Transcorneal electrical stimulation (TES) is a novel therapeutic approach to activate the retina and related downstream structures. TES has multiple advantages over traditional treatments, such as being minimally in...Transcorneal electrical stimulation (TES) is a novel therapeutic approach to activate the retina and related downstream structures. TES has multiple advantages over traditional treatments, such as being minimally invasive and readily applicable in a routine manner. Series of animal experiments have shown that TES protects the retinal neuron from traumatic or genetic induced degeneration. These laboratory evidences support its utilization in ophthalmological therapies against various retinal and optical diseases including retinitis pigmentosa (RP), traumatic optic neuropathy, anterior ischemic optic neuropathy (AION), and retinal artery occlusions (RAOs). Several pioneering explorations sought to clarify the functional mechanism underlying the neuroprotective effects of TES. It seems that the neuroprotective effects should not be attributed to a solitary pathway, on the contrary, multiple mechanisms might contribute collectively to maintain cellular homeostasis and promote cell survival in the retina. More precise evaluations y/a functional and morphological techniques would determine the exact mechanism underlying the remarkable neuroprotective effect of TES. Further studies to determine the optimal parameters and the long-term stability of TES are crucial to justify the clinical significance and to establish TES as a popularized therapeutic modality against retinal and optic neuropathy.展开更多
BACKGROUND The coexistence with patent ductus arteriosus(PDA),mitral valve prolapse(MVP),atrial fibrillation(AF)and hyperthyroidism is extremely rare and complex.The optimal therapeutic strategy is difficult to develo...BACKGROUND The coexistence with patent ductus arteriosus(PDA),mitral valve prolapse(MVP),atrial fibrillation(AF)and hyperthyroidism is extremely rare and complex.The optimal therapeutic strategy is difficult to develop.CASE SUMMARY A 27-year-old female with PDA,MVP,AF and hyperthyroidism presented with severe dyspnea.Given that a one-stage operation for PDA,MVP and AF is high risk,we preferred a sequential multidisciplinary minimally invasive therapeutic strategy.First,PDA transcatheter closure was performed.Hyperthyroidism and heart failure were simultaneously controlled via medical treatment.Video-assisted thoracoscopic mitral valve repair and left atrial appendage occlusion were performed when heart failure was controlled.Under this therapeutic strategy,the patient’s sinus rhythm was restored and maintained.Two years after the treatment,the symptoms of heart failure were relieved,and the enlarged heart was reversed.CONCLUSION Sequential multidisciplinary therapeutic strategies,which take advantage of both internal medicine and surgical approaches,might be reasonable for this type of disease.展开更多
Background: Helicobacter pylori (Hp) infection is the most widespread bacterial infection in the world. The infection is generally acquired in childhood, but can persist into adulthood. Eradication therapy has undergo...Background: Helicobacter pylori (Hp) infection is the most widespread bacterial infection in the world. The infection is generally acquired in childhood, but can persist into adulthood. Eradication therapy has undergone several modifications. The aim of this study was to evaluate the different therapeutic strategies used in the eradication of Helicobacter pylori infection in the Centre Hospitalier Universitaire La Reference Nationale of N’Djaména. Patients and Methods: This was a prospective, descriptive analytical study spread over one year, from September 2021 to September 2022. Patients at least 15 years of age presenting with dyspeptic symptoms, seen consecutively in a hepato-gastroenterology consultation and with a positive stool test for H. pylori infection, were included in the study. Equally, 1/3 of patients were treated with dual or triple therapy. The remaining third received quadritherapy. Results: A total of 268 patients were included in the study (mean age 38.40 ± 14.66 with extremes of 16 and 80 years). Males predominated in 58% of cases. Overall therapeutic efficacy was 88.9%. According to different therapeutic strategies, efficacy was 90.75% for dual therapy with PPI (Rabeprazole) and Amoxicillin. On the other hand, efficacy was 87% and 88.88% for PPI-based triple therapy and dual antibiotic therapy, and for PPI-based quadruple therapy and triple antibiotic therapy. Conclusion: H. pylori infection is a common disease in Chad. Dual therapy with rabeprazole combined with a high dose of amoxicillin over a period of at least two weeks showed similar if not better efficacy than triple or quadruple therapy.展开更多
Ischemic stroke caused by intracranial vascular occlusion has become increasingly prevalent with considerable mortality and disability,which gravely burdens the global economy.Current relatively effective clinical tre...Ischemic stroke caused by intracranial vascular occlusion has become increasingly prevalent with considerable mortality and disability,which gravely burdens the global economy.Current relatively effective clinical treatments are limited to intravenous alteplase and thrombectomy.Even so,patients still benefit little due to the short therapeutic window and the risk of ischemia/reperfusion injury.It is therefore urgent to figure out the neuronal death mechanisms following ischemic stroke in order to develop new neuroprotective strategies.Regarding the pathogenesis,multiple pathological events trigger the activation of cell death pathways.Particular attention should be devoted to excitotoxicity,oxidative stress,and inflammatory responses.Thus,in this article,we first review the principal mechanisms underlying neuronal death mediated by these significant events,such as intrinsic and extrinsic apoptosis,ferroptosis,parthanatos,pyroptosis,necroptosis,and autophagic cell death.Then,we further discuss the possibility of interventions targeting these pathological events and summarize the present pharmacological achievements.展开更多
In recent years, multiple disciplines have focused on mitochondrial biology and contributed to understanding its relevance towards adult-onset neurodegenerative disorders. These are complex dynamic organelles that hav...In recent years, multiple disciplines have focused on mitochondrial biology and contributed to understanding its relevance towards adult-onset neurodegenerative disorders. These are complex dynamic organelles that have a variety of functions in ensuring cellular health and homeostasis. The plethora of mitochondrial functionalities confers them an intrinsic susceptibility to internal and external stressors(such as mutation accumulation or environmental toxins), particularly so in long-lived postmitotic cells such as neurons. Thus, it is reasonable to postulate an involvement of mitochondria in aging-associated neurological disorders, notably neurodegenerative pathologies including Alzheimer’s disease and Parkinson’s disease. On the other hand, biological effects resulting from neurodegeneration can in turn affect mitochondrial health and function, promoting a feedback loop further contributing to the progression of neuronal dysfunction and cellular death. This review examines state-of-the-art knowledge, focus on current research exploring mitochondrial health as a contributing factor to neuroregeneration, and the development of therapeutic approaches aimed at restoring mitochondrial homeostasis in a pathological setting.展开更多
One of the significant health issues in the world is the prevalence of ulcerative colitis(UC).UC is a chronic disorder that mainly affects the colon,beginning with the rectum,and can progress from asymptomatic mild in...One of the significant health issues in the world is the prevalence of ulcerative colitis(UC).UC is a chronic disorder that mainly affects the colon,beginning with the rectum,and can progress from asymptomatic mild inflammation to extensive inflammation of the entire colon.Understanding the underlying molecular mechanisms of UC pathogenesis emphasizes the need for innovative therapeutic approaches based on identifying molecular targets.Interestingly,in response to cellular injury,the NLR family pyrin domain containing 3(NLRP3)inflammasome is a crucial part of the inflammation and immunological reaction by promoting caspase-1 activation and the release of interleukin-1β.This review discusses the mechanisms of NLRP3 inflammasome activation by various signals and its regulation and impact on UC.展开更多
Cardioembolic stroke,referred to as cardiogenic stroke,is a clinical syndrome in which emboli from the heart pass through the circulatory system and cause cerebral artery embolism and corresponding brain dysfunction.C...Cardioembolic stroke,referred to as cardiogenic stroke,is a clinical syndrome in which emboli from the heart pass through the circulatory system and cause cerebral artery embolism and corresponding brain dysfunction.Compared to other subtypes of ischemic stroke,cardiogenic stroke presents with more etiologies,greater severity,worse prognosis,and a higher recurrence rate.In this minireview,we provide new insights into the etiological classification,diagnostic methods,and interventions of cardiogenic stroke.展开更多
Pancreatic cancer remains one of the most lethal diseases worldwide owing to its late diagnosis,early metastasis,and poor prognosis.Because current therapeutic options are limited,there is an urgent need to investigat...Pancreatic cancer remains one of the most lethal diseases worldwide owing to its late diagnosis,early metastasis,and poor prognosis.Because current therapeutic options are limited,there is an urgent need to investigate novel targeted treatment strategies.Pancreatic cancer faces significant metabolic challenges,principally hypoxia and nutrient deprivation,due to specific microenvironmental constraints,including an extensive desmoplastic stromal reaction.Pancreatic cancer cells have been shown to rewire their metabolism and energy production networks to support rapid survival and proliferation.Increased glucose uptake and glycolytic pathway activity during this process have been extensively described.However,growing evidence suggests that pancreatic cancer cells are glutamine addicted.As a nitrogen source,glutamine directly(or indirectly via glutamate conversion)contributes to many anabolic processes in pancreatic cancer,including amino acids,nucleobases,and hexosamine biosynthesis.It also plays an important role in redox homeostasis,and when converted toα-ketoglutarate,glutamine serves as an energy and anaplerotic carbon source,replenishing the tricarboxylic acid cycle intermediates.The present study aims to provide a comprehensive overview of glutamine metabolic reprogramming in pancreatic cancer,focusing on potential therapeutic approaches targeting glutamine metabolism in pancreatic cancer.展开更多
Thermal ablation(TA),including radiofrequency ablation(RFA)and microwave ablation(MWA),has become the main treatment for early-stage hepatocellular carcinoma(HCC)due to advantages such as safety and minimal invasivene...Thermal ablation(TA),including radiofrequency ablation(RFA)and microwave ablation(MWA),has become the main treatment for early-stage hepatocellular carcinoma(HCC)due to advantages such as safety and minimal invasiveness.However,HCC is prone to local recurrence,with more aggressive malignancies after TA closely related to TA-induced changes in epithelial-mesenchymal transition(EMT)and remodeling of the tumor microenvironment(TME).According to many studies,various components of the TME undergo complex changes after TA,such as the recruitment of innate and adaptive immune cells,the release of tumor-associated antigens(TAAs)and various cytokines,the formation of a hypoxic microenvironment,and tumor angiogenesis.Changes in the TME after TA can partly enhance the anti-tumor immune response;however,this response is weak to kill the tumor completely.Certain components of the TME can induce an immunosuppressive microenvironment through complex interactions,leading to tumor recurrence and progression.How the TME is remodeled after TA and the mechanism by which the TME promotes HCC recurrence and progression are unclear.Thus,in this review,we focused on these issues to highlight potentially effective strategies for reducing and preventing the recurrence and progression of HCC after TA.展开更多
The inflammasome is a multiprotein complex involved in innate immunity that mediates the inflammatory response leading to pyroptosis,which is a lytic,inflammatory form of cell death.There is accumulating evidence that...The inflammasome is a multiprotein complex involved in innate immunity that mediates the inflammatory response leading to pyroptosis,which is a lytic,inflammatory form of cell death.There is accumulating evidence that nucleotide-binding domain and leucine-rich repeat pyrin domain containing 3(NLRP3)inflammasome-mediated microglial pyroptosis and NLRP1 inflammasome-mediated neuronal pyroptosis in the brain are closely associated with the pathogenesis of Alzheimer’s disease.In this review,we summarize the possible pathogenic mechanisms of Alzheimer’s disease,focusing on neuroinflammation.We also describe the structures of NLRP3 and NLRP1 and the role their activation plays in Alzheimer’s disease.Finally,we examine the neuroprotective activity of small-molecule inhibitors,endogenous inhibitor proteins,microRNAs,and natural bioactive molecules that target NLRP3 and NLRP1,based on the rationale that inhibiting NLRP3 and NLRP1 inflammasome-mediated pyroptosis can be an effective therapeutic strategy for Alzheimer’s disease.展开更多
This letter is intended to arouse your interest in a recent review of comprehensive scientometrics and clinical trials on immunotherapy for gastric cancer(GC).Our study reviews recent advances in immunotherapy in the ...This letter is intended to arouse your interest in a recent review of comprehensive scientometrics and clinical trials on immunotherapy for gastric cancer(GC).Our study reviews recent advances in immunotherapy in the field of GC and highlights its new prospects as a treatment for GC.Our research reveals China’s leadership in this field,as well as new therapeutic strategies such as immune checkpoint inhibitors,cellular immunotherapy,and vaccines.The combined findings highlight the potential of immunotherapy to improve survival and quality of life in patients with stomach cancer.We believe that this study will provide important guidance for the future direction of the GC treatment field.展开更多
Osteoarthritis(OA)is a prevalent degenerative joint disease characterized by cartilage loss and accounts for a major source of pain and disability worldwide.However,effective strategies for cartilage repair are lackin...Osteoarthritis(OA)is a prevalent degenerative joint disease characterized by cartilage loss and accounts for a major source of pain and disability worldwide.However,effective strategies for cartilage repair are lacking,and patients with advanced OA usually need joint replacement.Better comprehending OA pathogenesis may lead to transformative therapeutics.Recently studies have reported that exosomes act as a new means of cell-to-cell communication by delivering multiple bioactive molecules to create a particular microenvironment that tunes cartilage behavior.Specifically,exosome cargos,such as noncoding RNAs(ncRNAs)and proteins,play a crucial role in OA progression by regulating the proliferation,apoptosis,autophagy,and inflammatory response of joint cells,rendering them promising candidates for OA monitoring and treatment.This review systematically summarizes the current insight regarding the biogenesis and function of exosomes and their potential as therapeutic tools targeting cell-to-cell communication in OA,suggesting new realms to improve OA management.展开更多
Hepatocellular carcinoma(HCC)is the fourth leading cause of cancer-related deaths worldwide.The prognosis of patients with HCC remains poor largely due to the late diagnosis and lack of effective treatments.Despite be...Hepatocellular carcinoma(HCC)is the fourth leading cause of cancer-related deaths worldwide.The prognosis of patients with HCC remains poor largely due to the late diagnosis and lack of effective treatments.Despite being widely used,alpha-fetoprotein serology and ultrasonography have limited diagnostic performance for early-stage HCC.The emergence of omics strategies has contributed to significant advances in the development of non-invasive biomarkers for the early diagnosis of HCC including proteins,metabolites,circulating tumor deoxyribonucleic acid,and circulating non-coding ribonucleic acid.Early diagnosis is beneficial to patients as it increases the proportion who can be treated with curative treatment,thus prolonging survival outcomes.Currently,multiple clinical trials involving locoregional,systemic therapies,and combinations of these modalities are changing therapeutic strategies for different stage HCC.Success in several preclinical trials that involve immunotherapeutic innovations has created the potential to complement and enforce other treatment strategies in the future.This review summarizes the most recent advances in noninvasive early molecular detection,current therapy strategies,and potential immunotherapeutic innovations of HCC.展开更多
A review of recent animal models of Huntington’s disease showed many microRNAs had altered expression levels in the striatum and cerebral cortex,and which were mostly downregulated.Among the altered microRNAs were mi...A review of recent animal models of Huntington’s disease showed many microRNAs had altered expression levels in the striatum and cerebral cortex,and which were mostly downregulated.Among the altered microRNAs were miR-9/9*,miR-29b,miR-124a,miR-132,miR-128,miR-139,miR-122,miR-138,miR-23b,miR-135b,miR-181(all downregulated)and miR-448(upregulated),and similar changes had been previously found in Huntington’s disease patients.In the animal cell studies,the altered microRNAs included miR-9,miR-9*,miR-135b,miR-222(all downregulated)and miR-214(upregulated).In the animal models,overexpression of miR-155 and miR-196a caused a decrease in mutant huntingtin mRNA and protein level,lowered the mutant huntingtin aggregates in striatum and cortex,and improved performance in behavioral tests.Improved performance in behavioral tests also occurred with overexpression of miR-132 and miR-124.In the animal cell models,overexpression of miR-22 increased the viability of rat primary cortical and striatal neurons infected with mutant huntingtin and decreased huntingtin-enriched foci of≥2μm.Also,overexpression of miR-22 enhanced the survival of rat primary striatal neurons treated with 3-nitropropionic acid.Exogenous expression of miR-214,miR-146a,miR-150,and miR-125b decreased endogenous expression of huntingtin mRNA and protein in HdhQ111/HdhQ111 cells.Further studies with animal models of Huntington’s disease are warranted to validate these findings and identify specific microRNAs whose overexpression inhibits the production of mutant huntingtin protein and other harmful processes and may provide a more effective means of treating Huntington’s disease in patients and slowing its progression.展开更多
Although gastroenteropancreatic neuroendocrine neoplasms(GEP-NENs)have always been considered rare tumors,their incidence has risen over the past few decades.They represent a highly heterogeneous group of neoplasms wi...Although gastroenteropancreatic neuroendocrine neoplasms(GEP-NENs)have always been considered rare tumors,their incidence has risen over the past few decades.They represent a highly heterogeneous group of neoplasms with several prognostic factors,including disease stage,proliferative index(Ki67),and tumor differentiation.Most of these neoplasms express somatostatin receptors on the cell surface,a feature that has important implications in terms of prognosis,diagnosis,and therapy.Although International Guidelines propose algorithms aimed at guiding therapeutic strategies,GEP-NEN patients are still very different from one another,and the need for personalized treatment continues to increase.Radical surgery is always the best option when feasible;however,up to 80%of cases are metastatic upon diagnosis.Regarding medical treatments,as GEP-NENs are characterized by relatively long overall survival,multiple therapy lines are adopted during the lifetime of these patients,but the optimum sequence to be followed has never been clearly defined.Furthermore,although new molecular markers aimed at predicting the response to therapy,as well as prognostic scores,are currently being studied,their application is still far from being part of daily clinical practice.As they represent a complex disease,with therapeutic protocols that are not completely standardized,GEP-NENs require a multidisciplinary approach.This review will provide an overview of the available therapeutic options for GEP-NENs and attempts to clarify the possible approaches for the management of these patients and to discuss future perspectives in this field.展开更多
<div style="text-align:justify;"> <span style="font-family:Verdana;">Spinocerebellar ataxia type 3 (SCA3), also known as Machado-Joseph Disease (MJD), is an autosomal dominant neurodege...<div style="text-align:justify;"> <span style="font-family:Verdana;">Spinocerebellar ataxia type 3 (SCA3), also known as Machado-Joseph Disease (MJD), is an autosomal dominant neurodegenerative disorder that predominantly involves the cerebellar, pyramidal, extrapyramidal, motor neuron and oculomotor systems. SCA3 presents strong phenotypic heterogeneity and its causative mutation of SCA3 consists of an expansion of a CAG tract in exon 10 of the <em>ATXN3</em> gene, situated at 14q32.1. The <em>ATXN3</em> gene is ubiquitously expressed in neuronal and non-neuronal tissues, and also participates in cellular protein quality control pathways. Mutated <em>ATXN3</em> alleles present about 45 to 87CAG repeats, which result in an expanded polyglutamine tract in ataxin-3. After mutation, the polyQ tract reaches the pathological threshold (about 50 glutamine residues);the protein is considered that it might gain a neurotoxic function through some unclear mechanisms. We reviewed the literature on the pathogenesis and therapeutic strategies of spinocerebellar ataxia type 3 patients. Conversion of the expanded protein is possible by enhancing protein refolding and degradation or preventing proteolytic cleavage and prevents the protein to reach the site of toxicity by altering its ability to translocate between the nucleus and cytoplasm. Proteasomal degradation and enhancing autophagic aggregate clearance are currently proposed remarkable therapy. In spite of extensive research, the molecular mechanisms of cellular toxicity resulting from mutant ataxin-3 remain no preventive treatment is currently available. These therapeutic strategies might be able to improve sign symptoms of SCA3 as well as slow the disease progression.</span> </div>展开更多
Neurodegeneration affects a large number of cell types including neurons,astrocytes or oligodendrocytes,and neural stem cells.Neural stem cells can generate new neuronal populations through proliferation,migration,and...Neurodegeneration affects a large number of cell types including neurons,astrocytes or oligodendrocytes,and neural stem cells.Neural stem cells can generate new neuronal populations through proliferation,migration,and differentiation.This neurogenic potential may be a relevant factor to fight neurodegeneration and aging.In the last years,we can find growing evidence suggesting that melatonin may be a potential modulator of adult hippocampal neurogenesis.The lack of therapeutic strategies targeting neurogenesis led researchers to explore new molecules.Numerous preclinical studies with melatonin observed how melatonin can modulate and enhance molecular and signaling pathways involved in neurogenesis.We made a special focus on the connection between these modulation mechanisms and their implication in neurodegeneration,to summarize the current knowledge and highlight the therapeutic potential of melatonin.展开更多
Cancer constitutes the second leading cause of death globally and is considered to have been responsible for an estimated 9.6 million fatalities in 2018.Although treatments against gastrointestinal tumors have recentl...Cancer constitutes the second leading cause of death globally and is considered to have been responsible for an estimated 9.6 million fatalities in 2018.Although treatments against gastrointestinal tumors have recently advanced,those interventions can only be applied to a minority of patients at the time of diagnosis.Therefore,new therapeutic options are necessary for advanced stages of the disease.Glycosylation of antitumor agents,has been found to improve pharmacokinetic parameters,reduce side effects,and expand drug half-life in comparison with the parent compounds.In addition,glycosylation of therapeutic agents has been proven to be an effective strategy for their targeting tumor tissue,thereby reducing the doses of the glycodrugs administered to patients.This review focusses on the effect of the targeting properties of glycosylated antitumor agents on gastrointestinal tumors.展开更多
Alzheimer’s disease(AD)is the most common progressive neurodegenerative disorder.It is often lethal and currently lacks a satisfactory therapy.The disease has a specific neuro-pathological profile:accumulation of pro...Alzheimer’s disease(AD)is the most common progressive neurodegenerative disorder.It is often lethal and currently lacks a satisfactory therapy.The disease has a specific neuro-pathological profile:accumulation of proteinaceous deposits in the brain–amyloid plaques(containingβ-amyloid peptides)and neurofibrillary tangles which are accumulation of a profusion of long stringy tangles of proteins called tau.Between the two highly recognized AD hypotheses,amyloid beta(Aβ)peptide aggregation and accumulation play a significant role and are considered as an important mechanism of AD pathology.Aβis a proteolytic product of amyloid precursor protein and genetic studies supported the relevance of Aβin AD pathogenesis.A large number of small molecules were studied for their ability to inhibit Aβ-aggregation in oligomer form or after fibrillization.However,the protein-misfolding process has certain setbacks which are inevitable due to the different morphology of protein.In recent years,it has been demonstrated that tau also plays a central role in pathogenesis of this disease.Moreover,abnormal post-translational modifications of tau,in particular,increases in acetylation at specific sites likely contribute to the toxicity of tau.Although it is evident that tau with these aberrant post-translational modifications likely facilitates neurodegeneration,the precise cellular mechanisms by which tau compromises neuronal function remain unknown.In addition,much remains to be learned about new interventions that might be developed to prevent or reduce the negative impact of tau posttranslational modifications-related damage.This review article addresses the key roles of amyloid beta and tau protein in AD as well as the possible therapeutic agents that can reduce the toxic levels of both the proteins,and thus providing beneficial effect for the AD patients.展开更多
Brain tumors are a diverse group of malignancies that remain refractory to conventional treatment approaches.Molecular neuro-oncologyhas now begun to clarify the transformed phenotype of brain tumors and identify onco...Brain tumors are a diverse group of malignancies that remain refractory to conventional treatment approaches.Molecular neuro-oncologyhas now begun to clarify the transformed phenotype of brain tumors and identify oncogenic pathways that might be amenable to targetedtherapy.Activity of the phosphoinositide 3;kinase(PI3K)/Akt pathway is often upregulated in brain tumors due to excessive stimu-lation by growth factor receptors and Ras.Loss of function of the tumor suppressor gene PTEN also frequently contributesto展开更多
基金Supported by the National Key Basic Research Program of China (973 Program, No. 2013CB967001)
文摘Transcorneal electrical stimulation (TES) is a novel therapeutic approach to activate the retina and related downstream structures. TES has multiple advantages over traditional treatments, such as being minimally invasive and readily applicable in a routine manner. Series of animal experiments have shown that TES protects the retinal neuron from traumatic or genetic induced degeneration. These laboratory evidences support its utilization in ophthalmological therapies against various retinal and optical diseases including retinitis pigmentosa (RP), traumatic optic neuropathy, anterior ischemic optic neuropathy (AION), and retinal artery occlusions (RAOs). Several pioneering explorations sought to clarify the functional mechanism underlying the neuroprotective effects of TES. It seems that the neuroprotective effects should not be attributed to a solitary pathway, on the contrary, multiple mechanisms might contribute collectively to maintain cellular homeostasis and promote cell survival in the retina. More precise evaluations y/a functional and morphological techniques would determine the exact mechanism underlying the remarkable neuroprotective effect of TES. Further studies to determine the optimal parameters and the long-term stability of TES are crucial to justify the clinical significance and to establish TES as a popularized therapeutic modality against retinal and optic neuropathy.
基金Supported by National Natural Science Foundation of China,No.81800342 and 81800138Zhejiang Provincial Natural Science Foundation of China,No.LQ20H020012.
文摘BACKGROUND The coexistence with patent ductus arteriosus(PDA),mitral valve prolapse(MVP),atrial fibrillation(AF)and hyperthyroidism is extremely rare and complex.The optimal therapeutic strategy is difficult to develop.CASE SUMMARY A 27-year-old female with PDA,MVP,AF and hyperthyroidism presented with severe dyspnea.Given that a one-stage operation for PDA,MVP and AF is high risk,we preferred a sequential multidisciplinary minimally invasive therapeutic strategy.First,PDA transcatheter closure was performed.Hyperthyroidism and heart failure were simultaneously controlled via medical treatment.Video-assisted thoracoscopic mitral valve repair and left atrial appendage occlusion were performed when heart failure was controlled.Under this therapeutic strategy,the patient’s sinus rhythm was restored and maintained.Two years after the treatment,the symptoms of heart failure were relieved,and the enlarged heart was reversed.CONCLUSION Sequential multidisciplinary therapeutic strategies,which take advantage of both internal medicine and surgical approaches,might be reasonable for this type of disease.
文摘Background: Helicobacter pylori (Hp) infection is the most widespread bacterial infection in the world. The infection is generally acquired in childhood, but can persist into adulthood. Eradication therapy has undergone several modifications. The aim of this study was to evaluate the different therapeutic strategies used in the eradication of Helicobacter pylori infection in the Centre Hospitalier Universitaire La Reference Nationale of N’Djaména. Patients and Methods: This was a prospective, descriptive analytical study spread over one year, from September 2021 to September 2022. Patients at least 15 years of age presenting with dyspeptic symptoms, seen consecutively in a hepato-gastroenterology consultation and with a positive stool test for H. pylori infection, were included in the study. Equally, 1/3 of patients were treated with dual or triple therapy. The remaining third received quadritherapy. Results: A total of 268 patients were included in the study (mean age 38.40 ± 14.66 with extremes of 16 and 80 years). Males predominated in 58% of cases. Overall therapeutic efficacy was 88.9%. According to different therapeutic strategies, efficacy was 90.75% for dual therapy with PPI (Rabeprazole) and Amoxicillin. On the other hand, efficacy was 87% and 88.88% for PPI-based triple therapy and dual antibiotic therapy, and for PPI-based quadruple therapy and triple antibiotic therapy. Conclusion: H. pylori infection is a common disease in Chad. Dual therapy with rabeprazole combined with a high dose of amoxicillin over a period of at least two weeks showed similar if not better efficacy than triple or quadruple therapy.
基金This review was supported by the National Natural Science Foundation of China(81920108017,82130036,and 81630028)the Key Research and Development Program of Jiangsu Province of China(BE2020620)Jiangsu Province Key Medical Discipline(ZDXKA2016020).
文摘Ischemic stroke caused by intracranial vascular occlusion has become increasingly prevalent with considerable mortality and disability,which gravely burdens the global economy.Current relatively effective clinical treatments are limited to intravenous alteplase and thrombectomy.Even so,patients still benefit little due to the short therapeutic window and the risk of ischemia/reperfusion injury.It is therefore urgent to figure out the neuronal death mechanisms following ischemic stroke in order to develop new neuroprotective strategies.Regarding the pathogenesis,multiple pathological events trigger the activation of cell death pathways.Particular attention should be devoted to excitotoxicity,oxidative stress,and inflammatory responses.Thus,in this article,we first review the principal mechanisms underlying neuronal death mediated by these significant events,such as intrinsic and extrinsic apoptosis,ferroptosis,parthanatos,pyroptosis,necroptosis,and autophagic cell death.Then,we further discuss the possibility of interventions targeting these pathological events and summarize the present pharmacological achievements.
基金supported by a grant from the Fundacao para a Ciencia e Tecnologia of the Ministerio da Educacao e Ciencia (2020.02006.CEECIND)iBiMED,University of Aveiro and the Fundacao para a Ciência e Tecnologia of the Ministerio da Educacao e Ciencia (to DT)。
文摘In recent years, multiple disciplines have focused on mitochondrial biology and contributed to understanding its relevance towards adult-onset neurodegenerative disorders. These are complex dynamic organelles that have a variety of functions in ensuring cellular health and homeostasis. The plethora of mitochondrial functionalities confers them an intrinsic susceptibility to internal and external stressors(such as mutation accumulation or environmental toxins), particularly so in long-lived postmitotic cells such as neurons. Thus, it is reasonable to postulate an involvement of mitochondria in aging-associated neurological disorders, notably neurodegenerative pathologies including Alzheimer’s disease and Parkinson’s disease. On the other hand, biological effects resulting from neurodegeneration can in turn affect mitochondrial health and function, promoting a feedback loop further contributing to the progression of neuronal dysfunction and cellular death. This review examines state-of-the-art knowledge, focus on current research exploring mitochondrial health as a contributing factor to neuroregeneration, and the development of therapeutic approaches aimed at restoring mitochondrial homeostasis in a pathological setting.
文摘One of the significant health issues in the world is the prevalence of ulcerative colitis(UC).UC is a chronic disorder that mainly affects the colon,beginning with the rectum,and can progress from asymptomatic mild inflammation to extensive inflammation of the entire colon.Understanding the underlying molecular mechanisms of UC pathogenesis emphasizes the need for innovative therapeutic approaches based on identifying molecular targets.Interestingly,in response to cellular injury,the NLR family pyrin domain containing 3(NLRP3)inflammasome is a crucial part of the inflammation and immunological reaction by promoting caspase-1 activation and the release of interleukin-1β.This review discusses the mechanisms of NLRP3 inflammasome activation by various signals and its regulation and impact on UC.
文摘Cardioembolic stroke,referred to as cardiogenic stroke,is a clinical syndrome in which emboli from the heart pass through the circulatory system and cause cerebral artery embolism and corresponding brain dysfunction.Compared to other subtypes of ischemic stroke,cardiogenic stroke presents with more etiologies,greater severity,worse prognosis,and a higher recurrence rate.In this minireview,we provide new insights into the etiological classification,diagnostic methods,and interventions of cardiogenic stroke.
基金Supported by the National Natural Science Foundation of China,No.81602056 and No.82273393the Natural Science Foundation of Shandong Province,No.ZR2016HQ45 and No.ZR2020LZL004the Shandong Traditional Chinese Medicine Science and Technology Project,No.2021M161.
文摘Pancreatic cancer remains one of the most lethal diseases worldwide owing to its late diagnosis,early metastasis,and poor prognosis.Because current therapeutic options are limited,there is an urgent need to investigate novel targeted treatment strategies.Pancreatic cancer faces significant metabolic challenges,principally hypoxia and nutrient deprivation,due to specific microenvironmental constraints,including an extensive desmoplastic stromal reaction.Pancreatic cancer cells have been shown to rewire their metabolism and energy production networks to support rapid survival and proliferation.Increased glucose uptake and glycolytic pathway activity during this process have been extensively described.However,growing evidence suggests that pancreatic cancer cells are glutamine addicted.As a nitrogen source,glutamine directly(or indirectly via glutamate conversion)contributes to many anabolic processes in pancreatic cancer,including amino acids,nucleobases,and hexosamine biosynthesis.It also plays an important role in redox homeostasis,and when converted toα-ketoglutarate,glutamine serves as an energy and anaplerotic carbon source,replenishing the tricarboxylic acid cycle intermediates.The present study aims to provide a comprehensive overview of glutamine metabolic reprogramming in pancreatic cancer,focusing on potential therapeutic approaches targeting glutamine metabolism in pancreatic cancer.
基金supported by National Natural Science Foundation of China(82001929,82172043)Basic and Applied Basic Research Foundation of Guangdong Province(2020A1515110654)
文摘Thermal ablation(TA),including radiofrequency ablation(RFA)and microwave ablation(MWA),has become the main treatment for early-stage hepatocellular carcinoma(HCC)due to advantages such as safety and minimal invasiveness.However,HCC is prone to local recurrence,with more aggressive malignancies after TA closely related to TA-induced changes in epithelial-mesenchymal transition(EMT)and remodeling of the tumor microenvironment(TME).According to many studies,various components of the TME undergo complex changes after TA,such as the recruitment of innate and adaptive immune cells,the release of tumor-associated antigens(TAAs)and various cytokines,the formation of a hypoxic microenvironment,and tumor angiogenesis.Changes in the TME after TA can partly enhance the anti-tumor immune response;however,this response is weak to kill the tumor completely.Certain components of the TME can induce an immunosuppressive microenvironment through complex interactions,leading to tumor recurrence and progression.How the TME is remodeled after TA and the mechanism by which the TME promotes HCC recurrence and progression are unclear.Thus,in this review,we focused on these issues to highlight potentially effective strategies for reducing and preventing the recurrence and progression of HCC after TA.
基金supported by the Natural Science Foundation of Zhejiang Province of China,Nos.LQ22H090003(to JJ),LTGY23C090001(to XZ),LY23H020008(to BH)Sci-Tech Planning Project of Jiaxing,Nos.2021AY30001(to XZ)and 2022AY30020(to JJ).
文摘The inflammasome is a multiprotein complex involved in innate immunity that mediates the inflammatory response leading to pyroptosis,which is a lytic,inflammatory form of cell death.There is accumulating evidence that nucleotide-binding domain and leucine-rich repeat pyrin domain containing 3(NLRP3)inflammasome-mediated microglial pyroptosis and NLRP1 inflammasome-mediated neuronal pyroptosis in the brain are closely associated with the pathogenesis of Alzheimer’s disease.In this review,we summarize the possible pathogenic mechanisms of Alzheimer’s disease,focusing on neuroinflammation.We also describe the structures of NLRP3 and NLRP1 and the role their activation plays in Alzheimer’s disease.Finally,we examine the neuroprotective activity of small-molecule inhibitors,endogenous inhibitor proteins,microRNAs,and natural bioactive molecules that target NLRP3 and NLRP1,based on the rationale that inhibiting NLRP3 and NLRP1 inflammasome-mediated pyroptosis can be an effective therapeutic strategy for Alzheimer’s disease.
基金the Discipline Promotion Program of Shanghai Fourth People’s Hospital,No.SY-XKZT-2020-1021.
文摘This letter is intended to arouse your interest in a recent review of comprehensive scientometrics and clinical trials on immunotherapy for gastric cancer(GC).Our study reviews recent advances in immunotherapy in the field of GC and highlights its new prospects as a treatment for GC.Our research reveals China’s leadership in this field,as well as new therapeutic strategies such as immune checkpoint inhibitors,cellular immunotherapy,and vaccines.The combined findings highlight the potential of immunotherapy to improve survival and quality of life in patients with stomach cancer.We believe that this study will provide important guidance for the future direction of the GC treatment field.
基金funded by the National Natural Science Foundation of China(No.81974347)the Science and Technology Program of Sichuan Province(No.2021YJ0444)+1 种基金China Postdoctoral Science Foundation(No.2021M702351)Post-Doctor Research Project,West China Hospital,Sichuan University(No.2020HXBH081)。
文摘Osteoarthritis(OA)is a prevalent degenerative joint disease characterized by cartilage loss and accounts for a major source of pain and disability worldwide.However,effective strategies for cartilage repair are lacking,and patients with advanced OA usually need joint replacement.Better comprehending OA pathogenesis may lead to transformative therapeutics.Recently studies have reported that exosomes act as a new means of cell-to-cell communication by delivering multiple bioactive molecules to create a particular microenvironment that tunes cartilage behavior.Specifically,exosome cargos,such as noncoding RNAs(ncRNAs)and proteins,play a crucial role in OA progression by regulating the proliferation,apoptosis,autophagy,and inflammatory response of joint cells,rendering them promising candidates for OA monitoring and treatment.This review systematically summarizes the current insight regarding the biogenesis and function of exosomes and their potential as therapeutic tools targeting cell-to-cell communication in OA,suggesting new realms to improve OA management.
基金Supported by the National Natural Science Foundation of China(General Program),No.81972726.
文摘Hepatocellular carcinoma(HCC)is the fourth leading cause of cancer-related deaths worldwide.The prognosis of patients with HCC remains poor largely due to the late diagnosis and lack of effective treatments.Despite being widely used,alpha-fetoprotein serology and ultrasonography have limited diagnostic performance for early-stage HCC.The emergence of omics strategies has contributed to significant advances in the development of non-invasive biomarkers for the early diagnosis of HCC including proteins,metabolites,circulating tumor deoxyribonucleic acid,and circulating non-coding ribonucleic acid.Early diagnosis is beneficial to patients as it increases the proportion who can be treated with curative treatment,thus prolonging survival outcomes.Currently,multiple clinical trials involving locoregional,systemic therapies,and combinations of these modalities are changing therapeutic strategies for different stage HCC.Success in several preclinical trials that involve immunotherapeutic innovations has created the potential to complement and enforce other treatment strategies in the future.This review summarizes the most recent advances in noninvasive early molecular detection,current therapy strategies,and potential immunotherapeutic innovations of HCC.
文摘A review of recent animal models of Huntington’s disease showed many microRNAs had altered expression levels in the striatum and cerebral cortex,and which were mostly downregulated.Among the altered microRNAs were miR-9/9*,miR-29b,miR-124a,miR-132,miR-128,miR-139,miR-122,miR-138,miR-23b,miR-135b,miR-181(all downregulated)and miR-448(upregulated),and similar changes had been previously found in Huntington’s disease patients.In the animal cell studies,the altered microRNAs included miR-9,miR-9*,miR-135b,miR-222(all downregulated)and miR-214(upregulated).In the animal models,overexpression of miR-155 and miR-196a caused a decrease in mutant huntingtin mRNA and protein level,lowered the mutant huntingtin aggregates in striatum and cortex,and improved performance in behavioral tests.Improved performance in behavioral tests also occurred with overexpression of miR-132 and miR-124.In the animal cell models,overexpression of miR-22 increased the viability of rat primary cortical and striatal neurons infected with mutant huntingtin and decreased huntingtin-enriched foci of≥2μm.Also,overexpression of miR-22 enhanced the survival of rat primary striatal neurons treated with 3-nitropropionic acid.Exogenous expression of miR-214,miR-146a,miR-150,and miR-125b decreased endogenous expression of huntingtin mRNA and protein in HdhQ111/HdhQ111 cells.Further studies with animal models of Huntington’s disease are warranted to validate these findings and identify specific microRNAs whose overexpression inhibits the production of mutant huntingtin protein and other harmful processes and may provide a more effective means of treating Huntington’s disease in patients and slowing its progression.
文摘Although gastroenteropancreatic neuroendocrine neoplasms(GEP-NENs)have always been considered rare tumors,their incidence has risen over the past few decades.They represent a highly heterogeneous group of neoplasms with several prognostic factors,including disease stage,proliferative index(Ki67),and tumor differentiation.Most of these neoplasms express somatostatin receptors on the cell surface,a feature that has important implications in terms of prognosis,diagnosis,and therapy.Although International Guidelines propose algorithms aimed at guiding therapeutic strategies,GEP-NEN patients are still very different from one another,and the need for personalized treatment continues to increase.Radical surgery is always the best option when feasible;however,up to 80%of cases are metastatic upon diagnosis.Regarding medical treatments,as GEP-NENs are characterized by relatively long overall survival,multiple therapy lines are adopted during the lifetime of these patients,but the optimum sequence to be followed has never been clearly defined.Furthermore,although new molecular markers aimed at predicting the response to therapy,as well as prognostic scores,are currently being studied,their application is still far from being part of daily clinical practice.As they represent a complex disease,with therapeutic protocols that are not completely standardized,GEP-NENs require a multidisciplinary approach.This review will provide an overview of the available therapeutic options for GEP-NENs and attempts to clarify the possible approaches for the management of these patients and to discuss future perspectives in this field.
文摘<div style="text-align:justify;"> <span style="font-family:Verdana;">Spinocerebellar ataxia type 3 (SCA3), also known as Machado-Joseph Disease (MJD), is an autosomal dominant neurodegenerative disorder that predominantly involves the cerebellar, pyramidal, extrapyramidal, motor neuron and oculomotor systems. SCA3 presents strong phenotypic heterogeneity and its causative mutation of SCA3 consists of an expansion of a CAG tract in exon 10 of the <em>ATXN3</em> gene, situated at 14q32.1. The <em>ATXN3</em> gene is ubiquitously expressed in neuronal and non-neuronal tissues, and also participates in cellular protein quality control pathways. Mutated <em>ATXN3</em> alleles present about 45 to 87CAG repeats, which result in an expanded polyglutamine tract in ataxin-3. After mutation, the polyQ tract reaches the pathological threshold (about 50 glutamine residues);the protein is considered that it might gain a neurotoxic function through some unclear mechanisms. We reviewed the literature on the pathogenesis and therapeutic strategies of spinocerebellar ataxia type 3 patients. Conversion of the expanded protein is possible by enhancing protein refolding and degradation or preventing proteolytic cleavage and prevents the protein to reach the site of toxicity by altering its ability to translocate between the nucleus and cytoplasm. Proteasomal degradation and enhancing autophagic aggregate clearance are currently proposed remarkable therapy. In spite of extensive research, the molecular mechanisms of cellular toxicity resulting from mutant ataxin-3 remain no preventive treatment is currently available. These therapeutic strategies might be able to improve sign symptoms of SCA3 as well as slow the disease progression.</span> </div>
文摘Neurodegeneration affects a large number of cell types including neurons,astrocytes or oligodendrocytes,and neural stem cells.Neural stem cells can generate new neuronal populations through proliferation,migration,and differentiation.This neurogenic potential may be a relevant factor to fight neurodegeneration and aging.In the last years,we can find growing evidence suggesting that melatonin may be a potential modulator of adult hippocampal neurogenesis.The lack of therapeutic strategies targeting neurogenesis led researchers to explore new molecules.Numerous preclinical studies with melatonin observed how melatonin can modulate and enhance molecular and signaling pathways involved in neurogenesis.We made a special focus on the connection between these modulation mechanisms and their implication in neurodegeneration,to summarize the current knowledge and highlight the therapeutic potential of melatonin.
基金Supported by the Agencia Nacional de Promoción Científica y Tecnológica,No.ANPCy TPICT2018-02032 RES-2019-401-APN-DANPCYT#ANPCYT(To Molejon MI),No.ANPCy TPICT2017-2070 RES-2017-310/18(To Breccia JD),and No.ANPCy TPICT2016-2258 RES-2017-285-APNDANPCYT#MCTUniversity of Buenos Aires-UBACy T2018,RES(CS)No1041/18(To Vaccaro MI)+1 种基金the National Scientific and Technical Research Council(CONICET)the National University of La Pampa
文摘Cancer constitutes the second leading cause of death globally and is considered to have been responsible for an estimated 9.6 million fatalities in 2018.Although treatments against gastrointestinal tumors have recently advanced,those interventions can only be applied to a minority of patients at the time of diagnosis.Therefore,new therapeutic options are necessary for advanced stages of the disease.Glycosylation of antitumor agents,has been found to improve pharmacokinetic parameters,reduce side effects,and expand drug half-life in comparison with the parent compounds.In addition,glycosylation of therapeutic agents has been proven to be an effective strategy for their targeting tumor tissue,thereby reducing the doses of the glycodrugs administered to patients.This review focusses on the effect of the targeting properties of glycosylated antitumor agents on gastrointestinal tumors.
基金Guha S wishes to thank UR PDA Career Enhancement Award 2020 for covering the subscription fee of bio-render and other bureaucratic cost.Subramaniyam R wishes to thank DST-inspire program for the research grant(No.DST/INSPIRE/04/2015/001945).
文摘Alzheimer’s disease(AD)is the most common progressive neurodegenerative disorder.It is often lethal and currently lacks a satisfactory therapy.The disease has a specific neuro-pathological profile:accumulation of proteinaceous deposits in the brain–amyloid plaques(containingβ-amyloid peptides)and neurofibrillary tangles which are accumulation of a profusion of long stringy tangles of proteins called tau.Between the two highly recognized AD hypotheses,amyloid beta(Aβ)peptide aggregation and accumulation play a significant role and are considered as an important mechanism of AD pathology.Aβis a proteolytic product of amyloid precursor protein and genetic studies supported the relevance of Aβin AD pathogenesis.A large number of small molecules were studied for their ability to inhibit Aβ-aggregation in oligomer form or after fibrillization.However,the protein-misfolding process has certain setbacks which are inevitable due to the different morphology of protein.In recent years,it has been demonstrated that tau also plays a central role in pathogenesis of this disease.Moreover,abnormal post-translational modifications of tau,in particular,increases in acetylation at specific sites likely contribute to the toxicity of tau.Although it is evident that tau with these aberrant post-translational modifications likely facilitates neurodegeneration,the precise cellular mechanisms by which tau compromises neuronal function remain unknown.In addition,much remains to be learned about new interventions that might be developed to prevent or reduce the negative impact of tau posttranslational modifications-related damage.This review article addresses the key roles of amyloid beta and tau protein in AD as well as the possible therapeutic agents that can reduce the toxic levels of both the proteins,and thus providing beneficial effect for the AD patients.
文摘Brain tumors are a diverse group of malignancies that remain refractory to conventional treatment approaches.Molecular neuro-oncologyhas now begun to clarify the transformed phenotype of brain tumors and identify oncogenic pathways that might be amenable to targetedtherapy.Activity of the phosphoinositide 3;kinase(PI3K)/Akt pathway is often upregulated in brain tumors due to excessive stimu-lation by growth factor receptors and Ras.Loss of function of the tumor suppressor gene PTEN also frequently contributesto