Pathophysiological mechanisms of hepatic stellate cells activation in liver fibrosis

Liver fibrosis is a complex pathological process controlled by a variety of cells,mediators and signaling pathways.Hepatic stellate cells play a central role in the development of liver fibrosis.In chronic liver disease,hepatic stellate cells undergo dramatic phenotypic activation and acquire fibrogenic properties.This review focuses on the pathophysiological mechanisms of hepatic stellate cells activation in liver fibrosis.They enter the cell cycle under the influence of various triggers.The“Initiation”phase of hepatic stellate cells activation overlaps and continues with the“Perpetuation”phase,which is characterized by a pronounced inflammatory and fibrogenic reaction.This is followed by a resolution phase if the injury subsides.Knowledge of these pathophysiological mechanisms paved the way for drugs aimed at preventing the development and progression of liver fibrosis.In this respect,impairments in intracellular signaling,epigenetic changes and cellular stress response can be the targets of therapy where the goal is to deactivate hepatic stellate cells.Potential antifibrotic therapy may focus on inducing hepatic stellate cells to return to an inactive state through cellular aging,apoptosis,and/or clearance by immune cells,and serve as potential antifibrotic therapy.It is especially important to prevent the formation of liver cirrhosis since the only radical approach to its treatment is liver transplantation which can be performed in only a limited number of countries.

Paroxysmal Kinesigenic Dyskinesia:Genetics and Pathophysiological Mechanisms

Paroxysmal kinesigenic dyskinesia(PKD),the most common type of paroxysmal movement disorder,is characterized by sudden and brief attacks of choreoathetosis or dystonia triggered by sudden voluntary movements.PKD is mainly caused by mutations in the PRRT2 or TMEM151A gene.The exact pathophysiological mechanisms of PKD remain unclear,although the function of PRRT2 protein has been well characterized in the last decade.Based on abnormal ion channels and disturbed synaptic transmission in the absence of PRRT2,PKD may be channelopathy or synaptopathy,or both.In addition,the cerebellum is regarded as the key pathogenic area.Spreading depolarization in the cerebellum is tightly associated with dyskinetic episodes.Whereas,in PKD,other than the cerebellum,the role of the cerebrum including the cortex and thalamus needs to be further investigated.

Sensitive skin syndrome: Research progress on mechanisms and applications

Sensitive skin is a clinical syndrome characterized by a hyper-reactive state of the skin,primarily on the face.It is accompanied by subjective symptoms such as burning,stinging,itching,and tightness when exposed to physical,chemical,or psychological stimuli.Objective signs,such as erythema,scales,and dilated blood vessels,may or may not be present.The discomfort associated with sensitive skin can be triggered by various endogenous and exogenous factors,which usually have no significant effect on the individual and do not induce irritant reactions.Sensitive skin often presents as a subjective state without clinical signs and exhibits diversity,posing challenges in sensitive skin research and care.This review summarizes the prevalence,key factors,pathophysiological mechanisms,diagnosis,and progress in daily care for sensitive skin.The aim is to provide a clearer and more systematic understanding of sensitive skin and offer guidance for sensitive skin care.

Neutrophil elastase:From mechanisms to therapeutic potential

Neutrophil elastase(NE),a major protease in the primary granules of neutrophils,is involved in microbicidal activity.NE is an important factor promoting inflammation,has bactericidal effects,and shortens the inflammatory process.NE also regulates tumor growth by promoting metastasis and tumor microenvironment remodeling.However,NE plays a role in killing tumors under certain conditions and promotes other diseases such as pulmonary ventilation dysfunction.Additionally,it plays a complex role in various physiological processes and mediates several diseases.Sivelestat,a specific NE inhibitor,has strong potential for clinical application,particularly in the treatment of coronavirus disease 2019(COVID-19).This review discusses the pathophysiological processes associated with NE and the potential clinical applications of sivelestat.

The pathophysiological mechanism between hypopituitarism and nonalcoholic fatty liver disease

Nonalcoholic fatty liver disease(NAFLD)is a common chronic metabolic liver disease worldwide.It is closely related to diseases of the cardiovascular system and chronic kidney disease.It can also occur secondary to many other diseases.Current research shows that patients with hypopituitarism have a high risk of developing NAFLD.After the adenohypophysis is dominated by hypothalamic hormones,hormones are secreted to act on the corresponding tissues or organs.It is characterized by a decrease in the thyroid hormone,cortisol,and growth hormone levels.In this review,we analyzed the mechanisms related to NAFLD through thyroid secretion,growth hormone secretion,sex hormone,and prolactin axes in patients with hypopituitarism,which will provide information and a theoretical basis for clinical diagnosis and treatment.

Intervention on toll-like receptors in pancreatic cancer

Pancreatic ductal adenocarcinoma(PDA)is a devastating disease with pronounced morbidity and a high mortality rate.Currently available treatments lack convincing cost-efficiency determinations and are in most cases not associated with relevant success rate.Experimental stimulation of the immune system in murine PDA models has revealed some promising results.Tolllike receptors(TLRs)are pillars of the immune system that have been linked to several forms of malignancy,including lung,breast and colon cancer.In humans,TLRs are expressed in the pancreatic cancer tissue and in several cancer cell lines,whereas they are not expressed in the normal pancreas.In the present review,we explore the current knowledge concerning the role of different TLRs associated to PDA.Even if almost all known TLRs are expressed in the pancreatic cancer microenvironment,there are only five TLRs suggested as possible therapeutic targets.Most data points at TLR2 and TLR9 as effective tumor markers and agonists could potentially be used as e.g.future adjuvant therapies.The elucidation of the role of TLR3 in PDA is only in its initial phase.The inhibition/blockage of TLR4-related pathways has shown some promising effects,but there are still many steps left before TLR4 inhibitors can be considered as possible therapeutic agents.Finally,TLR7 antagonists seem to be potential candidates for therapy.Independent of their potential in immunotherapies,all existing data indicate that TLRs are strongly involved in the pathophysiology and development of PDA.

Acute liver injury in COVID-19 patients hospitalized in the intensive care unit:Narrative review

In recent years,humanity has been confronted with a global pandemic due to coronavirus disease 2019(COVID-19),which has caused an unprecedented health and economic crisis worldwide.Apart from the respiratory symptoms,which are considered the principal manifestations of COVID-19,it has been recognized that COVID-19 constitutes a systemic inflammatory process affecting multiple organ systems.Across the spectrum of organ involvement in COVID-19,acute liver injury(ALI)has been gradually gaining increasing attention by the international scientific community.COVID-19 associated liver impairment can affect a considerable proportion of COVID-19 patients and seems to correlate with the severity of the disease course.Indeed,COVID-19 patients hospitalized in the intensive care unit(ICU)run a greater risk of developing ALI due to the severity of their clinical condition and in the context of multi-organ failure.The putative pathophysiological mechanisms of COVID-19 induced ALI in ICU patients remain poorly understood and appear to be multifactorial in nature.Several theories have been proposed to explain the occurrence of ALI in the ICU setting,such as hypoperfusion and ischemia due to hemodynamic instability,passive liver congestion as a result of congestive heart failure,ischemia-reperfusion injury,hypoxia due to respiratory failure,mechanical ventilation itself,sepsis and septic shock,cytokine storm,endotheliitis with concomitant coagulopathy,druginduced liver injury,parenteral nutrition and direct cytopathic viral effect.It should be noted that no specific therapy for COVID-19 induced ALI exists.Therefore,the therapeutic approach lies in preventive measures and is exclusively supportive once ALI ensues.The aim of the current review is to scrutinize the existing evidence on COVID-19 associated ALI in ICU patients,explore its clinical implications,shed light on the underlying pathophysiological mechanisms and propose potential therapeutic approaches.Ongoing research on the particular scientific field will further elucidate the pathophysiology behind ALI and address unresolved issues,in the hope of mitigating the tremendous health consequences imposed by COVID-19 on ICU patients.

Tako-tsubo cardiomyopathy

Tako-tsubo cardiomyopathy（TC） is a recently described acute cardiac syndrome, which the latest cardiomyopathy classification of the European Society of Cardiology describes as an unclassified cardiomyopathy. TC mimics acute myocardial infarction（AMI） and is characterised by ischaemic chest symptoms, an elevated electrocardiogram ST-segment, and moderately increased levels of cardiac disease markers. However, patients with TC have no coronary angiogram-detectable or non-obstructive coronary arterial disease（CAD）, and left ventriculography documents transient left apical and middle ventricular wall dysfunction. In this review, we describe TC and evaluate epidemiological, clinical and instrumental features, pathophysiological mechanisms, therapy and prognosis of this syndrome,with a view to raising awareness of the disease.