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Nonalcoholic fatty liver disease-A multisystem disease?

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World Journal of Gastroenterology 2016年第43期22卷 9488-9505页

作者： Ivana Mikolasevic sandra milic Tamara Turk Wensveen Ivana Grgic Ivan Jakopcic Davor Stimac Felix Wensveen Lidija Orlic Department of Gastroenterology UHC Rijeka51000 Rijeka Croatia Department of Endocrinology Diabetes and Metabolic Diseases UHC Rijeka51000 Rijeka Croatia Department of Cardiology UHC Rijeka51000 Rijeka Croatia School of Medicine 51000 Rijeka Croatia Department of Histology and Embryology School of Medicine51000 Rijeka Croatia Department of Nephrology Dialysis and Kidney Transplantation UHC Rijeka51000 Rijeka Croatia

Non-alcoholic fatty liver disease(NAFLD) is one of the most common comorbidities associated with overweight and metabolic syndrome(Met S). Importantly, NAFLD is one of its most dangerous complications because it can lead to severe liver pathologies, including fibrosis, cirrhosis and hepatic cellular carcinoma. Given the increasing worldwide prevalence of obesity, NAFLD has become the most common cause of chronic liver disease and therefore is a major global health problem. Currently, NAFLD is predominantly regarded as a hepatic manifestation of Met S. However, accumulating evidence indicates that the effects of NAFLD extend beyond the liver and are negatively associated with a range of chronic diseases, most notably cardiovascular disease(CVD), diabetes mellitus type 2(T2DM) and chronic kidney disease(CKD). It is becoming increasingly clear that these diseases are the result of the same underlying pathophysiological processes associated with Met S, such as insulin resistance, chronic systemic inflammation and dyslipidemia. As a result, they have been shown to be independent reciprocal risk factors. In addition, recent data have shown that NAFLD actively contributes to aggravation of the pathophysiology of CVD, T2 DM, and CKD, as well as several other pathologies. Thus, NAFLD is a direct cause of many chronic diseases associated with MetS, and better detection and treatment of fatty liver disease is therefore urgently needed. As non-invasive screening methods for liver disease become increasingly available, detection and treatment of NAFLD in patients with MetS should therefore be considered by both(sub-) specialists and primary care physicians.

关键词：不含酒精的脂肪肝疾病新陈代谢的症候群糖尿病 mellitus 类型 2 心血管的疾病长期的肾疾病 Multisystem 疾病

Nonalcoholic fatty liver disease and liver transplantation-Where do we stand?

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World Journal of Gastroenterology 2018年第14期24卷 1491-1506页

作者： Ivana Mikolasevic Tajana Filipec-Kanizaj Maja Mijic Ivan Jakopcic sandra milic Irena Hrstic Nikola Sobocan Davor Stimac Patrizia Burra Department of Gastroenterology UHC Rijeka School of Medicine University of Rijeka Department of Gastroenterology University Hospital MerkurSchool of Medicine University of Zagreb Department of Internal medicine General Hospital Pula Pula School of Medicine University of Rijeka and Zagreb Multivisceral Transplant Unit Department of Surgery Oncology and Gastroenterology Padua University Hospital

Nonalcoholic fatty liver disease/nonalcoholic steatohepatitis(NAFLD/NASH) is a challenging and multisystem disease that has a high socioeconomic impact. NAFLD/NASH is a main cause of macrovesicular steatosis and has multiple impacts on liver transplantation(LT), on patients on the waiting list for transplant, on posttransplant setting as well as on organ donors. Current data indicate new trends in the area of chronic liver disease. Due to the increased incidence of metabolic syndrome(Met S) and its components, NASH cirrhosis and hepatocellular carcinoma caused by NASH will soon become a major indication for LT. Furthermore, due to an increasing incidence of Met S and, consequently, NAFLD, there will be more steatotic donor livers and less high quality organs available for LT, in addition to a lack of available liver allografts. Patients who have NASH and are candidates for LT have multiple comorbidities and are unique LT candidates. Finally, we discuss long-term grafts and patient survival after LT, the recurrence of NASH and NASH appearing de novo after transplantation. In addition, we suggest topics and areas that require more research for improving the health care of this increasing patient population.

关键词： nonalcoholic steatohepatitis chronic liver disease liver transplantation nonalcoholic fatty liver disease outcome

Non-alcoholic fatty liver disease and obesity: Biochemical, metabolic and clinical presentations

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World Journal of Gastroenterology 2014年第28期20卷 9330-9337页

作者： sandra milic Davorka Lulic Davor Stimac Division of Gastroenterology Department of Internal MedicineUniversity Hospital Rijeka

Non-alcoholic fatty liver disease(NAFLD)is the most common liver disease in the world.Presentation of the disease ranges from simple steatosis to non-alcoholic steatohepatitis(NASH).NAFLD is a hepatic manifestation of metabolic syndrome that includes central abdominal obesity along with other components.Up to80%of patients with NAFLD are obese,defined as a body mass index(BMI)>30 kg/m2.However,the distribution of fat tissue plays a greater role in insulin resistance than the BMI.The large amount of visceral adipose tissue(VAT)in morbidly obese(BMI>40 kg/m2)individuals contributes to a high prevalence of NAFLD.Free fatty acids derived from VAT tissue,as well as from dietary sources and de novo lipogenesis,are released to the portal venous system.Excess free fatty acids and chronic low-grade inflammation from VAT are considered to be two of the most important factors contributing to liver injury progression in NAFLD.In addition,secretion of adipokines from VAT as well as lipid accumulation in the liver further promotes inflammation through nuclear factor kappa B signaling pathways,which are also activated by free fatty acids,and contribute to insulin resistance.Most NAFLD patients are asymptomatic on clinical presentation,even though some may present with fatigue,dyspepsia,dull pain in the liver and hepatosplenomegaly.Treatment for NAFLD and NASH involves weight reduction through lifestyle modifications,anti-obesity medication and bariatric surgery.This article reviews the available information on the biochemical and metabolic phenotypes associated with obesity and fatty liver disease.The relative contribution of visceral and liver fat to insulin resistance is discussed,and recommendations for clinical evaluation of affected individuals is provided.

关键词： Fatty liver Insulin resistance Intra-abdominal fat

Liver disease in the era of COVID-19: Is the worst yet to come?

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World Journal of Gastroenterology 2021年第36期27卷 6039-6052页

作者： Ivana Mikolasevic Dorotea Bozic Tajana Pavić Alen Ruzic Goran Hauser Marija Radic Delfa Radic-Kristo Melanija Razov-Radas Zeljko Puljiz sandra milic Department of Gastroenterology Clinical Hospital Center RijekaRijeka 51000Croatia Department of Gastroenterology University Hospital MerkurZagreb 10000Croatia Faculty of Medicine University of RijekaRijeka 51000Croatia Department for Gastroenterology and Hepatology University Hospital Center SplitSplit 21000Croatia Department of Gastroenterology and Hepatology Faculty of MedicineSestre Milosrdnice University Hospital CenterZagreb 10000Croatia Clinic for Cardiology University Hospital Center RijekaRijeka 51000Croatia Faculty of Health Studies University of RijekaRijeka 51000Croatia Faculty of Medicine Zagreb 10000Croatia Department of Hematology University Hospital MerkurZagreb 10000Croatia Division of Gastroenterology General Hospital ZadarZadar 23000Croatia University of Split School of MedicineSplit 21000Croatia

The global social,economic and political crises related to coronavirus disease 2019(COVID-19)presumably had more indirect than direct negative impacts on health systems.Drastic lifestyle changes,social isolation and distancing,and individual and global financial crises resulted in robust populations forfeiting healthy habits and seeking comfort in alcoholic beverages,drugs and unhealthy diets.The inevitable consequences are increases in the incidence of nonalcoholic fatty liver disease,viral hepatitis,acute alcoholic hepatitis,liver cirrhosis decompensation and ultimately liver-related mortality.The inaccessibility of regular clinical and sonographic monitoring systems has caused difficulties in the treatment of patients with chronic liver disease(CLD)and has prevented prompt hepatocellular carcinoma detection and treatment.A dramatic reduction in the number of liver donors and the transformation of numerous transplantation centers into COVID-19 units drastically decreased the rate of orthotopic liver transplantation.The indirect,unavoidable effects of the COVID-19 pandemic in the following years have yet to be determined.Substantial efforts in the management of patients with liver disease in order to overcome the inevitable COVID-19-related morbidity and mortality that will follow have yet to be initiated.Several questions regarding the impact of the COVID-19 pandemic on liver disease remain.The most important question for general CLD patients is:How will the modification of clinical practice during this pandemic affect the outcomes of CLD patients?This article reviews the influence of COVID-19 on patients with liver disease during the pandemic,with particular emphasis on the disease course associated with pandemic resolution.

关键词： COVID-19 Pandemic Chronic liver disease Management Impact Liverrelated mortality

Transient elastography(Fibro Scan~?) with controlled attenuation parameter in the assessment of liver steatosis and fibrosis in patients with nonalcoholic fatty liver disease- Where do we stand?

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World Journal of Gastroenterology 2016年第32期22卷 7236-7251页

作者： Ivana Mikolasevic Lidija Orlic Neven Franjic Goran Hauser Davor Stimac sandra milic Department of Gastroenterology UHC Rijeka Department of Nephrology Dialysis and Kidney Transplantation UHC Rijeka

Non-alcoholic fatty liver disease(NAFLD) is the most common cause of chronic liver disease worldwide. Currently, the routinely used modalities are unable to adequately determine the levels of steatosis and fibrosis(laboratory tests and ultrasonography) or cannot be applied as a screening procedure(liver biopsy). Among the non-invasive tests, transient elastography(Fibro Scan?, TE) with controlled attenuation parameter(CAP) has demonstrated good accuracy in quantifying the levels of liver steatosis and fibrosis in patients with NAFLD, the factors associated with the diagnosis and NAFLD progression. The method is fast, reliable and reproducible, with good intra- and interobserver levels of agreement, thus allowing for population-wide screening and disease follow-up. The initial inability of the procedure to accurately determine fibrosis and steatosis in obese patients has been addressed with the development of the obese-specific XL probe. TE with CAP is a viable alternative to ultrasonography, both as an initial assessment and during follow-up of patients with NAFLD. Its ability to exclude patients with advanced fibrosis may be used to identify low-risk NAFLD patients in whom liver biopsy is not needed, therefore reducing the risk of complications and the financial costs.

关键词： Non-alcoholic fatty liver disease Transient elastography Controlled attenuation parameter

Tocotrienol isoforms:The molecular mechanisms underlying their effects in cancer therapy and their implementation in clinical trials

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Journal of Integrative Medicine 2024年第1期22卷 1-11页

作者： Maria Younes Ghady Loubnane Christopher Sleiman sandra Rizk Department of Natural Sciences Lebanese American UniversityByblosLebanon

Tocotrienols are found in a variety of natural sources,like rice bran,annatto seeds and palm oil,and have been shown to have several health-promoting properties,particularly against chronic diseases such as cancer.The incidence of cancer is rapidly increasing around the world,not only a result of continued aging and population growth,but also due to the adoption of aspects of the Western lifestyle,such as high-fat diets and low-physical activity.The literature provides strong evidence that tocotrienols are able to inhibit the growth of various cancers,including breast,lung,ovarian,prostate,liver,brain,colon,myeloma and pancreatic cancers.These findings,along with the reported safety profile of tocotrienols in healthy human volunteers,encourage further research into these compounds’potential use in cancer prevention and treatment.The current review provided detailed information about the molecular mechanisms of action of different tocotrienol isoforms in various cancer models and evaluated the potential therapeutic effects of different vitamin E analogues on important cancer hallmarks,such as cellular proliferation,apoptosis,angiogenesis and metastasis.MEDLINE/PubMed and Scopus databases were used to identify recently published articles that investigated the anticancer effects of vitamin E derivatives in various types of cancer in vitro and in vivo along with clinical evidence of adjuvant chemopreventive benefits.Following an overview of pre-clinical studies,we describe several completed and ongoing clinical trials that are paving the way for the successful implementation of tocotrienols in cancer chemotherapy.

关键词： Vitamin E Tocotrienols Cancer Molecular mechanism Clinical trials

Targeting KRAS in pancreatic cancer

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Oncology Research 2024年第5期32卷 799-805页

作者： sandra STICKLER BARBARA RATH GERHARD HAMILTON Institute of Pharmacology Medical University of ViennaViennaA-1090Austria

Pancreatic cancer has a dismal prognosis due to late detection and lack of efficient therapies.The Kirsten rat sarcoma virus(KRAS)oncogene is mutated in up to 90%of all pancreatic ductal adenocarcinomas(PDACs)and constitutes an attractive target for therapy.However,the most common KRAS mutations in PDAC are G12D(44%),G12V(34%)and G12R(20%)that are not amenable to treatment by KRAS G12C-directed cysteine-reactive KRAS inhibitors such as Sotorasib and Adagrasib that exhibit clinical efficacy in lung cancer.KRAS G12C mutant pancreatic cancer has been treated with Sotorasib but this mutation is detected only in 2%–3%of PDAC.Recently,the KRAS G12D-directed MRTX1133 inhibitor has entered clinical trials and more of such inhibitors are in development.The other KRAS mutations may be targeted indirectly via inhibition of the cognate guanosine exchange factor(GEF)Son of Sevenless 1 that drives KRAS.These agents seem to provide the means to target the most frequent KRAS mutations in PDAC and to improve patient outcomes.

关键词： Pancreatic cancer PDAC KRAS SOS1 PROTAC

Pandemic punch:SARS-CoV-2 hits pancreas

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Signal Transduction and Targeted Therapy 2024年第5期9卷 1779-1780页

作者： Ninel Azoitei sandra Heller Alexander Kleger Institute of Molecular Oncology and Stem Cell Biology Ulm UniversityUlmGermany Division of Interdisciplinary Pancreatology Clinic of Internal Medicine IUniversity Hospital UlmUlmGermany

The COVID-19 pandemic has profoundly impacted global health systems,revealing the extensive repercussions of SARS-CoV-2 beyond respiratory symptoms.Indeed,traditionally considered a respiratory virus,SARS-CoV-2’s showcased the ability to target multiple organ systems including pancreas,an organ crucial for regulating blood sugar levels and aiding digestion.

关键词： pancreas respiratory traditionally

Design multifunctional Mg–Zr coatings regulating Mg alloy bioabsorption

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Journal of Magnesium and Alloys 2024年第4期12卷 1461-1478页

作者： Zohra Benzarti Sandesh Itani JoséDavid Castro sandra Carvalho Ana Sofia Ramos University of Coimbra CEMMPREARISEDepartment of Mechanical EngineeringRua Luís Reis Santos3030-788CoimbraPortugal Laboratory of Multifunctional Materials and Applications(LaMMA) Department of PhysicsFaculty of Sciences of SfaxUniversity of SfaxSoukra Road km 3.5B.P.1171Sfax3000Tunisia

Magnesium(Mg)alloys are widely used for temporary bone implants due to their favorable biodegradability,cytocompatibility,hemocompatibility,and close mechanical properties to bone.However,rapid degradation and inadequate strength limit their applicability.To overcome this,the direct current magnetron sputtering technique is employed for surface coating in Mg-based alloys using various zirconium(Zr)content.This approach presents a promising strategy for simultaneously improving corrosion resistance,maintaining biocompatibility,and enhancing strength without compromising osseointegration.By leveraging Mg’s inherent biodegradability,it has the potential to minimize the need for secondary surgeries,thereby reducing costs and resources.This paper is a systematic study aimed at understanding the corrosion mechanisms of Mg–Zr coatings,denoted Mg-xZr(x=0–5 at.%).Zr-doped coatings exhibited columnar growth leading to denser and refined structures with increasing Zr content.XRD analysis confirmed the presence of the Mg(00.2)basal plane,shifting towards higher angles(1.15°)with 5 at.%Zr doping due to lattice parameter changes(i.e.,decrease and increase of“c”and“a”lattice parameters,respectively).Mg–Zr coatings exhibited“liquidphilic”behavior,while Young’s modulus retained a steady value around 80 GPa across all samples.However,the hardness has significantly improved across all samples’coating,reaching the highest value of(2.2±0.3)GPa for 5 at.%Zr.Electrochemical testing in simulated body fluid(SBF)at 37℃ revealed a significant enhancement in corrosion resistance for Mg–Zr coatings containing 1.0–3.4 at.%Zr.Compared with the 5 at.%Zr coating which exhibited a corrosion rate of 32 mm/year,these coatings displayed lower corrosion rates,ranging from 1 to 12 mm/year.This synergistic enhancement in mechanical properties and corrosion resistance,achieved with 2.0–3.4 at.%Zr,suggests potential ability for reducing stress shielding and controlled degradation performance,and consequently,promising functional biodegradable materials f

关键词： Mg-Zr coatings Magnetron sputtering Nanoindentation Corrosion resistance Bone implants