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Journal of Controlled Release :... Jan 2023Colonic drug delivery can facilitate access to unique therapeutic targets and has the potential to enhance drug bioavailability whilst reducing off-target effects.... (Review)
Review
Colonic drug delivery can facilitate access to unique therapeutic targets and has the potential to enhance drug bioavailability whilst reducing off-target effects. Delivering drugs to the colon requires considered formulation development, as both oral and rectal dosage forms can encounter challenges if the colon's distinct physiological environment is not appreciated. As the therapeutic opportunities surrounding colonic drug delivery multiply, the success of novel pharmaceuticals lies in their design. This review provides a modern insight into the key parameters determining the effective design and development of colon-targeted medicines. Influential physiological features governing the release, dissolution, stability, and absorption of drugs in the colon are first discussed, followed by an overview of the most reliable colon-targeted formulation strategies. Finally, the most appropriate in vitro, in vivo, and in silico preclinical investigations are presented, with the goal of inspiring strategic development of new colon-targeted therapeutics.
Topics: Drug Delivery Systems; Colon; Pharmaceutical Preparations; Administration, Oral; Biological Availability
PubMed: 36528195
DOI: 10.1016/j.jconrel.2022.12.029 -
Gastroenterology Mar 2018Inflammatory bowel diseases (IBD) increase risk for colorectal cancer. Mutations in the Mediterranean fever gene (MEFV or pyrin) are associated with hereditary...
BACKGROUND & AIMS
Inflammatory bowel diseases (IBD) increase risk for colorectal cancer. Mutations in the Mediterranean fever gene (MEFV or pyrin) are associated with hereditary autoinflammatory disease and severe IBD. Expression of MEFV, a sensor protein that the initiates assembly of the inflammasome complex, is increased in colon biopsies from patients with IBD. We investigated the role of pyrin in intestinal homeostasis in mice.
METHODS
Mefv mice and C57/BL6 mice (controls) were given azoxymethane followed by multiple rounds of dextran sodium sulfate (DSS) to induce colitis and tumorigenesis. In some experiments, Mefv mice were given injections of recombinant interleukin 18 (rIL18) or saline (control) during DSS administration. Colon tissues were collected at different time points during colitis development and analyzed by histology, immunohistochemistry, immunoblots, or ELISAs (to measure cytokines). Spleen and mesenteric lymph node were collected, processed, and analyzed by flow cytometry. Colon epithelial permeability was measured in mice with colitis by gavage of fluorescent dextran and quantification of serum levels.
RESULTS
MEFV was expressed in colons of control mice and expression increased during chronic and acute inflammation; high levels were detected in colon tumor and adjacent non-tumor tissues. Mefv-/- mice developed more severe colitis than control mice, with a greater extent of epithelial hyperplasia and a larger tumor burden. Levels of inflammatory cytokines (IL6) and chemokines were significantly higher in colons of Mefv-/- mice than control mice following colitis induction, whereas the level IL18, which depends on the inflammasome for maturation and release, was significantly lower in colons of Mefv-/- mice. Mefv-/- mice had increased epithelial permeability following administration of DSS than control mice, and loss of the tight junction proteins occludin and claudin-2 from intercellular junctions. STAT3 was activated (phosphorylated) in inflamed colon tissues from Mefv-/-, which also had increased expression of stem cell markers (OLFM4, BMI1, and MSI1) compared with colons from control mice. Administration of rIL18 to Mefv-/- mice reduced epithelial permeability, intestinal inflammation, the severity of colitis, and colon tumorigenesis.
CONCLUSIONS
In studies with DSS-induced colitis, we found that pyrin (MEFV) is required for inflammasome activation and IL18 maturation, which promote intestinal barrier integrity and prevent colon inflammation and tumorigenesis. Strategies to increase activity of MEFV or IL18 might be developed for the treatment of IBD and prevention of colitis-associated tumorigenesis.
Topics: Animals; Azoxymethane; Cell Transformation, Neoplastic; Colitis; Colon; Colonic Neoplasms; Dextran Sulfate; Disease Models, Animal; Genetic Predisposition to Disease; Inflammasomes; Interleukin-18; Mice, Inbred C57BL; Mice, Knockout; Permeability; Phenotype; Phosphorylation; Pyrin; STAT3 Transcription Factor; Signal Transduction; Tight Junctions; Time Factors; Tumor Burden; Tumor Microenvironment
PubMed: 29203393
DOI: 10.1053/j.gastro.2017.11.276 -
FASEB Journal : Official Publication of... Apr 2015Gut microbiota alterations have been described in several diseases with altered gastrointestinal (GI) motility, and awareness is increasing regarding the role of the gut...
Gut microbiota alterations have been described in several diseases with altered gastrointestinal (GI) motility, and awareness is increasing regarding the role of the gut microbiome in modulating GI function. Serotonin [5-hydroxytryptamine (5-HT)] is a key regulator of GI motility and secretion. To determine the relationship among gut microbes, colonic contractility, and host serotonergic gene expression, we evaluated mice that were germ-free (GF) or humanized (HM; ex-GF colonized with human gut microbiota). 5-HT reduced contractile duration in both GF and HM colons. Microbiota from HM and conventionally raised (CR) mice significantly increased colonic mRNAs Tph1 [(tryptophan hydroxylase) 1, rate limiting for mucosal 5-HT synthesis; P < 0.01] and chromogranin A (neuroendocrine secretion; P < 0.01), with no effect on monoamine oxidase A (serotonin catabolism), serotonin receptor 5-HT4, or mouse serotonin transporter. HM and CR mice also had increased colonic Tph1 protein (P < 0.05) and 5-HT concentrations (GF, 17 ± 3 ng/mg; HM, 25 ± 2 ng/mg; and CR, 35 ± 3 ng/mg; P < 0.05). Enterochromaffin (EC) cell numbers (cells producing 5-HT) were unchanged. Short-chain fatty acids (SCFAs) promoted TPH1 transcription in BON cells (human EC cell model). Thus, gut microbiota acting through SCFAs are important determinants of enteric 5-HT production and homeostasis.
Topics: Animals; Cell Count; Cell Line; Chromogranin A; Colon; Digestive System; Enterochromaffin Cells; Fatty Acids, Volatile; Female; Gastrointestinal Motility; Germ-Free Life; Humans; Male; Mice; Microbiota; RNA, Messenger; Serotonin; Signal Transduction; Tryptophan Hydroxylase
PubMed: 25550456
DOI: 10.1096/fj.14-259598 -
The International Journal of... May 2021Sensory nerve endings within the wall of the gastrointestinal (GI) tract may respond to bacterial signalling, providing the basis for key biological processes that... (Review)
Review
Sensory nerve endings within the wall of the gastrointestinal (GI) tract may respond to bacterial signalling, providing the basis for key biological processes that underlie intestinal motility and microbial homeostasis. Enteric neurons and smooth muscle cells are well known to express an array of receptors, including G-protein coupled receptors and ligand-gated ion channels, that can sense chemical ligands and other bacterially-derived substances. These include short chain fatty acids, secondary bile acids and lipopolysaccharide. For neural detection of microbial activators to occur, luminal substances must first interact with enterocytes for direct signalling or cross paracellularly. Recent studies indicate that bacterial-derived microvesicles can cross the gut epithelial barrier and affect motility. This suggests a possible intercellular communication pathway between the GI tract and the ENS. We explore the idea that bacterial microvesicles can behave as a delivery package for communication between microbe and host.
Topics: Animals; Bacteria; Biological Phenomena; Colon; Gastrointestinal Motility; Gastrointestinal Tract; Humans; Receptors, G-Protein-Coupled; Sensory Receptor Cells; Signal Transduction
PubMed: 33636395
DOI: 10.1016/j.biocel.2021.105963 -
Nutrients Jan 2015Globally, zinc deficiency is widespread, despite decades of research highlighting its negative effects on health, and in particular upon child health in low-income... (Review)
Review
Globally, zinc deficiency is widespread, despite decades of research highlighting its negative effects on health, and in particular upon child health in low-income countries. Apart from inadequate dietary intake of bioavailable zinc, other significant contributors to zinc deficiency include the excessive intestinal loss of endogenously secreted zinc and impairment in small intestinal absorptive function. Such changes are likely to occur in children suffering from environmental (or tropical) enteropathy (EE)-an almost universal condition among inhabitants of developing countries characterized by morphologic and functional changes in the small intestine. Changes to the proximal gut in environmental enteropathy will likely influence the nature and amount of zinc delivered into the large intestine. Consequently, we reviewed the current literature to determine if colonic absorption of endogenous or exogenous (dietary) zinc could contribute to overall zinc nutriture. Whilst we found evidence that significant zinc absorption occurs in the rodent colon, and is favoured when microbially-fermentable carbohydrates (specifically resistant starch) are consumed, it is unclear whether this process occur in humans and/or to what degree. Constraints in study design in the few available studies may well have masked a possible colonic contribution to zinc nutrition. Furthermore these few available human studies have failed to include the actual target population that would benefit, namely infants affected by EE where zinc delivery to the colon may be increased and who are also at risk of zinc deficiency. In conducting this review we have not been able to confirm a colonic contribution to zinc absorption in humans. However, given the observations in rodents and that feeding resistant starch to children is feasible, definitive studies utilising the dual stable isotope method in children with EE should be undertaken.
Topics: 6-Phytase; Animals; Biological Availability; Colon; Homeostasis; Humans; Hydrolysis; Intestine, Small; Models, Animal; Phytic Acid; Zinc
PubMed: 25594440
DOI: 10.3390/nu7010572 -
World Journal of Gastroenterology Feb 2012Epithelial-to-mesenchymal and mesenchymal-to-epithelial transitions are well established biological events which have an important role in not just normal tissue and... (Review)
Review
Epithelial-to-mesenchymal and mesenchymal-to-epithelial transitions are well established biological events which have an important role in not just normal tissue and organ development, but in the pathogenesis of diseases. Increasing evidence has established their presence in the human colon during colorectal carcinogenesis and cancer invasion, chronic inflammation-related fibrosis and in the course of mucosal healing. A large body of evidence supports the role for transforming growth factor-β and its downstream Smad signaling, the phosphatidylinositol 3'-kinase/Akt/mTOR axis, the Ras-mitogen-activated protein kinase/Snail/Slug and FOXC2 pathway, and Hedgehog signaling and microRNAs in the development of colorectal cancers via epithelial-to-mesenchymal transition. C-met and Frizzled-7, among others, seem to be the principle effectors of mesenchymal-to-epithelial transition, hence have a role not just in mucosal regeneration but in the progression of colonic wall fibrosis. Here we discuss a role for these pathways in the initiation and development of the transition events. A better understanding of their induction and regulation may lead to the identification of pathways and factors that could be potent therapeutic targets. The inhibition of epithelial-to-mesenchymal transition using mTOR kinase inhibitors targeting the ATP binding pocket and which inhibit both mTORC1 and mTORC2, RNA aptamers or peptide mimetics, such as a Wnt5A-mimetic, may all be useful in both cancer treatment and delaying fibrosis, while the induction of mesenchymal-to-epithelial transition in induced pluripotent stem cells may enhance epithelial healing in the case of severe mucosal damage. The preliminary results of the current studies are promising, but more clinical investigations are needed to develop new and safe therapeutic strategies for diseases of the colon.
Topics: Colon; Colonic Diseases; Epithelial-Mesenchymal Transition; Humans; Signal Transduction
PubMed: 22363130
DOI: 10.3748/wjg.v18.i7.601 -
Canadian Journal of Gastroenterology &... 2018Colon cancer is still one of the most common causes of cancer in human and is characterized by lymphocyte infiltrates and originates from the epithelial cells found in... (Review)
Review
Colon cancer is still one of the most common causes of cancer in human and is characterized by lymphocyte infiltrates and originates from the epithelial cells found in the lining of colon or rectum of the gastrointestinal tract. Mesenchymal stem cells (MSCs) are composed of the multipotent stem cell group of stroma and can be differentiated as various cell lineages, such as fibroblasts, osteoblasts, and adipocytes. MSCs provide mechanical and structural support and have potential functions during tumor growth and metastasis. The efficacy of MSC-based therapies is partly dependent on the migration and homing of MSCs to tumors and metastatic sites. However, their migratory and engraftment potential is poorly understood. In this review, the characteristics and mechanisms of MSC's dynamic interaction with colon cancer were summarized, particularly the potential functions of MSCs on colon cancer, including its role in improving tumor growth and as a potential candidate for tumor therapy. Understanding MSC homing provides new insights into the manipulation of MSC and the improvement of their efficacy for colon cancer therapy.
Topics: Cell Differentiation; Colon; Colonic Neoplasms; Humans; Mesenchymal Stem Cell Transplantation; Mesenchymal Stem Cells
PubMed: 30533404
DOI: 10.1155/2018/7628763 -
The Journal of Surgical Research Jan 2024Concurrent colonic injury among patients with gunshot-related fractures presents a potential risk for infectious complications. We hypothesized that colon injuries are... (Review)
Review
INTRODUCTION
Concurrent colonic injury among patients with gunshot-related fractures presents a potential risk for infectious complications. We hypothesized that colon injuries are associated with more infectious orthopedic complications among gunshot victims with concurrent fractures.
MATERIALS AND METHODS
We reviewed trauma patients arriving at our level 1 trauma center from January 1, 2019 to May 31, 2022 who suffered any gunshot-related fracture and also underwent an exploratory laparotomy. Of these patients, those with colon injuries were compared to those without colon injuries. Baseline characteristics, including antibiotic regimens, were collected in addition to outcomes of length of stay, intensive care unit admission, ventilator requirement, and development of infectious orthopedic complications.
RESULTS
Overall, 56 of the 107 included patients had colon injuries. Age, sex, race/ethnicity, and Injury Severity Score were similar between groups. Of patients with colonic injuries, 16.1% received early, repeat dosing of broad-spectrum antibiotics, while only 3.9% of patients without colonic injuries received this antibiotic dosing (P = 0.04). Interestingly, only patients with colon injuries developed infectious orthopedic complications and none of the patients without colon injuries developed such complications (10.7% versus 0.0%, P = 0.03). All patients with orthopedic infections had infected pelvic fractures. Length of stay was 3 d longer in the colon injury group (P = 0.04). There was no difference in intensive care unit admission, ventilator requirement, or death.
CONCLUSIONS
Concurrent colon injuries among patients with gunshot-related fractures are associated with higher risk of infectious orthopedic complications, likely from direct spread of fecal contaminant. Early, broad-spectrum antibiotics may be associated with reduced infectious orthopedic complications.
Topics: Humans; Retrospective Studies; Fractures, Bone; Hospitalization; Colon; Anti-Bacterial Agents; Abdominal Injuries; Thoracic Injuries; Wounds, Gunshot
PubMed: 37774592
DOI: 10.1016/j.jss.2023.09.042 -
The British Journal of Radiology Nov 2012Colorectal cancer is often preventable if the precursor adenoma is detected and removed. Although ultrasound is clearly not one of the widely accepted screening... (Review)
Review
Colorectal cancer is often preventable if the precursor adenoma is detected and removed. Although ultrasound is clearly not one of the widely accepted screening techniques, this non-invasive and radiation-free modality is also capable of detecting colonic polyps, both benign and malignant. Such colon lesions may be encountered when not expected, usually during general abdominal sonography. The discovery of large colonic polyps is important and can potentially help reduce the incidence of a common cancer, whereas detection of a malignant polyp at an early stage may result in a curative intervention. This pictorial review highlights our experience of sonographic detection of colonic polyps in 43 adult patients encountered at our institutions over a 2-year period. 4 out of 50 discovered polyps were found to be malignant lesions, 3 polyps were hyperplastic, 1 polyp was a hamartomatous polyp and the rest were benign adenomas. The smallest of the detected polyps was 1.3 cm in diameter, the largest one was 4.0 cm (mean 1.7 cm; median 1.6 cm). In each case, polyps were discovered during a routine abdominal or pelvic examination, particularly when scanning was supplemented by a brief focused sonographic inspection of the colon with a 6-10 MHz linear transducer. In this paper, we illustrate the key sonographic features of different types of commonly encountered colonic polyps in the hope of encouraging more observers to detect these lesions, which may be subtle.
Topics: Adult; Colon; Colonic Polyps; Humans; Ultrasonography
PubMed: 22806624
DOI: 10.1259/bjr/60593124 -
MBio Jul 2019We have previously identified a crypt-specific core microbiota (CSCM) in the colons of healthy laboratory mice and related wild rodents. Here, we confirm that a CSCM...
We have previously identified a crypt-specific core microbiota (CSCM) in the colons of healthy laboratory mice and related wild rodents. Here, we confirm that a CSCM also exists in the human colon and appears to be altered during colon cancer. The colonic microbiota is suggested to be involved in the development of colorectal cancer (CRC). Because the microbiota identified in fecal samples from CRC patients does not directly reflect the microbiota associated with tumor tissues themselves, we sought to characterize the bacterial communities from the crypts and associated adjacent mucosal surfaces of 58 patients (tumor and normal homologous tissue) and 9 controls with normal colonoscopy results. Here, we confirm that bacteria colonize human colonic crypts in both control and CRC tissues, and using laser-microdissected tissues and 16S rRNA gene sequencing, we further show that right and left crypt- and mucosa-associated bacterial communities are significantly different. In addition to and , and as with murine proximal colon crypts, environmental nonfermentative are found in human colonic crypts. and are more abundant in right-side tumors, whereas is more prevalent in left-side tumors. More precisely, is more abundant in crypts from cancerous samples in the right colon than in associated nontumoral samples from adjacent areas but not in left-side colonic samples. Future analysis of the interaction between these bacteria and the crypt epithelium, particularly intestinal stem cells, will allow deciphering of their possible oncogenic potential. Due to the huge number of bacteria constituting the human colon microbiota, alteration in the balance of its constitutive taxa (i.e., dysbiosis) is highly suspected of being involved in colorectal oncogenesis. Indeed, bacterial signatures in association with CRC have been described. These signatures may vary if bacteria are identified in feces or in association with tumor tissues. Here, we show that bacteria colonize human colonic crypts in tissues obtained from patients with CRC and with normal colonoscopy results. Aerobic nonfermentative previously identified as constitutive of the crypt-specific core microbiota in murine colonic samples are similarly prevalent in human colonic crypts in combination with other anaerobic taxa. We also show that bacterial signatures characterizing the crypts of colonic tumors vary depending whether right-side or left-side tumors are analyzed.
Topics: Aged; Aged, 80 and over; Animals; Bacteria; Biodiversity; Colon; Colonic Neoplasms; Dysbiosis; Female; Gastrointestinal Microbiome; Gene Expression Profiling; Humans; In Situ Hybridization, Fluorescence; Male; Mice; Middle Aged; Neoplasm Staging; Real-Time Polymerase Chain Reaction; Tumor Burden
PubMed: 31311881
DOI: 10.1128/mBio.01315-19