Oral cancer(OC)is one of the most recurrent cancers in the head and neck squamous cancer(SCCHN)category.Recently,the genome-wide association studies(GWAS)have gained growing interest in the scientific community.GWAS h...Oral cancer(OC)is one of the most recurrent cancers in the head and neck squamous cancer(SCCHN)category.Recently,the genome-wide association studies(GWAS)have gained growing interest in the scientific community.GWAS have identified several pathways involved in the interactions among general risk factors and genomic variants affecting SCCHN.This systematic overview aims to critically evaluate the latest data reported within the scientific literature.The aim was to investigate the impact of genetic aspects on SCCHN onset and prognosis,involving other clinical and systemic co-factors.PubMed,Google Scholar,and Cancer Genetics Web databases have been systematically investigated for original articles published in the last two years,reporting studies on the main queries addressed in this work.This review also comparatively describes the impact of environmental and pathological co-factors in different types of cancers,clarifying and updating the role of genetic factors in SCCHN onset and development.The main outcomes reported may be helpful to drive clinicians towards their clinical evaluations for the most appropriate therapeutic approach in SCCHN.展开更多
Investigations into the inheritance of the three risk alleles R702W, G908R and 1007 fsInsC in NOD2 associated with susceptibility to Crohn＇s disease have demonstrated a remarkable amount of heterogeneity across ethni...Investigations into the inheritance of the three risk alleles R702W, G908R and 1007 fsInsC in NOD2 associated with susceptibility to Crohn＇s disease have demonstrated a remarkable amount of heterogeneity across ethnicities and populations, with regional variation across Europe for example, suggesting local founder effects. In nonCaucasian populations Crohn＇s disease continues to increase in incidence but this increase appears not to be a consequence of variation in NOD2, further advancing the accumulating evidence for other susceptibility loci. Frequencies of the known alleles are compared across populations in health and disease and evidence for additional alleles in NOD2 is reviewed. Based on its position on chromosome 16 coincident with some other autoimmune disease susceptibility Iocalizations, research has targeted NOD2 variation as the potential cause of other autoimmune disorders. While these investigations have mostly returned negative findings, two diseases, Blau Syndrome and Graft versus Host Disease, have been shown to be caused by risk alleles in NOD2. As is frequent in complex disease investigations, some results await validation, but the identification of NOD2 and the differences within and across population raises intriguing questions about the population genetics of the variation at this locus.展开更多
Wiedemann-Steiner syndrome(OMIM#605130)is a rare congenital malformation syndrome characterized by hypertrichosis cubiti associated with short stature;consistent facial features,including long eyelashes,thick or arche...Wiedemann-Steiner syndrome(OMIM#605130)is a rare congenital malformation syndrome characterized by hypertrichosis cubiti associated with short stature;consistent facial features,including long eyelashes,thick or arched eyebrows with a lateral flare,wide nasal bridge,and downslanting and vertically narrow palpebral fissures;mild to moderate intellectual disability;behavioral difficulties;and hypertrichosis on the back.It is caused by heterozygous pathogenic variants in KMT2A.This gene has an established role in histone methylation,which explains the overlap of Wiedemann-Steiner syndrome with other chromatinopathies,a heterogeneous group of syndromic conditions that share a common trigger:The disruption of one of the genes involved in chromatin modification,leading to dysfunction of the epigenetic machinery.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
Background: Androgen insensitivity syndrome(AIS), a disorder of sexual development in 46, XY individuals, is caused by loss-of-function mutations in the androgen receptor(AR) gene. A variety of tumors have been report...Background: Androgen insensitivity syndrome(AIS), a disorder of sexual development in 46, XY individuals, is caused by loss-of-function mutations in the androgen receptor(AR) gene. A variety of tumors have been reported in association with AIS, but no cases with colorectal cancer(CRC) have been described.Case presentation: Here, we present a male patient with AIS who developed multiple early-onset CRCs and his pedigree. His first cousin was diagnosed with AIS and harbored the same AR gene mutation, but with no signs of CRC. The difference in clinical management for the two patients was that testosterone treatment was given to the proband for a much longer time compared with the cousin. The CRC family history was negative, and no germline mutations in well-known CRC-related genes were identified. A single nucleotide polymorphism array revealed a microduplication on chromosome 22q11.22 that encompassed a micro RNA potentially related to CRC pathogenesis. In the proband, whole exome sequencing identified a polymorphism in an oncogene and 13 rare loss-of-function variants, of which two were in CRC-related genes and four were in genes associated with other human cancers.Conclusions: By pathway analysis, all inherited germline genetic events were connected in a unique network whose alteration in the proband, together with continuous testosterone stimulation, may have played a role in CRC pathogenesis.展开更多
The application of microarray-based techniques for the diagnosis of genomic rearrangements has been steadily growing in popularity since its introduction in 2004.Given the many advantages of these techniques over conv...The application of microarray-based techniques for the diagnosis of genomic rearrangements has been steadily growing in popularity since its introduction in 2004.Given the many advantages of these techniques over conventional cytogenetics,there is increasing pressure towards their application in prenatal diagnosis.However,there remain several important issues that must be addressed.For example,microarray-based techniques(comparative genomic hybridization-based arrays and single nucleotide polymorphism-based arrays) allow detection of even very small genomic imbalances that can determine pathological clinical conditions.In addition,there are other copy number variations which represent normal variation,with no detectable effects on phenotype.Given the still incomplete knowledge of the changes in our genome and the associated phenotypes,microarray-based diagnosis is likely to find variants of uncertain and unknown clinical significance.The interpretation of these variants is now a major challenge for the medical geneticist,who often find it difficult to establish precise correlations between genotype and phenotype.There is sufficient available evidence to justify the use of microarray-based diagnostics for a select number of specific conditions,but there is also an inevitable trend towards ever wider application.It is very important that this drift does not progress in an unchecked and uncontrolled manner under the thrust of commercial interests.Therefore,we recommend that scientific societies be vigilant and take an advisory role in the adopting of these technologies as new scientific knowledge becomes available.展开更多
Gitelman's syndrome(GS) is a salt-losing tubulopathy with an autosomal recessive inheritance caused by mutations of SLC12A3, which encodes for the thiazidesensitive Na Cl cotransporter. In this study we report a n...Gitelman's syndrome(GS) is a salt-losing tubulopathy with an autosomal recessive inheritance caused by mutations of SLC12A3, which encodes for the thiazidesensitive Na Cl cotransporter. In this study we report a new mutation of SLC12A3 found in two brothers affected by GS. Hypokalemia, hypocalciuria and hyperreninemia were present in both patients while hypomagnesemia was detected only in one. Both patients are compound heterozygotes carrying one well known GS associated mutation(c.2581 C > T) and a new one(c.283 del C) in SLC12A3 gene. The new mutation results in a possible frame-shift with a premature stopcodon(pG ln95 Argfs X19). The parents of the patients, heterozygous carriers of the mutations found in SLC12A3, have no disease associated phenotype. Therefore, the new mutation is causative of GS.展开更多
Background: Corticosteroid, hyaluronic acid (HA) injections and Anti-inflammatory agents are considered as non-invasive treatments for knee osteoarthritis (OA), Chronic Tendinitis (CT) and Tennis elbow (TE) that are s...Background: Corticosteroid, hyaluronic acid (HA) injections and Anti-inflammatory agents are considered as non-invasive treatments for knee osteoarthritis (OA), Chronic Tendinitis (CT) and Tennis elbow (TE) that are supposed to provide symptomatic relief and to help surgical delay intervention. Platelet rich plasma (PRP) is a biological component shown to be beneficial for different orthopedic dysfunctionalities treatment. The presence of GFs in PRPs such as transforming growth factor-β, insulin-like growth factor 1co-stimulate the mesenchymal stem cells and fibroblasts secretions and promotes the fibrin matrix formation which effectively drive the healing process, induces regenerative response and lead to the damage structure repair in orthopedics trauma. Methods: Three groups of a total of 30 patients presenting OA, CT and TE diagnosis, non-responding to corticosteroid, HA and non-steroid anti-inflammatory treatments were randomized to undergo one intra-articular injections of single high dose of PRP. The efficacy of Intra-articular PRP Injections was evaluated before the injection and one month after. The efficiency assessment score was based on [1] Knee injury and Osteoarthritis Outcome Score, [2] Physical Function Short Form (KOOS-PS) Arabic (KSA) version LK 1.0, [3] HOOS-Physical Function Short form (HOOS-PS), and [4] Macdermid patient-rated Tennis Elbow. Results: A significant reduction of pain and a marked improvement in movements was observed in the 3 patient’s groups, PRP-injected patients showed significantly higher values compared with baseline: (p < 0.005 vs baseline), improve functional status and reduce clearly the articular dysfunctions over the time. In our study, single High dose injection of PRP provided an overall superior clinical improvement compared with HA and corticosteroid treatments over the time and the different follow-up checkpoints of the study.展开更多
Pompe disease (PD) is a rare inborn error of metabolism due to an abnormal acid alpha-glucosidase (GAA) activity that comprises glycogen breakdown mainly in the lysosomes. Since the introduction of enzyme replacement ...Pompe disease (PD) is a rare inborn error of metabolism due to an abnormal acid alpha-glucosidase (GAA) activity that comprises glycogen breakdown mainly in the lysosomes. Since the introduction of enzyme replacement therapy (ERT), with recombinant human GAA for the early onset PD patient, a relevant field of clinical research due to the benefits regarding survival rate has been widely documented worldwide. Objective: To describe the clinical characteristics and the ERT effects in a series of Brazilian patients with infantile onset PD (IOPD) under ERT. Methods: Brazilian patients diagnosed with IOPD under ERT were recruited through their physicians participating in the International Pompe Disease Registry from 2009 to 2017. Data were collected by an online survey. Results: 10 IOPD patients were identified through the survey with a death rate of 30% and technology dependency rate reported as 80% (motor, respiratory or nutritional fields) of the patients. After the third year of ERT, motor disabilities were lost in 50% of ambulated patients. The overall characteristics were similar to international studies. Conclusion: Despite ERT benefits in cardiac involvement, motor disabilities seem to be much more compromised in IOPD patients, with high technology dependence, especially after three years of age.展开更多
Nonalcoholic fatty liver disease(NAFLD) is characterized by hepatic steatosis and insulin resistance and there are currently no approved drugs for its treatment.Hyperactivation of mTOR complex1(mTORCl) and subsequent ...Nonalcoholic fatty liver disease(NAFLD) is characterized by hepatic steatosis and insulin resistance and there are currently no approved drugs for its treatment.Hyperactivation of mTOR complex1(mTORCl) and subsequent impairment of the transcription factor EB(TFEB)-mediated autophagy-lysosomal pathway(ALP) are implicated in the development of NAFLD.Accordingly,agents that augment hepatic TFEB transcriptional activity may have therapeutic potential against NAFLD.The objective of this study was to investigate the effects of nuciferine,a major active component from lotus leaf,on NAFLD and its underlying mechanism of action.Here we show that nuciferine activated ALP and alleviated steatosis,insulin resistance in the livers of NAFLD mice and palmitic acid-challenged hepatocytes in a TFEB-dependent manner.Mechanistic investigation revealed that nuciferine interacts with the Ragulator subunit hepatitis B X-interacting protein and impairs the interaction of the Ragulator complex with Rag GTPases,thereby suppressing lysosomal localization and activity of mTORC1,which activates TFEB-mediated ALP and further ameliorates hepatic steatosis and insulin resistance.Our present results indicate that nuciferine may be a potential agent for treating NAFLD and that regulation of the mTORCl-TFEB-ALP axis could represent a novel pharmacological strategy to combat NAFLD.展开更多
MicroRNAs are small non-coding RNAs that play crucial roles in the regulation of gene expression and protein synthesis during brain development. MiR-3099 is highly expressed throughout embryogenesis, especially in the...MicroRNAs are small non-coding RNAs that play crucial roles in the regulation of gene expression and protein synthesis during brain development. MiR-3099 is highly expressed throughout embryogenesis, especially in the developing central nervous system. Moreover, miR-3099 is also expressed at a higher level in differentiating neurons in vitro, suggesting that it is a potential regulator during neuronal cell development. This study aimed to predict the target genes of miR-3099 via in-silico analysis using four independent prediction algorithms（miRDB,miRanda, Target Scan, and DIANA-micro-T-CDS） with emphasis on target genes related to brain development and function. Based on the analysis, a total of 3,174 miR-3099 target genes were predicted. Those predicted by at least three algorithms（324 genes） were subjected to DAVID bioinformatics analysis to understand their overallfunctional themes and representation. The analysis revealed that nearly 70% of the target genes were expressed in the nervous system and a significant proportion were associated with transcriptional regulation and protein ubiquitination mechanisms. Comparison of in situ hybridization（ISH） expression patterns of miR-3099 in both published and in-house-generated ISH sections with the ISH sections of target genes from the Allen Brain Atlas identified 7 target genes（Dnmt3a, Gabpa, Gfap, Itga4,Lxn, Smad7, and Tbx18） having expression patterns complementary to miR-3099 in the developing and adult mouse brain samples. Of these, we validated Gfap as a direct downstream target of miR-3099 using the luciferase reporter gene system. In conclusion, we report the successful prediction and validation of Gfap as an miR-3099 target gene using a combination of bioinformatics resources with enrichment of annotations based on functional ontologies and a spatio-temporal expression dataset.展开更多
文摘Oral cancer(OC)is one of the most recurrent cancers in the head and neck squamous cancer(SCCHN)category.Recently,the genome-wide association studies(GWAS)have gained growing interest in the scientific community.GWAS have identified several pathways involved in the interactions among general risk factors and genomic variants affecting SCCHN.This systematic overview aims to critically evaluate the latest data reported within the scientific literature.The aim was to investigate the impact of genetic aspects on SCCHN onset and prognosis,involving other clinical and systemic co-factors.PubMed,Google Scholar,and Cancer Genetics Web databases have been systematically investigated for original articles published in the last two years,reporting studies on the main queries addressed in this work.This review also comparatively describes the impact of environmental and pathological co-factors in different types of cancers,clarifying and updating the role of genetic factors in SCCHN onset and development.The main outcomes reported may be helpful to drive clinicians towards their clinical evaluations for the most appropriate therapeutic approach in SCCHN.
基金Supported by National Health andMedical Research Council,Australia
文摘Investigations into the inheritance of the three risk alleles R702W, G908R and 1007 fsInsC in NOD2 associated with susceptibility to Crohn＇s disease have demonstrated a remarkable amount of heterogeneity across ethnicities and populations, with regional variation across Europe for example, suggesting local founder effects. In nonCaucasian populations Crohn＇s disease continues to increase in incidence but this increase appears not to be a consequence of variation in NOD2, further advancing the accumulating evidence for other susceptibility loci. Frequencies of the known alleles are compared across populations in health and disease and evidence for additional alleles in NOD2 is reviewed. Based on its position on chromosome 16 coincident with some other autoimmune disease susceptibility Iocalizations, research has targeted NOD2 variation as the potential cause of other autoimmune disorders. While these investigations have mostly returned negative findings, two diseases, Blau Syndrome and Graft versus Host Disease, have been shown to be caused by risk alleles in NOD2. As is frequent in complex disease investigations, some results await validation, but the identification of NOD2 and the differences within and across population raises intriguing questions about the population genetics of the variation at this locus.
文摘Wiedemann-Steiner syndrome(OMIM#605130)is a rare congenital malformation syndrome characterized by hypertrichosis cubiti associated with short stature;consistent facial features,including long eyelashes,thick or arched eyebrows with a lateral flare,wide nasal bridge,and downslanting and vertically narrow palpebral fissures;mild to moderate intellectual disability;behavioral difficulties;and hypertrichosis on the back.It is caused by heterozygous pathogenic variants in KMT2A.This gene has an established role in histone methylation,which explains the overlap of Wiedemann-Steiner syndrome with other chromatinopathies,a heterogeneous group of syndromic conditions that share a common trigger:The disruption of one of the genes involved in chromatin modification,leading to dysfunction of the epigenetic machinery.
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supported in part by funds obtained through an Italian law that allows taxpayers to allocate 0.5 percent share of their income tax contribution to a research institution of their choice
文摘Background: Androgen insensitivity syndrome(AIS), a disorder of sexual development in 46, XY individuals, is caused by loss-of-function mutations in the androgen receptor(AR) gene. A variety of tumors have been reported in association with AIS, but no cases with colorectal cancer(CRC) have been described.Case presentation: Here, we present a male patient with AIS who developed multiple early-onset CRCs and his pedigree. His first cousin was diagnosed with AIS and harbored the same AR gene mutation, but with no signs of CRC. The difference in clinical management for the two patients was that testosterone treatment was given to the proband for a much longer time compared with the cousin. The CRC family history was negative, and no germline mutations in well-known CRC-related genes were identified. A single nucleotide polymorphism array revealed a microduplication on chromosome 22q11.22 that encompassed a micro RNA potentially related to CRC pathogenesis. In the proband, whole exome sequencing identified a polymorphism in an oncogene and 13 rare loss-of-function variants, of which two were in CRC-related genes and four were in genes associated with other human cancers.Conclusions: By pathway analysis, all inherited germline genetic events were connected in a unique network whose alteration in the proband, together with continuous testosterone stimulation, may have played a role in CRC pathogenesis.
文摘The application of microarray-based techniques for the diagnosis of genomic rearrangements has been steadily growing in popularity since its introduction in 2004.Given the many advantages of these techniques over conventional cytogenetics,there is increasing pressure towards their application in prenatal diagnosis.However,there remain several important issues that must be addressed.For example,microarray-based techniques(comparative genomic hybridization-based arrays and single nucleotide polymorphism-based arrays) allow detection of even very small genomic imbalances that can determine pathological clinical conditions.In addition,there are other copy number variations which represent normal variation,with no detectable effects on phenotype.Given the still incomplete knowledge of the changes in our genome and the associated phenotypes,microarray-based diagnosis is likely to find variants of uncertain and unknown clinical significance.The interpretation of these variants is now a major challenge for the medical geneticist,who often find it difficult to establish precise correlations between genotype and phenotype.There is sufficient available evidence to justify the use of microarray-based diagnostics for a select number of specific conditions,but there is also an inevitable trend towards ever wider application.It is very important that this drift does not progress in an unchecked and uncontrolled manner under the thrust of commercial interests.Therefore,we recommend that scientific societies be vigilant and take an advisory role in the adopting of these technologies as new scientific knowledge becomes available.
文摘Gitelman's syndrome(GS) is a salt-losing tubulopathy with an autosomal recessive inheritance caused by mutations of SLC12A3, which encodes for the thiazidesensitive Na Cl cotransporter. In this study we report a new mutation of SLC12A3 found in two brothers affected by GS. Hypokalemia, hypocalciuria and hyperreninemia were present in both patients while hypomagnesemia was detected only in one. Both patients are compound heterozygotes carrying one well known GS associated mutation(c.2581 C > T) and a new one(c.283 del C) in SLC12A3 gene. The new mutation results in a possible frame-shift with a premature stopcodon(pG ln95 Argfs X19). The parents of the patients, heterozygous carriers of the mutations found in SLC12A3, have no disease associated phenotype. Therefore, the new mutation is causative of GS.
文摘Background: Corticosteroid, hyaluronic acid (HA) injections and Anti-inflammatory agents are considered as non-invasive treatments for knee osteoarthritis (OA), Chronic Tendinitis (CT) and Tennis elbow (TE) that are supposed to provide symptomatic relief and to help surgical delay intervention. Platelet rich plasma (PRP) is a biological component shown to be beneficial for different orthopedic dysfunctionalities treatment. The presence of GFs in PRPs such as transforming growth factor-β, insulin-like growth factor 1co-stimulate the mesenchymal stem cells and fibroblasts secretions and promotes the fibrin matrix formation which effectively drive the healing process, induces regenerative response and lead to the damage structure repair in orthopedics trauma. Methods: Three groups of a total of 30 patients presenting OA, CT and TE diagnosis, non-responding to corticosteroid, HA and non-steroid anti-inflammatory treatments were randomized to undergo one intra-articular injections of single high dose of PRP. The efficacy of Intra-articular PRP Injections was evaluated before the injection and one month after. The efficiency assessment score was based on [1] Knee injury and Osteoarthritis Outcome Score, [2] Physical Function Short Form (KOOS-PS) Arabic (KSA) version LK 1.0, [3] HOOS-Physical Function Short form (HOOS-PS), and [4] Macdermid patient-rated Tennis Elbow. Results: A significant reduction of pain and a marked improvement in movements was observed in the 3 patient’s groups, PRP-injected patients showed significantly higher values compared with baseline: (p < 0.005 vs baseline), improve functional status and reduce clearly the articular dysfunctions over the time. In our study, single High dose injection of PRP provided an overall superior clinical improvement compared with HA and corticosteroid treatments over the time and the different follow-up checkpoints of the study.
文摘Pompe disease (PD) is a rare inborn error of metabolism due to an abnormal acid alpha-glucosidase (GAA) activity that comprises glycogen breakdown mainly in the lysosomes. Since the introduction of enzyme replacement therapy (ERT), with recombinant human GAA for the early onset PD patient, a relevant field of clinical research due to the benefits regarding survival rate has been widely documented worldwide. Objective: To describe the clinical characteristics and the ERT effects in a series of Brazilian patients with infantile onset PD (IOPD) under ERT. Methods: Brazilian patients diagnosed with IOPD under ERT were recruited through their physicians participating in the International Pompe Disease Registry from 2009 to 2017. Data were collected by an online survey. Results: 10 IOPD patients were identified through the survey with a death rate of 30% and technology dependency rate reported as 80% (motor, respiratory or nutritional fields) of the patients. After the third year of ERT, motor disabilities were lost in 50% of ambulated patients. The overall characteristics were similar to international studies. Conclusion: Despite ERT benefits in cardiac involvement, motor disabilities seem to be much more compromised in IOPD patients, with high technology dependence, especially after three years of age.
基金supported by the National Natural Science Foundation of China (Beijing, Chinagrant Nos. U20A2062, 32022084, and 32002349)+1 种基金Jilin Province Science and Technology Development Project (Changchun, Chinagrant No. 20210508011RQ)
文摘Nonalcoholic fatty liver disease(NAFLD) is characterized by hepatic steatosis and insulin resistance and there are currently no approved drugs for its treatment.Hyperactivation of mTOR complex1(mTORCl) and subsequent impairment of the transcription factor EB(TFEB)-mediated autophagy-lysosomal pathway(ALP) are implicated in the development of NAFLD.Accordingly,agents that augment hepatic TFEB transcriptional activity may have therapeutic potential against NAFLD.The objective of this study was to investigate the effects of nuciferine,a major active component from lotus leaf,on NAFLD and its underlying mechanism of action.Here we show that nuciferine activated ALP and alleviated steatosis,insulin resistance in the livers of NAFLD mice and palmitic acid-challenged hepatocytes in a TFEB-dependent manner.Mechanistic investigation revealed that nuciferine interacts with the Ragulator subunit hepatitis B X-interacting protein and impairs the interaction of the Ragulator complex with Rag GTPases,thereby suppressing lysosomal localization and activity of mTORC1,which activates TFEB-mediated ALP and further ameliorates hepatic steatosis and insulin resistance.Our present results indicate that nuciferine may be a potential agent for treating NAFLD and that regulation of the mTORCl-TFEB-ALP axis could represent a novel pharmacological strategy to combat NAFLD.
基金supported by the Science Fund(02-01-04-SF2336)the Fundamental Research Grant Scheme,Ministry of Higher Education,Malaysia(FRGS-04-01-15-1663FR)
文摘MicroRNAs are small non-coding RNAs that play crucial roles in the regulation of gene expression and protein synthesis during brain development. MiR-3099 is highly expressed throughout embryogenesis, especially in the developing central nervous system. Moreover, miR-3099 is also expressed at a higher level in differentiating neurons in vitro, suggesting that it is a potential regulator during neuronal cell development. This study aimed to predict the target genes of miR-3099 via in-silico analysis using four independent prediction algorithms（miRDB,miRanda, Target Scan, and DIANA-micro-T-CDS） with emphasis on target genes related to brain development and function. Based on the analysis, a total of 3,174 miR-3099 target genes were predicted. Those predicted by at least three algorithms（324 genes） were subjected to DAVID bioinformatics analysis to understand their overallfunctional themes and representation. The analysis revealed that nearly 70% of the target genes were expressed in the nervous system and a significant proportion were associated with transcriptional regulation and protein ubiquitination mechanisms. Comparison of in situ hybridization（ISH） expression patterns of miR-3099 in both published and in-house-generated ISH sections with the ISH sections of target genes from the Allen Brain Atlas identified 7 target genes（Dnmt3a, Gabpa, Gfap, Itga4,Lxn, Smad7, and Tbx18） having expression patterns complementary to miR-3099 in the developing and adult mouse brain samples. Of these, we validated Gfap as a direct downstream target of miR-3099 using the luciferase reporter gene system. In conclusion, we report the successful prediction and validation of Gfap as an miR-3099 target gene using a combination of bioinformatics resources with enrichment of annotations based on functional ontologies and a spatio-temporal expression dataset.
