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Pakistan Journal of Medical Sciences Jul 2024To determine the relationship between Gly64Asp (rs77630697) polymorphism of multidrug and toxin extrusion-1 (MATE-1) and therapeutic response of metformin in Type-2...
Association of Genetic Polymorphism rs 77630697(Gly64Asp) of Multidrug and Toxin Extrusion -1 with glycemic response to metformin in patients with Type 2 Diabetes Mellitus.
OBJECTIVE
To determine the relationship between Gly64Asp (rs77630697) polymorphism of multidrug and toxin extrusion-1 (MATE-1) and therapeutic response of metformin in Type-2 diabetic patients.
METHODS
A longitudinal study was conducted at Riphah International Hospital, Islamabad from June 2020 to December 2021. Type-2 diabetic patients (n=200) on metformin monotherapy fulfilling the inclusion criteria were enrolled and followed up till three months. Based on change in HbA1c, they were divided into responders and non-responders. DNA was extracted and genotyping was done by TETRA ARMS PCR. Data was entered and association was analyzed by SPSS 22.
RESULTS
Out of 200 participants, 104 were categorized as responders and 96 as non-responders. The genotype and allelic distribution of rs77630697 was significantly different between responders and non-responders. The variant genotype (GG) was most prevalent among the study population and among responders. After follow up of three months, difference in glycemic response was found to be statistically significant ( < 0.05) among three genotypes (GG, GA and AA). The decline in HbA1c was highest in GG genotype with almost two-fold reduction in comparison with GA and AA. Carriers of allele A were significantly associated with impaired response to metformin.
CONCLUSION
The variable therapeutic response to metformin in the responders and non-responders may be contributed to rs77630697 isoform variation of MATE-1.
PubMed: 38952525
DOI: 10.12669/pjms.40.6.8170 -
Frontiers in Microbiology 2024African swine fever (ASF) is an infectious disease characterized by hemorrhagic fever, which is highly pathogenic and causes severe mortality in domestic pigs. It is...
African swine fever (ASF) is an infectious disease characterized by hemorrhagic fever, which is highly pathogenic and causes severe mortality in domestic pigs. It is caused by the African swine fever virus (ASFV). ASFV is a large DNA virus and primarily infects porcine monocyte macrophages. The interaction between ASFV and host macrophages is the major reason for gross pathological lesions caused by ASFV. Necroptosis is an inflammatory programmed cell death and plays an important immune role during virus infection. However, whether and how ASFV induces macrophage necroptosis and the effect of necroptosis signaling on host immunity and ASFV infection remains unknown. This study uncovered that ASFV infection activates the necroptosis signaling and macrophage necroptosis . Further evidence showed that ASFV infection upregulates the expression of ZBP1 and RIPK3 to consist of the ZBP1-RIPK3-MLKL necrosome and further activates macrophage necroptosis. Subsequently, multiple Z-DNA sequences were predicted to be present in the ASFV genome. The Z-DNA signals were further confirmed to be present and colocalized with ZBP1 in the cytoplasm and nucleus of ASFV-infected cells. Moreover, ZBP1-mediated macrophage necroptosis provoked the extracellular release of proinflammatory cytokines, including TNF-α and IL-1β induced by ASFV infection. Finally, we demonstrated that ZBP1-mediated necroptosis signaling inhibits ASFV replication in host macrophages. Our findings uncovered a novel mechanism by which ASFV induces macrophage necroptosis by facilitating Z-DNA accumulation and ZBP1 necrosome assembly, providing significant insights into the pathogenesis of ASFV infection.
PubMed: 38952452
DOI: 10.3389/fmicb.2024.1419615 -
Frontiers in Microbiology 2024The unique dormancy of plays a significant role in the major clinical treatment challenge of tuberculosis, such as its long treatment cycle, antibiotic resistance,...
INTRODUCTION
The unique dormancy of plays a significant role in the major clinical treatment challenge of tuberculosis, such as its long treatment cycle, antibiotic resistance, immune escape, and high latent infection rate.
METHODS
To determine the function of MtrA, the only essential response regulator, one strategy was developed to establish its regulatory network according to high-quality genome-wide binding sites.
RESULTS AND DISCUSSION
The complex modulation mechanisms were implied by the strong bias distribution of MtrA binding sites in the noncoding regions, and 32.7% of the binding sites were located inside the target genes. The functions of 288 potential MtrA target genes predicted according to 294 confirmed binding sites were highly diverse, and DNA replication and damage repair, lipid metabolism, cell wall component biosynthesis, cell wall assembly, and cell division were the predominant pathways. Among the 53 pathways shared between dormancy/resuscitation and persistence, which accounted for 81.5% and 93.0% of the total number of pathways, respectively, MtrA regulatory genes were identified not only in 73.6% of their mutual pathways, but also in 75.4% of the pathways related to dormancy/resuscitation and persistence respectively. These results suggested the pivotal roles of MtrA in regulating dormancy/resuscitation and the apparent relationship between dormancy/resuscitation and persistence. Furthermore, the finding that 32.6% of the MtrA regulons were essential and/or for provided new insight into its indispensability. The findings mentioned above indicated that MtrA is a novel promising therapeutic target for tuberculosis treatment since the crucial function of MtrA may be a point of weakness for .
PubMed: 38952446
DOI: 10.3389/fmicb.2024.1415554 -
Molecular Therapy. Nucleic Acids Sep 2024p47 -deficient chronic granulomatous disease (p47-CGD) is a primary immunodeficiency caused by mutations in the neutrophil cytosolic factor 1 () gene, resulting in...
p47 -deficient chronic granulomatous disease (p47-CGD) is a primary immunodeficiency caused by mutations in the neutrophil cytosolic factor 1 () gene, resulting in defective NADPH oxidase function in phagocytes. Due to its complex genomic context, the locus is not suited for safe gene editing with current genome editing technologies. Therefore, we developed a targeted coding sequence knock-in by CRISPR-Cas9 ribonucleoprotein and viral vector template delivery, to restore p47 expression under the control of the endogenous locus. encodes for p67 , an NADPH oxidase subunit that closely interacts with p47 and is predominantly expressed in myeloid cells. This approach restored p47 expression and NADPH oxidase function in p47-CGD patient hematopoietic stem and progenitor cells (HSPCs) and in p47 -deficient mouse HSPCs, with the transgene expression following a myeloid differentiation pattern. Adeno-associated viral vectors performed favorably over integration-deficient lentiviral vectors for template delivery, with fewer off-target integrations and higher correction efficacy in HSPCs. Such myeloid-directed gene editing is promising for clinical CGD gene therapy, as it leads to the co-expression of p47 and p67 , ensuring spatiotemporal and near-physiological transgene expression in myeloid cells.
PubMed: 38952440
DOI: 10.1016/j.omtn.2024.102229 -
Frontiers in Pediatrics 2024Preterm birth is a growing problem worldwide. Staying at a neonatal intensive care unit (NICU) after birth is critical for the survival of preterm infants whose feeding...
INTRODUCTION
Preterm birth is a growing problem worldwide. Staying at a neonatal intensive care unit (NICU) after birth is critical for the survival of preterm infants whose feeding often requires the use of nasogastric enteral feeding tubes (NEFT). These can be colonized by hospital-associated pathobionts that can access the gut of the preterm infants through this route. Since the gut microbiota is the most impactful factor on maturation of the immune system, any disturbance in this may condition their health. Therefore, the aim of this study is to assess the impact of NEFT-associated microbial communities on the establishment of the gut microbiota in preterm infants.
MATERIAL AND METHODS
A metataxonomic analysis of fecal and NEFT-related samples obtained during the first 2 weeks of life of preterm infants was performed. The potential sharing of strains isolated from the same set of samples of bacterial species involved in NICU's outbreaks, was assessed by Random Amplification of Polymorphic DNA (RAPD) genotyping.
RESULTS
In the samples taken 48 h after birth (NEFT-1 and Me/F1), spp. was the most abundant genera (62% and 14%, respectively) and it was latter displaced to 5.5% and 0.45%, respectively by . Significant differences in beta diversity were detected in NEFT and fecal samples taken at day 17 after birth (NEFT-3 and F3) ( = 0.003 and = 0.024, respectively). Significant positive correlations were found between the most relevant genera detected in NEFT-3 and F3. 28% of the patients shared at least one RAPD-PCR profile in fecal and NEFT samples and 11% of the total profiles were found at least once simultaneously in NEFT and fecal samples from the same patient.
CONCLUSION
The results indicate a parallel bacterial colonization of the gut of preterm neonates and the NEFTs used for feeding, potentially involving strain sharing between these niches. Moreover, the same bacterial RAPD profiles were found in neonates hospitalized in different boxes, suggesting a microbial transference within the NICU environment. This study may assist clinical staff in implementing best practices to mitigate the spread of pathogens that could threaten the health of preterm infants.
PubMed: 38952433
DOI: 10.3389/fped.2024.1397398 -
Clinical, Cosmetic and Investigational... 2024Hypohidrotic ectodermal dysplasia (HED) is a genetic disorder that influences structures of ectodermal origin, such as teeth, hair, and sweat glands. Compared with...
INTRODUCTION
Hypohidrotic ectodermal dysplasia (HED) is a genetic disorder that influences structures of ectodermal origin, such as teeth, hair, and sweat glands. Compared with autosomal recessive and dominant modes of inheritance, the X-linked HED (XLHED) characterized by Hypodontia/Oligodontia teeth, Absent/sparse hair, Anhidrosis/hypohidrosis, and characteristic facial features, is the most frequent and its primary cause is the mutation of ectodysplasin A (EDA) gene. This research aimed to expound the clinical and molecular features of a Chinese male with XLHED and to summarize and compare several previous findings.
METHODS
Genomic DNA was obtained from the peripheral blood of the proband and his family members, then Sanger sequencing was used to perform a mutational analysis of . Real-time quantitative PCR and Western blotting were used to detect EDA expression. The transcriptional activity of NF-κB was detected using a luciferase assay.
RESULTS
The probandwith XLHED was identified a novel mutation, c.1119G>C(p.M373I), that affected the molecular analysis of transmembrane protein exon8 mutations, inherited from the mother. He showed a severe multiple-tooth loss, with over 20 permanent teeth missing and sparse hair and eyebrows, dry, thin, and itching skin. Furthermore, his sweating function was abnormal to a certain extent.
DISCUSSION
The functional study showed that this novel mutant led to a significant decrease in the EDA expression level and transcriptional activity of NF-κB. Our findings extend the range of mutations in XLHED patients, which provides the basis and idea for further exploring the pathogenesis of XLHED.
PubMed: 38952411
DOI: 10.2147/CCID.S451125 -
Heliyon Jun 2024DIP2B is related to cancer progression. This study investigated the roles and pathways of DIP2B in lung adenocarcinoma (LUAD).
Downregulation of DIP2B as a prognostic marker inhibited cancer proliferation and migration and was associated with immune infiltration in lung adenocarcinoma via CCND1 and MMP2.
BACKGROUND
DIP2B is related to cancer progression. This study investigated the roles and pathways of DIP2B in lung adenocarcinoma (LUAD).
METHODS
DIP2B expression and the relationship between survival time of cancer patients and DIP2B expression were analyzed. The relationship between DIP2B expression and survival time in LUAD patients was evaluated by a meta-analysis. Cox and survival analyses were used to evaluate the prognostic factors and construct a prognostic nomogram. The mechanisms and effects of DIP2B and the relationship between DIP2B expression and the immune microenvironment were investigated using bioinformatics, CCK-8, western blotting, and transwell experiments.
RESULTS
DIP2B was overexpressed in LUAD tissues. DIP2B overexpression was associated with shorter prognosis and was an unfavorable risk factor for prognosis in LUAD patients. DIP2B co-expressed genes were involved in cell division, DNA repair, cell cycle, and others. Inhibition of DIP2B expression could downregulate the proliferation, migration, and invasion of LUAD A549 and H1299 cells, which was related to the decrease in CCND1 and MMP2 protein expression. BRCA1 overexpression was associated with short prognosis, and the nomogram formed by DIP2B and BRCA1 was associated with a poor prognosis in LUAD patients. DIP2B expression correlated with immune cells (such as CD8 T cells, Tcm, and iDCs) and cell markers.
CONCLUSION
DIP2B is a potential biomarker of poor prognosis and the immune microenvironment in LUAD. Inhibition of DIP2B expression downregulated cancer cell proliferation, migration, and invasion, which might be related to the decrease in CCND1 and MMP2 protein expression. DIP2B-related nomograms might be useful tools for predicting the prognosis of LUAD patients.
PubMed: 38952374
DOI: 10.1016/j.heliyon.2024.e32025 -
Heliyon Jun 2024Radiotherapy causes apoptosis mainly through direct or indirect damage to DNA via ionizing radiation, leading to DNA strand breaks. However, the efficacy of radiotherapy... (Review)
Review
Radiotherapy causes apoptosis mainly through direct or indirect damage to DNA via ionizing radiation, leading to DNA strand breaks. However, the efficacy of radiotherapy is attenuated in malignant tumor microenvironment (TME), such as hypoxia. Tumor vasculature, due to the imbalance of various angiogenic and anti-angiogenic factors, leads to irregular morphology of tumor neovasculature, disordered arrangement of endothelial cells, and too little peripheral coverage. This ultimately leads to a TME characterized by hypoxia, low pH and high interstitial pressure. This deleterious TME further exacerbates the adverse effects of tumor neovascularization and weakens the efficacy of conventional radiotherapy. Whereas normalization of blood vessels improves TME and thus the efficacy of radiotherapy. In addition to describing the research progress of radiotherapy sensitization and vascular normalization, this review focuses on the strategy and application prospect of modulating vascular normalization to improve the efficacy of radiotherapy sensitization.
PubMed: 38952362
DOI: 10.1016/j.heliyon.2024.e32598 -
Zhongguo Xue Xi Chong Bing Fang Zhi Za... Jun 2024To investigate the origin of in China, so as to provide insights into assessment of schistosomiasis mansoni transmission risk and control.
OBJECTIVE
To investigate the origin of in China, so as to provide insights into assessment of schistosomiasis mansoni transmission risk and control.
METHODS
Guanlan River, Dasha River, Shenzhen Reservoir, upper and lower reaches of Kuiyong River, and Xinzhen River in Shenzhen, China, were selected as sampling sites. Ten samples were collected from each site, and genomic DNA was extracted from samples. DNA samples were obtained from 15 sampled from 5 sampling sites in Minas Gerais State, Pará State, Federal District, Pernambuco State, and Sao Paulo State in Brazil, South America. Cytochrome c oxidase I () and mitochondrial 16S ribosomal RNA () genes were sampled using the above DNA templates, and the amplified products were sequenced. The and gene sequences were downloaded from GenBank, and the sampling sites were acquired. All and 1 gene sequences were aligned and evolutionary trees of were created based on and gene sequences to identify the genetic similarity and evolutionary relationship between samples from China and South America.
RESULTS
A total of 60 gene sequences with a length of 529 bp and 3 haplotypes were obtained from sampled from China. There were 165 gene sequences of retrieved from GenBank, and following alignment with the above 60 gene sequences, a total of 33 haplotypes were obtained. Phylogenetic analysis showed that the three haplotypes of from China were clustered into one clade, among which the haplotype China11 and three samples from Brazil retrieved from GenBank belonged to the same haplotype. Geographical evolution analysis showed that the samples from three sampling sites along eastern coasts of Brazil had the same haplotype with China11, and samples from other two sampling sites were closely, genetically related to China11. A total of 60 gene sequences with approximately 322 bp in length were amplified from in China, with 2 haplotypes identified. A total of 70 gene sequences of were captured from GenBank. Phylogenetic analysis showed that snails collected from China were clustered into a clade, and the haplotype China64 and the haplotype 229BS from Brazil shared the same haplotype. The 49 gene sequences of from 25 sampling sites in southern Brazil, which were captured from GenBank, were included in the present analysis, and the from 3 sampling sites shared the same haplotype with China64 in China. Geographical evolution analysis based on and gene sequences showed that sampled from eastern coastal areas of Brazil shared the same haplotypes in two gene fragment sequences with snails collected from China.
CONCLUSIONS
The snails in China are characterized as , which have a low genetic diversity. The snails in China have a high genetic similarity with sampled from eastern coastal areas of Brazil, which may have originated from the eastern coastal areas of Brazil.
Topics: Animals; China; Phylogeny; RNA, Ribosomal, 16S; Biomphalaria; Electron Transport Complex IV; Haplotypes
PubMed: 38952313
DOI: 10.16250/j.32.1374.2024069 -
Journal of the American Society For... Jul 2024Irradiation of the major conformation of duplex DNA found in cells (B form) produces cyclobutane pyrimidine dimers (CPDs) from adjacent pyrimidines in a head-to-head...
Irradiation of the major conformation of duplex DNA found in cells (B form) produces cyclobutane pyrimidine dimers (CPDs) from adjacent pyrimidines in a head-to-head orientation () with the C5 substituents in a cis stereochemistry. These CPDs have crucial implications in skin cancer. Irradiation of G-quadruplexes and other non-B DNA conformations in vitro produces, however, CPDs between nonadjacent pyrimidines in nearby loops with syn and head-to-tail orientations () with both cis and trans stereochemistry to yield a mixture of six possible isomers of the T=T dimer. This outcome is further complicated by formation of mixtures of nonadjacent CPDs of C=T, T=C, and C=C, and successful analysis depends on development of specific and sensitive methods. Toward meeting this need, we investigated whether ion mobility mass spectrometry (IMMS) and MS/MS can distinguish the and T=T CPDs. Ion mobility can afford baseline separation and give relative mobilities that are in accord with predicted cross sections. Complementing this ability to distinguish isomers is MS/MS collisional activation where fragmentation also distinguishes the two isomers and confirms conclusions drawn from ion mobility analysis. The observations offer early support that ion mobility and MS/MS can enable the distinction of DNA photoproduct isomers.
PubMed: 38952267
DOI: 10.1021/jasms.4c00133