Hepatocyte nuclear factor 1 alpha(HNF1A),hepatocyte nuclear factor 4 alpha(HNF4A),and forkhead box protein A2(FOXA2)are key transcription factors that regulate a complex gene network in the liver,cre-ating a regulator...Hepatocyte nuclear factor 1 alpha(HNF1A),hepatocyte nuclear factor 4 alpha(HNF4A),and forkhead box protein A2(FOXA2)are key transcription factors that regulate a complex gene network in the liver,cre-ating a regulatory transcriptional loop.The Encode and ChIP-Atlas databases identify the recognition sites of these transcription factors in many glycosyltransferase genes.Our in silico analysis of HNF1A,HNF4A.and FOXA2 binding to the ten candidate glyco-genes studied in this work confirms a significant enrich-ment of these transcription factors specifically in the liver.Our previous studies identified HNF1A as a master regulator of fucosylation,glycan branching,and galactosylation of plasma glycoproteins.Here,we aimed to functionally validate the role of the three transcription factors on downstream glyco-gene transcriptional expression and the possible effect on glycan phenotype.We used the state-of-the-art clus-tered regularly interspaced short palindromic repeats/dead Cas9(CRISPR/dCas9)molecular tool for the downregulation of the HNF1A,HNF4A,and FOXA2 genes in HepG2 cells-a human liver cancer cell line.The results show that the downregulation of all three genes individually and in pairs affects the transcrip-tional activity of many glyco-genes,although downregulation of glyco-genes was not always followed by an unambiguous change in the corresponding glycan structures.The effect is better seen as an overall change in the total HepG2 N-glycome,primarily due to the extension of biantennary glycans.We propose an alternative way to evaluate the N-glycome composition via estimating the overall complexity of the glycome by quantifying the number of monomers in each glycan structure.We also propose a model showing feedback loops with the mutual activation of HNF1A-FOXA2 and HNF4A-FOXA2 affecting glyco-genes and protein glycosylation in HepG2 cells.展开更多
Objective:To explore the clinical effect of internal fixation and fusion with the paraspinal muscle gap approach in the treatment of spinal fracture patients.Methods:104 spinal fracture patients admitted to Central Ho...Objective:To explore the clinical effect of internal fixation and fusion with the paraspinal muscle gap approach in the treatment of spinal fracture patients.Methods:104 spinal fracture patients admitted to Central Hospital of TCM from October 2022 to April 2024 were selected as the study subjects and were randomly divided into the control group(n=52)and the observation group(n=52)according to the random number table method.The control group was treated with the conventional approach of internal fixation surgery,and the observation group was treated with the paraspinal muscular interspace approach of internal fixation fusion.The two groups’general data,surgical indexes,pain,lumbar spine function,and postoperative complications were observed.Results:The baseline data of the two groups of patients were not statistically significant(all P>0.05)while the intraoperative bleeding,the first postoperative time getting up from bed,and the length of hospital stay of the patients in the observation group were shorter than that of the control group(all P=0.000<0.001),and the duration of the operation was longer than that of the control group(t=2.644,P=0.010<0.05);at 3 months postoperatively,the VAS scores of the patients in the observation group were significantly lower than those in the control group(t=10.768,P=0.000<0.001),and the JOA score was higher than that of the control group(t=6.498,P=0.000<0.001);the total complication rate of patients in the observation group(3/5.77%)was significantly lower than that of the control group(12/23.08%)(χ^(2)=6.310,P=0.012<0.05).Conclusion:In the treatment of spinal fracture patients,compared with the conventional approach to internal fixation surgery,the paraspinal muscular gap approach to internal fixation and fusion treatment is less traumatic,postoperative lumbar spine function recovery is faster,and can reduce the incidence of postoperative complications.展开更多
Orphan diseases are rare diseases that affect less than 200000 individuals within the United States.Most orphan diseases are of neurologic and genetic origin.With the current advances in technology,more funding has be...Orphan diseases are rare diseases that affect less than 200000 individuals within the United States.Most orphan diseases are of neurologic and genetic origin.With the current advances in technology,more funding has been devoted to developing therapeutic agents for patients with these conditions.In our review,we highlight emerging options for patients with neurologic orphan diseases,specifically including diseases resulting in muscular deterioration,epilepsy,seizures,neurodegenerative movement disorders,inhibited cognitive development,neuron deterioration,and tumors.After extensive literature review,gene therapy offers a promising route for the treatment of neurologic orphan diseases.The use of clustered regularly interspaced palindromic repeats/Cas9 has demonstrated positive results in experiments investigating its role in several diseases.Additionally,the use of adeno-associated viral vectors has shown improvement in survival,motor function,and developmental milestones,while also demonstrating reversal of sensory ataxia and cardiomyopathy in Friedreich ataxia patients.Antisense oligonucleotides have also been used in some neurologic orphan diseases with positive outcomes.Mammalian target of rapamycin inhibitors are currently being investigated and have reduced abnormal cell growth,proliferation,and angiogenesis.Emerging innovations and the role of genetic treatments open a new window of opportunity for the treatment of neurologic orphan diseases.展开更多
Pancreatic cancer(PC)remains one of the most challenging diseases,with a very poor 5-year overall survival of around 11.5%.Kirsten rat sarcoma virus(KRAS)mutation is seen in 90%-95%of PC patients and plays an importan...Pancreatic cancer(PC)remains one of the most challenging diseases,with a very poor 5-year overall survival of around 11.5%.Kirsten rat sarcoma virus(KRAS)mutation is seen in 90%-95%of PC patients and plays an important role in cancer cell proliferation,differentiation,metabolism,and survival,making it an essential mutation for targeted therapy.Despite extensive efforts in studying this oncogene,there has been little success in finding a drug to target this pathway,labelling it for decades as“undruggable”.In this article we summarize some of the efforts made to target the KRAS pathway in PC,discuss the challenges,and shed light on promising clinical trials.展开更多
Recently, an epoch-making genome engineering technology using clustered regularly at interspaced short palindromic repeats(CRISPR) and CRISPR associated(Cas) nucleases, was developed. Previous technologies for genome ...Recently, an epoch-making genome engineering technology using clustered regularly at interspaced short palindromic repeats(CRISPR) and CRISPR associated(Cas) nucleases, was developed. Previous technologies for genome manipulation require the time-consuming design and construction of genome-engineered nucleases for each target and have, therefore, not been widely used in mouse research where standard techniques based on homologous recombination are commonly used. The CRISPR/Cas system only requires the design of sequences complementary to a target locus, making this technology fast and straightforward. In addition, CRISPR/Cas can be used to generate mice carrying mutations in multiple genes in a single step, an achievement not possible using other methods. Here, we review the uses of this technology in genetic analysis and manipulation, including achievements made possible to date and the prospects for future therapeutic applications.展开更多
Alzheimer’s disease (AD) is an increasingly pressing worldwide public-health, social, political and economic concern. Despite significant investment in multiple traditional therapeutic strategies that have achieved...Alzheimer’s disease (AD) is an increasingly pressing worldwide public-health, social, political and economic concern. Despite significant investment in multiple traditional therapeutic strategies that have achieved success in preclinical models addressing the pathological hallmarks of the disease, these efforts have not translated into any effective disease-modifying therapies. This could be because interventions are being tested too late in the disease process. While existing therapies provide symptomatic and clinical benefit, they do not fully address the molecular abnormalities that occur in AD neurons. The pathophysiology of AD is complex; mitochondrial bioenergetic deficits and brain hypometabolism coupled with increased mitochondrial oxidative stress are antecedent and potentially play a causal role in the disease pathogenesis. Dysfunctional mitochondria accumulate from the combination of impaired mitophagy, which can also induce injurious inflammatory responses, and inadequate neuronal mitochondrial biogenesis. Altering the metabolic capacity of the brain by modulating/potentiating its mitochondrial bioenergetics may be a strategy for disease prevention and treatment. We present insights into the mechanisms of mitochondrial dysfunction in AD brain as well as an overview of emerging treatments with the potential to prevent, delay or reverse the neurodegenerative process by targeting mitochondria.展开更多
The scientific community is continuously working to translate the novel biomedical techniques into effective medical treatments.CRISPR-Cas9 system(Clustered Regularly Interspaced Short Palindromic Repeats-9),commonly ...The scientific community is continuously working to translate the novel biomedical techniques into effective medical treatments.CRISPR-Cas9 system(Clustered Regularly Interspaced Short Palindromic Repeats-9),commonly known as the“molecular scissor”,represents a recently developed biotechnology able to improve the quality and the efficacy of traditional treatments,related to several human diseases,such as chronic diseases,neurodegenerative pathologies and,interestingly,oral diseases.Of course,dental medicine has notably increased the use of biotechnologies to ensure modern and conservative approaches:in this landscape,the use of CRISPR-Cas9 system may speed and personalize the traditional therapies,ensuring a good predictability of clinical results.The aim of this critical overview is to provide evidence on CRISPR efficacy,taking into specific account its applications in oral medicine.展开更多
Chimeric antigen receptor T(CAR-T)cell therapy is the novel treatment strategy for hematological malignancies such as acute lymphoblastic leukemia(ALL),lymphoma and multiple myeloma.However,treatment-related toxicitie...Chimeric antigen receptor T(CAR-T)cell therapy is the novel treatment strategy for hematological malignancies such as acute lymphoblastic leukemia(ALL),lymphoma and multiple myeloma.However,treatment-related toxicities such as cytokine release syndrome(CRS)and immune effector cell-associated neurotoxicity syndrome(ICANS)have become significant hurdles to CAR-T treatment.Multiple strategies were established to alter the CAR structure on the genomic level to improve efficacy and reduce toxicities.Recently,the innovative gene-editing technology-clustered regularly interspaced short palindromic repeats(CRISPR)/CRISPR-associated nuclease9(Cas9)system,which particularly exhibits preponderance in knock-in and knockout at specific sites,is widely utilized to manufacture CAR-T products.The application of CRISPR/Cas9 to CAR-T cell therapy has shown promising clinical results with minimal toxicity.In this review,we summarized the past achievements of CRISPR/Cas9 in CAR-T therapy and focused on the potential CAR-T targets.展开更多
Liver diseases are one of the leading causes of mortality in the world. The hepatic illnesses, which include inherited metabolic disorders, hemophilias and viralhepatitides, are complex and currently difficult to trea...Liver diseases are one of the leading causes of mortality in the world. The hepatic illnesses, which include inherited metabolic disorders, hemophilias and viralhepatitides, are complex and currently difficult to treat. The maturation of gene therapy has heralded new avenues for developing effective intervention for these diseases. DNA modification using gene therapy is now possible and available technology may be exploited to achieve long term therapeutic benefit. The ability to edit DNA sequences specifically is of paramount importance to advance gene therapy for application to liver diseases. Recent development of technologies that allow for this has resulted in rapid advancement of gene therapy to treat several chronic illnesses. Improvements in application of derivatives of zinc finger proteins(ZFPs), transcription activator-like effectors(TALEs), homing endonucleases(HEs) and clustered regularly interspaced palindromic repeats(CRISPR) and CRISPR associated(Cas) systems have been particularly important. These sequence-specific technologies may be used to modify genes permanently and also to alter gene transcription for therapeutic purposes. This review describes progress in development of ZFPs, TALEs, HEs and CRISPR/Cas for application to treating liver diseases.展开更多
This review chronicles the development of the research on CRISPR/Cas9 (Clustered Regularly Interspaced Short Palindromic Repeat/CRISPR associated protein 9) during the last 30 years from the discovery of CRISPR sequen...This review chronicles the development of the research on CRISPR/Cas9 (Clustered Regularly Interspaced Short Palindromic Repeat/CRISPR associated protein 9) during the last 30 years from the discovery of CRISPR sequence, of biological significance and of the molecular mechanism for adaptive bacterial immunity. It describes recent works on structural and functional diversity of CRISPR/Cas systems, and on three-dimensional structure-based improvements of on-target specificity of CRISPR/Cas9 and Cpf1 endonucleases. The review ends with the application of CRISPR/Cas9 to targeted editing of plant genomes. Importantly, plant commodities modified by CRISPR-Cas9 have not been considered as genetically modified organisms (GMO) as long as foreign DNAs from plant pests were not introduced, according to the recent determination by the USDA.展开更多
Gene editing has recently emerged as a promising technology to engineer genetic modifications precisely in the genome to achieve long-term relief from corneal disorders.Recent advances in the molecular biology leading...Gene editing has recently emerged as a promising technology to engineer genetic modifications precisely in the genome to achieve long-term relief from corneal disorders.Recent advances in the molecular biology leading to the development of clustered regularly interspaced short palindromic repeats(CRISPRs) and CRISPR-associated systems,zinc finger nucleases and transcription activator like effector nucleases have ushered in a new era for high throughput in vitro and in vivo genome engineering.Genome editing can be successfully used to decipher complex molecular mechanisms underlying disease pathophysiology,develop innovative next generation gene therapy,stem cell-based regenerative therapy,and personalized medicine for corneal and other ocular diseases.In this review we describe latest developments in the field of genome editing,current challenges,and future prospects for the development of personalized genebased medicine for corneal diseases.The gene editing approach is expected to revolutionize current diagnostic and treatment practices for curing blindness.展开更多
The sequencing of complete human genome revolutionized the genomic medicine.However,the complex interplay of gene-environment-lifestyle and influence of non-coding genomic regions on human health remain largely unexpl...The sequencing of complete human genome revolutionized the genomic medicine.However,the complex interplay of gene-environment-lifestyle and influence of non-coding genomic regions on human health remain largely unexplored.Genomic medicine has great potential for diagnoses or disease prediction,disease prevention and,targeted treatment.However,many of the promising tools of genomic medicine are still in their infancy and their application may be limited because of the limited knowledge we have that precludes its use in many clinical settings.In this review article,we have reviewed the evolution of genomic methodologies/tools,their limitations,and scope,for current and future clinical application.展开更多
Despite relative effectiveness of current hepatitis B therapies,there is still no curative agents available.The new emerging approaches hold promise to achieve cure and loss of hepatitis B surface antigen.Studies or c...Despite relative effectiveness of current hepatitis B therapies,there is still no curative agents available.The new emerging approaches hold promise to achieve cure and loss of hepatitis B surface antigen.Studies or clinical trials investigating new therapies remain small and either focus on patients with low viral load and without hepatotoxic injury or patients with hepatitis D co-infection,which makes it challenging to assess their effectiveness and side effect profile in hepatitis B population.展开更多
BACKGROUND Autism spectrum disorder(ASD)is a complex neurodevelopmental condition characterized by heterogeneous symptoms and genetic underpinnings.Recent advancements in genetic and epigenetic research have provided ...BACKGROUND Autism spectrum disorder(ASD)is a complex neurodevelopmental condition characterized by heterogeneous symptoms and genetic underpinnings.Recent advancements in genetic and epigenetic research have provided insights into the intricate mechanisms contributing to ASD,influencing both diagnosis and therapeutic strategies.AIM To explore the genetic architecture of ASD,elucidate mechanistic insights into genetic mutations,and examine gene-environment interactions.METHODS A comprehensive systematic review was conducted,integrating findings from studies on genetic variations,epigenetic mechanisms(such as DNA methylation and histone modifications),and emerging technologies[including Clustered Regularly Interspaced Short Palindromic Repeats(CRISPR)-Cas9 and single-cell RNA sequencing].Relevant articles were identified through systematic searches of databases such as PubMed and Google Scholar.RESULTS Genetic studies have identified numerous risk genes and mutations associated with ASD,yet many cases remain unexplained by known factors,suggesting undiscovered genetic components.Mechanistic insights into how these genetic mutations impact neural development and brain connectivity are still evolving.Epigenetic modifications,particularly DNA methylation and non-coding RNAs,also play significant roles in ASD pathogenesis.Emerging technologies like CRISPR-Cas9 and advanced bioinformatics are advancing our understanding by enabling precise genetic editing and analysis of complex genomic data.CONCLUSION Continued research into the genetic and epigenetic underpinnings of ASD is crucial for developing personalized and effective treatments.Collaborative efforts integrating multidisciplinary expertise and international collaborations are essential to address the complexity of ASD and translate genetic discoveries into clinical practice.Addressing unresolved questions and ethical considerations surrounding genetic research will pave the way for improved diagnostic tools and targeted therapies,ultimately enhancing outcomes for individuals affected by ASD.展开更多
Clustered regularly interspaced short palindromic repeats(CRISPR)/CRISPR-associated(Cas)systems are becoming powerful tools for disease biomarkers detection.Due to the specific recognition,cis-cleavage and nonspecific...Clustered regularly interspaced short palindromic repeats(CRISPR)/CRISPR-associated(Cas)systems are becoming powerful tools for disease biomarkers detection.Due to the specific recognition,cis-cleavage and nonspecific trans-cleavage capabilities,CRISPR/Cas systems have implemented the detection of nucleic acid targets(DNA and RNA)as well as non-nucleic acid targets(e.g.,proteins,exosomes,cells,and small molecules).In this review,we first summarize the principles and characteristics of various CRISPR/Cas systems,including CRISPR/Cas9,Cas12,Cas13 and Cas14 systems.Then,various types of applications of CRISPR/Cas systems used in detecting nucleic and non-nucleic acid targets are introduced emphatically.Finally,the prospects and challenges of their applications in biosensing are discussed.展开更多
基金the European Structural and Investment Funded Grant"Cardio Metabolic"(#KK.01.2.1.02.0321)the Croatian National Centre of Research Excellence in Personalized Healthcare Grant(#KK.01.1.1.01.0010)+2 种基金the European Regional Development Fund Grant,project"CRISPR/Cas9-CasMouse"(#KK.01.1.1.04.0085)the European Structural and Investment Funded Project of Centre of Competence in Molecular Diagnostics(#KK.01.2.2.03.0006)the Croatian National Centre of Research Excellence in Personalized Healthcare Grant(#KK.01.1.1.01.0010).
文摘Hepatocyte nuclear factor 1 alpha(HNF1A),hepatocyte nuclear factor 4 alpha(HNF4A),and forkhead box protein A2(FOXA2)are key transcription factors that regulate a complex gene network in the liver,cre-ating a regulatory transcriptional loop.The Encode and ChIP-Atlas databases identify the recognition sites of these transcription factors in many glycosyltransferase genes.Our in silico analysis of HNF1A,HNF4A.and FOXA2 binding to the ten candidate glyco-genes studied in this work confirms a significant enrich-ment of these transcription factors specifically in the liver.Our previous studies identified HNF1A as a master regulator of fucosylation,glycan branching,and galactosylation of plasma glycoproteins.Here,we aimed to functionally validate the role of the three transcription factors on downstream glyco-gene transcriptional expression and the possible effect on glycan phenotype.We used the state-of-the-art clus-tered regularly interspaced short palindromic repeats/dead Cas9(CRISPR/dCas9)molecular tool for the downregulation of the HNF1A,HNF4A,and FOXA2 genes in HepG2 cells-a human liver cancer cell line.The results show that the downregulation of all three genes individually and in pairs affects the transcrip-tional activity of many glyco-genes,although downregulation of glyco-genes was not always followed by an unambiguous change in the corresponding glycan structures.The effect is better seen as an overall change in the total HepG2 N-glycome,primarily due to the extension of biantennary glycans.We propose an alternative way to evaluate the N-glycome composition via estimating the overall complexity of the glycome by quantifying the number of monomers in each glycan structure.We also propose a model showing feedback loops with the mutual activation of HNF1A-FOXA2 and HNF4A-FOXA2 affecting glyco-genes and protein glycosylation in HepG2 cells.
基金Hebei Province’s 2020 Medical Scientific Research Topics“Clinical Study on Simultaneous Treatment of Multi-Segment Lumbar Disc Herniation with Transforaminal Endoscopy”(Project No.:1951ZF073)。
文摘Objective:To explore the clinical effect of internal fixation and fusion with the paraspinal muscle gap approach in the treatment of spinal fracture patients.Methods:104 spinal fracture patients admitted to Central Hospital of TCM from October 2022 to April 2024 were selected as the study subjects and were randomly divided into the control group(n=52)and the observation group(n=52)according to the random number table method.The control group was treated with the conventional approach of internal fixation surgery,and the observation group was treated with the paraspinal muscular interspace approach of internal fixation fusion.The two groups’general data,surgical indexes,pain,lumbar spine function,and postoperative complications were observed.Results:The baseline data of the two groups of patients were not statistically significant(all P>0.05)while the intraoperative bleeding,the first postoperative time getting up from bed,and the length of hospital stay of the patients in the observation group were shorter than that of the control group(all P=0.000<0.001),and the duration of the operation was longer than that of the control group(t=2.644,P=0.010<0.05);at 3 months postoperatively,the VAS scores of the patients in the observation group were significantly lower than those in the control group(t=10.768,P=0.000<0.001),and the JOA score was higher than that of the control group(t=6.498,P=0.000<0.001);the total complication rate of patients in the observation group(3/5.77%)was significantly lower than that of the control group(12/23.08%)(χ^(2)=6.310,P=0.012<0.05).Conclusion:In the treatment of spinal fracture patients,compared with the conventional approach to internal fixation surgery,the paraspinal muscular gap approach to internal fixation and fusion treatment is less traumatic,postoperative lumbar spine function recovery is faster,and can reduce the incidence of postoperative complications.
文摘Orphan diseases are rare diseases that affect less than 200000 individuals within the United States.Most orphan diseases are of neurologic and genetic origin.With the current advances in technology,more funding has been devoted to developing therapeutic agents for patients with these conditions.In our review,we highlight emerging options for patients with neurologic orphan diseases,specifically including diseases resulting in muscular deterioration,epilepsy,seizures,neurodegenerative movement disorders,inhibited cognitive development,neuron deterioration,and tumors.After extensive literature review,gene therapy offers a promising route for the treatment of neurologic orphan diseases.The use of clustered regularly interspaced palindromic repeats/Cas9 has demonstrated positive results in experiments investigating its role in several diseases.Additionally,the use of adeno-associated viral vectors has shown improvement in survival,motor function,and developmental milestones,while also demonstrating reversal of sensory ataxia and cardiomyopathy in Friedreich ataxia patients.Antisense oligonucleotides have also been used in some neurologic orphan diseases with positive outcomes.Mammalian target of rapamycin inhibitors are currently being investigated and have reduced abnormal cell growth,proliferation,and angiogenesis.Emerging innovations and the role of genetic treatments open a new window of opportunity for the treatment of neurologic orphan diseases.
文摘Pancreatic cancer(PC)remains one of the most challenging diseases,with a very poor 5-year overall survival of around 11.5%.Kirsten rat sarcoma virus(KRAS)mutation is seen in 90%-95%of PC patients and plays an important role in cancer cell proliferation,differentiation,metabolism,and survival,making it an essential mutation for targeted therapy.Despite extensive efforts in studying this oncogene,there has been little success in finding a drug to target this pathway,labelling it for decades as“undruggable”.In this article we summarize some of the efforts made to target the KRAS pathway in PC,discuss the challenges,and shed light on promising clinical trials.
基金Supported by The Grants from the Ministry of EducationCulture+7 种基金SportsScience and Technology of Japanthe Ministry of HealthLabour and Welfare of Japanthe National Institute of Biomedical Innovationthe Asahi Glass Foundationthe Ichiro Kanehara Foundationthe Program for Cultivating Global Leaders in Heavy Ion Therapeutics and Engineering
文摘Recently, an epoch-making genome engineering technology using clustered regularly at interspaced short palindromic repeats(CRISPR) and CRISPR associated(Cas) nucleases, was developed. Previous technologies for genome manipulation require the time-consuming design and construction of genome-engineered nucleases for each target and have, therefore, not been widely used in mouse research where standard techniques based on homologous recombination are commonly used. The CRISPR/Cas system only requires the design of sequences complementary to a target locus, making this technology fast and straightforward. In addition, CRISPR/Cas can be used to generate mice carrying mutations in multiple genes in a single step, an achievement not possible using other methods. Here, we review the uses of this technology in genetic analysis and manipulation, including achievements made possible to date and the prospects for future therapeutic applications.
文摘Alzheimer’s disease (AD) is an increasingly pressing worldwide public-health, social, political and economic concern. Despite significant investment in multiple traditional therapeutic strategies that have achieved success in preclinical models addressing the pathological hallmarks of the disease, these efforts have not translated into any effective disease-modifying therapies. This could be because interventions are being tested too late in the disease process. While existing therapies provide symptomatic and clinical benefit, they do not fully address the molecular abnormalities that occur in AD neurons. The pathophysiology of AD is complex; mitochondrial bioenergetic deficits and brain hypometabolism coupled with increased mitochondrial oxidative stress are antecedent and potentially play a causal role in the disease pathogenesis. Dysfunctional mitochondria accumulate from the combination of impaired mitophagy, which can also induce injurious inflammatory responses, and inadequate neuronal mitochondrial biogenesis. Altering the metabolic capacity of the brain by modulating/potentiating its mitochondrial bioenergetics may be a strategy for disease prevention and treatment. We present insights into the mechanisms of mitochondrial dysfunction in AD brain as well as an overview of emerging treatments with the potential to prevent, delay or reverse the neurodegenerative process by targeting mitochondria.
文摘The scientific community is continuously working to translate the novel biomedical techniques into effective medical treatments.CRISPR-Cas9 system(Clustered Regularly Interspaced Short Palindromic Repeats-9),commonly known as the“molecular scissor”,represents a recently developed biotechnology able to improve the quality and the efficacy of traditional treatments,related to several human diseases,such as chronic diseases,neurodegenerative pathologies and,interestingly,oral diseases.Of course,dental medicine has notably increased the use of biotechnologies to ensure modern and conservative approaches:in this landscape,the use of CRISPR-Cas9 system may speed and personalize the traditional therapies,ensuring a good predictability of clinical results.The aim of this critical overview is to provide evidence on CRISPR efficacy,taking into specific account its applications in oral medicine.
基金the National Natural Science Foundation of China(No.81230014,No.81470341,No.81520108002 and No.81500157)the Key Project of Science and Technology Department of Zhejiang Province(No.2018C03016-2)the Key Research and Development Program of Zhejiang Province(No.2019C03016).
文摘Chimeric antigen receptor T(CAR-T)cell therapy is the novel treatment strategy for hematological malignancies such as acute lymphoblastic leukemia(ALL),lymphoma and multiple myeloma.However,treatment-related toxicities such as cytokine release syndrome(CRS)and immune effector cell-associated neurotoxicity syndrome(ICANS)have become significant hurdles to CAR-T treatment.Multiple strategies were established to alter the CAR structure on the genomic level to improve efficacy and reduce toxicities.Recently,the innovative gene-editing technology-clustered regularly interspaced short palindromic repeats(CRISPR)/CRISPR-associated nuclease9(Cas9)system,which particularly exhibits preponderance in knock-in and knockout at specific sites,is widely utilized to manufacture CAR-T products.The application of CRISPR/Cas9 to CAR-T cell therapy has shown promising clinical results with minimal toxicity.In this review,we summarized the past achievements of CRISPR/Cas9 in CAR-T therapy and focused on the potential CAR-T targets.
基金The South African National Research Foundation(NRF,GUNs 81768,81692,68339,85981 and 77954)Poliomyelitis Research Foundation+1 种基金Claude Leon Foundation(SAN)The University of the Witwatersrand Research Council(BM)and Medical Research Council
文摘Liver diseases are one of the leading causes of mortality in the world. The hepatic illnesses, which include inherited metabolic disorders, hemophilias and viralhepatitides, are complex and currently difficult to treat. The maturation of gene therapy has heralded new avenues for developing effective intervention for these diseases. DNA modification using gene therapy is now possible and available technology may be exploited to achieve long term therapeutic benefit. The ability to edit DNA sequences specifically is of paramount importance to advance gene therapy for application to liver diseases. Recent development of technologies that allow for this has resulted in rapid advancement of gene therapy to treat several chronic illnesses. Improvements in application of derivatives of zinc finger proteins(ZFPs), transcription activator-like effectors(TALEs), homing endonucleases(HEs) and clustered regularly interspaced palindromic repeats(CRISPR) and CRISPR associated(Cas) systems have been particularly important. These sequence-specific technologies may be used to modify genes permanently and also to alter gene transcription for therapeutic purposes. This review describes progress in development of ZFPs, TALEs, HEs and CRISPR/Cas for application to treating liver diseases.
文摘This review chronicles the development of the research on CRISPR/Cas9 (Clustered Regularly Interspaced Short Palindromic Repeat/CRISPR associated protein 9) during the last 30 years from the discovery of CRISPR sequence, of biological significance and of the molecular mechanism for adaptive bacterial immunity. It describes recent works on structural and functional diversity of CRISPR/Cas systems, and on three-dimensional structure-based improvements of on-target specificity of CRISPR/Cas9 and Cpf1 endonucleases. The review ends with the application of CRISPR/Cas9 to targeted editing of plant genomes. Importantly, plant commodities modified by CRISPR-Cas9 have not been considered as genetically modified organisms (GMO) as long as foreign DNAs from plant pests were not introduced, according to the recent determination by the USDA.
文摘Gene editing has recently emerged as a promising technology to engineer genetic modifications precisely in the genome to achieve long-term relief from corneal disorders.Recent advances in the molecular biology leading to the development of clustered regularly interspaced short palindromic repeats(CRISPRs) and CRISPR-associated systems,zinc finger nucleases and transcription activator like effector nucleases have ushered in a new era for high throughput in vitro and in vivo genome engineering.Genome editing can be successfully used to decipher complex molecular mechanisms underlying disease pathophysiology,develop innovative next generation gene therapy,stem cell-based regenerative therapy,and personalized medicine for corneal and other ocular diseases.In this review we describe latest developments in the field of genome editing,current challenges,and future prospects for the development of personalized genebased medicine for corneal diseases.The gene editing approach is expected to revolutionize current diagnostic and treatment practices for curing blindness.
文摘The sequencing of complete human genome revolutionized the genomic medicine.However,the complex interplay of gene-environment-lifestyle and influence of non-coding genomic regions on human health remain largely unexplored.Genomic medicine has great potential for diagnoses or disease prediction,disease prevention and,targeted treatment.However,many of the promising tools of genomic medicine are still in their infancy and their application may be limited because of the limited knowledge we have that precludes its use in many clinical settings.In this review article,we have reviewed the evolution of genomic methodologies/tools,their limitations,and scope,for current and future clinical application.
文摘Despite relative effectiveness of current hepatitis B therapies,there is still no curative agents available.The new emerging approaches hold promise to achieve cure and loss of hepatitis B surface antigen.Studies or clinical trials investigating new therapies remain small and either focus on patients with low viral load and without hepatotoxic injury or patients with hepatitis D co-infection,which makes it challenging to assess their effectiveness and side effect profile in hepatitis B population.
文摘BACKGROUND Autism spectrum disorder(ASD)is a complex neurodevelopmental condition characterized by heterogeneous symptoms and genetic underpinnings.Recent advancements in genetic and epigenetic research have provided insights into the intricate mechanisms contributing to ASD,influencing both diagnosis and therapeutic strategies.AIM To explore the genetic architecture of ASD,elucidate mechanistic insights into genetic mutations,and examine gene-environment interactions.METHODS A comprehensive systematic review was conducted,integrating findings from studies on genetic variations,epigenetic mechanisms(such as DNA methylation and histone modifications),and emerging technologies[including Clustered Regularly Interspaced Short Palindromic Repeats(CRISPR)-Cas9 and single-cell RNA sequencing].Relevant articles were identified through systematic searches of databases such as PubMed and Google Scholar.RESULTS Genetic studies have identified numerous risk genes and mutations associated with ASD,yet many cases remain unexplained by known factors,suggesting undiscovered genetic components.Mechanistic insights into how these genetic mutations impact neural development and brain connectivity are still evolving.Epigenetic modifications,particularly DNA methylation and non-coding RNAs,also play significant roles in ASD pathogenesis.Emerging technologies like CRISPR-Cas9 and advanced bioinformatics are advancing our understanding by enabling precise genetic editing and analysis of complex genomic data.CONCLUSION Continued research into the genetic and epigenetic underpinnings of ASD is crucial for developing personalized and effective treatments.Collaborative efforts integrating multidisciplinary expertise and international collaborations are essential to address the complexity of ASD and translate genetic discoveries into clinical practice.Addressing unresolved questions and ethical considerations surrounding genetic research will pave the way for improved diagnostic tools and targeted therapies,ultimately enhancing outcomes for individuals affected by ASD.
基金This work was financially supported by the National Natural Science Foundation of China(Nos.81771968 and 22204104)the Shanghai Sailing Program(No.21YF1444900)+3 种基金the Shanghai Municipal Natural Science Foundation(No.22ZR1459600)the Medical-Engineering Joint Funds from the Shanghai Jiao Tong University(Nos.YG2023ZD07 and YG2021QN23)the Foundation of Shanghai Municipal Health Commission(No.2022JC002)the Innovative Research Team of High-Level Local Universities in Shanghai,China.
文摘Clustered regularly interspaced short palindromic repeats(CRISPR)/CRISPR-associated(Cas)systems are becoming powerful tools for disease biomarkers detection.Due to the specific recognition,cis-cleavage and nonspecific trans-cleavage capabilities,CRISPR/Cas systems have implemented the detection of nucleic acid targets(DNA and RNA)as well as non-nucleic acid targets(e.g.,proteins,exosomes,cells,and small molecules).In this review,we first summarize the principles and characteristics of various CRISPR/Cas systems,including CRISPR/Cas9,Cas12,Cas13 and Cas14 systems.Then,various types of applications of CRISPR/Cas systems used in detecting nucleic and non-nucleic acid targets are introduced emphatically.Finally,the prospects and challenges of their applications in biosensing are discussed.