BACKGROUND Obstructed defecation syndrome (ODS) represents the most prevalent form of chronic constipation, affecting a diverse patient population, leading to numerous complications, and imposing a significant burden on healthcare resources. Most ODS patients have insufficient rectal propulsion, but the exact mechanism underlying the pathogenesis of ODS remains unclear. AIM To explore the molecular mechanism underlying the pathogenesis of ODS. METHODS A total of 30 pairs of rectal samples were collected from patients with ODS (ODS group) or grade IV prolapsed hemorrhoids without constipation (control group) for quantitative proteomic and bioinformatic analysis. Subsequently, 50 pairs of paraffin-embedded rectal specimens were selected for immunohistochemistry and immunofluorescence studies to validate the analysis results. Human intestinal smooth cell contractile function experiments and electrophysiological experiments were conducted to verify the physiological functions of target proteins. Cellular ultrastructure was detected using transmission electron microscopy. RESULTS In comparison to the control group, the expression level of dystrophin (DMD) in rectal specimens from ODS patients was markedly reduced. This finding was corroborated using immunohistochemistry and immunofluorescence techniques. The diminished expression of DMD compromised the contractile function of intestinal smooth muscle cells. At the molecular level, nucleoporin protein 153 and L-type voltage-gated calcium channel were found to be overexpressed in intestinal smooth muscle cells exhibiting downregulated DMD expression. Electrophysiological experiments confirmed an excessive influx of calcium ions into these cells. Moreover, vacuolar-like structures which may be associated with excessive calcium influx were observed in the cells by transmission electron microscopy. CONCLUSION Decreased DMD expression in intestinal smooth muscle may upregulate L-type voltage-gated calcium channel expression, leading to excessive calcium influx which may cause a decrease in rectal propulsion, thereby contributing to the pathogenesis of ODS.
Background & AimsParenteral nutrition (PN) is a lifesaving therapy for patients with intestinal failure. Hepatic steatosis is a potentially fatal complication of long-term PN, but the involved pathological mechanisms are incompletely unclarified. Herein, we identify the role of protein phosphatase 2A (PP2A) in the pathogenesis of parenteral nutrition-associated hepatic steatosis (PNAHS).MethodsProteomic/phosphoproteomic analyses of liver samples from patients with PNAHS were applied to identify the mechanism of PNAHS. Total parenteral nutrition (TPN) mice model, in vivo, and in vitro experiments were used to assess the effect of PP2A-Cα on liver fatty acid metabolism.ResultsReduced expression of PP2A-Cα (catalytic subunit) enhanced activation of serine/threonine kinase Akt2 and decreased activation of adenosine monophosphate-activated protein kinase (AMPK) were associated with hepatic steatosis in patients with PNAHS. Mice given PN for 14 days developed hepatic steatosis, down-regulation of PP2A-Cα, activation of Akt2, and inhibition of AMPK. Hepatocyte-specific deletion of PP2A-Cα in mice given PN exacerbated Akt2 activation, AMPK inhibition, and hepatic steatosis through an effect on fatty acid degradation, whereas hepatocyte-specific PP2A-Cα overexpression significantly ameliorated hepatic steatosis accompanied with Akt2 suppression and AMPK activation. Additionally, pharmacological activation of Akt2 in mice overexpressing PP2A-Cα led to the aggravation of hepatic steatosis.ConclusionsOur findings demonstrate that hepatic PP2A-Cα serves as a protective factor of PNAHS due to ameliorating hepatic steatosis and improving liver function. Our study provides a strong rationale that PP2A-Cα may be involved in the pathogenesis of PNAHS. Parenteral nutrition (PN) is a lifesaving therapy for patients with intestinal failure. Hepatic steatosis is a potentially fatal complication of long-term PN, but the involved pathological mechanisms are incompletely unclarified. Herein, we identify the role of protein phosphatase 2A (PP2A) in the pathogenesis of parenteral nutrition-associated hepatic steatosis (PNAHS). Proteomic/phosphoproteomic analyses of liver samples from patients with PNAHS were applied to identify the mechanism of PNAHS. Total parenteral nutrition (TPN) mice model, in vivo, and in vitro experiments were used to assess the effect of PP2A-Cα on liver fatty acid metabolism. Reduced expression of PP2A-Cα (catalytic subunit) enhanced activation of serine/threonine kinase Akt2 and decreased activation of adenosine monophosphate-activated protein kinase (AMPK) were associated with hepatic steatosis in patients with PNAHS. Mice given PN for 14 days developed hepatic steatosis, down-regulation of PP2A-Cα, activation of Akt2, and inhibition of AMPK. Hepatocyte-specific deletion of PP2A-Cα in mice given PN exacerbated Akt2 activation, AMPK inhibition, and hepatic steatosis through an effect on fatty acid degradation, whereas hepatocyte-specific PP2A-Cα overexpression significantly ameliorated hepatic steatosis accompanied with Akt2 suppression and AMPK activation. Additionally, pharmacological activation of Akt2 in mice overexpressing PP2A-Cα led to the aggravation of hepatic steatosis. Our findings demonstrate that hepatic PP2A-Cα serves as a protective factor of PNAHS due to ameliorating hepatic steatosis and improving liver function. Our study provides a strong rationale that PP2A-Cα may be involved in the pathogenesis of PNAHS.
Obstructed defecation syndrome (ODS) is a functional disorder commonly encountered by colorectal surgeons and gastroenterologists, and greatly affects the quality of life of patients from both societal and psychological aspects. The underlying anatomical and pathophysiological changes of ODS are complex. However, intra-rectal intussusception and rectocele are frequently found in patients with ODS and both are thought to play an important role in the pathogenesis of ODS. With the development of evaluation methods in anorectal physiology laboratories and radiology studies, a great variety of new operative procedures, especially transanal procedures, have been invented to treat ODS. However, no procedure has been proved to be superior to others at present. Each operation has its own merits and defects. Thus, choosing appropriate transanal surgical procedures for the treatment of ODS remains a challenge for all surgeons. This review provides an introduction of the current problems and options for treatment of ODS and a detailed summary of the essential assessments needed for patient evaluation before carrying out transanal surgery. Besides, an overview of the benefits and problems of current transanal surgical procedures for treatment of ODS is summarized in this review. A report of clinical experience of some transanal surgical techniques used in the authors' center is also presented.
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