Hubert Zatorski

Experimental colitis in mice is attenuated by changes in the levels of endocannabinoid metabolites induced by selective inhibition of fatty acid amide hydrolase (FAAH)

BACKGROUND AND AIMS Pharmacological treatment and/or maintenance of remission in inflammatory bowel diseases (IBD) is currently one of the biggest challenge in the field of gastroenterology. Available therapies are mostly limited to overcoming the symptoms, but not the cause of the disease. Recently, the endocannabinoid system has been proposed as a novel target in the treatment of IBD. Here we aimed to assess the anti-inflammatory action of the novel fatty acid amide hydrolase (FAAH) inhibitor PF-3845 and its effect on the endocannabinoid and related lipid metabolism during the course of experimental colitis. METHODS We used two models of experimental colitis in mice (TNBS- and DSS-induced) and additionally, we employed LC/MS/MS spectrometry to determine the changes in biolipid levels in the mouse colon during inflammation. RESULTS We showed that the FAAH inhibitor PF-3845 reduced experimental TNBS-induced colitis in mice and its anti-inflammatory action is associated with altering the levels of selected biolipids (arachidonic and oleic acid derivatives, prostaglandins and biolipids containing glycine in the mouse colon). CONCLUSIONS We show that FAAH is a promising pharmacological target and the FAAH-dependent biolipids play a major role in colitis. Our results highlight and promote therapeutic strategy based on targeting FAAH-dependent metabolic pathways in order to alleviate intestinal inflammation.

Selective inhibition of FAAH produces antidiarrheal and antinociceptive effect mediated by endocannabinoids and cannabinoid-like fatty acid amides

The endogenous cannabinoid system (ECS) plays a crucial role in multiple physiological processes in the central nervous system and in the periphery. The discovery that selective cannabinoid (CB) receptor agonists exert a potent inhibitory action on gastrointestinal (GI) motility and pain has placed the ECS in the center of attention as a possible target for the treatment of functional GI diseases. However, side effects of CB agonists prompted the search for novel therapeutic targets. Here, the effect of PF‐3845, a potent and selective fatty acid amide hydrolase (FAAH) inhibitor in the GI tract was investigated.

Current overview of extrinsic and intrinsic factors in etiology and progression of inflammatory bowel diseases

Inflammatory bowel diseases (IBD) are chronic, relapsing disorders affecting gastrointestinal (GI) tract and associated with intestinal mucosa damage and inflammation. The principal therapeutic goals in IBD include control of the intestinal inflammation and treatment of the major symptoms, mainly abdominal pain and diarrhea. Current therapeutic strategies for IBD rely on the use of non-specific anti-inflammatory agents and immunosuppressive drugs (e.g. aminosalicylates, monoclonal antibodies, and antibiotics), which cause severe side effects, and - in a significant number of patients - do not induce long-term benefits. In this review, we summarize the epidemiology and the most important risk factors of IBD, including genetic, immunological and environmental. Our main focus is to discuss pharmacological targets for current and future treatments of IBD.

Chinese Herbal Medicines in the Treatment of IBD and Colorectal Cancer: A Review

Opinion statementInflammatory bowel diseases (IBD) are a group of chronic inflammatory gastrointestinal (GI) disorders, mainly represented by Crohns disease and ulcerative colitis. Although the etiology of IBD is not fully understood, there is substantial evidence that immunologic, genetic, and environmental factors are the main contributors in IBD pathogenesis. Conventional therapies for IBD include anti-inflammatory and immunosuppressive drugs, such as 5-aminosalicylic acid, corticosteroids, antibiotics, and biologicals, such as anti-TNFα antibodies. However, because of low efficacy and high risk of side effects, there is a clear need for the development of novel and efficient pharmacologic strategies in IBD treatment. Among various complementary and alternative medicine (CAM) approaches, which are used for the treatment of gastrointestinal (GI) disorders, traditional Chinese medicine (TCM) is one of the most developed and diversified. TCM encompasses methods and therapies that emerged over centuries and is based mostly on ethnic wisdom and observations transmitted from generation to generation. In the recent years, the efficacy of TCM as treatment of IBD has been extensively characterized in preclinical and clinical studies, which resulted in a significant number of research reports. Moreover, the popularity of TCM among patients with IBD has rapidly increased not only in Asia, but also in the Western hemisphere.

Synthesis and evaluation of anti-inflammatory properties of silver nanoparticle suspensions in experimental colitis in mice

The aim of our study was to investigate the effect of newly developed silver nanoparticle aqueous suspensions NanoAg1 and NanoAg2 in the mouse models mimicking ulcerative colitis and Crohns disease. NanoAg1 and NanoAg2 were synthesized in aqueous medium with the involvement of tannic acid. To elucidate their anti‐inflammatory activity, semi‐chronic mouse models of inflammation induced by dextrane sulfate sodium addition to drinking water and intracolonic (i.c.) administration of 2,4,6‐trinitrobenzenesulfonic acid were used. NanoAg1 and NanoAg2 (500 mg/dm3, 100 μl/animal, i.c., once daily) significantly ameliorated colitis in dextrane sulfate sodium‐ and 2,4,6‐trinitrobenzenesulfonic acid‐induced mouse models of colonic inflammation, as indicated by reduced macroscopic, ulcer and microscopic scores. The anti‐inflammatory effect was dependent on the shape and diameter of silver nanoparticles, as indicated by weaker effect of NanoAg1 than NanoAg2. In addition, administration of NanoAg2, but not NanoAg1, modulated colonic microbiota, as indicated by reduced number of Escherichia coli and Clostridium perfringens, and increased number of Lactobacillus sp. Summarizing, NanoAg1 and NanoAg2 after administered i.c. effectively alleviate colitis in experimental models of ulcerative colitis and Crohns disease in mice. Therefore, NanoAg1 and NanoAg2 administered i.c. have the potential to become valuable agents for the treatment of inflammatory bowel diseases.

Role of environmental pollution in irritable bowel syndrome

Irritable bowel syndrome (IBS), with the prevalence of 10%-20 % of the population has become an emerging problem worldwide. IBS is a functional gastrointestinal (GI) disorder characterized by abdominal pain or discomfort and altered bowel habits. The etiology of IBS contains genetic, psychological, and immunological factors, and has not been fully elucidated; of note, recent studies also point at environmental pollution and its role in the development of functional GI diseases. In this review we focus on several environmental factors, such as bacterial contamination, air pollution, radiation and even stress as potential triggers of IBS. We discuss associated disturbances in homeostasis, such as changes in intestinal microbiome and related pathophysiological mechanisms. Based on the effect of environmental factors on the GI tract, we also propose novel targets in IBS treatment.

Future Treatment of Constipation-associated Disorders: Role of Relamorelin and Other Ghrelin Receptor Agonists

There is an unmet need for effective pharmacological therapies for constipation, a symptom that significantly deteriorates patients’ quality of life and impacts health care. Ghrelin is an endogenous ligand for the growth hormone secretagogue receptor and has been shown to exert prokinetic effects on gastrointestinal (GI) motility via the vagus and pelvic nerves. The pharmacological potential of ghrelin is hampered by its short half-life. Ghrelin receptor (GRLN-R) agonists with enhanced pharmacokinetics were thus developed. Centrally penetrant GRLN-R agonists stimulate defecation and improve impaired lower GI transit in animals and humans. This review summarizes the current knowledge on relamorelin, a potent ghrelin mimetic, and other GRLN-R analogs which are in preclinical or clinical stages of development for the management of disorders with underlying GI hypomotility, like constipation.

Is insulin-like growth factor 1 (IGF-1) system an attractive target inflammatory bowel diseases? Benefits and limitation of potential therapy

Inflammatory bowel diseases (IBD) are chronic gastrointestinal disorders with unknown etiology, whose incidence dramatically increased over the past 50 years. Currently available strategies for IBD treatment, such as biological therapies, corticosteroids, and immunosuppressive agents are effective, but their side effects and economic costs cannot be ignored. Better understanding of IBD etiology and new therapeutics are thus needed. The aim of this paper is to briefly discuss IGF-1 dependent functions, with particular focus on IGF-1 use in IBD therapy. Data collection was based on records found in medical literature. Data analysis included records published between 1984 and 2014. The IGF-1 system is involved in major physiological functions, such as cell proliferation and metabolism, and growth promotion. Most importantly IGF-1 has anti-inflammatory properties and its use in IBD treatment can be recommended. However, potential IGF-1 therapy has some limitations, which include aggravation of fibrosis in Crohns patients and facilitated transformation to malignancy. Taken into consideration their possible side effects, IGF-1 analogs and recombinants are nonetheless a promising target for IBD therapy for a specific group of patients. Further studies, at the clinical level are thus recommended.

Evaluation of anti-inflammatory effect of silver-coated glass beads in mice with experimentally induced colitis as a new type of treatment in inflammatory bowel disease

BACKGROUND Recent studies point at the anti-inflammatory action of silver through induction of apoptosis of inflammatory cells via oxidative stress, promotion of wound healing as well as antimicrobial effect. Our aim was to design a new formulation based on silver and validate its anti-inflammatory activity in the mouse models of colitis. METHODS Silver-coated glass beads were prepared using a magnetron sputtering method and a standard magnetron sputtering gun equipped with pure silver target. Colitis was induced by the ic administration of TNBS into colon (to mimic Crohns disease) and addition of DSS to drinking water (to imitate ulcerative colitis). Evaluation of inflammation was performed based on macroscopic and microscopic scoring, quantification of the myeloperoxidase activity and colonic microflora analysis. RESULTS Silver-coated glass beads administered ic alleviated intestinal inflammation in mouse models of colitis, induced by TNBS and DSS. This alleviation of colitis resulted principally from changes in the gut microflora. The anti-inflammatory action of the new formulation was associated predominantly with the presence of the silver nanolayer on the beads, and to a lesser extent the size of glass polymer units. CONCLUSIONS The application of the newly developed formulation employing silver-coated glass beads has the potential to be translated to clinical conditions for the efficient treatment of IBD.BACKGROUND Recent studies point at the anti-inflammatory action of silver through induction of apoptosis of inflammatory cells via oxidative stress, promotion of wound healing as well as antimicrobial effect. Our aim was to design a new formulation based on silver and validate its anti-inflammatory activity in the mouse models of colitis. METHODS Silver-coated glass beads were prepared using a magnetron sputtering method and a standard magnetron sputtering gun equipped with pure silver target. Colitis was induced by the ic administration of TNBS into colon (to mimic Crohns disease) and addition of DSS to drinking water (to imitate ulcerative colitis). Evaluation of inflammation was performed based on macroscopic and microscopic scoring, quantification of the myeloperoxidase activity and colonic microflora analysis. RESULTS Silver-coated glass beads administered ic alleviated intestinal inflammation in mouse models of colitis, induced by TNBS and DSS. This alleviation of colitis resulted principally from changes in the gut microflora. The anti-inflammatory action of the new formulation was associated predominantly with the presence of the silver nanolayer on the beads, and to a lesser extent the size of glass polymer units. CONCLUSIONS The application of the newly developed formulation employing silver-coated glass beads has the potential to be translated to clinical conditions for the efficient treatment of IBD.

Highly selective CB2 receptor agonist A836339 has gastroprotective effect on experimentally induced gastric ulcers in mice

Cannabinoid type 2 (CB2) receptors are distributed in central and peripheral tissues, including immunocytes and the gastrointestinal (GI) tract, suggesting that CB2 receptor agonists represent potential therapeutics in GI inflammatory states. In this study, we investigated the effect of highly selective CB2 agonist, A836339, on the development of gastric lesions. We used two models of gastric ulcer (GU) induced by ethanol (EtOH) and diclofenac. To confirm the involvement of CB2 receptors, a selective CB2 antagonist, AM630 was used. Clinical parameters for gastroprotection were assessed based on inhibition of the gastric lesion area. To investigate the anti-inflammatory effect of A836339, the expression of TNF-α and IL-1β was assessed. To establish the mechanism of gastroprotective action, catalase (CAT), superoxide dismutase (SOD) activity and H2O2 and glutathione (GSH) levels were measured. Moreover, expression of CB2 and cyclooxygenase-2 (COX-2) was characterized using immunohistochemistry (IHC). A836339 reduced ulcer index in a dose-dependent manner in both EtOH- and diclofenac-induced GU models. This effect was reversed by the CB2 antagonist AM630. Administration of A836339 reduced TNF-α and IL-1β levels in gastric tissue. Furthermore, A836339 exhibited potent anti-oxidant activity, as demonstrated by reduced H2O2 levels and increased CAT and SOD activities. IHC studies revealed a co-localization of CB2 receptors and COX-2 in the gastric tissue. Activation of CB2 receptors exhibited gastroprotective effect through enhancement of anti-oxidative pathways in the stomach. Activation of CB2 receptors may thus become a novel therapeutic approach in the treatment of GU.