Overexpression of P-glycoprotein, MRP2, and CYP3A4 impairs intestinal absorption of octreotide in rats with portal hypertension.

BACKGROUND: Portal hypertension (PH) is the main cause of complications and death in liver cirrhosis. The effect of oral administration of octreotide (OCT), a drug that reduces PH by the constriction of mesenteric arteries, is limited by a remarkable intestinal first-pass elimination. METHODS: The bile duct ligation (BDL) was used in rats to induce liver cirrhosis with PH to examine the kinetics and molecular factors such as P-glycoprotein (P-gp), multidrug resistance-associated protein 2 (MRP2) and cytochrome P450 3A4 (CYP3A4) influencing the intestinal OCT absorption via in situ and in vitro experiments on jejunal segments, transportation experiments on Caco-2 cells and experiments using intestinal microsomes and recombinant human CYP3A4. Moreover, RT-PCR, western blot, and immunohistochemistry were performed. RESULTS: Both in situ and in vitro experiments in jejunal segments showed that intestinal OCT absorption in both control and PH rats was largely controlled by P-gp and, to a lesser extent, by MRP2. OCT transport mediated by P-gp and MRP2 was demonstrated on Caco-2 cells. The results of RT-PCR, western blot, and immunohistochemistry suggested that impaired OCT absorption in PH was in part due to the jejunal upregulation of these two transporters. The use of intestinal microsomes and recombinant human CYP3A4 revealed that CYP3A4 metabolized OCT, and its upregulation in PH likely contributed to impaired drug absorption. CONCLUSIONS: Inhibition of P-gp, MRP2, and CYP3A4 might represent a valid option for decreasing intestinal first-pass effects on orally administered OCT, thereby increasing its bioavailability to alleviate PH in patients with cirrhosis.

Bezafibrate protects blood-brain barrier (BBB) integrity against traumatic brain injury mediated by AMPK.

Bezafibrate (BEZ) has displayed a wide range of neuroprotective effects in different types of neurological diseases. However, its pharmacological function in traumatic brain injury (TBI) is still unknown. In the current study, a TBI model was constructed in mice to examine the potential beneficial roles of BEZ. After TBI, mice were daily dieted with BEZ or vehicle solution. The motor function, learning and memory, brain edema, vascular inflammatory factors, the integrity of the blood-brain barrier (BBB), and the expression of the tight junction zona occludens 1 (ZO-1) were assessed. The findings demonstrate that after TBI, BEZ treatment significantly promoted the recovery of motor function and cognitive function deficits. Moreover, BEZ attenuated brain edema by reducing the levels of brain water content. We also found that administration of BEZ alleviated cerebral vascular pro-inflammation by suppressing the expression of ICAM-1, VCAM-1, and E-selectin. Notably, BEZ improved the impaired BBB integrity in TBI mice by restoring the expression of the tight junction (TJ) protein ZO-1. Further in vitro experiments show that treatment with BEZ prevented the aggravation of endothelial permeability and restored the reduction of trans-epithelial electrical resistance (TEER) as well as the expression of ZO-1 in TBI-exposed brain bEnd.3 cells. Mechanistically, we prove that the protective effects of BEZ are mediated by AMPK. Based on these findings, we conclude that BEZ improves TBI-induced BBB injury and it might be considered for the treatment or management of TBI.

Pan-cancer molecular analysis of EGFR large fragment deletion in the Asian population.

BACKGROUND: Large fragment deletion (LFD) of EGFR was associated with carcinogenesis in many types of cancers. However, the molecular features of EGFR-LFD have not been studied in the Asian cancer population. METHOD: Here we retrospectively analyzed the targeted sequencing data from a large cancer database. RESULTS: EGFR-LFD was detected at a frequency of 0.03% with EGFRvIII being the most frequently observed LFD. TERTp variants were identified in 60% of the cases. TP53 alterations (33%) were mutually exclusive with TERTp variants and coexisted with EGFR-LFD in lung cancer and colorectal cancer. EGFR amplification (67%) and chromosome 10p deletion (53%) were the most focal-level and arm-level CNV in this cohort. EGFR exon2-17 skipping was found in the tumor tissue of one patient after progressing on osimertinib. CONCLUSION: Our study provided valuable insights into the distribution and molecular characteristics of EGFR-LFD, hoping to shed light on the treatment management for EGFR-LFD carriers.

Erratum: Inhibition of P-glycoprotein, multidrug resistance-associated protein 2 and cytochrome P450 3A4 improves the oral absorption of octreotide in rats with portal hypertension.

[This corrects the article DOI: 10.3892/etm.2016.3808.].

Characteristics and endovascular treatment of intracranial vertebral artery aneurysms.

OBJECTIVE: The clinical and angiographic characteristics of vertebral artery (VA) aneurysm were evaluated to demonstrate the safety and efficacy of endovascular techniques of VA aneurysms. MATERIALS AND METHODS: Case records of 38 consecutive patients with 40 VA aneurysms admitted during a 2-year period were reviewed. The data analyzed included age, sex, size of aneurysm, ruptured or unruptured, endovascular techniques, angiographic results after embolization, duration of follow-up, angiographic follow-up results and Glasgow Outcome Score at follow-up. RESULTS: Of the 38 patients, 33 patients had 35 dissecting aneurysms and five patients had five saccular aneurysms. Seventeen (42.5%) aneurysms were ruptured. Of the 34 patients treated with endovascular techniques, immediate post-procedural angiograms showed complete and subtotal occlusion (>90%) of 27 (67.5%) aneurysms and incomplete and no occlusion of 13 (32.5%) aneurysms, including four conservatively treated aneurysms. A clinical improvement or stable outcome was achieved in all the patients (100%) during a mean 12.1-month follow-up. There was no complication related to endovascular treatment and no rebleeding during the follow-up period. Angiographic follow-up (mean of 7.2 months, range 1-18 months) was available in all the patients. Complete and subtotal occlusion was observed in 31 (81.6%) patients, including one spontaneous thrombosis of a conservatively treated VA dissecting aneurysm. Recanalization in two patients (5.9%) at 6 and 9 months did not require retreatment. CONCLUSION: This series demonstrates the safety and efficacy of multimodality of endovascular techniques for VA aneurysms.

Transcutaneous Neuromodulation improved inflammation and sympathovagal ratio in patients with primary biliary ssscholangitis and inadequate response to Ursodeoxycholic acid: a pilot study.

BACKGROUND: At present, ursodeoxycholic acid (UDCA) is internationally recognized as a therapeutic drug in clinic. However, about 40% Primary Biliary Cholangitis (PBC) patients are poor responders to UDCA. It has been demonstrated that Transcutaneous Neuromodulation (TN) can be involved in gut motility, metabolism of bile acids, immune inflammation, and autonomic nerve. Therefore, this study aimed to explore the effect of TN combined with UDCA on PBC and related mechanisms. METHODS: According to inclusion and exclusion criteria, 10 healthy volunteers and 15 PBC patients were recruited to control group and TN group, respectively. PBC patients were alternately but blindly assigned to group A (TN combined with UDCA) and group B (sham-TN combined with UDCA), and a crossover design was used. The TN treatment was performed via the posterior tibial nerve and acupoint ST36 (Zusanli) 1 h twice/day for 2 weeks. T test and nonparametric test were used to analyze the data. RESULTS: 1. TN combined with UDCA improved the liver function of PBC patients shown by a significant decrease of alkaline phosphatase and gamma-glutamyltransferase (γ-GT) (P < 0.05). 2. The treatment also decreased serum IL-6 levels (P < 0.05), but not the level of Tumor Necrosis Factor-α, IL-1ß or IL-10. 3. TN combined with UDCA regulated autonomic function, enhanced vagal activity, and decreased the sympathovagal ratio assessed by the spectral analysis of heart rate variability (P < 0.05). 4. There was no change in 13 bile acids in serum or stool after TN or sham-TN. CONCLUSIONS: TN cssombined with UDCA can significantly improve the liver function of PBC patients. It is possibly via the cholinergic anti-inflammatory pathway. TN might be a new non-drug therapy for PBC. Further studies are required. TRIAL REGISTRATION: The study protocol was registered in Chinese Clinical Trial Registry (number ChiCTR1800014633 ) on 25 January 2018.

A case series study of hypopituitarism in older patients with and without gastrointestinal symptoms.

OBJECTIVES: Some older individuals who present with gastrointestinal symptoms as their chief complaint were ultimately diagnosed with hypopituitarism instead of gastrointestinal diseases. The aim of this study was to find the characteristics of biochemical indicators in these patients so as to reduce early misdiagnosis. METHODS: We conducted a retrospective review of 45 patients with hypopituitarism who were at least 60 years of age. Two groups were included: group of hypopituitarism patients with gastrointestinal symptoms (Group G) included 23 patients with gastrointestinal symptoms and group of hypopituitarism patients without gastrointestinal symptoms (Group N) included 22 patients without these symptoms. In Group G, we investigated the prevalence of different gastrointestinal symptoms, the response of these symptoms to treatment, the occurrence of electrolyte disorders, and target gland dysfunction. Then, we compared the electrolyte and target gland function indices between the two groups. RESULTS: Nausea and vomiting were the most common complaints, accounting for 69.57% of the gastrointestinal symptoms in Group G. Hyponatremia was the most common electrolyte disorder, occurring in 72.86% (n = 18) of patients in Group G. Hypoadrenalism and hypothyroidism were reported by 69.57% and 60.78% of patients, respectively, in Group G. None of the gastrointestinal symptoms were relieved by 4 weeks of treatment with antacid and motility drugs. As mentioned, 18 patients also experienced refractory hyponatremia during early treatment including regular sodium supplements; however, their gastrointestinal symptoms and hyponatremia improved after only a week of treatment for hypopituitarism. Regarding the biochemical indicators, only serum sodium and cortisol in Group G were statistically lower compared with those in Group N (P < .05). CONCLUSION: Nausea and vomiting were the most common gastrointestinal symptoms in older patients with hypopituitarism, which were associated with lower serum sodium and cortisol. In addition, we hope to share the research to our gastroenterologists that serum sodium and cortisol should be tested when meeting elder patients with unexplained gastrointestinal symptoms.

Home-Based Transcutaneous Neuromodulation Improved Constipation via Modulating Gastrointestinal Hormones and Bile Acids.

This study aims to investigate the role of transcutaneous neuromodulation (TN) on the regulation of gastrointestinal hormones and bile acids in patients with functional constipation (FC). Twenty FC patients were treated with TN for four weeks. The effects of TN on symptoms were evaluated by questionnaires. Plasma levels of serotonin (5-HT), motilin, somatostatin, and vasoactive intestinal peptide (VIP) were measured by ELISA and 12 individual bile acids assayed by liquid chromatography tandem mass spectrometry. Results were as follows. (1) TN treatment increased the frequency of spontaneous bowel movement, improved the Bristol Stool Score, and reduced Patient Assessment of Constipation Symptom score and Patient Assessment of Constipation Quality of Life score. (2) FC patients showed decreased plasma levels of 5-HT, motilin, and VIP and an increased plasma level of somatostatin (P < 0.05). Four-week TN treatment increased plasma levels of 5-HT and motilin and decreased the plasma level of somatostatin in the FC patients (P < 0.05). (3) Taurocholic deoxycholate, taurocholic acid, and taurocholic lithocholic acid were increased in the FC patients (P < 0.005) but reduced by TN treatment (P < 0.05). This study has suggested that the therapy may improve the symptoms of FC by alleviating the disorders of gastrointestinal hormones and bile acids.

Inhibition of P-glycoprotein, multidrug resistance-associated protein 2 and cytochrome P450 3A4 improves the oral absorption of octreotide in rats with portal hypertension.

The aim of the present study was to increase the intestinal transport of octreotide (OCT) by targeting the first-pass impact to identify a potential method for decreasing portal vein pressure (PVP) using oral OCT. Thus, the bioavailability of intestinally absorbed OCT was evaluated in normal rats and rats with portal hypertension (PH) that had been administered P-glycoprotein/multidrug resistance-associated protein 2/cytochrome P450 3A4 (P-gp/MRP2/CYP3A4) inhibitors. The mRNA and protein expression levels of P-gp, MRP2 and CYP3A4 were evaluated in normal and PH rats with or without OCT and the inhibitors using RT-PCR, western blot and immunohistochemical analyses. The potential effects of the inhibitor administration on PVP were also examined. The results suggest that P-gp, MRP2 and CYP3A4 play important roles in prohibiting the enteral absorption of OCT, particularly under a PH environment. Moreover, inhibitors of P-gp, MRP2 and CYP3A4 decrease the first-pass effects of OCT and effectively reduce PVP under PH conditions. Therefore, the present results suggest P-gp, MRP2 and CYP3A4 are key factors in the intestinal absorption of OCT. The inhibition of P-gp, MRP2 and CYP3A4 can markedly decrease the first-pass effects of OCT, and their use may facilitate the use of orally administered OCT.

pH-sensitive microemulsion-based gels for removal of colonic ammonia: a novel preventative oral preparation for hepatic encephalopathy in rats.

Microemulsions with limited stability in mimetic gastrointestinal environments have previously demonstrated potential for the effective removal of ammonia from artificial colonic fluid. Specialized pH­sensitive microemulsion­based gels for the removal of colonic ammonia (MBG­RCA), however, possess relative stability in the gastrointestinal (GI) tract of normal rats, indicating potential use in in vivo applications. An investigation of the effects of oral MBG­RCA was conducted in order to evaluate the reduction of intestinal ammonia and the prevention of hepatic encephalopathy (HE) in rat models. Eighty rats were allocated into eight 4­day treatment groups: The HE model (intraperitoneal injection of thioacetamide) group; the high­, medium­ and low­dose MBG­RCA therapeutic groups (15, 10 and 5 ml/kg MBG­RCA, respectively); and the normal, blank, lactulose and acetic acid control groups, each of which received daily treatment administration. Oral MBG­RCA effects were identified using behavioral monitoring observed by an infrared night vision supervisory control system, electroencephalograms, blood ammonia levels, intestinal ammonia levels, liver functionality and pathological observation. High­ and medium­dose oral administrations of MBG­RCA significantly decreased the blood and intestinal ammonia levels (P<0.05), improved liver functionality and reduced the clinical manifestations of HE in rats. MBG­RCA demonstrated high clearance of rat colonic ammonia while maintaining sufficient stability in the GI tract, indicating the potential for the development of new clinically relevant oral preparations for the prevention of HE. Additionally, such preparations are advantageous in that ammonia is eliminated without the production of potentially harmful metabolic byproducts.

Sinomenine sensitizes multidrug-resistant colon cancer cells (Caco-2) to doxorubicin by downregulation of MDR-1 expression.

Chemoresistance in multidrug-resistant (MDR) cells over expressing P-glycoprotein (P-gp) encoded by the MDR1 gene, is a major obstacle to successful chemotherapy for colorectal cancer. Previous studies have indicated that sinomenine can enhance the absorption of various P-gp substrates. In the present study, we investigated the effect of sinomenine on the chemoresistance in colon cancer cells and explored the underlying mechanism. We developed multidrug-resistant Caco-2 (MDR-Caco-2) cells by exposure of Caco-2 cells to increasing concentrations of doxorubicin. We identified overexpression of COX-2 and MDR-1 genes as well as activation of the NF-κB signal pathway in MDR-Caco-2 cells. Importantly, we found that sinomenine enhances the sensitivity of MDR-Caco-2 cells towards doxorubicin by downregulating MDR-1 and COX-2 expression through inhibition of the NF-κB signaling pathway. These findings provide a new potential strategy for the reversal of P-gp-mediated anticancer drug resistance.

A study on the position and etiology of infection in cirrhotic patients: A potential precipitating factor contributing to hepatic encephalopathy.

Hepatic encephalopathy (HE) is a severe and high-mortality complication in cirrhotic patients. In this study, we analyzed infection, one of the common precipitating factors of HE in patients with cirrhosis, in order to identify common infection sites and the etiology. In addition, we aimed to identify information useful in the early prevention and effective treatment of HE. Ninety-two patients presenting with hepatitis B virus-related cirrhosis with HE (HBC-HE) and 45 patients presenting with alcoholic cirrhosis with HE (ALD-HE) were enrolled in this study. We collected and analyzed data concerning the precipitating factors of HE using blood tests, biochemical detection and bacterial culture to identify which precipitating factor was the most common. Fifty-three patients with HE (37 with HBC-HE and 16 with HBC-HE) had infection as the precipitating factor. These infections included respiratory tract infection (56.6%), intestinal tract infection (20.7%), peritoneal infection (17.0%) and urinary tract infection (5.7%). The white blood cell (WBC) counts increased in 17 cases (32.1%) and neutrophil (NEUT) numbers increased in 39 cases (73.6%), while WBC counts were lower in the patients with respiratory tract infection compared with those in the patients with infections at other sites (P<0.05). The levels of plasma ammonia were significantly higher in patients with intestinal tract infection than in those with other sites of infection (P<0.05). The proportions of patients with hyperammonemia, increased NEUT numbers, hyponatremia and low albumin were higher in the infection group compared with those in the non-infection group (P<0.05). Pneumococci and E. coli were common bacteria that induced infection in the respiratory tract and at other infection sites, respectively. Respiratory tract infection was identified to be the most common precipitating factor for HE.