P-glycoprotein multidrug transporter in inflammatory bowel diseases: More questions than answers

The gastrointestinal barrier is constantly exposed to numerous environmental substrates that are foreign and potentially harmful. These xenobiotics can cause shifts in the intestinal microbiota composition, affect mucosal immune responses, disturb tissue integrity and impair regeneration. The multidrug transporter ABCB1/MDR1 p-glycoprotein (p-gp) plays a key role at the front line of host defence by efficiently protecting the gastrointestinal barrier from xenobiotic accumulation. This Editorial discusses how altered expression and function of ABCB1/MDR1 p-gp may contribute to the development and persistence of chronic intestinal inflammation in inflammatory bowel diseases (IBD). Recent evidence implies multiple interactions between intestinal microbiota, innate immunity and xenobiotic metabolism via p-gp. While decreased efflux activity may promote disease susceptibility and drug toxicity, increased efflux activity may confer resistance to therapeutic drugs in IBD. Mice deficient in MDR1 A develop spontaneously chronic colitis, providing a highly valuable murine IBD model for the study of intestinal epithelial barrier function, immunoregulation, infectious co-triggers and novel therapeutic approaches. Possible associations of human ABCB1 gene polymorphisms with IBD susceptibility have been evaluated, but results are inconsistent. Future studies must focus on further elucidation of the pathophysiological relevance and immunological functions of p-gp and how its ambiguous effects could be therapeutically targeted in IBD.

New challenges in perioperative management of pancreatic cancer

Pancreatic ductal adenocarcinoma(PDAC)is the fourth leading cause of cancer-related death in the industrialized world.Despite progress in the understanding of the molecular and genetic basis of this disease,the5-year survival rate has remained low and usually does not exceed 5%.Only 20%-25%of patients present with potentially resectable disease and surgery represents the only chance for a cure.After decades of gemcitabine hegemony and limited therapeutic options,more active chemotherapies are emerging in advanced PDAC,like 5-Fluorouracil,folinic acid,irinotecan and oxaliplatin and nab-paclitaxel plus gemcitabine,that have profoundly impacted therapeutic possibilities.PDAC is considered a systemic disease because of the high rate of relapse after curative surgery in patients with resectable disease at diagnosis.Neoadjuvant strategies in resectable,borderline resectable,or locally advanced pancreatic cancer may improve outcomes.Incorporation of tissue biomarker testing and imaging techniques into preoperative strategies should allow clinicians to identify patients who may ultimately achieve curative benefit from surgery.This review summarizes current knowledge of adjuvant and neoadjuvant treatment for PDAC and discusses the rationale for moving from adjuvant to preoperative and perioperative therapeutic strategies in the current era of more active chemotherapies and personalized medicine.We also discuss the integration of good specimen collection,tissue biomarkers,and imaging tools into newly designed preoperative and perioperative strategies.

N-acetylcysteine and glycyrrhizin combination:Benefit outcome in a murine model of acetaminophen-induced liver failure

BACKGROUND Acetaminophen overdose is the most frequent cause of drug-induced liver failure in developed countries.Substantial progress has been made in understanding the mechanism of hepatocellular injury,but N-acetylcysteine remains the only effective treatment despite its short therapeutic window.Thus,other hepatoprotective drugs are needed for the delayed treatment of acetaminopheninduced hepatotoxicity.Our interest focused on glycyrrhizin for its role as an inhibitor of high mobility group box 1(HMGB1)protein,a member of the family of damage-associated molecular pattern,known to play an important pathological role in various diseases.AIM To investigate the efficacy of the N-acetylcysteine/glycyrrhizin combination compared to N-acetylcysteine alone in the prevention of liver toxicity.METHODS Eight-week-old C57BL/6J wild-type female mice were used for all our experiments.Mice fasted for 15 h were treated with acetaminophen(500 mg/kg)or vehicle(phosphate-buffered saline)by intraperitoneal injection and separated into the following groups:Glycyrrhizin(200 mg/kg);N-acetylcysteine(150 mg/kg);and N-acetylcysteine/glycyrrhizin.In all groups,mice were sacrificed 12 h following acetaminophen administration.The assessment of hepatotoxicity was performed by measuring plasma levels of alanine aminotransferase,aspartate aminotransferase and lactate dehydrogenase.Hepatotoxicity was also evaluated by histological examination of hematoxylin and eosin-stained tissues sections.Survival rates were compared between various groups using Kaplan-Meier curves.RESULTS Consistent with data published in the literature,we confirmed that intraperitoneal administration of acetaminophen(500 mg/kg)in mice induced severe liver injury as evidenced by increases in alanine aminotransferase,aspartate aminotransferase and lactate dehydrogenase but also by liver necrosis score.Glycyrrhizin administration was shown to reduce the release of HMGB1 and significantly decreased the severity of liver injury.Thus,the co-administration of glycyrrhizin and N-acetylcysteine was investigated.Administered concomitantly with acetaminophen,the combination significantly reduced the severity of liver injury.Delayed administration of the combination of drugs,2 h or 6 h after acetaminophen,also induced a significant decrease in hepatocyte necrosis compared to mice treated with N-acetylcysteine alone.In addition,administration of N-acetylcysteine/glycyrrhizin combination was associated with an improved survival rate compared to mice treated with only N-acetylcysteine.CONCLUSION We demonstrate that,compared to N-acetylcysteine alone,co-administration of glycyrrhizin decreases the liver necrosis score and improves survival in a murine model of acetaminophen-induced liver injury.Our study opens a potential new therapeutic pathway in the prevention of acetaminophen hepatotoxicity.

Helminths as an alternative therapy for intestinal diseases

Animal models and clinical studies have shown that helminth infections exert immunomodulatory activity,altering intestinal permeability and providing a potential beneficial action on autoimmune and inflammatory disorders in human beings,such as inflammatory bowel disease(IBD) and celiac disease. This is consistent with the theory that intestinal microbiota is responsible for shaping human immunological responses. With the arrival of the immunobiologic era and the use of antibodies,we propose a distinctive pathway for treating patients with IBD and celiac disease. We have some evidence about the safety and tolerability of helminth use,but evidence about their impact on disease activity is lacking. Using worms to treat diseases could be a possible way to lower treatment costs,since the era of immunobiologic agents is responsible for a significant rise in expenses. Some questions remain to be investigated regarding the use of helminths in intestinal disease,such as the importance of the specific species of helminths used,appropriate dosing regimens,optimal timing of treatment,the role of host genetics,diet,environment,and the elucidation of the exact mechanisms of action. One promising approach is the use of helminth-derived anti-inflammatory molecules as drugs. Yet there are still many challenges with this method,especially with regard to safety. Studies on intestinal permeability point to Strongyloides stercoralis as a useful nematode for these purposes.

Crohn's disease-related'gastrocnemius myalgia syndrome'successfully treated with infliximab:A case report

BACKGROUND Extra-intestinal manifestations in inflammatory bowel diseases(IBD)are frequent and involve virtually all organs.Conversely,the clinical characteristics and course of inflammatory myopathies in IBD remain poorly described and mostly related to orbital myositis.Moreover,alternative therapeutic strategies in non-responder patients to corticosteroid therapy must still be clarified.CASE SUMMARY A 33-year-old woman with a history of unclassified colitis presented with acute bilateral calf pain.On admission,her clinical and biological examinations were non-specific.However,magnetic resonance imaging showed bilateral inflammatory changes in gastrocnemius muscles suggestive of myositis.Muscle biopsy confirmed the diagnosis of myositis and demonstrated an inflammatory infiltrate mainly located in the perimysial compartment including lympho-plasmocytic cells with the formation of several granulomatous structures while the endomysium was relatively spared.The combined clinical,biological and histomyopathological findings were concordant with the diagnosis of‘gastrocnemius myalgia syndrome’(GMS),a rare disorder associated with Crohn’s disease(CD).Ileocolonoscopy confirmed CD diagnosis and systemic corticosteroids(CS)therapy was started,resulting in a rapid clinical improvement.During CS tapering,however,she experienced a relapse of GMS together with a severe active ileocolitis.Infliximab was started and allowed a sustained remission of both conditions at the latest follow-up(20 mo).CONCLUSION The GMS represent a rare CD-associated inflammatory myopathy for which anti-tumour necrosis factor-αtherapy might be considered as an effective therapeutic option.

Ophthalmologic manifestations of celiac disease

Celiac disease is an autoimmune disorder that affects the small intestine of genetically predisposed individuals.Ophthalmic manifestations are within the extra-intestinal manifestations,and can be divided into those of autoimmune disorders or those due to absorptive disabilities.This article reviewed the ophthalmologic manifestation of celiac disease.Ophthalmic symptoms are rare,but should be investigated in patients with celiac disease and taken into consideration as the first systemic manifestation.

The intestinal epithelial response to damage

The constant renewal of the intestinal epithelium is fueled by intestinal stem cells(ISCs) lying at the base of crypts, and these ISCs continuously give rise to transit-amplifying progenitor cells during homeostasis. Upon injury and loss of ISCs, the epithelium has the ability to regenerate by the dedifferentiation of progenitor cells that then regain stemness and repopulate the pool of ISCs. Epithelial cells receive cues from immune cells, mesenchymal cells and the microbiome to maintain homeostasis.This review focuses on the response of the epithelium to damage and the interplay between the different intestinal compartments.

Genetics of alcohol-related hepatocellular carcinoma - its role in risk prediction

Hepatocellular carcinoma(HCC)is the most common primary liver malignancy,with increasing incidence worldwide.Alcohol-related cirrhosis(AC)accounts for 30%of the global incidence of HCC and HCC-related deaths.With the decline of hepatitis C virus(HCV)and decreasing HCV-related HCC,AC will soon become the leading cause of HCC.Excess alcohol consumption(>80 g per day for>10 years)increases the risk of HCC by 5-fold.However,only up to 35%of excessive drinkers develop cirrhosis and its associated HCC risk.Individual variation in susceptibility to HCC is known,but there is limited information to predict who among the patients is at high risk of progressing to HCC.Clinical risk factors for HCC include male gender,older age,severity of cirrhosis,obesity and presence of type 2 diabetes.In addition to ethnic variability in HCC risk,genetic variants are known to alter the risk of alcohol-related HCC.For example,single nucleotide polymorphisms in PNPLA3(rs738409,C>G)and TM6SF2(rs58542926,C>T)increase the risk of AC-related HCC,whereas HSD17B13(T>A)reduces the risk for HCC.Studies have also confirmed PNPLA3 and TM6SF2 to be independent risk factors for AC-related(but not HCV-related)HCC.Combining genetic risk factors with phenotypic/clinical risk factors has been explored for stratification of patients for HCC development.Risk allele rs378409-G in PNPLA3 when combined with phenotypic/clinical risk factors(BMI,age,sex)has enabled HCC risk stratification of AC patients into low-,intermediate-and high-risk subgroups.Similarly,a combination of the two genetic variants PNPLA3-G and TM6SF2-T has been independently associated with risk of HCC onset.Using a polygenic risk score approach of incorporating several genetic variants,prognostic performance of polygenic risk score that included PNPLA3 rs378409 and TM6SF2 rs58542926 improved HCC prediction better than with either variant alone.Incorporating new variants and risk factors has the potential to build better algorithms/models to predict onset,early diagnosis and treatments for AC-related HCC.However,clinical usefulness of these approaches is yet to be determined.