Natural products in treatment of ulcerative colitis and peptic ulcer

Ulcerative colitis is an inflammatory chronic disease that affects the mucosa and submucosa of the colon and rectum. Several types of drugs are available such as aminosalicylates. Peptic ulcer disease (PUD) is a common disorder that affects millions of individuals worldwide and it can be considered one of the most important common diseases in the world. Treatment of peptic ulcers depends on using a number of synthetic drugs that reduce the rate of stomach acid secretion (Antiacids), protect the mucous tissues that line the stomach and upper portion of the small intestine (Demulcents) or to eliminate Helicobacter pylori (H. pylori). In most cases, incidence of relapses and adverse reactions is seen in the following synthetic antiulcer therapy. Accordingly, the main concern of the current article is to introduce a safe drug (or more) of natural origin, to be used for the management of gastric ulcers without side effects.A widespread search has been launched to identify new anti-ulcer therapies from natural sources. Herbs, medicinal plants, spices, vegetables and crude drug substances are considered to be a potential source to control various diseases including gastric ulcer and ulcerative colitis. In the scientific literature, a large number of medicinal plants and their secondary metabolites with potential anti-ulcer (anti-peptic ulcer and antiulcerative colitis) activities have been reported. Treatment with natural products produces promising results and fewer side effects. Our goal is to collect the published data in the last 24 years and reviews the natural products reported in the treatment of these diseases and their mechanism of action.     

Identification of the polymorphisms in IFITM3 gene and their association in a Korean population with ulcerative colitis

Interferons play critical roles in tumor pathogenesis by controlling apoptosis and through cellular anti-proliferative and differentiation activities. Interferon inducible transmembrane protein (IFITM) family genes have been implicated in several cellular processes such as the homotypic cell adhesion functions of IFN and cellular anti-proliferative activities. Expression levels of IFITM genes have been found to be up-regulated in gastric cancer cells and colorectal tumors. IFITM3 (also known as 1-8U) is a member of the IFITM family, and has been described as a key player in specification of germ cell fate. IFITM3 was first isolated from a genetic screen aimed at identifying genes involved in acquisition of germ cell competence. It has been proposed that epiblast cells have the highest expression of IFITM3 initiated germ cell specification and that homotypic association can discriminate germ cells from their somatic neighbors. In an attempt to better understand the genetic influences of IFITM3 on ulcerative colitis, we have identified possible variation sites and single nucleotide polymorphisms (SNPs) through two exons and their boundary IFITM3 intron sequences including the ~2.1 kb promoter regions. To determine whether or not these IFITM3 SNPs are associated with susceptibility to ulcerative colitis, frequencies of the genotype and allele of IFITM3 polymorphisms were analyzed on genomic DNAs isolated from patients with ulcerative colitis and from healthy controls. We also investigated the haplotype frequencies constructed by these SNPs in both groups. In this study, we also showed that expression level of IFITM3 mRNA was significantly higher in tissues of the ileum and cecum of the digestive system. We identified a total of seven SNPs and multiple variation regions in the IFITM3 gene. The genotype frequency of the g.-204T>G polymorphism in patients with ulcerative colitis was significantly different from that of the control group. Our results strongly suggest that polymorphisms of the IFITM3 gene may be associated with susceptibility to ulcerative colitis.     

Astragalus membranaceus ultrafine powder alleviates hyperuricemia by regulating the gut microbiome and reversing bile acid and adrenal hormone biosynthesis dysregulation

Ethnopharmacological relevanceMetabolic syndrome is closely related to the intestinal microbiota and disturbances in the host metabolome. Hyperuricemia (HUA), a manifestation of metabolic syndrome, can induce various cardiovascular diseases and gout, seriously affecting a patient’s quality of life. Astragalus membranaceus has a long history as a commonly used traditional Chinese medicine to treat kidney disease in China and East Asia.Materials and methodsWe compared the therapeutic effect of benzbromarone and two different doses Astragalus membranaceus ultrafine powder (AMUP) in rats with HUA. Ultra-performance liquid chromatography-mass spectrometer was used to analyze the AMUP metabolism in the plasma, urine, and feces. Further, 16S ribosome RNA sequencing and feces metabolomic were performed to capture the variation of the gut microbiota and metabolites changes before and after drug administration.ResultsAMUP had a notable impact on reducing blood uric acid levels while protecting the liver and kidney. Drug metabolism analysis demonstrated that effective constituent flavonoids are distributed in the blood, whereas saponins remain in the intestine. Gut microbiota analysis showed that low-dose AMUP ameliorated HUA-induced gut dysbiosis by reducing the abundance of harmful bacteria and increasing that of some beneficial bacteria with anti-inflammatory properties, such as Clostridia, Lachnospiraceae, and Muribaculaceae. In addition, HUA-induced changes in metabolite contents in bile acid and adrenal hormone biosynthesis pathways were restored after treatment with AMUP.ConclusionLow-dose AMUP exerts remarkable therapeutic effects on HUA by regulating the gut microbiome and mediating gut metabolism pathways associated with uric acid excretion.     

The association of eotaxin-2 and eotaxin-3 gene polymorphisms in a Korean population with ulcerative colitis

The eotaxin gene family (eotaxin, eotaxin-2 and eotaxin-3) have been implicated in the recruitment of eosinophils, basophiles and helper T (Th) 2 lymphocytes that is a central aspect of allergic disease. We previously suggested that Eo2+179T>C and Eo2 +275C>T of the eotaxin-2, and Eo3 +2497T>G of the eotaxin-3 were significantly associated with susceptibility to asthma. To determine whether the single nucleotide polymorphisms (SNPs) of eotaxin-2 and eotaxin-3 gene family are associated with the susceptibility of ulcerative colitis (UC), we analyzed the genotype of 119 patients with UC and 303 controls using single-base extension (SBE) method. We also calculated the haplotype frequencies among Eo2 +179T>C and Eo2 +275C >T of the eotaxin-2 and Eo3 +2497T>G of the eotaxin-3 in both control and UC patients. The genotype frequency of Eo2 +179T>C and Eo2 +275C>T between UC patients and controls were significantly different (P=0.006 and 0.022, respectively). The genotype and allele frequencies of EoA2497T>G in UC patients were not significantly different from those in the controls without UC patients. Our results suggest that Eo2 +179T>C and Eo2 +275C>T of eotaxin-2 might be associated with the susceptibility of UC.     

A novel strategy for high-specificity,high-sensitivity,and high-throughput study for gut microbiome metabolism of aromatic carboxylic acids

Aromatic carboxylic acids(ACAs) may be as transformed key metabolites via gut microbiome for playing better pharmacological effects. However, it’s rare to achieve high-specificity, high-sensitivity, and highthroughput detection simultaneously, especially, for tracing trace ACAs in gut microbiome. In this work,firstly, a novel dual-template and double-shelled molecularly imprinted 96-well microplates(DDMIPs)was designed and amplified signal for p-hydroxybenzoic acid(PBA) and 3,4,5-trimethoxycinna...     

Oral delivery of superoxide dismutase by lipid polymer hybrid nanoparticles for the treatment of ulcerative colitis

Protein-based drugs have received extensive attention in the field of drug research in recent years. However, protein-based drug activity is difficult to maintain during oral delivery, which limits its application. This study developed bifunctional oral lipid polymer hybrid nanoparticles (R8-PEG-PPNPs) that deliver superoxide dismutase (SOD) for the treatment of ulcerative colitis (UC). R8-PEG-PPNPs was composed of PCADK, PLGA, lecithin, and co-modified with stearic acid-octa-arginine and polyethylene glycol. The nanoparticles (NPs) are uniformly dispersed with a complete spherical structure. In vitro stability and release studies showed that R8-PEG-PPNPs exhibited good stability and protection. In vitro cell culture experiments demonstrated that R8-PEG-PPNPs as carriers have no significant toxic effects on cells at concentration below 1000 µg/mL and promote cellular uptake. In experiments with ulcerative colitis mice, R8-PEG- PPNPs were able to enhance drug absorption by intestinal epithelial cells and accumulate effectively at the site of inflammation. Its therapeutic effect further demonstrates that R8-PEG-PPNPs are a promising delivery system for oral delivery of protein-based drugs.     

The effects of different dietary fiber pectin structures on the gastrointestinal immune barrier: impact via gut microbiota and direct effects on immune cells

Pectins are dietary fibers with different structural characteristics. Specific pectin structures can influence the gastrointestinal immune barrier by directly interacting with immune cells or by impacting the intestinal microbiota. The impact of pectin strongly depends on the specific structural characteristics of pectin; for example, the degree of methyl-esterification, acetylation and rhamnogalacturonan I or rhamnogalacturonan II neutral side chains. Here, we review the interactions of specific pectin structures with the gastrointestinal immune barrier. The effects of pectin include strengthening the mucus layer, enhancing epithelial integrity, and activating or inhibiting dendritic cell and macrophage responses. The direct interaction of pectins with the gastrointestinal immune barrier may be governed through pattern recognition receptors, such as Toll-like receptors 2 and 4 or Galectin-3. In addition, specific pectins can stimulate the diversity and abundance of beneficial microbial communities. Furthermore, the gastrointestinal immune barrier may be enhanced by short-chain fatty acids. Moreover, pectins can enhance the intestinal immune barrier by favoring the adhesion of commensal bacteria and inhibiting the adhesion of pathogens to epithelial cells. Current data illustrate that pectin may be a powerful dietary fiber to manage and prevent several inflammatory conditions, but additional human studies with pectin molecules with well-defined structures are urgently needed.Subject terms: Mucosal immunology, Translational immunology     

Strategies and opportunities of micro/nano delivery systems for targeted therapy of ulcerative colitis: Focus on underlying mechanisms and future perspectives

Ulcerative colitis(UC) is a common progressive inflammatory disease whose incidence has increased rapidly in recent years, and can develop into colorectal cancer in severe cases. There are currently no adequate or effective treatments for UC due to the fact that some patients have found suboptimal results after repeated administration, while others have experienced adverse effects. With the rapid development of nanotechnology, developing innovative colon-targeting platforms is essential to impro...     

Protein tango: the toolbox to capture interacting partners

The evaluation of protein function in the context of the whole cell is crucial for understanding of living systems. In this context, the identification and modulation of protein-protein interactions in and outside cells is of ample importance. Several methods have been developed in the past years to detect and/or actively induce protein-protein interactions in living cells. As a result, tools are now available to manipulate intracellular events by reversible or irreversible cross-linking of proteins in a specific manner. These techniques open many new doors and enable the dissection of complicated protein networks. Herein we describe which cross-linkers and inducers of dimerization are out there and how to make use of this great toolbox.     

Copper and manganese: two concordant partners in the catalytic oxidation of p-cresol to p-hydroxybenzaldehyde

Copper and manganese were found to be two concordant partners in the synthesis of p-hydroxybenzaldehyde from p-cresol; under mild conditions, this research realised 95.6% selectivity for p-hydroxybenzaldehyde at 98.5% conversion of p-cresol.     

A new horizon of precision medicine: combination of the microbiome and extracellular vesicles

Over several decades, the disease pattern of intractable disease has changed from acute infection to chronic disease accompanied by immune and metabolic dysfunction. In addition, scientific evidence has shown that humans are holobionts; of the DNA in humans, 1% is derived from the human genome, and 99% is derived from microbial genomes (the microbiome). Extracellular vesicles (EVs) are lipid bilayer-delimited nanoparticles and key messengers in cell-to-cell communication. Many publications indicate that microbial EVs are both positively and negatively involved in the pathogenesis of various intractable diseases, including inflammatory diseases, metabolic disorders, and cancers. Microbial EVs in feces, blood, and urine show significant differences in their profiles between patients with a particular disease and healthy subjects, demonstrating the potential of microbial EVs as biomarkers for disease diagnosis, especially for assessing disease risk. Furthermore, microbial EV therapy offers a variety of advantages over live biotherapeutics and human cell EV (or exosome) therapy for the treatment of intractable diseases. In summary, microbial EVs are a new tool in medicine, and microbial EV technology might provide us with innovative diagnostic and therapeutic solutions in precision medicine.Subject terms: Biomarkers, Biological therapy     

Rotating magnetic particle microrheometry in biopolymer fluid dynamics: mucus microrheology

The polymer properties of canine mucus were investigated through the method of rotating magnetic particle microrheometry. Mucus is visualized as a physically entangled biopolymer of low polydispersity in a water-based solution. Mucus was modeled according to the constitutive law of a Doi-Edwards fluid. The magnetic-particle equation of rotational motion is analytically solved in the linear viscoelastic limit rendering theoretical flow profiles which are used to fit the experimental trace signals of the particle remanent-magnetic-field decay. The zero-shear-rate viscosity was found to be 18,000 P and the relaxation time at about 42 s. The molecular weight between entanglements for mucins was estimated at 1.7 MDa rendering an estimation of about seven physical cross-links per molecule. Rheological investigations were extended also to diluted and concentrated rations of the normal mucus simulating the conditions found in more physiological extremes.     

Cellulasic activity in the gut ofEisenia foetida

The evaluation of the free cellulasic activity in the gut ofEisenia foetida under different conditions of breeding (earthworms on manure, on treated municipal wastes, in sterile conditions) has been done by testing the production of reducing sugars (RS) from the carboxymethylcellulose (CMC) and filter paper (FP). Whatever the breeding conditions are, a cellulasic activity can be observed even for disinfected worms kept in almost sterile conditions. The alimentary canal contains the complete enzyme system as reducing sugars are produced from CMC and FP. Localization: The different regions (crop, gizzard, fore, mid, hind gut) contain cellulases except the pharynx. The greatest activities have been found in the fore and mid gut. Even after five washings of the gut wall of holoxenic and disinfected worms with sterile water, a cellulasic activity is still measurable. As anaerobic cellulolytic bacteria are still present on the gut wall, even after disinfection, we cannot presume upon the origin of the enzymes. Origin: Enzymes produced by the worm rather than by microorganisms? The screening of the cellulolytic ability of 100 bacteria isolated from the gut contents on cellulose azur, shows that many species are cellulolytic and can lead the production of reducing sugars in 3 h. On the other hand, the cellulolysis has been evaluated in two groups of Eisenia foetida worms with or without astomatous ciliates enfeoffed to the gut. The results expressed in μg RS/mg gut show no difference between the two groups. Only really axenic worms will resolve the problem of the origin of the cellulase. This research is actually in progress.     

Of men in mice: the development and application of a humanized gnotobiotic mouse model for microbiome therapeutics

Considerable evidence points to the critical role of the gut microbiota in physiology and disease. The administration of live microbes as a therapeutic modality is increasingly being considered. However, key questions such as how to identify candidate microorganisms and which preclinical models are relevant to recapitulate human microbiota remain largely unanswered. The establishment of a humanized gnotobiotic mouse model through the fecal microbiota transplantation of human feces into germ-free mice provides an innovative and powerful tool to mimic the human microbial system. However, numerous considerations are required in designing such a model, as various elements, ranging from the factors pertaining to human donors to the mouse genetic background, affect how microbes colonize the gut. Thus, it is critical to match the murine context to that of human donors to provide a continuous and faithful progression of human flora in mice. This is of even greater importance when the need for accuracy and reproducibility across global research groups are taken into account. Here, we review the key factors that affect the formulation of a humanized mouse model representative of the human gut flora and propose several approaches as to how researchers can effectively design such models for clinical relevance.Subject terms: Experimental models of disease, Translational research     

Anodic coupling reactions: the use of N,O-ketene acetal coupling partners

Intramolecular anodic olefin coupling reactions utilizing N,O-ketene acetals have been studied. Coupling reactions with both enol ether and allylsilane terminating groups were examined. The reactions involving the coupling of the N,O-ketene acetals with allylsilane groups were found to be much more efficient than corresponding reactions utilizing dithioketene acetal groups and allylsilanes. The reactions were also more efficient than the intramolecular coupling reactions between enol ethers and allylsilanes studied earlier.