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1.
Cancers (Basel) ; 13(7)2021 Mar 24.
Article in English | MEDLINE | ID: mdl-33804927

ABSTRACT

Colorectal cancer (CRC) is a disease with high incidence and mortality. Colonoscopy is a gold standard among tests used for CRC traceability. However, serious complications, such as colon perforation, may occur. Non-invasive diagnostic procedures are an unmet need. We aimed to identify a plasma microRNA (miRNA) signature for CRC detection. Plasma samples were obtained from subjects (n = 109) at different stages of colorectal carcinogenesis. The patients were stratified into a non-cancer (27 healthy volunteers, 17 patients with hyperplastic polyps, 24 with adenomas), and a cancer group (20 CRC and 21 metastatic CRC). miRNAs (381) were screened by TaqMan Low-Density Array. A classifier based on four differentially expressed miRNAs (miR-28-3p, let-7e-5p, miR-106a-5p, and miR-542-5p) was able to discriminate cancer versus non-cancer cases. The overexpression of these miRNAs was confirmed by RT-qPCR, and a cross-study validation step was implemented using eight data series retrieved from Gene Expression Omnibus (GEO). In addition, another external data validation using CRC surgical specimens from The Cancer Genome Atlas (TCGA) was carried out. The predictive model's performance in the validation set was 76.5% accuracy, 59.4% sensitivity, and 86.8% specificity (area under the curve, AUC = 0.716). The employment of our model in the independent publicly available datasets confirmed a good discrimination performance in five of eight datasets (median AUC = 0.823). Applying this algorithm to the TCGA cohort, we found 99.5% accuracy, 99.7% sensitivity, and 90.9% specificity (AUC = 0.998) when the model was applied to solid colorectal tissues. Overall, we suggest a novel signature of four circulating miRNAs, i.e., miR-28-3p, let-7e-5p, miR-106a-5p, and miR-542-5p, as a predictive tool for the detection of CRC.

2.
Circulation ; 138(7): 696-711, 2018 08 14.
Article in English | MEDLINE | ID: mdl-29348263

ABSTRACT

BACKGROUND: Anthracyclines, such as doxorubicin (DOX), are potent anticancer agents for the treatment of solid tumors and hematologic malignancies. However, their clinical use is hampered by cardiotoxicity. This study sought to investigate the role of phosphoinositide 3-kinase γ (PI3Kγ) in DOX-induced cardiotoxicity and the potential cardioprotective and anticancer effects of PI3Kγ inhibition. METHODS: Mice expressing a kinase-inactive PI3Kγ or receiving PI3Kγ-selective inhibitors were subjected to chronic DOX treatment. Cardiac function was analyzed by echocardiography, and DOX-mediated signaling was assessed in whole hearts or isolated cardiomyocytes. The dual cardioprotective and antitumor action of PI3Kγ inhibition was assessed in mouse mammary tumor models. RESULTS: PI3Kγ kinase-dead mice showed preserved cardiac function after chronic low-dose DOX treatment and were protected against DOX-induced cardiotoxicity. The beneficial effects of PI3Kγ inhibition were causally linked to enhanced autophagic disposal of DOX-damaged mitochondria. Consistently, either pharmacological or genetic blockade of autophagy in vivo abrogated the resistance of PI3Kγ kinase-dead mice to DOX cardiotoxicity. Mechanistically, PI3Kγ was triggered in DOX-treated hearts, downstream of Toll-like receptor 9, by the mitochondrial DNA released by injured organelles and contained in autolysosomes. This autolysosomal PI3Kγ/Akt/mTOR/Ulk1 signaling provided maladaptive feedback inhibition of autophagy. PI3Kγ blockade in models of mammary gland tumors prevented DOX-induced cardiac dysfunction and concomitantly synergized with the antitumor action of DOX by unleashing anticancer immunity. CONCLUSIONS: Blockade of PI3Kγ may provide a dual therapeutic advantage in cancer therapy by simultaneously preventing anthracyclines cardiotoxicity and reducing tumor growth.


Subject(s)
Antibiotics, Antineoplastic/pharmacology , Autophagy/drug effects , Breast Neoplasms/drug therapy , Doxorubicin/pharmacology , Heart Diseases/prevention & control , Myocytes, Cardiac/drug effects , Phosphoinositide-3 Kinase Inhibitors , Protein Kinase Inhibitors/pharmacology , Quinoxalines/pharmacology , Thiazolidinediones/pharmacology , Tumor Burden/drug effects , Animals , Antibiotics, Antineoplastic/toxicity , Autophagy-Related Proteins/genetics , Autophagy-Related Proteins/metabolism , Breast Neoplasms/enzymology , Breast Neoplasms/genetics , Breast Neoplasms/pathology , Cardiotoxicity , Class Ib Phosphatidylinositol 3-Kinase/genetics , Class Ib Phosphatidylinositol 3-Kinase/metabolism , Cytoprotection , Disease Models, Animal , Doxorubicin/toxicity , Female , Genes, erbB-2 , Heart Diseases/chemically induced , Heart Diseases/enzymology , Heart Diseases/pathology , Mice, Inbred BALB C , Mice, Transgenic , Mutation , Myocytes, Cardiac/enzymology , Myocytes, Cardiac/pathology , Toll-Like Receptor 9/genetics , Toll-Like Receptor 9/metabolism
3.
Phytother Res ; 31(2): 312-320, 2017 Feb.
Article in English | MEDLINE | ID: mdl-27910140

ABSTRACT

Intestinal mucositis (IM) is the critical side effect of irinotecan (CPT-11), which is the front-line drug used for the treatment of colorectal cancer. This study aimed to evaluate the effectiveness of latex proteins (LP) from Calotropis procera to prevent IM and diarrhea in animals. Swiss mice were treated daily with saline or LP (1, 5, or 50 mg/kg, i.v.) 24 h prior to CTP-11 (75 mg/kg/4 days, i.p) and for additional 6 days. Animal survival, body weight variation, and diarrhea were registered. After animal sacrifice (day 7 post first injection of CPT-11), intestinal samples were collected to study morphology and inflammatory parameters. Animals given LP exhibited improved parameters (survival, body weight, and absence of diarrhea) as compared with the CPT-11 control. The severity of IM observed in animals given CPT-11 was reduced in animals treated with LP. Treatment with LP also prevented the reduction in the villus/crypt ratio promoted by CPT-11. The rise in MPO activity and pro-inflammatory cytokines, over-contractility of the smooth muscle, and diarrhea were all abrogated in LP-treated mice. Markedly reduced immunostaining intensity for COX-2, TNF-α, IL-1ß, iNOS, and NF-κB was observed in the intestinal tissue of animals treated with LP. The side-effects of CPT-11 were eliminated by LP treatment in experimental animals and improved clinical parameters characteristic of IM All known biochemical pathogenesis. Copyright © 2016 John Wiley & Sons, Ltd.


Subject(s)
Apocynaceae/chemistry , Calotropis/chemistry , Camptothecin/analogs & derivatives , Colonic Neoplasms/drug therapy , Latex/pharmacology , Animals , Camptothecin/adverse effects , Colonic Neoplasms/pathology , Disease Models, Animal , Irinotecan , Male , Mice
4.
Eur J Pharmacol ; 693(1-3): 57-63, 2012 Oct 15.
Article in English | MEDLINE | ID: mdl-22884438

ABSTRACT

Hydrogen sulphide (H(2)S) has shown to relax gastrointestinal muscle. Here in, we evaluated the effects of H(2)S donors on gastric emptying and in pyloric sphincter muscle relaxation, and whether these effects involved K(ATP) channels or TRPV1 receptors. Mice were treated with l-cysteine (alone or with propargylglycine-an inhibitor of H(2)S synthesis), NaHS, Lawesson's reagent (H(2)S donors) or saline. After 30 min, mice were gavaged with a liquid meal containing a nonabsorbable marker and then killed at 10, 20 or 30 min intervals to assess marker recovery from the stomach and intestine. This experiment was repeated in mice pre-treated with K(ATP) channel (glibenclamide) or TRPV1 receptor (capsazepine) antagonists. In addition, pyloric sphincter muscles were mounted in an organ bath, incubated with saline, glibenclamide or capsazepine, and NaHS dose-responses were determined. H(2)S donors and l-cysteine enhanced gastric emptying in a dose-dependent manner; propargylglycine reversed the effect of l-cysteine. Both glibenclamide and capsazepine abolished l-cysteine and H(2)S donors' augmentation of gastric emptying. Dose-dependent inductions of pyloric sphincter relaxation by NaHS were abolished by glibenclamide or capsazepine. These data suggest that H(2)S donors-induced acceleration of gastric emptying and relaxation of pyloric sphincter muscle by K(ATP) channel and TRPV1 receptor activations.


Subject(s)
Gastric Emptying/physiology , Hydrogen Sulfide , KATP Channels/physiology , TRPV Cation Channels/physiology , Animals , Capsaicin/analogs & derivatives , Capsaicin/pharmacology , Gastric Emptying/drug effects , Glyburide/pharmacology , KATP Channels/antagonists & inhibitors , Male , Mice , Muscle Relaxation/drug effects , Potassium Channel Blockers/pharmacology , Pylorus/drug effects , Pylorus/physiology , TRPV Cation Channels/antagonists & inhibitors
5.
Naunyn Schmiedebergs Arch Pharmacol ; 385(10): 981-90, 2012 Oct.
Article in English | MEDLINE | ID: mdl-22797601

ABSTRACT

Oral mucositis is an important dose-limiting and costly side effect of cancer chemotherapy. Soluble proteins obtained of the latex of Calotropis procera have been extensively characterized as anti-inflammatory in different experimentally induced inflammatory conditions, including arthritis and sepsis. In this study, the phytomodulatory laticifer proteins (LP) were challenged to regress the inflammatory events associated with 5-fluorouracil-induced oral mucositis. We also evaluated the expression of pro-inflammatory cytokines and inducible enzymes, such as cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS). Oral mucositis was induced in hamsters by two injections of 5-fluorouracil (5-FU; 60 and 40 mg/kg, i.p., on experimental days 1 and 2, respectively). LP (5 mg/kg, i.p.) was injected 24 h before and 24 h after mechanical trauma of the cheek pouches. A normal control group received only saline. On day 10, the animals were sacrificed, and the cheek pouches were excised for macroscopic and histopathological analysis, myeloperoxidase activity measurement, and immunohistochemical assessment of tumor necrosis factor-α (TNF-α), interleukin-1ß (IL-1ß), iNOS, and COX-2. LP significantly inhibited macroscopic histopathological scores and myeloperoxidase activity compared with the 5-FU control group. 5-Fluorouracil also induced marked immunostaining of TNF-α, IL-1ß, iNOS, and COX-2 on inflamed conjunctive and epithelial tissue compared with the normal control group. Such damage was significantly inhibited (p < 0.05) by LP treatment compared with the 5-FU group. These findings demonstrate an anti-inflammatory effect of LP on 5-FU-induced oral mucositis. The protective mechanism appears to involve inhibition of the expression of iNOS, COX-2, TNF-α, and IL-1ß.


Subject(s)
Antimetabolites, Antineoplastic/adverse effects , Calotropis/chemistry , Fluorouracil/adverse effects , Immunologic Factors/immunology , Latex/chemistry , Plant Proteins/therapeutic use , Stomatitis/prevention & control , Animals , Cricetinae , Cyclooxygenase 2/biosynthesis , Cyclooxygenase 2/immunology , Cytokines/biosynthesis , Cytokines/immunology , Disease Models, Animal , Down-Regulation , Immunohistochemistry , Immunologic Factors/biosynthesis , Male , Mesocricetus , Nitric Oxide Synthase Type II/biosynthesis , Nitric Oxide Synthase Type II/immunology , Peroxidase/metabolism , Plant Proteins/administration & dosage , Plant Proteins/isolation & purification , Stomatitis/chemically induced , Stomatitis/immunology , Stomatitis/pathology
6.
Cancer Chemother Pharmacol ; 69(4): 931-42, 2012 Apr.
Article in English | MEDLINE | ID: mdl-22101361

ABSTRACT

PURPOSE: Intestinal mucositis and the closely associated diarrhea are common costly side effects of irinotecan. Cytokine modulators, such as thalidomide and pentoxifylline, are found capable of attenuating intestinal mucositis progression. Nitric oxide (NO) seems to be a key mediator of the antineoplastic drug toxicity. The aim of this study was to investigate the role of NO on the pathogenesis of intestinal mucositis, as well as the participation of cytokines upon inducible nitric oxide synthase (iNOS) expression in irinotecan-induced intestinal mucositis. METHODS: iNOS-knockout (iNOS(-/-)) and C57BL/6 (WT, wild type) animals (n = 5-6) were given either saline or irinotecan (60 mg/kg i.p for 4 days), with or without pretreatment with aminoguanidine (50 mg/kg s.c.), thalidomide (60 mg/kg s.c), infliximab (5 mg/kg i.v.), or pentoxifylline (1.7 mg/kg s.c). On day 5, diarrhea was assessed, and following euthanasia, proximal intestinal samples were obtained for myeloperoxidase (MPO) and iNOS activity, morphometric analysis, western blot and immunohistochemistry to iNOS, cytokine dosage, and for in vitro evaluation of gut contractility. RESULTS: Irinotecan induced severe diarrhea and intestinal smooth muscle over-contractility, accompanied with histopathological changes. Additionally, increased MPO and iNOS activity and iNOS immunoexpression were found in WT animals treated with irinotecan. The rise in MPO, smooth muscle over-contractility, and diarrhea were abrogated in aminoguanidine-treated and iNOS(-/-) mice. Moreover, through western blot, we verified that infliximab and pentoxifylline significantly inhibited irinotecan-induced iNOS expression. In addition, cytokine concentration was found only partially decreased in irinotecan-treated iNOS(-/-) mice when compared with wild-type animals that were given irinotecan. CONCLUSIONS: This study suggests a role of nitric oxide in the pathogenesis of irinotecan-induced intestinal mucositis and also provides evidence for the participation of cytokines on iNOS induction.


Subject(s)
Camptothecin/analogs & derivatives , Cytokines/metabolism , Intestinal Mucosa/drug effects , Mucositis/chemically induced , Nitric Oxide Synthase Type II/metabolism , Nitric Oxide/metabolism , Animals , Antineoplastic Agents, Phytogenic/toxicity , Camptothecin/toxicity , Disease Models, Animal , Enzyme Activation , Immunohistochemistry , Intestinal Mucosa/metabolism , Intestinal Mucosa/pathology , Irinotecan , Mice , Mice, Inbred C57BL , Mice, Knockout , Mucositis/metabolism , Mucositis/pathology
7.
Dig Dis Sci ; 56(2): 314-22, 2011 Feb.
Article in English | MEDLINE | ID: mdl-20552398

ABSTRACT

BACKGROUND: Amifostine has been widely tested as a cytoprotective agent against a number of aggressors in different organs. Recently, a gastroprotective effect was observed for this drug in a model of indomethacin-induced gastric injury. Our objective was to investigate the effect of amifostine on ethanol-induced gastric injury and the role played in this mechanism by afferent sensory neurons, non-protein sulfhydryl groups, nitric oxide, ATP-sensitive potassium channels, and cyclooxygenase-2. METHODS: Rats were treated with amifostine (22.5, 45, 90, or 180 mg/kg, PO or SC). After 30 min, the rats received absolute ethanol (5 ml kg(-1), PO). One hour later, gastric damage was quantified with a planimeter. Samples from the stomach were also taken for histopathological assessment and for assays of non-protein sulfhydryl groups. The other groups were pretreated with L-NAME (10 mg kg(-1), IP), glibenclamide (10 mg kg(-1), PO), or celecoxib (10 mg kg(-1), PO). After 30 min, the animals were given amifostine (90 mg kg(-1), PO or SC), followed 30 min later by gavage with absolute ethanol (5 ml kg(-1)). Other rats were desensitized with capsaicin (125 mg kg(-1), SC) 8 days prior to amifostine treatment. RESULTS: Amifostine administration PO and SC significantly and dose-dependently reduced ethanol-induced macroscopic and microscopic gastric damage by restoring glutathione levels in the stomach mucosa. Amifostine-promoted gastroprotection against ethanol-induced stomach injury was reversed by pretreatment with neurotoxic doses of capsaicin, but not by L-NAME, glibenclamide, or celecoxib. CONCLUSIONS: Amifostine protects against ethanol-induced gastric injury by increasing glutathione levels and stimulating the afferent sensory neurons in the stomach.


Subject(s)
Amifostine/pharmacology , Capsaicin/pharmacology , Ethanol/toxicity , Neurons, Afferent/drug effects , Stomach Diseases/chemically induced , Sulfhydryl Compounds/metabolism , Amifostine/administration & dosage , Animals , Dose-Response Relationship, Drug , Drug Administration Routes , Gastric Mucosa/drug effects , Male , Radiation-Protective Agents/pharmacology , Rats , Rats, Wistar , Stomach Diseases/prevention & control
8.
J Pharmacol Exp Ther ; 330(3): 764-70, 2009 Sep.
Article in English | MEDLINE | ID: mdl-19491326

ABSTRACT

The aim of this study was to evaluate the protective effect of hydrogen sulfide (H(2)S) on ethanol-induced gastric lesions in mice and the influence of ATP-sensitive potassium (K(ATP)) channels, capsaicin-sensitive sensory afferent neurons, and transient receptor potential vanilloid (TRPV) 1 receptors on such an effect. Saline and L-cysteine alone or with propargylglycine, sodium hydrogen sulfide (NaHS), or Lawesson's reagent were administrated for testing purposes. For other experiments, mice were pretreated with glibenclamide, neurotoxic doses of capsaicin, or capsazepine. Afterward, mice received L-cysteine, NaHS, or Lawesson's reagent. After 30 min, 50% ethanol was administrated by gavage. After 1 h, mice were sacrificed, and gastric damage was evaluated by macroscopic and microscopic analyses. L-cysteine, NaHS, and Lawesson's reagent treatment prevented ethanol-induced macroscopic and microscopic gastric damage in a dose-dependent manner. Administration of propargylglycine, an inhibitor of endogenous H(2)S synthesis, reversed gastric protection induced by L-cysteine. Glibenclamide reversed L-cysteine, NaHS, or Lawesson's reagent gastroprotective effects against ethanol-induced macroscopic damage in a dose-dependent manner. Chemical ablation of sensory afferent neurons by capsaicin reversed gastroprotective effects of L-cysteine or H(2)S donors (NaHS or Lawesson's reagent) in ethanol-induced macroscopic gastric damage. Likewise, in the presence of the TRPV1 antagonist capsazepine, the gastroprotective effects of L-cysteine, NaHS, or Lawesson's reagent were also abolished. Our results suggest that H(2)S prevents ethanol-induced gastric damage. Although there are many mechanisms through which this effect can occur, our data support the hypothesis that the activation of K(ATP) channels and afferent neurons/TRPV1 receptors is of primary importance.


Subject(s)
Air Pollutants/pharmacology , Capsaicin/pharmacology , Central Nervous System Depressants/antagonists & inhibitors , Central Nervous System Depressants/toxicity , Ethanol/antagonists & inhibitors , Ethanol/toxicity , Hydrogen Sulfide/pharmacology , KATP Channels/physiology , Neurons, Afferent/drug effects , Stomach Diseases/chemically induced , Stomach Diseases/prevention & control , Alkynes/pharmacology , Animals , Cysteine/pharmacology , Dose-Response Relationship, Drug , Enzyme Inhibitors/pharmacology , Gastric Mucosa/pathology , Glutathione/metabolism , Glyburide/pharmacology , Glycine/analogs & derivatives , Glycine/pharmacology , Hypoglycemic Agents/pharmacology , KATP Channels/drug effects , Male , Malondialdehyde/metabolism , Mice , Protective Agents/pharmacology , Stomach Diseases/pathology , TRPV Cation Channels/physiology
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