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.

Gut virome:New key players in the pathogenesis of inflammatory bowel disease

Inflammatory bowel disease(IBD)is a chronic inflammatory illness of the intes-tine.While the mechanism underlying the pathogenesis of IBD is not fully under-stood,it is believed that a complex combination of host immunological response,environmental exposure,particularly the gut microbiota,and genetic suscept-ibility represents the major determinants.The gut virome is a group of viruses found in great frequency in the gastrointestinal tract of humans.The gut virome varies greatly among individuals and is influenced by factors including lifestyle,diet,health and disease conditions,geography,and urbanization.The majority of research has focused on the significance of gut bacteria in the progression of IBD,although viral populations represent an important component of the microbiome.We conducted this review to highlight the viral communities in the gut and their expected roles in the etiopathogenesis of IBD regarding published research to date.

Acute and chronic excitotoxicity in ischemic stroke and late-onset Alzheimer's disease

Stroke and Alzheimer's disease are common neurological disorders and often occur in the same individuals.The comorbidity of the two neurological disorders represents a grave health threat to older populations.This review presents a brief background of the development of novel concepts and their clinical potentials.The activity of glutamatergic N-methyl-D-aspartate receptors and N-methyl-D-aspartate receptor-mediated Ca^(2+)influx is critical for neuronal function.An ischemic insult induces prompt and excessive glutamate release and drastic increases of intracellular Ca^(2+)mainly via N-methyl-D-aspartate receptors,particularly of those at the extrasynaptic site.This Ca^(2+)-evoked neuronal cell death in the ischemic core is dominated by necrosis within a few hours and days known as acute excitotoxicity.Furthermore,mild but sustained Ca^(2+)increases under neurodegenerative conditions such as in the distant penumbra of the ischemic brain and early stages of Alzheimer's disease are not immediately toxic,but gradually set off deteriorating Ca^(2+)-dependent signals and neuronal cell loss mostly because of activation of programmed cell death pathways.Based on the Ca^(2+)hypothesis of Alzheimer's disease and recent advances,this Ca^(2+)-activated“silent”degenerative excitotoxicity evolves from years to decades and is recognized as a unique slow and chronic neuropathogenesis.The N-methyl-D-aspartate receptor subunit GluN3A,primarily at the extrasynaptic site,serves as a gatekeeper for the N-methyl-D-aspartate receptor activity and is neuroprotective against both acute and chronic excitotoxicity.Ischemic stroke and Alzheimer's disease,therefore,share an N-methyl-D-aspartate receptor-and Ca^(2+)-mediated mechanism,although with much different time courses.It is thus proposed that early interventions to control Ca^(2+)homeostasis at the preclinical stage are pivotal for individuals who are susceptible to sporadic late-onset Alzheimer's disease and Alzheimer's disease-related dementia.This early treatment simultaneously serves as a preconditioning therapy against ischemic stroke that often attacks the same individuals during abnormal aging.

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.

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.

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, inflam- matory 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.

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.

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.

Dextran sodium sulfate colitis murine model: An indispensable tool for advancing our understanding of inflammatory bowel diseases pathogenesis

Inflammatory bowel diseases(IBD),including Crohn's disease and ulcerative colitis,are complex diseases that result from the chronic dysregulated immune response in the gastrointestinal tract. The exact etiology is not fully understood,but it is accepted that it occurs when an inappropriate aggressive inflammatory respon-se in a genetically susceptible host due to inciting environmental factors occurs. To investigate the path-ogenesis and etiology of human IBD,various animal models of IBD have been developed that provided indispensable insights into the histopathological and morphological changes as well as factors associated with the pathogenesis of IBD and evaluation of therapeutic options in the last few decades. The most widely used experimental model employs dextran sodium sulfate(DSS) to induce epithelial damage. The DSS colitis model in IBD research has advantages over other various chemically induced experimental models due to its rapidity,simplicity,reproducibility and controllability. In this manuscript,we review the newer publicized advances of research in murine colitis models that focus upon the disruption of the barrier function of the intestine,effects of mucin on the development of colitis,alterations found in microbial balance and resultant changes in the metabolome specifically in the DSS colitis murine model and its relation to the pathogenesis of IBD.

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.

Overview of cytokines and nitric oxide involvement in immuno-pathogenesis of inflammatory bowel diseases

Inflammatory bowel diseases(IBDs), including Crohn's disease and ulcerative colitis are complex disorders with undetermined etiology. Several hypotheses suggest that IBDs result from an abnormal immune response against endogenous flora and luminal antigens in genetically susceptible individuals. The dysfunction of the mucosal immune response is implicated in the pathogenesis of IBD. The balance between pro-inflammatory cytokines [tumor necrosis factor(TNF)-α, interleukin(IL)-1b, IL-8, and IL-17A], anti-inflammatory cytokines(IL-4 and IL-13), and immunoregulatory cytokines(IL-10 and transforming growth factors b) is disturbed. Moreover, evidence from animal and clinical studies demonstrate a positive correlation between an increased concentration of nitric oxide(NO) and the severity of the disease. Interestingly, proinflammatory cytokines are involved in the up-regulation of inducible oxide synthase(iN OS) expression in IBD. However, anti-inflammatory and immunoregulatory cytokines are responsible for the negative regulation of iN OS. A positive correlation between NO production and increased pro-inflammatory cytokine levels(TNF-α, IL-6, IL-17, IL-12, and interferon-γ) were reported in patients with IBD. This review focuses on the role of cytokines in intestinal inflammation and their relationship with NO in IBD.

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.

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.

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.

Adverse Effects of Inactivated Foot-and-Mouth Disease Vaccine—Possible Causes Analysis and Countermeasures

Foot-and-mouth disease (FMD) is an infectious and sometimes fatal viral disease that affects cloven-hoofed animals, and Chinese government adopts compulsory immunization measures for FMD. The adverse effects of FMD vaccine to pigs, cattle and goats have been reported increasingly frequent during the spring and autumn seasons when large numbers of farm livestock are vaccinated. The financial losses caused by vaccine adverse effects have been a serious concern for both farmers and primary prevention personnel. There are various causative factors reported to involve into adverse effect of FMD vaccine, including the inappropriate vaccine production, transportation and storage, livestock poor tolerance, and unqualified vaccinating manipulations. Symptomatic treatment and early drug prevention have a certain effect on the adverse effects. To analyze causes and propose countermeasures, in the current study possible reasons during the production and processing procedures of inactivated FMD vaccine were reviewed and corresponding countermeasures were recommended. The review may provide references for better use of vaccine to prevent FMD.

Pathogenesis and Prevention of Progression of Chronic Kidney Disease

This treatise of chronic kidney disease (CKD) describes association of hypertension, diabetes and congestive heart failure (CHF) with CKD. CKD is defined by estimated glomerular filtration rate (eGFR) of less than 60 ml/min for three months or more. CKD is generally irreversible but not necessarily progressive. Thus progression of CKD into end stage renal disease (ESRD) is the concern here and what can be done to reduce the progression of CKD. Exact data of CKD with progression are unavailable but high incidence of ESRD (dialysis) eleven times more in 2011 than in 1980 accordingly to United States (US) Renal Data System is a testimonial to progression of CKD in patients with diabetes, hypertension, CHF and other renal diseases. US Renal Data System reveals that ESRD has soared in parallel with marketing of angiotensin converting enzyme inhibitor (ACEI) and angiotensin receptor blocker (ARB) drugs, providing strong indirect evidence that these drugs are someway instrumental in the progression of CKD into ESRD. These drugs produce acute renal failure which is an independent risk factor for CKD. Thus shift in therapy with enthusiastic use of ACEI/ARB drugs has led to dialysis bonanza throughout the world benefiting the professionals and corporations at the expense of vegetative life of the patients associated with family and societal burdens. The ways to turn the pendulum is to treat diabetes with insulin and hypertension with beta blocker, calcium channel blocker and diuretic therapy, and avoid the use of ACEI/ARB drugs. It is important to understand that diuretic orally, by intravenous boluses or by continuous infusion, is the cornerstone of therapy for CHF, whereas ACEI/ARB drugs markedly impair the efficacy of diuretics by lowering the blood pressure to a very low level thereby reducing renal perfusion. An evidence for that is marked elevation of BUN with comparatively slight increase of serum creatinine. Thus with the approaches stated above, CKD is less likely to progress;hence rate of ESRD is likely to decrease.

Effect of Body Mass Index on All-cause Mortality and Incidence of Cardiovascular Diseases─Report for Meta-Analysis of Prospective Studies on Optimal Cut-off Points of Body Mass Index in Chinese Adults

Objective To verify the optimal cut-off points for overweight and obesity in Chinese adults based on the relationship of baseline body mass index (BMI) to all-cause mortality, and incidence of cardiovascular diseases from pooled data of Chinese cohorts. Methods The prospective study data of existing cohort studies in China were collected, and the age-adjusted all-cause mortality stratified by BMI were estimated. The similar analysis was repeated after excluding deaths within the first three years of follow-up and after excluding smokers. The incidence of age-adjusted coronary heart disease (CHD) and stroke stratified by BMI were also analyzed. Multiple Cox regression coefficients of BMI for the incidence of CHD and stroke after controlling other risk factors were pooled utilizing the methods of weighting by inverse of variance to reveal whether BMI had independent effect and its strength on the incidence of CHD and stroke. Results The data of 4 cohorts including 76 227 persons, with 745 346 person-years of follow-up were collected and analyzed. The age-adjusted all-cause mortality stratified by BMI showed a U-shaped curve, even after excluding deaths within the first three years of follow-up and excluding smokers. Age-adjusted all-cause mortality increased when BMI was lower than 18.5 and higher than 28. The incidence of CHD and stroke, especially ishemic stroke increased with increasing BMI, this was consistent with parallel increasing of risk factors. Cox regression analysis showed that BMI was an independent risk factor for both CHD and stroke. Each amount of 2 kg/m2 increase in baseline BMI might cause 15.4%, 6.1% and 18.8 % increase in relative risk of CHD, total stroke and ischemic stroke. Reduction of BMI to under 24 might prevent the incidence of CHD by 11% and that of stroke by 15 % for men, and 22 % of both diseases for women. Conclusion BMI ≤18.5, 24-27.9 and ≥28 (kg/m2) is the appropriate cut-off points for underweight, overweight and obesity in Chinese adults.

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.

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.