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)

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.

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)

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.

Evaluation of the application of enemas containing sucralfate in tissue content of neutral and acid mucins in experimental model of diversion colitis

PURPOSE: To evaluate the effects of sucralfate on tissue content of neutral and acids mucins in rats with diversion colitis. METHODS: Thirty-six rats were submitted to a proximal right colostomy and a distal mucous fistula. They were divided into two groups according to sacrifice to be performed two or four weeks after intervention. Each group was divided into three subgroups according daily application of enemas containing saline, sucralfate at 1.0 g/kg/day or 2.0 g/kg/day. Colitis was diagnosed by histological analysis and neutral and acid mucins by Periodic Acid Schiff and Alcian Blue techniques, respectively. The contents of mucins were quantified by computer-assisted image analysis. Student's t paired and ANOVA test were used to compare the contents of both types of mucins among groups, and to verify the variance with time, establishing level of signification of 5% for both (p<0.05). RESULTS: Enemas containing sucralfate improves the inflammation and increases the tissue contents of neutral and acid mucins. The content of neutral mucins does not change with the time or concentration of sucralfate used, while acid mucins increases with concentration and time of intervention. CONCLUSIONS: Sucralfate enemas improve the inflammatory process and increase the tissue content of neutral and acid mucins in colon without fecal stream. .

Mucin secretion in the rat tracheal epithelial cells by epidermal growth factor and Pseudomonas aeruginosa extracts

BACKGROUND: Hypersecretion of mucin due to goblet cell hyperplasia is frequently encountered in many chronic airway diseases, such as chronic bronchitis, bronchiectasis, bronchial asthma and cystic fibrosis. Even in normal individuals, viral infection or bacterial pneumonia frequently provoke huge amounts of bronchial secretions which may cause airway obstruction. The production of mucin was regulated by epidermal growth factor (EGF) in vitro. To know whether this EGF system regulates mucin secretion in vivo and Pseudomonas also stimulates the mucin secretion by the same pathway, we studied these relationships in the cultured rat tracheal epithelial cells. METHODS: Rat tracheal epithelial cells were obtained by pronase dissociation from the male Fisher 344 rats. When cells became confluent, they were divided into 6 groups and stimulated with either EGF for 24 hours or Pseudomonas extracts for 12 hours with or without selective EGF-R tyrosine kinase inhibitor tyrphostin AG1478. RESULTS: We found that both EGF and Pseudomonas extracts phosphorylated the tyrosine residue in the EGF receptor from the rat tracheal epithelial cells and this tyrosine phosphorylation was nearly completely blocked by selective EGF-R tyrosine kinase inhibitor tyrphostin AG1478. The mucin secretion was also stimulated by either EGF or Pseudomonas extracts but more strong secretion of mucin and MUC5AC gene expression in the rat tracheal epithelial cell was done by Pseudomonas extracts. CONCLUSION: These data suggest that Pseudomonas secretes the mucin by way of the EGF receptor and MUC5AC gene expression and the inhibitors of EGF receptor tyrosine phosphorylation would be useful to prevent the huge production of mucin due to Pseudomonas aeruginosa lung infection.