Behcet’s disease (BD) is a chronic inflammatory disorder that can affect many systems in the body. Cardiac involvement increases the risk of cardiovascular mortality and occurs in 1%-5% of patients with BD. Ventricul...Behcet’s disease (BD) is a chronic inflammatory disorder that can affect many systems in the body. Cardiac involvement increases the risk of cardiovascular mortality and occurs in 1%-5% of patients with BD. Ventricular arrythmias are believed to be the cause of this increased risk of cardiovascular mortality and it is also thought to be related with cardiac autonomic dysfunction. Heart rate turbulence (HRT) is a new predictor of cardiac autonomic activity. HRT is an independent and powerful predictor of mortality. In this study, we investigated the cardiac autonomic activity which can be determined by HRT in patients with BD. Forty patients with BD (20 men, mean age: 40 ± 9 years, range: 27-55 years) were diagnosed according to the International Study Group Criteria (ISGC) and gender and age matched healthy volunteers (20 men, mean age: 39 ± 8 years, range: 26-56 years) were included in this study. All of the participants (patients and controls) underwent 24 hours Holter electrocardiogram. HRT parameters, turbulence onset (TO) and turbulence slope (TS) were calculated with HRT (View Version 0.60-0.1 of Software Program). There were no significant differences in TO and TS values between patients with BD and control subject (TO-BD: 0.014 ± 0.03, TO-Control: 0.011 ± 0.04;TS-BD: 7.88 ± 4.9, TS-Control: 9.42 ± 6.7 respectively). Although increased cardiovascular mortality rates in BD have been shown in many studies, HRT values—detecting the risk of sudden death—do not seem to be altered in this disease.展开更多
BACKGROUND Colonoscopy is essential for the diagnosis of intestinal Behcet’s disease(BD),which is characterized by a typical oval-shaped ulcer in the ileocecal region.However,potential risks of colonoscopy have rarel...BACKGROUND Colonoscopy is essential for the diagnosis of intestinal Behcet’s disease(BD),which is characterized by a typical oval-shaped ulcer in the ileocecal region.However,potential risks of colonoscopy have rarely been reported.CASE SUMMARY Herein,we describe a patient with intestinal BD who presented with decreased oxygen saturation and shortness of breath during a diagnostic colonoscopy.Bilateral pneumothorax,pneumomediastinum,pneumoperitoneum,pneumoretroperitoneum and subcutaneous emphysema of the neck,chest,abdomen,back and scrotum were confirmed by computed tomography scan.The sudden change in condition was considered to be associated with iatrogenic bowel perforation.After receiving closed thoracic drainage and conservative therapy,the patient was discharged in stable condition.CONCLUSION Endoscopists should be aware of the risks of colonoscopy in patients with intestinal BD and the possibility of pneumothorax associated with intestinal perforation and make adequate preparations before colonoscopy.展开更多
Background: Behcet’s disease is a vasculitis affecting several organs. A renal involvement is rarely described. It is most of the time about a renal amyloidosis. Patients and methods: It is a descriptive retrospectiv...Background: Behcet’s disease is a vasculitis affecting several organs. A renal involvement is rarely described. It is most of the time about a renal amyloidosis. Patients and methods: It is a descriptive retrospective study concerning the patients followed in our department for a Behcet’s disease having presented a renal amyloidosis. Results: It is about 4 men with average age of 38.25 years old. The renal involvement was revealed after an average delay of 5.7 years by a nephrotic syndrome in all cases. A renal insufficiency was noted in 3 cases with an average serum creatinine of 587 μmol/l (127 - 1490). The type of the amyloidosis was AA in 2 cases. The treatment contained colchicines in every case. The evolution was marked by the worsening of the renal function leading to end stage renal disease in 3 cases. Death occurred in 1 case and one patient lost to follow up. Discussion: Renal amyloidosis can complicate the evolution of a Behcet’s disease. It occurs generally 1 to 10 years after the beginning of the disease. Once installed, it evolves generally towards the chronic renal insufficiency and can condition the forecast of this affection. Conclusion: Amyloidosis is a rare complication of the Behcet’s disease. Its screening is so desirable to improve the renal prognosis of these patients.展开更多
Background: Behçet’s Syndrome (BS) is characterized by a heterogeneous vessel involvement, a fluctuating natural history and by the absence of biological markers correlated to disease activity that’s why ob...Background: Behçet’s Syndrome (BS) is characterized by a heterogeneous vessel involvement, a fluctuating natural history and by the absence of biological markers correlated to disease activity that’s why objective clinical scores are needed for the assessment of its activity. The Behçet’s Disease Clinical Activity Form (BDCAF) is the most recent and widely used clinical activity score. Objectives: To perform a cross-cultural adaptation of the Behçet’s Disease Current Activity Form (BDCAF) to the Tunisian Dialect (Arabic Language) and to evaluate the metrological characteristics of the Tunisian version (Tu-BDCAF) especially its reliability in BD activity evaluation. Methods: Cross-cultural adaptation was done according to the established guidelines. Reliability of Tu-BDCAF was tested among 40 BD patients (mean age: 38 years, sex ratio: 1.37). Patients were questioned by two BD specialists at 20 minutes interval to evaluate inter-observer reproducibility and twice by the same physician at 48 hours interval to assess the intra-observer reproducibility. k Coefficient was used to test the concordance between qualitative variables and correlation between quantitative variables was evaluated used Pearson coefficient and Bland and Altman graphical method. Results: There was a good correlation between global scores calculated by the two physicians on the same day (r = 0.94, p < 0.0001) and also between the scores calculated by the same clinician at different times (r = 0.98, p k Coefficient analyses demonstrated a good intra and inter observer reliability for all the Tu-BDCAF items excepted for diarrhea and Clinician’s impression. As the original version, Tu-BDCAF is an objective, easy-calculated and reliable index for assessing disease activity in BD. The main limit of the BDCAF score remains the absence of a cut-off point defining BD activity. Conclusion: Tu-BDACF is a Tunisian version of the BDCAF score which can be used in routine to assess BD activity but also in international studies and clinical trials.展开更多
Behcet’s disease (BD) is a large vessel vasculitis with a wide range of clinical manifestations. Some of these manifestation may be life threatening and rapid suppression of the inflammation with effective immunosupp...Behcet’s disease (BD) is a large vessel vasculitis with a wide range of clinical manifestations. Some of these manifestation may be life threatening and rapid suppression of the inflammation with effective immunosuppressive agent is crucial. There are traditional drugs with different response rates and all have efficacy on different manifestations of the disease. The most frightening manifestations of the disease are ocular, neurologic, intestinal and vascular types of involvement. Besides benign and easily treated manifestations there are also refractory cases with complicated involvement. The novel biologic agents have been used for these resistant patients and favorable response rates have been reported. In this review, we have shared our experience with biologic agents in BD and also reviewed the literature for the efficacy and safety for these novel agents for refractory patients.展开更多
BACKGROUND Anaplastic large cell lymphoma(ALCL)is a CD30-positive T cell lymphoma,a rare type of non-Hodgkin lymphoma.The current World Health Organization classification system divides ALCLs into anaplastic lymphoma ...BACKGROUND Anaplastic large cell lymphoma(ALCL)is a CD30-positive T cell lymphoma,a rare type of non-Hodgkin lymphoma.The current World Health Organization classification system divides ALCLs into anaplastic lymphoma kinase(ALK)-positive and ALK-negative groups.ALCL rarely presents in the gastrointestinal tract.CASE SUMMARY A 54-year-old male was admitted to the department of gastroenterology for abdominal pain.He presented with lower abdominal pain,diarrhea and recurrent oral and penile ulcers.He was misdiagnosed with Behcet's disease and treated with prednisone.But after one month,he was hospitalized in another hospital for reexamination.This time,the lesion on the penis was biopsied for histological examination.The final pathological diagnosis was ALCL,ALKnegative.The patient was treated with cyclophosphamide,doxorubicin,vincristine,prednisolone chemotherapy.However,he died within one month.CONCLUSION Gastrointestinal ALCL needs to be considered in the differential diagnosis to avoid delaying treatment.Repeated biopsy is the most important for early diagnosis and treatment.展开更多
Although cardiac involvement during Behcet syndrome is uncommon and intracardiac thrombosis is exceptional, it concerns the right ventricle much more than the left one. We report an illustrative case of left intracard...Although cardiac involvement during Behcet syndrome is uncommon and intracardiac thrombosis is exceptional, it concerns the right ventricle much more than the left one. We report an illustrative case of left intracardiac thrombosis revealing Behcet’s disease in a 33-year-old Tunisian man.展开更多
Introduction: The Behcet’s disease is deemed to be scarce in Black Africa where data are still scattered. The purpose of our study is to describe the epidemiological, clinical, paraclinic and evolutive particularitie...Introduction: The Behcet’s disease is deemed to be scarce in Black Africa where data are still scattered. The purpose of our study is to describe the epidemiological, clinical, paraclinic and evolutive particularities of the patients whose presenting symptoms of the Behcet’s diseases were a venous thrombosis. Patients and Methods: It was a descriptive, multicenter, and cross-sectional study lasting 15 months. We brought together all the cases of the Behcet’s disease revealed by venous thrombosis. The diagnosis was based on clinical criteria of the international group of study of the Behcet’s disease in 2007. Results: We have grouped 10 revealing thrombosis cases of the Behcet’s diseases during our study period. The average age was 34. The average wait period between the appearances of the early symptoms and the diagnosis of the very disease was 30 months. The admission motives were the abdominal pain (2 cases), a thrombophlebitis of the lower limb (2 cases), headaches (1 case), coma (1 case), a thrombophlebitis of the upper limb (3 cases). The thrombotic symptoms were exclusively venous-located. The seats of the thrombosis were the vena cava superior in 30% of the cases, the vena cava inferior in 20% of the cases, the veins of the lower limb in 20% of the cases, the cerebral vein in 20% of the cases, and the auxiliary vein in 10% of the cases. The treatment of the deep venous thrombosis consisted in all the cases of an effective anticoagulation associated with the colchicine. Primarily, the corticotherapy with a high dose was used in all the patients. One of them in the comatose stage, manifesting both cerebral thrombophlebitis and aseptic meningitis, had died. Conclusion: Behcet’s disease is a disease of the young adult, but it must be evoked even in old age, with a view to appropriate management, in order to avoid the complications of the disease. Although it is rare in our regions, it should be sought in the etiological assessment of venous thrombosis whatever the location.展开更多
BACKGROUND Behcet's disease(BD)is an inflammatory disorder known for various symptoms,including oral and genital ulcers and ocular inflammation.Panuveitis,a severe eye condition,is rare as the first sign of BD.CAS...BACKGROUND Behcet's disease(BD)is an inflammatory disorder known for various symptoms,including oral and genital ulcers and ocular inflammation.Panuveitis,a severe eye condition,is rare as the first sign of BD.CASE SUMMARY We present an unusual case of a 30-year-old man who developed panuveitis after receiving the mRNA-based coronavirus disease 2019(COVID-19)vaccine(Moderna).Laboratory tests ruled out infections,but he had a positive HLA-B51 result and a history of genital ulcer and oral ulcers,leading to a BD diagnosis.Treatment with corticosteroids improved his condition.Interestingly,he had another episode of panuveitis after the second mRNA vaccine dose,which also responded to corticosteroids.CONCLUSION This case highlights the rare onset of BD following mRNA COVID-19 vaccination,suggesting a potential link between these vaccines and BD's eye symptoms,emphasizing the importance of quick treatment in similar cases.展开更多
Alzheimer’s disease is a debilitating,progressive neurodegenerative disorder characterized by the progressive accumulation of abnormal proteins,including amyloid plaques and intracellular tau tangles,primarily within...Alzheimer’s disease is a debilitating,progressive neurodegenerative disorder characterized by the progressive accumulation of abnormal proteins,including amyloid plaques and intracellular tau tangles,primarily within the brain.Lysosomes,crucial intracellular organelles responsible for protein degradation,play a key role in maintaining cellular homeostasis.Some studies have suggested a link between the dysregulation of the lysosomal system and pathogenesis of neurodegenerative diseases,including Alzheimer’s disease.Restoring the normal physiological function of lysosomes hold the potential to reduce the pathological burden and improve the symptoms of Alzheimer’s disease.Currently,the efficacy of drugs in treating Alzheimer’s disease is limited,with major challenges in drug delivery efficiency and targeting.Recently,nanomaterials have gained widespread use in Alzheimer’s disease drug research owing to their favorable physical and chemical properties.This review aims to provide a comprehensive overview of recent advances in using nanomaterials(polymeric nanomaterials,nanoemulsions,and carbon-based nanomaterials)to enhance lysosomal function in treating Alzheimer’s disease.This review also explores new concepts and potential therapeutic strategies for Alzheimer’s disease through the integration of nanomaterials and modulation of lysosomal function.In conclusion,this review emphasizes the potential of nanomaterials in modulating lysosomal function to improve the pathological features of Alzheimer’s disease.The application of nanotechnology to the development of Alzheimer’s disease drugs brings new ideas and approaches for future treatment of this disease.展开更多
Netrin-1 and its receptors play crucial roles in inducing axonal growth and neuronal migration during neuronal development.Their profound impacts then extend into adulthood to encompass the maintenance of neuronal sur...Netrin-1 and its receptors play crucial roles in inducing axonal growth and neuronal migration during neuronal development.Their profound impacts then extend into adulthood to encompass the maintenance of neuronal survival and synaptic function.Increasing amounts of evidence highlight several key points:(1)Diminished Netrin-1 levels exacerbate pathological progression in animal models of Alzheimer’s disease and Parkinson’s disease,and potentially,similar alterations occur in humans.(2)Genetic mutations of Netrin-1 receptors increase an individuals’susceptibility to neurodegenerative disorders.(3)Therapeutic approaches targeting Netrin-1 and its receptors offer the benefits of enhancing memory and motor function.(4)Netrin-1 and its receptors show genetic and epigenetic alterations in a variety of cancers.These findings provide compelling evidence that Netrin-1 and its receptors are crucial targets in neurodegenerative diseases.Through a comprehensive review of Netrin-1 signaling pathways,our objective is to uncover potential therapeutic avenues for neurodegenerative disorders.展开更多
In this article,we explored the role of adipose tissue,especially mesenteric adipose tissue and creeping fat,and its association with the gut microbiota in the pathophysiology and progression of Crohn’s disease(CD).C...In this article,we explored the role of adipose tissue,especially mesenteric adipose tissue and creeping fat,and its association with the gut microbiota in the pathophysiology and progression of Crohn’s disease(CD).CD is a form of inflammatory bowel disease characterized by chronic inflammation of the gastrointestinal tract,influenced by genetic predisposition,gut microbiota dysbiosis,and environmental factors.Gut microbiota plays a crucial role in modulating immune response and intestinal inflammation and is associated with the onset and progression of CD.Further,visceral adipose tissue,particularly creeping fat,a mesenteric adipose tissue characterized by hypertrophy and fibrosis,has been implicated in CD pathogenesis,inflammation,and fibrosis.The bacteria from the gut microbiota may translocate into mesenteric adipose tissue,contributing to the formation of creeping fat and influencing CD progression.Although creeping fat may be a protective barrier against bacterial invasion,its expansion can damage adjacent tissues,leading to complications.Modulating gut microbiota through interventions such as fecal microbiota transplantation,probiotics,and prebiotics has shown potential in managing CD.However,more research is needed to clarify the mechanisms linking gut dysbiosis,creeping fat,and CD progression and develop targeted therapies for microbiota modulation and fat-related complications in patients with CD.展开更多
Parkinson’s disease is the second most common progressive neurodegenerative disorder,and few reliable biomarkers are available to track disease progression.The proteins,DNA,mRNA,and lipids carried by exosomes reflect...Parkinson’s disease is the second most common progressive neurodegenerative disorder,and few reliable biomarkers are available to track disease progression.The proteins,DNA,mRNA,and lipids carried by exosomes reflect intracellular changes,and thus can serve as biomarkers for a variety of conditions.In this study,we investigated alterations in the protein content of plasma exosomes derived from patients with Parkinson’s disease and the potential therapeutic roles of these proteins in Parkinson’s disease.Using a tandem mass tag-based quantitative proteomics approach,we characterized the proteomes of plasma exosomes derived from individual patients,identified exosomal protein signatures specific to patients with Parkinson’s disease,and identified N-acetyl-alpha-glucosaminidase as a differentially expressed protein.N-acetyl-alpha-glucosaminidase expression levels in exosomes from the plasma of patients and healthy controls were validated by enzyme-linked immunosorbent assay and western blot.The results demonstrated that the exosomal N-acetyl-alpha-glucosaminidase concentration was not only lower in Parkinson’s disease,but also decreased with increasing Hoehn-Yahr stage,suggesting that N-acetyl-alpha-glucosaminidase could be used to rapidly evaluate Parkinson’s disease severity.Furthermore,western blot and immunohistochemistry analysis showed that N-acetyl-alpha-glucosaminidase levels were markedly reduced both in cells treated with 1-methyl-4-phenylpyridinium and cells overexpressingα-synuclein compared with control cells.Additionally,N-acetyl-alpha-glucosaminidase overexpression significantly increased cell viability and inhibitedα-synuclein expression in 1-methyl-4-phenylpyridinium-treated cells.Taken together,our findings demonstrate for the first time that exosomal N-acetyl-alpha-glucosaminidase may serve as a biomarker for Parkinson’s disease diagnosis,and that N-acetyl-alpha-glucosaminidase may reduceα-synuclein expression and 1-methyl-4-phenylpyridinium-induced neurotoxicity,thus providing a new therapeutic target for Parkinson’s disease.展开更多
Acetyltransferases,required to transfer an acetyl group on protein are highly conserved proteins that play a crucial role in development and disease.Protein acetylation is a common post-translational modification pivo...Acetyltransferases,required to transfer an acetyl group on protein are highly conserved proteins that play a crucial role in development and disease.Protein acetylation is a common post-translational modification pivotal to basic cellular processes.Close to 80%-90%of proteins are acetylated during translation,which is an irreversible process that affects protein structure,function,life,and localization.In this review,we have discussed the various N-acetyltransferases present in humans,their function,and how they might play a role in diseases.Furthermore,we have focused on N-acetyltransferase 9 and its role in microtubule stability.We have shed light on how N-acetyltransferase 9 and acetylation of proteins can potentially play a role in neurodegenerative diseases.We have specifically discussed the N-acetyltransferase 9-acetylation independent function and regulation of c-Jun N-terminal kinase signaling and microtubule stability during development and neurodegeneration.展开更多
Parkinson’s disease is a common neurodegenerative disease with movement disorders associated with the intracytoplasmic deposition of aggregate proteins such asα-synuclein in neurons.As one of the major intracellular...Parkinson’s disease is a common neurodegenerative disease with movement disorders associated with the intracytoplasmic deposition of aggregate proteins such asα-synuclein in neurons.As one of the major intracellular degradation pathways,the autophagy-lysosome pathway plays an important role in eliminating these proteins.Accumulating evidence has shown that upregulation of the autophagy-lysosome pathway may contribute to the clearance ofα-synuclein aggregates and protect against degeneration of dopaminergic neurons in Parkinson’s disease.Moreover,multiple genes associated with the pathogenesis of Parkinson’s disease are intimately linked to alterations in the autophagy-lysosome pathway.Thus,this pathway appears to be a promising therapeutic target for treatment of Parkinson’s disease.In this review,we briefly introduce the machinery of autophagy.Then,we provide a description of the effects of Parkinson’s disease–related genes on the autophagy-lysosome pathway.Finally,we highlight the potential chemical and genetic therapeutic strategies targeting the autophagy–lysosome pathway and their applications in Parkinson’s disease.展开更多
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 choli...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.展开更多
BACKGROUND Mucosal healing(MH)is the major therapeutic target for Crohn's disease(CD).As the most commonly involved intestinal segment,small bowel(SB)assessment is crucial for CD patients.Yet,it poses a significan...BACKGROUND Mucosal healing(MH)is the major therapeutic target for Crohn's disease(CD).As the most commonly involved intestinal segment,small bowel(SB)assessment is crucial for CD patients.Yet,it poses a significant challenge due to its limited accessibility through conventional endoscopic methods.AIM To establish a noninvasive radiomic model based on computed tomography enterography(CTE)for MH assessment in SBCD patients.METHODS Seventy-three patients diagnosed with SBCD were included and divided into a training cohort(n=55)and a test cohort(n=18).Radiomic features were obtained from CTE images to establish a radiomic model.Patient demographics were analysed to establish a clinical model.A radiomic-clinical nomogram was constructed by combining significant clinical and radiomic features.The diagnostic efficacy and clinical benefit were evaluated via receiver operating characteristic(ROC)curve analysis and decision curve analysis(DCA),respectively.RESULTS Of the 73 patients enrolled,25 patients achieved MH.The radiomic-clinical nomogram had an area under the ROC curve of 0.961(95%confidence interval:0.886-1.000)in the training cohort and 0.958(0.877-1.000)in the test cohort and provided superior clinical benefit to either the clinical or radiomic models alone,as demonstrated by DCA.CONCLUSION These results indicate that the CTE-based radiomic-clinical nomogram is a promising imaging biomarker for MH and serves as a potential noninvasive alternative to enteroscopy for MH assessment in SBCD patients.展开更多
Extensive research has investigated the etiology of Crohn’s disease(CD),encompassing genetic predisposition,lifestyle factors,and environmental triggers.Recently,the gut microbiome,recognized as the human body’s sec...Extensive research has investigated the etiology of Crohn’s disease(CD),encompassing genetic predisposition,lifestyle factors,and environmental triggers.Recently,the gut microbiome,recognized as the human body’s second-largest gene pool,has garnered significant attention for its crucial role in the patho-genesis of CD.This paper investigates the mechanisms underlying CD,focusing on the role of‘creeping fat’in disease progression and exploring emerging therapeutic strategies,including fecal microbiota transplantation,enteral nutri-tion,and therapeutic diets.Creeping fat has been identified as a unique patho-logical feature of CD and has recently been found to be associated with dysbiosis of the gut microbiome.We characterize this dysbiotic state by identi-fying key microbiome-bacteria,fungi,viruses,and archaea,and their contributions to CD pathogenesis.Additionally,this paper reviews contemporary therapies,empha-sizing the potential of biological therapies like fecal microbiota transplantation and dietary interventions.By elucidating the complex interactions between host-microbiome dynamics and CD pathology,this article aims to advance our under-standing of the disease and guide the development of more effective therapeutic strategies for managing CD.展开更多
The complex morphological,anatomical,physiological,and chemical mechanisms within the aging brain have been the hot topic of research for centuries.The aging process alters the brain structure that affects functions a...The complex morphological,anatomical,physiological,and chemical mechanisms within the aging brain have been the hot topic of research for centuries.The aging process alters the brain structure that affects functions and cognitions,but the worsening of such processes contributes to the pathogenesis of neurodegenerative disorders,such as Alzheimer's disease.Beyond these observable,mild morphological shifts,significant functional modifications in neurotransmission and neuronal activity critically influence the aging brain.Understanding these changes is important for maintaining cognitive health,especially given the increasing prevalence of age-related conditions that affect cognition.This review aims to explore the age-induced changes in brain plasticity and molecular processes,differentiating normal aging from the pathogenesis of Alzheimer's disease,thereby providing insights into predicting the risk of dementia,particularly Alzheimer's disease.展开更多
γ-Secretase,called“the proteasome of the membrane,”is a membrane-embedded protease complex that cleaves 150+peptide substrates with central roles in biology and medicine,including amyloid precursor protein and the ...γ-Secretase,called“the proteasome of the membrane,”is a membrane-embedded protease complex that cleaves 150+peptide substrates with central roles in biology and medicine,including amyloid precursor protein and the Notch family of cell-surface receptors.Mutations inγ-secretase and amyloid precursor protein lead to early-onset familial Alzheimer’s disease.γ-Secretase has thus served as a critical drug target for treating familial Alzheimer’s disease and the more common late-onset Alzheimer’s disease as well.However,critical gaps remain in understanding the mechanisms of processive proteolysis of substrates,the effects of familial Alzheimer’s disease mutations,and allosteric modulation of substrate cleavage byγ-secretase.In this review,we focus on recent studies of structural dynamic mechanisms ofγ-secretase.Different mechanisms,including the“Fit-Stay-Trim,”“Sliding-Unwinding,”and“Tilting-Unwinding,”have been proposed for substrate proteolysis of amyloid precursor protein byγ-secretase based on all-atom molecular dynamics simulations.While an incorrect registry of the Notch1 substrate was identified in the cryo-electron microscopy structure of Notch1-boundγ-secretase,molecular dynamics simulations on a resolved model of Notch1-boundγ-secretase that was reconstructed using the amyloid precursor protein-boundγ-secretase as a template successfully capturedγ-secretase activation for proper cleavages of both wildtype and mutant Notch,being consistent with biochemical experimental findings.The approach could be potentially applied to decipher the processing mechanisms of various substrates byγ-secretase.In addition,controversy over the effects of familial Alzheimer’s disease mutations,particularly the issue of whether they stabilize or destabilizeγ-secretase-substrate complexes,is discussed.Finally,an outlook is provided for future studies ofγ-secretase,including pathways of substrate binding and product release,effects of modulators on familial Alzheimer’s disease mutations of theγ-secretase-substrate complexes.Comprehensive understanding of the functional mechanisms ofγ-secretase will greatly facilitate the rational design of effective drug molecules for treating familial Alzheimer’s disease and perhaps Alzheimer’s disease in general.展开更多
文摘Behcet’s disease (BD) is a chronic inflammatory disorder that can affect many systems in the body. Cardiac involvement increases the risk of cardiovascular mortality and occurs in 1%-5% of patients with BD. Ventricular arrythmias are believed to be the cause of this increased risk of cardiovascular mortality and it is also thought to be related with cardiac autonomic dysfunction. Heart rate turbulence (HRT) is a new predictor of cardiac autonomic activity. HRT is an independent and powerful predictor of mortality. In this study, we investigated the cardiac autonomic activity which can be determined by HRT in patients with BD. Forty patients with BD (20 men, mean age: 40 ± 9 years, range: 27-55 years) were diagnosed according to the International Study Group Criteria (ISGC) and gender and age matched healthy volunteers (20 men, mean age: 39 ± 8 years, range: 26-56 years) were included in this study. All of the participants (patients and controls) underwent 24 hours Holter electrocardiogram. HRT parameters, turbulence onset (TO) and turbulence slope (TS) were calculated with HRT (View Version 0.60-0.1 of Software Program). There were no significant differences in TO and TS values between patients with BD and control subject (TO-BD: 0.014 ± 0.03, TO-Control: 0.011 ± 0.04;TS-BD: 7.88 ± 4.9, TS-Control: 9.42 ± 6.7 respectively). Although increased cardiovascular mortality rates in BD have been shown in many studies, HRT values—detecting the risk of sudden death—do not seem to be altered in this disease.
文摘BACKGROUND Colonoscopy is essential for the diagnosis of intestinal Behcet’s disease(BD),which is characterized by a typical oval-shaped ulcer in the ileocecal region.However,potential risks of colonoscopy have rarely been reported.CASE SUMMARY Herein,we describe a patient with intestinal BD who presented with decreased oxygen saturation and shortness of breath during a diagnostic colonoscopy.Bilateral pneumothorax,pneumomediastinum,pneumoperitoneum,pneumoretroperitoneum and subcutaneous emphysema of the neck,chest,abdomen,back and scrotum were confirmed by computed tomography scan.The sudden change in condition was considered to be associated with iatrogenic bowel perforation.After receiving closed thoracic drainage and conservative therapy,the patient was discharged in stable condition.CONCLUSION Endoscopists should be aware of the risks of colonoscopy in patients with intestinal BD and the possibility of pneumothorax associated with intestinal perforation and make adequate preparations before colonoscopy.
文摘Background: Behcet’s disease is a vasculitis affecting several organs. A renal involvement is rarely described. It is most of the time about a renal amyloidosis. Patients and methods: It is a descriptive retrospective study concerning the patients followed in our department for a Behcet’s disease having presented a renal amyloidosis. Results: It is about 4 men with average age of 38.25 years old. The renal involvement was revealed after an average delay of 5.7 years by a nephrotic syndrome in all cases. A renal insufficiency was noted in 3 cases with an average serum creatinine of 587 μmol/l (127 - 1490). The type of the amyloidosis was AA in 2 cases. The treatment contained colchicines in every case. The evolution was marked by the worsening of the renal function leading to end stage renal disease in 3 cases. Death occurred in 1 case and one patient lost to follow up. Discussion: Renal amyloidosis can complicate the evolution of a Behcet’s disease. It occurs generally 1 to 10 years after the beginning of the disease. Once installed, it evolves generally towards the chronic renal insufficiency and can condition the forecast of this affection. Conclusion: Amyloidosis is a rare complication of the Behcet’s disease. Its screening is so desirable to improve the renal prognosis of these patients.
文摘Background: Behçet’s Syndrome (BS) is characterized by a heterogeneous vessel involvement, a fluctuating natural history and by the absence of biological markers correlated to disease activity that’s why objective clinical scores are needed for the assessment of its activity. The Behçet’s Disease Clinical Activity Form (BDCAF) is the most recent and widely used clinical activity score. Objectives: To perform a cross-cultural adaptation of the Behçet’s Disease Current Activity Form (BDCAF) to the Tunisian Dialect (Arabic Language) and to evaluate the metrological characteristics of the Tunisian version (Tu-BDCAF) especially its reliability in BD activity evaluation. Methods: Cross-cultural adaptation was done according to the established guidelines. Reliability of Tu-BDCAF was tested among 40 BD patients (mean age: 38 years, sex ratio: 1.37). Patients were questioned by two BD specialists at 20 minutes interval to evaluate inter-observer reproducibility and twice by the same physician at 48 hours interval to assess the intra-observer reproducibility. k Coefficient was used to test the concordance between qualitative variables and correlation between quantitative variables was evaluated used Pearson coefficient and Bland and Altman graphical method. Results: There was a good correlation between global scores calculated by the two physicians on the same day (r = 0.94, p < 0.0001) and also between the scores calculated by the same clinician at different times (r = 0.98, p k Coefficient analyses demonstrated a good intra and inter observer reliability for all the Tu-BDCAF items excepted for diarrhea and Clinician’s impression. As the original version, Tu-BDCAF is an objective, easy-calculated and reliable index for assessing disease activity in BD. The main limit of the BDCAF score remains the absence of a cut-off point defining BD activity. Conclusion: Tu-BDACF is a Tunisian version of the BDCAF score which can be used in routine to assess BD activity but also in international studies and clinical trials.
文摘Behcet’s disease (BD) is a large vessel vasculitis with a wide range of clinical manifestations. Some of these manifestation may be life threatening and rapid suppression of the inflammation with effective immunosuppressive agent is crucial. There are traditional drugs with different response rates and all have efficacy on different manifestations of the disease. The most frightening manifestations of the disease are ocular, neurologic, intestinal and vascular types of involvement. Besides benign and easily treated manifestations there are also refractory cases with complicated involvement. The novel biologic agents have been used for these resistant patients and favorable response rates have been reported. In this review, we have shared our experience with biologic agents in BD and also reviewed the literature for the efficacy and safety for these novel agents for refractory patients.
基金Supported by National Natural Science Foundation of China,No.U1802282,No.81660100,and No.81670501MDT Innovation Team to Digestive Diseases of S&T Department of Yunnan Province,No.2017HC005Digestive Diseases S&T Innovation Team of Kunming Medical University,No.CXTD201611
文摘BACKGROUND Anaplastic large cell lymphoma(ALCL)is a CD30-positive T cell lymphoma,a rare type of non-Hodgkin lymphoma.The current World Health Organization classification system divides ALCLs into anaplastic lymphoma kinase(ALK)-positive and ALK-negative groups.ALCL rarely presents in the gastrointestinal tract.CASE SUMMARY A 54-year-old male was admitted to the department of gastroenterology for abdominal pain.He presented with lower abdominal pain,diarrhea and recurrent oral and penile ulcers.He was misdiagnosed with Behcet's disease and treated with prednisone.But after one month,he was hospitalized in another hospital for reexamination.This time,the lesion on the penis was biopsied for histological examination.The final pathological diagnosis was ALCL,ALKnegative.The patient was treated with cyclophosphamide,doxorubicin,vincristine,prednisolone chemotherapy.However,he died within one month.CONCLUSION Gastrointestinal ALCL needs to be considered in the differential diagnosis to avoid delaying treatment.Repeated biopsy is the most important for early diagnosis and treatment.
文摘Although cardiac involvement during Behcet syndrome is uncommon and intracardiac thrombosis is exceptional, it concerns the right ventricle much more than the left one. We report an illustrative case of left intracardiac thrombosis revealing Behcet’s disease in a 33-year-old Tunisian man.
文摘Introduction: The Behcet’s disease is deemed to be scarce in Black Africa where data are still scattered. The purpose of our study is to describe the epidemiological, clinical, paraclinic and evolutive particularities of the patients whose presenting symptoms of the Behcet’s diseases were a venous thrombosis. Patients and Methods: It was a descriptive, multicenter, and cross-sectional study lasting 15 months. We brought together all the cases of the Behcet’s disease revealed by venous thrombosis. The diagnosis was based on clinical criteria of the international group of study of the Behcet’s disease in 2007. Results: We have grouped 10 revealing thrombosis cases of the Behcet’s diseases during our study period. The average age was 34. The average wait period between the appearances of the early symptoms and the diagnosis of the very disease was 30 months. The admission motives were the abdominal pain (2 cases), a thrombophlebitis of the lower limb (2 cases), headaches (1 case), coma (1 case), a thrombophlebitis of the upper limb (3 cases). The thrombotic symptoms were exclusively venous-located. The seats of the thrombosis were the vena cava superior in 30% of the cases, the vena cava inferior in 20% of the cases, the veins of the lower limb in 20% of the cases, the cerebral vein in 20% of the cases, and the auxiliary vein in 10% of the cases. The treatment of the deep venous thrombosis consisted in all the cases of an effective anticoagulation associated with the colchicine. Primarily, the corticotherapy with a high dose was used in all the patients. One of them in the comatose stage, manifesting both cerebral thrombophlebitis and aseptic meningitis, had died. Conclusion: Behcet’s disease is a disease of the young adult, but it must be evoked even in old age, with a view to appropriate management, in order to avoid the complications of the disease. Although it is rare in our regions, it should be sought in the etiological assessment of venous thrombosis whatever the location.
文摘BACKGROUND Behcet's disease(BD)is an inflammatory disorder known for various symptoms,including oral and genital ulcers and ocular inflammation.Panuveitis,a severe eye condition,is rare as the first sign of BD.CASE SUMMARY We present an unusual case of a 30-year-old man who developed panuveitis after receiving the mRNA-based coronavirus disease 2019(COVID-19)vaccine(Moderna).Laboratory tests ruled out infections,but he had a positive HLA-B51 result and a history of genital ulcer and oral ulcers,leading to a BD diagnosis.Treatment with corticosteroids improved his condition.Interestingly,he had another episode of panuveitis after the second mRNA vaccine dose,which also responded to corticosteroids.CONCLUSION This case highlights the rare onset of BD following mRNA COVID-19 vaccination,suggesting a potential link between these vaccines and BD's eye symptoms,emphasizing the importance of quick treatment in similar cases.
基金supported by the Natural Science Foundation of Shanghai,No.22ZR147750Science and Technology Innovation Action Plan of Shanghai Science and Technology Commission,No.23Y11906600Shanghai Changzheng Hospital Innovative Clinical Research Project,No.2020YLCYJ-Y02(all to YY).
文摘Alzheimer’s disease is a debilitating,progressive neurodegenerative disorder characterized by the progressive accumulation of abnormal proteins,including amyloid plaques and intracellular tau tangles,primarily within the brain.Lysosomes,crucial intracellular organelles responsible for protein degradation,play a key role in maintaining cellular homeostasis.Some studies have suggested a link between the dysregulation of the lysosomal system and pathogenesis of neurodegenerative diseases,including Alzheimer’s disease.Restoring the normal physiological function of lysosomes hold the potential to reduce the pathological burden and improve the symptoms of Alzheimer’s disease.Currently,the efficacy of drugs in treating Alzheimer’s disease is limited,with major challenges in drug delivery efficiency and targeting.Recently,nanomaterials have gained widespread use in Alzheimer’s disease drug research owing to their favorable physical and chemical properties.This review aims to provide a comprehensive overview of recent advances in using nanomaterials(polymeric nanomaterials,nanoemulsions,and carbon-based nanomaterials)to enhance lysosomal function in treating Alzheimer’s disease.This review also explores new concepts and potential therapeutic strategies for Alzheimer’s disease through the integration of nanomaterials and modulation of lysosomal function.In conclusion,this review emphasizes the potential of nanomaterials in modulating lysosomal function to improve the pathological features of Alzheimer’s disease.The application of nanotechnology to the development of Alzheimer’s disease drugs brings new ideas and approaches for future treatment of this disease.
基金supported by the National Natural Science Foundation of China(Youth Science Fund Project),No.81901292(to GC)the National Key Research and Development Program of China,No.2021YFC2502100(to GC)the National Natural Science Foundation of China,No.82071183(to ZZ).
文摘Netrin-1 and its receptors play crucial roles in inducing axonal growth and neuronal migration during neuronal development.Their profound impacts then extend into adulthood to encompass the maintenance of neuronal survival and synaptic function.Increasing amounts of evidence highlight several key points:(1)Diminished Netrin-1 levels exacerbate pathological progression in animal models of Alzheimer’s disease and Parkinson’s disease,and potentially,similar alterations occur in humans.(2)Genetic mutations of Netrin-1 receptors increase an individuals’susceptibility to neurodegenerative disorders.(3)Therapeutic approaches targeting Netrin-1 and its receptors offer the benefits of enhancing memory and motor function.(4)Netrin-1 and its receptors show genetic and epigenetic alterations in a variety of cancers.These findings provide compelling evidence that Netrin-1 and its receptors are crucial targets in neurodegenerative diseases.Through a comprehensive review of Netrin-1 signaling pathways,our objective is to uncover potential therapeutic avenues for neurodegenerative disorders.
基金Supported by the Postdoctoral Scholarship Grant,No.5552/2024 PROPG/PROPE N°06/2024.
文摘In this article,we explored the role of adipose tissue,especially mesenteric adipose tissue and creeping fat,and its association with the gut microbiota in the pathophysiology and progression of Crohn’s disease(CD).CD is a form of inflammatory bowel disease characterized by chronic inflammation of the gastrointestinal tract,influenced by genetic predisposition,gut microbiota dysbiosis,and environmental factors.Gut microbiota plays a crucial role in modulating immune response and intestinal inflammation and is associated with the onset and progression of CD.Further,visceral adipose tissue,particularly creeping fat,a mesenteric adipose tissue characterized by hypertrophy and fibrosis,has been implicated in CD pathogenesis,inflammation,and fibrosis.The bacteria from the gut microbiota may translocate into mesenteric adipose tissue,contributing to the formation of creeping fat and influencing CD progression.Although creeping fat may be a protective barrier against bacterial invasion,its expansion can damage adjacent tissues,leading to complications.Modulating gut microbiota through interventions such as fecal microbiota transplantation,probiotics,and prebiotics has shown potential in managing CD.However,more research is needed to clarify the mechanisms linking gut dysbiosis,creeping fat,and CD progression and develop targeted therapies for microbiota modulation and fat-related complications in patients with CD.
基金supported by the Science and Technology(S&T)Program of Hebei Province,No.22377798D(to YZ).
文摘Parkinson’s disease is the second most common progressive neurodegenerative disorder,and few reliable biomarkers are available to track disease progression.The proteins,DNA,mRNA,and lipids carried by exosomes reflect intracellular changes,and thus can serve as biomarkers for a variety of conditions.In this study,we investigated alterations in the protein content of plasma exosomes derived from patients with Parkinson’s disease and the potential therapeutic roles of these proteins in Parkinson’s disease.Using a tandem mass tag-based quantitative proteomics approach,we characterized the proteomes of plasma exosomes derived from individual patients,identified exosomal protein signatures specific to patients with Parkinson’s disease,and identified N-acetyl-alpha-glucosaminidase as a differentially expressed protein.N-acetyl-alpha-glucosaminidase expression levels in exosomes from the plasma of patients and healthy controls were validated by enzyme-linked immunosorbent assay and western blot.The results demonstrated that the exosomal N-acetyl-alpha-glucosaminidase concentration was not only lower in Parkinson’s disease,but also decreased with increasing Hoehn-Yahr stage,suggesting that N-acetyl-alpha-glucosaminidase could be used to rapidly evaluate Parkinson’s disease severity.Furthermore,western blot and immunohistochemistry analysis showed that N-acetyl-alpha-glucosaminidase levels were markedly reduced both in cells treated with 1-methyl-4-phenylpyridinium and cells overexpressingα-synuclein compared with control cells.Additionally,N-acetyl-alpha-glucosaminidase overexpression significantly increased cell viability and inhibitedα-synuclein expression in 1-methyl-4-phenylpyridinium-treated cells.Taken together,our findings demonstrate for the first time that exosomal N-acetyl-alpha-glucosaminidase may serve as a biomarker for Parkinson’s disease diagnosis,and that N-acetyl-alpha-glucosaminidase may reduceα-synuclein expression and 1-methyl-4-phenylpyridinium-induced neurotoxicity,thus providing a new therapeutic target for Parkinson’s disease.
基金supported by 1RO1EY032959-01 and RO1 supplement from NIH,Schuellein Chair Endowment Fund and STEM Catalyst Grant from the University of Dayton(to AS).
文摘Acetyltransferases,required to transfer an acetyl group on protein are highly conserved proteins that play a crucial role in development and disease.Protein acetylation is a common post-translational modification pivotal to basic cellular processes.Close to 80%-90%of proteins are acetylated during translation,which is an irreversible process that affects protein structure,function,life,and localization.In this review,we have discussed the various N-acetyltransferases present in humans,their function,and how they might play a role in diseases.Furthermore,we have focused on N-acetyltransferase 9 and its role in microtubule stability.We have shed light on how N-acetyltransferase 9 and acetylation of proteins can potentially play a role in neurodegenerative diseases.We have specifically discussed the N-acetyltransferase 9-acetylation independent function and regulation of c-Jun N-terminal kinase signaling and microtubule stability during development and neurodegeneration.
基金supported by the National Natural Science Foundation of China,No.82101340(to FJ).
文摘Parkinson’s disease is a common neurodegenerative disease with movement disorders associated with the intracytoplasmic deposition of aggregate proteins such asα-synuclein in neurons.As one of the major intracellular degradation pathways,the autophagy-lysosome pathway plays an important role in eliminating these proteins.Accumulating evidence has shown that upregulation of the autophagy-lysosome pathway may contribute to the clearance ofα-synuclein aggregates and protect against degeneration of dopaminergic neurons in Parkinson’s disease.Moreover,multiple genes associated with the pathogenesis of Parkinson’s disease are intimately linked to alterations in the autophagy-lysosome pathway.Thus,this pathway appears to be a promising therapeutic target for treatment of Parkinson’s disease.In this review,we briefly introduce the machinery of autophagy.Then,we provide a description of the effects of Parkinson’s disease–related genes on the autophagy-lysosome pathway.Finally,we highlight the potential chemical and genetic therapeutic strategies targeting the autophagy–lysosome pathway and their applications in Parkinson’s disease.
基金supported by the National Natural Science Foundation of China,No.82271214(to ZY)the Natural Science Foundation of Hubei Province of China,No.2022CFB109(to ZY)。
文摘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.
基金Supported by Natural Science Foundation of Anhui Medical University,No.2023xkj130.
文摘BACKGROUND Mucosal healing(MH)is the major therapeutic target for Crohn's disease(CD).As the most commonly involved intestinal segment,small bowel(SB)assessment is crucial for CD patients.Yet,it poses a significant challenge due to its limited accessibility through conventional endoscopic methods.AIM To establish a noninvasive radiomic model based on computed tomography enterography(CTE)for MH assessment in SBCD patients.METHODS Seventy-three patients diagnosed with SBCD were included and divided into a training cohort(n=55)and a test cohort(n=18).Radiomic features were obtained from CTE images to establish a radiomic model.Patient demographics were analysed to establish a clinical model.A radiomic-clinical nomogram was constructed by combining significant clinical and radiomic features.The diagnostic efficacy and clinical benefit were evaluated via receiver operating characteristic(ROC)curve analysis and decision curve analysis(DCA),respectively.RESULTS Of the 73 patients enrolled,25 patients achieved MH.The radiomic-clinical nomogram had an area under the ROC curve of 0.961(95%confidence interval:0.886-1.000)in the training cohort and 0.958(0.877-1.000)in the test cohort and provided superior clinical benefit to either the clinical or radiomic models alone,as demonstrated by DCA.CONCLUSION These results indicate that the CTE-based radiomic-clinical nomogram is a promising imaging biomarker for MH and serves as a potential noninvasive alternative to enteroscopy for MH assessment in SBCD patients.
文摘Extensive research has investigated the etiology of Crohn’s disease(CD),encompassing genetic predisposition,lifestyle factors,and environmental triggers.Recently,the gut microbiome,recognized as the human body’s second-largest gene pool,has garnered significant attention for its crucial role in the patho-genesis of CD.This paper investigates the mechanisms underlying CD,focusing on the role of‘creeping fat’in disease progression and exploring emerging therapeutic strategies,including fecal microbiota transplantation,enteral nutri-tion,and therapeutic diets.Creeping fat has been identified as a unique patho-logical feature of CD and has recently been found to be associated with dysbiosis of the gut microbiome.We characterize this dysbiotic state by identi-fying key microbiome-bacteria,fungi,viruses,and archaea,and their contributions to CD pathogenesis.Additionally,this paper reviews contemporary therapies,empha-sizing the potential of biological therapies like fecal microbiota transplantation and dietary interventions.By elucidating the complex interactions between host-microbiome dynamics and CD pathology,this article aims to advance our under-standing of the disease and guide the development of more effective therapeutic strategies for managing CD.
文摘The complex morphological,anatomical,physiological,and chemical mechanisms within the aging brain have been the hot topic of research for centuries.The aging process alters the brain structure that affects functions and cognitions,but the worsening of such processes contributes to the pathogenesis of neurodegenerative disorders,such as Alzheimer's disease.Beyond these observable,mild morphological shifts,significant functional modifications in neurotransmission and neuronal activity critically influence the aging brain.Understanding these changes is important for maintaining cognitive health,especially given the increasing prevalence of age-related conditions that affect cognition.This review aims to explore the age-induced changes in brain plasticity and molecular processes,differentiating normal aging from the pathogenesis of Alzheimer's disease,thereby providing insights into predicting the risk of dementia,particularly Alzheimer's disease.
基金supported in part by Award 2121063 from National Science Foundation(to YM)AG66986 from the National Institutes of Health(to MSW).
文摘γ-Secretase,called“the proteasome of the membrane,”is a membrane-embedded protease complex that cleaves 150+peptide substrates with central roles in biology and medicine,including amyloid precursor protein and the Notch family of cell-surface receptors.Mutations inγ-secretase and amyloid precursor protein lead to early-onset familial Alzheimer’s disease.γ-Secretase has thus served as a critical drug target for treating familial Alzheimer’s disease and the more common late-onset Alzheimer’s disease as well.However,critical gaps remain in understanding the mechanisms of processive proteolysis of substrates,the effects of familial Alzheimer’s disease mutations,and allosteric modulation of substrate cleavage byγ-secretase.In this review,we focus on recent studies of structural dynamic mechanisms ofγ-secretase.Different mechanisms,including the“Fit-Stay-Trim,”“Sliding-Unwinding,”and“Tilting-Unwinding,”have been proposed for substrate proteolysis of amyloid precursor protein byγ-secretase based on all-atom molecular dynamics simulations.While an incorrect registry of the Notch1 substrate was identified in the cryo-electron microscopy structure of Notch1-boundγ-secretase,molecular dynamics simulations on a resolved model of Notch1-boundγ-secretase that was reconstructed using the amyloid precursor protein-boundγ-secretase as a template successfully capturedγ-secretase activation for proper cleavages of both wildtype and mutant Notch,being consistent with biochemical experimental findings.The approach could be potentially applied to decipher the processing mechanisms of various substrates byγ-secretase.In addition,controversy over the effects of familial Alzheimer’s disease mutations,particularly the issue of whether they stabilize or destabilizeγ-secretase-substrate complexes,is discussed.Finally,an outlook is provided for future studies ofγ-secretase,including pathways of substrate binding and product release,effects of modulators on familial Alzheimer’s disease mutations of theγ-secretase-substrate complexes.Comprehensive understanding of the functional mechanisms ofγ-secretase will greatly facilitate the rational design of effective drug molecules for treating familial Alzheimer’s disease and perhaps Alzheimer’s disease in general.
