Antifungal chemosensitization through induction of oxidative stress: A model for control of candidiasis based on the Lippia origanoides essential oil.

In this work, evaluated the antifungal chemosensitizing effect of the Lippia origanoides essential oil (EO) through the induction of oxidative stress. The EO was obtained by hydrodistillation and analyzed by GC-MS. To evaluate the antifungal chemosensitizing effect through induction of oxidative stress, cultures of the model yeast Saccharomyces cerevisiae ∆ycf1 were exposed to sub-inhibitory concentrations of the EO, and the expression of genes known, due be overexpressed in response to oxidative and mutagenic stress was analyzed by quantitative real-time polymerase chain reaction (qRT-PCR) method. Carvacrol and thymol were identified as the main components. The EO was effective in preventing or reducing the growth of the microorganisms tested. The gene expression profiles showed that EO promoted changes in the patterns of expression of genes involved in oxidative and mutagenic stress resistance. The combined use of the L. origanoides EO with fluconazole has been tested on Candida yeasts and the strategy resulted in a synergistic enhancement of the antifungal action of the azolic chemical product. Indeed, in association with EO, the fluconazole MICs dropped. Thus, the combinatorial use of L. origanoides EO as a chemosensitizer agent should contribute to enhancing the efficiency of conventional antifungal drugs, reducing their negative side effects.

In Vitro and in Vivo Antimalarial Activity, Cytotoxicity and Phytochemical HRMS2 Profile of Plants from the Western Pará State, Brazilian Amazonia.

Ethnopharmacology and botanical taxonomy are valid criteria used to selecting plants for antimalarial bioprospection purposes. Based on these two criteria, ethanol extracts of 11 plants from Santarém City vicinities, Western Pará State, Brazilian Amazonia, had their in vitro antiplasmodial activity against chloroquine-resistant Plasmodium falciparum (W2 clone) assessed by the PfLDH method, whereas their cytotoxicity to HepG2-A16 cells was assessed through MTT assay. Acmella oleracea, Siparuna krukovii and Trema micrantha extracts disclosed the highest rate of parasite growth inhibition (90 %) in screening tests. In vivo antimalarial assays were conducted with these extracts against Plasmodium berghei (NK 65 strain) infected mice. Inhibition rate of parasite multiplication ranged from 41.4 % to 60.9 % at the lowest extract dose (25 mg/kg). HPLC-ESI-HRMS2 analyses allowed the putative identification of alkylamides, fatty acids, flavonoid glycosides and alkaloids in ethanol extracts deriving from these three plant species. Results pointed towards A. oleracea flowers ethanol extract as the most promising potential candidate to preclinical studies aiming the development of antimalarial phytomedicine.

Seasonal Variation in Essential Oil Composition and Antioxidant Capacity of Aniba canelilla (Lauraceae): A Reliable Source of 1-Nitro-2-phenylethane.

Aniba canelilla (Kunth) Mez essential oil has many biological activities due to its main compound 1-nitro-2-phenylethane (1N2F), followed by methyleugenol, a carcinogenic agent. This study analyzed the influence of seasonality on yields, antioxidant capacity, and 1N2F content of A. canelilla leaf and twig essential oils. Essential oils (EOs) were extracted with hydrodistillation and analyzed with gas chromatography coupled to mass spectrometry and a flame ionization detector. Antioxidant capacity was measured using the free radical scavenging method (DPPH). Chemometric analyses were carried out to verify the influence of climatic factors on the production and composition of EOs. 1-Nitro-2-phenylethane was the major constituent in A. canelilla EOs throughout the seasonal period (68.0-89.9%); methyleugenol was not detected. Essential oil yields and the 1N2F average did not show a statistically significant difference between the dry and rainy seasons in leaves and twigs. Moderate and significant correlations between major compounds and climate factor were observed. The twig oils (36.0 ± 5.9%) a showed greater antioxidant capacity than the leaf oils (20.4 ± 5.0%). The PCA and HCA analyses showed no statistical differences between the oil samples from the dry and rainy seasons. The absence of methyleugenolin in all months of study, described for the first time, makes this specimen a reliable source of 1N2F.

Seasonal Variability of a Caryophyllane Chemotype Essential Oil of Eugenia patrisii Vahl Occurring in the Brazilian Amazon.

Eugenia patrisii Vahl is a native and non-endemic myrtaceous species of the Brazilian Amazon. Due to few botanical and phytochemical reports of this species, the objective of the present work was to evaluate the seasonal variability of their leaf essential oils, performed by GC and GC-MS and chemometric analysis. The results indicated that the variation in oil yields (0.7 ± 0.1%) could be correlated with climatic conditions and rainy (R) and dry seasons (D). (E)-caryophyllene (R = 17.1% ± 16.0, D = 20.2% ± 17.7) and caryophyllene oxide (R = 30.1% ± 18.4, D = 14.1% ± 19.3) are the major constituents and did not display significant differences between the two seasons. However, statistically, a potential correlation between the main constituents of E. patrisii essential oil and the climatic parameters is possible. It was observed that the higher temperature and insolation rates and the lower humidity rate, which are characteristics of the dry season, lead to an increase in the (E)-caryophyllene contents, while lower temperature and insolation and higher humidity, which occur in the rainy season, lead to an increase in the caryophyllene oxide content. The knowledge of variations in the E. patrisii essential oil composition could help choose the best plant chemical profile for medicinal purposes.

A Low Energy Approach for the Preparation of Nano-Emulsions with a High Citral-Content Essential Oil.

Pectis elongata is found in the northern and northeastern regions of Brazil. It is considered a lemongrass due to its citric scent. The remarkable citral content and the wide antimicrobial properties and bioactive features of this terpene make this essential oil (EO) eligible for several industrial purposes, especially in cosmetics and phytotherapics. However, to address the problems regarding citral solubility, nano-emulsification is considered a promising strategy thanks to its improved dispersability. Thus, in this paper we propose a low-energy approach for the development of citral-based nano-emulsions prepared with P. elongata EO. The plant was hydrodistillated to produce the EO, which was characterized with a gas chromatograph coupled to mass spectrometry. The nano-emulsion prepared by a non-heated water titrating (low-energy) method was composed of 5% (w/w) EO, 5% (w/w) non-ionic surfactants and 90% (w/w) deionized water and was analyzed by dynamic light scattering. Levels of citral of around 90% (neral:geranial-4:5) were detected in the EO and no major alteration in the ratio of citral was observed after the nano-emulsification. The nano-emulsion was stable until the 14th day (size around 115 nm and polydispersity index around 0.2) and no major alteration in droplet size was observed within 30 days of storage. Understanding the droplet size distribution as a function of time and correlating it to concepts of compositional ripening, as opposing forces to the conventional Ostwald ripening destabilization mechanism, may open interesting approaches for further industrial application of novel, low-energy, ecofriendly approaches to high citral essential oil-based nano-emulsions based on lemongrass plants.

Lethal concentration of Cymbopogon citratus (Poaceae) essential oil for Dolops discoidalis and Argulus sp. (Crustacea: Argulidae).

This study investigated the acute toxicity (LC50-24 hr ) effects of the essential oil of Cymbopogon citratus for adult Argulus sp. and Dolops discoidalis, before and during oviposition. In vitro acute toxicity (LC50-24 hr ) was tested using 20, 40, 60, 80, 100, 120, 140 and 160 µg/L of C. citratus essential oil, and two control groups (one with cultivation tank water and one with cultivation tank water + alcohol) were used. Specimens of Argulus sp. and D. discoidalis submitted to acute toxicity were evaluated using histological procedures. The major chemical compounds of C. citratus essential oil were geranial (47.5%), neral (35.6%) and myrcene (6.7%). The LC50-24 hr for Argulus sp. adults was 67.97 µg/L, while for D. discoidalis it was 59.55 µg/L. In the oviposition of both species of argulids, maximum mortality began with treatments of 140 µg/L, while the LC50-24 hr for Argulus sp. and D. discoidalis was 83.98 µg/L and 82.48 µg/L, respectively. In both argulid species exposed to C. citratus essential oil, morphological alterations were observed only in the eyes, and they occurred in the ommatidium and rhabdomeres and were dependent on the concentration of C. citratus essential oil and the parasite species.

Chemical and Genotypic Variations in Aniba rosiodora from the Brazilian Amazon Forest.

Aniba rosiodora has been exploited since the end of the nineteenth century for its essential oil, a valuable ingredient in the perfumery industry. This species occurs mainly in Northern South America, and the morphological similarity among different Aniba species often leads to misidentification, which impacts the consistency of products obtained from these plants. Hence, we compared the profiles of volatile organic compounds (essential oils) and non-volatile organic compounds (methanolic extracts) of two populations of A. rosiodora from the RESEX and FLONA conservation units, which are separated by the Tapajós River in Western Pará State. The phytochemical profile indicated a substantial difference between the two populations: samples from RESEX present α-phellandrene (22.8%) and linalool (39.6%) in their essential oil composition, while samples from FLONA contain mainly linalool (83.7%). The comparison between phytochemical profiles and phylogenetic data indicates a clear difference, implying genetic distinction between these populations.

Involvement of HPI-axis in anesthesia with Lippia alba essential oil citral and linalool chemotypes: gene expression in the secondary responses in silver catfish.

In teleost fish, stress initiates a hormone cascade along the hypothalamus-pituitary-interrenal (HPI) axis to provoke several physiological reactions in order to maintain homeostasis. In aquaculture, a number of factors induce stress in fish, such as handling and transport, and in order to reduce the consequences of this, the use of anesthetics has been an interesting alternative. Essential oil (EO) of Lippia alba is considered to be a good anesthetic; however, its distinct chemotypes have different side effects. Therefore, the present study aimed to investigate, in detail, the expression of genes involved with the HPI axis and the effects of anesthesia with the EOs of two chemotypes of L. alba (citral EO-C and linalool EO-L) on this expression in silver catfish, Rhamdia quelen. Anesthesia with the EO-C is stressful for silver catfish because there was an upregulation of the genes directly related to stress: slc6a2, crh, hsd20b, hspa12a, and hsp90. In this study, it was also possible to observe the importance of the hsd11b2 gene in the response to stress by handling. The use of EO-C as anesthetics for fish is not recommended, but, the use of OE-L is indicated for silver catfish as it does not cause major changes in the HPI axis.

The essential oil of Lippia alba and its components affect Drosophila behavior and synaptic physiology.

Lippia alba is a flowering shrub in the verbena family and its essential oil (EO) is known for its sedative, antidepressant and analgesic properties. In the Amazon region of Brazil, it is used in aquaculture to anesthetize fish during transport. Many of the specialized metabolites found in EOs presumably evolved to protect plants from herbivores, especially insects. We used Drosophila to test the behavioral and physiological actions of this EO and its components. We found that a 150 min exposure to the EO vapors resulted in immobilization of adult flies. Gas chromatography-mass spectrometry identified the major components of the EO as the monoterpenes citral (59%), carvone (7%) and limonene (7%). Fly immobilization by the EO was due to citral and carvone, with citral producing more rapid effects than carvone. We tested whether the EO affected synaptic physiology by applying it to the larval neuromuscular junction. The EO delivered at 0.012% (v/v) produced over a 50% reduction in excitatory postsynaptic potential (EPSP) amplitude within 3-4 min. When the EO components were applied at 0.4 mmol l-1, citral and carvone produced a significant reduction in EPSP amplitude, with citral producing the largest effect. Measurement of miniature EPSP amplitudes demonstrated that citral produced over a 50% reduction in transmitter release. Calcium imaging experiments showed that citral produced about 30% reduction in presynaptic Ca2+ influx, which likely resulted in the decrease in transmitter release. Thus, the EO blocks synaptic transmission, largely due to citral, and this likely contributes to its behavioral effects.

Citral and linalool chemotypes of Lippia alba essential oil as anesthetics for fish: a detailed physiological analysis of side effects during anesthetic recovery in silver catfish (Rhamdia quelen).

The viability using Lippia alba essential oil as an anesthetic for fish was studied, particularly with respect to physiological effects during recovery. Anesthesia of silver catfish (Rhamdia quelen) using 100 and 300 µL L-1 of two different chemotypes of L. alba essential oil (citral EO-C and linalool EO-L) prevented the increase of plasma cortisol levels caused by handling, but did not avoid alterations in energetic metabolism. Silver catfish did not have increased the levels of thiobarbituric acid reactive species in the kidney and liver during recovery after anesthesia with either EO, avoiding lipid damage. On the other hand, fish anesthetized with EO-C showed higher protein carbonylation levels, superoxide dismutase, catalase, and glutathione S-transferase activities and non-protein thiol group levels in both tissues compared to controls. Our results suggest that both oils show antioxidant capacity, but anesthesia with EO-L does not cause damage to lipids or proteins, only temporary changes, typical of physiological adjustments during recovery from anesthesia. Therefore, EO-L is an effective anesthetic for silver catfish with fewer side effects than EO-C.

Oxidative and biochemical responses in Brycon amazonicus anesthetized and sedated with Myrcia sylvatica (G. Mey.) DC. and Curcuma longa L. essential oils.

OBJECTIVE: To investigate the effects of rapid anesthesia and long-term sedation with the essential oils (EOs) of Myrcia sylvatica (EOMS) and Curcuma longa (EOCL) on biochemical and oxidative parameters in matrinxã. STUDY DESIGN: Prospective, randomized, laboratory experiment. ANIMALS: A total of 72 matrinxã (Brycon amazonicus) adults weighing 404.8 ± 27.9 g were divided into eight groups of nine fish. METHODS: Biochemical and oxidative effects were investigated in plasma and tissues of matrinxã subjected to rapid anesthesia (5 minutes) or long-term sedation (360 minutes, simulating the practice of transport) with EOMS (200 µL L-1 and 10 µL L-1, respectively) and EOCL (500 µL L-1 and 40 µL L-1, respectively). RESULTS: Transport simulation without sedation or anesthesia increased lipid peroxidation levels in the gills and kidney of fish in the control group. Anesthesia and sedation with EOs decreased cortisol concentrations and increased lactate concentrations compared with controls. Lipid peroxidation was lower in the brain, gills, liver and kidney of sedated and anesthetized fish, than in the control group. Anesthesia with EOs increased the activity of superoxide dismutase and glutathione-S-transferase in the brain, and catalase in the liver and gills, compared with controls. Long-term sedation with EOs increased superoxide dismutase, glutathione peroxidase and glutathione reductase activities in the brain, catalase in the liver, glutathione peroxidase and glutathione reductase in the gills and superoxide dismutase in the kidney. In general, nonprotein thiols content and total reactive antioxidant potential of tissues were higher after anesthesia and sedation with EOs compared with the control group. CONCLUSIONS AND CLINICAL RELEVANCE: The concentrations of EOMS and EOCL used were effective at preventing a stress response and excess of reactive oxygen species formation. For these reasons, these substances may be recommended for use in the transportation of fish to improve survival and animal welfare.

Antibacterial action against food-borne microorganisms and antioxidant activity of carvacrol-rich oil from Lippia origanoides Kunth.

BACKGROUND: Lippia origanoides Kunth from Northeast Brazil is a plant of pleasant odor used by local people as a food seasoning in substitution the oregano where its carvacrol-rich oil has showed significant antimicrobial activity against human pathogens. METHODS: GC and GC-MS analyzed the plant oil composition and its antibacterial activity was evaluated by disk diffusion and microdilution broth methods. The determination of oil antioxidant activity was made by DPPH radical scavenging assay. Oil toxicity was performed on mice. RESULTS: The main constituents of the oil were carvacrol (47.2%), thymol (12.8%), p-cymene (9.7%), and p-methoxythymol (7.4%). The oil was active against the bacteria of Bacillus cereus, B. subtilis, and Salmonella typhimurium, except for Pseudomonas aeruginosa. The antioxidant activity has displayed a high dose-response (r(2) = 0.92), with the inhibition of DPPH radical from 15 to 82%, at concentrations from 5 to 50 µg/mL, and also by the ß-carotene bleaching assay, which showed a high inhibition of 85.2 ± 6.8 %, corresponding to about 80% of the inhibition of Trolox (93.4 ± 0.7%), used as a standard. The lethal dose (LD50) of the oil was determined in 1673.84 mg mL(-1). CONCLUSION: The results confirmed that the oil of L. origanoides could be utilized for the prevention of food bacterial growth, and as an antioxidative agent for retardation of food oxidation process. The oil has low toxicity, allowing its application in the food industry. Graphical Abstract Aerial parts of Lippia origanoides Kunth.

Antimicrobial and seasonal evaluation of the carvacrol-chemotype oil from Lippia origanoides kunth.

This study evaluated the influence of seasonal variation on the yield and composition of essential oil of Lippia origanoides occurring in the Middle Rio Amazonas, Brazil, and the impact on its antimicrobial potential. The average oil yield was 1.7% ± 0.2% in the rainy season and 1.6% ± 0.3% in the dry season. Some correlations with climatic parameters were observed. The major components were carvacrol (rainy, 43.5% ± 1.9%; dry, 41.4% ± 2.04%), thymol (rainy, 10.7% ± 1.1%; dry, 10.6% ± 0.9%), p-cymene (rainy, 9.8% ± 0.7%; dry, 10.0% ± 1.4%) and p-methoxythymol (rainy, 9.6% ± 0.8%; dry, 10.4% ± 1.4%). It was found that the antibacterial activity of L. origanoides against Staphylococcus aureus and Escherichia coli was little influenced by the changes in oil composition due to seasonal variation. Against S. aureus, the oil Minimum Inhibitory Concentration (MIC) value was 1.25 µL/mL over ten months. Against E. coli, the oil MIC values ranged from 0.15 µL/mL to 0.31 µL/mL in different months of the year. The Minimum Bactericidal Concentration (MBC) value was 2.5 µL/mL against S. aureus and 1.25 µL/mL against E. coli. The results suggest that the antimicrobial activity identified in the oil remain unchanged for the full year, allowing its medicinal use without any risk of loss or absence of the active principles of the plant.

Brazilian plants with antimalarial activity: A review of the period from 2011 to 2022.

ETHNOPHARMACOLOGICAL RELEVANCE: Malaria continues to be a serious global public health problem in subtropical and tropical countries of the world. The main drugs used in the treatment of human malaria, quinine and artemisinin, are isolates of medicinal plants, making the use of plants a widespread practice in countries where malaria is endemic. Over the years, due to the increased resistance of the parasite to chloroquine and artemisinin in certain regions, new strategies for combating malaria have been employed, including research with medicinal plants. AIM: This review focuses on the scientific production regarding medicinal plants from Brazil whose antimalarial activity was evaluated during the period from 2011 to 2022. 2. METHODOLOGY: For this review, four electronic databases were selected for research: Pubmed, ScienceDirect, Scielo and Periódicos CAPES. Searches were made for full texts published in the form of scientific articles written in Portuguese or English and in a digital format. In addition, prospects for new treatments as well as future research that encourages the search for natural products and antimalarial derivatives are also presented. RESULTS: A total of 61 publications were encountered, which cited 36 botanical families and 92 species using different Plasmodium strains in in vitro and in vivo assays. The botanical families with the most expressive number of species found were Rubiaceae, Apocynaceae, Fabaceae and Asteraceae (14, 14, 9 and 6 species, respectively), and the most frequently cited species were of the genera Psychotria L. (8) and Aspidosperma Mart. (12), which belong to the families Rubiaceae and Apocynaceae. Altogether, 75 compounds were identified or isolated from 28 different species, 31 of which are alkaloids. In addition, the extracts of the analyzed species, including the isolated compounds, showed a significant reduction of parasitemia in P. falciparum and P. berghei, especially in the clones W2 CQ-R (in vitro) and ANKA (in vivo), respectively. The Brazilian regions with the highest number of species analyzed were those of the north, especially the states of Pará and Amazonas, and the southeast, especially the state of Minas Gerais. CONCLUSION: Although many plant species with antimalarial potential have been identified in Brazil, studies of new antimalarial molecules are slow and have not evolved to the production of a phytotherapeutic medicine. Given this, investigations of plants of traditional use and biotechnological approaches are necessary for the discovery of natural antimalarial products that contribute to the treatment of the disease in the country and in other endemic regions.

Volatile Constituents of Some Myrtaceous Edible and Medicinal Fruits from the Brazilian Amazon.

Native and exotic fruits from the Amazon have varied characteristics, with aroma being a decisive factor in their acceptance for medicinal use as a nutraceutical supplement. This work aimed to analyze the chemical constituents of the volatile concentrates of some Myrtaceous fruit species sampled in the Brazilian Amazon. The fruit's pulps were subjected to simultaneous distillation-extraction, and gas chromatography-mass spectrometry was used to analyze their volatile chemical composition. In the volatile concentrate of Eugenia stipitata (Araçá-boi) α-pinene (17.5%), citronellyl butanoate (15.6%), and pogostol (13.5%) were identified as primary constituents; Eugenia uniflora (Ginja) concentrate comprised curzerene (30.5%), germacrone (15.4%), atractylone (13.1%), and (E)-ß-ocimene (11.1%); in Myrciaria dubia (Camu-Camu), α-pinene (55.8%), (E)-ß-ocimene (13.1%), and α-terpineol (10.0%) were present; in Psidium guajava (Goiaba) were (2E)-hexenal (21.7%), hexanal (15.4%), caryophylla-4(12),8(13)-dien-5-ß-ol (10.5%), caryophyllene oxide (9.2%), and pogostol (8.3%); and in Psidium guineense (Araçá), limonene (25.2%), ethyl butanoate (12.1%), epi-ß-bisabolol (9.8%), and α-pinene (9.2%) were the main constituents. The analyzed volatile concentrates of these fruit species presented a significant diversity of constituents with a predominance of functional groups, such as monoterpenes, sesquiterpenes, and fatty acid derivatives, originating from the plant's secondary metabolism and playing an important role in their nutritional and medicinal uses.

Molecular modelling and anticholinesterase activity of the essential oil from three chemotypes of Lippia alba (Mill.) N.E.Br. ex Britton & P. Wilson (Verbenaceae).

Lippia alba (Mill.) N.E. Brown (Verbenaceae), popularly known as "erva cidreira", is one of the most used plants in Brazilian folk medicine. The species has several chemotypes and its volatile constituents have already been characterized, and present different chemical markers with known pharmacological properties, such as analgesic, sedative and antifungal properties. The objective of this study was to evaluate the anticholinesterase activity (AChE) of the essential oil of three chemotypes of Lippia alba and, by using molecular anchoring, determine the best receptor-ligand interaction energies of the main constituents present in the samples of oil. The essential oils were obtained via hydrodistillation (LA1 and LA2) and steam drag (LA3), and their volatile constituents determined using GC-MS. For the determination of anticholinesterase activity, direct bioautography and colorimetry assays based on Ellman's method were used. Molecular docking was performed using a multiple solution genetic algorithm and Merck molecular force field 94 (MMFF94) as the scoring function. In the main constituents of the oil samples, three chemotypes were identified for L. alba: LA1 is rich in citral, LA2 is rich in carvone and LA3 is rich in linalool. All L. alba chemotypes showed AChE enzyme inhibition with an IC50 of 3.57 µg/mL (LA1), 0.1 µg/mL (LA2) and 4.34 µg/mL (LA3). The molecular docking study complemented the results of the experiment and demonstrated significant interactions between the main constituents of the oils and the amino acid residues of the AChE enzyme. Irrespective of the chemotype, Lippia alba presents biotechnological potential for the discovery of anticholinesterase substances, with the chemotype LA2 (rich in carvone) being the most active.

Antiedema and antinociceptive potential of the essential oil of Pectis elongata Kunt (Asteraceae) from the Brazilian Amazon.

ETHNOPHARMACOLOGICAL RELEVANCE: Pectis elongata, a herbaceous species that is known in northern Brazil as "cominho" or "limãozinho", is traditionally used in the region for the treatment of fevers, colds, hypotension, genitourinary and gastric disorders, and pain. AIM OF THE STUDY: Determine the chemical composition and acute oral toxicity and evaluate whether Pectis elongata essential oil (PeEO) has antiedema and antinociceptive activity. MATERIALS AND METHODS: The chemical composition was determined using gas chromatography coupled to mass spectrometry (GC/MS) and the degree of toxicity determined by the LD50. The antiedema and antinociceptive potential was evaluated via the λ-carrageenan-induced paw edema test and formalin test, respectively. RESULTS: Citral (geranial and neral) was characterized as a major component of the PeEO, representing 89% of the total identified compounds. According to OECD criteria (2002), the EO was considered non-toxic since it presented LD50 values over 2000 mg kg-1. Its antiedema potential was observed at doses of 200 and 400 mg kg-1 (p ≤ 0.05). At a dose of 400 mg kg-1, PeEO also showed antinociceptive potential (p ≤ 0.05), both in the neurogenic phase and in the inflammatory phase. CONCLUSIONS: PeEO, which is rich in citral, did not induce any characteristic signs of acute oral toxicity and was also efficient in reducing carrageenan-induced paw edema, in addition to presenting antinociceptive potential and acting on both central and peripheral pain. It is thus a promising candidate for the development of a new herbal medicine with anti-inflammatory and analgesic action.

Lippia alba essential oil: A powerful and valuable antinociceptive and anti-inflammatory medicinal plant from Brazil.

ETHNOPHARMACOLOGICAL RELEVANCE: In Brazilian popular medicine, Lippia alba leaves are used in teas to treat pain and inflammatory diseases. AIM OF THE STUDY: to evaluate the chemical composition, antinociceptive, and anti-inflammatory activities of Lippia alba essential oil and its major compound geraniol. MATERIAL AND METHODS: Lippia alba leaves were collected in Pará state, Brazil. The leaf essential oil was obtained using a modified Clevenger-type extractor. Then, the oil was analyzed by GC and GC-MS analyses. To evaluate the toxicity of LaEO and geraniol, the doses of 50, 300, and 2000 mg/kg were used in a mouse model. For antinociception tests, abdominal contortion, hot plate, and formalin tests were used; all groups were treated with LaEO and geraniol at doses of 25, 50, and 100 mg/kg; and to evaluate inflammation using the ear edema model. RESULTS: The constituents identified in the highest content were oxygenated monoterpenes: geraniol (37.5%), geranial (6.7%) and neral (3.8%). The animals treated with LaEO and geraniol demonstrated atypical behaviors with aspects of lethargy and drowsiness, characteristics of animals in a state of sedation; the relative weights showed no significant difference compared to the controls. In the abdominal contortion test, LaEO at 25 mg/kg, 50 mg/kg doses, and 100 mg/kg reduced the number of contortions, representing a percentage reduction of 84.64%, 81.23%, and 66.21% respectively. In the hot plate test, LaEO and geraniol increased the latency time at doses of 25, 50, and 100 mg/kg in all test periods; there was no statistical difference between LaEO and geraniol. In the first phase of the formalin test, only doses of 25 mg/kg and 100 mg/kg of LaEO showed significant activity, reducing the latency time by 53.40% and 58.90%. LaEO at doses of 25 mg/kg and 100 mg/kg reduced the size of the edema, demonstrating an anti-inflammatory activity of 59.38% (25 mg/kg) and 50% (100 mg/kg). CONCLUSION: Lippia alba essential oil and geraniol showed central/peripheral analgesic and anti-inflammatory potential and can be used as an alternative or complementary treatment to conventional drugs. More studies are needed to evaluate its action mechanisms and its analgesic effects.

Exploring the impact of seasonal variations on the chemical composition, antinociceptive, and anti-inflammatory properties of Pogostemon heyneanus Benth. essential oil.

Background: Pogostemon heyneanus leaves infusions are relevant in ethnopharmacology for treating colds, coughs, headaches, and asthma. Purpose: The essential oil chemical composition of a Pogostemon heyneanus specimen was monthly monitored from October 2021 to July 2022 to evaluate the climatic influences on its yield and chemical composition and antinociceptive, andanti-inflammatory properties. Methods: The leaves, collected monthly over a 10-month period, were submitted to hydrodistillation. The oils obtained were analyzed by gas chromatography coupled to a mass spectrometer and gas chromatography coupled to flame ionization detector. The P. heyneanus essential oil (PhEO) was tested in vivo to evaluate its peripheral analgesic actions through the abdominal writhing test induced by acetic acid, and peripheral analgesia by tail immersion. Neurogenic and inflammatory pain were evaluated by formalin test, and acute oral toxicity of the oil was also verified. Results: PhEO presented 27 chemical constituents with the highest predominance of patchoulol (43.6%-76.9%), α-bulnesene (0.2%-12.7%), α-guaiene (0.4%-8.9%), seychellene (3.8%-5.1%) and pogostol (0.0%-8.2%). The climatic parameters insolation, humidity, rainfall, and temperature did not influence the essential oil yield or the main chemical constituents, except for pogostol, which presented a strong (r = 0.73) and statistically significant (p < 0.05) correlation with temperature. PhEO did not display toxicity at the maximum 300 mg/kg dosage. The oil showed low peripheral and central analgesic action at 100 mg/kg, while in the neurogenic and inflammatory pain inhibition tests, no actions related to PhEO were observed. In the carrageenan-induced peritonitis test, PhEO did not reduce the migration of leukocytes to the peritoneal cavity compared to the control group. Conclusion: Pogostemon heyneanus is a resistant plant to seasonal influences and a source of patchoulol. Despite ethnopharmacological indications, no in-vivo biological activities such as neurogenic or inflammatory pain were identified in the present work. So, the low influence of the climatic parameters on chemical composition can infer that the low pharmacological activity is also not subject to climatic variations, that is, it does not change due to the climate.

GQ-16, a novel peroxisome proliferator-activated receptor γ (PPARγ) ligand, promotes insulin sensitization without weight gain.

The recent discovery that peroxisome proliferator-activated receptor γ (PPARγ) targeted anti-diabetic drugs function by inhibiting Cdk5-mediated phosphorylation of the receptor has provided a new viewpoint to evaluate and perhaps develop improved insulin-sensitizing agents. Herein we report the development of a novel thiazolidinedione that retains similar anti-diabetic efficacy as rosiglitazone in mice yet does not elicit weight gain or edema, common side effects associated with full PPARγ activation. Further characterization of this compound shows GQ-16 to be an effective inhibitor of Cdk5-mediated phosphorylation of PPARγ. The structure of GQ-16 bound to PPARγ demonstrates that the compound utilizes a binding mode distinct from other reported PPARγ ligands, although it does share some structural features with other partial agonists, such as MRL-24 and PA-082, that have similarly been reported to dissociate insulin sensitization from weight gain. Hydrogen/deuterium exchange studies reveal that GQ-16 strongly stabilizes the ß-sheet region of the receptor, presumably explaining the compound's efficacy in inhibiting Cdk5-mediated phosphorylation of Ser-273. Molecular dynamics simulations suggest that the partial agonist activity of GQ-16 results from the compound's weak ability to stabilize helix 12 in its active conformation. Our results suggest that the emerging model, whereby "ideal" PPARγ-based therapeutics stabilize the ß-sheet/Ser-273 region and inhibit Cdk5-mediated phosphorylation while minimally invoking adipogenesis and classical agonism, is indeed a valid framework to develop improved PPARγ modulators that retain antidiabetic actions while minimizing untoward effects.