineral surfaces in the (photo)chemical evolution, transport, and distribution of organics in our solar system and beyond. In preparation for the OREOcube ISS experiment, we report here laboratory measurements of the photostability of thin films of the 9,10-anthraquinone derivative anthrarufin (51 nm thick) layered upon ultrathin films of iron oxides magnetite and hematite (4 nm thick), as well as supported directly on fused silica. During irradiation with UV and visible light simulating the photon flux and spectral distribution on the surface of Mars, anthrarufin/iron oxide bilayer thin films were exposed to CO2 (800 Pa), the main constituent (and pressure) of the martian atmosphere. The time-dependent photodegradation of anthrarufin thin films revealed the inhibition of degradation by both types of underlying iron oxides relative to anthrarufin on bare fused silica. Interactions between the organic and inorganic thin films, apparent in spectral shifts of the anthrarufin bands, are consistent with presumed free-electron quenching of semiquinone anion radicals by the iron oxide layers, effectively protecting the organic compound from photodegradation. Combining such in situ real-time kinetic measurements of thin films in future space exposure experiments on the ISS with postflight sample return and analysis will provide time-course studies complemented by in-depth chemical analysis. This will facilitate the characterization and modeling of the chemistry of organic species associated with mineral surfaces in astrobiological contexts.

Targeting Leishmania Promastigotes and Amastigotes Forms through Amino Acids and Peptides: A Promising Therapeutic Strategy.

Millions of people worldwide are affected by leishmaniasis, caused by the Leishmania parasite. Effective treatment is challenging due to the biological complexity of the parasite, drug toxicity, and increasing resistance to conventional drugs. To combat this disease, the development of specific strategies to target and selectively eliminate the parasite is crucial. This Review highlights the importance of amino acids in the developmental stages of Leishmania as a factor determining whether the infection progresses or is suppressed. It also explores the use of peptides as alternatives in parasite control and the development of novel targeted treatments. While these strategies show promise for more effective and targeted treatment, further studies to address the remaining challenges are imperative.

Benznidazole-Loaded Polymeric Nanoparticles for Oral Chemotherapeutic Treatment of Chagas Disease.

Chagas disease (CD) is a worldwide public health problem. Benznidazole (BZ) is the drug used to treat it. However, in its commercial formulation, it has significant side effects and is less effective in the chronic phase of the infection. The development of particulate systems containing BZ is therefore being promoted. The objective of this investigation was to develop polymeric nanoparticles loaded with BZ and examine their trypanocidal impact in vitro. Two formulas (BNP1 and BNP2) were produced through double emulsification and freeze drying. Subsequent to physicochemical and morphological assessment, both formulations exhibited adequate yield, average particle diameter, and zeta potential for oral administration. Cell viability was assessed in H9C2 and RAW 264.7 cells in vitro, revealing no cytotoxicity in cardiomyocytes or detrimental effects in macrophages at specific concentrations. BNP1 and BNP2 enhanced the effect of BZ within 48 h using a treatment of 3.90 µg/mL. The formulations notably improved NO reduction, particularly BNP2. The findings imply that the compositions are suitable for preclinical research, underscoring their potential as substitutes for treating CD. This study aids the quest for new BZ formulations, which are essential in light of the disregard for the treatment of CD and the unfavorable effects associated with its commercial product.

Protium spruceanum Extract Enhances Mupirocin Activity When Combined with Nanoemulsion-Based Hydrogel: A Multi-Target Strategy for Treating Skin and Soft Tissue Infections.

The treatment of skin and soft tissue infections (SSTIs) can be challenging due to bacterial resistance, particularly from strains like MRSA and biofilm formation. However, combining conventional antibiotics with natural products shows promise in treating SSTIs. The objective of this study is to develop a nanoemulsion-based hydrogel containing Protium spruceanum extract and mupirocin and evaluate its potential for the treatment of SSTIs. The nanoemulsion was obtained by phase inversion and subsequently characterized. The antibacterial activity was evaluated in vitro against S. aureus MRSA, including the synergism of the combination, changes in membrane permeability using flow cytometry, and the anti-biofilm effect. In addition, the irritative potential was evaluated by the HET-CAM assay. The combination exhibited synergistic antibacterial activity against S. aureus and MRSA due to the extract enhancing membrane permeability. The hydrogel demonstrated suitable physicochemical properties, inhibited biofilm formation, and exhibited low irritation. The formulation was nanometric (176.0 ± 1.656 nm) and monodisperse (polydispersity index 0.286 ± 0.011). It exhibited a controlled release profile at 48 h and high encapsulation efficacy (94.29 ± 4.54% for quercitrin and 94.20 ± 5.44% for mupirocin). Therefore, these findings suggest that the hydrogel developed could be a safe and effective option for treating SSTIs.

Poly(methylmethacrylate-co-dimethyl acrylamide)-silver nanocomposite prevents biofilm formation in medical devices.

Aim: To investigate whether medical devices coated with a synthesized nanocomposite of poly(methylmethacrylate-co-dimethyl acrylamide) (PMMDMA) and silver nanoparticles (AgNPs) could improve their antibiofilm and antimicrobial activities. We also investigated the nanocomposite's safety. Materials & methods: The nanocomposite was synthesized and characterized using analytical techniques. Medical devices coated with the nanocomposite were evaluated for bacterial adhesion and hemolytic activity in vitro. Results: The nanocomposite formation was demonstrated with the incorporation of AgNPs into the polymer matrix. The nanocomposite proved to be nonhemolytic and significantly inhibited bacterial biofilm formation. Conclusion: The PMMDMA-AgNPs nanocomposite was more effective in preventing biofilm formation than PMMDMA alone and is a promising strategy for coating medical devices and reducing mortality due to hospital-acquired infections.

Nanoemulsified Essential Oil of Melaleuca leucadendron Leaves for Topical Application: In Vitro Photoprotective, Antioxidant and Anti-Melanoma Activities.

Melanoma, primarily caused by solar ultraviolet (UV) radiation, can be prevented by the use of sunscreens. However, the use of synthetic sunscreens raises environmental concerns. Natural compounds with antioxidant photoprotective properties and cytotoxic effects against cancer cells can be promising for the prevention and treatment of melanoma with less environmental effect. This study focuses on Melaleuca leucadendron essential oil (EO) for photoprotection and antitumor applications. EO was hydrodistilled from M. leucadendron leaves with a 0.59% yield. Gas chromatography-mass spectrometry detected monoterpenes and sesquiterpenes. Nanoemulsions were prepared with (NE-EO) and without EO (NE-B) using the phase inversion method, showing good stability, spherical or oval morphology, and a pseudoplastic profile. Photoprotective activity assessed spectrophotometrically showed that the NE-EO was more effective than NE-B and free EO. Antioxidant activity evaluated by DPPH and ABTS methods indicated that pure and nanoemulsified EO mainly inhibited the ABTS radical, showing IC50 40.72 and 5.30 µg/mL, respectively. Cytotoxicity tests on L-929 mouse fibroblasts, NGM human melanocyte, B16-F10 melanoma, and MeWo human melanoma revealed that EO and NE-EO were more cytotoxic to melanoma cells than to non-tumor cells. The stable NE-EO demonstrates potential for melanoma prevention and treatment. Further research is required to gain a better understanding of these activities.

A Systematic Review of Drug-Carrying Nanosystems Used in the Treatment of Leishmaniasis.

Leishmaniasis is an infectious disease responsible for a huge rate of morbidity and mortality in humans. Chemotherapy consists of the use of pentavalent antimonial, amphotericin B, pentamidine, miltefosine, and paromomycin. However, these drugs are associated with some drawbacks such as high toxicity, administration by parenteral route, and most seriously the resistance of some strains of the parasite to them. Several strategies have been used to increase the therapeutic index and reduce the toxic effects of these drugs. Among them, the use of nanosystems that have great potential as a site-specific drug delivery system stands out. This review aims to compile results from studies that were carried out using first- and second-line antileishmanial drug-carrying nanosystems. The articles referred to here were published between 2011 and 2021. This study shows the promise of effective applicability of drug-carrying nanosystems in the field of antileishmanial therapeutics, with the perspective of providing better patient adherence to treatment, increased therapeutic efficacy, reduced toxicity of conventional drugs, as well as the potential to efficiently improve the treatment of leishmaniasis.

Modulation of Long Non-coding RNAs by Different Classes of Secondary Metabolites from Plants: A Mini-review on Antitumor Effects.

The broad pharmacological spectrum of plants is related to their secondary metabolism, which is responsible for the synthesis of different compounds that have multiple effects on cellular physiology. Among the biological effects presented by phytochemicals, their use for the prevention and treatment of cancer can be highlighted. This occurs due to several mechanisms of antitumor action demonstrated by these compounds, including regulation of the cell signaling pathways and inhibition of tumor growth. In this way, long non-coding RNAs (lncRNAs) appear to be promising targets for the treatment of cancer. Their deregulation has already been related to a variety of clinicalpathological parameters. However, the effects of secondary metabolites on lncRNAs are still restricted. For this reason, the present review aimed to gather data on phytochemicals with action on lncRNAs in order to confirm their possible antitumor potential. According to the literature, terpenoid and flavonoid are the main examples of secondary metabolites involved with lncRNAs activity. In addition, the lncRNAs H19, CASC2, HOTAIR, NKILA, CCAT1, MALAT1, AFAP1-AS1, MEG3, and CDKN2B-AS1 can be highlighted as important targets in the search for new anti-tumor agents since they act as modulating pathways related to cell proliferation, cell cycle, apoptosis, cell migration and invasion. Finally, challenges for the use of natural products as a commercial drug were also discussed. The low yield, selectivity index and undesirable pharmacokinetic parameters were emphasized as a difficulty for obtaining these compounds on a large scale and for improving the potency of its biological effect. However, the synthesis and/or development of formulations were suggested as a possible approach to solve these problems. All of these data together confirm the potential of secondary metabolites as a source of new anti-tumor agents acting on lncRNAs.

Cytotoxic activity of butanolic extract from Sambucus nigra L. flowers in natura and vehiculated in micelles in bladder cancer cells and fibroblasts.

Bladder cancer has a high incidence and recurrence rate among patients worldwide. This study aimed to evaluate the cytotoxic activity of fractions of Sambucus nigra L. flower extracts on bladder carcinoma cells (T24 cells) and human fibroblast cells (MRC-5). The butanolic fraction (F-BuOH) was characterized by UPLC-DAD-MS/MS and nine flavonoids were identified. Rutin was the major compound. The cytotoxic activity of this fraction was observed in the T24 cells but not in MRC-5 cells, indicating selectivity. F-BuOH was incorporated in micellar solutions of Pluronic® F127 and cytotoxic effect for T24 cells was observed again. In vitro assay demonstrated a controlled release of the fraction from the micelles. The results obtained showed that flavonoids are the possible responsible for cytotoxic activity in bladder carcinoma cells. In addition, micellar solutions act together to increase the action of the butanolic fraction.

Associating chitosan and microemulsion as a topical vehicle for the administration of herbal medicines.

A viscous solution of low molecular weight chitosan (CH) at 5% w/v (10.2 kDa, 75 % deacetylated, 1451 cP at 25 °C) was associated with a microemulsion (ME) that undergoes a phase transition after water absorption in situ (≈28 % w/w), forming a more viscous liquid crystal, which was potentially evaluated as a topical vehicle. The ME was selected from a phase diagram, selecting a composition based on Tween® 80 (52 %), myristate isopropyl (28 %), and the aqueous phase (water and polyethylene glycol 400, 60:40 w/w) (20 %), which was after replaced by CH and herbal medicines (HM). HM are alternatives to treat candidiasis, and Stryphnodendron adstringens shell extract, characterized by molecular networking, and Melaleuca alternifolia Chell essential oil (46 % of terpinen-4-ol), showed in vitro activity against Candida albicans. Associating CH in ME improved the mechanical properties of the topical formulation, as adhesiveness, which is an advantageous feature for the topical treatment of vulvovaginal candidiasis.

Antitumor effect of Cymbopogon densiflorus (Linneu) essential oil in bladder cancer cells.

The aim of this study was to analyse the antitumor effect of the Cymbopogon densiflorus essential oil in silico and in vitro on bladder cancer cells RT4 and T24, with different TP53 status. The oil was extracted by hydrodistillation and the gas chromatography coupled to the mass spectrometry was used for characterisation. In silico analysis was carried out by Pass online software. Cytotoxicity, cell proliferation, cell cycle progression, apoptosis and wound healing assays were performed. Five major compounds were identified. In silico analysis showed that major compounds present high potential for antitumor activities. The treatment with C. densiflorus essential oil reduced cell viability of bladder cancer cells. Only in wild-type cells, the increase of apoptosis rates and the decrease of cell migration were observed. In conclusion, the C. densiflorus essential oil presents antitumor effects on TP53 wild-type and mutated bladder cancer cells, however, the mechanism of action is TP53 status-dependent.[Figure: see text].

The analysis of alendronate action in bone fracture healing in rats.

INTRODUCTION: Osteoporosis is defined as a systemic skeletal disease characterized by reduced bone mass and degeneration of bone tissue microarchitecture which leads to bone fragility and fracture risk. Annually, 100 to 200 million people around the world are at risk for osteoporotic fractures. One way to prevent osteoporosis fracture is by using medications such as bisphosphonates. Alendronate is the most prescribed bisphosphonate in the world. The objective of this article is to evaluate the effect of alendronate on bone fracture healing. MATERIAL AND METHODS: 15 adult male rats that were 60 days old were used, divided into three groups: A or Control, B (non-osteoporotic bones plus alendronate application) and C (osteoporotic bones plus alendronate application). Osteoporotic bones were compared with non-osteoporotic bones that underwent bone window creation and administration of alendronate sodium. These bones were submitted to radiographic and histological analysis. RESULTS: All of Group A had complete bone healing, reaching the phase of bone remodeling. While in groups B and C, the rats were in the repair phase. CONCLUSIONS: The drug alendronate interferes with delayed fracture healing and delayed bone remodeling. The article advises that studies in humans are needed in order to assess whether the alendronate interferes with bone healing.

Melaleuca leucadendron (L.) L. flower extract exhibits antioxidant and photoprotective activities in human keratinocytes exposed to ultraviolet B radiation.

Recently, there has been a demand for the replacement of chemical sunscreens with natural compounds that could prevent or restore UV-induced skin damage. Here, we investigated the photoprotective influence of the Melaleuca leucadendron ethanolic flower extract (EEMec) on factors involved in cellular and molecular UVB-induced oxidative stress in human skin keratinocytes (HaCaT). The phytochemical constituents, antioxidant potential by DPPH assay, content of total phenolic and flavonoid compounds in EEMec were evaluated. HaCaT cells were treated with EEMec followed by irradiation with UVB. CAT activity; GSH and ROS levels; and SOD1, GPx, CAT and COX-2 expression assays were employed to verify the oxidative stress, as well as EEMec effect on transmembrane transport, and pro-inflammatory and pro-apoptotic protein expression. EEMec reverted the viability loss of HaCaT cells after irradiation with UVB, exhibited significant antioxidant capacity and free radical scavenging activity in vitro, inhibited COX-2 expression and ensure protection of DNA-damage. EEMec shown a great photoprotective property to prevent keratinocytes damage induced by UV radiation and, thus a candidate potential to application as an adjuvant in sunscreen formulations as a strategy to reduce risk of sunburn and prevent skin diseases associated with UV-induced inflammation and cancer.

Functionalized rifampicin-loaded nanostructured lipid carriers enhance macrophages uptake and antimycobacterial activity.

Tuberculosis is an infectious bacterial disease that causes millions of deaths worldwide. Current treatment recommended by WHO is effective, however it is an extensive and arduous process associated to severe adverse effects, which induces a low patient compliance and the emerging of multidrug resistant tuberculosis. Thus, as a main goal of this study, rifampicin nanoparticles were surface functionalized with a tuftsin-modifed peptide to selectively recognize receptors located on infected alveolar macrophages, enhancing nanoparticles uptake by these cells and improving antimycobacterial activity. A tuftsin-based modified peptide was synthesized and successfully attached to nanoparticles interface (NP-pRIF). In parallel, nanoparticles without peptide were also developed for comparison (NP-RIF). Physicochemical characterization demonstrated that stable and monodisperse nanodelivery systems were obtained, with a controlled drug release profile and non-cytotoxic potential. Moreover, nanoparticles containing peptide were significantly more internalized by macrophages than nanoparticles without peptide over a wide range of time. Both nanoparticles were 2-fold more effective against M. tuberculosis than free rifampicin, suggesting NP-pRIF as a promising strategy for the management of tuberculosis treatment.