Alcohol,inflammation,and gut-liver-brain interactions in tissue damage and disease development

Chronic inflammation is often associated with alcoholrelated medical conditions. The key inducer of such inflammation, and also the best understood, is gut microflora-derived lipopolysaccharide (LPS). Alcohol can significantly increase the translocation of LPS from the gut. In healthy individuals, the adverse effects of LPS are kept in check by the actions and interactions of multiple organs. The liver plays a central role in detoxifying LPS and producing a balanced cytokine milieu. The central nervous system contributes to anti-inflammatory regulation through neuroimmunoendocrine actions. Chronic alcohol use impairs not only gut and liver functions, but also multi-organ interactions, leading to persistent systemic inflammation and ultimately, to organ damage. The study of these interactions may provide potential new targets for therapeutic intervention.

Diagnostic Prospectives with Tau Protein and Imaging Techniques to Detect Development of Chronic Traumatic Encephalopathy

Brain damage sustained from repeated blows in boxing, wrestling, and other combat sports has serious physical and mental health consequences. The degenerative brain disease, chronic traumatic encephalopathy (CTE), presents clinically with memory loss, aggression, difficulty in rational thinking and other cognitive problems. This spectrum, which mimics Alzheimer’s disease, is diagnosed post-mortem through a brain biopsy in many professional athletes. However, little is known about the process of development and how to identify vulnerable individuals who may be on course for developing CTE. Boxing is a sport that has a severe toll on athletes’ health, primarily on their brain health and function. This review addresses the concerns of brain injury, describes the pathologies that manifest in multiple scales, e.g., molecular and cognitive, and also proposes possible diagnostic and prognostic markers to characterize the early onset of CTE along with the aim to identify a starting point for future precautions and interventions.

Aldehyde dehydrogenase 2 suppresses cirrhosis and alcohol-induced hepatocellular carcinoma via the inhibition of acetaldehyde-derived DNA damage and multiple oncogenic signaling pathways

Objective:Hepatocellular carcinoma(HCC)is the most common primary liver cancer,the fifth most common cancer and the third most common global cause of cancer related deaths.Chronic alcohol consumption is a well-known risk factor for HCC.Acetaldehyde,a main metabolite of ethanol oxidation.

Neuroprotective effects of berry fruits on neurodegenerative diseases

Recent clinical research has demonstrated that berry fruits can prevent age-related neurodegenerative diseases and improve motor and cognitive functions. The berry fruits are also capable of modulating signaling pathways involved in inflammation, cell survival, neurotransmission and enhancing neuroplasticity. The neuroprotective effects of berry fruits on neurodegenerative diseases are related to phytochemicals such as anthocyanin, caffeic acid, catechin, quercetin, kaempferol and tannin. In this review, we made an attempt to clearly describe the beneficial effects of various types of berries as promising neuroprotective agents.

What' s New in Alcoholic Hepatitis

Alcoholic hepatitis (AH) was first reported in 1961 as an acute disease in alcoholics with severe clinical syndromes including jaundice, anorexia, nausea, upper abdominal pain, hepatomegaly and fever etc. 1 Today, it is generally accepted that severe AH is a form of acute - on - chronic liver failure in patients with underlying chronic alcohol - related liver disease ( ALD). The detailed diagnosis of AH was recently defined by the National Institute on Alcohol Abuse and Alcoholism ( NIAAA)- supported consortia and published in 2016. 2 The first diagnostic criterion is alcohol drinking history, which includes heavy drinking > 5 years, recent drinking > 6 months with < 60 days of abstinence before the onset of jaundice, and men with >4 drinks ( 50 -60 g)/day, and women with >3 drinks ( 40 g)/day. The typical clinical sign is jaundice with some non - specific signs and symptoms including malaise, tender hepatomegaly, decompensation (ascites, encephalopathy, bacterial infection, variceal bleeding).

Thoracotomy of an asymptomatic, functional, posterior mediastinal paraganglioma: A case report

BACKGROUND Paragangliomas in the mediastinum are rare, accounting for only 1%-2% of all paragangliomas and < 0.3% of all mediastinal tumors. Most paragangliomas are nonfunctional, therefore, asymptomatic functional paragangliomas in the left posterior mediastinum are extremely rare. Perioperative management including preoperative preparation, careful intraoperative procedures, and strict postoperative care is important, and one-stage surgical resection should be performed only after appropriate perioperative measures are undertaken. Because those tumors are rare, it is necessary to report known cases to raise awareness regarding them. CASE SUMMARY We report the case of a 47-year-old male who was admitted to our hospital with the chief complaints of intermittent tearing pain on the left side of the chest and back for more than 10 mo. A chest contrast-enhanced computed tomography scan revealed a round, solid mass in the left posterior mediastinum, with low-density cystic lesions in the middle, and no enlarged lymph nodes in the hilum or mediastinum (Figure 1). After the diagnosis of paraganglioma, the patient was preoperatively given an oral adrenoceptor blocking drug (phenoxybenzamine), and intravenous fluid resuscitation for two weeks, subsequently the patient underwent a one-stage resection of lesions via left thoracotomy. The patient’s blood pressure increased to 220/120 mmHg when the tumor was touched, which could be relieved by symptomatic treatment such as accelerating liquid transfusion or other intervention to lower blood pressure. The patient recovered uneventfully after surgery, with no abnormal blood pressure or recurrence during one year of follow-up visits.CONCLUSION Surgical resection is the preferred treatment for asymptomatic functional paragangliomas.

Beneficial effects of date palm fruits on neurodegenerative diseases

Date palm tree（Phoenix dactylifera L.）is an important crop,which is cultivated in many countries extending from North Africa to the Middle East,including many of the GCC（Gulf Cooperation Council）Countries（Allaith,2008）.

The alteration of immune cells in the pathogenesis of non-alcoholic fatty liver disease and non-alcoholic steatohepatitis

The prevalence of non-alcoholic fatty liver disease(NAFLD)increases rapidly in recent decades.NAFLD has become a major public health problem in China and the whole world,and it is considered as the main cause for the chronic liver diseases.However,there is still not specific and effective treatment for non-alcoholic steatohepatitis(NASH),the advanced form of NAFLD.The inflammation in the liver is the hallmark of NASH.Actually,the dysregulation of immune cells happened in the early stage of NAFLD.Targeting immune cells in the liver may represent one of the effective ways for NASH treatment.A better understanding of the change of immune cells in the pathogenesis of NAFLD will be very helpful for developing new treatments for NAFLD and NASH.Here we summarized how the immune cells were affected in different stages of NAFLD and how these immune cells contributed to the development of NAFLD.

急性胆囊炎:世界急诊外科学会立场声明

背景:关于急性结石性胆囊炎的诊断、严重性分级、治疗策略、手术时机等方面仍存在较大的争议。材料与方法:本研究是关于急性胆囊炎治疗的系统性回顾,同时,根据所得结论对近期相关指南中所提及的推荐意见进行验证。结果:回顾性分析结果支持指南中关于应用腹腔镜下胆囊切除术治疗急性胆囊炎的推荐意见。同时,由于早期处理可以降低住院天数以及不会增加手术并发症的发生率和术后继发合并症的机会,因此,建议一经诊断应尽快手术。关于抗菌药物的作用所持观点并不一致,还应关注其耐药情况。部分学者主张对有进行性加重的炎症或出现严重并发症的急性胆囊炎患者进行手术或经皮穿刺胆囊引流,回顾性分析结果暂不支持这一观点,有待进一步研究。

JAK-STAT信号通路及STAT蛋白在慢性肝病中的研究进展

1 JAK-STAT通路及其激活和调控1.1 JAK-STAT通路组成JAKs是一类胞浆内可溶性非受体酪氨酸蛋白激酶,分子量在120～140 kD左右。JAKs具有7个保守的同源结构域（JAK homology domain,JH）JH1～JH7。家族中已发现四个成员,即JAK1、JAK2、JAK3和Tyk2。

IL-6-deficient Mice Are Susceptible to Ethanol-induced Hepatic Steatosis:IL-6 Protects against Ethanol-induced Oxidative Stress and Mitochondrial Permeability Transition in the Liver

Interleukin-6(IL-6)-deficient mice are prone to ethanol-induced apoptosis and steatosis in the liver;however, the underlying mechanism is not fully understood.Mitochondrial dysfunction caused by oxidative stress is an early event that plays an important role in the pathogenesis of alcoholic liver disease.Therefore,we hypothesize that the protective role of IL-6 in ethanol-induced liver injury is mediated via suppression of ethanol-induced oxidative stress and mitochondrial dysfunction.To test this hypothesis,we examined the effects of IL-6 on ethanol-induced oxidative stress,mitochondrial injury,and energy depletion in the livers of IL-6(-/-)mice and hepatocytes from ethanol-fed rats.Ethanol consumption leads to stronger induction of malondialdehyde(MDA) in IL-6(-/-)mice compared to wild-type control mice,which can be corrected by administration of IL-6.In vitro, IL-6 treatment prevents ethanol-mediated induction of reactive oxygen species(ROS),MDA,mitochondrial permeability transition(MPT),and ethanol-mediated depletion of adenosine triphosphate(ATP)in hepatocytes from ethanol-fed rats.Administration of IL-6 in vivo also reverses ethanol-induced MDA and ATP depletion in hepatocytes.Finally,IL-6 treatment induces metallothionein protein expression,but not superoxide dismutase and glutathione peroxidase in cultured hepatocytes.In conclusion,IL-6 protects against ethanol-induced oxidative stress and mitochondrial dysfunction in hepatocytes via induction of metailothionein protein expression,which may account for the protective role of IL-6 in alcoholic liver disease.Cellular & Molecular Immunology.2004;1(3):205-211.

Kupffer cell restoration after partial hepatectomy is mainly driven by local cell proliferation in IL-6-dependent autocrine and paracrine manners

Kupffer cells(KCs),which are liver-resident macrophages,originate from the fetal yolk sac and represent one of the largest macrophage populations in the body.However,the current data on the origin of the cells that restore macrophages during liver injury and regeneration remain controversial.Here,we address the question of whether liver macrophage restoration results from circulating monocyte infiltration or local KC proliferation in regenerating livers after partial hepatectomy(PHx)and uncover the underlying mechanisms.By using several strains of genetically modified mice and performing immunohistochemical analyses,we demonstrated that local KC proliferation mainly contributed to the restoration of liver macrophages after PHx.Peak KC proliferation was impaired in Il6-knockout(KO)mice and restored after the administration of IL-6 protein,whereas KC proliferation was not affected in Il4-KO or Csf2-KO mice.The source of IL-6 was identified using hepatocyte-and myeloid-specific Il6-KO mice and the results revealed that both hepatocytes and myeloid cells contribute to IL-6 production after PHx.Moreover,peak KC proliferation was also impaired in myeloid-specific Il6 receptor-KO mice after PHx,suggesting that IL-6 signaling directly promotes KC proliferation.Studies using several inhibitors to block the IL-6 signaling pathway revealed that sirtuin 1(SIRT1)contributed to IL-6-mediated KC proliferation in vitro.Genetic deletion of the Sirt1 gene in myeloid cells,including KCs,impaired KC proliferation after PHx.In conclusion,our data suggest that KC repopulation after PHx is mainly driven by local KC proliferation,which is dependent on IL-6 and SIRT1 activation in KCs.

Ketamine use disorder:preclinical,clinical,and neuroimaging evidence to support proposed mechanisms of actions

Ketamine,a noncompetitive N-methyl-D-aspartate(NMDA)receptor antagonist,has been exclusively used as an anesthetic in medicine and has led to new insights into the pathophysiology of neuropsychiatric disorders.Clinical studies have shown that low subanesthetic doses of ketamine produce antidepressant effects for individuals with depression.However,its use as a treatment for psychiatric disorders has been limited due to its reinforcing effects and high potential for diversion and misuse.Preclinical studies have focused on understanding the molecular mechanisms underlying ketamine’s antidepressant effects,but a precise mechanism had yet to be elucidated.Here we review different hypotheses for ketamine’s mechanism of action including the direct inhibition and disinhibition of NMDA receptors,aminomethylphosphonic acid receptors(AMPAR)activation,and heightened activation of monoaminergic systems.The proposed mechanisms are not mutually exclusive,and their combined influence may exert the observed structural and functional neural impairments.Long term use of ketamine induces brain structural,functional impairments,and neurodevelopmental effects in both rodents and humans.Its misuse has increased rapidly in the past 20 years and is one of the most common addictive drugs used in Asia.The proposed mechanisms of action and supporting neuroimaging data allow for the development of tools to identify‘biotypes’of ketamine use disorder(KUD)using machine learning approaches,which could inform intervention and treatment.

Th17 cells and their associated cytokines in liver diseases

T helper 17(Th17)cells are a newly identified subset of T helper cells that play important roles in host defense against extracellular bacteria as well as in the pathogenesis of autoimmune disease.The functions of Th17 cells are mediated via the production of several cytokines including interleukin(IL)-17 and IL-22.Recent studies show that the frequency of IL-171 cells is significantly elevated in a variety of chronic liver diseases including alcoholic liver disease,viral hepatitis and hepatocellular carcinoma.IL-17 receptor is expressed virtually on all types of liver cells,while IL-22 receptor expression is restricted to epithelial cells including hepatocytes in the liver.IL-17 seems to play an important role in inducing liver inflammation via stimulating multiple types of liver nonparenchymal cells to produce proinflammatory cytokines and chemokines,while IL-22 appears to be an important factor in promoting hepatocyte survival and proliferation.

Immunopathobiology and therapeutic targets related to cytokines in liver diseases

Chronic liver injury with any etiology can progress to fibrosis and the end-stage diseases cirrhosis and hepatocellular carcinoma.The progression of liver disease is controlled by a variety of factors,including liver injury,inflammatory cells,inflammatory mediators,cytokines,and the gut microbiome.In the current review,we discuss recent data on a large number of cytokines that play important roles in regulating liver injury,inflammation,fibrosis,and regeneration,with a focus on interferons and T helper(Th)1,Th2,Th9,Th17,interleukin(IL)-1 family,IL-6 family,and IL-20 family cytokines.Hepatocytes can also produce certain cytokines(such as IL-7,IL-11;and IL-33),and the functions of these cytokines in the liver are briefly summarized.Several cytokines have great therapeutic potential,and some are currently being tested as therapeutic targets in clinical trials for the treatment of liver diseases,which are also described.

Invariant natural killer T cells contribute to chronic-plus-binge ethanol-mediated liver injury by promoting hepatic neutrophil infiltration

Neutrophil infiltration is a hallmark of alcoholic steatohepatitis; however, the underlying mechanisms remain unclear. We previously reported that chronic-plus-binge ethanol feeding synergistically induces hepatic recruitment of neutrophils, which contributes to liver injury. In this paper, we investigated the roles of invariant natural killer T （iNKT） cells in chronic-plus-binge ethanol feeding-induced hepatic neutrophil infiltration and liver injury. Wild-type and two strains of iNKT cell-deficient mice （CDld- and Ja18-deficient mice） were subjected to chronic-plus-binge ethanol feeding. Liver injury and inflammation were examined. Chronic-plus-binge ethanol feeding synergistically increased the number of hepatic iNKT cells and induced their activation, compared with chronic feeding or binge alone, iNKT cell-deficient mice were protected from chronic-plus-binge ethanol-induced hepatic neutrophil infiltration and liver injury. Moreover, chronic-plus-binge ethanol feeding markedly upregulated the hepatic expression of several genes associated with inflammation and neutrophil recruitment in wild-type mice, but induction of these genes was abrogated in iNKT cell-deficient mice. Importantly, several cytokines and chemokines （e.g., MIP-2, MIP-1, IL-4, IL-6 and osteopontin） involved in neutrophil infiltration were upregulated in hepatic NKT cells isolated from chronic-plus-binge ethanol-fed mice compared to pair-fed mice. Finally, treatment with CDld blocking antibody, which blocks iNKT cell activation, partially prevented chronic-plus-binge ethanol-induced liver injury and inflammation. Chronic-plus-binge ethanol feeding activates hepatic iNKT cells, which play a critical role in the development of early alcoholic liver injury, in part by releasing mediators that recruit neutrophils to the liver, and thus, iNKT cells represent a potential therapeutic target for the treatment of alcoholic liver disease.

Altered Endothelin-1 Signaling in Production of Thromboxane A_(2) in Kupffer Cells from Bile Duct Ligated Rats

Kupffer cells(KCs),the liver resident macrophages accounting for 80-90%of the total population of fixed tissue macrophages in the body,not only play a key role in host defense via removing particulate materials from the portal circulation,but may also contribute to the pathogenesis of various liver diseases.We have previously demonstrated that KCs play an important role in controlling portal hypertension and hepatocellular injury via releasing thromboxane A_(2)(TXA_(2))in early fibrosis induced by one-week bile duct ligation(BDL).Production of TXA_(2) is controlled by cytosolic phospholipase A_(2)(cPLA_(2))that is activated by the interaction of entothelin-1(ET-1)with its G-protein coupled ET receptor B(ETBR).However,the signaling pathways that contribute to the ET-1-induced activation of cPLA_(2) and production of TXA_(2) in KCs in the normal healthy or injured livers are not yet clear,which are investigated in the present study using isolated KCs from one-week BDL or sham rats.The pharmacological inhibition of cPLA_(2) or chelation of intracellular calcium abrogated the ET-1 induction of TXA_(2) from KCs.Compared to those from sham rats,KCs from BDL animals displayed a significantly enhanced responsiveness of p38 MAPK to ET-1,increased ETBR and Gai subunit but decreased Gaq and Ga11 expression.Inhibition of ERK1/2 or Gq signaling abrogated significantly the ET-1 induction of TXA_(2) in sham KCs but only slightly in BDL KCs.In contrast,inhibition of p38 MAPK and Gi signaling markedly attenuated the ET-1 induction of TXA_(2) in BDL KCs but had no effect in sham KCs.Lastly,inhibition of PLC or PKC abrogated ET-1 induction of TXA_(2) in KCs from both sham and BDL groups.The hepatic stress(such as BDL)induces significant modifications in the receptor and intermediates of ET-1 signaling in KC and subsequently alters ET-1 signaling mechanisms,particularly a shift from Gq induced signaling to Gi induced signaling,in the activation of cPLA_(2) and production of TXA_(2) in response to ET-1.

Interleukin-22 in the pathogenesis and potential treatment of liver diseases

Interleukin(IL)-22,a member of the IL-10 cytokine family,plays critical roles in tissue repair and host defense.IL-22 binds to its hetereodimeric receptor(R)composed of IL-22R1 and IL-10R2 and activates downstream signaling,including Signal transducer and activator of transcription 3(STAT3)pathways.IL-22 promotes the expression of survival genes in a STAT3-dependent manner.IL-22R1 expression is restricted mainly in epithelial cells while IL-10R2 is ubiquitously expressed in almost all cell types.In the liver,IL-22R1 is expressed in hepatocytes,liver progenitor cells,hepatic stellate cells and liver cancer cells.IL-22 protects the liver in various liver damage models and promotes liver regeneration after liver injury.IL-22 also helps to resolve liver fibrosis by inducing hepatic stellate cell senescence.IL-22 is considered a pro-inflammatory cytokine in viral hepatitis although it does not directly act on immune cells.IL-22 is reported to be involved in the development of liver cancer and in regulating energy metabolism.Studies on IL-22 in liver inflammation,injury and repair will provide valuable information to clarify IL-22 as a potential candidate for treating liver injury and fibrosis.

Fatty liver diseases:Recent advances and challenges

Fatty liver diseases including alcoholic and non-alcoholic forms are the leading causes of chronic liver diseases in the western countries,and are becoming the leading causes of chronic liver diseases in China due to the effective treatment and prevention of viral hepatitis.

Hepatocytes： a key cell type for innate immunity

Hepatocytes, the major parenchymal cells in the liver, play pivotal roles in metabolism, detoxification, and protein synthesis. Hepatocytes also activate innate immunity against invading microorganisms by secreting innate immunity proteins. These proteins include bactericidal proteins that directly kill bacteria, opsonins that assist in the phagocytosis of foreign bacteria, iron-sequestering proteins that block iron uptake by bacteria, several soluble factors that regulate lipopolysaccharide signaling, and the coagulation factor fibrinogen that activates innate immunity. In this review, we summarize the wide variety of innate immunity proteins produced by hepatocytes and discuss liver-enriched transcription factors （e.g. hepatocyte nuclear factors and CCAAT/enhancer-binding proteins）, pro-inflammatory mediators （e.g. interleukin （IL）-6, IL-22, IL-lp and tumor necrosis factor-a）, and downstream signaling pathways （e.g. signal transducer and activator of transcription factor 3 and nuclear factor-KB） that regulate the expression of these innate immunity proteins. We also briefly discuss the dysregulation of these innate immunity proteins in chronic liver disease, which may contribute to an increased susceDtibilitv to bacterial infection in oatients with cirrhosis.