In the present study,we investigated the synergistic effects of targeted methotrexate-selenium nanostructure containing Myc decoy oligodeoxynucleotides along with X-irradiation exposure as a combination therapy on LNC...In the present study,we investigated the synergistic effects of targeted methotrexate-selenium nanostructure containing Myc decoy oligodeoxynucleotides along with X-irradiation exposure as a combination therapy on LNCaP prostate cancer cells.Myc decoy ODNs were designed based on the promoter of Bcl-2 gene and analyzed by molecular docking and molecular dynamics assays.ODNs were loaded on the synthesized Se@BSA@Chi-MTX nanostructure.The physicochemical characteristics of nanostructures were determined by FTIR,DLS,UV-vis,TEM,EDX,in vitro release,and hemolysis tests.Subsequently,the cytotoxicity properties of them with and without X-irradiation were investigated by uptake,MTT,cell cycle,apoptosis,and scratch assays on the LNCaP cell line.The results of DLS and TEM showed negative charge(−9 mV)and nanometer size(40 nm)for Se@BSA@Chi-DEC-MTX NPs,respectively.The results of FTIR,UV-vis,and EDX showed the proper interaction of different parts and the correct synthesis of nanoparticles.The results of hemolysis showed the hemocompatibility of this nanoparticle in concentrations less than 6 mg/mL.The ODNs release from the nanostructures showed a pH-dependent manner,and the release rate was 15%higher in acidic pH.The targeted Se@BSA@Chi-labeled ODN-MTX NPs were efficiently taken up by LNCaP cells by targeting the prostate-specific membrane antigen(PSMA).The significant synergistic effects of nanostructure(containing MTX drug)treatment along with X-irradiation showed cell growth inhibition,apoptosis induction(~57%),cell cycle arrest(G2/M phase),and migration inhibition(up to 90%)compared to the control.The results suggested that the Se@BSA@Chi-DEC-MTX NPs can potentially suppress the cell growth of LNCaP cells.This nanostructure system can be a promising approach for targeted drug delivery and chemoradiotherapy in prostate cancer treatment.展开更多
In recent years, the improvement of technology and the increase in knowledge have shifted several strongly held paradigms. This is particularly true in gastroenterology, and specifically in the field of the so-called ...In recent years, the improvement of technology and the increase in knowledge have shifted several strongly held paradigms. This is particularly true in gastroenterology, and specifically in the field of the so-called "functional" or "idiopathic" disease, where conditions thought for decades to be based mainly on alterations of visceral perception or aberrant psychosomatic mechanisms have, in fact, be reconducted to an organic basis (or, at the very least, have shown one or more demonstrable abnormalities). This is particularly true, for instance, for irritable bowel syndrome, the prototype entity of "functional" gastrointestinal disorders, where low-grade inflammation of both mucosa and myenteric plexus has been repeatedly demonstrated. Thus, researchers have also investigated other functional/idiopathic gastrointestinal disorders, and found that some organic ground is present, such as abnormal neurotransmission and myenteric plexitis in esophageal achalasia and mucosal immune activation and mild eosinophilia in functional dyspepsia. Here we show evidence, based on our own and other authors' work, that chronic constipation has several abnormalities reconductable to alterations in the enteric nervous system, abnormalities mainly characterized by a constant decrease of enteric glial cells and interstitial cells of Cajal (and, sometimes, of enteric neurons). Thus, we feel that (at least some forms of) chronic constipation should no more be considered as a functional/idiopathic gastrointestinal disorder, but instead as a true enteric neuropathic abnormality.展开更多
Artificial intelligence(AI)refers to the simulation of human intelligence in machines programmed to convert raw input data into decision-making actions,like humans.AI programs are designed to make decisions,often usin...Artificial intelligence(AI)refers to the simulation of human intelligence in machines programmed to convert raw input data into decision-making actions,like humans.AI programs are designed to make decisions,often using deep learning and computer-guided programs that analyze and process raw data into clinical decision making for effective treatment.New techniques for predicting cancer at an early stage are needed as conventional methods have poor accuracy and are not applicable to personalized medicine.AI has the potential to use smart,intelligent computer systems for image interpretation and early diagnosis of cancer.AI has been changing almost all the areas of the medical field by integrating with new emerging technologies.AI has revolutionized the entire health care system through innovative digital diagnostics with greater precision and accuracy.AI is capable of detecting cancer at an early stage with accurate diagnosis and improved survival outcomes.AI is an innovative technology of the future that can be used for early prediction,diagnosis and treatment of cancer.展开更多
The biomolecular mechanisms that regulate tooth root development and odontoblast differentiation are poorly understood.We found that Atp6i deficient mice(Atp6i^(−/−))arrested tooth root formation,indicated by truncate...The biomolecular mechanisms that regulate tooth root development and odontoblast differentiation are poorly understood.We found that Atp6i deficient mice(Atp6i^(−/−))arrested tooth root formation,indicated by truncated Hertwig’s epithelial root sheath(HERS)progression.Furthermore,Atp6i deficiency significantly reduced the proliferation and differentiation of radicular odontogenic cells responsible for root formation.Atp6i^(−/−)mice had largely decreased expression of odontoblast differentiation marker gene expression profiles(Col1a1,Nfic,Dspp,and Osx)in the alveolar bone.Atp6i^(−/−)mice sample RNA-seq analysis results showed decreased expression levels of odontoblast markers.Additionally,there was a significant reduction in Smad2/3 activation,inhibiting transforming growth factor-β(TGF-β)signaling in Atp6i^(−/−)odontoblasts.Through treating pulp precursor cells with Atp6i^(−/−)or wild-type OC bone resorption-conditioned medium,we found the latter medium to promote odontoblast differentiation,as shown by increased odontoblast differentiation marker genes expression(Nfic,Dspp,Osx,and Runx2).This increased expression was significantly blocked by anti-TGF-β1 antibody neutralization,whereas odontoblast differentiation and Smad2/3 activation were significantly attenuated by Atp6i^(−/−)OC conditioned medium.Importantly,ectopic TGF-β1 partially rescued root development and root dentin deposition of Atp6i^(−/−)mice tooth germs were transplanted under mouse kidney capsules.Collectively,our novel data shows that the prevention of TGF-β1 release from the alveolar bone matrix due to OC dysfunction may lead to osteopetrosis-associated root formation via impaired radicular odontoblast differentiation.As such,this study uncovers TGF-β1/Smad2/3 as a key signaling pathway regulating odontoblast differentiation and tooth root formation and may contribute to future therapeutic approaches to tooth root regeneration.展开更多
In the post-genome era,different omics methods have been used to establish the relationship between clinical phenotypes and molecular characterizations.The combination of genomics,proteomics,and metabolomics has unrav...In the post-genome era,different omics methods have been used to establish the relationship between clinical phenotypes and molecular characterizations.The combination of genomics,proteomics,and metabolomics has unraveled the etiology and pathophysiology of various diseases in a big-data fashion and the recent Genome-Wide Association Studies(GWAS)have provided a powerful systematic method to investigate the impact of common genomic variations on human cardiovascular pathophysiology and disease.But,these studies also revealed unmatched relationships between the genomic variability and the much narrower definition of various clinical phenotypes of cardiovascular diseases in individual patients.In the majority of GWAS a single targeted disease or a pre-defined and limited phenotype(trait)was studied and the accrual of such a large number of single gene variant-phenotype associations has led to the serendipitous identification of single loci associated with multiple diseases,or one gene being responsible or affecting more than one phenotypic characteristic(pleiotropy).Clearly,Western medicine is now facing the same challenges as traditional Chinese medicine(TCM)and newer approaches are needed for the redefinition of diseases using the underlying molecular causes and other factors in addition to traditional signs and symptoms.These are the same old questions for TCM for many years.A new method named″Phenome-Wide Association Study(PheWAS)″as an alternative approach that complements GWAS and utilizes phenomics and big-data technologies to analyze all genetic/proteomic variants and all available phenotypic information in the estimation of association between genome-phenome and detection of pleiotropy.Phenomics is a recently developed new transdiscipline that provides a suite of new technologies and platforms for the transition from focused phenotype-genotype study to a systematic phenome-genome approach,which can be used to redefine the clinical phenotypes of diseases.Accordingly,disease will be defined as a clinical phenome that is the sum total of a patient′s clinical characteristics or phenomic traits that signify the expression of the whole genome,proteome,and metabolome under specific environmental influence.With the fast advance and development of big-data technology and phenomics,we believe that the application of PheWAS in medicine opens important avenues to enhance systematically-integrated analysis of the genomic basis of human disease and responses to drug therapy and to reform our understanding and clinical treatment of diseases with a new concept of wholism.With well-defined clinical disease phenome,a new transdiscipline termed″pharmacophenomics″has been emerging.As a complement of pharmacogenomics,pharmacoproteomics,and pharmacometabolomics,pharmacophenomics offers a suite of new technologies and platforms for the transition from focused phenotype-genotype study to a systematic phenome-genome approach and refine drug research with systematically-defined drug response and therapeutic targets.Therefore,pharmacophenomics will provide a new paradigm for the study of drug response including effects and toxicities at the level of systems biology and will identify the corresponding therapeutic targets suitable for personalized medicine.展开更多
Neurodegenerative disease etiology is still unclear,but different contributing factors,such as lifestyle and genetic factors are involved.Altered components of the gut could play a key role in the gut-brain axis,which...Neurodegenerative disease etiology is still unclear,but different contributing factors,such as lifestyle and genetic factors are involved.Altered components of the gut could play a key role in the gut-brain axis,which is a bidirectional system between the central nervous system and the enteric nervous system.Variations in the composition of the gut microbiota and its function between healthy people and patients have been reported for a variety of human disorders comprising metabolic,autoimmune,cancer,and,notably,neurodegenerative disorders.Diet can alter the microbiota composition,affecting the gutbrain axis function.Different nutraceutical interventions have been devoted to normalizing gut microbiome dysbiosis and to improving biological outcomes in neurological conditions,including the use of probiotics.Preclinical and clinical investigations discussed in this review strengthen the correlation between intestinal microbiota and brain and the concept that modifying the microbiome composition may improve brain neurochemistry,modulating different pathways.This review will discuss the potential use of probiotics for Parkinson’s disease prevention or treatment or as adjuvant therapy,confirming that gut microbiota modulation influences different pro-survival pathways.Future investigations in Parkinson’s disease should consider the role of the gut-brain axis and additional comprehension of the underlying mechanisms is extremely necessary.展开更多
Skeletal muscle is a dynamic tissue in which homeostasis and function are guaranteed by a very defined three-dimensional organization of myofibers in respect to other nonmuscular components,including the extracellular...Skeletal muscle is a dynamic tissue in which homeostasis and function are guaranteed by a very defined three-dimensional organization of myofibers in respect to other nonmuscular components,including the extracellular matrix and the nervous network.In particular,communication between myofibers and the nervous system is essential for the overall correct development and function of the skeletal muscle.A wide range of chronic,acute and genetic-based human pathologies that lead to the alteration of muscle function are associated with modified preservation of the fine interaction between motor neurons and myofibers at the neuromuscular junction.Recent advancements in the development of in vitro models for human skeletal muscle have shown that three-dimensionality and integration of multiple cell types are both key parameters required to unveil pathophysiological relevant phenotypes.Here,we describe recent achievement reached in skeletal muscle modeling which used biomaterials for the generation of three-dimensional constructs of myotubes integrated with motor neurons.展开更多
Bax is an important protein involved in apoptotic process. Mutations of the Bax gene are known to af- fect protein expression and function. A promotor polymorphism G(-248)A in the 5’UTR of Bax gene may alter regulati...Bax is an important protein involved in apoptotic process. Mutations of the Bax gene are known to af- fect protein expression and function. A promotor polymorphism G(-248)A in the 5’UTR of Bax gene may alter regulation of apoptosis in carcinogenesis. Our study was performed to test the association be- tween G(-248)A polymorphisms in the Bax gene and breast cancer risk and progression. G(-248)A poly- morphism was genotyped in a Turkish breast cancer, case-control population including 53 female cancer patients (mean age ± SD: 60.9 ± 11.9 years) and 82 controls (mean age ± SD: 57.2 ± 17.5 years) using PCR-RFLP analysis. Genotype and allele frequencies were assessed with the chi-square test. There was no difference in the distribution of Bax genotypes, and allele frequencies were G (87.7% versus 88.4%) and A (12.3% versus 11.6%) in the cancer patients and controls, respectively. Within the cancer group, the presence of a polymorphic Bax G(-248)A allele was not associated with clinico-pathological parameters such as advanced tumor stage, lymph node or distant metastasis. We present the first to report on Bax G(-248)A polymorphisms in breast cancer. Our re- sults suggest that Bax G(-248)A polymorphism do not modify individual susceptibility to invasive breast cancer in Turkish women.展开更多
Introduction: Beta-thalassemia is characterized by absence or reduced synthesis of the β-globin. Carriers of β-thalas- semia, typically have microcytic hypochromic anemia and elevated hemoglobin HbA2 and normal HbF ...Introduction: Beta-thalassemia is characterized by absence or reduced synthesis of the β-globin. Carriers of β-thalas- semia, typically have microcytic hypochromic anemia and elevated hemoglobin HbA2 and normal HbF level. On the other hand carriers of severe alpha-thalassemia also have similar CBC parameters to that of β-thalassemia with normal HbA2 level. Co-presence of mutations in the β-globin and delta-globin genes (point mutations or deletions) usually give normal HbA2 and elevated HbF level. We report a β-thal carrier with normal level of HbA2 and increased level of HbF who had a point mutation in CD39 on the beta-globin gene and a point mutation in CD27 on the δ-globin gene named Hb-Yialousa. Materials & Methods: An individual with low hematological indices, normal HbA2 and elevated HbF was referred to our center as routine premarital screening program. Mutations in the β-globin and δ-globin genes were screened using ARMS and sequencing methods. Results: The mutation in β- and δ-globin genes were identified as CD39 and CD27 (HbYialousa) respectively. No point mutation or deletion in α-globin gene was identified. Discussion: We showed that normal HBA2 with elevated HbF level is due to co-inheritance of delta-globin gene mutation with mutation in the β-globin gene. When screening for β-thalassemia, one has to either rule out presence of α-globin gene mutation of mutation in the delta-globin gene.展开更多
Insulin resistance is the rate-limiting step in the development of metabolic diseases,including type 2 diabetes.The gut microbiota has been implicated in host energy metabolism and metabolic diseases and is recognized...Insulin resistance is the rate-limiting step in the development of metabolic diseases,including type 2 diabetes.The gut microbiota has been implicated in host energy metabolism and metabolic diseases and is recognized as a quantitatively important organelle in host metabolism,as the human gut harbors 10 trillion bacterial cells.Gut microbiota break down various nutrients and produce metabolites that play fundamental roles in host metabolism and aid in the identification of possible therapeutic targets for metabolic diseases.Therefore,understanding the various effects of bacterial metabolites in the development of insulin resistance is critical.Here,we review the mechanisms linking gut microbial metabolites to insulin resistance in various insulin-responsive tissues.展开更多
Introduction: HIV infection represents a major public health problem for both developing and developed countries as it has grown to global pandemic. Spectrum of clinical presentation of HIV can greatly vary with geopo...Introduction: HIV infection represents a major public health problem for both developing and developed countries as it has grown to global pandemic. Spectrum of clinical presentation of HIV can greatly vary with geopolitical, socioeconomic and cultural environment. Aims: The aim of this study was to estimate the prevalence, socio-demographic conditions, clinical presentations, opportunistic infections and the possible associated risk factors for acquiring HIV infection. Materials and Methods: An observational prospective study was conducted from January 2010 to December 2014 at our centre situated in north India. As per the strategy and policy prescribed by NACO, tests were performed on the serum samples. Results: Out of the total 35369 clients tested for HIV infection, 292 were found to be HIV-1 seropositive. Two HIV-2 cases were found among the studied population. The seroprevalence of HIV was found to be 0.83% (294/35369). Mean age of the study group was 30 ± 5.65 (range: 02 - 80) years. Overall positivity rates among attendees were found to be 0.97% (138/14098), 0.96% (35/3610), 0.82% (7/850), 0.78% (22/2810) and 0.65% (92/14001) in the years 2010, 2011, 2012, 2013 and 2014 respectively. Heterosexual route of transmission was the major route of infection in 78.2 % patients. At the time of presentation, it was observed that Tuberculosis (14.9%) was the most common opportunistic infection. Conclusion: The study shows that there is a decreasing trend in the HIV prevalence in North India. However, the number of HIV cases is still significant and suggests the need for focused prevention efforts in high-risk groups.展开更多
Pentraxin-3(PTX3),the prototype of long pentraxins,seems to influence complement system(CS)modulation.PTX3 and CS sustain carcinogenesis,enriching tumor microenvironment(TME)with pro-inflammatory molecules promoting a...Pentraxin-3(PTX3),the prototype of long pentraxins,seems to influence complement system(CS)modulation.PTX3 and CS sustain carcinogenesis,enriching tumor microenvironment(TME)with pro-inflammatory molecules promoting angiogenesis in prostate cancer(PC)and renal cell carcinoma(RCC).Furthermore,cancer cells overexpress complement regulatory proteins,such as CD46,CD55 and CD59,which negatively affect complement pathways for support cancer cells survival.This viewpoint aims to elucidate the ambivalent role of PTX3 and the CS in the context of tumor microenvironment(TME).展开更多
Background: L-selectin (CD62L) is a cell surface adhesion molecule recently shown to play a critical role in determining endometrial receptivity and implantation in humans. By contrast, the L-selectin ligand is missin...Background: L-selectin (CD62L) is a cell surface adhesion molecule recently shown to play a critical role in determining endometrial receptivity and implantation in humans. By contrast, the L-selectin ligand is missing from the rodent endometrium. Interestingly, CD62L (L-selectin)-deficient BALB/c mice delivered significantly higher numbers of viable offspring than wild type controls via mechanisms yet to be defined. Methods: Nulliparous CD62L-deficient (8-10-week-old, n = 25) or wild type (n = 18) females were mated with 43 age-matched males. Animals were sacrificed at gestational day (GD) 9.5. Tissue samples were analyzed by immunostaining and flow cytometry. Results: Mating wild type and CD62L-deficient BALB/c mice revealed that the increased birth rate was due to the CD62L deficiency in females. Flow cytometric analysis demonstrated significant differences in the number of natural killer (NK) cells present in the uterus of pregnant CD62L- deficient mice compared to controls. Immunohistochemistry confirmed NK cell accumulation at the fetal-maternal interface. Discussion: Uterine NK cells have been shown to peak at GD 8-10 at the fetal-maternal interface. NK cells might regulate mouse fertility rates by facilitating development of the maternal spiral arteries, thereby stimulating the formation of larger vessels that facilitate intrauterine survival, however, their role is not obligate to spiral artery development. Conclusions: Diminished CD62L expression modified immune cell trafficking into the uterus of pregnant mice generating a microenvironment primarily dominated by NK cells resulting in improved embryonic survival rates.展开更多
Posttraumatic stress disorder (PTSD) is a psychiatric disorder found in individuals afflicted by a traumatic event. Multiple environmental and genetic factors can contribute to PTSD susceptibility. Since it is rare to...Posttraumatic stress disorder (PTSD) is a psychiatric disorder found in individuals afflicted by a traumatic event. Multiple environmental and genetic factors can contribute to PTSD susceptibility. Since it is rare to find members of the same family afflicted by the same catastrophic event, it is not practical to determine PTSD susceptibility genes by a gene linkage analysis. A natural disaster, such as the 2004 Tsunami, provided us with a rare chance for a genetic analysis of PTSD. To identify SNPs associated with PTSD susceptibility, we conducted a genome-association study (GWAS) in Thai-Tsunami survivors. Initial phase of the study with 396 chronic PTSD patients and 457 controls, we identified top ninety SNPs (P -4), which were further assessed in the second phase with 395 chronic PTSD patients and 798 controls. Two SNPs (rs267950 and rs954406), were identified in the second phase, and subjected to fine mapping using a data set from both phases. SNP rs267943 showed the strongest association with PTSD susceptibility and was in complete linkage disequilibrium with SNP rs267950 with P = 6.15 × 10-8, OR = 1.46 and 95% CI = 1.19 - 1.79, reaching genome-wide significance. SNP rs267943 is located on chromosome 5 in the intron of the death-associated protein 1 (DAP1) gene and, when linked to a synthetic promoter, could regulate transcription. To our knowledge, this is the first GWAS for PTSD susceptibility in an Asian population which could provide an important insight into the genetic contribution of PTSD and may lead to new treatment strategies for PTSD.展开更多
The epileptic mouse model BALB/cByJ-Kv1.1mceph/mceph (mceph/mceph) is homozygous for a spontaneous mutation truncating the Shaker-like voltage gated potassium channel, Kv1.1 (Kcna1). The mceph/mceph mice are asymptoma...The epileptic mouse model BALB/cByJ-Kv1.1mceph/mceph (mceph/mceph) is homozygous for a spontaneous mutation truncating the Shaker-like voltage gated potassium channel, Kv1.1 (Kcna1). The mceph/mceph mice are asymptomatic at birth, but develop from 3 weeks of age epileptic seizures, overgrowth and neuronal hyperplasia of the hippocampus. Hippocampal cognitive function of the mice was examined by investigating emotional memory using the aversive Passive Avoidance (PA) task combined with studies of explorative behavior using the non-aversive Novel Cage test (NCT). The behavioural results were examined by multivariate analysis. Compared to wild type and heterozygous mice, the mceph/mceph mice displayed lower exploratory and safety assessment behavior in the NCT and impairment in PA retention 24 hours after training, indicating an impairment in cognitive functions. In conclusion, the epileptic mouse model BALB/cByJ-Kv1.1mceph/mceph, with chronic epilepsy related to potassium-channelopathy, display a behavioural phenotype characterized by impairments in emotional memory and defensive motivational responses probably related to hippocampal dysfunctions.展开更多
Protein post-translational modifications(PTMs)are at the heart status of cellular signaling events and broadly involved in tumor progression.CD147 is a tumor biomarker with various PTMs,promoting tumor metastasis and ...Protein post-translational modifications(PTMs)are at the heart status of cellular signaling events and broadly involved in tumor progression.CD147 is a tumor biomarker with various PTMs,promoting tumor metastasis and metabolism reprogramming.Nevertheless,the relationship between the PTMs of CD147 and apoptosis has not been reported.In our study,we produced a specific anti-CD147-K71 di-methylation(CD147-K71me2)antibody by immunizing with a di-methylated peptide and observed that the level of CD147-K71me2 in non-small cell lung cancer(NSCLC)tissues were lower than that in NSCLC adjacent tissues.SETDB1 was identified as the methyltransferase catalyzing CD147 to generate CD147-K71me2.RNA-seq showed that FOSB was the most significant differentially expressed gene(DEG)between wild-type CD147(CD147-WT)and K71-mutant CD147(CD147-K71R)groups.Subsequently,we found that CD147-K71me2 promoted the expression of FOSB by enhancing the phosphorylation of p38,leading to tumor cell apoptosis.In vivo experiments showed that CD147-K71me2 significantly inhibited tumor progression by promoting cell apoptosis.Taken together,our findings indicate the inhibitory role of CD147-K71me2 in tumor progression from the perspective of post-translational modification,which is distinct from the pro-cancer function of CD147 itself,broadening our perspective on tumor-associated antigen CD147.展开更多
The CD9 gene,also known as the Tspan29 gene,codes for a protein called CD9,which is a member of the tetraspanin family of transmembrane proteins.^(1) The CD9 protein is involved in various cellular processes,including...The CD9 gene,also known as the Tspan29 gene,codes for a protein called CD9,which is a member of the tetraspanin family of transmembrane proteins.^(1) The CD9 protein is involved in various cellular processes,including cell proliferation,differentiation,adhesion,and migration.^(1,2) CD9 has also been found to play a role in the regulation of stem cell proliferation and differentiation.展开更多
基金Zanjan University of Medical Sciences supported the present study(Grant Number:A-12-1244-18).
文摘In the present study,we investigated the synergistic effects of targeted methotrexate-selenium nanostructure containing Myc decoy oligodeoxynucleotides along with X-irradiation exposure as a combination therapy on LNCaP prostate cancer cells.Myc decoy ODNs were designed based on the promoter of Bcl-2 gene and analyzed by molecular docking and molecular dynamics assays.ODNs were loaded on the synthesized Se@BSA@Chi-MTX nanostructure.The physicochemical characteristics of nanostructures were determined by FTIR,DLS,UV-vis,TEM,EDX,in vitro release,and hemolysis tests.Subsequently,the cytotoxicity properties of them with and without X-irradiation were investigated by uptake,MTT,cell cycle,apoptosis,and scratch assays on the LNCaP cell line.The results of DLS and TEM showed negative charge(−9 mV)and nanometer size(40 nm)for Se@BSA@Chi-DEC-MTX NPs,respectively.The results of FTIR,UV-vis,and EDX showed the proper interaction of different parts and the correct synthesis of nanoparticles.The results of hemolysis showed the hemocompatibility of this nanoparticle in concentrations less than 6 mg/mL.The ODNs release from the nanostructures showed a pH-dependent manner,and the release rate was 15%higher in acidic pH.The targeted Se@BSA@Chi-labeled ODN-MTX NPs were efficiently taken up by LNCaP cells by targeting the prostate-specific membrane antigen(PSMA).The significant synergistic effects of nanostructure(containing MTX drug)treatment along with X-irradiation showed cell growth inhibition,apoptosis induction(~57%),cell cycle arrest(G2/M phase),and migration inhibition(up to 90%)compared to the control.The results suggested that the Se@BSA@Chi-DEC-MTX NPs can potentially suppress the cell growth of LNCaP cells.This nanostructure system can be a promising approach for targeted drug delivery and chemoradiotherapy in prostate cancer treatment.
文摘In recent years, the improvement of technology and the increase in knowledge have shifted several strongly held paradigms. This is particularly true in gastroenterology, and specifically in the field of the so-called "functional" or "idiopathic" disease, where conditions thought for decades to be based mainly on alterations of visceral perception or aberrant psychosomatic mechanisms have, in fact, be reconducted to an organic basis (or, at the very least, have shown one or more demonstrable abnormalities). This is particularly true, for instance, for irritable bowel syndrome, the prototype entity of "functional" gastrointestinal disorders, where low-grade inflammation of both mucosa and myenteric plexus has been repeatedly demonstrated. Thus, researchers have also investigated other functional/idiopathic gastrointestinal disorders, and found that some organic ground is present, such as abnormal neurotransmission and myenteric plexitis in esophageal achalasia and mucosal immune activation and mild eosinophilia in functional dyspepsia. Here we show evidence, based on our own and other authors' work, that chronic constipation has several abnormalities reconductable to alterations in the enteric nervous system, abnormalities mainly characterized by a constant decrease of enteric glial cells and interstitial cells of Cajal (and, sometimes, of enteric neurons). Thus, we feel that (at least some forms of) chronic constipation should no more be considered as a functional/idiopathic gastrointestinal disorder, but instead as a true enteric neuropathic abnormality.
文摘Artificial intelligence(AI)refers to the simulation of human intelligence in machines programmed to convert raw input data into decision-making actions,like humans.AI programs are designed to make decisions,often using deep learning and computer-guided programs that analyze and process raw data into clinical decision making for effective treatment.New techniques for predicting cancer at an early stage are needed as conventional methods have poor accuracy and are not applicable to personalized medicine.AI has the potential to use smart,intelligent computer systems for image interpretation and early diagnosis of cancer.AI has been changing almost all the areas of the medical field by integrating with new emerging technologies.AI has revolutionized the entire health care system through innovative digital diagnostics with greater precision and accuracy.AI is capable of detecting cancer at an early stage with accurate diagnosis and improved survival outcomes.AI is an innovative technology of the future that can be used for early prediction,diagnosis and treatment of cancer.
基金supported by the National Institutes of Health[DE023813 and DE028264 to Y.P.L.,and AG056438 and AR070135 to W.C.]the UAB National Institutes of Health National Institute of Dental and Craniofacial Research[Dental Academic Research Training Grant(DART)5T90DE022736 to J.W.].
文摘The biomolecular mechanisms that regulate tooth root development and odontoblast differentiation are poorly understood.We found that Atp6i deficient mice(Atp6i^(−/−))arrested tooth root formation,indicated by truncated Hertwig’s epithelial root sheath(HERS)progression.Furthermore,Atp6i deficiency significantly reduced the proliferation and differentiation of radicular odontogenic cells responsible for root formation.Atp6i^(−/−)mice had largely decreased expression of odontoblast differentiation marker gene expression profiles(Col1a1,Nfic,Dspp,and Osx)in the alveolar bone.Atp6i^(−/−)mice sample RNA-seq analysis results showed decreased expression levels of odontoblast markers.Additionally,there was a significant reduction in Smad2/3 activation,inhibiting transforming growth factor-β(TGF-β)signaling in Atp6i^(−/−)odontoblasts.Through treating pulp precursor cells with Atp6i^(−/−)or wild-type OC bone resorption-conditioned medium,we found the latter medium to promote odontoblast differentiation,as shown by increased odontoblast differentiation marker genes expression(Nfic,Dspp,Osx,and Runx2).This increased expression was significantly blocked by anti-TGF-β1 antibody neutralization,whereas odontoblast differentiation and Smad2/3 activation were significantly attenuated by Atp6i^(−/−)OC conditioned medium.Importantly,ectopic TGF-β1 partially rescued root development and root dentin deposition of Atp6i^(−/−)mice tooth germs were transplanted under mouse kidney capsules.Collectively,our novel data shows that the prevention of TGF-β1 release from the alveolar bone matrix due to OC dysfunction may lead to osteopetrosis-associated root formation via impaired radicular odontoblast differentiation.As such,this study uncovers TGF-β1/Smad2/3 as a key signaling pathway regulating odontoblast differentiation and tooth root formation and may contribute to future therapeutic approaches to tooth root regeneration.
基金The project supported by National Institute of Health R01HL113598
文摘In the post-genome era,different omics methods have been used to establish the relationship between clinical phenotypes and molecular characterizations.The combination of genomics,proteomics,and metabolomics has unraveled the etiology and pathophysiology of various diseases in a big-data fashion and the recent Genome-Wide Association Studies(GWAS)have provided a powerful systematic method to investigate the impact of common genomic variations on human cardiovascular pathophysiology and disease.But,these studies also revealed unmatched relationships between the genomic variability and the much narrower definition of various clinical phenotypes of cardiovascular diseases in individual patients.In the majority of GWAS a single targeted disease or a pre-defined and limited phenotype(trait)was studied and the accrual of such a large number of single gene variant-phenotype associations has led to the serendipitous identification of single loci associated with multiple diseases,or one gene being responsible or affecting more than one phenotypic characteristic(pleiotropy).Clearly,Western medicine is now facing the same challenges as traditional Chinese medicine(TCM)and newer approaches are needed for the redefinition of diseases using the underlying molecular causes and other factors in addition to traditional signs and symptoms.These are the same old questions for TCM for many years.A new method named″Phenome-Wide Association Study(PheWAS)″as an alternative approach that complements GWAS and utilizes phenomics and big-data technologies to analyze all genetic/proteomic variants and all available phenotypic information in the estimation of association between genome-phenome and detection of pleiotropy.Phenomics is a recently developed new transdiscipline that provides a suite of new technologies and platforms for the transition from focused phenotype-genotype study to a systematic phenome-genome approach,which can be used to redefine the clinical phenotypes of diseases.Accordingly,disease will be defined as a clinical phenome that is the sum total of a patient′s clinical characteristics or phenomic traits that signify the expression of the whole genome,proteome,and metabolome under specific environmental influence.With the fast advance and development of big-data technology and phenomics,we believe that the application of PheWAS in medicine opens important avenues to enhance systematically-integrated analysis of the genomic basis of human disease and responses to drug therapy and to reform our understanding and clinical treatment of diseases with a new concept of wholism.With well-defined clinical disease phenome,a new transdiscipline termed″pharmacophenomics″has been emerging.As a complement of pharmacogenomics,pharmacoproteomics,and pharmacometabolomics,pharmacophenomics offers a suite of new technologies and platforms for the transition from focused phenotype-genotype study to a systematic phenome-genome approach and refine drug research with systematically-defined drug response and therapeutic targets.Therefore,pharmacophenomics will provide a new paradigm for the study of drug response including effects and toxicities at the level of systems biology and will identify the corresponding therapeutic targets suitable for personalized medicine.
文摘Neurodegenerative disease etiology is still unclear,but different contributing factors,such as lifestyle and genetic factors are involved.Altered components of the gut could play a key role in the gut-brain axis,which is a bidirectional system between the central nervous system and the enteric nervous system.Variations in the composition of the gut microbiota and its function between healthy people and patients have been reported for a variety of human disorders comprising metabolic,autoimmune,cancer,and,notably,neurodegenerative disorders.Diet can alter the microbiota composition,affecting the gutbrain axis function.Different nutraceutical interventions have been devoted to normalizing gut microbiome dysbiosis and to improving biological outcomes in neurological conditions,including the use of probiotics.Preclinical and clinical investigations discussed in this review strengthen the correlation between intestinal microbiota and brain and the concept that modifying the microbiome composition may improve brain neurochemistry,modulating different pathways.This review will discuss the potential use of probiotics for Parkinson’s disease prevention or treatment or as adjuvant therapy,confirming that gut microbiota modulation influences different pro-survival pathways.Future investigations in Parkinson’s disease should consider the role of the gut-brain axis and additional comprehension of the underlying mechanisms is extremely necessary.
基金supported by IRP Consolidator Grant 2021(Grant Code:21/05 Irp),Fondazione Cittàdella Speranza,Italy(to AU)。
文摘Skeletal muscle is a dynamic tissue in which homeostasis and function are guaranteed by a very defined three-dimensional organization of myofibers in respect to other nonmuscular components,including the extracellular matrix and the nervous network.In particular,communication between myofibers and the nervous system is essential for the overall correct development and function of the skeletal muscle.A wide range of chronic,acute and genetic-based human pathologies that lead to the alteration of muscle function are associated with modified preservation of the fine interaction between motor neurons and myofibers at the neuromuscular junction.Recent advancements in the development of in vitro models for human skeletal muscle have shown that three-dimensionality and integration of multiple cell types are both key parameters required to unveil pathophysiological relevant phenotypes.Here,we describe recent achievement reached in skeletal muscle modeling which used biomaterials for the generation of three-dimensional constructs of myotubes integrated with motor neurons.
文摘Bax is an important protein involved in apoptotic process. Mutations of the Bax gene are known to af- fect protein expression and function. A promotor polymorphism G(-248)A in the 5’UTR of Bax gene may alter regulation of apoptosis in carcinogenesis. Our study was performed to test the association be- tween G(-248)A polymorphisms in the Bax gene and breast cancer risk and progression. G(-248)A poly- morphism was genotyped in a Turkish breast cancer, case-control population including 53 female cancer patients (mean age ± SD: 60.9 ± 11.9 years) and 82 controls (mean age ± SD: 57.2 ± 17.5 years) using PCR-RFLP analysis. Genotype and allele frequencies were assessed with the chi-square test. There was no difference in the distribution of Bax genotypes, and allele frequencies were G (87.7% versus 88.4%) and A (12.3% versus 11.6%) in the cancer patients and controls, respectively. Within the cancer group, the presence of a polymorphic Bax G(-248)A allele was not associated with clinico-pathological parameters such as advanced tumor stage, lymph node or distant metastasis. We present the first to report on Bax G(-248)A polymorphisms in breast cancer. Our re- sults suggest that Bax G(-248)A polymorphism do not modify individual susceptibility to invasive breast cancer in Turkish women.
文摘Introduction: Beta-thalassemia is characterized by absence or reduced synthesis of the β-globin. Carriers of β-thalas- semia, typically have microcytic hypochromic anemia and elevated hemoglobin HbA2 and normal HbF level. On the other hand carriers of severe alpha-thalassemia also have similar CBC parameters to that of β-thalassemia with normal HbA2 level. Co-presence of mutations in the β-globin and delta-globin genes (point mutations or deletions) usually give normal HbA2 and elevated HbF level. We report a β-thal carrier with normal level of HbA2 and increased level of HbF who had a point mutation in CD39 on the beta-globin gene and a point mutation in CD27 on the δ-globin gene named Hb-Yialousa. Materials & Methods: An individual with low hematological indices, normal HbA2 and elevated HbF was referred to our center as routine premarital screening program. Mutations in the β-globin and δ-globin genes were screened using ARMS and sequencing methods. Results: The mutation in β- and δ-globin genes were identified as CD39 and CD27 (HbYialousa) respectively. No point mutation or deletion in α-globin gene was identified. Discussion: We showed that normal HBA2 with elevated HbF level is due to co-inheritance of delta-globin gene mutation with mutation in the β-globin gene. When screening for β-thalassemia, one has to either rule out presence of α-globin gene mutation of mutation in the delta-globin gene.
基金National Research Foundation Funded by the Korean Ministry of Science,No.NRF-2018M3A9F3056405No.NRF-2020R1A2B5B01002789.
文摘Insulin resistance is the rate-limiting step in the development of metabolic diseases,including type 2 diabetes.The gut microbiota has been implicated in host energy metabolism and metabolic diseases and is recognized as a quantitatively important organelle in host metabolism,as the human gut harbors 10 trillion bacterial cells.Gut microbiota break down various nutrients and produce metabolites that play fundamental roles in host metabolism and aid in the identification of possible therapeutic targets for metabolic diseases.Therefore,understanding the various effects of bacterial metabolites in the development of insulin resistance is critical.Here,we review the mechanisms linking gut microbial metabolites to insulin resistance in various insulin-responsive tissues.
文摘Introduction: HIV infection represents a major public health problem for both developing and developed countries as it has grown to global pandemic. Spectrum of clinical presentation of HIV can greatly vary with geopolitical, socioeconomic and cultural environment. Aims: The aim of this study was to estimate the prevalence, socio-demographic conditions, clinical presentations, opportunistic infections and the possible associated risk factors for acquiring HIV infection. Materials and Methods: An observational prospective study was conducted from January 2010 to December 2014 at our centre situated in north India. As per the strategy and policy prescribed by NACO, tests were performed on the serum samples. Results: Out of the total 35369 clients tested for HIV infection, 292 were found to be HIV-1 seropositive. Two HIV-2 cases were found among the studied population. The seroprevalence of HIV was found to be 0.83% (294/35369). Mean age of the study group was 30 ± 5.65 (range: 02 - 80) years. Overall positivity rates among attendees were found to be 0.97% (138/14098), 0.96% (35/3610), 0.82% (7/850), 0.78% (22/2810) and 0.65% (92/14001) in the years 2010, 2011, 2012, 2013 and 2014 respectively. Heterosexual route of transmission was the major route of infection in 78.2 % patients. At the time of presentation, it was observed that Tuberculosis (14.9%) was the most common opportunistic infection. Conclusion: The study shows that there is a decreasing trend in the HIV prevalence in North India. However, the number of HIV cases is still significant and suggests the need for focused prevention efforts in high-risk groups.
基金This work was supported by grant funding from University of Foggia(University Research Projects 2019“PRA 2019”granted to G.S.N.,2019).The funders had no role in study design,data collection and analysis,decision to publish,or preparation of the manuscript.The contents are solely the responsibility of the author and do not necessarily represent the official views of the University of Foggia.
文摘Pentraxin-3(PTX3),the prototype of long pentraxins,seems to influence complement system(CS)modulation.PTX3 and CS sustain carcinogenesis,enriching tumor microenvironment(TME)with pro-inflammatory molecules promoting angiogenesis in prostate cancer(PC)and renal cell carcinoma(RCC).Furthermore,cancer cells overexpress complement regulatory proteins,such as CD46,CD55 and CD59,which negatively affect complement pathways for support cancer cells survival.This viewpoint aims to elucidate the ambivalent role of PTX3 and the CS in the context of tumor microenvironment(TME).
文摘同情的 neuronal 区别与 neuroblastoma (NB ) 的有利预后被联系，早童年的最普通的颅外的稳固的肿瘤。区别代理人在 NB 治疗的临床的协议证明了有用，但是因为唯一的治疗不是足够的在病人导致肿瘤消除，使用他们。因此，互补途径例如免疫疗法，被保证。这里，我们证明 NB 房间线和前 vivo 的那区别孤立肿瘤房间响应生理或药理学刺激与增加的 antigenicity 的获得被联系。这是增加了表面专业的表示表明组织亲和性一级建筑群和 ICAM-1 分子并且由细胞毒素的 T 淋巴细胞(CTL ) 和生来的杀手(NK ) 翻译成 NB 房间的增加的敏感到细胞溶解房间。后者是由形式免疫者 conjugates 的区分的房间的提高的能力的 paralleled 并且把 granzyme B 的增加的数量绑在房间表面。 Wedemonstrate ，第一次那不管使用的刺激，在 NB 的区别状态与由细胞毒素的淋巴细胞启用肿瘤房间的更多的有效消除并且在 NB 病人作为一条辅助途径为导致区别的代理人和免疫疗法的联合申请铺平道路的增加的肿瘤 antigenicity 被联系。
文摘Background: L-selectin (CD62L) is a cell surface adhesion molecule recently shown to play a critical role in determining endometrial receptivity and implantation in humans. By contrast, the L-selectin ligand is missing from the rodent endometrium. Interestingly, CD62L (L-selectin)-deficient BALB/c mice delivered significantly higher numbers of viable offspring than wild type controls via mechanisms yet to be defined. Methods: Nulliparous CD62L-deficient (8-10-week-old, n = 25) or wild type (n = 18) females were mated with 43 age-matched males. Animals were sacrificed at gestational day (GD) 9.5. Tissue samples were analyzed by immunostaining and flow cytometry. Results: Mating wild type and CD62L-deficient BALB/c mice revealed that the increased birth rate was due to the CD62L deficiency in females. Flow cytometric analysis demonstrated significant differences in the number of natural killer (NK) cells present in the uterus of pregnant CD62L- deficient mice compared to controls. Immunohistochemistry confirmed NK cell accumulation at the fetal-maternal interface. Discussion: Uterine NK cells have been shown to peak at GD 8-10 at the fetal-maternal interface. NK cells might regulate mouse fertility rates by facilitating development of the maternal spiral arteries, thereby stimulating the formation of larger vessels that facilitate intrauterine survival, however, their role is not obligate to spiral artery development. Conclusions: Diminished CD62L expression modified immune cell trafficking into the uterus of pregnant mice generating a microenvironment primarily dominated by NK cells resulting in improved embryonic survival rates.
文摘Posttraumatic stress disorder (PTSD) is a psychiatric disorder found in individuals afflicted by a traumatic event. Multiple environmental and genetic factors can contribute to PTSD susceptibility. Since it is rare to find members of the same family afflicted by the same catastrophic event, it is not practical to determine PTSD susceptibility genes by a gene linkage analysis. A natural disaster, such as the 2004 Tsunami, provided us with a rare chance for a genetic analysis of PTSD. To identify SNPs associated with PTSD susceptibility, we conducted a genome-association study (GWAS) in Thai-Tsunami survivors. Initial phase of the study with 396 chronic PTSD patients and 457 controls, we identified top ninety SNPs (P -4), which were further assessed in the second phase with 395 chronic PTSD patients and 798 controls. Two SNPs (rs267950 and rs954406), were identified in the second phase, and subjected to fine mapping using a data set from both phases. SNP rs267943 showed the strongest association with PTSD susceptibility and was in complete linkage disequilibrium with SNP rs267950 with P = 6.15 × 10-8, OR = 1.46 and 95% CI = 1.19 - 1.79, reaching genome-wide significance. SNP rs267943 is located on chromosome 5 in the intron of the death-associated protein 1 (DAP1) gene and, when linked to a synthetic promoter, could regulate transcription. To our knowledge, this is the first GWAS for PTSD susceptibility in an Asian population which could provide an important insight into the genetic contribution of PTSD and may lead to new treatment strategies for PTSD.
基金supported by The Swedish Research Council,Karolinska Institutet Foundations and Thuring Foundations.
文摘The epileptic mouse model BALB/cByJ-Kv1.1mceph/mceph (mceph/mceph) is homozygous for a spontaneous mutation truncating the Shaker-like voltage gated potassium channel, Kv1.1 (Kcna1). The mceph/mceph mice are asymptomatic at birth, but develop from 3 weeks of age epileptic seizures, overgrowth and neuronal hyperplasia of the hippocampus. Hippocampal cognitive function of the mice was examined by investigating emotional memory using the aversive Passive Avoidance (PA) task combined with studies of explorative behavior using the non-aversive Novel Cage test (NCT). The behavioural results were examined by multivariate analysis. Compared to wild type and heterozygous mice, the mceph/mceph mice displayed lower exploratory and safety assessment behavior in the NCT and impairment in PA retention 24 hours after training, indicating an impairment in cognitive functions. In conclusion, the epileptic mouse model BALB/cByJ-Kv1.1mceph/mceph, with chronic epilepsy related to potassium-channelopathy, display a behavioural phenotype characterized by impairments in emotional memory and defensive motivational responses probably related to hippocampal dysfunctions.
基金supported by the Science and Technology Project of Shaanxi Province,China(No.2021 PT-047,2022 PT-43,2022JQ-874)the Young Elite Scientist Sponsorship Program by Cast(China Association for Science andTechnology)(No.2020QNRC001).
文摘Protein post-translational modifications(PTMs)are at the heart status of cellular signaling events and broadly involved in tumor progression.CD147 is a tumor biomarker with various PTMs,promoting tumor metastasis and metabolism reprogramming.Nevertheless,the relationship between the PTMs of CD147 and apoptosis has not been reported.In our study,we produced a specific anti-CD147-K71 di-methylation(CD147-K71me2)antibody by immunizing with a di-methylated peptide and observed that the level of CD147-K71me2 in non-small cell lung cancer(NSCLC)tissues were lower than that in NSCLC adjacent tissues.SETDB1 was identified as the methyltransferase catalyzing CD147 to generate CD147-K71me2.RNA-seq showed that FOSB was the most significant differentially expressed gene(DEG)between wild-type CD147(CD147-WT)and K71-mutant CD147(CD147-K71R)groups.Subsequently,we found that CD147-K71me2 promoted the expression of FOSB by enhancing the phosphorylation of p38,leading to tumor cell apoptosis.In vivo experiments showed that CD147-K71me2 significantly inhibited tumor progression by promoting cell apoptosis.Taken together,our findings indicate the inhibitory role of CD147-K71me2 in tumor progression from the perspective of post-translational modification,which is distinct from the pro-cancer function of CD147 itself,broadening our perspective on tumor-associated antigen CD147.
文摘The CD9 gene,also known as the Tspan29 gene,codes for a protein called CD9,which is a member of the tetraspanin family of transmembrane proteins.^(1) The CD9 protein is involved in various cellular processes,including cell proliferation,differentiation,adhesion,and migration.^(1,2) CD9 has also been found to play a role in the regulation of stem cell proliferation and differentiation.
