Purified Micronized Flavonoid Fraction Ameliorates the Injury of Spleen and Ileum Secondary to Hepatic Ischemia–Reperfusion in Rats

Background

Flavonoids have been subjected to considerable investigations due to their antioxidant and anti-inflammatory properties. Yet the effects of flavonoids on the ileum and spleen against hepatic ischemia–reperfusion injury have so far not been addressed.

Aims

We aimed to investigate whether micronized purified flavonoid fraction (MPFF) protects the ileum and spleen against hepatic ischemia–reperfusion injury.

Methods

Rats were subjected to hepatic ischemia by clamping the hilar area of the rats for 60 min, followed by 60 min of reperfusion. Rats in the treatment group were treated with MPFF (80 mg/kg/day) by gavage for 3 days before surgery, 30 min prior to ischemia and just before the reperfusion. After the reperfusion period, all rats were sacrificed. Ileal and splenic tissues were taken for histological evaluation and determination of the total antioxidant capacity (TAC), catalase, total oxidant status (TOS), oxidative stress index (OSI) and myeloperoxidase (MPO) levels.

Results

TAC levels in the splenic tissue and intestinal tissue were significantly higher in the treatment group than in the control group (P < 0.01 for both). TOS, OSI, and MPO in splenic tissue (P < 0.01, P < 0.05, and P < 0.05, respectively) and intestinal tissue (P < 0.01, P < 0.01, and P < 0.001, respectively) were significantly lower in the treatment group than in the control group. Histological tissue damage of intestinal tissue was milder in the treatment group than in the control group.

Conclusion

The results of this study indicated that MPFF pretreatment significantly limited the injury to the small intestine and spleen induced by hepatic ischemia–reperfusion in rats.     

Probiotics Can Alleviate Cardiopulmonary Bypass-Induced Intestinal Mucosa Damage in Rats

Background

Cardiopulmonary bypass (CPB) is commonly applied to support circulation during heart surgery but frequently causes adverse effects.

Aims

The purpose of this study was to examine the potential of probiotics to improve small intestinal mucosa barrier function after CPB.

Methods

Twenty-four adult male SD rats were randomly divided into sham-operated (S), CPB-operated (CPB), and probiotic-fed (Y) groups. Diamine oxidase (DAO) activity and concentrations of D-lactic acid, endotoxin, TNFα, and IL-6 were measured in portal vein blood. IgA concentrations were determined in plasma and the small intestine. Vena cava blood and tissue samples were used to monitor bacterial growth. Intestinal epithelial ultrastructure was analyzed by transmission electron microscopy (TEM). Occludin and ZO-1 expression levels in the intestinal epithelium were detected by western blotting and immunohistochemistry, respectively.

Results

D-lactic acid, endotoxin, TNFα and IL-6 levels, DAO activity, and bacterial translocation rate were increased (P < 0.05) in CPB and Y compared to the S group. The above indices were relatively lower (P < 0.05) in Y than in CPB. Plasma and small intestinal IgA levels were significantly lower (P < 0.05) in CPB, while in Y they were significantly increased (P < 0.05) but lower than in S (P < 0.05). These results were confirmed by TEM. Consistently, occludin and ZO-1 expression levels were significantly higher in Y than in CPB (P < 0.05) but still lower compared to S (P < 0.05).

Conclusion

Pre-administration of probiotics can improve, to some extent, intestinal barrier function after CPB in rats, and this effect is likely related to inhibition of the CPB-induced inflammatory response, improvement in local intestinal immune function, and increased expression of intestinal epithelial tight junction proteins.     

Is l-Glutathione More Effective Than l-Glutamine in Preventing Enteric Diabetic Neuropathy?

Background

Diabetes and its complications appear to be multifactorial. Substances with antioxidant potential have been used to protect enteric neurons in experimental diabetes.

Aim

This study evaluated the effects of supplementation with l-glutamine and l-glutathione on enteric neurons in the jejunum in diabetic rats.

Methods

Rats at 90 days of age were distributed into six groups: normoglycemic, normoglycemic supplemented with 2 % l-glutamine, normoglycemic supplemented with 1 % l-glutathione, diabetic (D), diabetic supplemented with 2 % l-glutamine (DG), and diabetic supplemented with 1 % l-glutathione (DGT). After 120 days, the jejunums were immunohistochemically stained for HuC/D+ neuronal nitric oxide synthase (nNOS) and vasoactive intestinal polypeptide (VIP). Western blot was performed to evaluate nNOS and VIP. Submucosal and myenteric neurons were quantitatively and morphometrically analyzed.

Results

Diabetic neuropathy was observed in myenteric HuC/D, nNOS, and VIP neurons (p < 0.05). In the submucosal plexus, diabetes did not change nitrergic innervation but increased VIPergic neuronal density and body size (p < 0.05). Supplementation with l-glutathione prevented changes in HuC/D neurons in the enteric plexus (p < 0.05), showing that supplementation with l-glutathione was more effective than with l-glutamine. Myenteric nNOS neurons in the DGT group exhibited a reduced density (34.5 %) and reduced area (p < 0.05). Submucosal neurons did not exhibit changes. The increase in VIP-expressing neurons was prevented in the submucosal plexus in the DG and DGT groups (p < 0.05).

Conclusion

Supplementation with l-glutathione exerted a better neuroprotective effect than l-glutamine and may prevent the development of enteric diabetic neuropathy.     

A survey of current practices used to maintain surgically induced remission following intestinal resection for Crohn’s disease

Background and aims

Post-operative Crohn’s disease (CD) recurrence is common after intestinal resection. The European Crohn’s and Colitis Organization has issued guidelines regarding the optimal post-operative management of patients who have undergone intestinal resection for CD. The current study aims to assess the current adjuvant therapy practices of colorectal surgeons and gastroenterologists.

Methods

An electronic-based survey was sent to members of the Association of Coloproctology of Great Britain and Ireland and the Irish Society of Gastroenterology.

Results

One hundred twenty-five surgeons and gastroenterologists responded. Gastroenterologists more frequently assessed for pre-clinical recurrence with serum inflammatory markers (97 vs. 51 %, P?<?0.001), faecal calprotectin (30 vs. 10 %, P?=?0.008) and ileocolonoscopy (67 vs. 23 %, P?<?0.001), while surgeons more frequently performed a CT scan (23 vs. 6 %, P?=?0.037). The majority of respondents estimated the 1-year endoscopic recurrence to be 10–25 %, and 36 % of respondents offered prophylaxis to all post-operative patients. Budesonide (8 vs. 4 %, P?=?0.006) and azathioprine/mercaptopurine (60 vs. 33 %, P?<?0.001) were more often prescribed for high-risk patients, while imidazole antibiotics (11 vs. 5 %, P?<?0.001) and 5-ASA derivatives were more often prescribed for low-risk patients (51 vs. 14 %, P?<?0.001).

Conclusion

Currently, surgeons and gastroenterologists involved in the peri-operative care of patients with CD underestimate the risk of recurrence following intestinal resection and under-utilize ileocolonoscopy to tailor adjuvant therapy.     

Concomitant iguratimod therapy in patients with active rheumatoid arthritis despite stable doses of methotrexate: a randomized, double-blind, placebo-controlled trial

Objectives

To investigate the efficacy and safety of iguratimod (T-614) in Japanese patients with active rheumatoid arthritis who had inadequate response to stable background methotrexate (MTX) alone.

Methods

In this multicenter, double-blind, controlled trial, a total of 253 patients were randomized at 2:1 ratio to either the iguratimod group or the placebo group. Iguratimod was orally administered at dosages of 25 mg/day for the first 4 weeks (25 mg once daily) and 50 mg/day for the subsequent 20 weeks (25 mg twice daily). MTX at dosage of 6 or 8 mg/week was administered to patients in both groups.

Results

The rate of 20 % improvement in American College of Rheumatology criteria (ACR20) at week 24 was 69.5 % in the iguratimod group compared with 30.7 % in the placebo group (P < 0.001). Significant improvements in the ACR50, ACR70, Health Assessment Questionnaire Disability Index, Disease Activity Score 28 <3.2, and rheumatoid factor were also observed. The most commonly reported adverse events (AEs) were blood iron decrease, nasopharyngitis, and lymphocyte decrease. These AEs were mild or moderate in severity. No deaths occurred.

Conclusion

The study results suggest that iguratimod in combination with MTX was efficacious and had a manageable safety profile.     

Doxycycline Prevents Acute Pulmonary Embolism-Induced Mortality and Right Ventricular Deformation in Rats

Purpose

Acute pulmonary embolism (APE) is a critical cardiopulmonary condition associated with right ventricular (RV) failure and death. While pharmacological inhibition of matrix metalloproteinases (MMPs) attenuated APE-induced hemodynamic alterations, no previous study has evaluated whether this approach decreases APE-induced mortality and RV deformation. We tested this hypothesis in rats.

Methods

Wistar rats received an intraperitoneal injection of 30 mg/kg doxycycline (or saline) and after 30 min a sterile suspension of 300 μm microsphere (21 mg/kg or saline) was injected into the tail vein. After 24 h, surviving animals were killed and the RVs were collected and used for histological and morphometric analyses. RV samples were also homogenized and assayed by SDS-polyacrilamide gel electrophoresis gelatin zymography to evaluate MMP-2 and MMP-9 activity. In situ zymography was carried out in RV to assess MMP activity and neutrophil accumulation in myocardial tissue was determined by myeloperoxidase activity measurement. Dihydroethidium was used to assess RV reactive oxygen species concentrations.

Results

APE caused 72.5 % mortality during the first hour of follow up. Pretreatment with doxycycline was associated with significant decrease in APE-induced mortality rate to 50 % (P?<?0.05). Embolized animals showed significant RV dilation, and pretreatment with doxycycline blunted this alteration (P?<?0.05). APE increased the number of RV neutrophils and MMP-9 levels (P?<?0.05). Pretreatment with doxycycline blunted APE-induced increases in RV myocardial ROS concentrations and MMP gelatinolytic activity (both P?<?0.05).

Conclusions

These findings show that MMP inhibition with doxycycline protects against APE-induced mortality and RV enlargement. These beneficial effects are probably due to attenuation of APE-induced oxidative stress and increases in ventricular proteolytic activity and suggest that doxycycline may have promising protective effects in patients with APE.     

A randomized,double-blinded,placebo-controlled,multicenter trial,healing effect of rebamipide in patients with low-dose aspirin and/or non-steroidal anti-inflammatory drug induced small bowel injury

Background

It is not clear what kind of drug is appropriate to heal NSAID-induced enteropathy. Several reports showed the preventive effect of prostaglandin analogue or inducer using healthy subjects who took NSAIDs. However there was no report for healing effect and for patients. The aim of this study was to evaluate the healing effect of rebamipide in patients with NSAIDs-induced enteropathy. In addition, we evaluated for nutritional parameter.

Methods

This study was conducted as a randomized, double-blinded, placebo-controlled, multicenter trial. Study protocol was approved by each hospital’s ethical committees. Patients with LDA and/or NSAID more than 3 months were enrolled. Patients with enteropathy were divided into the placebo and the rebamipide groups. Rebamipide 100 mg three times daily was administered during 4 weeks. Capsule endoscopies were performed at 0 and 4 week. The number of small intestinal ulcer and erosion were evaluated. Total protein was analyzed as nutritional parameter.

Results

Sixty one participants were completed this study. Change in number of small intestinal erosion in the rebamipide group was ?2.5 ± 3.4, and 2.1 ± 3.9 in the placebo group (P < 0.0001). Change in number of small intestinal ulcer in the rebamipide group was ?0.5 ± 1.6, and 0.1 ± 0.7 in the placebo group (P = 0.024). Change in serum total protein levels in the rebamipide group was 0.06 ± 0.36, and ?0.27 ± 0.34 in the placebo group (P = 0.0005).

Conclusions

Rebamipide has not only the healing effect for NSAIDs-induced enteropathy compared with placebo, but the improvement of nutritional condition. These results showed a tentative therapeutical strategy for chronic NSAIDs users.     

Specialty Use Among Patients With Treated Hypertension in a Patient-Centered Medical Home

BACKGROUND

Little is known about how delivery of primary care in the patient-centered medical home (PCMH) influences outpatient specialty care use.

OBJECTIVE

To describe changes in outpatient specialty use among patients with treated hypertension during and after PCMH practice transformation.

DESIGN

One-group, 48-month interrupted time series across baseline, PCMH implementation and post-implementation periods.

PATIENTS

Adults aged 18–85 years with treated hypertension.

INTERVENTION

System-wide PCMH redesign implemented across 26 clinics in an integrated health care delivery system, beginning in January 2009.

MAIN MEASURES

Resource Utilization Band variables from the Adjusted Clinical Groups case mix software characterized overall morbidity burden (low, medium, high). Negative binomial regression models described adjusted annual differences in total specialty care visits. Poisson regression models described adjusted annual differences in any use (yes/no) of selected medical and surgical specialties.

KEY RESULTS

Compared to baseline, the study population averaged 7 % fewer adjusted specialty visits during implementation (P?<?0.001) and 4 % fewer adjusted specialty visits in the first post-implementation year (P?=?0.02). Patients were 12 % less likely to have any cardiology visits during implementation and 13 % less likely during the first post-implementation year (P?<?0.001). In interaction analysis, patients with low morbidity had at least 27 % fewer specialty visits during each of 3 years following baseline (P?<?0.001); medium morbidity patients had 9 % fewer specialty visits during implementation (P?<?0.001) and 5 % fewer specialty visits during the first post-implementation year (P?=?0.007); high morbidity patients had 3 % (P?=?0.05) and 5 % (P?=?0.009) higher specialty use during the first and second post-implementation years, respectively.

CONCLUSIONS

Results suggest that more comprehensive primary care in this PCMH redesign enabled primary care teams to deliver more hypertension care, and that many needs of low morbidity patients were within the scope of primary care practice. New approaches to care coordination between primary care teams and specialists should prioritize high morbidity, clinically complex patients.     

Clinical characteristics and risk factors for Pneumocystis jirovecii pneumonia in patients with rheumatoid arthritis receiving adalimumab: a retrospective review and case–control study of 17 patients

Objectives

To investigate the clinical characteristics and risk factors of Pneumocystis jirovecii pneumonia (PCP) in rheumatoid arthritis (RA) patients treated with adalimumab.

Methods

We conducted a multicenter, retrospective, case–control study to compare RA patients treated with adalimumab with and without PCP. Data from 17 RA patients who were diagnosed with PCP and from 89 RA patients who did not develop PCP during adalimumab treatment were collected.

Results

For the PCP patients, the median age was 68 years old, with a median RA disease duration of eight years. The median length of time from the first adalimumab injection to the development of PCP was 12 weeks. At the onset of PCP, the median dosages of prednisolone and methotrexate were 5.0 mg/day and 8.0 mg/week, respectively. The patients with PCP were significantly older (p < 0.05) and had more structural changes (p < 0.05) than the patients without PCP. Computed tomography of the chest revealed ground-glass opacity without interlobular septal boundaries in the majority of the patients with PCP. Three PCP patients died.

Conclusions

PCP may occur early in the course of adalimumab therapy in patients with RA. Careful monitoring, early diagnosis, and proper management are mandatory to secure a good prognosis for these patients.     

The Outcomes of Patients with Severe Hyperbilirubinemia Following Living Donor Liver Transplantation

Background

Prolonged hyperbilirubinemia (HB) following living donor liver transplantation (LDLT) can be a risk factor for early graft loss and mortality. However, some recipients who present with postoperative hyperbilirubinemia do recover and maintain a good liver function.

Aim

The purpose of this study was to investigate the risk factors for hyperbilirubinemia following LDLT and to identify predictors of the outcomes in patients with post-transplant hyperbilirubinemia.

Methods

A total of 107 consecutive adults who underwent LDLT in Nagasaki University Hospital were investigated retrospectively. The patients were divided into two groups according to postoperative peak serum bilirubin level (HB group: ≥30 mg/dl; non-HB group: <30 mg/dl). These two groups of patients and the prognosis of patients in the HB group were analyzed using several parameters.

Results

Seventeen patients (15.9 %) presented with hyperbilirubinemia, and their overall survival was significantly worse than patients in the non-HB group (n = 90). Donor age was significantly higher in the HB group (P < 0.05). Of the 17 patients in the HB group, nine survived. The postoperative serum prothrombin level at the time when the serum bilirubin level was >30 mg/dl was significantly higher in surviving patients (P < 0.01).

Conclusions

The use of a partial liver graft from an aged donor is a significant risk factor for severe hyperbilirubinemia and a poorer outcome. However, those patients who maintain their liver synthetic function while suffering from hyperbilirubinemia may recover from hyperbilirubinemia and eventually achieve good liver function, thus resulting in a favorable survival.     

Omega-3 Polyunsaturated Fatty Acids Increase Plasma Adiponectin to Leptin Ratio in Stable Coronary Artery Disease

Background

Growing evidence suggests a cardioprotective role of omega-3 polyunsaturated fatty acids (PUFA). However, the exact mechanisms underlying the effects of omega-3 PUFA in humans have not yet been fully clarified.

Purpose

We sought to evaluate omega-3 PUFA-mediated effects on adipokines in patients with stable coronary artery disease (CAD) undergoing elective percutaneous coronary intervention (PCI).

Methods

We conducted a prospective, double-blind, placebo-controlled, randomized study, in which adiponectin, leptin and resistin were determined at baseline, 3–5 days and 30 days during administration of omega-3 PUFA 1 g/day (n?=?20) or placebo (n?=?28).

Results

As compared to controls administration of omega-3 PUFA resulted in increase of adiponectin by 13.4 % (P?<?0.0001), reduction of leptin by 22 % (P?<?0.0001) and increase of adiponectin to leptin (A/L) ratio by 45.5 % (P?<?0.0001) at 30 days, but not at 3–5 days. Compared with placebo adiponectin was 12.7 % higher (P?=?0.0042), leptin was 16.7 % lower (P?<?0.0001) and A/L ratio was 33.3 % higher (P?<?0.0001) in the omega-3 PUFA group at 30 days. Resistin decreased similarly in both groups after 1 month, without intergroup differences (P?=?0.32). The multivariate model showed that the independent predictors of changes in adiponectin at 1 month (P?<?0.001) were: omega-3 PUFA treatment, baseline platelet count, total cholesterol and those in leptin (P?<?0.0001) were: omega-3 PUFA treatment and waist circumference. Independent predictors of A/L ratio changes (P?<?0.0001) were: assigned treatment, current smoking and hyperlipidemia.

Conclusions

In high risk stable coronary patients after PCI omega-3 PUFA supplementation improves adipokine profile in circulating blood. This might be a novel, favourable mechanism of omega-3 PUFA action.     

Phase II dose–response study of abatacept in Japanese patients with active rheumatoid arthritis with an inadequate response to methotrexate

Objective

The objective of this study was to assess the response to abatacept at doses of 2 mg/kg and 10 mg/kg compared to placebo in patients with active rheumatoid arthritis (RA) with an inadequate clinical response to methotrexate (MTX).

Methods

In this multicenter, placebo-controlled, double-blind, parallel-group, dose–response study, 195 Japanese patients with active RA with an inadequate response to MTX were randomized 1:1:1 to receive 10 mg/kg or 2 mg/kg abatacept plus MTX, or placebo plus MTX, for 24 weeks.

Results

Abatacept demonstrated a dose–response relationship when given at 2 and 10 mg/kg. Based on the American College of Rheumatology criteria (20, 50, and 70 %), the responses to 10 mg/kg abatacept were significantly greater than those to placebo at week 24 (p < 0.001). Smaller yet statistically significant responses were also seen in the 2 mg/kg abatacept group. Overall rates of adverse events, serious adverse events, and treatment discontinuations because of adverse events were comparable in all three groups.

Conclusions

Abatacept (2 mg/kg and 10 mg/kg) showed a dose–response relationship in Japanese patients with active RA with an inadequate clinical response to MTX. Administration of abatacept in combination with MTX for 24 weeks was well tolerated.     

Notch Signaling Promotes Intestinal Crypt Fission in the Infant Rat

Background

Growth of the small intestine in the infant rat is promoted by crypt fission and later by increased crypt cell proliferation. Notch signaling could promote crypt fission. Hes-1 is a Notch target gene.

Aim

We assessed the effect of Notch signaling on intestinal crypt fission and on growth of the intestine in the infant rat.

Methods

Hes-1 expression was determined in the small intestine of litters of Hooded Wistar rats aged between 3 and 72 days. Hes-1 RNA expression was measured by quantitative RT-PCR. Four groups of rats (n = 8 or 9) were injected daily, ip, either with vehicle or with the Notch inhibitor DAPT at doses of 3, 10, and 30 mg/kg, from days 9 to 13 of life, and killed on day 14. A microdissection technique was used to measure crypt fission, mitotic count, and apoptotic count. Data were analyzed by ANOVA and by use of Dunnett’s F test.

Results

Hes-1 expression and crypt fission peaked on day 14. DAPT reduced Hes-1 immunostaining in proportion to dose. DAPT reduced villous area to 72 % (p < 0.01), 53 % (p < 0.001), and 38 % (p < 0.001) of control values for 3, 10 and 30 mg/kg doses, respectively, and reduced crypt fission to 53 % (p < 0.001) and 38 % (p < 0.001) of control values, respectively, for 10 and 30 mg/kg doses. Crypt mitotic count was not affected by any DAPT dose. DAPT at 10 and 30 mg/kg significantly increased apoptosis in crypts, by 6.5 and 4.8-fold, respectively.

Conclusions

We conclude that Notch signaling promotes crypt fission and growth of the intestine by maintaining low apoptosis of crypt cells.     

Cardioprotection by Farnesol: Role of the Mevalonate Pathway

Purpose

Farnesol is a key metabolite of the mevalonate pathway and known as an antioxidant. We examined whether farnesol treatment protects the ischemic heart.

Methods

Male Wistar rats were treated orally with 0.2, 1, 5, and 50 mg/kg/day farnesol/vehicle for 12 days, respectively. On day 13, the effect of farnesol treatment on cardiac ischemic tolerance and biochemical changes was tested. Therefore, hearts were isolated and subjected either to 30 min coronary occlusion followed by 120 min reperfusion to measure infarct size or to 10 min aerobic perfusion to measure cardiac mevalonate pathway end-products (protein prenylation, cholesterol, coenzyme Q9, coenzyme Q10, dolichol), and 3-nitrotyrosine (oxidative/nitrosative stress marker), respectively. The cytoprotective effect of farnesol was also tested in cardiomyocytes subjected to simulated ischemia/reperfusion.

Results

Farnesol pretreatment decreased infarct size in a U-shaped dose–response manner where 1 mg/kg/day dose reached a statistically significant reduction (22.3?±?3.9 % vs. 40.9?±?6.1 % of the area at risk, p?<?0.05). Farnesol showed a similar cytoprotection in cardiomyocytes. The cardioprotective dose of farnesol (1 mg/kg/day) significantly increased the marker of protein geranylgeranylation, but did not influence protein farnesylation, cardiac tissue cholesterol, coenzyme Q9, coenzyme Q10, and dolichol. While the cardioprotective dose of farnesol did not influence 3-nitrotyrosine, the highest dose of farnesol (50 mg/kg/day) tested did not show cardioprotection, however, it significantly decreased cardiac 3-nitrotyrosine.

Conclusions

This is the first demonstration that oral farnesol treatment reduces infarct size. The cardioprotective effect of farnesol likely involves increased protein geranylgeranylation and seems to be independent of the antioxidant effect of farnesol.     

Impact of hepatic lymph node metastasis on survival of patients with synchronous resectable or unresectable liver metastases of colorectal cancer

Background

The goals of this retrospective study were to comprehensively evaluate the impact of hepatic lymph node (HLN) involvement on survival in patients with synchronous resectable or unresectable liver metastases from colorectal cancer and to highlight how to deal with such cases in the light of recent advances in chemotherapy.

Methods

The impact of HLN involvement on survival, along with various clinical, pathological, and therapeutic factors, was retrospectively evaluated in 61 patients with synchronous liver metastases from colorectal cancer (resectable, 26; unresectable, 35), undergoing resection of the primary tumor and histopathological evaluation between July 2000 and April 2008.

Results

The proportion with HLN metastasis was 11.5 % in resectable cases and 28.6 % in unresectable cases. On multivariate analysis using the Cox proportional hazards model, HLN metastasis (P < 0.001), along with non-resection of hepatic lesions (P < 0.001), larger metastatic tumor volume (P < 0.001), non-use of oxaliplatin-based chemotherapy (P < 0.001), involvement of 4 or more regional lymph nodes (P < 0.001), and excessive lymphatic invasion (P = 0.02), was identified as an independent risk factor for shorter survival.

Conclusions

To establish a new therapeutic strategy for synchronous liver metastasis of colorectal cancer, the HLNs should be examined histologically in patients undergoing resection of their primary colon and rectal cancer.     

Cotransfection of Survivin and CD44v3 Short Hairpin RNAs Affects Proliferation, Apoptosis, and Invasiveness of Colorectal Cancer

Introduction

Colorectal cancer is one of the common malignant tumors in humans, and the incidence rate is gradually increasing year by year. Survivin and CD44v3 are ideal targets for gene therapy due to their overexpression in colorectal cells. Studies show that downregulation of survivin could promote apoptosis and depress proliferation, and reduction of CD44v3 expression could inhibit tumor invasive capacity. It is difficult to achieve satisfactory curative effect.

Objective

In this study, we use survivin and CD44v3 short hairpin RNAs (shRNA) combined transfection into colorectal cancer cell line SW480 to investigate its effects on the cell apoptosis, proliferation and invasiveness.

Methods

ShRNA plasmids targeting survivin and CD44v3 were singly or co-transfected into SW480 cells.

Results

The co-transfection group exhibited the most significant inhibitory effect on cell growth (P < 0.05) and the highest apoptosis rate (P < 0.05). In addition, the invasive capacity in the co-transfected group was the least. The tumor inhibition rate of the cotransfected group in xenograft tumor mice was significantly higher than other groups (P < 0.05). Moreover, the microvessel density of the co-transfected group was significantly decreased compared with other groups (P < 0.05).

Conclusion

These results suggest combined transfection of survivin shRNA and CD44v3 shRNA may produce a synergistic effect on gene therapy in colorectal cancer.     

Dipeptidyl Peptidase IV Inhibition Prevents the Formation and Promotes the Healing of Indomethacin-Induced Intestinal Ulcers in Rats

Backgrounds and Aims

We studied the intestinotrophic hormone glucagon-like peptide-2 (GLP-2) as a possible therapy for non-steroidal anti-inflammatory drug (NSAID)-induced intestinal ulcers. Luminal nutrients release endogenous GLP-2 from enteroendocrine L cells. Since GLP-2 is degraded by dipeptidyl peptidase IV (DPPIV), we hypothesized that DPPIV inhibition combined with luminal administration of nutrients potentiates the effects of endogenous GLP-2 on intestinal injury.

Methods

Intestinal injury was induced by indomethacin (10 mg/kg, sc) in fed rats. The long-acting DPPIV inhibitor K579 was given intragastrically (ig) or intraperitoneally (ip) before or after indomethacin treatment. l-Alanine (l-Ala) and inosine 5′-monophosphate (IMP) were co-administered ig after the treatment.

Results

Indomethacin treatment induced intestinal ulcers that gradually healed after treatment. Pretreatment with ig or ip K579 given at 1 mg/kg reduced total ulcer length, whereas K579 at 3 mg/kg had no effect. Exogenous GLP-2 also reduced intestinal ulcers. The preventive effect of K579 was dose-dependently inhibited by a GLP-2 receptor antagonist. Daily treatment with K579 (1 mg/kg), GLP-2, or l-Ala + IMP after indomethacin treatment reduced total ulcer length. Co-administration (ig) of K579 and l-Ala + IMP further accelerated intestinal ulcer healing.

Conclusion

DPPIV inhibition and exogenous GLP-2 prevented the formation and promoted the healing of indomethacin-induced intestinal ulcers, although high-dose DPPIV inhibition reversed the preventive effect. Umami receptor agonists also enhanced the healing effects of the DPPIV inhibitor. The combination of DPPIV inhibition and luminal nutrient-induced GLP-2 release may be a useful therapeutic tool for the treatment of NSAIDs-induced intestinal ulcers.     

Prognostic nutritional index predicts outcomes of malignant pleural mesothelioma

Purpose

Nutritional status has been associated with long-time outcomes in cancer patients. We investigated whether the prognostic nutritional index (PNI), an indicator of nutritional status, affects overall survival in patients with malignant pleural mesothelioma (MPM).

Methods

We enrolled 121 patients with histologically confirmed MPM, who had successfully undergone biopsy by medical thoracoscopy in this study. Demographic, clinical and laboratory data were collected retrospectively. The PNI was calculated as 10× serum albumin value (g/dl) + 0.005 × total lymphocyte count (per mm³) in peripheral blood. Univariate and multivariate analyses were used to identify prognostic factors.

Results

Mean pretreatment PNI was 44.6. PNI was significantly associated with age (P = 0.031), smoking habits (P = 0.039) and weight loss (P = 0.029). Survival analysis showed PNI to be an independent prognostic factor in MPM. Patients with lower PNIs (PNI < 44.6) had greater risk of death than those with higher PNIs (PNI ≥ 44.6; hazard ratio: 2.290; 95 % confidence interval: 1.415–3.706; P = 0.001). These analyses were adjusted for patient age, gender, smoking habits, dyspnea, chest pain, weight loss, primary site of tumor, histology, platinum-based systemic chemotherapy, hospital and stage.

Conclusions

Pretreatment PNI is a novel independent prognostic factor in MPM.