Background and Purpose
Intestinal mucositis refers to mucosal damage caused by cancer treatment, and irinotecan is one of the agents most associated with this condition. Focusing on the development ...of alternatives to prevent this important adverse effect, we evaluated the activity of the flavonoid luteolin, which has never been tested for this purpose despite its biological potential.
Experimental Approach
The effects of luteolin were examined on irinotecan‐induced intestinal mucositis in mice. Clinical signs were evaluated. Moreover, histological, oxidative, and inflammatory parameters were analysed, as well as the possible interference of luteolin in the anti‐tumour activity of irinotecan.
Key Results
Luteolin (30 mg·kg−1; p.o. or i.p.) prevented irinotecan‐induced intestinal damage by reducing weight loss and diarrhoea score and attenuating the shortening of the duodenum and colon. Histological analysis confirmed that luteolin (p.o.) prevented villous shortening, vacuolization, and apoptosis of cells and preserved mucin production in the duodenum and colon. Moreover, luteolin treatment mitigated irinotecan‐induced oxidative stress, by reducing the levels of ROS and LOOH and augmenting endogenous antioxidants, and inflammation by decreasing MPO enzymic activity, TNF, IL‐1β, and IL‐6 levels and increasing IL‐4 and IL‐10. Disruption of the tight junctions ZO‐1 and occludin was also prevented by luteolin treatment. Importantly, luteolin did not interfere with the anti‐tumour activity of irinotecan.
Conclusion and Implications
Luteolin prevents intestinal mucositis induced by irinotecan and therefore could be a potential adjunct in anti‐tumour therapy to control this adverse effect, increasing treatment adherence and consequently the chances of cancer remission.
Chemotherapy-induced neuropathic pain (CINP) is one of the most severe side effects of anticancer agents, such as platinum- and taxanes-derived drugs (oxaliplatin, cisplatin, carboplatin and ...paclitaxel). CINP may even be a factor of interruption of treatment and consequently increasing the risk of death. Besides that, it is important to take into consideration that the incidence of cancer is increasing worldwide, including colorectal, gastric, lung, cervical, ovary and breast cancers, all treated with the aforementioned drugs, justifying the concern for medical community and issues regarding quality of live. Several physiopathological mechanisms have already been described for CINP, such as changes in axonal transport, mitochondrial damage, increased ion channel activity and inflammation in the central nervous system (CNS). Another less frequent event that may occur after chemotherapy, particularly under oxaliplatin treatment, is the central neurotoxicity leading to disorders such as mental confusion, catatonia, hyporeflexia, etc. To date, no pharmacological therapy has shown satisfactory effect in these cases. In this scenario, duloxetine is the only drug currently in clinical use. Peroxisome proliferator-activated receptors (PPAR) belong to the class of nuclear receptors and are present in several tissues, mainly participating in lipid and glucose metabolism and inflammatory response. There are 3 PPAR isoforms: α, β/δ and . PPAR, the protagonist of this review, is expressed in adipose tissue, large intestine, spleen and neutrophils. This subtype also plays important role in energy balance, lipid biosynthesis and adipogenesis. The effects of PPARy agonists, known for their positive activity on type II diabetes mellitus, have been explored and present promising effects in the control of neuropathic pain, including CINP, and also cancer. This review focuses largely on the mechanisms involved in chemotherapy-induced neuropathy and the effects of the activation of PPAR to treat CINP. It is the aim of this review to help understanding and developing novel CINP therapeutic strategies integrating PPAR signalling.
Myrcia is a genus widespread in South America with many species presenting anti-inflammatory and biological properties. We investigated the anti-inflammatory activity of crude hydroalcoholic extract ...of Myrcia pubipetala leaves (CHE-MP) using macrophages (RAW 264.7), and the air pouch model in mice to evaluate leukocyte migration and mediator's release. Adhesion molecule expression, CD49 and CD18, was evaluated in neutrophils. In vitro, the CHE-MP significantly reduced nitric oxide (NO), interleukin (IL)-1β, IL-6, and tumor necrosis factor (TNF) levels in the exudate and the supernatant culture. CHE-MP did not present cytotoxicity and modulated the percentage of positive neutrophils for CD18 and its expression per cell, without modifying the expression of CD49, which corroborated with significantly reduced neutrophil migration to inflammatory exudate and subcutaneous tissue. Taken together, the data demonstrate that CHE-MP presents a potential activity on innate inflammatory.
Chalcones present potential therapeutic activities reported on literature, which led us to evaluate the anti-inflammatory effects and the acute toxicity of 2′,6′-dihydroxy-4′-methoxydihydrochalcone ...(DHMDC) using in vitro and in vivo models. The anti-inflammatory activity was firstly in vitro investigated using macrophages (RAW 264.7) and neutrophils previously treated with DHMCD activated with lipopolysaccharide (LPS). Nitrite, IL-1β, and TNF levels were measured in the macrophage culture supernatant, and the adhesion molecule expression (CD62L, CD49D, and CD18) was evaluated in neutrophils. Then, carrageenan-induced inflammation was performed in the subcutaneous tissue of male Swiss mice. Leukocyte migration and histological analysis were performed in the pouches. Toxicological studies were carried out on female Swiss mice (600 mg/kg) through biochemical parameters and histopathological analysis. In vitro, the DHMCD significantly reduced the IL-1β, TNF, and nitrite levels. The DHMCD was also able to modulate the percentage of positive neutrophils for CD62L, without modifying the expression of CD18 or CD49d. In vivo, DHMCD (3 mg/kg, p.o.) significantly reduced neutrophil migration to inflammatory exudate and subcutaneous tissue. No evidence of toxic effect was observed considering the biochemical parameters and histopathological analysis of liver and kidney. Together, the obtained data shows that DHMCD presents anti-inflammatory activity by modulating the macrophage inflammatory protein secretion and also by blocking the CD62L cleavage in neutrophils. Furthermore, there was not any evidence of toxic effect in acute toxicological analysis.
Background. Solanum diploconos (Mart.) Bohs is a native Brazilian plant belonging to the Solanaceae family, popularly known as “tomatinho do mato” and poorly investigated. Herein, we presented for ...the first time evidence for the anti-inflammatory and wound healing activities of S. diploconos fruit hydroalcoholic extract. Material and Methods. In vitro fMLP-induced chemotaxis, LPS-induced inflammatory mediator levels (cytokines by ELISA and NO release by Griess reaction), and adhesion molecule expression (CD62L, CD49d, and CD18, by flow-cytometry) were assessed in neutrophils treated with different concentrations of the extract. Inflammation resolution was measured by the efferocytosis assay and the healing activity by in vivo and in vitro assays. The air pouch model of carrageenan-induced inflammation in Swiss mice was used to investigate the in vivo anti-inflammatory effects of the extract. Leukocyte influx (by optical microscopy) and cytokine release were quantified in the pouch exudates. Additionally, the acute and subacute toxic and genotoxic effects of the extract were evaluated. Results. In vitro, the extract impaired neutrophil chemotaxis and its ability to produce and/or release cytokines (TNFα, IL-1β, and IL-6) and NO upon LPS stimuli (p<0.01). LPS-treated neutrophils incubated with the extract presented increased CD62L expression (p<0.01), indicating a reduced activation. An enhanced efferocytosis of apoptotic neutrophils by macrophages was observed and accompanied by higher IL-10 and decreased TNFα secretion (p<0.01). In vivo, similar results were noted, including reduction of neutrophil migration, protein exudation, and cytokine release (p<0.01). Also, the extract increased fibroblast proliferation and promoted skin wound healing (p<0.01). No signs of toxicity or genotoxicity were observed for the extract. Conclusion. S. diploconos fruit extract is anti-inflammatory by modulating neutrophil migration/activation as well macrophage-dependent efferocytosis and inflammatory mediator release. It also indicates its potential use as a healing agent. Finally, the absence of acute toxic and genotoxic effects reinforces its possible use as medicinal product.
The ostrich oil (OO) has been topically used for decades to treat skin diseases. Its oral use has been encouraged through e-commerce advertising several health benefits to OO without scientific ...evidence on its safety or effectiveness. This study presents the chromatographic profile of a commercially available OO and its acute and 28-day repeated dose in vivo toxicological profiles. OO anti-inflammatory and antinociceptive effects were also investigated. Omega-9 (ω-9; oleic acid; 34.6%) and −6 (linoleic acid; 14.9%) were detected as OO main constituents. A high single dose of the OO (2 g/kg of ω-9) demonstrated no or low acute toxicity. However, when orally treated with OO (30–300 mg/kg of ω-9) for 28 consecutive days, mice exhibited altered locomotor and exploratory activities, hepatic damage, and increased hindpaw sensitivity accompanied by increased levels of cytokine and brain-derived neurotrophic factor in their spinal cords and brains. Lack of anti-inflammatory or antinociceptive activities was also evidenced in 15-day-OO treated mice. These results indicate that chronic consumption of OO induces hepatic injury, in addition to neuroinflammation and subsequent hypersensitivity and behavioural changes. Thus, there is no evidence to support OO use to treating illness in humans.
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•The ostrich oil (OO) presents a mix of acids in different proportion.•The OO presents toxic effect changing liver morphology and mice behavior.•The OO caused neuroinflammation and mechanical hypersensitivity in mice.•No anti-inflammatory or anti-nociceptive activities was evidenced for the OO.
Peripheral neuropathy is an important adverse effect caused by some chemotherapeutic agents, including oxaliplatin (OXA). OXA-induced peripheral neuropathy (OIPN) is a challenging condition due to ...diagnostic complexities and a lack of effective treatment. In this study, we investigated the antiallodynic effect of β-caryophyllene (BCP), a cannabinoid type 2 (CB2) receptor agonist, in a mouse model of OIPN. BCP treatment inhibited OXA-induced mechanical and cold allodynia in both preventive and therapeutic drug treatment regimens. Experiments with the CB2 receptor agonist GW405833 confirmed the role of CB2 receptors in OIPN. The CB2 antagonist SR144528 abrogated the anti-nociceptive effect of BCP on mechanical allodynia, without impacting OXA-induced sensitivity to cold. BCP decreased neuroinflammation, as inferred from TNF, IL-1β, IL-6, and IL-10 profiling, and also reduced ROS production, lipid peroxidation, and 4-hydroxynonenal protein adduct formation in the spinal cords of OXA-treated mice. BCP did not affect the antitumor response to OXA or its impact on blood cell counts, implying that the cytotoxicity of OXA was preserved. These results underscore BCP as a candidate drug for OIPN treatment via CB2 receptor-dependent mechanisms, and anti-inflammatory and antioxidant responses in the spinal cord.
Garcinia humilis
is popularly used to treat digestive, intestinal and inflammatory illness. We investigated the in vivo and in vitro effects of the methanol extract of
G. humilis
leaves (MEGh) on ...inflammatory cells behavior (migration and chemical mediators release) and hypersensitivity. Anti-inflammatory activity was investigated using carrageenan-induced inflammation in the subcutaneous tissue of male Swiss mice treated orally with MEGh (0.1–30 mg/kg). Leucocyte migration, chemical mediators secretion (TNF, IL-1β, IL-6 and CXCL1) and protein exudation were quantified in the exudate. The adhesion molecules expression (CD62L and CD18), chemical mediators and chemotaxis was evaluated using neutrophils or macrophages RAW.264.7 previously treated with the extract (1–100 µg/mL) and activated with LPS. The anti-inflammatory activity of the isolated compounds friedelin, canophyllol, amentoflavone and 3-desmethyl-2-geranyl-4-prenylbellidypholine xanthone (10 μM) was evaluated in macrophages nitric oxide (NO) and TNF release. MEGh, given orally (30 mg/kg), significantly reduced neutrophil migration and decreased TNF, IL-1β and CXCL1 levels, without interfering with protein exudation and IL-6. In vitro, the extract significantly reduced IL-1β and IL-6 levels but did not alter TNF and CXCL1. The MEGh also reduced the expression of CD62L and CD18 and consequently neutrophil chemotaxis. The compounds friedelin, amentoflavone and 3-demethyl-2-geranyl-4-prenylbellidypholine xanthone decreased the secretion of NO and TNF by RAW264.7. The MEGh effects were extended to the pain-like behaviour induced by carrageenan in the mice hindpaw. MEGh presented important anti-inflammatory effects probably due to its activity on neutrophil migration and on important chemical mediator release, scientifically reinforcing its use as medicinal plant.
Passiflora edulis f. flavicarpa O. Deg. is a native Brazilian fruit known as sour or yellow passion fruit. From its peel, mainly in the northeast of Brazil, is produced a flour that is largely used ...as folk medicine to treat diabetes and other metabolic conditions.
The aim of the study was to show the effects of P. edulis peel flour (PEPF) in metabolic disorders caused by cafeteria diet in mice.
The antioxidant activity in vitro of PEPF extract was determined by ferric reducing/antioxidant power, β-carotene/linoleic acid system and nitric oxide scavenging activity assay. C57BL/6 mice divided in 3 groups: Control group, fed on a standard diet (AIN); Cafeteria diet (CAF) group, fed on a cafeteria diet, and PEPF group, fed on a cafeteria diet containing 15% of PEPF, during 16 weeks. The glucose tolerance and insulin sensitivity were evaluated through the glucose tolerance test (GTT) and the insulin tolerance test (ITT). After the intervention period, blood, hepatic, pancreatic and adipose tissues were collected for biochemical and histological analysis. Cholesterol, triglyceride, interleukins and antioxidant enzymes were measured in the liver tissue.
PEPF extract presented antioxidant activity in the higher concentrations in the performed assays. The PEPF intake decreased the body weight gain, fat deposition, predominantly in the liver, improved the glucose tolerance and insulin sensitivity in metabolic changes caused by cafeteria diet.
Together, the data herein obtained points out that P. edulis peel flour supplementation in metabolic syndrome condition induced by CAF-diet, prevents insulin and glucose resistance, hepatic steatosis and adiposity.
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Neurotrophic factors (NTFs), namely nerve growth factor (NGF), glial cell line-derived neurotrophic factor (GDNF), brain-derived neurotrophic factor (BDNF) and neurotrophin-3 (NT-3), have recently ...emerged as a new exciting class of potential targets for the development of drugs to treat chronic pain. We have recently reported that brachial plexus avulsion (BPA) results in a marked and long-lasting mechanical hypernociception in rodents. Here we demonstrate that antibodies against NGF, NT-3, GDNF and BDNF were able to postpone the mechanical hypernociception in mice when dosed locally, systemically or intrathecally (i.t.) at the time of surgery. However, none of them were able to interfere with the mechanical hypernociception when administered intraventricularly (i.c.v.) at the moment of surgery or even i.p. on the 4th day after the injury. Interestingly, the anti-BDNF antibody was the only one that substantially reversed the mechanical hypernociceptive state when administered i.t. or i.c.v. on the 4th day after the BPA. We might suggest that NTFs, notably BDNF, are involved in the mechanisms underlying neuropathic pain-like behavior following BPA. These pieces of evidence corroborate the notion that NTF blockers might represent a new and interesting option for the management of neuropathic pain.
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