Classical bovine spongiform encephalopathy and chronic wasting disease:two sides of the prion coin

Transmissible spongiform encephalopathies(TSEs)are a group of progressive and ultimately fatal neurologic diseases of man and animals,all resulting from the propagated misfolding of the host's normal cellular prion protein.These diseases can be spontaneous,heritable,anthropogenic/iatrogenic,or in some cases horizontally transmissible,and include such notable TSEs as bovine spongiform encephalopathy(BSE)of cattle and chronic wasting disease(CWD)of cervids.Although they are both unequivocally protein misfolding disorders,they differ markedly in their pathogenesis,transmissibility,and zoonotic potential.While the BSE epidemic has largely abated over the past three decades following global feed bans on ruminant meat and bone meal,CWD,which is readily transmitted through various forms of excreta,has rapidly expanded from its original endemic zone to encompass much of North America,along with recently identified foci in Scandinavia.Most importantly,although the classical form of BSE has proven transmissible to humans consuming contaminated beef or beef products,so far there have been no conclusive reports on the zoonotic transmission of cWD to humans.The underlying basis for these differences-whether host or agent directed-are not well understood,though may be due to inherent differences in the three-dimensional structure of the misfolded BSE or CWD prion proteins or the expression levels and tissue distribution of respective cellular prion proteins.With the uncontrolled geographic spread of CWD,it is imperative that we improve our understanding of the factors governing prion disease pathogenesis,transmission,and zoonotic potential.

Glycolytic dysregulation in Alzheimer's disease:unveiling new avenues for understanding pathogenesis and improving therapy

Alzheimer's disease poses a significant global health challenge owing to the progressive cognitive decline of patients and absence of curative treatments.The current therapeutic strategies,primarily based on cholinesterase inhibitors and N-methyl-Daspartate receptor antagonists,offer limited symptomatic relief without halting disease progression,highlighting an urgent need for novel research directions that address the key mechanisms underlying Alzheimer's disease.Recent studies have provided insights into the critical role of glycolysis,a fundamental energy metabolism pathway in the brain,in the pathogenesis of Alzheimer's disease.Alterations in glycolytic processes within neurons and glial cells,including microglia,astrocytes,and oligodendrocytes,have been identified as significant contributors to the pathological landscape of Alzheimer's disease.Glycolytic changes impact neuronal health and function,thus offering promising targets for therapeutic intervention.The purpose of this review is to consolidate current knowledge on the modifications in glycolysis associated with Alzheimer's disease and explore the mechanisms by which these abnormalities contribute to disease onset and progression.Comprehensive focus on the pathways through which glycolytic dysfunction influences Alzheimer's disease pathology should provide insights into potential therapeutic targets and strategies that pave the way for groundbreaking treatments,emphasizing the importance of understanding metabolic processes in the quest for clarification and management of Alzheimer's disease.

Team players in the pathogenesis of metabolic dysfunctionsassociated steatotic liver disease:The basis of development of pharmacotherapy

Nutrient metabolism is regulated by several factors.Social determinants of health with or without genetics are the primary regulator of metabolism,and an unhealthy lifestyle affects all modulators and mediators,leading to the adaptation and finally to the exhaustion of cellular functions.Hepatic steatosis is defined by presence of fat in more than 5%of hepatocytes.In hepatocytes,fat is stored as triglycerides in lipid droplet.Hepatic steatosis results from a combination of multiple intracellular processes.In a healthy individual nutrient metabolism is regulated at several steps.It ranges from the selection of nutrients in a grocery store to the last step of consumption of ATP as an energy or as a building block of a cell as structural component.Several hormones,peptides,and genes have been described that participate in nutrient metabolism.Several enzymes participate in each nutrient metabolism as described above from ingestion to generation of ATP.As of now several publications have revealed very intricate regulation of nutrient metabolism,where most of the regulatory factors are tied to each other bidirectionally,making it difficult to comprehend chronological sequence of events.Insulin hormone is the primary regulator of all nutrients’metabolism both in prandial and fasting states.Insulin exerts its effects directly and indirectly on enzymes involved in the three main cellular function processes;metabolic,inflammation and repair,and cell growth and regeneration.Final regulators that control the enzymatic functions through stimulation or suppression of a cell are nuclear receptors in especially farnesoid X receptor and peroxisome proliferator-activated receptor/RXR ligands,adiponectin,leptin,and adiponutrin.Insulin hormone has direct effect on these final modulators.Whereas blood glucose level,serum lipids,incretin hormones,bile acids in conjunction with microbiota are intermediary modulators which are controlled by lifestyle.The purpose of this review is to overview the key players in the pathogenesis of metabolic dysfunction-associated steatotic liver disease(MASLD)that help us understand the disease natural course,risk stratification,role of lifestyle and pharmacotherapy in each individual patient with MASLD to achieve personalized care and target the practice of precision medicine.PubMed and Google Scholar databases were used to identify publication related to metabolism of carbohydrate and fat in states of health and disease states;MASLD,cardiovascular disease and cancer.More than 1000 publications including original research and review papers were reviewed.

Immune and metabolic cross-links in the pathogenesis of comorbid non-alcoholic fatty liver disease

In recent years,there has been a steady growth of interest in non-alcoholic fatty liver disease(NAFLD),which is associated with negative epidemiological data on the prevalence of the disease and its clinical significance.NAFLD is closely related to the metabolic syndrome and these relationships are the subject of active research.A growing body of evidence shows cross-linkages between metabolic abnormalities and the innate immune system in the development and progression of NAFLD.These links are bidirectional and largely still unclear,but a better understanding of them will improve the quality of diagnosis and management of patients.In addition,lipid metabolic disorders and the innate immune system link NAFLD with other diseases,such as atherosclerosis,which is of great clinical importance.

Clinical characteristics of acute non-varicose upper gastrointestinal bleeding and the effect of endoscopic hemostasis

BACKGROUND Acute non-variceal upper gastrointestinal bleeding(ANVUGIB)constitutes a prevalent emergency within Gastroenterology,encompassing 80%-90%of all gastrointestinal hemorrhage incidents.This condition is distinguished by its abrupt onset,swift progression,and notably elevated mortality rate.AIM To gather clinical data from patients with ANVUGIB at our hospital in order to elucidate the clinical characteristics specific to our institution and analyze the therapeutic effectiveness of endoscopic hemostasis.METHODS We retrospectively retrieved the records of 532 patients diagnosed with ANVUGIB by endoscopy at our hospital between March 2021 and March 2023,utilizing our medical record system.Data pertaining to general patient information,etiological factors,disease outcomes,and other relevant variables were meticulously collected and analyzed.RESULTS Among the 532 patients diagnosed with ANVUGIB,the male-to-female ratio was 2.91:1,with a higher prevalence among males.Notably,43.6%of patients presented with black stool as their primary complaint,while 27.4%had hematemesis as their initial symptom.Upon admission,17%of patients exhibited both hematemesis and black stool,while most ANVUGIB patients primarily complained of overt gastrointestinal bleeding.Urgent routine blood examinations at admission revealed that 75.8%of patients had anemia,with 63.4%experiencing moderate to severe anemia,and 1.5%having extremely severe anemia(hemoglobin<30 g/L).With regard to etiology,53.2%of patients experienced bleeding without a definitive trigger,24.2%had a history of using gastric mucosa-irritating medications,24.2%developed bleeding after alcohol consumption,2.8%attributed it to improper diet,1.7%to emotional excitement,and 2.3%to fatigue preceding the bleeding episode.Drug-induced ANVUGIB was more prevalent in the elderly than middle-aged and young individuals,while bleeding due to alcohol consumption showed the opposite trend.Additionally,diet-related bleeding was more common among the young age group compared to the middle-aged group.Gastrointestinal endoscopy identified peptic ulcers as the most frequent cause of ANVUGIB(73.3%),followed by gastrointestinal malignancies(10.9%),acute gastric mucous lesions(9.8%),and androgenic upper gastrointestinal bleeding(1.5%)among inpatients with ANVUGIB.Of the 532 patients with gastrointestinal bleeding,68 underwent endoscopic hemostasis,resulting in an endoscopic treatment rate of 12.8%,with a high immediate hemostasis success rate of 94.1%.

Advances in the research of intestinal fungi in Crohn's disease

This article reviews of the original research published by Wu et al in the World Journal of Gastroenterology,delving into the pivotal role of the gut microbiota in the pathogenesis of Crohn's disease(CD).Insights were gained from fecal microbiota transplantation(FMT)in mouse models,revealing the intricate interplay between the gut microbiota,mesenteric adipose tissue(MAT),and creeping fat.The study uncovered the characteristics of inflammation and fibrosis in the MAT and intestinal tissues of patients with CD;moreover,through the FMT mouse model,it observed the impact of samples from healthy patients and those with CD on symptoms.The pathogenesis of CD is complex,and its etiology remains unclear;however,it is widely believed that gut microbiota dysbiosis plays a significant role.Recently,with the development and application of next-generation sequen-cing technology,research on the role of fungi in the pathogenesis and chronicity of CD has deepened.This editorial serves as a supplement to the research by Wu et al who discussed advances related to the study of fungi in CD.

Advances in microRNA and inflammatory bowel disease and their related mechanisms

Inflammatory bowel disease(IBD)is a complex and multifactorial disease characterized by chronic inflammation of the gastrointestinal tract,mainly manifested by the accumulation of immune cells and pro-inflammatory cytokines in the intestinal mucosa.It is a kind of immune digestive system disease with high incidence in humans and can be divided into ulcerative colitis(UC)and Crohn's disease(CD).The pathogenesis of IBD is complex,and numerous studies have shown that genetic,environmental,microbial,immune,autophagy and other factors may be involved in the pathogenesis of IBD.MicroRNAs(miRNAs)play an important role in the pathophysiology of IBD.Studies have confirmed that miRNA play an important role in the targeted regulation of intestinal barrier homeostasis,immune response,and intestinal epithelial autophagy.MiRNA have not only been confirmed as important diagnostic biomarkers for IBD.It also shows new prospects for treatment strategies for IBD.This article mainly describes the differences in miRNA expression between UC and CD,summarizes the relationship between miRNA and intestinal barrier,immune homeostasis and autophagy mechanism in the pathogenesis of IBD,and the research progress of miRNA involved in the diagnosis and treatment of IBD,so as to provide new insights for the development of IBD.

On the role of RNA binding proteins in polyglutamine diseases:from pathogenesis to therapeutics

Polyglutamine(polyQ) diseases are a group of different neurodegenerative disorders characterized by an abnormal expansion of the trinucleotide cytosine-adenine-guanine(CAG)within coding regions of each disease-associated gene.The abnormal expansion translates into a protein bearing an abnormally long tract of glutamines.

Mortality from chronic liver disease:Recent trends and impact of the COVID-19 pandemic

Prepandemic time trends in mortality from chronic liver disease(CLD)differed according to specific cause of death(decreasing for liver cirrhosis,stable or increasing for liver cancer),etiology(increasing for nonalcoholic fatty liver disease,generally decreasing for other etiologies),and world region(decreasing in areas with the highest burden of hepatitis B virus,increasing in Eastern Europe and other countries).The coronavirus disease 2019(COVID-19)pandemic affected mortality of patients with CLD both directly,with a higher risk for severe illness and death depending on age,stage and etiology of the disease,and indirectly,through social isolation and loss of support,harmful drinking,and difficulties in access to care.Nevertheless,only sparse data are available on variations in CLD as a cause of death during the pandemic.In the USA,in 2020-2021 a growth in mortality was registered for all liver diseases,more marked for alcoholic liver disease,especially among young people aged 25-44 years and in selected ethnic groups.COVID-19 related deaths accounted only for a minor part of the excess.Further data from mortality registers of other countries are warranted,preferably adopting the so-called multiple cause-of-death approach,and extended to deaths attributed to viral hepatitis and liver cancer.

Role of IL-2/IL-2 receptor in pathogenesis of autoimmune disorders:Genetic and therapeutic aspects

Interleukin-2(IL-2)is an important cytokine that plays a key role in the immune response.The IL-2 receptor(IL-2R)is composed of three subunits,alpha,beta,and gamma,with the alpha subunit having the highest affinity for IL-2.Several studies reported that immune dysregulation of IL-2 may cause tissue injury as well as damage leading to the pathogenesis of various autoimmune diseases such as acute necrotizing vasculitis in systemic lupus erythematosus(SLE),inflammatory synovitis in rheumatoid arthritis(RA),salivary and lacrimal gland dysfunction in Sjogren syndrome(SS),obliterative vasculopathy fibrosis in systemic sclerosis(SSc),and inflammatory demyelination in multiple sclerosis(MS).The aim of this review paper was to examine the role of IL-2/IL-2R in various autoimmune disorders,taking into account recent advancements and discoveries,gaps in the current literature,ongoing debates,and potential avenues for future research.The focus of this review is on systemic lupus erythematosus,rheumatoid arthritis,systemic sclerosis,sjogren syndrome,and multiple sclerosis,which are all linked to the malfunctioning of IL-2/IL-2R.In genetic studies,gene polymorphisms of IL-2 such as IL-2330/T,IL-2330/G,and rs2069763 are involved in increasing the risk of SLE.Furthermore,genetic associations of IL-2/IL-2R such as rs791588,rs2281089,rs2104286,rs11594656,and rs35285258 are significantly associated with RA susceptibility.The IL-2 polymorphism including rs2069762A,rs6822844T,rs6835457G,and rs907715T are significant connections with systemic sclerosis.In addition,rs2104286(IL-2),rs11594656(IL-2RA),rs35285258(IL-2RB)gene polymorphism significant increases the risk of multiple sclerosis.In therapeutic approaches,low-dose IL-2 therapy could regulate Tfr and Tfh cells,resulting in a reduction in disease activity in the SLE patients.In addition,elevated sIL-2R levels in the peripheral blood of SLE patients could be linked to an immunoregulatory imbalance,which may contribute to the onset and progression of SLE.Consequently,sIL-2R could potentially be a target for future SLE therapy.Moreover,Low dose-IL2 was well-tolerated,and low levels of Treg and high levels of IL-21 wereassociated with positive responses to Ld-IL2 suggested to be a safe and effective treatment for RA.Additionally,low-dose IL-2 treatment improves the exocrine glands'ability to secrete saliva in SS-affected mice.Whereas,Basiliximab targets the alpha chain of the IL-2 receptor suggested as a potential treatment for SSc.Also,pre-andpost-treatment with Tregs,MDSCs,and IL-2 may have the potential to prevent EAE induction in patients with MS.It is suggested that further studies should be conducted on IL-2 polymorphism in Sjogren syndrome.

Pathogenesis of non-alcoholic fatty liver disease in children and adolescence: From “two hit theory” to “multiple hit model”

Nonalcoholic fatty liver disease(NAFLD) has become the dominant form of chronic liver disease in children and adolescents with the increasing prevalence of obesity worldwide. NAFLD represents a wide spectrum of conditions, ranging from fatty liver-which generally follows a benign, non-progressive clinical course-to non-alcoholic steatohepatitis, a subset of NAFLD that may progress to cirrhosis and end-stage liver disease or liver carcinoma. The underlying pathophysiological mechanism of "pediatric" NAFLD remains unclear, although it is strongly associated with obesity and insulin resistance. In this review we provide a general overview on the current understanding of NAFLD in children and adolescents, which underpins practice, enabling early diagnosis and appropriate therapeutic intervention for this life-threatening liver disease.

Understanding mechanisms of the pathogenesis of nonalcoholic fatty liver disease

A central issue in the understanding of the pathogenesis of nonalcoholic fatty liver disease is the problem of the underlying mechanisms which are not fully understood.In the setting of excessive central adiposity,insulin resistance is the major underlying cause of fat accumulation in hepatocytes.Because of the difficulties with human trials,several animal models have been developed for this purpose mainly characterized as follows:genetically disturbed or murine fatty liver,methionine-choline deficient diet fed or murine steatohepatitis,and high-fat or sucrose diet fed models.Although these animal models have provided useful information,none of them accurately reflect genetic,metabolic and biochemical characteristics of the human disease.

Current concept on the pathogenesis of inflammatory bowel disease-crosstalk between genetic and microbial factors:Pathogenic bacteria and altered bacterial sensing or changes in mucosal integrity take"toll"?

The pathogenesis of inflammatory bowel disease （IBD） is only partially understood. Various environmental and host （e.g. genetic-, epithelial-, immune and nonimmune） factors are involved. It is a multifactorial polygenic disease with probable genetic heterogeneity. Some genes are associated with IBD itself, while others increase the risk of ulcerative colitis （UC） or Crohn＇ s disease （CD） or are associated with disease location and/or behaviour. This review addresses recent advances in the genetics of IBD. The article discusses the current information on the crosstalk between microbial and genetic factors （e.g. NOD2/CARD15, SLC22A46A5 and DLG5）. The genetic data acquired in recent years help in understanding the pathogenesis of IBD and can identify a number of potential targets for therapeutic intervention. In the future, genetics may help more accurately diagnose and predict disease course in IBD.

HSP_(60), HSP_(70) in the Pathogenesis of Kawasaki Disease:Implication and Action

HSP(60), HSP(70) in plasma of 11 cases of Kawasaki diseases (KD) and 23 healthy children were determined. The two groups were controlled for age. Determination of HSP(60), HSP(70) was conducted in lymphocytes of 14 cases of KD and 26 healthy children. The results were compared with those of 12 patients with febrile diseases and 10 patients with tuberculosis. Our results showed that except a significant difference in plasma HSP(70) found between acute phase and convalescent phase of KD (P<0. 01), no significant difference was found in HSP(60), HSP(70)among all groups (P>0. 05). The differences in HSP(60), HS(70), in lymphocytes were relatively obvious among all groups. The levels of HSP(60), HSP(70) in acute phase of KD were significantly higher than those in convalescent phase or in healthy controls (P<0. 01). The levels of HSP(60) in KD were significantly higher than those of patients with febrile diseases. HSP(60) of KD children was significantly lower than those of children with tuberculosis (P<0.01). The findings showed that HSP(60), HSP(70) might contribute to the pathogenesis of KD. Determination of HSP(60), HSP(70) in lymphocytes is of help in the diagnosis of KD.

Further Investigation on the Role of Selenium Deficiency in the Aetiology and Pathogenesis of Keshan Disease

Selenium supplements were not able to restore the ultrastructural changes in the myocardiurn of latent Keshan disease patients taken by using cardiac catheter endomyocardial biopsy. Observations on the changes of seleniurn status and the incidence of Keshan disease showed that new latent and naturally-occurring chronic cases were found in the endemic area even after selenium levels had been elevated in the residents to the levels typical in the non-endemic area. These results indicate that although selenium deficiency might be a primary pathogenetic geogen in the occurrence of Keshan disease, it is rather a conditional predisposing factor than a specific or initiative aetiologic factor for the occurrence of Keshan disease. Selenium supplmentation could apparently alleviate the higher platelet responsiveness of residents in the endemic area, which might contribute to eliminating the basis for the occurrence of the multifocal perivascular necroses in myocardium of acute and subacute Keshan disease

Regulation of ciliary trafficking of polycystin-2 and the pathogenesis of autosomal dominant polycystic kidney disease

Autosomal dominant polycystic kidney disease(ADPKD)is one of the most common human hereditary disorder characteristic of development of bilateral multiple fluid-filled kidney cysts.Accumulated evidence has suggested that primary cilium of renal epithelial cell plays a key role in cystogenesis.In this article we will give an overview on the basic information about polycystic kidney disease(PKD)and summarize the recent progresses in studies of regulation of polycystin-1 and-2 trafficking to cilia.We will also discuss the possible role of trafficking defects of polycystins on the pathogenesis of ADPKD.

Pathogenesis of Parkinson＇s disease： oxidative stress, environmental impact factors and inflammatory processes

Current hypothesis of neuronal degeneration in Parkinson＇s disease （PD） have been proposed, including formation of free radicals and oxidative stress, mitochondrial dysfunction, excitotoxicity, trophic factor deficiency, inflammatory processes, genetic factors, environmental impact factors, toxic action of nitric oxide, apoptosis, and so on. This review mainly discussed oxidative stress, environmental impact factors, and inflammatory processes in PD.

Progress on the Pathogenesis and Treatment of Alzheimer’s Disease

Background: Alzheimer’s disease (AD), commonly known as senile dementia, is a neurodegenerative disease with clinical manifestations of memory impairment, personality and behavior changes. The pathogenesis of AD is complex and inconclusive in the point of view of western medicine, which is the fundamental reason for the lack of drugs that can reverse the course of the disease. People have gradually shifted from simple amyloid hypothesis to new pathogenesis theories, such as gamma oscillation, prion like transmission, and so on. As an effective means to treat AD, traditional Chinese medicine has made some research progress in recent years. This article mainly reviews the etiology, pathogenesis and treatment of AD, so as to provide reference for the prevention and treatment of AD. Methods: Through systematic literature research, comparison and analysis, the main pathogenesis, influencing factors, progress and development tendency of traditional Chinese medicine and Western medicine in the treatment of AD are presented. Results: Alzheimer’s disease is a kind of multiple neurodegenerative diseases. The pathogenesis and related targets of AD still need to be further explored. The main pathological phenomenon of AD is senile plaques formed by intracellular neurofibrillary tangles and extracellular amyloid protein aggregation. Existing possible pathogenesis includes β-amyloid cascade hypothesis, tau protein hypothesis, cholinergic hypothesis and so on. As the pathogenesis of AD has not been clarified, so far no effective therapeutic drugs or means have been found. The traditional drugs used to treat AD mainly include acetylcholinesterase inhibitor kabbalatin, galantamine, donepezil, and N-methyl-D-aspartate receptor antagonist memantine. However, although these marketed drugs can slow down the course of the disease and alleviate symptoms, they cannot totally cure the disease. Traditional Chinese medicine has the characteristics of personalized differentiation and treatment. The Western medicine can accurately determine the lesion location and target. Conclusions: Integrated traditional Chinese medicine and West medicine is the most promising direction in the treatment of Alzheimer’s disease.

Advances in the pathogenesis and ultrasonic diagnosis of senile calcific valvular disease of the heart

Objective:Senile calcific valvular disease of the heart is an endemic valvular heart disease in the elderly patients. The disease is mainly characterized by degenerative change, thickening, fibrosis and calcification of the valvular connective tissue, which leads to the dysfunction of the valve and its stent. The pathogenesis of calcified valvular heart disease has not been fully elucidated, and it may be related to hemodynamics, atherosclerosis and sex. Echocardiography is the basic method and important basis for clinical diagnosis of calcified valvular heart disease, and it might detect the valvular thickening or calcification. This article aimed to analyze the pathogenesis of senile calcified valvular heart disease. At the same time, this research tried to review the progress on ultrasonic diagnosis of senile calcified valvular heart disease in order to provide references for clinical diagnosis and treatment.

Influence of Underlying Diseases and Age on the Association between Obesity and All-Cause Mortality in Post-Middle Age

Background: Studies on the association between obesity and all-cause mortality have found that the degree of obesity is directly proportional to all-cause mortality. In contrast, there have been studies indicating that obese people with underlying diseases have a higher survival rate. We hypothesized that age and underlying diseases lead to such contrasting results. Therefore, we conducted a study to clarify the influence of post-middle age obesity and underlying diseases on all-cause mortality. Methods: This study used data from longitudinal studies in the United States, which conducted follow-up for 19 years on 33,708 participants in different age groups: ≥45, 45 - 64, and ≥65 years. Hazard ratio (HR) was determined using the Cox proportional hazards model to analyze a group consisting of all participants, a group of those with underlying diseases, and a group of those without underlying diseases, considering age, gender, education history, marital status, household income, smoking history, and BMI category as covariates. Results: In the group aged ≥65 without underlying diseases, HR was almost 1 in those with BMI 25 - 35 kg/m2. Further, HR was higher in the 45 - 64 age group without underlying diseases if BMI was >35 kg/m2. However, HR was approximately 1 in the ≥65 age group. Conclusions: The study revealed that among individuals aged ≥65 years without underlying diseases, there was no association between obesity and all-cause mortality. Among individuals without underlying diseases, HR was higher in the 45 - 64 age group with BMI > 35 kg/m2 but was approximately 1 among those aged ≥65 years. Therefore, an interaction based on age was detected. These findings may lead to recommendations regarding the need to modify the advice and education provided to obese individuals in different age groups.