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During a 2023 outbreak of Mycoplasma pneumoniae-associated community-acquired pneumonia among children in northern Vietnam, we analyzed M. pneumoniae isolated from nasopharyngeal samples. In almost half (6 of 13) of samples tested, we found known A2063G mutations (macrolide resistance) and a novel C2353T variant on the 23S rRNA gene.
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Mutação , Mycoplasma pneumoniae , Pneumonia por Mycoplasma , RNA Ribossômico 23S , Mycoplasma pneumoniae/genética , Mycoplasma pneumoniae/classificação , Humanos , Vietnã/epidemiologia , RNA Ribossômico 23S/genética , Pneumonia por Mycoplasma/microbiologia , Pneumonia por Mycoplasma/epidemiologia , Pneumonia por Mycoplasma/história , Criança , Pré-Escolar , Infecções Comunitárias Adquiridas/microbiologia , Infecções Comunitárias Adquiridas/epidemiologia , Antibacterianos/farmacologia , Antibacterianos/uso terapêutico , Farmacorresistência Bacteriana/genéticaRESUMO
Alzheimer's disease (AD) and type 2 diabetes mellitus (T2DM) are two common diseases that affect the elderly population worldwide. The identification of common genes associated with AD and T2DM holds promise for potential biomarkers and intriguing pathogenesis of these two complicated diseases. This study utilized a comprehensive approach by integrating transcriptome data from multiple cohorts, encompassing both AD and T2DM. The analysis incorporated various data types, including blood and tissue samples as well as single-cell datasets, allowing for a detailed assessment of gene expression patterns. From the brain region-specific single-cell analysis, PIP4K2A, which encodes phosphatidylinositol-5-phosphate 4-kinase type 2 alpha, was found to be expressed mainly in oligodendrocytes compared to other cell types. Elevated levels of PIP4K2A in AD and T2DM patients' blood were found to be associated with key cellular processes such as vesicle-mediated transport, negative regulation of autophagosome assembly, and cytosolic transport. The identification of PIP4K2A's potential roles in the cellular processes of AD and T2DM offers valuable insights into the development of biomarkers for diagnosis and therapy, especially in the complication of these two diseases.
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Doença de Alzheimer , Diabetes Mellitus Tipo 2 , Oligodendroglia , Fosfotransferases (Aceptor do Grupo Álcool) , Doença de Alzheimer/metabolismo , Doença de Alzheimer/genética , Humanos , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/genética , Oligodendroglia/metabolismo , Oligodendroglia/patologia , Fosfotransferases (Aceptor do Grupo Álcool)/genética , Fosfotransferases (Aceptor do Grupo Álcool)/metabolismo , Biomarcadores , Transcriptoma , Análise de Célula Única , Perfilação da Expressão Gênica , MultiômicaRESUMO
The composition, structural features, surface morphology, roughness parameters, particle size, and magnetic features of nanostructured Fe-Co-Ni deposits manufactured on conducting indium tin oxide-coated glasses at various electrolyte pH values are studied. The deposit produced at low electrolyte pH contains slightly higher Fe and Co contents but lower Ni content compared to deposits fabricated at high pH values. Further composition analysis confirms that the reduction rates of Fe2+ and Co2+ are higher than the Ni2+ reduction rate. The films consist of nano-sized crystallites with a strong [111] preferred orientation. The results also reveal that the crystallization of the thin films is affected by the electrolyte pH. Surface analysis shows that the deposit surfaces are composed of nano-sized particles with different diameters. The mean particle diameter and surface roughness decrease as the pH of the electrolyte decreases. The effect of the electrolyte pH on the morphology is also discussed in terms of surface skewness and kurtosis parameters. Magnetic analysis shows that the resultant deposits have in-plane hysteresis loops with low and close SQR parameters ranging from 0.079 to 0.108. The results also reveal that the coercive field of the deposits increases from 29.4 Oe to 41.3 Oe as the electrolyte pH decreases from 4.7 to 3.2.
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This study characterized genetic diversity and population structure of four indigenous Vietnamese duck breeds and an exotic breed for setting the conservation priority. A total of 200 samples from four duck breeds (Sincheng, Minhhuong, Muongchieng and Bauben) and an exotic breed (Supermeat) were genotyped for fifteen microsatellite markers. The average number of alleles per locus was 14.07. A moderate genetic diversity was observed for indigenous breeds as mean of observed and expected heterozygosity as Ho = 0.50 and He = 0.57, respectively. The Bauben had the lowest values of Ho (0.41) and He (0.48) while Sincheng had the highest values of Ho (0.6) and He (0.69), respectively. The inbreeding coefficients (FIS) ranged from 0.12 to 0.16, and all breeds were significantly under heterozygote deficit. Nei's genetic distance was the shortest between Minhhuong and Muongkhieng. The discriminant analysis of principal components of studied breeds resulted in four genetic clusters. The Minhhuong and Muongkhieng breeds joined the same genetic cluster while other breeds had their own clusters. These results indicated that the possibility to combine Minhhuong and Muongkhieng for reducing the cost of conservation and suggested that conservation of the Bauben should be prioritized to avoid inbreeding depression and genetic drift.
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Patos , Variação Genética , Animais , Patos/genética , Variação Genética/genética , Vietnã , Repetições de Microssatélites/genética , AlelosRESUMO
Since hepatocellular carcinoma (HCC) is a typical hypervascular malignant tumor with poor prognosis, targeting angiogenesis is an important therapeutic strategy for advanced HCC. Involvement of bone morphologic protein 9 (BMP9), a transforming growth factor-beta superfamily member, has recently been reported in the development of liver diseases and angiogenesis. Here, we aimed to elucidate the role of BMP9 signaling in promoting HCC angiogenesis and to assess the antiangiogenic effect of BMP receptor inhibitors in HCC. By analyzing HCC tissue gene expression profiles, we found that BMP9 expression was significantly correlated with angiogenesis-associated genes, including HIF-1α and VEGFR2. In vitro, BMP9 induced HCC cell HIF-1α/VEGFA expression and VEGFA secretion. Silencing of the inhibitor of DNA-binding protein 1 (ID1), a transcription factor targeted by BMP9 signaling, suppressed BMP9-induced HIF-1α/VEGFA expression and VEGFA secretion, resulting in decreased human umbilical vein endothelial cell (HUVEC) lumen formation. BMP receptor inhibitors, which inhibit BMP9-ID1 signaling, suppressed BMP9-induced HIF-1α/VEGFA expression, VEGFA secretion, and HUVEC lumen formation. In vivo, the BMP receptor inhibitor LDN-212854 successfully inhibited HCC tumor growth and angiogenesis by inhibiting BMP9-ID1 signaling. In summary, BMP9-ID1 signaling promotes HCC angiogenesis by activating HIF-1α/VEGFA expression. Thus, targeting BMP9-ID1 signaling could be a pivotal therapeutic option for advanced HCC.
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Carcinoma Hepatocelular , Fator 2 de Diferenciação de Crescimento , Subunidade alfa do Fator 1 Induzível por Hipóxia , Proteína 1 Inibidora de Diferenciação , Neoplasias Hepáticas , Proteínas de Neoplasias , Neovascularização Patológica , Fator A de Crescimento do Endotélio Vascular , Animais , Carcinoma Hepatocelular/irrigação sanguínea , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/metabolismo , Fator 2 de Diferenciação de Crescimento/genética , Fator 2 de Diferenciação de Crescimento/metabolismo , Células Hep G2 , Células Endoteliais da Veia Umbilical Humana , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Proteína 1 Inibidora de Diferenciação/genética , Proteína 1 Inibidora de Diferenciação/metabolismo , Neoplasias Hepáticas/irrigação sanguínea , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Neovascularização Patológica/genética , Neovascularização Patológica/metabolismo , Fator A de Crescimento do Endotélio Vascular/genética , Fator A de Crescimento do Endotélio Vascular/metabolismoRESUMO
BACKGROUND: Poor early-life nutrition is a major barrier to good health and cognitive development, and is a global health priority. Alive & Thrive (A&T) was a multi-pronged initiative to improve infant and young child feeding behaviors. It aimed to achieve at-scale child health and nutrition improvements via a comprehensive approach that included nutrition counseling by health workers, policy change, social mobilization and mass media activities. This study evaluated the sustainability of activities introduced during A&T implementation (2009-2014) in Bangladesh and Vietnam. METHODS: This was a mixed methods study that used a quasi-experimental design. Quantitative data (surveys with 668 health workers, and 269 service observations) were collected in 2017; and analysis compared outcomes (primarily dose and fidelity of activities, and capacity) in former A&T intervention areas versus areas that did not receive the full A&T intervention. Additionally, we conducted interviews and focus groups with 218 stakeholders to explore their impressions about the determinants of sustainability, based on a multi-level conceptual framework. RESULTS: After program conclusion, stakeholders perceive declines in mass media campaigns, policy and advocacy activities, and social mobilization activities - but counseling activities were institutionalized and continued in both countries. Quantitative data show a persisting modest intervention effect: health workers in intervention areas had significantly higher child feeding knowledge, and in Bangladesh greater self-efficacy and job satisfaction, compared to their counterparts who did not receive the full package of A&T activities. While elements of the program were integrated into routine services, stakeholders noted dilution of the program focus due to competing priorities. Qualitative data suggest that some elements, such as training, monitoring, and evaluation, which were seen as essential to A&T's success, have declined in frequency, quality, coverage, or were eliminated altogether. CONCLUSIONS: The inclusion of multiple activities in A&T and efforts to integrate the program into existing institutions were seen as crucial to its success but also made it difficult to sustain, particularly given unstable financial support and human resource constraints. Future complex programs should carefully plan for institutionalization in advance of the program by cultivating champions across the health system, and designing unique and complementary roles for all stakeholders including donors.
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Serviços de Saúde da Criança , Promoção da Saúde/organização & administração , Bangladesh , Criança , Saúde da Criança , Fenômenos Fisiológicos da Nutrição Infantil , Pré-Escolar , Aconselhamento , Feminino , Pessoal de Saúde , Promoção da Saúde/métodos , Humanos , Lactente , Masculino , Meios de Comunicação de Massa , Estado Nutricional , Avaliação de Programas e Projetos de Saúde/métodos , VietnãRESUMO
BACKGROUND: Multiple epiphyseal dysplasia (MED) is a common skeletal dysplasia that is characterized by variable degrees of epiphyseal abnormality primarily involving the hip and knee joints. Mutations in a gene encoding matrilin-3 (MATN3) have been reported as disease causing of autosomal dominant MED. The current study identified a novel c.572 C > A variant (p.A191D) in exon 2 of MATN3 in a Vietnamese family with MED. CASE PRESENTATION: A standard clinical tests and radiological examination were performed in an 8-year-old Vietnamese girl patient. The clinical examination showed that patient height was under average, with bent lower limbs, limited mobility and dislocation of the joints at both knees. Radiological documentation revealed abnormal cartilage development at the epiphysis of the femur and patella. The patient has a varus deformity of the lower limbs. The patient was diagnosed with autosomal dominant MED using molecular testing in the order of the coding sequences and flanking sequences of five genes: COMP (exons 8-19), MATN3 (exon 2), COL9A2 (exon 3), COL9A3 (exon 3), COL9A1 (exon 8) by Sanger sequencing. A novel heterozygous missense variant (c.572 C > A, p.A191D) in MATN3 was identified in this family, which were not inherited from parents. The p.A191D was predicted and classified as a pathogenic variant. When the two predicted structures of the wild type and mutant matrilin-3 were compared, the p.A191D substitution caused conformational changes near the substitution site, resulting in deformity of the ß-sheet of the single A domain of matrilin- 3. CONCLUSIONS: This is the first Vietnamese MED family attributed to p.A191D matrilin-3 variant, and our clinical, radiological and molecular data suggest that the novel de novo missense variant in MATN3 contributed to MED.
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Mutação de Sentido Incorreto , Osteocondrodisplasias/genética , Povo Asiático/genética , Criança , Éxons/genética , Família , Feminino , Humanos , Proteínas Matrilinas/genética , Osteocondrodisplasias/diagnóstico por imagem , Linhagem , RadiografiaRESUMO
Hematopoietic regeneration following chemotherapy may be distinct from regeneration following radiation. While we have shown that epidermal growth factor (EGF) accelerates regeneration following radiation, its role following chemotherapy is currently unknown. We sought to identify EGF as a hematopoietic growth factor for chemotherapy-induced myelosuppression. Following 5-fluorouracil (5-FU), EGF accelerated hematopoietic stem cell regeneration and prolonged survival compared with saline-treated mice. To mitigate chemotherapy-induced injury to endothelial cells in vivo, we deleted Bax in VEcadherin+ cells (VEcadherinCre;BaxFL/FL mice). Following 5-FU, VEcadherinCre;BaxFL/FL mice displayed preserved hematopoietic stem/progenitor content compared with littermate controls. 5-FU and EGF treatment resulted in increased cellular proliferation, decreased apoptosis, and increased DNA double-strand break repair by non-homologous end-joining recombination compared with saline-treated control mice. When granulocyte colony stimulating factor (G-CSF) is given with EGF, this combination was synergistic for regeneration compared with either G-CSF or EGF alone. EGF increased G-CSF receptor (G-CSFR) expression following 5-FU. Conversely, G-CSF treatment increased both EGF receptor (EGFR) and phosphorylation of EGFR in hematopoietic stem/progenitor cells. In humans, the expression of EGFR is increased in patients with colorectal cancer treated with 5-FU compared with cancer patients not on 5-FU. Similarly, EGFR signaling is responsive to G-CSF in humans in vivo with both increased EGFR and phospho-EGFR in healthy human donors following G-CSF treatment compared with donors who did not receive G-CSF. These data identify EGF as a hematopoietic growth factor following myelosuppressive chemotherapy and that dual therapy with EGF and G-CSF may be an effective method to accelerate hematopoietic regeneration. Stem Cells 2018;36:252-264.
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Fator de Crescimento Epidérmico/farmacologia , Fator Estimulador de Colônias de Granulócitos/farmacologia , Animais , Apoptose/efeitos dos fármacos , Ciclo Celular/efeitos dos fármacos , Receptores ErbB/metabolismo , Fluoruracila/farmacologia , Hematopoese/efeitos dos fármacos , Células-Tronco Hematopoéticas/citologia , Células-Tronco Hematopoéticas/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL , Transdução de Sinais/efeitos dos fármacosRESUMO
Arylhydrazones of active methylene compounds (AHAMCs) are potent chemotherapy agents for the cancer treatment. AHAMCs enhance the apoptotic cell death and antiproliferation properties in cancer cells. In this study, a series of AHAMCs, 13 compounds, was assayed for cytotoxicity, apoptosis, externalization of phosphatidylserine, heterogeneity and cellular calcium level changes. The in vitro cytotoxicity study against HEK293T cells suggests that AHAMCs have significant cytotoxic effect over the concentrations. Top 5 compounds, 5-(2-(2-hydroxyphenyl) hydrazono)pyrimidine-2,4,6(1H,3H,5H)-trione (5), 4-hydroxy-5-(2-(2,4,6-trioxo-tetrahydro-pyrimidin-5(6H) ylidene)hydrazinyl)benzene-1,3-disulfonic acid (6), 5-chloro-3-(2-(4,4-dimethyl-2,6-dioxocyclohexylidene)hydrazinyl)-2-hydroxybenzenesulfonic acid (8), 5-(2-(4,4-dimethyl-2,6-dioxocyclohexylidene)hydrazinyl)-4-hydroxybenzene-1,3-disulfonic acid (9) and 2-(2-sulfophenylhydrazo)malononitrile (10) were chosen for the pharmacodynamics study. Among these, compound 5 exhibited the better cytotoxic effect with the IC50 of 50.86⯱â¯2.5â¯mM. DNA cleavage study revealed that 5 induces cell death through apoptosis and shows more effects after 24 and/or 48â¯h. Independent validation of apoptosis by following the externalization of phosphatidylserine using Annexin-V is also in agreement with the potential activity of 5. Single cell image analysis of Annexin-V bound cells confirms the presence of mixture of early, mid and late apoptotic cells in the population of the cells treated with 5 and a decreased trend in cell-to-cell variation over the phase was also identified. Additionally, intracellular calcium level measurements identified the Ca2+ up-regulation in compound treated cells. A brief inspection of the effect of the compound 5 against multiple human brain astrocytoma cells showed a better cell growth inhibitory effect at micro molar level. These systematic studies provide insights in the development of novel AHAMACs compounds as potential cell growth inhibitors for cancer treatment.
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Stable nitroxyl radical-containing compounds, such as 2,2,6,6-tetramethylpiperidine-N-oxyl (TEMPO) and its derivatives, are capable of electrocatalytically oxidizing a wide range of alcohols under mild and environmentally friendly conditions. Herein, we examine the structure-function relationships that determine the catalytic activity of a diverse range of water-soluble nitroxyl radical compounds. A strong correlation is described between the difference in the electrochemical oxidation potentials of a compound and its electrocatalytic activity. Additionally, we construct a simple computational model that is able to accurately predict the electrochemical potential and catalytic activity of a wide range of nitroxyl radical derivatives.
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PURPOSE: This retrospective study compared computed tomography (CT) imaging to routine dental periapical radiographs in diagnosing radiolucencies around endodontically treated teeth. MATERIALS AND METHODS: Of the 244 CT scans evaluated, 104 had no teeth on the scan. On the remaining 140 scans, 353 teeth fell into the following categories: 59 maxillary molars, 30 mandibular molars, 66 maxillary premolars, 56 mandibular premolars, and 141 anterior teeth. Positive and negative predictive values were calculated, as were sensitivity, specificity, and prevalence assuming the CT scan was the test standard. RESULTS: For the total tooth population periapical radiograph - CT slice sensitivity was 52, specificity was 90, the positive predictive value (PPV) was 97, the negative predictive value (NPV) was 25, and the prevalence 85. CONCLUSION: In the population studied, the CT scan had a greater ability to show radiolucencies that were not evident on periapical radiographs.
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Técnicas e Procedimentos Diagnósticos/instrumentação , Técnicas e Procedimentos Diagnósticos/estatística & dados numéricos , Doenças Periapicais/diagnóstico por imagem , Radiografia Dentária/instrumentação , Radiografia Dentária/métodos , Radiografia Dentária/estatística & dados numéricos , Tomografia Computadorizada por Raios X/métodos , Tomografia Computadorizada por Raios X/estatística & dados numéricos , Dente não Vital/diagnóstico por imagem , Humanos , Prevalência , Estudos Retrospectivos , Sensibilidade e Especificidade , Dente , Ápice Dentário/diagnóstico por imagem , Ápice Dentário/patologiaRESUMO
Hematopoietic stem cells (HSCs) reside in proximity to bone marrow endothelial cells (BM ECs) and maintenance of the HSC pool is dependent upon EC-mediated c-kit signaling. Here, we used genetic models to determine whether radioprotection of BM ECs could facilitate hematopoietic regeneration following radiation-induced myelosuppression. We developed mice bearing deletion of the proapoptotic proteins, BAK and BAX, in Tie2(+) ECs and HSCs (Tie2Bak/Bax(Fl/-) mice) and compared their hematopoietic recovery following total body irradiation (TBI) with mice which retained Bax in Tie2(+) cells. Mice bearing deletion of Bak and Bax in Tie2(+) cells demonstrated protection of BM HSCs, preserved BM vasculature, and 100% survival following lethal dose TBI. In contrast, mice that retained Bax expression in Tie2(+) cells demonstrated depletion of BM HSCs, disrupted BM vasculature, and 10% survival post-TBI. In a complementary study, VEcadherinBak/Bax(Fl/-) mice, which lack Bak and Bax in VEcadherin(+) ECs, also demonstrated increased recovery of BM stem/progenitor cells following TBI compared to mice which retained Bax in VEcadherin(+) ECs. Importantly, chimeric mice that lacked Bak and Bax in HSCs but retained Bak and Bax in BM ECs displayed significantly decreased HSC content and survival following TBI compared to mice lacking Bak and Bax in both HSCs and BM ECs. These data suggest that the hematopoietic response to ionizing radiation is dependent upon HSC-autonomous responses but is regulated by BM EC-mediated mechanisms. Therefore, BM ECs may be therapeutically targeted as a means to augment hematopoietic reconstitution following myelosuppression.
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Células da Medula Óssea/metabolismo , Células Endoteliais/metabolismo , Células-Tronco Hematopoéticas/metabolismo , Lesões Experimentais por Radiação/metabolismo , Receptores Proteína Tirosina Quinases/genética , Irradiação Corporal Total , Animais , Células da Medula Óssea/patologia , Células da Medula Óssea/efeitos da radiação , Caderinas/genética , Caderinas/metabolismo , Células Endoteliais/patologia , Células Endoteliais/efeitos da radiação , Expressão Gênica/efeitos da radiação , Transplante de Células-Tronco Hematopoéticas , Células-Tronco Hematopoéticas/patologia , Células-Tronco Hematopoéticas/efeitos da radiação , Camundongos , Camundongos Transgênicos , Lesões Experimentais por Radiação/genética , Lesões Experimentais por Radiação/mortalidade , Lesões Experimentais por Radiação/patologia , Receptores Proteína Tirosina Quinases/metabolismo , Receptor TIE-2 , Regeneração/efeitos da radiação , Transdução de Sinais/efeitos da radiação , Análise de Sobrevida , Proteína Killer-Antagonista Homóloga a bcl-2/deficiência , Proteína Killer-Antagonista Homóloga a bcl-2/genética , Proteína X Associada a bcl-2/deficiência , Proteína X Associada a bcl-2/genéticaRESUMO
Small-cell neuroendocrine cervical carcinoma (NECC) is a rare histology, and diagnosis and treatment of this condition are challenging because of its rarity, non-specific abdominopelvic symptoms, and less favorable prognosis compared to other cervical cancers. Here, we present a case of a 20-year-old patient diagnosed with small-cell NECC, defined within a cervical polyp, initially mimicking a benign lesion. Because of the difficulty in diagnosis, the patient underwent thorough diagnostics and interventions, including imaging, histopathology, and immunohistochemistry. Initially, the patient underwent a distinctive treatment plan encompassing four cycles of cisplatin and etoposide chemotherapy with minimal side effects. Subsequently, she received comprehensive surgical interventions, including hysterectomy, lymphadenectomy, and bilateral salpingectomy. Ovarian preservation, justified by the patient's youth and small cervical lesions (<4 cm) without parametrial disease or metastatic signs, was pursued. For long-term outcomes, the patient demonstrated no metastasis or recurrence during a five-year follow-up. This case emphasizes the requirement for strengthened awareness of neuroendocrine tumors in cervical masses, particularly in young patients, and the importance of individualized treatment approaches for optimal clinical outcomes. Continued documentation of such cases increases our understanding of managing infrequent cervical malignancies.
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The whole genomic sequence of fowl adenovirus C (FAdV-4) strain FAdV-4/Pasouk, isolated from chickens with hepatitis-hydropericardium syndrome (HHS) from an outbreak in Iran, has been deposited in GenBank under accession number ON652872. Notably, this FAdV-4 isolate exhibited significant genetic similarities to contemporary isolates originating from China, indicating a shared ancestry.
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BACKGROUND AND PURPOSE: Colorectal cancer (CRC) is the second most lethal disease, with high mortality due to its heterogeneity and chemo-resistance. Here, we have focused on the epidermal growth factor receptor (EGFR) as an effective therapeutic target in CRC and studied the effects of polyphenols known to modulate several key signalling mechanisms including EGFR signalling, associated with anti-proliferative and anti-metastatic properties. EXPERIMENTAL APPROACH: Using ligand- and structure-based cheminformatics, we developed three potent, selective alkylaminophenols, 2-[(3,4-dihydroquinolin-1(2H)-yl)(p-tolyl)methyl]phenol (THTMP), 2-[(1,2,3,4-tetrahydroquinolin-1-yl)(4-methoxyphenyl)methyl]phenol (THMPP) and N-[2-hydroxy-5-nitrophenyl(4'-methylphenyl)methyl]indoline (HNPMI). These alkylaminophenols were assessed for EGFR interaction, EGFR-pathway modulation, cytotoxic and apoptosis induction, caspase activation and transcriptional and translational regulation. The lead compound HNPMI was evaluated in mice bearing xenografts of CRC cells. KEY RESULTS: Of the three alkylaminophenols tested, HNPMI exhibited the lowest IC50 in CRC cells and potential cytotoxic effects on other tumour cells. Modulation of EGFR pathway down-regulated protein levels of osteopontin, survivin and cathepsin S, leading to apoptosis. Cell cycle analysis revealed that HNPMI induced G0/G1 phase arrest in CRC cells. HNPMI altered the mRNA for and protein levels of several apoptosis-related proteins including caspase 3, BCL-2 and p53. HNPMI down-regulated the proteins crucial to oncogenesis in CRC cells. Assays in mice bearing CRC xenografts showed that HNPMI reduced the relative tumour volume. CONCLUSIONS AND IMPLICATIONS: HNPMI is a promising EGFR inhibitor for clinical translation. HNPMI regulated apoptosis and oncogenesis by modulating BCL-2/BAX and p53 in CRC cell lines, showing potential as a therapeutic agent in the treatment of CRC.
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Antineoplásicos , Neoplasias do Colo , Neoplasias Colorretais , Humanos , Animais , Camundongos , Proteína X Associada a bcl-2/metabolismo , Proteína X Associada a bcl-2/farmacologia , Proteína X Associada a bcl-2/uso terapêutico , Proteína Supressora de Tumor p53/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Apoptose , Neoplasias do Colo/tratamento farmacológico , Neoplasias do Colo/metabolismo , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Proteínas Reguladoras de Apoptose/metabolismo , Receptores ErbB/metabolismo , Carcinogênese , Transformação Celular Neoplásica , Fenóis/farmacologia , Linhagem Celular Tumoral , Proliferação de Células , Neoplasias Colorretais/tratamento farmacológicoRESUMO
Alzheimer's disease (AD) is a prevalent neurodegenerative disorder afflicting the elderly population worldwide. The identification of potential gene candidates for AD holds promises for diagnostic biomarkers and therapeutic targets. Employing a comprehensive strategy, this study integrated transcriptomic data from diverse data sources, including microarray and single-cell datasets from blood and tissue samples, enabling a detailed exploration of gene expression dynamics. Through this thorough investigation, 19 notable candidate genes were found with consistent expression changes across both blood and tissue datasets, suggesting their potential as biomarkers for AD. In addition, single cell sequencing analysis further highlighted their specific expression in excitatory and inhibitory neurons, the primary functional units in the brain, underscoring their relevance to AD pathology. Moreover, the functional enrichment analysis revealed that three of the candidate genes were downregulated in synaptic signaling pathway. Further validation experiments significantly showed reduced levels of rabphilin-3A (RPH3A) in 3xTg-AD model mice, implying its role in disease pathogenesis. Given its role in neurotransmitter exocytosis and synaptic function, further investigation into RPH3A and its interactions with neurotrophic proteins may provide valuable insights into the complex molecular mechanisms underlying synaptic dysfunction in AD.
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Doença de Alzheimer , Biomarcadores , Perfilação da Expressão Gênica , Rabfilina-3A , Doença de Alzheimer/genética , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Animais , Camundongos , Humanos , Biomarcadores/metabolismo , Rabfilina-3A/metabolismo , Rabfilina-3A/genética , Sinapses/metabolismo , Transcriptoma , Modelos Animais de Doenças , Camundongos Transgênicos , Neurônios/metabolismo , Análise de Célula Única/métodosRESUMO
Background: Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive and behavioral decline. Acrolein, an environmental pollutant and endogenous compound, is implicated in AD development. This research employs bibliometric analysis to assess current trends and key areas concerning acrolein-AD interaction. Methods: The Web of Science was used to extensively review literature on acrolein and AD. Relevant data were systematically gathered and analyzed using VOSviewer, CiteSpace, and an online bibliometric tool. Results: We identified 120 English publications in this specialized field across 19 journals. The Journal of Alzheimer's Disease was the most prominent. The primary contributors, both in terms of scientific output and influence, were the USA, the University of Kentucky, and Ramassamy C, representing countries/regions, institutions, and authors, respectively. In this field, the primary focus was on thoroughly studying acrolein, its roles, and its mechanisms in AD utilizing both in vivo and in vitro approaches. A significant portion of the research was based on proteomics, revealing complex molecular processes. The main focuses in the field were "oxidative stress," "lipid peroxidation," "amyloid-beta," and "cognitive impairment." Anticipated future research trajectories focus on the involvement of the internalization pathway, covering key areas such as synaptic dysfunction, metabolism, mechanisms, associations, neuroinflammation, inhibitors, tau phosphorylation, acrolein toxicity, brain infarction, antioxidants, chemistry, drug delivery, and dementia. Our analysis also supported our previous hypothesis that acrolein can interact with amyloid-beta to form a protein adduct leading to AD-like pathology and altering natural immune responses. Conclusion: This study provides a broad and all-encompassing view of the topic, offering valuable insights and guidance to fellow researchers. These emerging directions underscore the continuous exploration of the complexities associated with AD. The analyses and findings aim to enhance our understanding of the intricate relationship between acrolein and AD for future research.
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Prostate cancer exhibits high prevalence and accounts for a high number of cancer-related deaths. The discovery and characterization of molecular determinants of aggressive prostate cancer represents an active area of research. The Immediate Early Response (IER) family of genes, which regulate Protein Phosphatase 2A (PP2A) activity, has emerged among the factors that influence cancer biology. Here, we show that the less studied member of this family, Immediate Early Response 5 like (IER5L), is upregulated in aggressive prostate cancer. Interestingly, the upregulation of IER5L expression exhibits a robust association with metastatic disease in prostate and is recapitulated in other cancer types. In line with this observation, IER5L silencing reduces foci formation, migration and invasion ability in a variety of human and murine prostate cancer cell lines. In vivo, using zebrafish and immunocompromised mouse models, we demonstrate that IER5L-silencing reduces prostate cancer tumor growth, dissemination, and metastasis. Mechanistically, we characterize the transcriptomic and proteomic landscapes of IER5L-silenced cells. This approach allowed us to identify DNA replication and monomeric G protein regulators as downstream programs of IER5L through a pathway that is consistent with the regulation of PP2A. In sum, we report the alteration of IER5L in prostate cancer and beyond and provide biological and molecular evidence of its contribution to tumor aggressiveness.
Assuntos
Progressão da Doença , Neoplasias da Próstata , Proteína Fosfatase 2 , Masculino , Neoplasias da Próstata/patologia , Neoplasias da Próstata/genética , Neoplasias da Próstata/metabolismo , Humanos , Proteína Fosfatase 2/metabolismo , Proteína Fosfatase 2/genética , Animais , Camundongos , Linhagem Celular Tumoral , Regulação Neoplásica da Expressão Gênica , Peixe-Zebra , Movimento Celular/genética , Proliferação de CélulasRESUMO
Rice grassy stunt virus (RGSV, Tenuivirus) recently emerged on rice in Vietnam, causing high yield losses during 2006-2009. The genetic diversity of RGSV is poorly documented. In this study, the two genes encoded by each ambisense segment RNA3 and RNA5 of RGSV isolates from six provinces of South Vietnam were sequenced. P3 and Pc3 (RNA3) have unknown function, P5 (RNA5) encodes the putative silencing suppressor, and Pc5 (RNA5) encodes the nucleocapsid protein (N). The sequences of 17 Vietnamese isolates were compared with reference isolates from North and South Philippines. The average nucleotide diversity among the isolates was low. We confirmed a higher variability of RNA3 than RNA5 and Pc3 than P3. No relationships between the genetic diversity and the geographic distribution of RGSV isolates could be ascertained, likely because of the long-distance migration of the insect vector. This data will contribute to a better understanding on the RGSV epidemiology in South Vietnam, a prerequisite for further management of the disease and rice breeding for resistance.
Assuntos
Variação Genética , Oryza/virologia , Doenças das Plantas/virologia , Tenuivirus/genética , Tenuivirus/isolamento & purificação , Dados de Sequência Molecular , Proteínas do Nucleocapsídeo/genética , Filogenia , Tenuivirus/classificação , VietnãRESUMO
BACKGROUND: Antimicrobial resistance is a major contemporary public health threat. Strategies to contain antimicrobial resistance have been comprehensively set forth, however in developing countries where the need for effective antimicrobials is greatest implementation has proved problematic. A better understanding of patterns and determinants of antibiotic use and resistance in emerging economies may permit more appropriately targeted interventions.Viet Nam, with a large population, high burden of infectious disease and relatively unrestricted access to medication, is an excellent case study of the difficulties faced by emerging economies in controlling antimicrobial resistance. METHODS: Our working group conducted a situation analysis of the current patterns and determinants of antibiotic use and resistance in Viet Nam. International publications and local reports published between 1-1-1990 and 31-8-2012 were reviewed. All stakeholders analyzed the findings at a policy workshop and feasible recommendations were suggested to improve antibiotic use in Viet Nam.Here we report the results of our situation analysis focusing on: the healthcare system, drug regulation and supply; antibiotic resistance and infection control; and agricultural antibiotic use. RESULTS: Market reforms have improved healthcare access in Viet Nam and contributed to better health outcomes. However, increased accessibility has been accompanied by injudicious antibiotic use in hospitals and the community, with predictable escalation in bacterial resistance. Prescribing practices are poor and self-medication is common - often being the most affordable way to access healthcare. Many policies exist to regulate antibiotic use but enforcement is insufficient or lacking.Pneumococcal penicillin-resistance rates are the highest in Asia and carbapenem-resistant bacteria (notably NDM-1) have recently emerged. Hospital acquired infections, predominantly with multi-drug resistant Gram-negative organisms, place additional strain on limited resources. Widespread agricultural antibiotic use further propagates antimicrobial resistance. CONCLUSIONS: Future legislation regarding antibiotic access must alter incentives for purchasers and providers and ensure effective enforcement. The Ministry of Health recently initiated a national action plan and approved a multicenter health improvement project to strengthen national capacity for antimicrobial stewardship in Viet Nam. This analysis provided important input to these initiatives. Our methodologies and findings may be of use to others across the world tackling the growing threat of antibiotic resistance.