Pathological mechanism of immune disorders in diabetic kidney disease and intervention strategies

Diabetic kidney disease is one of the most severe chronic microvascular complications of diabetes and a primary cause of end-stage renal disease.Clinical studies have shown that renal inflammation is a key factor determining kidney damage during diabetes.With the development of immunological technology,many studies have shown that diabetic nephropathy is an immune complex disease,and that most patients have immune dysfunction.However,the immune response associated with diabetic nephropathy and autoimmune kidney disease,or caused by ischemia or infection with acute renal injury,is different,and has a complicated pathological mechanism.In this review,we discuss the pathogenesis of diabetic nephropathy in immune disorders and the intervention mechanism,to provide guidance and advice for early intervention and treatment of diabetic nephropathy.

Lamotrigine protects against cognitive deficits,synapse and nerve cell damage,and hallmark neuropathologies in a mouse model of Alzheimer’s disease

Lamotrigine(LTG)is a widely used drug for the treatment of epilepsy.Emerging clinical evidence suggests that LTG may improve cognitive function in patients with Alzheimer’s disease.However,the underlying molecular mechanisms remain unclear.In this study,amyloid precursor protein/presenilin 1(APP/PS1)double transgenic mice were used as a model of Alzheimer’s disease.Five-month-old APP/PS1 mice were intragastrically administered 30 mg/kg LTG or vehicle once per day for 3 successive months.The cognitive functions of animals were assessed using Morris water maze.Hyperphosphorylated tau and markers of synapse and glial cells were detected by western blot assay.The cell damage in the brain was investigated using hematoxylin and eosin staining.The levels of amyloid-βand the concentrations of interleukin-1β,interleukin-6 and tumor necrosis factor-αin the brain were measured using enzyme-linked immunosorbent assay.Differentially expressed genes in the brain after LTG treatment were analyzed by high-throughput RNA sequencing and real-time polymerase chain reaction.We found that LTG substantially improved spatial cognitive deficits of APP/PS1 mice;alleviated damage to synapses and nerve cells in the brain;and reduced amyloid-βlevels,tau protein hyperphosphorylation,and inflammatory responses.High-throughput RNA sequencing revealed that the beneficial effects of LTG on Alzheimer’s disease-related neuropathologies may have been mediated by the regulation of Ptgds,Cd74,Map3k1,Fosb,and Spp1 expression in the brain.These findings revealed potential molecular mechanisms by which LTG treatment improved Alzheimer’s disease.Furthermore,these data indicate that LTG may be a promising therapeutic drug for Alzheimer’s disease.

Profiling neuroprotective potential of trehalose in animal models of neurodegenerative diseases:a systematic review

Trehalose,a unique nonreducing crystalline disaccharide,is a potential disease-modifying treatment for neurodegenerative diseases associated with protein misfolding and aggregation due to aging,intrinsic mutations,or autophagy dysregulation.This systematic review summarizes the effects of trehalose on its underlying mechanisms in animal models of selected neurodegenerative disorders(tau pathology,synucleinopathy,polyglutamine tract,and motor neuron diseases).All animal studies on neurodegenerative diseases treated with trehalose published in Medline(accessed via EBSCOhost)and Scopus were considered.Of the 2259 studies screened,29 met the eligibility criteria.According to the SYstematic Review Center for Laboratory Animal Experiment(SYRCLE)risk of bias tool,we reported 22 out of 29 studies with a high risk of bias.The present findings support the purported role of trehalose in autophagic flux and protein refolding.This review identified several other lesser-known pathways,including modifying amyloid precursor protein processing,inhibition of reactive gliosis,the integrity of the blood-brain barrier,activation of growth factors,upregulation of the downstream antioxidant signaling pathway,and protection against mitochondrial defects.The absence of adverse events and improvements in the outcome parameters were observed in some studies,which supports the transition to human clinical trials.It is possible to conclude that trehalose exerts its neuroprotective effects through both direct and indirect pathways.However,heterogeneous methodologies and outcome measures across the studies rendered it impossible to derive a definitive conclusion.Translational studies on trehalose would need to clarify three important questions:1)bioavailability with oral administration,2)optimal time window to confer neuroprotective benefits,and 3)optimal dosage to confer neuroprotection.

Dynamic Pathology and Antigen Location Study on Broiler Breeders with Coinfection of Marek's Disease Virus and Reticuloendotheliosis Virus

To further understand the generation and development of coinfection of Marek＇s disease virus （MDV） and reticuloendotheliosis virus （REV） in broiler breeders, and then find the method and optimal time of differential diagnosis for complex clinic multiple infection, the authors studied the pathohistological changes, apoptosis, immunohistochemistry （immunofluorescence）, and ultrastructure of tumor tissues of broiler breeders inoculated with MDV and REV. The study showed that proliferation of small lymphocytes was seen in the main organs at the age of 1 week, then immature lymphocytes, all kinds of lymphocytes, primitive reticulum cells, and Marek＇s disease cells （MDCs） were observed at 2-9 weeks. Apoptosis of lymphocytes could not be seen until the age of 10 weeks in the immune system. Immunohistochemistry detection showed that the positive signs of MDV and REV antigen were observed in the main organs at 2 weeks of age. Multi-morphology lymphocytes, MDV, and REV, mitotic figures and apoptosis of lymphocytes were observed with the help of transmission electron microscopy. MDV cooperating with REV promotes the course of disease of coinfection. Differential diagnosis can be done by immunohistochemistry in the early stage （before 2 weeks）, and histopathology in the late stage （post 4 weeks）. MDCs, primitive reticulum cells, immature lymphocytes, and two kinds of virions can serve as a basis for bistopathology differential diagnosis.

Putative roles of cathepsin B in Alzheimer's disease pathology: the good, the bad, and the ugly in one?

Alzheimer＇s disease（AD）is a fatal progressive neurodegenerative disorder characterized by loss in memory,cognition,and executive function and activities of daily living.AD pathogenesis has been shown to involve loss of neurons and synapses,cholinergic deficits,amyloid-beta protein（Aβ）deposition,tau protein hyperphosphorylation, and neuroinflammation.

Correlation of MRI-determined small bowel Crohn’s disease categories with medical response and surgical pathology

AIM: To determine whether magnetic resonance imaging (MRI) can be used to categorize small bowel Crohn's disease (SB CD) into groups that correlate with response to medical therapy and surgical pathology.METHODS: Data was collected from all patients with MRI evidence of SB CD without significant colonic disease over a 32-mo period. Two radiologists, blinded to clinical findings, evaluated each MRI and grouped them based on bowel wall thickness and wall enhancement. These categories were: (1) "fibrosis", (2) "mild segmental hyper-enhancement and mild wall thickening", (3) "mild segmental hyper-enhancement and marked wall thickening", (4) "marked segmental transmural hyper-enhancement". Patient response to additional medical therapy post-MRI was prospectively determined at 8-wk. Non-responders underwent endoscopy and were offered therapeutic endoscopy or surgery. Surgical pathology was assessed against the MRI category. RESULTS: Fifty-five patients were included. Females and category "2" patients were more likely, and patients with luminal narrowing and hold-up less likely, to respond to medical therapy (P < 0.05). Seventeen patients underwent surgery. The surgical pathologicalfindings of fibrosis and the severity of inflammation correlated with the MRI category in all cases.CONCLUSION: Our fi ndings suggest that SB CD can be grouped by the MRI f indings and that these groups are associated with patients more likely to respond to continued medical therapy. The MRI categories also correlated with the presence and level of intestinal inflammation and fibrosis on surgical pathology, and may be of prognostic use in the management of CD patients.

Soluble alpha-synuclein post-translational modifications:unexpected regulators of pathological alpha-synuclein amplification

The build-up of misfoldedα-synuclein(α-syn)in the central nervous system is the pathological hallmark of a number of neurodegenerative diseases that are known asα-synucleinopathies.These include Parkinson’s disease(PD),Parkinson’s disease with dementia(PDD),dementia with Lewy body(LB),multiple system atrophy(MSA),and a subset of Alzheimer’s disease.Growing evidence underscores that the intercellular transmission and amplification of pathologicalα-syn are critical processes underlying the progression ofα-synucleinopathies(Peng et al.,2020),and as such,the study of these processes could lead to the identification of promising therapeutics to mitigate disease progression.Most previous studies have focused solely on pathological seeds in relation to disease progression.

Analysis of Alzheimer’s Disease:From Pathological Mechanism to Therapeutic Approach in Autophagy

As a“non-curable”disease,Alzheimer’s disease(AD)is the most common neurodegenerative disease in the aged population.Physical and mental pain exerts on every AD patient and their families.Even though there is no worldwide approved treatment against AD now,researchers have never given up on investigating and exploring potential approaches for curing AD.Gene therapy and drug treatment arise for alleviating AD symptoms.This paper illustrates the pathological mechanism of AD and focuses on the role of autophagy in AD pathology.Autophagy is a self-degrading mechanism to clear out dysfunctional cells;abnormal autophagy can directly trigger AD.This paper summarizes the effective and novel therapeutic approaches to treating AD by promoting autophagy activity,as well as AD diagnosis and assessment from early to severe stage,which provides promising approaches for researchers who are interested in AD treatments and feasible directions for science translational medicine.

Anal Pathologies: What Management at the Reference Health Center of Bamako’s Commune V?

Anal pathologies are conditions affecting the anal margin and the anal canal. The aim of our study was to update data on anal diseases. Non-specific, it can reveal an emergency, a serious illness, a chronic disease or a benign condition. It was a prospective, descriptive and analytical study from April 2022 to March 2023, carried out in the hepato-gastroenterology unit of the Centre de Santé de Référence de la commune V du District de Bamako in Mali. Out of seven hundred and forty-nine (749) patients seen in consultation, 98 had anal pathology, i.e. a prevalence of 13.08%. The mean age was 40 ± 15.15 years and the sex ratio was 1.5. Hemorrhoidal disease and anal fissure were the most frequent pathologies in 66.4% and 24.4% of cases respectively. Medical treatment was initiated in 91.9% of patients with hemorrhoidal disease and 91.7% with anal fissure. Anal pathologies are common in young male patients. In our context, they are dominated by benign conditions.

Developing a better mouse model of Alzheimer disease with clinically relevant phenotypes in tau pathology

OBJECTIVE Transgenic mouse model has been widely used in pathogenesis study and preclinical drug evaluation in Alzheimer disease(AD).However,key differences are found between current animal models and clinical AD patients regarding phenotypes.Lack of complete models that recapitulate broad spectrum of human AD neuropathology restricts efficacy of research projects and leads to frequent failure in AD drug development at clinical trial stages.This study aims to develop better mouse models of AD through modifying key phenotype insufficiency.METHODS By crossing different single and double transgenic mice with different mutations of APP/PS1 or tau and under prion,Thy1 or PDGF-β promoter,as well as selected knockout mice,I produced a dozen of bigenic models for neuropathology screening.Further neurochemical,behavioral and pharmacological validations were conducted in the optimized mouse model.RESULTS Neuropathology phenotyping found remarkable differences in tau pathology and neurodegeneration among individual APP/PS1/tau transgenic models.I had identified a triple mouse model named FADT that showed(1) huge mature tau pathology in hippocampus and cortex;(2) abundant tau truncation,as seen in human AD brain;(3)progressive neurodegeneration;(4)selective brain atrophy in hippocampus and entorhinal cortex;(5) reproducible and late onset spatial memory defects,etc.Importantly,remarkable tau pathology in this FADT model is mainly driven by beta-amyloid pathology,which differs from high expression of tau in rTg4510 model.CONCLUSION I had developed a new triple transgenic mouse model that recapitulates broad spectrum of human AD neuropathology features.This study will not only establish a solid model basis for AD pathophysiology investigation and drug development,but also reveal important clues on the interaction of beta-amyloid and tau pathologies in the brain.

Cerebellar pathology in motor neuron disease:neuroplasticity and neurodegeneration

Amyotrophic lateral sclerosis is a relentlessly progressive multi-system condition.The clinical picture is dominated by upper and lower motor neuron degeneration,but extra-motor pathology is increasingly recognized,including cerebellar pathology.Post-mortem and neuroimaging studies primarily focus on the chara cterization of supratentorial disease,des pite emerging evidence of cerebellar degeneration in amyotrophic lateral sclerosis.Cardinal clinical features of amyotrophic lateral sclerosis,such as dysarthria,dysphagia,cognitive and behavioral deficits,saccade abnormalities,gait impairment,respiratory weakness and pseudobulbar affect are likely to be exacerbated by co-existing cerebellar pathology.This review summarizes in vivo and post mortem evidence for cerebellar degeneration in amyotrophic lateral scle rosis.Structural imaging studies consistently capture cerebellar grey matter volume reductions,diffusivity studies readily detect both intra-cerebellar and cerebellar peduncle white matter alte rations and functional imaging studies commonly report increased functional connectivity with supratentorial regions.Increased functional connectivity is commonly interpreted as evidence of neuro plasticity representing compensatory processes despite the lack of post-mortem validation.There is a scarcity of post-mortem studies focusing on cerebellar alte rations,but these detect pTDP-43 in cerebellar nuclei.Ce rebellar pathology is an overloo ked facet of neurodegeneration in amyotrophic lateral sclerosis despite its contribution to a multitude of clinical symptoms,wides p read connectivity to spinal and supratentorial regions and putative role in compensating for the degeneration of primary motor regions.

Genetic variants associated with pathological changes in Alzheimer's diseases

Alzheimer's disease(AD)is the most prevalent dementia partially driven by genetics.Recently,a meta-analysis of large scale genome-wide association studies has identified a quantity of AD risk genes.To further investigate the correlation between the genetic variants and pathological progress,we examined 94 brain samples in the Chinese population from the National Human Brain Bank for Development and Function.

Simple pain measures reveal psycho-social pathology in patients with Crohn's disease

AIM To determine whether pain has psycho-social associations in adult Crohn's disease(CD) patients.METHODS Patients completed demographics, disease status, Patient Harvey-Bradshaw Index (P-HBI), Short Form Health Survey (SF-36), Short Inflammatory Bowel Disease Questionnaire (SIBDQ), and five sociopsychological questionnaires: Brief Symptom Inventory, Brief COPE Inventory, Family Assessment Device, Satisfaction with Life Scale, and Work Productivity and Activity Impairment Questionnaire. Pain sub-scales in P-HBI, SF-36 and SIBDQ measures were recoded into 4 identical scores for univariate and multinomial logistic regression analysis of associations with psycho-social variables.RESULTS The cohort comprised 594 patients, mean age 38.6±14.8 years, women 52.5%, P-HBI 5.76±5.15. P-HBI, SF-36 and SIBDQ broadly agreed in their assessment of pain intensity. More severe pain was significantly associated with female gender, low socioeconomic status, unemployment, Israeli birth and smoking. Higher pain scores correlated positively with psychological stress, dysfunctional coping strategies, poor family relationships, absenteeism, presenteeism, productivity loss and activity impairment and all WPAI sub-scores. Patients exhibiting greater satisfaction with life had less pain. The regression showed increasing odds ratios for psychological stress (lowest 2.26, highest 12.17) and female gender (highest 3.19) with increasing pain. Internet-recruited patients were sicker and differed from hardcopy questionnaire patients in their associations with pain.CONCLUSION Pain measures in P-HBI, SF-36 and SIBDQ correlate with psycho-social pathology in CD. Physicians should be aware also of these relationships in approaching CD patients with pain.

Pathological mechanisms and therapeutic strategies for Alzheimer's disease

Alzheimer's disease is a rather complex neurodegenerative disease,which is attributed to a combination of multiple factors.Among the many pathological pathways,synaptic dysfunctions,such as synapses loss and deficits in synaptic plasticity,were thought to be strongly associated with cognitive decline.The deficiencies in various sorts of neurotransmissions are responsible for the multifarious neurodegenerative symptoms in Alzheimer's disease,for example,the cholinergic and glutamatergic deficits for cognitive decline,the excitatory and inhibitory neurotransmission dyshomeostasis for synaptic plasticity deficits and epileptiform symptoms,and the monoamine neurotransmission for neuropsychiatric symptoms.Amyloid cascade hypothesis is the most popular pathological theory to explain Alzheimer's disease pathogenesis and attracts considerable attention.Multiple lines of genetic and pathological evidence support the predominant role of amyloid beta in Alzheimer's disease pathology.Neurofibrillary tangles assembled by microtubule-associated protein tau are other important histopathological characteristics in Alzheimer's disease brains.Cascade of tau toxicity was proved to lead to neuron damage,neuroinflammation and oxidative stress in brain.Ageing is the main risk factor of neurodegenerative diseases,and is associated with inflammation,oxidative stress,reduced metabolism,endocrine insufficiencies and organ failures.These aging related risk factors were also proved to be some of the risk factors contributing to Alzheimer's disease.In Alzheimer's disease drug development,many good therapeutic strategies have been investigated in clinical evaluations.However,complex mechanism of Alzheimer's disease and the interplay among different pathological factors call for the come out of allpowerful therapies with multiple curing functions.This review seeks to summarize some of the representative treatments targeting different pathological pathways currently under clinical evaluations.Multi-target therapies as an emerging strategy for Alzheimer's disease treatment will be highlighted.

Senktide blocks aberrant RTN3 interactome to retard memory decline and tau pathology in social isolated Alzheimer’s disease mice

Sporadic or late-onset Alzheimer’s disease(LOAD)accounts for more than 95%of Alzheimer’s disease(AD)cases without any family history.Although genome-wide association studies have identified associated risk genes and loci for LOAD,numerous studies suggest that many adverse environmental factors,such as social isolation,are associated with an increased risk of dementia.However,the underlying mechanisms of social isolation in AD progression remain elusive.In the current study,we found that 7 days of social isolation could trigger pattern separation impairments and presynaptic abnormalities of the mossy fibre-CA3 circuit in AD mice.We also revealed that social isolation disrupted histone acetylation and resulted in the downregulation of 2 dentate gyrus(DG)-enriched miRNAs,which simultaneously target reticulon 3(RTN3),an endoplasmic reticulum protein that aggregates in presynaptic regions to disturb the formation of functional mossy fibre boutons(MFBs)by recruiting multiple mitochondrial and vesicle-related proteins.Interestingly,the aggregation of RTN3 also recruits the PP2A B subunits to suppress PP2A activity and induce tau hyperphosphorylation,which,in turn,further elevates RTN3 and forms a vicious cycle.Finally,using an artificial intelligence-assisted molecular docking approach,we determined that senktide,a selective agonist of neurokinin3 receptors(NK3R),could reduce the binding of RTN3 with its partners.Moreover,application of senktide in vivo effectively restored DG circuit disorders in socially isolated AD mice.Taken together,our findings not only demonstrate the epigenetic regulatory mechanism underlying mossy fibre synaptic disorders orchestrated by social isolation and tau pathology but also reveal a novel potential therapeutic strategy for AD.

Application of Statistical Tools for Data Analysis and Interpretation in Rice Plant Pathology

There has been a significant advancement in the application of statistical tools in plant pathology during the past four decades. These tools include multivariate analysis of disease dynamics involving principal component analysis, cluster analysis, factor analysis, pattern analysis, discriminant analysis, multivariate analysis of variance, correspondence analysis, canonical correlation analysis, redundancy analysis, genetic diversity analysis, and stability analysis, which involve in joint regression, additive main effects and multiplicative interactions, and genotype-by-environment interaction biplot analysis. The advanced statistical tools, such as non-parametric analysis of disease association, meta-analysis, Bayesian analysis, and decision theory, take an important place in analysis of disease dynamics. Disease forecasting methods by simulation models for plant diseases have a great potentiality in practical disease control strategies. Common mathematical tools such as monomolecular, exponential, logistic, Gompertz and linked differential equations take an important place in growth curve analysis of disease epidemics. The highly informative means of displaying a range of numerical data through construction of box and whisker plots has been suggested. The probable applications of recent advanced tools of linear and non-linear mixed models like the linear mixed model, generalized linear model, and generalized linear mixed models have been presented. The most recent technologies such as micro-array analysis, though cost effective, provide estimates of gene expressions for thousands of genes simultaneously and need attention by the molecular biologists. Some of these advanced tools can be well applied in different branches of rice research, including crop improvement, crop production, crop protection, social sciences as well as agricultural engineering. The rice research scientists should take advantage of these new opportunities adequately in adoption of the new highly potential advanced technologies while planning experimental designs, data collection, analysis and interpretation of their research data sets.

Vanishing cerebral vasculitis in a patient with Lewy pathology

Immune-mediated mechanisms are involved in the pathogenesis of both cerebral vasculitis and Parkinson’s disease（PD, brainstem-predominant Lewy pathology）, but the presentation of cerebral vasculitis with comorbid Lewy pathology has not yet been reported. Here we present a case of pathologically confirmed vasculitis in a 73-year-old male patient whose postmortem examination revealed Lewy pathology diagnostic of PD. This case study suggests a comorbidity of cerebral vasculitis and Lewy pathology, as well as potential pathogenic interactions between these two disorders with immune-mediated mechanisms.

Ultrastructural Pathologic Observation on the Gut-Associated Lymphoid Tissues of Sacculus Rotundus of Rabbits Infected with Rabbit Haemorrhagic Disease Virus

Ultrastructural pathological changes in the gut-associated lymphoid tissues of sacculus rotundus (SR) of rabbits infected with rabbit haemorrhagic disease virus (RHDV) were first observed. There were numerous holes at the luminal and basement membrane surfaces of the dome epithelium (DE), consistently accompanied by necrosis of lymphocytes and M-cells, and pronounced depletion of lymphocytes in the domes and follicles, decrease of DE complex with formation of pseudomembranous structure on the surface of the dome epithelium. A specific finding in lymphocytes and macrophages was that severe destruction detraction of the membrane of rough endoplasmic reticulum(RER) was accompanied by conspicious increase of solitary, ribo-some-like particles in the cytoplasm, with appearances of intranuclear particles and intranuclear inclusions. It was found that there were many round and dense virion-like particles, with 26 nm in diameter, in the nuclei and cytoplasm of lymphoctes, plasma cells, macrophages and fibroblasts, or in degenerated cells and cellular debris. At the same time, another round virion-like particles about 34 nm in diameter were also seen in the cytoplasm of some cells and interstitium. The results indicated that the appearances of the ribosome-like particles, virion-like particles and inclusion bodies were related to the replication and assembly of RHDV. The present observations suggested that DE of sacculus rotundus could be a open pathway and a transporting route for the entry of antigens into hosts. While the antigen is profoundly deleterious, DE may be as a closed portal or a barrier preventing the foreign antigenic materials from invading.

Tau in Alzheimer’s Disease:Pathological Alterations and an Attractive Therapeutic Target

Alzheimer’s disease(AD)is an age-related neurodegenerative disease with two major hallmarks:extracellular amyloid plaques made of amyloid-β(Aβ)and intracellular neurofibrillary tangles(NFTs)of abnormally hyperphosphorylated tau.The number of NFTs correlates positively with the severity of dementia in AD patients.However,there is still no efficient therapy available for AD treatment and prevention so far.A deeper understanding of AD pathogenesis has identified novel strategies for the generation of specific therapies over the past few decades.Several studies have suggested that the prion-like seeding and spreading of tau pathology in the brain may be a key driver of AD.Tau protein is considered as a promising candidate target for the development of therapeutic interventions due to its considerable pathological role in a variety of neurodegenerative disorders.Abnormal tau hyperphosphorylation plays a detrimental pathological role,eventually leading to neurodegeneration.In the present review,we describe the recent research progresses in the pathological mechanisms of tau protein in AD and briefly discuss tau-based therapeutic strategies.

Pediatric metabolic liver diseases:Evolving role of liver transplantation

Metabolic liver diseases(MLD)are the second most common indication for liver transplantation(LT)in children.This is based on the fact that the majority of enzymes involved in various metabolic pathways are present within the liver and LT can cure or at least control the disease manifestation.LT is also performed in metabolic disorders for end-stage liver disease,its sequelae including hepatocellular cancer.It is also performed for preventing metabolic crisis’,arresting progression of neurological dysfunction with a potential to reverse symptoms in some cases and for preventing damage to end organs like kidneys as in the case of primary hyperoxalosis and methyl malonic acidemia.Pathological findings in explant liver with patients with metabolic disease include unremarkable liver to steatosis,cholestasis,inflammation,variable amount of fibrosis,and cirrhosis.The outcome of LT in metabolic disorders is excellent except for patients with mitochondrial disorders where significant extrahepatic involvement leads to poor outcomes and hence considered a contraindication for LT.A major advantage of LT is that in the post-operative period most patients can discontinue the special formula which they were having prior to the transplant and this increases their well-being and improves growth parameters.Auxiliary partial orthotopic LT has been described for patients with noncirrhotic MLD where a segmental graft is implanted in an orthotopic position after partial resection of the native liver.The retained native liver can be the potential target for future gene therapy when it becomes a clinical reality.