Natural products modulating interleukins and other inflammatory mediators in tumor-bearing animals: A systematic review.

BACKGROUND: Cancer is a group of diseases characterized by abnormal cell growth and proliferation. Natural products are a potentially important source for bioactive phytochemicals in the management of cancer, which regulate a broad range of biological events via the modulation of interleukins (ILs), pro- and anti-inflammatory modulators, and other cancer hallmark-mediated signaling pathways. PURPOSE: To systematically review the literature to identify in vivo studies investigating the anticancer properties of medicinal plants and natural molecules as modulators of ILs and their related pro- and anti-inflammatory signaling markers in tumor-bearing animals. METHODS: Articles published in English were searched, without any constraint in respect of countries. The electronic databases PubMed, Embase, Scopus, and Web of Science were used for the literature search for studies published between January 2010 and January 2022. The search terms used included medicinal plants, anticancer, antineoplasic agent, ILs, cytokine, and their combinations. A manual search to detect any articles not found in the databases was also made. The identified studies were then critically reviewed and relevant data were extracted and summarized. RESULTS: Natural products were found to modulate ILs, including IL-1ß, IL-2, IL-4, IL-6, IL-8, IL-18, IL-23, and IL-12, and interferon gamma; increase tissue inhibitor metalloprotease; decrease vascular endothelial growth factor, tumor necrosis factor alpha, granulocyte macrophage colony-stimulating factor, and nuclear factor kappa B; augment immunity by increasing the major histocompatibility complexes II and CD4+, cluster of differentiation 8 + T cell and class II trans-activator expression; and heighten the action of antioxidant enzymes, which are involved in the detoxification of free radicals and reactive oxygen species. CONCLUSION: Natural products discussed in this review show great potential to regulate ILs and weaken associated pro- and anti-inflammatory signaling markers in tumor-bearing animals. Flavonoids, polyphenols, polysaccharides, alkaloids and tannins are important phytochemicals in the modulation of ILs, especially pro-inflammatory ones. However, in terms of future research, the importance of clinical trials to investigate their beneficial properties should be warranted.

The quality of research on judicialization and its influence on public policies on access to medicines in Brazil: a systematic review.

Patients without access to medicines often resort to the judicial system. However, no systematic review has discussed the quality of studies and the factors that may influence the access to medicines from judicialization. This study aimed to characterize the quality of research on access to judicialized medicines and their influence on public policies in Brazil. A search was conducted in the LILACS, PubMed/Medline, Scopus, and Web of Science databases using the terms "judicialization" and "medication". Two reviewers identified articles that met the inclusion criteria. Only studies written in English, Portuguese, or Spanish published from 1990 to 2018 were included. The study selection resulted in a final sample of 45 articles. The retrospective descriptive design was the most common methods, based on reports and lawsuits. A high level of heterogeneity among the studies hindered the comparison and generation of evidence capable of supporting judges' decisions based on technical-scientific criteria. This review showed that studies were heterogeneous and had low methodological quality. Moreover, they did not propose viable solutions for health managers and formulators to face the problem.

Development of morin/hydroxypropyl-ß-cyclodextrin inclusion complex: Enhancement of bioavailability, antihyperalgesic and anti-inflammatory effects.

Morin is a flavonoid has been reported with several pharmacological effects such as, antioxidant, anti-inflammatory, anticancer, antidiabetic, etc. However, morin has low solubility in water, which decreases the bioavailability and limits its clinical application. In this way, to improve the pharmaceutical properties, morin was complexed in hydroxypropyl-ß-cyclodextrin (HP-ß-CD) and its oral bioavailability and anti-inflammatory effects were evaluated. Initially, a phase solubility study was performed, which showed that HP-ß-CD would be the better cyclodextrin for the formation of complexes with morin. The morin/HP-ß-CD inclusion complex (1:1) was prepared by freeze-drying method. The sample obtained was characterized by DSC, FTIR, PXRD, SEM and 1H NMR techniques, evidencing the formation of morin/HP-ß-CD inclusion complex. In addition, complexation efficiency (98.3%) and loading content (17.63%), determined by HPLC demonstrated that morin was efficiently complexed in HP-ß-CD. In vitro dissolution study confirmed that morin/HP-ß-CD inclusion complex increased the solubility and dissolution rate of morin. The oral bioavailability of the morin/HP-ß-CD complex and free morin were evaluated through a pharmacokinetic study in rat plasma. The oral bioavailability of morin complexed with HP-ß-CD was increased by 4.20 times compared with the free morin. Hyperalgesia induced by carrageenan and carrageenan-induced pleurisy were carried out in mice to evaluate the antihyperalgesic and anti-inflammatory activities of free morin and inclusion complex. Morin/HP-ß-CD inclusion complex showed antihyperalgesic effect in inflammatory pain model and anti-inflammatory effect decreasing leukocyte migration and TNF-α levels at a lower dose than free morin. Therefore, the morin/HP-ß-CD inclusion complex improved the solubility, dissolution rate, oral bioavailability, antihyperalgesic and anti-inflammatory effects of morin. In this way, the morin/HP-ß-CD inclusion complex exhibits potential for development of new pharmaceutical product for future clinical applications.

Effects of a Single Bout of Resistance Exercise in Different Volumes on Endothelium Adaptations in Healthy Animals.

BACKGROUND:: Resistance exercise (RE) has been recommended for patients with cardiovascular diseases. Recently, a few studies have demonstrated that the intensity of a single bout of RE has an effect on endothelial adaptations to exercise. However, there is no data about the effects of different volumes of RE on endothelium function. OBJECTIVE:: The aim of the study was to evaluate the effects of different volumes of RE in a single bout on endothelium-dependent vasodilatation and nitric oxide (NO) synthesis in the mesenteric artery of healthy animals. METHODS:: Male Wistar rats were divided into three groups: Control (Ct); low-volume RE (LV, 5 sets x 10 repetitions) and high-volume RE (HV, 15 sets x 10 repetitions). The established intensity was 70% of the maximal repetition test. After the exercise protocol, rings of mesenteric artery were used for assessment of vascular reactivity, and other mesenteric arteries were prepared for detection of measure NO production by DAF-FM fluorescence. Insulin responsiveness on NO synthesis was evaluated by stimulating the vascular rings with insulin (10 nM). RESULTS:: The maximal relaxation response to insulin increased in the HV group only as compared with the Ct group. Moreover, the inhibition of nitric oxide synthesis (L-NAME) completely abolished the insulin-induced vasorelaxation in exercised rats. NO production showed a volume-dependent increase in the endothelial and smooth muscle layer. In endothelial layer, only Ct and LV groups showed a significant increase in NO synthesis when compared to their respective group under basal condition. On the other hand, in smooth muscle layer, NO fluorescence increased in all groups when compared to their respective group under basal condition. CONCLUSIONS:: Our results suggest that a single bout of RE promotes vascular endothelium changes in a volume-dependent manner. The 15 sets x 10 repetitions exercise plan induced the greatest levels of NO synthesis. FUNDAMENTOS:: O exercício resistido (ER) tem sido recomendado para pacientes com doenças cardiovasculares. Recentemente, alguns estudos demonstraram que a intensidade de uma sessão de ER exerce um efeito sobre a disfunção endotelial. No entanto, não há dados sobre os efeitos de diferentes volumes de ER sobre a função endotelial. OBJETIVO:: O objetivo deste estudo foi avaliar os efeitos de diferentes volumes de ER, realizados em uma única sessão, sobre a vasodilatação dependente do endotélio e síntese de óxido nítrico (NO) em artéria mesentérica de animais saudáveis. MÉTODOS:: Ratos Wistar machos foram divididos em três grupos: Controle (Ct); baixo volume (BV, 5 séries x 10 repetições) e alto volume de ER (AV, 15 séries x 10 repetições). Foi estabelecida a intensidade de 70% do teste de repetição máxima. Após o protocolo de exercício, anéis de artéria mesentérica foram utilizados na avaliação da reatividade vascular, e outras artérias mesentéricas foram preparadas para a detecção da produção de NO por fluorescência com para do DAF-FM. A resposta à insulina pela síntese de NO foi avaliada estimulando-se os anéis vasculares com insulina (10nM). RESULTADOS:: A resposta máxima do relaxamento induzido por insulina foi aumentada somente no grupo AV em comparação ao grupo Ct. Além disso, a inibição da síntese do NO (L-NAME), aboliu completamente o relaxamento vascular induzido por insulina em ratos exercitados. A produção de NO mostrou um aumento dependente do volume no endotélio e no músculo liso. No endotélio, apenas os grupos Ct e BV mostraram aumento significativo na síntese de NO quando comparado aos seus respectivos grupos sob condição basal. No entanto, no músculo liso, a fluorescência foi aumentada em todos os grupos quando comparados aos seus respectivos grupos sob a condição basal. CONCLUSÕES:: Nossos resultados sugerem que uma única sessão de ER foi capaz de promover adaptações no endotélio vascular. Além disso, nós observamos que este efeito é volume-dependente e o volume de 15 séries x10 repetições induziu o maior aumento na síntese de NO.

Gastroprotective effect and mechanism of action of Croton rhamnifolioides essential oil in mice.

BACKGROUND: Croton rhamnifolioides Pax is a plant species that have been used in the folk medicine to treat ulcers, inflammations and hypertension. However, despite the relevant data obtained from ethnopharmacological studies, the pharmacological properties endorsing the efficacy of this plant to treat ulcer remain to be elucidated. HYPOTHESIS/PURPOSE: The present study aimed to characterize the chemical profile and evaluate the gastroprotective activity of the essential oil obtained from C. rhamnifolioides Pax (OECC) in mice. METHODS: The essential oil of Croton rhamnifolioides was obtained by hydrodistillation and analyzed by gas-phase chromatography coupled to mass spectrometry (GC/MS). The median lethal dose was determined employing an acute toxicity test. The gastroprotective activity of the OECC was investigated using animal models of gastric ulcer induced by the administration of absolute ethanol, acidified ethanol or indomethacin. Mechanisms of action were investigated using the physical barrier test and by in vivo evaluation of the involvement of the following molecular pathways: nitric oxide, ATP - dependent potassium channels, α2 - noradrenergic receptors, capsaicin - sensitive afferent neurons and opioid receptor. RESULTS: We identified the presence of 21 compounds in OECC, including spathulenol and 1,8 - cineole as major constituents. In orally administered mice, OECC caused no significant toxicity. OECC significantly prevented gastric lesions in all mice models. The barrier test demonstrated that the gastroprotective activity of OECC occurs in a systemic dimension. Our results demonstrated that the gastroprotective effect of OECC involves mechanisms that are related to modulation of opioid receptors and nitric oxide. CONCLUSION: In conclusion, OECC demonstrated significant gastroprotective activity associated with low toxicity, providing scientific evidences that C. rhamnifolioides have the potential for the development of new antiulcer drugs.

Chemical composition, antinociceptive, anti-inflammatory and redox properties in vitro of the essential oil from Remirea maritima Aubl. (Cyperaceae).

BACKGROUND: The present study was carried out to evaluate antioxidant, antinociceptive and anti-inflammatory activities of essential oil from R. maritima (RMO) in experimental protocols. METHODS: The essential oil from the roots and rhizomes of RMO were obtained by hydrodistillation using a Clevenger apparatus, and analyzed by gas chromatography/mass spectrometry (GC/MS). Here, we evaluated free radical scavenging activities and antioxidant potential of RMO using in vitro assays for scavenging activity against hydroxyl radicals, hydrogen peroxide, superoxide radicals, and nitric oxide. The total reactive antioxidant potential (TRAP) and total antioxidant reactivity (TAR) indexes and in vitro lipoperoxidation were also evaluated. The ability of RMO to prevent lipid peroxidation was measured by quantifying thiobarbituric acid-reactive substances (TBARS). NO radical generated at physiological pH was found to be inhibited by RMO, that showed scavenging effect upon SNP-induced NO production at all concentrations. Antinociceptive and anti-inflammatory properties were evaluated by acetic acid writhing reflex, Formalin-induced nociception and Carrageenan-induced edema test. RESULTS: The majors compounds identified was remirol (43.2%), cyperene (13.8%), iso-evodionol (5.8%), cyperotundone (5.7%), caryophyllene oxide (4.9%), and rotundene (4.6%). At the TRAP assay, RMO concentration of 1 mg.mL(-1) showed anti-oxidant effects and at concentration of 1 and 10 ng.mL(-1) RMO showed pro-oxidant effect. RMO at 1 mg.mL(-1) also showed significant anti-oxidant capacity in TAR measurement. Concentrations of RMO from 1 ng.mL(-1) to 100 µg.mL(-1) enhanced the AAPH-induced lipoperoxidation. RMO reduced deoxyribose oxidative damage, induced by the Fenton reaction induction system, at concentrations from 1 ng.mL(-1) to 100 µg.mL(-1). We observed that RMO caused a significant increase in rate of adrenaline auto-oxidation. On the other hand RMO did not present any scavenging effect in H2O2 formation in vitro. The results of this study revealed that RMO has both peripheral and central analgesic properties. The RMO, all doses, orally (p.o.) administered significantly inhibited (p < 0.05, p < 0.01 and p < 0.001) the acetic acid-induced writhings and two phases of formalin-induced nociception in mice. CONCLUSION: The RMO demonstrated antioxidant and analgesic profile which may be related to the composition of the oil.

Antidiabetic effect of the Chrysobalanus icaco L. aqueous extract in rats.

Chrysobalanus icaco L. is a medicinal plant popularly known in Brazil as "Grageru" or "Abageru." It is used in African and American continents as medicinal food in the treatment of several diseases, including diabetes. This study used phytochemical screening to determine the antioxidant and α-amylase inhibitor activities of the aqueous extract (AECI) of C. icaco, and evaluated its antidiabetic potential in rodents. Phytochemical screening was performed using colorimetric tests with specific reagents. The in vitro antioxidant activity was evaluated by the scavenging activity of 2,2-diphenyl-1-picril-hydrazyl. The lethality test and behavioral screening was performed using an oral administration of 5 g/kg of AECI. The antidiabetic potential of AECI was evaluated through the oral glucose tolerance test (OGTT) and chronic hypoglycemic test at the doses of 100, 200, and 400 mg/kg (orally). Metformin was used as a reference drug in all tests. Diabetes was induced by injection of alloxan (40 mg/kg; intravenously). Phytochemical screening showed the presence of various compounds, including tannins, flavones, triterpenoids, steroids, saponins, and alkaloids. The in vitro antioxidant test demonstrated that AECI presented potent antioxidant activity. The lethality test and behavioral screening did not show lethality signs. In the OGTT test, AECI administration was not able to inhibit the elevation of glycemia. However, chronically administrated, it was able to cause a significant (P<.05) reduction of glycemia from 335±27 up to 197±15 mg/dL. These results demonstrate that the AECI presents a potential beneficial effect for diabetes.

Borneol, a bicyclic monoterpene alcohol, reduces nociceptive behavior and inflammatory response in mice.

Borneol, a bicyclic monoterpene, has been evaluated for antinociceptive and anti-inflammatory activities. Antinociceptive and anti-inflammatory activities were studied by measuring nociception by acetic acid, formalin, hot plate, and grip strength tests, while inflammation was prompted by carrageenan-induced peritonitis. The rotarod test was used to evaluate motor coordination. Borneol produced a significant (P < 0.01) reduction of the nociceptive behavior at the early and late phases of paw licking and reduced the writhing reflex in mice (formalin and writhing tests, resp.). When the hot plate test was conducted, borneol (in higher dose) produced an inhibition (P < 0.05) of the nociceptive behavior. Such results were unlikely to be provoked by motor abnormality. Additionally, borneol-treated mice reduced the carrageenan-induced leukocytes migration to the peritoneal cavity. Together, our results suggest that borneol possess significant central and peripheral antinociceptive activity; it has also anti-inflammatory activity. In addition, borneol did not impair motor coordination.

Purification, physicochemical properties, thermal analysis and antinociceptive effect of atranorin extracted from Cladina kalbii.

Lichens and their secondary metabolites have attracted the interest of many researchers. Some species have been shown to contain substances with remarkable biologic activity, as antimicrobial, mainly against Gram positive bacteria; antineoplasic acting on solid and ascetic tumors, or in culture cells; antiviral; hypotensive; and spasmolytic effects. The aim of this study was to isolate and characterize atranorin, one of the major constituents which presents in Cladina kalbii (DES ABB.) AHTI., and analyze its antinociceptive effect. The antinociceptive activity was verified in acetic acid-induced writhing test and formalin test with mice. In this work it was observed that atranorin was effective in significant reducing (p<0.05) abdominal writhing at doses of 200 and 400 mg/kg (p.o.) by 52.6 and 61.3%, respectively, when compared to control group (vehicle). The formalin test showed in 200 and 400 mg/kg (p.o.) that atranorin injection was able to inhibit the inflammatory processes (second phase) dose dependently.