Current Pharmaceutical Design - Volume 26, Issue 25, 2020

Inflammatory bowel diseases (IBD), such as ulcerative colitis and Crohn's disease, are multifactorial, chronic, disabling, and progressive diseases characterised by cyclical nature, alternating between active and quiescent states. While the aetiology of IBD is not fully understood, this complex of diseases involve a combination of factors including the genetic predisposition and changes in microbiome as well as environmental risk factors such as high-fat and low-fibre diets, reduced physical activity, air pollution and exposure to various toxins and drugs such as antibiotics. The prevalence of both IBD and obesity is increasing in parallel, undoubtedly proving the existing interactions between these risk factors common to both disorders to unravel poorly recognized cell signaling and molecular alterations leading to human IBD. Therefore, there is still a significant and unmet need for supportive and adjunctive therapy for IBD patients directed against the negative consequences of visceral obesity and bacterial dysbiosis. Among the alternative therapies, a moderate-intensity exercise can benefit the health and well-being of IBD patients and improve both the healing of human IBD and experimental animal colitis. Intestinal alkaline phosphatase (IAP) plays an essential role in the maintenance of intestinal homeostasis intestinal and the mechanism of mucosal defence. The administration of exogenous IAP could be recommended as a therapeutic strategy for the cure of diseases resulting from the intestinal barrier dysfunction such as IBD. Curcumin, a natural anti-inflammatory agent, which is capable of stimulating the synthesis of endogenous IAP, represents another alternative approach in the treatment of IBD. This review was designed to discuss potential “nonpharmacological” alternative and supplementary therapeutic approaches taking into account epidemiological and pathophysiological links between obesity and IBD, including changes in the functional parameters of the intestinal mucosa and alterations in the intestinal microbiome.

Inflammatory bowel diseases (IBD) are chronic multifactorial diseases characterized by partially unclear pathogenic mechanisms including changes in intestinal microbiota. Despite the microbiota, alteration is well established in IBD patients, as reported by 16RNA sequencing analysis, an important goal is to define if it is just a consequence of the disease progression or a trigger factor of the disease itself. To date, gut microbiota composition and gut microbiota-related metabolites seem to affect the host healthy state both by modulating metabolic pathways or acting on the expression of different genes through epigenetic effects. Because of this, it has been suggested that intestinal microbiota might represent a promising therapeutic target for IBD patients. The aim of this review is to summarize both the most recent acquisitions in the field of gut microbiota and its involvement in intestinal inflammation together with the available strategies for the modulation of microbiota, such as prebiotics and/or probiotics administration or fecal microbiota transplantation.

The review considers the data on the physiological and pharmacological effects of glucocorticoids on the gastric mucosa and focuses on the gastroprotective role of stress-produced glucocorticoids as well as on the transformation of physiological gastroprotective effects of glucocorticoids to pathological proulcerogenic consequences. The results of experimental studies on the re-evaluation of the traditional notion that stress-produced glucocorticoids are ulcerogenic led us to the opposite conclusion suggested that these hormones play an important role in the maintenance of the gastric mucosal integrity. Exogenous glucocorticoids may exert both gastroprotective and proulcerogenic effects. Initially, gastroprotective effect of dexamethasone but not corticosterone, cortisol or prednisolone can be transformed into proulcerogenic one. The most significant factor for the transformation is the prolongation of its action rather the dose. Gastrointestinal injury can be accompanied by changes in somatic pain sensitivity and glucocorticoids contribute to these changes playing a physiological and pathological role.

The stable gastric pentadecapeptide BPC 157 protects stomach cells, maintains gastric integrity against various noxious agents such as alcohol, nonsteroidal anti-inflammatory drugs (NSAIDs), and exerts cytoprotection/ adaptive cytoprotection/organoprotection in other epithelia, that is, skin, liver, pancreas, heart, and brain. Especially BPC 157 counteracts gastric endothelial injury that precedes and induces damage to the gastric epithelium and generalizes "gastric endothelial protection" to protection of the endothelium of other vessels including thrombosis, prolonged bleeding, and thrombocytopenia. In this background, we put the importance of BPC 157 as a possible way of securing GI safety against NSAIDs-induced gastroenteropathy since still unmet medical needs to mitigate NSAIDs-induced cytotoxicity are urgent. Furthermore, gastrointestinal irritants such as physical or mental stress, NSAIDs administration, surfactants destroyer such as bile acids, alcohol can lead to leaky gut syndrome through increasing epithelial permeability. In this review article, we described the potential rescuing actions of BPC 157 against leaky gut syndrome after NSAIDs administration for the first time.

Stress gastric ulceration is a clinical condition leading to morbidity/mortality and complex etiopathological factors are involved. Pharmacotherapy of such gastric mucosal lesions is not consistent and novel strategies are being explored. Targeting gastrointestinal factors have showed equivocal results and there is a possibility of involvement of extra-gastrointestinal factors. Stress is a highly interactive biological response in which the brain plays a key role. The involvement of brain substrates like the limbic system (amygdala, cortex, hippocampus) and behavioral traits has been investigated and research data has shown that the limbic brain-gut axis may be involved in the regulation of gastric mucosal integrity during stressful situations. The amygdaloid complex, its connections with other limbic structures and their neural networks act in tandem to contribute to both stress ulceration and gastroprotection. Complex neurotransmitter interactions in these areas involving biogenic amines and neuropeptides have been shown to modulate stress ulcerogenesis in experimental models. The immune system and brain-immune interactions also appear to play a decisive role in the genesis of such stress gastric lesions and the possibility of a brain-gut-immune axis has been proposed during stress gastric lesions. More recent studies have shown the involvement of oxidative stress and nitric oxide as well as their interactions during such stress gastric pathology, indicating the possible role of antioxidants and NO modulators as gastroprotective agents for stress ulceration. In view of the complex pathophysiology, multiple targets and lack of consistent therapeutic modalities, newer/alternative hypotheses are constantly emerging, which could be explored for effective treatment strategies aimed at gastric cytoprotection. Herbal agents with adaptogenic properties could be worth exploring in this regard as some of these phytopharmaceutical agents used in traditional medicine have been shown to exhibit gastric cytoprotection as part of their anti-stress profile. Further, their interactions with brain neurotransmitters and immune mechanisms and their relative safety could make them prospective leads for stress ulcer prophylaxis and treatment.

This review is focused on the healing of fistulas and stable gastric pentadecapeptide BPC 157. Assuming that the healing of the various wounds is essential also for the gastrointestinal fistulas healing, the healing effect on fistulas in rats, consistently noted with the stable gastric pentadecapeptide BPC 157, may raise several interesting possibilities. BPC 157 is originally an anti-ulcer agent, native to and stable in human gastric juice (for more than 24 h). Likely, it is a novel mediator of Robert’s cytoprotection maintaining gastrointestinal mucosal integrity. Namely, it is effective in the whole gastrointestinal tract, and heals various wounds (i.e., skin, muscle, tendon, ligament, bone; ulcers in the entire gastrointestinal tract; corneal ulcer); LD1 is not achieved. It is used in ulcerative colitis clinical trials, and now in multiple sclerosis, and addressed in several reviews. Therefore, it is not surprising that BPC 157 has documented consistent healing of the various gastrointestinal fistulas, external (esophagocutaneous, gastrocutaneous, duodenocutaneous, colocutaneous) and internal (colovesical, rectovaginal). Taking fistulas as a pathological connection, this rescue is verified with the beneficial effects in rats with the various gastrointestinal anastomoses, esophagogastric, jejunoileal, colo-colonic, ileoileal, esophagojejunal, esophagoduodenal, and gastrojejunal. This beneficial effect occurs equally when the gastrointestinal anastomoses are impaired with the application of NSAIDs, cysteamine, large bowel resection, as well as concomitant esophageal, gastric, and duodenal lesions and/or ulcerative colitis presentation, short bowel syndrome progression, liver and brain disturbances presentation. Particular aspects of the BPC 157 healing of the fistulas are especially emphasized.

Although the morbidity of ulcers is statistically higher in males than females, the mechanism of this difference remains unknown. Recent studies show that duodenal HCO3- response to mucosal acidification is higher in females than males, and this may be a factor responsible for the sex difference in the mucosal protective mechanisms. In this article, we examined the duodenal HCO3- responses to various stimuli in male and female rats, including estrogen, and reviewed the mechanisms responsible for the sex difference in the acid-induced HCO3- secretion. Mucosal acidification was performed by exposing the duodenum to 10 mM HCl for 10 min. PGE2 was administered intravenously, while capsaicin was applied topically to the duodenum for 10 min. Tamoxifen was given s.c. 30 min before the acidification. Ovariectomy was performed 2 weeks before the experiments; half of the animals were given estrogen i.m. after the operation. Mucosal acidification increased duodenal HCO3- secretion in male rats, and this response was inhibited by indomethacin and sensory deafferentation. Although no sex difference was found in HCO3- responses to PGE2 and capsaicin, the response to acid was significantly greater in female than male rats. The different HCO3- response to acid disappeared on ovariectomy, and this effect was totally reversed by the repeated administration of estrogen. The gene expression of ASIC3 in female rats was greater than in male rats and down-regulated by ovariectomy or tamoxifen treatment in an estradiol- dependent manner, while no sex difference was observed in TRPV1 and CFTR expressions. In conclusion, the acid-induced HCO3- response is greater in female than male rats, and this phenomenon is not due to changes in PGE2 sensitivity or TRPV1/CFTR expressions but may be accounted for by increased expression of ASIC3 on sensory neurons, which is associated with the chronic influence of estrogen.

Mucosal serotonin (5-HT) is a key paracrine signaling molecule in the integrated physiology of enterochromaffin cells, enteric mast cells, spinal afferent nerves and the enteric nervous system (ENS). Enterochromaffin cells release 5-HT as a paracrine signal to enteric mast cells, spinal afferents and neurons in the ENS. Enteric mast cells release multiple mediators of paracrine signaling, among which are histamine and the serine proteases, chymase and tryptase, as well as serotonin. Some of these mediators diffuse to receptors on afferent nociceptive and mechanosensitive terminals and sensitize the terminals in a manner that may underlie abdominal pain and distension induced pain in the irritable bowel syndrome. Substance P and calcitonin gene-related peptide (CGRP), released by spinal afferent innervation, degranulate enteric mast cells. Substance P and CGRP are significant factors in mucosal inflammation evoked by bacteria in the colonic microbiome. Binding of immunoglobulin antibodies to FcRI receptors, on enteric mast cells, degranulate the mast cells and release paracrine mediators that overlay integrative microcircuitry in the ENS. An overlay of histamine “calls up” from the ENS library of programed gut behaviors, a defensive program consisting of a sequence of copious mucosal secretions, increased blood flow and powerful orthograde propulsion organized to move threats out of the colonic lumen. Symptoms of acute watery diarrhea, cramping abdominal pain and incontinence are associated with “running” of the defense program. Intestinal behavioral programs stored in the ENS library are described as working like digital “apps”.

Background: Effective and selective oral rinses are required in the daily medical and dental practice. Currently mouthwashes used have substantial side effects. Objectives: Our aim was to evaluate the efficacy of chlorine dioxide-containing mouthwashes in comparison with other previously established mouth rinses in healthy adults using oral hygiene indices. Methods: This work was registered in PROSPERO (CRD42018099059) and carried out using multiple databases and reported according to the PRISMA statement. The search terms used were “chlorine dioxide” AND “oral”, and only randomised controlled trials (RCTs) were included. The primary outcome was the alteration of the plaque index (PI), while the secondary outcomes were the gingival index (GI) and bacterial counts. For the risk of bias assessment, the Cochrane Risk of Bias Tool was used. Statistical analysis for data heterogeneity was performed by Q-value and I2-tests. Results: 364 articles were found in the databases. After the selection process, only five RCTs were eligible for meta-analysis. Data heterogeneity was low. There were no statistical differences in effectiveness between chlorine dioxide and other effective mouth rinses in PI (0.720±0.119 vs 0.745±0.131; 95%; confidence intervals (CIs): 0.487-0.952 vs 0.489-1.001, respectively) and GI (0.712±0.130 vs 0.745±0.131; 95% CIs: 0.457–0.967 vs 0.489– 1.001, respectively) and also in bacterial counts. Conclusion: Chlorine dioxide reduces both plaque and gingival indices and bacterial counts in the oral cavity similar to other routinely used oral rinses, however, the evidence supporting this outcome is very limited. Therefore, further large scale RCTs are needed to decrease the risk of bias.

Herpes zoster (HZ) causes considerable pain and distress, and γ-Aminobutyric acid (GABA) and its derivatives are assumed to control this, but the available data are inconsistent. This meta-analysis and systematic review aimed to assess the effectiveness of GABA derivatives in the prevention of acute herpetic pain. The metaanalysis was conducted following the PRISMA guidelines using PICO format, registered in PROSPERO number CRD42018095758. PubMed, Web of Science, Ovid, Scopus, and EMBASE databases were searched. Records were included if they were randomized controlled trials of patients undergoing HZ infection, investigating the effect of GABA derivatives versus placebo in the treatment of HZ pain. Eligible trials were evaluated for the risk of bias. Then data were extracted and analysed. The number of patients with observed presence of pain after treatment was used to calculate odds ratio in a random effect model with the DerSimonian-Laird estimator. The I2 statistic was analysed for heterogeneity. The potential risk of bias was measured using Egger’s regression test. The meta-analysis included three randomized controlled trials with a total of 297 patients. The incidence of acute HZ pain events for GABA group was significantly lower compared to placebo group,18/148 vs 44/149, respectively (OR = 0.36; 95% CI = 0.14 to 0.93; Z = 2.11; P = 0.035), Egger’s test yielded P = 0.308. In conclusion, the present meta-analysis demonstrates that GABA derivatives reduce the incidence of acute herpetic pain. However, additional, well-designed randomized clinical trials are needed to determine their dose- and time-dependency regarding this symptom.

Background: The hepatic and pulmonary MALT lymphoma (mucosa-associated lymphoid tissue lymphoma) is clinically occasionally observed but its pathogenesis is unknown and thought to be important to establish the treatment strategy. Objectives: The present study was designed to clarify the characteristics of these lymphomas and the effect of the Helicobacter eradication regimen and substance P antagonist. Methods: After the long term infection of Helicobacter suis to the C57BL/6 mice stomach, the whole organ was surveyed pathologically. Histochemical characteristics of the lesion and the localization of bacteria were observed. In addition, the effect of the administration of antibiotics and a proton pump inhibitor or the substance P antagonist was investigated. Results: We have detected the hepatic and pulmonary MALT lymphoma after the long term infection. In situ hybridization study revealed the positive reaction of Helicobacter suis in the hepatic and pulmonary MALT lymphoma. After the administration of antibiotics and a proton pump inhibitor, the bacterial number has significantly decreased and the tumor size in the fundus, liver and lung markedly reduced. Substance P immunoreactivity was clearly shown in the lymphoma cells in the liver and lung, and the spantide II administration induced the marked decrease in the size of tumors. Conclusion: By our experiments using the long term infection of Helicobacter suis to the C57BL/6 mice, we have detected the liver and pulmonary MALT lymphoma. In situ hybridization study suggested the direct interaction of this bacterium to the etiology of these lesions. Substance P within the lymphoma cells was suggested to work on the maintenance of the extragastric MALT lymphoma.