Possible therapeutics for Pseudomyxoma peritonei: a rare, lethal, and the least investigated disease

Pseudomyxoma peritonei (PMP) refers to a growth disorder characterized by glycoprotein neoplasm in the peritoneum, where mucin oversecretion occurs. The tumors of the appendix region are well associated with PMP; however, ovarian, colon, stomach, pancreas, and urachus tumors have also been linked to PMP. Other mucinous tumors in the pelvis, paracolic gutters, greater omentum, retrohepatic space, and Treitz ligament can be the reason for PMP. Despite being rare and having a slow growth rate, PMP can be lethal without treatment. It is treated with neoadjuvant chemotherapy with the option of cytoreductive surgery and intraperitoneal chemotherapy. In the current study, we hypothesize that there may be novel gentle ways to inhibit or eliminate the mucin. Dr. David Morris has used mucolytics - such as bromelain and N-acetyl cysteine to solubilize mucin. In the present review, we aimed to study the regulation of mucin expression by promoter methylation, and drugs that can inhibit mucin, such as boldine, amiloride, naltrexone, dexamethasone, and retinoid acid receptors antagonist. This review also explored some possible pathways, such as inhibition of Na + , Ca2+ channels and induction of DNA methyltransferase along with inhibition of ten-eleven translocation enzymes, which can be good targets to control mucin. Mucins are strong adhesive molecules that play great roles in clinging to cells or cell to cell. Besides, they have been greatly involved in metastasis and also act as disease markers for cancers. Diagnostic markers may have exclusive roles in disease initiation and progression. Therefore, the present review explores various drugs to control and target mucin in various diseases, specifically cancers. (AU)

Rifaximin-α reduces gut-derived inflammation and mucin degradation in cirrhosis and encephalopathy: RIFSYS randomised controlled trial.

BACKGROUND & AIMS: Rifaximin-α is efficacious for the prevention of recurrent hepatic encephalopathy (HE), but its mechanism of action remains unclear. We postulated that rifaximin-α reduces gut microbiota-derived endotoxemia and systemic inflammation, a known driver of HE. METHODS: In a placebo-controlled, double-blind, mechanistic study, 38 patients with cirrhosis and HE were randomised 1:1 to receive either rifaximin-α (550 mg BID) or placebo for 90 days. PRIMARY OUTCOME: 50% reduction in neutrophil oxidative burst (OB) at 30 days. SECONDARY OUTCOMES: changes in psychometric hepatic encephalopathy score (PHES) and neurocognitive functioning, shotgun metagenomic sequencing of saliva and faeces, plasma and faecal metabolic profiling, whole blood bacterial DNA quantification, neutrophil toll-like receptor (TLR)-2/4/9 expression and plasma/faecal cytokine analysis. RESULTS: Patients were well-matched: median MELD (11 rifaximin-α vs. 10 placebo). Rifaximin-α did not lead to a 50% reduction in spontaneous neutrophil OB at 30 days compared to baseline (p = 0.48). However, HE grade normalised (p = 0.014) and PHES improved (p = 0.009) after 30 days on rifaximin-α. Rifaximin-α reduced circulating neutrophil TLR-4 expression on day 30 (p = 0.021) and plasma tumour necrosis factor-α (TNF-α) (p <0.001). Rifaximin-α suppressed oralisation of the gut, reducing levels of mucin-degrading sialidase-rich species, Streptococcus spp, Veillonella atypica and parvula, Akkermansia and Hungatella. Rifaximin-α promoted a TNF-α- and interleukin-17E-enriched intestinal microenvironment, augmenting antibacterial responses to invading pathobionts and promoting gut barrier repair. Those on rifaximin-α were less likely to develop infection (odds ratio 0.21; 95% CI 0.05-0.96). CONCLUSION: Rifaximin-α led to resolution of overt and covert HE, reduced the likelihood of infection, reduced oralisation of the gut and attenuated systemic inflammation. Rifaximin-α plays a role in gut barrier repair, which could be the mechanism by which it ameliorates bacterial translocation and systemic endotoxemia in cirrhosis. CLINICAL TRIAL NUMBER: ClinicalTrials.gov NCT02019784. LAY SUMMARY: In this clinical trial, we examined the underlying mechanism of action of an antibiotic called rifaximin-α which has been shown to be an effective treatment for a complication of chronic liver disease which effects the brain (termed encephalopathy). We show that rifaximin-α suppresses gut bacteria that translocate from the mouth to the intestine and cause the intestinal wall to become leaky by breaking down the protective mucus barrier. This suppression resolves encephalopathy and reduces inflammation in the blood, preventing the development of infection.

The pH Dependence of Niclosamide Solubility, Dissolution, and Morphology: Motivation for Potentially Universal Mucin-Penetrating Nasal and Throat Sprays for COVID19, its Variants and other Viral Infections.

MOTIVATION: With the coronavirus pandemic still raging, prophylactic-nasal and early-treatment throat-sprays could help prevent infection and reduce viral load. Niclosamide has the potential to treat a broad-range of viral infections if local bioavailability is optimized as mucin-penetrating solutions that can reach the underlying epithelial cells. EXPERIMENTAL: pH-dependence of supernatant concentrations and dissolution rates of niclosamide were measured in buffered solutions by UV/Vis-spectroscopy for niclosamide from different suppliers (AK Sci and Sigma), as precipitated material, and as cosolvates. Data was compared to predictions from Henderson-Hasselbalch and precipitation-pH models. Optical-microscopy was used to observe the morphologies of original, converted and precipitated niclosamide. RESULTS: Niclosamide from the two suppliers had different polymorphs resulting in different dissolution behavior. Supernatant concentrations of the "AKSci-polymorph" increased with increasing pH, from 2.53µM at pH 3.66 to 300µM at pH 9.2, reaching 703µM at pH 9.63. However, the "Sigma-polymorph" equilibrated to much lower final supernatant concentrations, reflective of more stable polymorphs at each pH. Similarly, when precipitated from supersaturated solution, or as cosolvates, niclosamide also equilibrated to lower final supernatant concentrations. Polymorph equilibration though was avoided by using a solvent-exchange technique to make the solutions. CONCLUSIONS: Given niclosamide's activity as a host cell modulator, optimized niclosamide solutions could represent universal prophylactic nasal and early treatment throat sprays against COVID19, its more contagious variants, and other respiratory viral infections. They are the simplest and potentially most effective formulations from both an efficacy standpoint as well as manufacturing and distribution, (no cold chain). They now just need testing.

Evaluation of the toxicity of sodium dodecyl sulphate (SDS) in the MucilAir™ human airway model in vitro.

The aim of the study was to use multiple in vitro assays to assess the effects of a model irritant, sodium dodecyl sulphate (SDS) (≤10 mM (0.29 %, w/v)), on an in vitro model of the airway, MucilAir™. The use of MucilAir™ in recovery studies was also explored. A 24 h exposure increased IL-8 release at an SDS concentration ≥0.63 mM (0.018 %, w/v). Mucin secretion increased and transepithelial electrical resistance (TEER) decreased at SDS concentrations ≥1.25 mM (0.04 %, w/v). Cytotoxicity (lactate dehydrogenase (LDH) release into basolateral chamber) was observed at SDS concentrations of ≥2.5 mM (0.07 %, w/v). The sensitivity of the assays was IL-8 release > TEER = mucin secretion > LDH release. After 7 days, full or partial recovery was observed for intermediate concentrations of SDS using all assays but not at 5 and 10 mM SDS. Morphologically, erosion and cell loss were observed at these concentrations. Resazurin metabolism at 7 days tended to decrease in a dose-dependent manner at SDS concentrations above 2.5 mM (0.07 %, w/v). Together, these data support a No Observable Effect Level of 0.31 mM (0.009 % w/v) SDS and the use of MucilAir™ as a relevant model for airway toxicity studies.

An ovary-specific mucin is associated with choriogenesis mediated by prostaglandin signaling in Spodoptera exigua.

Polytrophic ovarioles of Spodoptera exigua, a lepidopteran insect, begins with the development of oocytes and differentiation of nurse cells followed by vitellogenesis and choriogenesis. Compared with previtellogenic and vitellogenic developments, choriogenesis has not been clearly understood yet in endocrine control. This study investigated the expression and function of a mucin-like structural protein of S. exigua called Se-Mucin1 in choriogenesis. It was highly expressed in ovarioles containing chorionated oocytes. The expression level of Se-Mucin1 was increased during adult stage as early as 18 h after adult emergence, reaching the maximal level at 24 h and later. Interestingly, DNA amount of Se-Mucin1 was increased by almost four folds during early adult stage while other genes (hexokinase and glyceraldehyde-3-phosphate dehydrogenase) not directly associated with chorion formation did not show genomic DNA increase, suggesting specific gene amplification of Se-Mucin1. RNA interference (RNAi) suppressed Se-Mucin1 expression by injecting 1 µg of double-strand RNA to teneral females (<5 h after emergence), which exhibited significantly impaired fecundity and egg hatching rate. Eggs laid by RNAi-treated females were malformed in eggshell structures with loss of mesh-like fibers. Treatment with aspirin, a prostaglandin (PG) biosynthesis inhibitor, suppressed the induction of Se-Mucin1 expression during early adult stage and impaired egg development. An addition of PGE2 significantly rescued such impairment in Se-Mucin1 expression and subsequent egg development. These results suggest that PGs mediate choriogenesis of S. exigua by activating the expression of chorion-associated genes including Se-Mucin1.

Functional redundancy of structural proteins of the peritrophic membrane in Trichoplusia ni.

The peritrophic membrane (or peritrophic matrix) (PM) in insects is formed by binding of PM proteins with multiple chitin binding domains (CBDs) to chitin fibrils. Multi-CBD chitin binding proteins (CBPs) and the insect intestinal mucin (IIM) are major PM structural proteins. To understand the biochemical and physiological role of IIM in structural formation and physiological function of the PM, Trichoplusia ni mutant strains lacking IIM were generated by CRISPR/Cas9 mutagenesis. The mutant T. ni larvae were confirmed to lack IIM, but PM formation was observed as in wild type larvae and lacking IIM in the PM did not result in changes of protease activities in the larval midgut. Larval growth and development of the mutant strains were similar to the wild type strain on artificial diet and cabbage leaves, but had a decreased survival in the 5th instar. The larvae of the mutant strains with the PM formed without IIM did not have a change of susceptibility to the infection of the baculovirus AcMNPV and the Bacillus thuringiensis (Bt) formulation Dipel, to the toxicity of the Bt toxins Cry1Ac and Cry2Ab and the chemical insecticide sodium aluminofluoride. Treatment of the mutant T. ni larvae with Calcofluor reduced the larval susceptibility to the toxicity of Bt Cry1Ac, as similarly observed in the wild type larvae. Overall, in the mutant T. ni larvae, the PM was formed without IIM and the lacking of IIM in the PM did not drastically impact the performance of larvae on diet or cabbage leaves under the laboratory conditions.

Aberrant MUC1 accumulation in salivary glands of Sjögren's syndrome patients is reversed by TUDCA in vitro.

OBJECTIVES: Xerostomia in SS patients has been associated with low quality and quantity of salivary mucins, which are fundamental for the hydration and protection of the oral mucosa. The aim of this study was to evaluate if cytokines induce aberrant mucin expression and whether tauroursodeoxycholic acid (TUDCA) is able to counteract such an anomaly. METHODS: Labial salivary glands from 16 SS patients and 15 control subjects, as well as 3D acini or human submandibular gland cells stimulated with TNF-α or IFN-γ and co-incubated with TUDCA, were analysed. mRNA and protein levels of Mucin 1 (MUC1) and MUC7 were determined by RT-qPCR and western blot, respectively. Co-immunoprecipitation and immunofluorescence assays for mucins and GRP78 [an endoplasmic reticulum (ER)-resident protein] were also performed. mRNA levels of RelA/p65 (nuclear factor-κB subunit), TNF-α, IL-1ß, IL-6, SEL1L and EDEM1 were determined by RT-qPCR, and RelA/p65 localization was evaluated by immunofluorescence. RESULTS: MUC1 is overexpressed and accumulated in the ER of labial salivary gland from SS patients, while MUC7 accumulates throughout the cytoplasm of acinar cells; however, MUC1, but not MUC7, co-precipitated with GRP78. TUDCA diminished the overexpression and aberrant accumulation of MUC1 induced by TNF-α and IFN-γ, as well as the nuclear translocation of RelA/p65, together with the expression of inflammatory and ER stress markers in 3D acini. CONCLUSION: Chronic inflammation alters the secretory process of MUC1, inducing ER stress and affecting the quality of saliva in SS patients. TUDCA showed anti-inflammatory properties decreasing aberrant MUC1 accumulation. Further studies are necessary to evaluate the potential therapeutic effect of TUDCA in restoring glandular homeostasis in SS patients.

Enemas with mesalazine increase the tissue contents of mucins in the colonic mucosa devoid of fecal stream.

PURPOSE: To evaluate the inflammatory reaction and measure the content of mucins, in the colonic mucosa without fecal stream submit to intervention with mesalazine. METHODS: Twenty-four rats were submitted to a left colostomy and a distal mucous fistula and divided into two groups according to euthanasia to be performed two or four weeks. Each group was divided into two subgroups according daily application of enemas containing saline or mesalazine at 1.0 g/kg/day. Colitis was diagnosed by histological analysis and the inflammatory reaction by validated score. Acidic mucins and neutral mucins were determined with the alcian-blue and periodic acid of Schiff techniques, respectively. Sulfomucin and sialomucin were identified by high iron diamine-alcian blue technique. The tissue contents of mucins were quantified by computer-assisted image analysis. Mann-Whitney test was used to analyze the results establishing the level of significance of 5%. RESULTS: Enemas with mesalazine in colonic segments without fecal stream decreased the inflammation score and increased the tissue content of all subtypes of mucins. The increase of tissue content of neutral, acid and sulfomucin was related to the time of intervention. CONCLUSION: Mesalazine enemas reduce the inflammatory process and preserve the content of mucins in colonic mucosa devoid of fecal stream.

Desmoglein 3 Silencing Inhibits Inflammation and Goblet Cell Mucin Secretion in a Mouse Model of Chronic Rhinosinusitis via Disruption of the Wnt/ß-Catenin Signaling Pathway.

Chronic rhinosinusitis (CRS) is a common disease characterized by inflammation of the nose and paranasal sinuses lasting over 12 weeks. This study aims to evaluate the effect of desmoglein 3 (DSG3) on inflammatory response and goblet cell mucin secretion in a mouse model of CRS. The CRS-related differentially expressed genes and disease genes were screened using microarray-based gene expression analysis. Subsequently, CRS mouse models were established. The levels of pro-inflammatory factors TNF-α, IL-6, and IL-8 were measured by ELISA. In addition, loss-of-function experiment was conducted using siRNAs targeting DSG3 and ß-catenin. The secretion of mucins MUC5B and MUC5AC in goblet cells was detected, and the apoptosis of goblet cells was assessed. The regulatory effect of DSG3 on the Wnt/ß-catenin signaling pathway was analyzed by determining the mRNA and protein levels of DSG3, Wnt, ß-catenin, and GSK3ß. DSG3 was identified to be an upregulated gene in CRS, which was further documented in CRS mice models. Elevated inflammation and mucin production were noted in CRS mice models. Also, it was found that DSG3 or ß-catenin silencing could decrease the levels of TNF-α, IL-6, and IL-8, and the positive rates of MUC5B and MUC5AC while enhancing goblet cell apoptosis. The Wnt/ß-catenin signaling pathway was blocked by DSG3, evidenced by downregulated Wnt and ß-catenin as well as upregulated GSK3ß mRNA and protein levels. Overall, this study provides evidence that silencing DSG3 could inhibit the activation of the Wnt/ß-catenin signaling pathway, thus alleviating CRS.

Effects of a probiotic on the morphology and mucin composition of pig intestine.

Although the use of probiotics in human and animal medicine is growing, their mode of action remains poorly understood. This study examined the effects of a multi-strain probiotic (SLAB51™) on the morphology and carbohydrate composition of mucins secreted by goblet cells of intestinal crypts in growing-finishing pigs. Sections of duodenum, caecum and colon from pigs fed for 12 weeks with an orally administered control basal diet (No-Pro) or one with a probiotic blend (Pro) were processed for microscopic analysis and stained with (1) haematoxylin-eosin for structural and morphometrical investigation; (2) conventional histochemistry (periodic acid-Schiff, Alcian Blue pH 2.5, high iron diamine staining) for neutral, acidic non-sulphated, and sulphated mucin analysis; and (3) FITC-labelled MAA-II and SNA lectins for α2,3- and α2,6-sialomucin identification. Compared with No-Pro samples, Pro samples displayed (1) increased goblet cell numbers in all investigated tract crypts; (2) an increase in acidic non-sulphomucins but a decrease in neutral, sulphated and α2,6-sialomucin-secreting goblet cells in the duodenum; (3) decreased crypt depth, an increase in α2,6-sialomucin secretory goblet cells, and a loss of goblet cell-secreting α2,3-sialomucins, which appeared on the apical surface of crypt fundus epithelial cells in the caecum; and (4) an increase in α2,6-sialomucin-producing goblet cells in the colon. Results suggest that treatment with SLAB51™ induces region-specific changes in the morphology and carbohydrate composition of mucins secreted along intestinal tracts of growing-finishing pigs. These changes could ameliorate the health status of the animals, which displayed higher growth performance and meat quality than controls (Tufarelli et al., 2017).

The role of mucins in mucositis.

PURPOSE OF REVIEW: Alimentary mucositis is a severe dose limiting side effect of chemotherapy and radiotherapy. Mucin expression and secretion are associated with mucositis. This article aims to review current studies involving mucin and mucositis. RECENT FINDINGS: Mucins have been shown to alter mucositis severity and key targets associated with mucositis. First, interventions increasing mucin content has been associated with reduce damage associated with mucositis. Second, mucins have also been shown to protect microbiota from radiation-induced damage. Finally, mucins have also been shown to be involved in lumen epithelial barrier interactions altering signalling for cell proliferation, motility, and the inhibition of apoptosis. SUMMARY: The current studies suggest that mucin expression prior to and during mucositis may be very important in reducing the severity of mucositis and further research into the area is warranted.

Enemas with mesalazine increase the tissue contents of mucins in the colonic mucosa devoid of fecal stream

Abstract Purpose: To evaluate the inflammatory reaction and measure the content of mucins, in the colonic mucosa without fecal stream submit to intervention with mesalazine. Methods: Twenty-four rats were submitted to a left colostomy and a distal mucous fistula and divided into two groups according to euthanasia to be performed two or four weeks. Each group was divided into two subgroups according daily application of enemas containing saline or mesalazine at 1.0 g/kg/day. Colitis was diagnosed by histological analysis and the inflammatory reaction by validated score. Acidic mucins and neutral mucins were determined with the alcian-blue and periodic acid of Schiff techniques, respectively. Sulfomucin and sialomucin were identified by high iron diamine-alcian blue technique. The tissue contents of mucins were quantified by computer-assisted image analysis. Mann-Whitney test was used to analyze the results establishing the level of significance of 5%. Results: Enemas with mesalazine in colonic segments without fecal stream decreased the inflammation score and increased the tissue content of all subtypes of mucins. The increase of tissue content of neutral, acid and sulfomucin was related to the time of intervention. Conclusion: Mesalazine enemas reduce the inflammatory process and preserve the content of mucins in colonic mucosa devoid of fecal stream.

Sulfated vizantin suppresses mucin layer penetration dependent on the flagella motility of Pseudomonas aeruginosa PAO1.

Pseudomonas aeruginosa is an opportunistic pathogen that causes severe infections, such as pneumonia and bacteremia. Several studies demonstrated that flagellar motility is an important virulence factor for P. aeruginosa infection. In this study, we determined whether sulfated vizantin affects P. aeruginosa flagellar motility in the absence of direct antimicrobial activity. We found that 100 µM sulfated vizantin suppressed P. aeruginosa PAO1 from penetrating through an artificial mucin layer by affecting flagellar motility, although it did not influence growth nor bacterial protease activity. To further clarify the mechanism in which sulfated vizantin suppresses the flagellar motility of P. aeruginosa PAO1, we examined the effects of sulfated vizantin on the composition of the flagellar filament and mRNA expression of several flagella-related genes, finding that sulfated vizantin did not influence the composition of the flagellar complex (fliC, motA, and motB) in P. aeruginosa PAO1, but significantly decreased mRNA expression of the chemotaxis-related genes cheR1, cheW, and cheZ. These results indicated that sulfated vizantin is an effective inhibitor of flagellar motility in P. aeruginosa.

Anti-allergic effects of sesquiterpene lactones from Saussurea costus (Falc.) Lipsch. determined using in vivo and in vitro experiments.

ETHNOPHARMACOLOGICAL RELEVANCE: Saussurea costus (Falc.) Lipsch. root has been used in Asian traditional medicine for the treatment of asthma, rheumatism, and other conditions. S. costus extracts were shown to alleviate house dust mite-induced atopic-like dermatitis in Nc/Nga mice; besides, sesquiterpene lactones were isolated from S. costus extracts. AIMS OF THE STUDY: We aimed to investigate the effects of sesquiterpene lactones (alantolactone, costunolide, and dehydrocostuslactone) in allergic asthma using female Balb/c mice and rat RBL-2H3 mast cells. MATERIALS AND METHODS: Antigen-induced degranulation was assessed by measuring ß-hexosaminidase activity in vitro. In addition, a murine ovalbumin-induced allergic asthma model was used to test the in vivo efficacy of sesquiterpene lactones. RESULTS: Sesquiterpene lactones inhibited antigen-induced degranulation, wherein dehydrocostuslactone > costunolide > alantolactone in potency. Administration of sesquiterpene lactones decreased the number of immune cells, particularly eosinophils, and reduced the expression and secretion of Th2 cytokines (IL-4 and IL-13) in the bronchoalveolar lavage fluid and lung tissues of mice with ovalbumin-induced allergic asthma. Histological studies showed that sesquiterpene lactones reduced inflammation and mucin production in the lungs. Similar to the in vitro study, dehydrocostuslactone showed the highest potency, followed by costunolide and alantolactone. CONCLUSION: These findings provide evidence that sesquiterpene lactones might be potential anti-allergic therapeutics.

Influence of the application of enemas with oily extract of curcumin (Curcuma longa) on the tissue content of neutral and acidic mucins in the colonic mucosa without fecal stream / Influência da aplicação de clisteres contendo extrato oleoso de curcumina (Curcuma longa) no conteúdo tecidual de mucinas neutras e ácidas na mucosa cólica sem trânsito intestinal

ABSTRACT Purpose: To verify if the application of enemas containing oily extracts of curcumin preserves the tissue content of mucins in the glands of the colonic mucosa without fecal stream. Method: Thirty-six Wistar rats were submitted to diversion of the fecal stream by proximal colostomy and distal mucous fistula. The animals were subdivided into three groups, and accordingly received enemas with saline and oily extract of curcumin at concentrations of 50 mg/kg/day or 200 mg/kg/day. After two or four weeks of intervention, the irrigated colic segments were removed. Neutral and acidic mucins were identified by Periodic-acid Schiff and Alcian-Blue techniques, respectively. The content of both mucin subtypes was measured by computerized morphometry. Mann-Whitney test was used to analyze the results, adopting a significance level of 5% (p ≤ 0.05). Results: There was an increase in the tissue content of neutral mucins in animals treated with curcumin at a concentration of 50 mg/kg/day for four weeks, whereas in the group treated with 200 mg/kg/day there was an increase independent of the time of intervention. The content of acidic mucins increased in animals treated with 200 mg/kg/day regardless of the intervention time, whereas in those treated with 50 mg/kg/day an increase was observed only after four weeks. Conclusion: Enemas with curcumin preserve the content of neutral and acidic mucins in the colonic epithelium without fecal stream.

RESUMO Objetivo: Verificar se a aplicação de clisteres com extrato oleoso de curcumina preserva o conteúdo de mucinas nas glândulas da mucosa cólica sem trânsito intestinal. Método: Trinta e seis ratos Wistar foram submetidos à derivação intestinal por colostomia proximal e fístula mucosa distal. Os animais foram subdivididos em três grupos, segundo receberem clisteres com soro fisiológico 0,9%, extrato oleoso de curcumina nas concentrações de 50 mg/kg/dia ou 200 mg/kg/dia. Após duas ou quatro semanas de intervenção foram removidos os segmentos cólicos irrigados. As mucinas neutras e ácidas foram identificadas pelas técnicas do PAS e Alcian-Blue, respectivamente. O conteúdo tecidual de ambos os subtipos de mucinas foi mensurado por morfometria computadorizada. Utilizou-se teste de Mann-Whitney para análise dos resultados adotando-se nível de significância de 5% (p ≤ 0,05). Resultados: Houve aumento no conteúdo de mucinas neutras nos animais tratados com curcumina na concentração de 50 mg/kg/dia por quatro semanas, enquanto nos tratados com 200 mg/kg/dia houve aumento independente do tempo de intervenção. O conteúdo de mucinas ácidas aumentou nos animais tratados com 200 mg/kg/dia independente do tempo de intervenção, enquanto nos tratados com 50 mg/kg/dia encontrou-se aumento apenas após quatro semanas. Conclusão: Clisteres com curcumina preservam o conteúdo de mucinas neutras e ácidas no epitélio cólico sem trânsito intestinal.

Tissue sulfomucin and sialomucin content in colon mucosa without intestinal transit subjected to intervention with Curcuma longa (curcumin).

PURPOSE:: To measure the tissue sulfomucin and sialomucin content of the colon mucosa without fecal flow, subjected to intervention with curcumin, and the influence of the concentration used and the intervention time. METHODS:: Thirty-six rats were subjected to proximal right colostomy and distal mucous fistula. They were divided into two groups according to whether sacrifice was performed two or four weeks after the intervention. Each group was divided into three subgroups according to the enema applied daily: saline alone; curcumin at 50 mg/kg/day or curcumin at 200 mg/kg/day. Acid mucins were diagnosed using the Alcian blue technique. The mucin content was quantified by means of computer-assisted image analysis. The significance level of 5% was used throughout (p < 0.05). RESULTS:: There were dose-related increases in the quantities of sulfomucins in the animals subjected to interventions with curcumin, both after two weeks (p < 0.00001) and after four weeks (p < 0.00001). There were increases in sialomucin quantity that were concentration-related (p < 0.00001) and time-related (p < 0.00001). CONCLUSION:: Curcumin enemas increase the quantity of acid mucins in the intestinal flow in the excluded colon, with dose and time dependency.

Tissue sulfomucin and sialomucin content in colon mucosa without intestinal transit subjected to intervention with Curcuma longa (curcumin)

Abstract Purpose: To measure the tissue sulfomucin and sialomucin content of the colon mucosa without fecal flow, subjected to intervention with curcumin, and the influence of the concentration used and the intervention time. Methods: Thirty-six rats were subjected to proximal right colostomy and distal mucous fistula. They were divided into two groups according to whether sacrifice was performed two or four weeks after the intervention. Each group was divided into three subgroups according to the enema applied daily: saline alone; curcumin at 50 mg/kg/day or curcumin at 200 mg/kg/day. Acid mucins were diagnosed using the Alcian blue technique. The mucin content was quantified by means of computer-assisted image analysis. The significance level of 5% was used throughout (p < 0.05). Results: There were dose-related increases in the quantities of sulfomucins in the animals subjected to interventions with curcumin, both after two weeks (p < 0.00001) and after four weeks (p < 0.00001). There were increases in sialomucin quantity that were concentration-related (p < 0.00001) and time-related (p < 0.00001). Conclusion: Curcumin enemas increase the quantity of acid mucins in the intestinal flow in the excluded colon, with dose and time dependency.

Uridine stimulate laxative effect in the loperamide-induced constipation of SD rats through regulation of the mAChRs signaling pathway and mucin secretion.

BACKGROUND: Uridine (Urd), which has been reported as a major component of RNA, plays an important role in various biological process including neuroprotection, biochemical modulation and glycolysis, although its role in constipation has yet to be established. Therefore, in this study, we investigated the laxative effects of Urd on chronic constipation. METHODS: The constipation phenotypes and their related mechanisms were investigated in the transverse colons of SD rats with loperamide (Lop)-induced constipation after treatment with 100 mg/kg of Urd. RESULTS: The number, weight and water contents of stools were significantly higher in the Lop + Urd treated group than the Lop + Vehicle treated group, while food intake and water consumption of the same group were maintained at a constant level. The thickness of the mucosa layer, muscle and flat luminal surface, as well as the number of goblet cells, paneth cells and lipid droplets were enhanced in the Lop + Urd treated group. Furthermore, the expression of the muscarinic acetylcholine receptors M2 and M3 (mAChR M2 and M3) at the transcriptional and translational level was recovered in the Lop + Urd treated group, while some markers such as Gα and inositol triphosphate (IP3) in their downstream signaling pathway were completely recovered by Urd treatment. Moreover, the ability for mucin secretion and the expression of membrane water channel (aquaporine 8, AQP8) were increased significantly in the Lop + Urd treated group compared with Lop + Vehicle treated group. Finally, the activity of Urd was confirmed in primary smooth muscle of rat intestine cells (pRISMC) based on Gα expression and IP3 concentration. CONCLUSIONS: The results of the present study provide the first strong evidence that Urd can be considered an important candidate for improving chronic constipation induced by Lop treatment in animal models.

Metformin Is Associated With Higher Relative Abundance of Mucin-Degrading Akkermansia muciniphila and Several Short-Chain Fatty Acid-Producing Microbiota in the Gut.

OBJECTIVE: Recent studies suggest the beneficial effects of metformin on glucose metabolism may be microbially mediated. We examined the association of type 2 diabetes, metformin, and gut microbiota in community-dwelling Colombian adults. On the basis of previous research, we hypothesized that metformin is associated with higher levels of short-chain fatty acid (SCFA)-producing and mucin-degrading microbiota. RESEARCH DESIGN AND METHODS: Participants were selected from a larger cohort of 459 participants. The present analyses focus on the 28 participants diagnosed with diabetes-14 taking metformin- and the 84 participants without diabetes who were matched (3-to-1) to participants with diabetes by sex, age, and BMI. We measured demographic information, anthropometry, and blood biochemical parameters and collected fecal samples from which we performed 16S rRNA gene sequencing to analyze the composition and structure of the gut microbiota. RESULTS: We found an association between diabetes and gut microbiota that was modified by metformin use. Compared with participants without diabetes, participants with diabetes taking metformin had higher relative abundance of Akkermansia muciniphila, a microbiota known for mucin degradation, and several gut microbiota known for production of SCFAs, including Butyrivibrio, Bifidobacterium bifidum, Megasphaera, and an operational taxonomic unit of Prevotella. In contrast, compared with participants without diabetes, participants with diabetes not taking metformin had higher relative abundance of Clostridiaceae 02d06 and a distinct operational taxonomic unit of Prevotella and a lower abundance of Enterococcus casseliflavus. CONCLUSIONS: Our results support the hypothesis that metformin shifts gut microbiota composition through the enrichment of mucin-degrading A. muciniphila as well as several SCFA-producing microbiota. Future studies are needed to determine if these shifts mediate metformin's glycemic and anti-inflammatory properties.

Mucolytic Agents Can Enhance HER2 Receptor Accessibility for [(89)Zr]Trastuzumab, Improving HER2 Imaging in a Mucin-Overexpressing Breast Cancer Xenograft Mouse Model.

PURPOSE: Binding of trastuzumab to HER2 receptors can be impaired by steric hindrance caused by mucin MUC4. As mucolytic drugs can breakdown disulfide bonds of mucoproteins, we checked if this approach could positively affect zirconium-89-labeled trastuzumab ([(89)Zr]T) binding/uptake. PROCEDURES: The effect of N-acetylcysteine (NAC) and MUC4 knockdown/stimulation on [(89)Zr]T binding/uptake were evaluated in MCF7(HER2-), BT474 and SKBr3(HER2+/MUC4-), and JIMT1(HER2+/MUC4+) cell lines. The results were then validated in SKBR3 and JIMT1 tumor-bearing nude mice with a microPET-CT and ex vivo analysis. RESULTS: Significant increases in [(89)Zr]T binding/uptake were observed in JIMT1 cells following MUC4 knockdown (62.4 ± 6.5%) and exposure to NAC (62.8 ± 19.4%). Compared to controls, mice treated with NAC showed a significant increase in [(89)Zr]T uptake in MUC4 tumors on microPET-CT (SUVmean (18.3 ± 4.7%), SUVmax (41.7 ± 8.4%)) and individual organ counting (37.3 ± 18.3%). In contrast, no significant differences were observed in SKBr3. CONCLUSION: NAC can enhance [(89)Zr]T accumulation and improve the HER2 imaging of MUC4-overexpressing tumors. The potential positive impact on trastuzumab-based treatment deserves further investigation.