As it is pointed out in this special issue of Current Pharmaceutical Design, despite the extensive and multidisciplinary research during the
last years, a lot of basic and clinical research is still needed to better understand the manifestations, central and peripheral molecular regulators
of new mechanisms of GI ulceration and healing, physiology, pharmacology and pathology, especially in relation to the classic modes
of prevention/management of gastrointestinal ulceration and healing or their transformation into new concepts and the treatment of gastrointestinal
ulceration and healing. This is particularly important for acquiring new vistas in the therapy of gastrointestinal tract disturbances.
Therefore, “New mechanisms of GI ulceration & healing: Physiology, pharmacology & pathology” attempts to cover a huge area of
the pertinent scientific research. Between various concepts, the Robert’s cytoprotection concept is still one of the most fascinating concepts in
science development, particular with respect to conceptual disagreements, or on the other hand, novel agents, and attempts to improve concept,
as well as to finally realize some or all of the concept postulates in gastrointestinal tract therapy. Therefore, it seems interesting to review
again this issue, covering a huge area, by eminent experts, providing their most recent findings, including the development of new medicines
and new approaches.
Bilski et al. [1] in their review Exploiting significance of physical exercise in prevention of gastrointestinal disorders revealed the particular
relationship between physical exercise with different intensity and alterations the morphology and function of the gut including its protective
influence on the lipid metabolism and chronic systematic inflammation as well as the diversity, distribution and metabolite of the gut
microbiota. Based on the evidence provided in this overview, the regular, moderate exercise can reduce the risk of colorectal cancer and exert
a beneficial effect on upper and lower GI-tract disorders such as reflux esophagitis, peptic ulcers, cholelithiasis, constipation and IBD leading
to the attenuation of the symptoms. On the other hand, the high-intensity training or prolonged endurance training can exert a negative influence
on these same entities [1].
Olsen et al. [2] in the review New approaches for weight loss: experiments in animal models emphasized the interesting points such as
animal models (i.e., VBLOC (implanted hunger-blocking device) and knockout of muscarinic acetylcholine M3 receptor) known to reduce
food intake and body weight versus the expression of energy-balance regulating peptides in the hypothalamus as a drive for increased food
intake. Finally, emphasizing that the brain-gut axis plays an important role in the regulation of body weight, they proposed that the brainstem
may be more important in the regulation of food intake than hypothalamus in the context of the brain-vagus nerve-gut axis [2].
Review Similar and distinct mechanisms in the protective processes of upper and lower GI tract by Gyires et al. [3] is an excellent overview
of the protective mechanisms of upper and lower gastrointestinal tract providing their own findings purposefully elaborated. This review
analyzed many factors involved in various forms and levels of protection of mucosal tissues, mucosal protection in the periphery (barriers and
mediators), intestinal defense mechanisms (mucosal barriers, bile acids), stimulation of gastrointestinal mucosal protection (pre-epithelial,
epithelial, sub-epithelial possibilities) and central nervous system involvement [3].
The authors, Kang E.A. and collaborators [4] in review BPC 157 as potential agent rescuing from cancer cachexia summarized signaling
pathways and promising drug candidates to treat cancer-associated cachexia and focused their review on the possible application of BPC 157
for cancer cachexia with the mode of action. They showed the significant relieving effects of BPC 157 on C-26 colon adenocarcinomainduced
muscle degeneration and inflammation. The presented review is very informative and may provide support for the potential use of
stable gastric pentadecapeptide BPC 157 as a cachexia-rescuing therapeutic agent [4].
The author, Gaetano Iaquinto [5] in his review, The several activities of 4-methypyrazole in animals and humans, reviews 4-
methypyrazole (4-MP), a pyrazole derivative in animal and humans. 4-MP is a potent competitive inhibitor of ADH activity with an affinity
about a 1000 times more than toxic alcohols. 4-MP was shown to reduce the formation of toxic metabolites in lethal methanol and ethylene
glycol poisoning in animal models and in methanol poisoning in humans, and in particular, 4-MP provides significant protection of the human
stomach against alcohol-induced acute mucosal injury [5].
Kodama et al. [6] in their review MALT lymphoma, stress ulcer and cholinergic nerves from the viewpoint of bilateral and unilateral
truncal vagotomy and substance P follow the evidence that the vagal nerves play an important role in gastric function providing rich innervation
to this area and that the vagal nerve activity was shown to be related to both gastric cancer development and progression, but its relation
to the mesenchymal tumors such as MALT lymphoma is not known. Thereby, the authors were focused on the effect of vagotomy on gastric
MALT lymphoma development by in the Helicobacter heilmannii-mouse infection model [6].
The review Role of formyl peptide receptors in gastrointestinal healing by Prevete and collaborators [7] assessed the role of a particular
class of PRRs, the Formyl Peptide Receptors (FRP), in gut mucosa homeostasis. They report studies that strongly suggest the possibility that FRP activation is crucial for the maintenance of gut homeostasis. Furthermore, they provide indications for the potential clinical relevance of
novel directions related to FPR modulation in various gastrointestinal disorders [7].
The authors, Seiwerth and collaborators [8], in review BPC 157 and standard angiogenic growth factors. Gastrointestinal tract healing,
lessons from tendon, ligament, muscle and bone healing focused on gastric pentadecapeptide BPC 157, a peptide always given alone vs. standard
peptidergic angiogenic growth factors such as EGF, FGF and VEGF, and numerous carriers. They also reviewed how the healing could
happen involving angiogenic growth factors in the gastrointestinal tract and in extra-gastrointestinal tissues, such tendon, ligament, muscle
and bone, providing a carrier, use (i.e., EGF, FGF and VEGF) or no use (BPC 157). The effects of EGF, FGF, VEGF, and BPC 157 were
compared in various injuries, such as gastrointestinal ulcer, tendon, ligament, muscle and bone healing. They found that BPC 157 was the
only factor being consistently effective in all of the models, given per-orally or locally, unlike FGF, EGF, and VEGF. The authors found that
on the healing mechanism of BPC 157 is related to its own angiogenic effect in the healing [8].
The authors, Sikiric and collaborators [9], in review Novel cytoprotective mediator, stable gastric pentadecapeptide BPC 157. Vascular
recruitment and gastrointestinal tract healing cover an intriguing story about the stable gastric pentadecapeptide BPC 157 and the whole
story about the concept of the cytoprotection and possibly new insights. The basic concept providing the stomach cytoprotection as the most
fundamental concept, stomach cell protection and endothelium protection was largely elaborated. Having managed these two points, stomach
cell protection and endothelium protection, either one or together, even much more than standard cytoprotective agents do, BPC 157 employed
large scale of its beneficial effects seen in various organs. This provides an additional realization of blood vessels controlling, described
as “vessel recruitment depending on injury”, “bypassing vessel occlusion” or “running toward the defect”, leading to reestablishing
blood flow. This was taken as a final implementation of the concept of cytoprotection. Obviously, the reestablished blood flow, and largely
reversed injurious course may practically implement the cytoprotection concept [9].
The authors K. Takeuchi and K. Amagase [10] in their review Roles of cyclooxygenase, prostaglandin E2 and EP receptors in mucosal
protection and ulcer healing in the gastrointestinal tract reviewed how the PGE2 prevents acid-reflux esophagitis and affords protection of
the stomach against NSAIDs through the activation of EP1 receptors. Although CRS-induced gastric lesions were aggravated in IP but not
EP1 KO mice, endogenous PGE2 may also be partly responsible for mucosal protection during CRS via the activation of EP4 receptors, in
addition to that afforded by PGI1
/IP receptors. Similar observations were done in the other parts of GI tract (duodenum, small intestine, stomach,
large bowel) [10].
Racz et al. [11] in their review Defense mechanisms against acid exposure by dental enamel formation, saliva and pancreatic juice production
review defense mechanisms of different tissues. The similarities of enamel, salivary glands and pancreas are well emphasized and
described. The authors highlight the importance of bicarbonate buffer system and highlight the possible failures as well. The intracellular
transport and secretion mechanism are also reviewed [11].
Yanaka in his review Contribution of NRF2 in gastrointestinal protection from oxidative injury [12] reviews the evidence that dietary
intake of sulforaphane, derived from broccoli sprouts, ameliorates H. pylori-induced gastritis, NSAIDs-induced small intestinal injury, and
functional constipation. The additional focus was on many other compounds, which enhance the nuclear factor erythroid 2-related factor 2-
mediated antioxidant system, and in particular on some reports, which have shown that excessive stimulation of nuclear factor erythroid 2-
related factor 2 enhances chemoresistance and facilitates the growth of cancer cells [12].
The review Lifestyle and peptic ulcer disease from Yegen [13] extends a general point such as the risk of developing peptic ulcer disease
shown to be associated with genetic inheritance, lifestyle and social status of the patients, to an extensive and very informative review providing
particular chapters (Stress, NSAIDs, Diet and body weight, Alcohol, Smoking, Physical activity, Sleep) with a list of the references that
seems to be quite extensive and well chosen [13].
We hope multidisciplinary topics discussed with the theme issue will promote further discussion among pharmaceutical industry and researchers.
As the guest editor, I would like to thank all the authors and co-authors for their excellent contributions. Also, I would sincerely
thank and acknowledge the diverse group of experts and colleagues who offered their substantial reviewing efforts and suggestions. Last but
not least, I would like to express my gratitude to the Bentham Science Publishers for the wonderful experience while working with the journal
on this thematic issue. It was a great pleasure working with the Director Kazim Baig and for the opportunity to publish in Current Pharmaceutical
Design. It was a wonderful experience working with Editorial Assistant Aamer M. Khan at the time of submission and processing of the
manuscripts. I would like to acknowledge the contributions of others who took care of editing and processing the manuscripts to obtain the
best final quality at the time of publication.
