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BACKGROUNDS & AIMS: Precancerous metaplasia progression to dysplasia can increase the risk of gastric cancers. However, effective strategies to specifically target these precancerous lesions are currently lacking. To address this, we aimed to identify key signaling pathways that are upregulated during metaplasia progression and critical for stem cell survival and function in dysplasia. METHODS: To assess the response to chemotherapeutic drugs, we used metaplastic and dysplastic organoids derived from Mist1-Kras mice and 20 human precancerous organoid lines established from patients with gastric cancer. Phospho-antibody array analysis and single-cell RNA-sequencing were performed to identify target cell populations and signaling pathways affected by pyrvinium, a putative anticancer drug. Pyrvinium was administered to Mist1-Kras mice to evaluate drug effectiveness in vivo. RESULTS: Although pyrvinium treatment resulted in growth arrest in metaplastic organoids, it induced cell death in dysplastic organoids. Pyrvinium treatment significantly downregulated phosphorylation of ERK and signal transducer and activator of transcription 3 (STAT3) as well as STAT3-target genes. Single-cell RNA-sequencing data analyses revealed that pyrvinium specifically targeted CD133+/CD166+ stem cell populations, as well as proliferating cells in dysplastic organoids. Pyrvinium inhibited metaplasia progression and facilitated the restoration of normal oxyntic glands in Mist1-Kras mice. Furthermore, pyrvinium exhibited suppressive effects on the growth and survival of human organoids with dysplastic features, through simultaneous blocking of the MEK/ERK and STAT3 signaling pathways. CONCLUSIONS: Through its dual blockade of MEK/ERK and STAT3 signaling pathways, pyrvinium can effectively induce growth arrest in metaplasia and cell death in dysplasia. Therefore, our findings suggest that pyrvinium is a promising chemotherapeutic agent for reprogramming the precancerous milieu to prevent gastric cancer development.
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Lesões Pré-Cancerosas , Neoplasias Gástricas , Humanos , Camundongos , Animais , Proteínas Proto-Oncogênicas p21(ras)/metabolismo , Neoplasias Gástricas/tratamento farmacológico , Neoplasias Gástricas/genética , Neoplasias Gástricas/prevenção & controle , Fator de Transcrição STAT3/metabolismo , Carcinogênese/genética , Carcinogênese/patologia , Hiperplasia , Lesões Pré-Cancerosas/patologia , Quinases de Proteína Quinase Ativadas por Mitógeno/metabolismo , Metaplasia/patologia , Células-Tronco/metabolismo , RNARESUMO
BACKGROUND & AIMS: Gastric carcinogenesis develops within a sequential carcinogenic cascade from precancerous metaplasia to dysplasia and adenocarcinoma, and oncogenic gene activation can drive the process. Metabolic reprogramming is considered a key mechanism for cancer cell growth and proliferation. However, how metabolic changes contribute to the progression of metaplasia to dysplasia remains unclear. We have examined metabolic dynamics during gastric carcinogenesis using a novel mouse model that induces Kras activation in zymogen-secreting chief cells. METHODS: We generated a Gif-rtTA;TetO-Cre;KrasG12D (GCK) mouse model that continuously induces active Kras expression in chief cells after doxycycline treatment. Histologic examination and imaging mass spectrometry were performed in the GCK mouse stomachs at 2 to 14 weeks after doxycycline treatment. Mouse and human gastric organoids were used for metabolic enzyme inhibitor treatment. The GCK mice were treated with a stearoyl- coenzyme A desaturase (SCD) inhibitor to inhibit the fatty acid desaturation. Tissue microarrays were used to assess the SCD expression in human gastrointestinal cancers. RESULTS: The GCK mice developed metaplasia and high-grade dysplasia within 4 months. Metabolic reprogramming from glycolysis to fatty acid metabolism occurred during metaplasia progression to dysplasia. Altered fatty acid desaturation through SCD produces a novel eicosenoic acid, which fuels dysplastic cell hyperproliferation and survival. The SCD inhibitor killed both mouse and human dysplastic organoids and selectively targeted dysplastic cells in vivo. SCD was up-regulated during carcinogenesis in human gastrointestinal cancers. CONCLUSIONS: Active Kras expression only in gastric chief cells drives the full spectrum of gastric carcinogenesis. Also, oncogenic metabolic rewiring is an essential adaptation for high-energy demand in dysplastic cells.
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Metabolismo Energético , Ácidos Graxos , Metaplasia , Organoides , Proteínas Proto-Oncogênicas p21(ras) , Neoplasias Gástricas , Animais , Neoplasias Gástricas/patologia , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/genética , Humanos , Ácidos Graxos/metabolismo , Proteínas Proto-Oncogênicas p21(ras)/genética , Proteínas Proto-Oncogênicas p21(ras)/metabolismo , Organoides/metabolismo , Camundongos , Modelos Animais de Doenças , Carcinogênese/metabolismo , Carcinogênese/genética , Carcinogênese/patologia , Celulas Principais Gástricas/metabolismo , Celulas Principais Gástricas/patologia , Transformação Celular Neoplásica/metabolismo , Transformação Celular Neoplásica/patologia , Transformação Celular Neoplásica/genética , Camundongos Transgênicos , Glicólise , Adenocarcinoma/patologia , Adenocarcinoma/metabolismo , Adenocarcinoma/genética , Progressão da Doença , Lesões Pré-Cancerosas/patologia , Lesões Pré-Cancerosas/metabolismo , Lesões Pré-Cancerosas/genéticaRESUMO
BACKGROUND: Mucosal gastric atrophy and intestinal metaplasia (IM) increase the risk for the development of gastric cancer (GC) as they represent a field for development of dysplasia and intestinal-type gastric adenocarcinoma. METHODS: We have investigated the expression of two dysplasia markers, CEACAM5 and TROP2, in human antral IM and gastric tumors to assess their potential as molecular markers. RESULTS: In the normal antral mucosa, weak CEACAM5 and TROP2 expression was only observed in the foveolar epithelium, while inflamed antrum exhibited increased expression of both markers. Complete IM exhibited weak CEACAM5 expression at the apical surface, but no basolateral TROP2 expression. On the other hand, incomplete IM demonstrated high levels of both CEACAM5 and TROP2 expression. Notably, incomplete IM with dysplastic morphology (dysplastic incomplete IM) exhibited higher levels of CEACAM5 and TROP2 expression compared to incomplete IM without dysplastic features (simple incomplete IM). In addition, dysplastic incomplete IM showed diminished SOX2 and elevated CDX2 expression compared to simple incomplete IM. CEACAM5 and TROP2 positivity in incomplete IM was similar to that of gastric adenomas and GC. Significant association was found between CEACAM5 and TROP2 positivity and histology of GC. CONCLUSIONS: These findings support the concept that incomplete IM is more likely associated with GC development. Overall, our study provides evidence of the heterogeneity of gastric IM and the distinct expression profiles of CEACAM5 and TROP2 in dysplastic incomplete IM. Our findings support the potential use of CEACAM5 and TROP2 as molecular markers for identifying individuals with a higher risk of GC development in the context of incomplete IM.
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Lesões Pré-Cancerosas , Neoplasias Gástricas , Humanos , Neoplasias Gástricas/patologia , Mucosa Gástrica/patologia , Lesões Pré-Cancerosas/patologia , Metaplasia , Antígeno Carcinoembrionário , Proteínas Ligadas por GPI/metabolismoRESUMO
The impact of microplastics (MPs) on the metabolic functions of the liver is currently unclear and not completely understood. To investigate the effects of the administration of MPs on the hepatic metabolism of normal and obese mice, alterations in the lipid, glucose (Glu), and amino acid regulation pathways were analyzed in the liver and adipose tissues of C57BL/6Korl (wild type, WT) or C57BL/6-Lepem1hwl/Korl mice (leptin knockout, Lep KO) orally administered polystyrene (PS) MPs for 9 weeks. Significant alterations in the lipid accumulation, adipogenesis, lipogenesis, and lipolysis pathways were detected in the liver tissue of MP-treated WT and Lep KO mice compared to the vehicle-treated group. These alterations in their liver tissues were accompanied by an upregulation of the serum lipid profile, as well as alterations in the adipogenesis, lipogenesis, and lipolysis pathways in the adipose tissues of MP-treated WT and Lep KO mice. Specifically, the level of leptin was increased in the adipose tissues of MP-treated WT mice without any change in their food intake. Also, MP-induced disruptions in the glycogenolysis, Glu transporter type 4 (GLUT4)-5' AMP-activated protein kinase (AMPK) signaling pathway, levels of lipid intermediates, and the insulin resistance of the liver tissues of WT and Lep KO mice were observed. Furthermore, the levels of seven endogenous metabolites were remarkably changed in the serum of WT and Lep KO mice after MP administrations. Finally, the impact of the MP administration observed in both types of mice was further verified in differentiated 3T3-L1 adipocytes and HepG2 cells. Thus, these results suggest that the oral administration of MPs for 9 weeks may be associated with the disruption of lipid, Glu, and amino acid metabolism in the liver tissue of obese WT and Lep KO mice.
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Aminoácidos , Glucose , Metabolismo dos Lipídeos , Fígado , Camundongos Endogâmicos C57BL , Camundongos Knockout , Microplásticos , Poliestirenos , Animais , Fígado/metabolismo , Fígado/efeitos dos fármacos , Camundongos , Glucose/metabolismo , Metabolismo dos Lipídeos/efeitos dos fármacos , Aminoácidos/metabolismo , Administração Oral , Leptina/metabolismo , Tecido Adiposo/metabolismo , Tecido Adiposo/efeitos dos fármacos , Adipogenia/efeitos dos fármacos , Masculino , Lipogênese/efeitos dos fármacos , Obesidade/metabolismo , Obesidade/etiologia , Obesidade/genética , Humanos , Lipólise/efeitos dos fármacosRESUMO
When using single atoms (SAs) as a co-catalyst in photocatalytic H2 generation, achieving a well-dispersed, evenly distributed and adjustable SA surface density on a semiconductor surface is a challenging task. In the present work we use the planar adsorption of tetrakis-(4-carboxyphenyl)-porphyrin (TCPP) and its platinum coordinated analogue, Pt-TCPP, onto anatase TiO2 surfaces to establish a spatially controlled decoration of SAs. We show that the surface Pt SA density can be very well controlled by co-adsorption of Pt-TCPP and TCPP in the planar monolayer regime, and by adjusting the Pt-TCPP to TCPP ratio a desired well dispersed surface density of SAs up to 2.6×105 â atoms µm-2 can be established (which is the most effective Pt SA loading for photocatalysis). This distribution and the SA state are maintained after a thermal treatment in air, and an optimized SA density as well as a most active form of Pt for photocatalytic H2 evolution can be established and maintained.
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BACKGROUND: Although the importance of oral and systemic healthcare for elderly people is increasing owing to the rapid ageing of the population in South Korea, studies on the relationship between oral health, systemic health, and cognitive function, as well as on the prediction of cognitive function by oral and systemic health depending upon age groups are lacking. METHODS: We included 5,975 out of 6,488 participants from the 8th wave of the Korean Longitudinal Study of Aging (KLoSA) panel data, divided the participants into three age groups, and performed a hierarchical multiple linear regression analysis to explain cognitive function with four types of predictors: oral health status, sociodemographic factors, objective health status, and subjective health status. RESULTS: Oral health status was positively correlated with systemic health status and cognitive function. Of all ages over 54, cognitive function was significantly predicted by oral health variables, such as the number of functional teeth, masticatory ability, and Geriatric Oral Health Assessment Index (GOHAI); sociodemographic variables, such as age, sex, education level, and residence; and systemic health variables, such as diagnosis of diabetes mellitus, cancer or malignant tumours, cerebrovascular disease and rheumatoid arthritis, depressive symptom, and self-rated health status. Oral health variables explained cognitive function differently by age group; GOHAI appeared important predictor in the group aged < 75 years, whereas the number of functional teeth did in the group aged ≥ 75 years. Educational level, masticatory ability, depressive symptoms, and self-rated health status were pivotal factors age-independently. CONCLUSIONS: The general and age-group-specific association between oral health, systemic health, and cognitive function were confirmed, suggesting that age-group-specific oral healthcare should be emphasized for the effective management of systemic and cognitive health in the elderly group.
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Saúde Bucal , Qualidade de Vida , Idoso , Humanos , Estudos Transversais , Estudos Longitudinais , Avaliação Geriátrica , CogniçãoRESUMO
The histogenesis of pleomorphic adenoma (PA) of the salivary glands remains controversial. PAs are characterized by the transition of epithelial cells to spindled mesenchymal cells, known as epithelial-mesenchymal transition (EMT). The present study aimed to identify a major EMT-inducing transcription factor (EMT-TF) in PAs. Real-time PCR analysis of SNAIL, SLUG, ZEB1, and TWIST1 demonstrated that only SLUG was significantly upregulated in normal salivary glands and PAs. Combined in situ hybridization for SLUG and multiplex immunohistochemistry for CK19 and P63 revealed that SLUG was specifically expressed in the myoepithelial cells of normal salivary glands. In PAs, SLUG was expressed in neoplastic myoepithelial cells and stromal cells but not in the luminal cells lining the inner layers of tumor glands. SLUG expression showed no correlation with PLAG1 expression, and in vitro experiments demonstrated that PLAG1 suppression in primary cultured PA cells or PLAG1 overexpression in HEK 293 T cells did not affect SLUG levels, indicating that PLAG1 was not involved in the upregulation of SLUG in PAs. The suppression of SLUG expression in cultured PA cells resulted in a morphology change to a less elongated shape and attenuated tumor growth. In addition, SLUG downregulation led to increased E-cadherin and decreased N-cadherin and vimentin expression levels along with decreased migratory activity in cultured PA cells. These findings suggest that SLUG is a major TF that can induce EMT in PAs. In summary, SLUG is specifically and highly expressed in the myoepithelial cells and stromal cells of PAs and is a key regulator of EMT in PAs.
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Adenoma Pleomorfo , Fatores de Transcrição da Família Snail , Adenoma Pleomorfo/química , Adenoma Pleomorfo/genética , Adenoma Pleomorfo/metabolismo , Transição Epitelial-Mesenquimal , Células HEK293 , Humanos , Imuno-Histoquímica , Fatores de Transcrição da Família Snail/genética , Fatores de Transcrição da Família Snail/metabolismoRESUMO
The core body temperature tends to decrease under general anesthesia. Consequently, monitoring the core body temperature during procedures involving general anesthesia is essential to ensure patient safety. In veterinary medicine, rectal temperature is used as an indicator of the core body temperature, owing to the accuracy and convenience of this approach. Some previous studies involving craniotomy reported differences between the brain and core temperatures under general anesthesia. However, noninvasive imaging techniques are required to ascertain this because invasive brain temperature measurements can cause unintended temperature changes by inserting the temperature sensors into the brain or by performing the surgical operations. In this study, we employed in vivo magnetic resonance thermometry to observe the brain temperatures of patients under general anesthesia using the proton resonance frequency shift method. The rectal temperature was also recorded using a fiber optic thermometer during the MR thermometry to compare with the brain temperature changes. When the rectal temperature decreased by 1.4 ± 0.5 °C (mean ± standard deviation), the brain temperature (white matter) decreased by 4.8 ± 0.5 °C. Furthermore, a difference in the temperature reduction of the different types of brain tissue was observed; the reduction in the temperature of white matter exceeded that of gray matter mainly due to the distribution of blood vessels in the gray matter. We also analyzed and interpreted the core temperature changes with the body conditioning scores of subjects to see how the body weight affected the temperature changes.
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Temperatura Corporal , Termometria , Anestesia Geral , Animais , Encéfalo/diagnóstico por imagem , Cães , Humanos , Espectroscopia de Ressonância Magnética , Termometria/métodosRESUMO
Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is the most common genetic disorder among those responsible for hereditary strokes, and it is caused by a mutation in the NOTCH3 gene on chromosome 19. Blood biomarkers related to the Notch signaling pathway have not been investigated extensively in CADASIL. In this study, we measured the serum and plasma levels of NOTCH3 extracellular domain (N3ECD) and its ligand, Jagged-1, in 279 healthy subjects. The levels of N3ECD and Jagged-1 showed significant correlations in both serum (p < 0.0001, r = 0.2681) and plasma (p < 0.0001, r = 0.4065). The N3ECD levels were significantly higher in the serum than in plasma and tend to increase with age. In contrast, there was no significant difference between the serum and plasma levels of Jagged-1 levels. To summarize, we were able to measure N3ECD and Jagged-1 protein levels in healthy human serum and plasma. Taken together, our findings provide the basis for further studies investigating the clinical use of blood N3ECD and Jagged-1 levels for CADASIL and other Notch signaling-related diseases.
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CADASIL , Biomarcadores , CADASIL/genética , Voluntários Saudáveis , Humanos , Proteína Jagged-1/genética , Ligantes , Mutação , Receptor Notch3/genética , Receptores Notch/genéticaRESUMO
In many ion-conducting polycrystalline oxides, grain boundaries are generally accepted as rate-limiting obstacles to rapid ionic diffusion, often resulting in overall sluggish transport. Consequently, based on a precise understanding of the structural and compositional features at grain boundaries, systematic control of the polycrystalline microstructure is a key factor to achieve better ionic conduction performance. In this study, we clarify that a nanometer-thick amorphous phase at most grain boundaries in proton-conducting BaCeO3 polycrystals is responsible for substantial retardation of proton migration and moreover is very reactive with water and carbon dioxide gas. By a combination of atomic-scale chemical analysis and physical imaging, we demonstrate that highly densified BaCeO3 polycrystals free of a grain-boundary amorphous phase can be easily fabricated by a conventional ceramic process and show sufficiently high proton conductivity together with significantly improved chemical stability. These findings emphasize the value of direct identification of intergranular phases and subsequent manipulation of their distribution in ion-conducting oxide polycrystals.
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OBJECTIVE: The purpose of this study is to perform a systematic review and meta-analysis of volume-based 18F-FDG PET/CT parameters regarding the prognostic value of metabolic tumor volume (MTV) and total lesion glycolysis (TLG) in patients with uterine cervical cancer. MATERIALS AND METHODS: The PubMed and EMBASE databases were systematically searched until January 19, 2018. We included studies that evaluated pretreatment MTV or TLG as a prognostic factor in uterine cervical cancer with event-free (EFS) and overall survival (OS) as the endpoints. Effect sizes of the prognostic value of MTV and TLG were measured in terms of hazard ratio (HR) and were meta-analytically pooled. Multiple subgroup analyses stratified to clinicopathologic and PET/CT variables were performed to explore heterogeneity. RESULTS: Twelve studies including 660 patients were included. Prognoses were worse in patients with high MTV and TLG, with pooled HRs of 5.89 (95% CI, 3.85-9.01; p < 0.00001) and 5.82 (95% CI, 3.62-9.35; p < 0.00001), respectively, for EFS and 6.62 (95% CI, 3.44-12.73; p < 0.00001) and 7.75 (95% CI, 3.48-17.27; p < 0.00001), respectively, for OS. At multiple subgroups analyses, the prognostic values of MTV and TLG for EFS were consistently significant, with pooled HRs of 5.08-7.30 and 4.80-15.83, respectively. CONCLUSION: Volume-based FDG PET/CT parameters were significant prognostic factors in patients with uterine cervical cancer. In spite of clinical and methodologic differences across the studies, patients with high MTV or TLG had a higher risk of adverse events or death.
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Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Neoplasias do Colo do Útero/diagnóstico por imagem , Neoplasias do Colo do Útero/metabolismo , Feminino , Fluordesoxiglucose F18 , Humanos , Prognóstico , Compostos Radiofarmacêuticos , Neoplasias do Colo do Útero/patologiaRESUMO
BACKGROUND: The prescription rate for antibiotics in dental clinics is not declining despite the increase in the antibiotic resistance problem. In this study, we observed the change in antibiotic prescription rates by dentists in a Korean dental hospital for various treatments after conducting interventions targeting dentists. METHODS: The first intervention was to distribute guidelines. The second intervention was to remove the bundled prescription button containing antibiotics from the Electronic Medical Record system. A total of 22,098 treatment records were divided into 12 main treatment categories, and Chi-square tests and logistic regression analyses were performed. RESULTS: After the interventions were applied, the overall prescription rate for antibiotics dropped. The antibiotic prescription rate decreased by an odds ratio of 0.774 (95% CI: 0.686-0.873) after intervention 1 and by an odds ratio of 0.574 (95% CI: 0.501-0.658) after intervention 2. The treatments with significantly reduced antibiotic prescription rates were extraction for orthodontic treatment, dental implant surgery, extraction of an impacted tooth and general extraction. These treatments are typically performed in patients without an active infection. The prescription rate did not change for periodontal treatments or endodontic treatments, which are usually performed in patients with an infection. The prescription rate also remained constant for minor operations and other basic treatments. CONCLUSION: The interventions induced behavioural changes in the dentists and were effective in lowering the antibiotic prescription rates in a dental hospital. In particular, there was a significant reduction in the prescription rates for implant surgery and tooth extraction in the absence of infection.
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Antibacterianos/uso terapêutico , Antibioticoprofilaxia/métodos , Odontologia Geral/estatística & dados numéricos , Padrões de Prática Odontológica/estatística & dados numéricos , Infecções Bacterianas/prevenção & controle , Humanos , Infecção da Ferida Cirúrgica/prevenção & controleRESUMO
BACKGROUND: This study evaluated full-arch rehabilitation of patients with immediately placed implants in terms of the cumulative implant survival rate, risk factors for implant failure, and patient satisfaction. METHODS: Time-to-event data of 52 completely edentulous jaws (370 implants) were collected using retrospective clinical chart review for the time period from 2008 to 2014. A conventional two stage approach for surgery was adopted to immediately placed implants in the maxilla, and immediate placement and immediate loading protocols for the mandible were followed. The study calculated the 7-year cumulative survival rates (CSR), and a Bayesian hierarchical Cox proportional hazard model was used to measure the effect of covariates. Patient satisfaction on chewing ability, esthetic appearance, and overall satisfaction was also measured with a face-to-face interview survey. RESULTS: Of the total 370 implants, 194 were immediate placement. Two delayed loading maxillary implants failed within the first year, and another one failed in the second year of loading. Two failures were recorded in the first year and one in seven years for the immediate loading mandibular implants. The 1-, 5-, and 7-year CSR of the 370 implants were 0.989 (0.979, 1.000), 0.986 (0.975, 0.998), and 0.978 (0.957, 0.999), respectively. Only the length of the implant affected implant failure (p < 0.05); other patient characteristics, systemic diseases, implant diameter, immediate loading, and immediate placement, did not have an effect on implant failure rates. Patients reported a high degree of satisfaction regardless of their age group or length of the observation period. CONCLUSIONS: Immediately placed implant had CSR as high as delayed placed implants, and 7-year CSRs of immediate loading were not significantly different from delayed loading. The procedure also had a high degree of chewing ability, esthetic appearance, and overall satisfaction. The study results suggested that the clinical procedures applied in this study to completely edentulous patients were acceptable rehabilitation procedures.
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Carga Imediata em Implante Dentário , Satisfação do Paciente/estatística & dados numéricos , Idoso , Falha de Restauração Dentária/estatística & dados numéricos , Feminino , Humanos , Carga Imediata em Implante Dentário/efeitos adversos , Carga Imediata em Implante Dentário/psicologia , Carga Imediata em Implante Dentário/estatística & dados numéricos , Masculino , Pessoa de Meia-Idade , Boca Edêntula/cirurgia , Estudos RetrospectivosRESUMO
In most proton-conducing perovskite oxides, the electrostatic attraction between negatively charged acceptor dopants and protonic defects having a positive charge is known to be a major cause of retardation of proton conduction, a phenomenon that is generally referred to as proton trapping. We experimentally show that proton trapping can be suppressed by clustering of positively charged oxygen vacancies to acceptors in BaZrO3-δ and BaCeO3-δ . In particular, to ensure the vacancy-acceptor association is effective against proton trapping, the valence electron density of acceptors should not significantly vary when the oxygen vacancies cluster, based on the weak hybridization between the valence d or p orbitals of acceptors and the 2p orbitals of oxygen.
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Since the first prediction by Frenkel, many follow-up studies have been carried out to show the presence of subsurface space-charge layers having the opposite sign to that of the excess charge at the surface, producing overall neutrality in ionic crystals. However, no precise experimental evidence demonstrating how the aliovalent solutes segregate in the space-charge region beneath the surface has been provided over the past several decades. By utilizing atomic-scale imaging and chemical probing in a perovskite oxide, the origin of the surface excess charge at the topmost surface and the position of segregated dopants in the space-charge region is precisely determined. The impact of the space-charge contribution to the dopant distribution near the surface in oxide crystals is explored.
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The glycoprotein CD98, or CD98 heavy chain (CD98hc), encoded by the SLC3A2 gene, plays a crucial role in cancer development and progression. CD98hc, forming heterodimeric complexes with various light chains, regulates neutral amino acid transport across cell membranes. The intricate interplay between CD98hc, integrins, and amino acid transporters shapes the tumor microenvironment and contributes to tumor growth. Elevated expression of CD98hc in various cancers correlates with poor prognosis, making it a potential prognostic marker. In colorectal cancer, CD98hc emerges as a potential therapeutic target, along with its partner LAT1, and inhibitors like JPH203 exhibit promise in preclinical studies. Targeting CD98hc/LAT1, alone or with conventional therapies, shows promise in inhibiting tumor growth. This review focuses on elucidating the multifaceted roles of CD98hc and its partner LAT1 in cancer, particularly its involvement in amino acid transport, signaling pathways, and its prognostic relevance in cancer.
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The employment of single atoms (SAs), especially Pt SAs, as co-catalysts in photocatalytic H2 generation has gained significant attention due to their exceptional efficiency. However, a major challenge in their application is the light-induced agglomeration of these SAs into less active nanosized particles under photocatalytic conditions. This study addresses the stability and reactivity of Pt SAs on TiO2 surfaces by investigating various post-deposition annealing treatments in air, Ar, and Ar-H2 environments at different temperatures. It is described that annealing in an Ar-H2 atmosphere optimally stabilizes SA configurations, forming stable 2D rafts of assembled SAs ≈0.5-1 nm in diameter. These rafts not only resist light-induced agglomeration but also exhibit significantly enhanced H2 production efficiency. The findings reveal a promising approach to maintaining the high reactivity of Pt SAs while overcoming the critical challenge of their stability under photocatalytic conditions.
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PURPOSE: Quantitative polymerase chain reaction (qPCR) has recently been employed to measure the number of bacterial cells by quantifying their DNA fragments. However, this method can yield inaccurate bacterial cell counts because the number of DNA fragments varies among different bacterial species. To resolve this issue, we developed a novel optimized qPCR method to quantify bacterial colony-forming units (CFUs), thereby ensuring a highly accurate count of bacterial cells. METHODS: To establish a new qPCR method for quantifying 6 oral bacteria namely, Porphyromonas gingivalis, Treponema denticola, Tannerella forsythia, Prevotella intermedia, Fusobacterium nucleatum, and Streptococcus mutans, the most appropriate primer-probe sets were selected based on sensitivity and specificity. To optimize the qPCR for predicting bacterial CFUs, standard curves were produced by plotting bacterial CFU against Ct values. To validate the accuracy of the predicted CFU values, a spiking study was conducted to calculate the recovery rates of the predicted CFUs to the true CFUs. To evaluate the reliability of the predicted CFU values, the consistency between the optimized qPCR method and shotgun metagenome sequencing (SMS) was assessed by comparing the relative abundance of the bacterial composition. RESULTS: For each bacterium, the selected primer-probe set amplified serial-diluted standard templates indicative of bacterial CFUs. The resultant Ct values and the corresponding bacterial CFU values were used to construct a standard curve, the linearity of which was determined by a coefficient of determination (r²) >0.99. The accuracy of the predicted CFU values was validated by recovery rates ranging from 95.1% to 106.8%. The reliability of the predicted CFUs was reflected by the consistency between the optimized qPCR and SMS, as demonstrated by a Spearman rank correlation coefficient (ρ) value of 1 for all 6 bacteria. CONCLUSIONS: The CFU-based qPCR quantification method provides highly accurate and reliable quantitation of oral pathogenic bacteria.
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Chronic oral inflammation and biofilm-mediated infections drive diseases such as dental caries and periodontitis. This study investigated the anti-inflammatory and antibacterial potential of an ethanol extract from Astilbe chinensis inflorescence (GA-13-6) as a prominent candidate for natural complex substances (NCS) with therapeutic potential. In LPS-stimulated RAW 264.7 macrophages, GA-13-6 significantly suppressed proinflammatory mediators, including interleukin-6 (IL-6), tumor necrosis factor (TNF), and nitric oxide (NO), surpassing purified astilbin, a known bioactive compound found in A. chinensis. Furthermore, GA-13-6 downregulated the expression of cyclooxygenase-2 (COX2) and inducible nitric oxide synthase (iNOS), indicating an inhibitory effect on the inflammatory cascade. Remarkably, GA-13-6 exhibited selective antibacterial activity against Streptococcus mutans, Streptococcus sanguinis, and Porphyromonas gingivalis, key players in dental caries and periodontitis, respectively. These findings suggest that complex GA-13-6 holds the potential for the treatment or prevention of periodontal and dental diseases, as well as various other inflammation-related conditions, while averting the induction of antibiotic resistance.
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Macrófagos , Extratos Vegetais , Animais , Camundongos , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Extratos Vegetais/farmacologia , Extratos Vegetais/química , Células RAW 264.7 , Antibacterianos/farmacologia , Inflamação/tratamento farmacológico , Etanol/química , Óxido Nítrico Sintase Tipo II/metabolismo , Anti-Inflamatórios/farmacologia , Inflorescência/química , Ciclo-Oxigenase 2/metabolismo , Ciclo-Oxigenase 2/genética , Óxido Nítrico/metabolismo , Interleucina-6/metabolismo , Lipopolissacarídeos , Fator de Necrose Tumoral alfa/metabolismoRESUMO
Tuft cells are chemosensory cells associated with luminal homeostasis, immune response, and tumorigenesis in the gastrointestinal tract. We aimed to elucidate alterations in tuft cell populations during gastric atrophy and tumorigenesis in humans with correlative comparison to relevant mouse models. Tuft cell distribution was determined in human stomachs from organ donors and in gastric pathologies including Ménétrier's disease, Helicobacter pylori gastritis, intestinal metaplasia (IM), and gastric tumors. Tuft cell populations were examined in Lrig1-KrasG12D , Mist1-KrasG12D , and MT-TGFα mice. Tuft cells were evenly distributed throughout the entire normal human stomach, primarily concentrated in the isthmal region in the fundus. Ménétrier's disease stomach showed increased tuft cells. Similarly, Lrig1-Kras mice and mice overexpressing TGFα showed marked foveolar hyperplasia and expanded tuft cell populations. Human stomach with IM or dysplasia also showed increased tuft cell numbers. Similarly, Mist1-Kras mice had increased numbers of tuft cells during metaplasia and dysplasia development. In human gastric cancers, tuft cells were rarely observed, but showed positive associations with well-differentiated lesions. In mouse gastric cancer xenografts, tuft cells were restricted to dysplastic well-differentiated mucinous cysts and were lost in less differentiated cancers. Taken together, tuft cell populations increased in atrophic human gastric pathologies, metaplasia, and dysplasia, but were decreased in gastric cancers. Similar findings were observed in mouse models, suggesting that, while tuft cells are associated with precancerous pathologies, their loss is most associated with the progression to invasive cancer.