RESUMO
BACKGROUND: Several studies show that natural foods are a source of compounds with anticancer properties that affect the gut microbiota and its metabolites. In the present study, we investigate the effect of a delactosed buffalo milk whey by-product (DMW) on colorectal carcinogenesis. METHODS: The effect of DMW on colorectal carcinoma (CRC) was investigated in the established mouse model of azoxymethane (AOM)-induced colon carcinoma, which closely resembles the human clinical condition of CRC. The effect of DMW on CRC immortalized cell lines was also evaluated to further identify the antineoplastic mechanism of action. RESULTS: Pretreatment of AOM-treated mice with DMW significantly (P < 0.05) reduced the percentage of mice bearing both aberrant crypt foci with more than four crypts (which are early precancerous lesions that progress to CRC) and tumors. In addition, DMW completely counteracted the effect of AOM on protein expression of caspase-9, cleaved caspase-3 and poly ADP-ribose polymerase in colonic tissue. Administration of DMW alone (i.e. without AOM) resulted in changes in the composition of the gut microbiota, leading to enrichment or depletion of genera associated with health and disease, respectively. DMW was also able to restore AOM-induced changes in specific genera of the gut microbiota. Specifically, DMW reduced the genera Atopobiaceae, Ruminococcus 1 and Lachnospiraceae XPB1014 and increased the genera Parabacteroides and Candidatus Saccharimonas, which were increased and reduced, respectively, by AOM. Blood levels of butyric acid and cancer diagnostic markers (5-methylcytidine and glycerophosphocholine), which were increased by AOM treatment, were reduced by DMW. Furthermore, DMW exerted cytotoxic effects on two human CRC cell lines (HCT116 and HT29) and these effects were associated with the induction of apoptotic signaling. CONCLUSIONS: Our results suggest that DMW exerts chemopreventive effects and restores the gut microbiota in AOM-induced CRC, and induces cytotoxic effect on CRC cells. DMW could be an important dietary supplement to support a healthy gut microbiota and reduce the prevalence of CRC in humans. Video Abstract.
Assuntos
Neoplasias Colorretais , Soro do Leite , Humanos , Animais , Camundongos , Búfalos , Leite , Carcinogênese , Neoplasias Colorretais/tratamento farmacológico , Azoximetano/toxicidade , Ácido ButíricoRESUMO
OBJECTIVE: To improve the biological and toxicological properties of Mefenamic acid (MA), the galactosylated prodrug of MA named MefeGAL was included in polymeric solid dispersions (PSs) composed of poly(glycerol adipate) (PGA) and Pluronic® F68 (MefeGAL-PS). MefeGAL-PS was compared with polymeric solid formulations of MA (MA-PS) or a mixture of equal ratio of MefeGAL/MA (Mix-PS). METHODS: The in vitro and in vivo pharmacological and toxicological profiles of PSs have been investigated. In detail, we evaluated the anti-inflammatory (carrageenan-induced paw edema test), analgesic (acetic acid-induced writhing test) and ulcerogenic activity in mice after oral treatment. Additionally, the antiproliferative activity of PSs was assessed on in vitro models of colorectal and non-small cell lung cancer. RESULTS: When the PSs were resuspended in water, MefeGAL's, MA's and their mixture's apparent solubilities improved due to the interaction with the polymeric formulation. By comparing the in-vivo biological performance of MefeGAL-PS with that of MA, MefeGAL and MA-PS, it was seen that MefeGAL-PS exhibited the same sustained and delayed analgesic and anti-inflammatory profile as MefeGAL but did not cause gastrointestinal irritation. The pharmacological effect of Mix-PS was present from the first hours after administration, lasting about 44â¯hours with only slight gastric mucosa irritation. In-vitro evaluation indicated that Mix-PS had statistically significant higher cytotoxicity than MA-PS and MefeGAL-PS. CONCLUSIONS: These preliminary data are promising evidence that the galactosylated prodrug approach in tandem with a polymer-drug solid dispersion formulation strategy could represent a new drug delivery route to improve the solubility and biological activity of NSAIDs.
Assuntos
Sistemas de Liberação de Medicamentos , Ácido Mefenâmico , Animais , Ácido Mefenâmico/farmacologia , Ácido Mefenâmico/administração & dosagem , Camundongos , Humanos , Masculino , Edema/tratamento farmacológico , Edema/induzido quimicamente , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/administração & dosagem , Pró-Fármacos/farmacologia , Pró-Fármacos/administração & dosagem , Analgésicos/farmacologia , Analgésicos/administração & dosagem , Analgésicos/toxicidade , Proliferação de Células/efeitos dos fármacos , Anti-Inflamatórios não Esteroides/administração & dosagem , Anti-Inflamatórios não Esteroides/farmacologia , Anti-Inflamatórios não Esteroides/toxicidade , Úlcera Gástrica/induzido quimicamente , Úlcera Gástrica/tratamento farmacológico , Úlcera Gástrica/patologia , Poloxâmero/químicaRESUMO
Nothing is known about the potential implication of gut microbiota in skeletal muscle disorders. Here, we provide evidence that fecal microbiota composition along with circulating levels of short-chain fatty acids (SCFAs) and related metabolites are altered in the mdx mouse model of Duchenne muscular dystrophy (DMD) compared with healthy controls. Supplementation with sodium butyrate (NaB) in mdx mice rescued muscle strength and autophagy, and prevented inflammation associated with excessive endocannabinoid signaling at CB1 receptors to the same extent as deflazacort (DFZ), the standard palliative care for DMD. In LPS-stimulated C2C12 myoblasts, NaB reduces inflammation, promotes autophagy, and prevents dysregulation of microRNAs targeting the endocannabinoid CB1 receptor gene, in a manner depending on the activation of GPR109A and PPARγ receptors. In sum, we propose a novel disease-modifying approach in DMD that may have benefits also in other muscular dystrophies.
Assuntos
Distrofia Muscular de Duchenne , Animais , Camundongos , Autofagia , Disbiose , Endocanabinoides/metabolismo , Inflamação/metabolismo , Camundongos Endogâmicos mdx , Músculo Esquelético/metabolismo , Distrofia Muscular de Duchenne/tratamento farmacológico , Distrofia Muscular de Duchenne/genética , IntestinosRESUMO
Chemotherapy-induced peripheral neuropathy (CIPN) is a common complication of antineoplastic drugs, particularly paclitaxel (PTX). It can affect the quality of patients' lives and increase the risk of developing mood disorders. Although several drugs are recommended, they yielded inconclusive results in clinical trials. The aim of the present work is to investigate whether the palmitoylethanolamide (PEA) would reduce PTX-induced CIPN and associated mood disorders. Moreover, the role PPAR-α and the endocannabinoid system will also be investigated. CIPN was induced by intraperitoneally injection of PTX (8 mg/kg) every other day for a week. PEA, 30 mg/kg, was orally administrated in a bioavailable form (i.e., ultramicronized PEA, um-PEA) one hour after the last PTX injection, for 7 days. In the antagonism experiments, AM281 (1 mg/kg) and GW6471 (2 mg/kg) were administrated 30 min before um-PEA. Our results demonstrated that um-PEA reduced the development of hypersensitivity with the effect being associated with the reduction in spinal and hippocampal pro-inflammatory cytokines, as well as antidepressive and anxiolytic effects. Moreover, the PPAR-α and CB1 receptor antagonists blocked the behavioral and antinociceptive effects of um-PEA. Our findings suggest that um-PEA is a promising adjunct in CIPN and associated mood disorders through the activation of PPAR-α, which influences the endocannabinoid system.
Assuntos
Neuralgia , Paclitaxel , Amidas , Animais , Endocanabinoides , Etanolaminas , Camundongos , Neuralgia/tratamento farmacológico , PPAR alfa , Paclitaxel/efeitos adversos , Ácidos PalmíticosRESUMO
Carbohydrates are one of the most abundant and important classes of biomolecules. The variety in their structures makes them valuable carriers that can improve the pharmaceutical phase, pharmacokinetics and pharmacodynamics of well-known drugs. D-galactose is a simple, naturally occurring monosaccharide sugar that has been extensively studied for use as a carrier and has proven to be valuable in this role. With the aim of validating the galactose-prodrug approach, we have investigated the galactosylated prodrugs ibuprofen, ketoprofen, flurbiprofen and indomethacin, which we have named IbuGAL, OkyGAL, FluGAL and IndoGAL, respectively. Their physicochemical profiles in terms of lipophilicity, solubility and chemical stability have been evaluated at different physiological pH values, as have human serum stability and serum protein binding. Ex vivo intestinal permeation experiments were performed to provide preliminary insights into the oral bioavailability of the galactosylated prodrugs. Finally, their anti-inflammatory, analgesic and ulcerogenic activities were investigated in vivo in mice after oral treatment. The present results, taken together with those of previous studies, undoubtedly validate the galactosylated prodrug strategy as a problem-solving technique that can overcome the disadvantages of NSAIDs.
RESUMO
Obesity is a health concern worldwide, and its onset is multifactorial. In addition to metabolic syndrome, a high-fat diet induces many deleterious downstream effects, such as chronic systemic inflammation, a loss of gut barrier integrity, and gut microbial dysbiosis, with a reduction of many butyrate-producing bacteria. These conditions can be ameliorated by increasing legumes in the daily diet. White and kidney beans (Phaseolus vulgaris L.) and their non-nutritive bioactive component phaseolamin were demonstrated to mitigate several pathological features related to a metabolic syndrome-like condition. The aim of the present study was to investigate the molecular pathways involved in the protective effects on the intestinal and liver environment of a chronic oral treatment with P. vulgaris extract (PHAS) on a murine model of the high-fat diet. Results show that PHAS treatment has an anti-inflammatory effect on the liver, colon, and cecum. This protective effect was mediated by peroxisome proliferator-activated receptor (PPAR)-α and γ. Moreover, we also observed that repeated PHAS treatment was able to restore tight junctions' expression and protective factors of colon and cecum integrity disrupted in HFD mice. This improvement was correlated with a significant increase of butyrate levels in serum and fecal samples compared to the HFD group. These data underline that prolonged treatment with PHAS significantly reduces some pathological features related to the metabolic syndrome-like condition, such as inflammation and intestinal barrier disruption; therefore, PHAS could be a valid tool to be associated with the therapeutic strategy.
RESUMO
Chemotherapy-induced peripheral neuropathy (CIPN) represents one of the most prevalent and potentially disabling side effects due to the use of anticancer drugs, one of the primary neuropathies detected is peripheral neuropathy induced by administration of taxanes, including paclitaxel. It has been demonstrated that gut microbiota is crucial for the therapeutic effect of chemotherapeutic drugs for inhibiting tumor growth and contributed to the pathogenesis of the CIPN. The use of nutraceuticals has receiving growing attention from the research community due to their phytochemical, biological, and pharmacological properties. It has been demonstrated that probiotic formulations may both reduce inflammation and modulate the expression of pain receptors. Our studies tested the efficacy of a probiotic formulation, SLAB51, in preventing paclitaxel-induced neuropathy. Interestingly, our probiotic formulation was able to keep the gut integrity, preserving its functionality, in CIPN-mice, moreover, it prevented the mechanical and cold hypersensitivity induced in paclitaxel-mice. Additionally, ex-vivo analysis showed that in CIPN-mice the pro-biotic treatment increased the expression of opioid and cannabinoid receptors in spinal cord, it prevented in the reduction in nerve fiber damage in the paws and modulated the serum proinflammatory cytokines concentration. On basis of these data, the use of this specific probiotic formulation may represent a valid adjuvant agent to paclitaxel, useful and not toxic for long-lasting therapies.
RESUMO
In our previous studies, a ketorolac-galactose conjugate (ketogal) showed prolonged anti-inflammatory and analgesic activity, causing less gastric ulcerogenic effect and renal toxicity than its parent drug ketorolac. In order to demonstrate the safer profile of ketogal compared to ketorolac, histopathological changes in the small intestine and liver using three staining techniques before and after repeated oral administration in mice with ketorolac or an equimolecular dose of its galactosylated prodrug ketogal were assessed. Cytotoxicity and oxidative stress parameters were evaluated and compared in ketorolac- and ketogal-treated Human Primary Colonic Epithelial cells at different concentrations and incubation times. Evidence of mitochondrial oxidative stress was found after ketorolac treatment; this was attributable to altered mitochondrial membrane depolarization and oxidative stress parameters. No mitochondrial damage was observed after ketogal treatment. In ketorolac-treated mice, severe subepithelial vacuolation and erosion with inflammatory infiltrates and edematous area in the intestinal tissues were noted, as well as alterations in sinusoidal spaces and hepatocytes with foamy cytoplasm. In contrast, treatment with ketogal provided a significant improvement in the morphology of both organs. The prodrug clearly demonstrated a safer profile than its parent drug both in vitro and ex vivo, confirming that ketogal is a strategic alternative to ketorolac.
RESUMO
Pain conditions, such as neuropathic pain (NP) and persistent inflammatory pain are therapeutically difficult to manage. Previous studies have shown the involvement of glutamate receptor in pain modulation and in particular same of these showed the key role of the AMPA ionotropic glutamate receptor subtype. Antiseizure medications (ASMs) are often used to treat this symptom, however the effect of perampanel (PER), an ASM acting as selective, non-competitive inhibitor of the AMPA receptor on the management of pain has not well been investigated yet. Here we tested the potential analgesic and anti-inflammatory effects of PER, in acute and chronic pain models. PER was given orally either in acute (5 mg/kg) or repeated administration (3 mg/kg/d for 4 days). Pain response was assessed using models of nociceptive sensitivity, visceral and inflammatory pain, and mechanical allodynia and hyperalgesia induced by chronic constriction injury to the sciatic nerve. PER significantly reduced pain perception in all behavioral tests as well as CCI-induced mechanical allodynia and hyperalgesia in acute regimen (5 mg/kg). This effect was also observed after repeated treatment using the dose of 3 mg/kg/d. The antinociceptive, antiallodynic and antihyperalgesic effects of PER were attenuated when the CB1 antagonist AM251 (1 mg/kg/i.p.) was administered before PER treatment, suggesting the involvement of the cannabinergic system. Moreover, Ex vivo analyses showed that PER significantly increased CB1 receptor expression and reduced inflammatory cytokines (i.e. TNFα, IL-1ß, and IL-6) in the spinal cord. In conclusion, these results extend our knowledge on PER antinociceptive and antiallodynic effects and support the involvement of cannabinergic system on its mode of action.