RESUMO
Atopic skin is dry and itchy and lacks integrity. Impaired skin barrier results from altered lipid composition of the skin. A crucial skin lipid, cholesterol, provides flexibility and homeostasis of the cell membranes' lipid bilayer. Cholesterol-based creams and natural oils, especially blackcurrant seed oil, are beneficial for skin care as they hydrate the skin and improve its integrity. The major atopic symptom, skin dryness, can be overcome by the application of porous patches enhanced with cholesterol and natural oil. The base of the patches is constructed of polyimide (PI) nanofibers with cholesterol coatings and externally added blackcurrant seed oil. The presence of cholesterol in PI mats hinders the passage of oil through the patches to the skin, resulting in sustained and prolonged skin hydration. The theoretical and numerical investigations of oil dynamics in porous mats confirmed the experimental results, showing a prolonged skin hydration effect up to 6 h. Additionally, as demonstrated by in vivo tests on atopic mice, cholesterol patches lower serum immunoglobulin E levels and expression of proinflammatory cytokines in the skin, thereby accelerating skin healing. Our results hold great promise for the long-term application of the patches in atopic dermatitis treatment.
Assuntos
Colesterol , Dermatite Atópica , Nanofibras , Pele , Colesterol/química , Nanofibras/química , Animais , Dermatite Atópica/tratamento farmacológico , Dermatite Atópica/patologia , Camundongos , Pele/efeitos dos fármacos , Pele/metabolismo , Pele/patologia , Inflamação/tratamento farmacológico , Óleos de Plantas/química , Óleos de Plantas/farmacologia , HumanosRESUMO
Colorectal cancer (CRC) is one of the most common neoplasms worldwide. Among the risk factors of CRC, inflammatory bowel disease (IBD) is one of the most important ones leading to the development of colitis-associated CRC (CAC). G-protein coupled receptors (GPCR) are transmembrane receptors that orchestrate a multitude of signaling cascades in response to external stimuli. Because of their functionality, they are promising targets in research on new strategies for CRC diagnostics and treatment. Recently, regulators of G-proteins (RGS) have been attracting attention in the field of oncology. Typically, they serve as negative regulators of GPCR responses to both physiological stimuli and medications. RGS activity can lead to both beneficial and harmful effects depending on the nature of the stimulus. However, the atypical RGS-AXIN uses its RGS domain to antagonize key signaling pathways in CRC development through the stabilization of the ß-catenin destruction complex. Since AXIN does not limit the efficiency of medications, it seems to be an even more promising pharmacological target in CRC treatment. In this review, we discuss the current state of knowledge on RGS significance in sporadic CRC and CAC with particular emphasis on the regulation of GPCR involved in IBD-related inflammation comprising opioid, cannabinoid and serotonin receptors.
Assuntos
Neoplasias Associadas a Colite , Doenças Inflamatórias Intestinais , Humanos , Proteína Axina , Proteínas de Ligação ao GTP , Transdução de Sinais , Doenças Inflamatórias Intestinais/complicaçõesRESUMO
INTRODUCTION: Pain is one of the most substantial factors responsible for lowering quality of life in patients with intestinal diseases. Its multifactorial pathogenesis makes intestinal pain difficult to manage with currently available medications, especially considering the risk of serious adverse effects and exacerbation of underlying disease. AREAS COVERED: The most commonly administered drugs in intestinal pain are medications forming the so-called analgesic ladder, which act directly on pain sensation: acetaminophen, non-steroidal anti-inflammatory drugs (NSAIDs), and opioids in full range of activity strength. However, there are also many groups of supportive medications, which target intestinal pain indirectly and therefore, differs in applicability depending on underlying conditions and their pathophysiology, e.g. antispasmodics, antidepressants, probiotics, and biological anti-inflammatory drugs. In this review, we concentrated on possible analgesic options in patients suffering from irritable bowel syndrome (IBS), inflammatory bowel diseases (IBD), and colorectal cancer (CRC). Moreover, we examined future perspectives in treating abdominal pain with medications targeting transient receptor potential channels, the endocannabinoid system and other promising options, including new formulations of already known drugs and new peripherally restricted opioids. EXPERT OPINION: There is constant need for improvement of intestinal analgesia and novel pharmacological approaches, from which interaction with TRP receptors is a particularly promising direction.
Assuntos
Síndrome do Intestino Irritável , Qualidade de Vida , Humanos , Anti-Inflamatórios não Esteroides/uso terapêutico , Dor Abdominal/tratamento farmacológico , Síndrome do Intestino Irritável/tratamento farmacológico , Analgésicos/efeitos adversosRESUMO
BACKGROUND: The role of the incretin hormone, glucagon-like peptide (GLP-1), in Crohn's disease (CD), is still poorly understood. The aim of this study was to investigate whether colitis is associated with changes in blood glucose levels and the possible involvement of the incretin system as an underlaying factor. METHODS: We used a murine model of colitis induced by 2,4,6-trinitrobenzenesulfonic acid (TNBS). Macroscopic and microscopic score and expression of inflammatory cytokines were measured. The effect of colitis on glucose level was studied by measurement of fasting glucose and GLP-1, dipeptidyl peptidase IV (DPP IV) levels, prohormone convertase 1/3 (PC 1/3) and GLP-1 receptor (GLP-1R) expression in mice. We also measured the level of GLP-1, DPP IV and expression of glucagon (GCG) and PC 1/3 mRNA in serum and colon samples from healthy controls and CD patients. RESULTS: Fasting glucose levels were increased in animals with colitis compared to controls. GLP-1 was decreased in both serum and colon of mice with colitis in comparison to the control group. DPP IV levels were significantly increased in serum, but not in the colon of mice with colitis as compared to healthy animals. Furthermore, PC 1/3 and GLP-1R expression levels were increased in mice with colitis as compared to controls. In humans, no differences were observed in fasting glucose level between healthy subjects and CD patients. GLP-1 levels were significantly decreased in the serum. Interestingly, GLP-1 level was significantly increased in colon samples of CD patients compared to healthy subjects. No significant differences in DPP IV levels in serum and colon samples were observed between groups. CONCLUSIONS: Changes in the incretin system during colitis seem to contribute to the impaired glucose levels. Differences in incretin levels seem to be modulated by degrading enzyme DPP-IV and PC 1/3. Obtained results suggest that the incretin system may become a novel therapeutic approach in the treatment of CD.
Assuntos
Glicemia/metabolismo , Colite/patologia , Doença de Crohn/patologia , Incretinas/metabolismo , Adulto , Animais , Estudos de Casos e Controles , Dipeptidil Peptidase 4/metabolismo , Modelos Animais de Doenças , Feminino , Peptídeo 1 Semelhante ao Glucagon/sangue , Humanos , Inflamação/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Pessoa de Meia-Idade , Pró-Proteína Convertase 1/genética , Ácido Trinitrobenzenossulfônico , Adulto JovemRESUMO
Diet is considered an important trigger in inflammatory bowel diseases (IBD), as feeding habits can affect intestinal permeability and clearance of bacterial antigens, consequently influencing the immune system. Free fatty acid receptors (FFARs), expressed on the intestinal epithelial cells, belong to the family of luminal-facing receptors that are responsive to nutrients. The objective of this study was to characterize the anti-inflammatory activity and the effect on intestinal barrier function of synthetic FFAR agonists in mouse models of colitis. Therapeutic activity of GW9508 (FFAR1 agonist), 4-CMTB (FFAR2 agonist), AR420626 (FFAR3 agonist), and GSK137647 (FFAR4 agonist) was investigated in two models of semi-chronic colitis: induced by trinitrobenzenesulfonic acid (TNBS), mimicking Crohn's disease, as well as induced by dextran sulfate sodium (DSS), which recapitulates ulcerative colitis in humans. Moreover, we assessed the influence of FFARs agonists on epithelial ion transport and measured the ion flow stimulated by forskolin and veratridine. Administration of FFAR4 agonist GSK137647 attenuated both TNBS-induced and DSS-induced colitis in mice, as indicated by macroscopic parameters and myeloperoxidase activity. The action of FFAR4 agonist GSK137647 was significantly blocked by pretreatment with selective FFAR4 antagonist AH7614. Moreover, FFAR1 and FFAR4 agonists reversed the increase in the colon permeability caused by inflammation. FFAR4 restored the tight junction genes expression in mouse colon. This is the first evaluation of the anti-inflammatory activity of selective FFAR agonists, showing that pharmacological intervention targeting FFAR4, which is a sensor of medium and long chain fatty acids, attenuates intestinal inflammation.
Assuntos
Compostos de Anilina/farmacologia , Anti-Inflamatórios/farmacologia , Colite/tratamento farmacológico , Colo/efeitos dos fármacos , Mucosa Intestinal/efeitos dos fármacos , Receptores Acoplados a Proteínas G/agonistas , Sulfonamidas/farmacologia , Animais , Células CACO-2 , Colite/induzido quimicamente , Colite/metabolismo , Colite/patologia , Colo/metabolismo , Colo/patologia , Citocinas/metabolismo , Sulfato de Dextrana , Modelos Animais de Doenças , Humanos , Mediadores da Inflamação/metabolismo , Mucosa Intestinal/metabolismo , Mucosa Intestinal/patologia , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Óxido Nítrico/metabolismo , Permeabilidade , Células RAW 264.7 , Receptores Acoplados a Proteínas G/metabolismo , Proteínas de Junções Íntimas/metabolismo , Junções Íntimas/efeitos dos fármacos , Junções Íntimas/metabolismo , Junções Íntimas/patologia , Ácido TrinitrobenzenossulfônicoRESUMO
INTRODUCTION: Adiponectin is a hormone secreted by adipocytes, which exhibits insulin-sensitizing and anti-inflammatory properties and acts through adiponectin receptors: AdipoR1 and AdipoR2. The aim of the study was to evaluate whether activation of adiponectin receptors AdipoR1 and AdipoR2 with an orally active agonist AdipoRon has gastroprotective effect and to investigate the possible underlying mechanism. METHODS: We used two well-established mouse models of gastric ulcer (GU) induced by oral administration of EtOH (80% solution in water) or diclofenac (30 mg/kg, p.o.). Gastroprotective effect of AdipoRon (dose 5 and 50 mg /kg p.o) was compared to omeprazole (20 mg/kg p.o.) or 5% DMSO solution (control). Clinical parameters of gastroprotection were assessed using macroscopic (gastric lesion area) and microscopic (evaluation of the gastric mucosa damage) scoring. To establish the molecular mechanism, we measured: myeloperoxidase (MPO), superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPX) activities; glutathione (GSH) level; and IL-1ß, adenosine monophosphate-activated protein kinase (AMPK), and phosphorylated AMPK expression in gastric tissue. RESULTS: AdipoRon produced a gastroprotective effect in both GU mouse models as evidenced by significantly lower macroscopic and microscopic damage scores. AdipoRon exhibited anti-inflammatory effect by reduction in MPO activity and IL-1ß expression in the gastric tissue. Moreover, AdipoRon induced antioxidative action, as demonstrated with higher GSH levels, and increased SOD and GPX activity. CONCLUSIONS: Activation of AdipoR1 and AdipoR2 using AdipoRon reduced gastric lesions and enhanced cell response to oxidative stress. Our data suggest that AdipoR1 and AdipoR2 activation may be an attractive therapeutic strategy to inhibit development of gastric ulcers.
Assuntos
Omeprazol/administração & dosagem , Estresse Oxidativo/efeitos dos fármacos , Piperidinas/administração & dosagem , Receptores de Adiponectina/agonistas , Úlcera Gástrica/tratamento farmacológico , Administração Oral , Animais , Catalase/metabolismo , Diclofenaco/efeitos adversos , Modelos Animais de Doenças , Etanol/efeitos adversos , Masculino , Camundongos , Omeprazol/farmacologia , Peroxidase/metabolismo , Piperidinas/farmacologia , Úlcera Gástrica/induzido quimicamente , Úlcera Gástrica/metabolismo , Superóxido Dismutase/metabolismo , Resultado do TratamentoRESUMO
In this review we focus on the pathophysiology of CRC-related pain and discuss currently applied pain management. Pain is a symptom reported by over 70 % of colorectal cancer (CRC) patients. It remains a feared and debilitating consequence of both cancer and cancer-related treatment. There are many options for pain management in CRC, consisting of intravenous, oral or topical medications. In order to address the full spectrum of pain, proper treatment should address the nociceptive, neuropathic and/or psychogenic pain component. Currently available methods do not bring pain relief to satisfying number of patients and, if used improperly, can cause a number of complications. Therefore, future treatments should focus primarily on alleviating pain, but also on reducing possible side effects. In this article we cover recent and promising pharmacological and non- pharmacological developments emerging in the field of CRC treatment.
Assuntos
Neoplasias Colorretais , Neuralgia , Neoplasias Colorretais/complicações , Neoplasias Colorretais/epidemiologia , Neoplasias Colorretais/terapia , Humanos , Manejo da DorRESUMO
BACKGROUND: the pharmacological treatment and/or maintenance of remission in inflammatory bowel diseases (IBDs) is currently one of the biggest challenges in the field of gastroenterology. METHOD: our aim was the synthesis of homo- and heterodimers of natural enkephalinase inhibitors (opiorphin; sialorphin; spinorphin) and the in vitro characterization of their effect on the degradation of enkephalin by neutral endopeptidase (NEP) and stability in human plasma. We investigated the in vivo heterodimer of Cys containing analogs of sialorphin and spinorphin (peptide X) in a mouse model of colitis. The extent of inflammation was evaluated based on the microscopic score; macroscopic score; ulcer score, colonic wall thickness, colon length and quantification of myeloperoxidase activity. RESULTS: we showed that the homo- and heterodimerization of analogs of sialorphin, spinorphin and opiorphin containing Cys residue at the N-terminal position resulted in dimeric forms which in vitro exhibited higher inhibitory activity against NEP than their parent and monomeric forms. We showed that peptide X was more stable in human plasma than sialorphin and spinorphin. Peptide X exerts potent anti-inflammatory effect in the mouse model of colitis. CONCLUSION: we suggest that peptide X has the potential to become a valuable template for anti-inflammatory therapeutics for the treatment of gastrointestinal (GI) tract inflammation.
Assuntos
Anti-Inflamatórios/química , Anti-Inflamatórios/farmacologia , Produtos Biológicos/química , Produtos Biológicos/farmacologia , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Neprilisina/antagonistas & inibidores , Sequência de Aminoácidos , Animais , Anti-Inflamatórios/farmacocinética , Produtos Biológicos/farmacocinética , Biomarcadores , Fenômenos Químicos , Colite/tratamento farmacológico , Dimerização , Modelos Animais de Doenças , Estabilidade de Medicamentos , Inibidores Enzimáticos/farmacocinética , Humanos , Imuno-Histoquímica , Mucosa Intestinal/metabolismo , Mucosa Intestinal/patologia , Masculino , Camundongos , Oligopeptídeos/química , Oligopeptídeos/farmacologia , Peptídeos/química , Peptídeos/farmacologiaRESUMO
Endogenous opioid system is involved in the maintenance of the intestinal homeostasis. Recently, we proved that stimulation of opioid receptors using P-317, a cyclic morphiceptin analog, resulted in the alleviation of acute colitis in mice. The aim of the current study was to assess the effect of P-317 during colitis and colitis-associated colorectal cancer in mice. Colitis was induced by addition of dextran sodium sulfate (DSS) into drinking water. Colitis-associated colorectal cancer was induced by a single intraperitoneal injection of azoxymethane (AOM) and subsequent addition of DSS into drinking water (week 2, 5, 8). During macroscopic damage evaluation the samples were collected and used for biochemical (MPO activity assay), molecular (qPCR and western blot) and histological studies. In experimental colitis, P-317 induced an anti-inflammatory response as indicated by macroscopic and microscopic scores. In the colitis-associated colorectal cancer model, a significant difference in colorectal tumor development was observed between vehicle- and P-317-treated mice. P-317 decreased the total number of colonic tumors and inhibited MPO activity. Hematoxylin and eosin staining confirmed anti-tumor activity of P-317. The expression of TNF-α was decreased in P-317-treated mice as compared to the vehicle-treated group. P-317 decreased proliferation as well as ß-catenin expression in tumors. P-317, a mixed MOP and KOP receptor agonist, induced an anti-inflammatory response in experimental colitis and decreased tumor development in colitis-associated colorectal cancer in mice.
Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Antineoplásicos/farmacologia , Colite/tratamento farmacológico , Neoplasias Colorretais/tratamento farmacológico , Endorfinas/farmacologia , Receptores Opioides kappa/agonistas , Receptores Opioides mu/agonistas , Animais , Anti-Inflamatórios não Esteroides/uso terapêutico , Antineoplásicos/uso terapêutico , Azoximetano , Carcinógenos , Proliferação de Células/efeitos dos fármacos , Colite/induzido quimicamente , Colite/complicações , Neoplasias Colorretais/etiologia , Sulfato de Dextrana , Endorfinas/uso terapêutico , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Fator de Necrose Tumoral alfa/antagonistas & inibidoresRESUMO
BACKGROUND: Inflammatory Bowel Disease (IBD) is categorized as Crohn's disease (CD) and Ulcerative colitis (UC) and is characterized by chronic inflammation in the gastrointestinal (GI) tract. Relapsing symptoms, including abdominal pain, increased stool frequency, loss of appetite as well as anemia contribute to significant deterioration of quality of life. IBD treatment encompasses chemotherapy (e.g. corticosteroids, thiopurines) and biological agents (e.g. antibodies targeting tumour necrosis factor α, interleukin 12/23) and surgery. However, efficacy of these therapies is not satisfactory. Thus, scientists are looking for new options in IBD treatment that could induce and maintain remission. OBJECTIVE: To summarize previous knowledge about role of different intestinal cells in IBD pathophysiology and application of stem cells in the IBD treatment. RESULTS: Recent studies have emphasized an important role of innate lymphoid cells (ILCs) as well as intestinal epithelial cells (IECs) in the IBD pathophysiology suggesting that these types of cells can be new targets for IBD treatment. Moreover, last studies show that stem cells transplantation reduces inflammation in patients suffering from IBD, which are resistant to conventional therapies. CONCLUSION: Both hematopoietic stem cells (HSCs) and mesenchymal stem cells (MSCs) are able to restore damaged tissue and regulate the immune system. Autologous HSCs transplantation eliminates autoreactive cells and replace them with new T-cells resulting a long-time remission. Whereas MSCs transplantation is effective therapy in one of the major complications of IBD, perianal fistulas.
Assuntos
Células Epiteliais/fisiologia , Células Epiteliais/transplante , Transplante de Células-Tronco Hematopoéticas/métodos , Imunidade Inata , Doenças Inflamatórias Intestinais/imunologia , Doenças Inflamatórias Intestinais/terapia , Transplante de Células-Tronco Mesenquimais/métodos , Animais , Humanos , Células-Tronco Neurais/fisiologia , Células-Tronco Neurais/transplanteRESUMO
Ulcerative colitis belongs to inflammatory bowel diseases, which is a group of chronic disorders of the gastrointestinal tract. It is a debilitating condition with a wide range of symptoms including rectal bleeding, diarrhea, and visceral pain. Current dietary habits often lead to imbalance in n-6/n-3 polyunsaturated fatty acids (PUFA) in favor of n-6 PUFA. Recent data showed the potential anti-inflammatory advantage of n-3 PUFA. Walnut oil (WO) is rich in those fatty acids and mainly consists of linoleic and linolenic acids that may act via free fatty acids receptors (FFARs). We assessed the anti-inflammatory effect of WO in the mouse model of dextran sulfate sodium (DSS)-induced colitis. Moreover, we examined changes in the expression of tight junction proteins (TJ), pro-inflammatory cytokines, and FFAR proteins in the inflamed mouse colon. WO improves the damage score in inflamed tissue, significantly restoring ion transport and colonic wall permeability. Inflammation caused changes in TJ, FFAR, and pro-inflammatory gene proteins expression, which WO was able to partially reverse. WO has anti-inflammatory properties; however, its exact mechanism of action remains unclear. This stems from the pleiotropic effects of n-3 PUFA ligands associated with receptor distribution and targeted signaling pathways.
Assuntos
Anti-Inflamatórios , Colite/tratamento farmacológico , Colite/metabolismo , Juglans/química , Óleos de Plantas/farmacologia , Óleos de Plantas/uso terapêutico , Animais , Colo/metabolismo , Citocinas/metabolismo , Modelos Animais de Doenças , Ácidos Graxos Ômega-3/isolamento & purificação , Ácidos Graxos Ômega-3/metabolismo , Ácidos Graxos Ômega-3/farmacologia , Ácidos Graxos Ômega-3/uso terapêutico , Mediadores da Inflamação/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Óleos de Plantas/química , Óleos de Plantas/isolamento & purificação , Receptores Acoplados a Proteínas G/metabolismo , Proteínas de Junções Íntimas/metabolismoRESUMO
Colorectal cancer (CRC) is one of the most common cancers worldwide. In developed countries, its mortality remains high, yet the prevalence has established owing to effective screening programs; however due to the westernization of lifestyle, the incidences in many other countries have increased. Although the treatment of CRC has improved in the last few years, the side effects of these approaches cannot be neglected. Recently, members of the family of free fatty acid receptors (FFARs) have become attractive pharmacological targets in many diseases, including asthma; studies also point to their role in carcinogenesis. Here, we discuss current knowledge and future directions in FFAR research related to CRC. Contradictory results of FFARs modulation may derive from the pleiotropic effects of FFAR ligands, receptor distribution and different signal transduction. Hence, we indicate directions of further studies to fully use the potential of FFARs in CRC.
Assuntos
Neoplasias Colorretais/metabolismo , Ácidos Graxos não Esterificados/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Animais , Neoplasias Colorretais/dietoterapia , Neoplasias Colorretais/tratamento farmacológico , Dieta , Microbioma Gastrointestinal , Humanos , Ligantes , Receptores Acoplados a Proteínas G/agonistas , Receptores Acoplados a Proteínas G/genéticaRESUMO
Inflammatory bowel diseases (IBD), including Crohn's disease (CD) and ulcerative colitis (UC), are chronic, relapsing, intestinal inflammatory disorders with complex and yet unrevealed pathogenesis in which genetic, immunological, and environmental factors play a role. Nowadays, a higher proportion of elderly IBD patients with coexisting conditions, such as cardiovascular disease and/or diabetes is recorded, who require more complex treatment and became a great challenge for gastroenterologists. Furthermore, some patients do not respond to anti-IBD therapy. These facts, together with increasing comorbidities in patients with IBD, imply that urgent, more complex, novel therapeutic strategies in the treatment are needed. Glucagon-like peptides (GLPs) possess numerous functions in the human body such as lowering blood glucose level, controlling body weight, inhibiting gastric emptying, reducing food ingestion, increasing crypt cell proliferation, and improving intestinal growth and nutrient absorption. Thus, GLPs and dipeptidyl peptidase IV (DPP-IV) inhibitors have recently gained attention in IBD research. Several animal models showed that treatment with GLPs may lead to improvement of colitis. This review presents data on the multitude effects of GLPs in the inflammatory intestinal diseases and summarizes the current knowledge on GLPs, which have the potential to become a novel therapeutic option in IBD therapy.
Assuntos
Anti-Inflamatórios/farmacologia , Inibidores da Dipeptidil Peptidase IV/farmacologia , Peptídeos Semelhantes ao Glucagon/análogos & derivados , Peptídeos Semelhantes ao Glucagon/metabolismo , Doenças Inflamatórias Intestinais/tratamento farmacológico , Animais , Anti-Inflamatórios/uso terapêutico , Inibidores da Dipeptidil Peptidase IV/uso terapêutico , Modelos Animais de Doenças , Peptídeos Semelhantes ao Glucagon/genética , Peptídeos Semelhantes ao Glucagon/uso terapêutico , Humanos , Doenças Inflamatórias Intestinais/imunologia , Doenças Inflamatórias Intestinais/metabolismoRESUMO
Lysophosphatidylcholine (LPC) is an endogenous ligand for GPR119 receptor, mediating glucose-stimulated insulin secretion (GSIS). We demonstrate that LPC facilitates GSIS in MIN6 pancreatic ß-cell line and murine islets of Langerhans by recognizing not only GPR119 but also GPR40 (free fatty acid receptor 1) and GPR55 activated by lysophosphatidylinositol. Natural LPCs are unstable when administered in vivo limiting their therapeutic value and therefore, we present phosphorothioate LPC analogues with increased stability. All the modified LPCs under study (12:0, 14:0, 16:0, 18:0, and 18:1) significantly enhanced GSIS. The 16:0 sulfur analogue was the most potent, evoking 2-fold accentuated GSIS compared to the native counterpart. Interestingly, LPC analogues evoked GPR40-, GPR55-and GPR119-dependent [Ca2+]i signaling, but did not stimulate cAMP accumulation as in the case of unmodified molecules. Thus, introduction of a phosphorothioate function not only increases LPC stability but also modulates affinity towards receptor targets and evokes different signaling pathways.
Assuntos
Secreção de Insulina/efeitos dos fármacos , Lisofosfatidilcolinas/farmacologia , Fosfatos/farmacologia , Receptores de Canabinoides/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Animais , Sinalização do Cálcio/efeitos dos fármacos , Linhagem Celular , AMP Cíclico/metabolismo , Endocanabinoides/farmacologia , Glucose/farmacologia , Lisofosfatidilcolinas/química , Masculino , Camundongos Endogâmicos C57BL , Ácidos Oleicos/farmacologia , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Receptores de Canabinoides/genética , Receptores Acoplados a Proteínas G/genéticaRESUMO
Protease inhibition has become a possible new approach in inflammatory bowel disease (IBD) therapy. A serine exopeptidase, dipeptidyl peptidase IV (DPP IV), is responsible for the inactivation of incretin hormone, glucagon-like peptide 2 (GLP-2), a potent stimulator of intestinal epithelium regeneration and growth. Recently, we showed that the novel peptide analog of endomorphin-2, Tyr-Pro-D-ClPhe-Phe-NH2 (EMDB-1) is a potent blocker of DPP IV and has an inhibitory effect on gastrointestinal (GI) smooth muscle contractility. The aim of this study was to characterize the anti-inflammatory effect and mechanism of action of EMDB-1 in the mouse GI tract. We used two models of experimental colitis (induced by TNBS and DSS). The anti-inflammatory effect of EMDB-1 was assessed by the determination of macroscopic score, ulcer score, colonic wall thickness, as well as myeloperoxidase activity. Additionally, we measured the expression of GLP-2, GLP2R, and DPP IV in the colon of control and colitic animals treated with the test compound. The expression of GLP-2 and GLP2R in the serum and colon of IBD patients and healthy control subjects has been assessed. We showed that EMDB-1 elevates the half-life of GLP-2 in vitro and attenuates acute, semichronic, and relapsing TNBS as well as DSS-induced colitis in mice after topical administration. The anti-inflammatory action of EMDB-1 is associated with changes in the level of colonic GLP-2 but not DPP IV expression. Our results validate DPP IV as a pharmacological target for the anti-IBD drugs, and its inhibitors based on natural substrates, such as EMDB-1, have the potential to become valuable anti-inflammatory therapeutic agents.
Assuntos
Colite/tratamento farmacológico , Colite/metabolismo , Dipeptidil Peptidase 4/metabolismo , Peptídeo 2 Semelhante ao Glucagon/metabolismo , Oligopeptídeos/administração & dosagem , Oligopeptídeos/farmacologia , Administração Tópica , Adulto , Idoso , Sequência de Aminoácidos , Animais , Anti-Inflamatórios/administração & dosagem , Anti-Inflamatórios/química , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/uso terapêutico , Doença de Crohn/tratamento farmacológico , Inibidores da Dipeptidil Peptidase IV/administração & dosagem , Inibidores da Dipeptidil Peptidase IV/química , Inibidores da Dipeptidil Peptidase IV/farmacologia , Inibidores da Dipeptidil Peptidase IV/uso terapêutico , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Receptor do Peptídeo Semelhante ao Glucagon 2/metabolismo , Meia-Vida , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Pessoa de Meia-Idade , Oligopeptídeos/química , Oligopeptídeos/uso terapêutico , Proteólise/efeitos dos fármacos , Adulto JovemRESUMO
AIM: The pharmacotherapy of inflammatory bowel disease is difficult and currently available treatments bring mostly poor and unsatisfactory results. RESULTS: The purpose of this work was the synthesis of opiorphin, sialorphin, spinorphin and a series of their analogs and the in vitro characterization of their effect on degradation of enkephalin by neutral endopeptidase and aminopeptidase N. Consequently, we investigated in vivo the anti-inflammatory effect of the most active inhibitors selected in the in vitro studies (Pal-KKQRFSR & Pal-KKQHNPR). Putative inhibitor - enzyme (neutral endopeptidase or aminopeptidase N) complexes are also presented and their binding interfaces are identified. CONCLUSION: Our results suggest that Pal-KKQHNPR has the potential to become a valuable template for anti-inflammatory therapeutics for the treatment of GI tract inflammation.
Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Produtos Biológicos/farmacologia , Colite/tratamento farmacológico , Modelos Animais de Doenças , Inibidores Enzimáticos/farmacologia , Neprilisina/antagonistas & inibidores , Animais , Anti-Inflamatórios não Esteroides/síntese química , Anti-Inflamatórios não Esteroides/química , Produtos Biológicos/síntese química , Produtos Biológicos/química , Colite/metabolismo , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Camundongos , Neprilisina/metabolismoRESUMO
Regulators of G protein signaling (RGS) proteins provide timely termination of G protein-coupled receptor (GPCR) responses. Serving as a central control point in GPCR signaling cascades, RGS proteins are promising targets for drug development. In this review, we discuss the involvement of RGS proteins in the pathophysiology of the gastrointestinal inflammation and their potential to become a target for anti-inflammatory drugs. Specifically, we evaluate the emerging evidence for modulation of selected receptor families: opioid, cannabinoid and serotonin by RGS proteins. We discuss how the regulation of RGS protein level and activity may modulate immunological pathways involved in the development of intestinal inflammation. Finally, we propose that RGS proteins may serve as a prognostic factor for survival rate in colorectal cancer. The ideas introduced in this review set a novel conceptual framework for the utilization of RGS proteins in the treatment of gastrointestinal inflammation, a growing major concern worldwide.
Assuntos
Analgésicos/uso terapêutico , Anti-Inflamatórios não Esteroides/uso terapêutico , Neoplasias Colorretais/genética , Doenças Inflamatórias Intestinais/tratamento farmacológico , Proteínas RGS/genética , Dor Visceral/tratamento farmacológico , Animais , Neoplasias Colorretais/diagnóstico , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/patologia , Motilidade Gastrointestinal/efeitos dos fármacos , Regulação da Expressão Gênica , Humanos , Doenças Inflamatórias Intestinais/genética , Doenças Inflamatórias Intestinais/metabolismo , Doenças Inflamatórias Intestinais/fisiopatologia , Intestinos/efeitos dos fármacos , Intestinos/fisiopatologia , Camundongos , Proteínas RGS/agonistas , Proteínas RGS/antagonistas & inibidores , Proteínas RGS/metabolismo , Receptores de Canabinoides/genética , Receptores de Canabinoides/metabolismo , Receptores Opioides/genética , Receptores Opioides/metabolismo , Receptores de Serotonina/genética , Receptores de Serotonina/metabolismo , Transdução de Sinais , Bibliotecas de Moléculas Pequenas/uso terapêutico , Dor Visceral/genética , Dor Visceral/metabolismo , Dor Visceral/fisiopatologiaRESUMO
Epidemiological data suggest that the consumption of polyphenol-rich foods reduces the incidence of cancer, coronary heart disease, and inflammation. Chlorogenic acid (CGA), an ester of caffeic and quinic acids, is one of the most abundant polyphenol compounds in human diet with proven biological effectiveness both in vitro and in vivo. The aim of the study is to investigate the possible anti-inflammatory effect of CGA in the gastrointestinal (GI) tract and its mechanism of action. We used a well-established model of colitis, induced by intracolonic (i.c.) administration of trinitrobenzenesulfonic acid (TNBS) in mice. The anti-inflammatory effect of CGA in the colon was evaluated based on the clinical and macroscopic and microscopic parameters. To investigate the mechanism of protective action of CGA, myeloperoxidase (MPO), H2O2, and NF-κB levels were assessed in the colon tissue. CGA administered i.c. at the dose of 20 mg/kg (two times daily) protected against TNBS-induced colitis more effectively than the same dose administered orally (p.o.), as evidenced by significantly lower macroscopic and ulcer scores. Furthermore, CGA (20 mg/kg, i.c.) reduced neutrophil infiltration, as demonstrated by decreased MPO activity. Moreover, CGA suppressed activation of NF-κB, as evidenced by lower levels of phospho-NF-κB/NF-κB ratio in the tissue. CGA did not affect the oxidative stress pathways. CGA exhibits anti-inflammatory properties through reduction of neutrophil infiltration and inhibition of NF-κB-dependent pathways. Our results suggest that CGA may have the potential to become a valuable supplement in the treatment of GI diseases.
Assuntos
Anti-Inflamatórios/uso terapêutico , Ácido Clorogênico/uso terapêutico , Colite/tratamento farmacológico , Administração Tópica , Animais , Anti-Inflamatórios/administração & dosagem , Anti-Inflamatórios/farmacologia , Ácido Clorogênico/administração & dosagem , Ácido Clorogênico/farmacologia , Colite/induzido quimicamente , Colite/metabolismo , Colite/patologia , Colo/efeitos dos fármacos , Colo/metabolismo , Colo/patologia , Peróxido de Hidrogênio/metabolismo , Masculino , Camundongos Endogâmicos BALB C , NF-kappa B/metabolismo , Peroxidase/metabolismo , Ácido TrinitrobenzenossulfônicoRESUMO
Inflammatory bowel diseases (IBD) are a group of chronic gastrointestinal disorders with alternating relapses and remissions. Two main types within IBD can be distinguished: Crohn's disease and ulcerative colitis. Considering the epidemiological, immunological and genetic data, it was concluded that IBD possess multifactorial etiology, where genetic and environmental factors form the immunological background for the disease. In this review we discuss the most important genes and their protein products in IBD etiology and their impact on IBD pharmacotherapy.
Assuntos
Colite Ulcerativa/genética , Doença de Crohn/genética , Adulto , Colite Ulcerativa/tratamento farmacológico , Colite Ulcerativa/fisiopatologia , Doença de Crohn/tratamento farmacológico , Doença de Crohn/fisiopatologia , Progressão da Doença , Predisposição Genética para Doença , Humanos , Pessoa de Meia-IdadeRESUMO
BACKGROUND: The endogenous opioid system constitutes an attractive target in the treatment of GI disorders, including inflammatory bowel diseases (IBD). The aim of our study was to characterize the anti-inflammatory and antinociceptive effect of P-317, a novel cyclic analog of opioid peptide morphiceptin, in animal models of IBD. METHODS: The anti-inflammatory effect of P-317 after intraperitoneal (ip) and oral (po) administration was assessed in two mouse models of IBD - Crohn's disease, induced by intracolonic instillation of trinitrobenzenesulfonic acid (TNBS) and ulcerative colitis, induced by addition of dextran sodium sulfate (DSS) into drinking water. The antinociceptive action of P-317 was characterized in mice with acute colitis using mustard oil-induced pain test. Real time RT PCR was used to assess semiquantitatively the expression of IL-1ß and TNF-α mRNA in mouse colonic samples. To translate our results to clinical conditions, MOP and KOP mRNA were quantified in human colonic biopsies from IBD patients. RESULTS: P-317 (0.1mg/kg, ip and 1mg/kg, po) alleviated colonic inflammation in TNBS- and DSS-treated mice in the opioid receptor-dependent manner. The anti-inflammatory effect of P-317 was associated with the decrease in mRNA expression of proinflammatory cytokines. The antinociceptive effect of P-317 was observed after ip and po administration in mice with acute colitis. CONCLUSION: Our results show a potent anti-inflammatory and antinociceptive effect of P-317 in mouse models of colitis upon activation of opioid receptors. The unique bioavailability of P-317 after oral administration suggests that it is a promising drug candidate for future treatment of IBD.