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Epstein-Barr virus (EBV) is a ubiquitous and oncogenic virus that is associated with various malignancies and non-malignant diseases and EBV DNA detection is widely used for the diagnosis and prognosis prediction for these diseases. The dried blood spots (DBS) sampling method holds great potential as an alternative to venous blood samples in geographically remote areas, for individuals with disabilities, or for newborn blood collection. Therefore, the objective of this study was to assess the viability of detecting EBV DNA load from DBS. Matched whole blood and DBS samples were collected for EBV DNA extraction and quantification detection. EBV DNA detection in DBS presented a specificity of 100 %. At different EBV DNA viral load in whole blood, the sensitivity of EBV DNA detection in DBS was 38.78 % (≥1 copies/mL), 43.18 % (≥500 copies/mL), 58.63 % (≥1000 copies/mL), 71.43 % (≥2000 copies/mL), 82.35 % (≥4000 copies/mL), and 92.86 % (≥5000 copies/mL), respectively. These results indicated that the sensitivity of EBV DNA detection in DBS increased with elevating viral load. Moreover, there was good correlation between EBV DNA levels measured in whole blood and DBS, and on average, the viral load measured in whole blood was about 6-fold higher than in DBS. Our research firstly demonstrated the feasibility of using DBS for qualitative and semi-quantitative detection of EBV DNA for diagnosis and surveillance of EBV-related diseases.
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PTP1B, a promising target for insulin sensitizers in type 2 diabetes treatment, can be effectively degraded using proteolysis-targeting chimera (PROTAC). This approach offers potential for long-acting antidiabetic agents. We report potent bifunctional PROTACs targeting PTP1B through the E3 ubiquitin ligase cereblon. Western blot analysis showed significant PTP1B degradation by PROTACs at concentrations from 5 nM to 5 µM after 48 h. Evaluation of five highly potent PROTACs revealed compound 75 with a longer PEG linker (23 atoms), displaying remarkable degradation activity after 48 and 72 h, with DC50 values of 250 nM and 50 nM, respectively. Compound 75 induced selective degradation of PTP1B, requiring engagement with both the target protein and CRBN E3 ligase, in a ubiquitination and proteasome-dependent manner. It significantly reduced blood glucose AUC0-2h to 29% in an oral glucose tolerance test and activated the IRS-1/PI3K/Akt signaling pathway in HepG2 cells, showing promise for long-term antidiabetic therapy.
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Hipoglicemiantes , Proteína Tirosina Fosfatase não Receptora Tipo 1 , Proteólise , Animais , Humanos , Camundongos , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Descoberta de Drogas , Células Hep G2 , Hipoglicemiantes/farmacologia , Hipoglicemiantes/química , Hipoglicemiantes/síntese química , Proteína Tirosina Fosfatase não Receptora Tipo 1/metabolismo , Proteína Tirosina Fosfatase não Receptora Tipo 1/antagonistas & inibidores , Proteólise/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Ubiquitina-Proteína Ligases/metabolismoRESUMO
Based on the neuroprotection of butylphthalide and donepezil, a series of indanone/benzofuranone and piperidine hybrids were designed and synthesized for assessment of their neuroprotective activities, aiming to enhance the bioavailability and therapeutic efficacy of natural phthalide analogues. Within this study, it was observed that most indanone derivatives bearing 1-methylpiperidine in the tail segment demonstrated superior neuroprotective effects on the oxygen glucose deprivation/reperfusion (OGD/R)-induced rat primary neuronal cell injury model in vitro compared to benzofuranone compounds. Among the synthesized compounds, 11 (4, 14, 15, 22, 26, 35, 36, 37, 48, 49, and 52) displayed robust cell viabilities in the OGD/R model, along with favorable blood-brain barrier permeability as confirmed by the parallel artificial membrane permeability assay. Notably, compound 4 showed significant neuronal cell viabilities within the concentration range of 3.125 to 100 µM, without inducing cytotoxicity. Further results from in vivo middle cerebral artery occlusion/R experiments revealed that 4 effectively ameliorated ischemia-reperfusion injury, reducing the infarct volume to 18.45% at a dose of 40 mg/kg. This outcome suggested a superior neuroprotective effect compared to edaravone at 20 mg/kg, further highlighting the potential therapeutic efficacy of compound 4 in addressing neurological disorders.
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Benzofuranos , Indanos , Fármacos Neuroprotetores , Piperidinas , Animais , Fármacos Neuroprotetores/farmacologia , Fármacos Neuroprotetores/síntese química , Piperidinas/farmacologia , Piperidinas/síntese química , Piperidinas/química , Indanos/farmacologia , Indanos/síntese química , Indanos/química , Benzofuranos/farmacologia , Benzofuranos/síntese química , Ratos , Ratos Sprague-Dawley , Traumatismo por Reperfusão/tratamento farmacológico , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Masculino , Sobrevivência Celular/efeitos dos fármacos , Barreira Hematoencefálica/efeitos dos fármacos , Barreira Hematoencefálica/metabolismo , Infarto da Artéria Cerebral Média/tratamento farmacológicoRESUMO
Systemic autoimmune diseases (SADs) are a growing spectrum of autoimmune disorders that commonly affect multiple organs. The role of Epstein-Barr virus (EBV) infection or reactivation as a trigger for the initiation and progression of SADs has been established, while the relationship between EBV envelope glycoproteins and SADs remains unclear. Here, we assessed the levels of IgG, IgA, and IgM against EBV glycoproteins (including gp350, gp42, gHgL, and gB) in serum samples obtained from patients with rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE), and found that RA and SLE patients exhibited a statistically significant increase in the levels of 8 and 11 glycoprotein antibodies, respectively, compared to healthy controls (p < 0.05). The LASSO model identified four factors as significant diagnostic markers for RA: gp350 IgG, gp350 IgA, gHgL IgM, and gp42 IgA; whereas for SLE it included gp350 IgG, gp350 IgA, gHgL IgA, and gp42 IgM. Combining these selected biomarkers yielded an area under the curve (AUC) of 0.749 for RA and 0.843 for SLE. We subsequently quantified the levels of autoantibodies associated with SADs in mouse sera following immunization with gp350. Remarkably, none of the tested autoantibody levels exhibited statistically significant alterations. Elevation of glycoprotein antibody concentration suggests that Epstein-Barr virus reactivation and replication occurred in SADs patients, potentially serving as a promising biomarker for diagnosing SADs. Moreover, the absence of cross-reactivity between gp350 antibodies and SADs-associated autoantigens indicates the safety profile of a vaccine based on gp350 antigen.
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Artrite Reumatoide , Doenças Autoimunes , Infecções por Vírus Epstein-Barr , Lúpus Eritematoso Sistêmico , Humanos , Animais , Camundongos , Infecções por Vírus Epstein-Barr/complicações , Herpesvirus Humano 4 , Anticorpos Antivirais , Artrite Reumatoide/complicações , Glicoproteínas , Doenças Autoimunes/complicações , Imunoglobulina G , Imunoglobulina A , Imunoglobulina MRESUMO
Neurodegenerative diseases (NDD) are characterized by the gradual deterioration of neuronal function and integrity, resulting in an overall decline in brain function. The existing therapeutic options for NDD, including Alzheimer's disease, Parkinson's disease, and Huntington's disease, fall short of meeting the clinical demand. A prominent pathological hallmark observed in numerous neurodegenerative disorders is the aggregation and misfolding of proteins both within and outside neurons. These abnormal proteins play a pivotal role in the pathogenesis of neurodegenerative diseases. Targeted degradation of irregular proteins offers a promising avenue for NDD treatment. Proteolysis-targeting chimeras (PROTACs) function via the ubiquitin-proteasome system and have emerged as a novel and efficacious approach in drug discovery. PROTACs can catalytically degrade "undruggable" proteins even at exceptionally low concentrations, allowing for precise quantitative control of aberrant protein levels. In this review, we present a compilation of reported PROTAC structures and their corresponding biological activities aimed at addressing NDD. Spanning from 2016 to present, this review provides an up-to-date overview of PROTAC-based therapeutic interventions. Currently, most protein degraders intended for NDD treatment remain in the preclinical research phase. Overcoming several challenges is imperative, including enhancing oral bioavailability and permeability across the blood-brain barrier, before these compounds can progress to clinical research or eventually reach the market. However, armed with an enhanced comprehension of the underlying pathological mechanisms and the emergence of innovative scaffolds for protein degraders, along with further structural optimization, we are confident that PROTAC possesses the potential to make substantial breakthroughs in the field of neurodegenerative diseases.
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Doenças Neurodegenerativas , Proteólise , Humanos , Doenças Neurodegenerativas/tratamento farmacológico , Doenças Neurodegenerativas/metabolismo , Proteólise/efeitos dos fármacos , Animais , Descoberta de Drogas , Estrutura Molecular , Quimera de Direcionamento de ProteóliseRESUMO
OBJECTIVE: An association exists between immune checkpoint inhibitors and hemophagocytic lymphohistiocytosis (HLH). Therefore, the main objective of this study was to collect data on this rare but potentially life-threatening immune-related adverse reaction to identify the medications that cause it, the clinical characteristics, and effective treatments. METHODS: Literature in English and Chinese on immune checkpoint inhibitors causing HLH published from August 2014 to March 2024 was analyzed. Immune checkpoint inhibitors, immunotherapy, anti-PD-1, PD-L1 inhibitors, HLH, hemophagocytic lymphohistiocytosis, hemophagocytic syndrome keywords were used to find the literature on China Knowledge Network, Wanfang, PubMed and Emabase Databases. RESULTS AND DISCUSSION: Twenty-four studies were included, with a total of 27 patients (18 males and 9 females) with a mean age of 58 years (range 26-86). The mean time to the onset of symptoms was 10.3 weeks (7 days-14 months). The main clinical characteristics were fever, cytopenia, splenomegaly, methemoglobinemia, hypofibrinogenemia, and bone marrow biopsy showed phagocytosis. Twenty-two patients improved after the treatment with steroids, cytokine blocking therapy and symptomatic treatment, four patients died, and one patient was not described. CONCLUSION: HLH should be not underestimated as a potentially serious adverse effect of immune checkpoint inhibitors since appropriate treatments may save the life of patients.
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Linfo-Histiocitose Hemofagocítica , Masculino , Feminino , Humanos , Adulto , Pessoa de Meia-Idade , Idoso , Idoso de 80 Anos ou mais , Linfo-Histiocitose Hemofagocítica/induzido quimicamente , Linfo-Histiocitose Hemofagocítica/diagnóstico , Inibidores de Checkpoint Imunológico/efeitos adversos , Biópsia , Medula Óssea/patologia , ImunoterapiaRESUMO
Chromosomal translocation serves as a crucial diagnostic marker in the classification of acute myeloid leukemia. Among the most prevalent cytogenetic abnormalities is t(8;21)(q22;q22), typically associated with the FAB subtype AML-M2. On occasion, alternative forms of t(8;21) have been observed. This report presents a case of AML with RUNX1::RUNX1T1, wherein the karyotype revealed t(2;2;21;8)(p21;q37;q22;q22), representing the first instance of a variant t(8;21) involving both chromosomes 2. The combination of routine karyotype analysis and fluorescence in situ hybridization proves to be an effective method for identifying complex translocations of t(8;21).
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Cromossomos Humanos Par 21 , Cromossomos Humanos Par 8 , Subunidade alfa 2 de Fator de Ligação ao Core , Leucemia Mieloide Aguda , Translocação Genética , Humanos , Leucemia Mieloide Aguda/genética , Cromossomos Humanos Par 21/genética , Cromossomos Humanos Par 8/genética , Subunidade alfa 2 de Fator de Ligação ao Core/genética , Hibridização in Situ Fluorescente , Masculino , Cromossomos Humanos Par 2/genética , Proteína 1 Parceira de Translocação de RUNX1/genética , Cariotipagem , Feminino , Adulto , Proteínas de Fusão Oncogênica/genéticaRESUMO
Alzheimer's disease (AD) is a multifactorial neurological disease, and the multitarget directed ligand (MTDL) strategy may be an effective approach to delay its progression. Based on this strategy, 27 derivatives of l-tryptophan, 3a-1-3d-1, were designed, synthesized, and evaluated for their biological activity. Among them, IC50 (inhibitor concentration resulting in 50% inhibitory activity) values of compounds 3a-18 and 3b-1 were 0.58 and 0.44 µM for human serum butyrylcholinesterase (hBuChE), respectively, and both of them exhibited more than 30-fold selectivity for human serum acetylcholinesterase. Enzyme kinetics studies showed that these two compounds were mixed inhibitors of hBuChE. In addition, these two derivatives possessed extraordinary antioxidant activity in OH radical scavenging and oxygen radical absorption capacity fluorescein assays. Meanwhile, these compounds could also prevent ß-amyloid (Aß) self-aggregation and possessed low toxicity on PC12 and AML12 cells. Molecular modeling studies revealed that these two compounds could interact with the choline binding site, acetyl binding site, and peripheral anionic site to exert submicromolar BuChE inhibitory activity. In the vitro blood-brain barrier permeation assay, compounds 3a-18 and 3b-1 showed enough blood-brain barrier permeability. In drug-likeness prediction, compounds 3a-18 and 3b-1 showed good gastrointestinal absorption and a low risk of human ether-a-go-go-related gene toxicity. Therefore, compounds 3a-18 and 3b-1 are potential multitarget anti-AD lead compounds, which could work as powerful antioxidants with submicromolar selective inhibitory activity for hBuChE as well as prevent Aß self-aggregation.
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Acetilcolinesterase , Doença de Alzheimer , Peptídeos beta-Amiloides , Antioxidantes , Barreira Hematoencefálica , Butirilcolinesterase , Inibidores da Colinesterase , Desenho de Fármacos , Triptofano , Doença de Alzheimer/tratamento farmacológico , Humanos , Antioxidantes/farmacologia , Antioxidantes/síntese química , Antioxidantes/química , Inibidores da Colinesterase/farmacologia , Inibidores da Colinesterase/síntese química , Inibidores da Colinesterase/química , Relação Estrutura-Atividade , Barreira Hematoencefálica/metabolismo , Butirilcolinesterase/metabolismo , Animais , Triptofano/farmacologia , Triptofano/química , Triptofano/análogos & derivados , Triptofano/síntese química , Peptídeos beta-Amiloides/antagonistas & inibidores , Peptídeos beta-Amiloides/metabolismo , Ratos , Acetilcolinesterase/metabolismo , Estrutura Molecular , Células PC12 , Relação Dose-Resposta a Droga , Modelos MolecularesRESUMO
BACKGROUND: The association between triglyceride-glucose (TyG) index and poor prognosis remains controversial. Whether renal function status affects the ability of the TyG index to predict poor prognosis has not yet been elucidated and merits further studies. METHODS: This retrospective cohort study included 22,031 participants from communities in the U.S. By juxtaposing the TyG categories with the estimated glomerular filtration rate (eGFR, either < 60 mL/min/1.73m2 or ≥ 60 mL/min/1.73m2), participants were categorized into four distinct groups: (1) TyG_L/eGFR_H; (2) TyG_H/eGFR_H; (3) TyG_L/eGFR_L; and (4) TyG_H/eGFR_L. The endpoint was the all-cause mortality rate. Standard Kaplan-Meier plots were constructed and multifactor Cox regression analyses were carried out and restricted cubic spline regression analysis was utilized to assess the association between death and the TyG index for different renal function statuses. RESULTS: No statistical differences were found in the TyG groups in participants with normal renal function after adjustment for all covariates (P = 0.070). However, in the high TyG index group with renal insufficiency, the risk of all-cause mortality rates was reduced by 18%. (HR, 0.82; CI, 0.69-0.98). The TyG index (high vs. low) and renal function (eGFR < 60 vs. eGFR ≥ 60) had statistically significant interactions with death (P < 0.001). When all covariates were adjusted, the risk of mortality for the TyG_L combined with eGFR_L group was 56% higher than that for the TyG_L combined with eGFR_H group (HR, 1.56; CI, 1.33-1.82). In the renal insufficiency population, a nonlinear relationship was observed between mortality and the TyG index, albeit with a differing pattern (P for nonlinearity < 0.001). CONCLUSIONS: While it has been known that TyG index was a prognosis marker of CVD, this research highlights that higher TyG index was associated with higher all-cause mortality rates for all participants. Furthermore, renal function status significantly moderates the effect of the TyG index on all-cause mortality in community-dwelling adults.
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Glucose , Insuficiência Renal , Adulto , Humanos , Estudos Retrospectivos , Triglicerídeos , Rim/fisiologia , Glicemia , Fatores de Risco , BiomarcadoresRESUMO
The objective of this study was to investigate the anticancer activities of biodegradable polymeric micelles composed of monomethoxy poly(ethylene glycol), polylactic acid, and nitric oxide (mPEG-PLA-NO) loaded with paclitaxel (PTX) as a nanomedicine delivery system. We aimed to compare the anticancer effects of these NO/PTX micelles with PTX alone and elucidate their mechanism of action. We evaluated the impact of NO/PTX and PTX on cell viability using Cell Counting Kit-8 (CCK8) assays conducted on the Bel-7402 liver cancer cell line. Additionally, we employed H22 xenografted mice to assess the in vivo tumor growth inhibitory activity of NO/PTX. To examine the cytotoxicity of NO/PTX, the intracellular levels of reactive oxygen species (ROS), and the expression of ferroptosis-related proteins, we conducted experiments in the presence of the ferroptosis inhibitor ferrostatin-1 (Fer-1) or the ROS inhibitor N-acetyl cysteine (NAC). Furthermore, we investigated the expression of endoplasmic reticulum stress (ERS) and apoptosis-associated proteins. Our results demonstrated that NO/PTX exhibited enhanced anticancer effects compared to PTX alone in both Bel-7402 cells and H22 xenografted mice. The addition of Fer-1 or NAC reduced the anticancer activity of NO/PTX, indicating the involvement of ferroptosis and ROS in its mechanism of action. Furthermore, NO/PTX modulated the expression of proteins related to ERS and apoptosis, indicating the activation of these cellular pathways. The anticancer effects of NO/PTX in liver cancer cells were mediated through the induction of ferroptosis, pyroptosis, ERS, and apoptosis-associated networks. Ferroptosis and pyroptosis were activated by treatment of NO/PTX at low concentration, whereas ERS was induced to trigger apoptosis at high concentration. The superior anti-tumor effect of NO/PTX may be attributed to the downregulation of a multidrug resistance transporter and the sensitization of cells to PTX chemotherapy. In summary, our study highlights the potential of mPEG-PLA-NO micelles loaded with PTX as a nanomedicine delivery system for liver cancer treatment. The observed enhancement in anticancer activity, combined with the modulation of key cellular pathways, provides valuable insights into the therapeutic potential of NO/PTX in overcoming resistance and improving treatment outcomes in liver cancer patients.
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[This corrects the article DOI: 10.1039/D3RA04861F.].
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OBJECTIVE: This multicenter study was designed to evaluate the relationship between preablation thyroglobulin antibody (TgAb) positivity and clinical outcomes in pediatric patients with papillary thyroid carcinoma (PTC). METHODS: In the period 2005-2020, all consecutive PTC patients 18 years or younger who underwent total thyroidectomy and radioiodine ablation at 3 tertiary hospitals in southwestern China were retrospectively included. Thyroglobulin antibody was measured before remnant ablation. Tumor characteristics and long-term outcomes were compared between TgAb-positive and TgAb-negative patients. RESULTS: One hundred thirty-two patients were analyzed. Preablation TgAb positivity was presented in 37.1% of patients. Tumor characteristics, lymph node metastases, and median duration of follow-up were similar between TgAb-positive and -negative patients. During follow-up, the percentage of patients with either surgical reintervention for lymph node metastases (4.1% vs 4.8%, P = 1.000) or repeated 131 I therapy (14.3% vs 20.5%, P = 0.373) was similar between TgAb-positive and -negative patients. At the final follow-up visit, the rates of structural disease did not differ between the 2 groups (6.1% vs 4.8%, P = 0.710). CONCLUSIONS: This multicentric study highlights no association of preablation TgAb positivity and clinical outcome in pediatric patients with PTC.
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Carcinoma Papilar , Neoplasias da Glândula Tireoide , Humanos , Criança , Câncer Papilífero da Tireoide/cirurgia , Tireoglobulina , Neoplasias da Glândula Tireoide/radioterapia , Neoplasias da Glândula Tireoide/cirurgia , Estudos Retrospectivos , Radioisótopos do Iodo/uso terapêutico , Metástase Linfática , Prognóstico , Carcinoma Papilar/patologia , Tireoidectomia , AutoanticorposRESUMO
OBJECTIVE: To investigate the association of multifocality with clinical outcomes in pediatric papillary thyroid cancer. STUDY DESIGN: Multicenter retrospective study of prospectively collected data. SETTING: Tertiary referral center. METHODS: This study included patients 18 years or younger who underwent total thyroidectomy and radioiodine ablation for papillary thyroid carcinoma (PTC) between 2005 and 2020 at 3 tertiary adult and pediatric hospitals in China. For disease-free survival (DFS), events were defined as persistent and/or recurrent diseases. The primary outcome was the association of tumor multifocality and DFS, assessed using Cox proportional hazards regression models. RESULTS: One hundred and seventy-three patients (median age 16 years [range, 5-18 years]) were recruited. Multifocal diseases were seen in 59 patients (34.1%). After a median follow-up of 57 (range, 12-193 months) months, 63 (36.4%) patients had persistent diseases. There was a significant association between tumor multifocality and decreased DFS on univariable analysis (hazard ratio [HR] = 1.90, p = .01), yet it was nonsignificant after multivariate adjustment (HR = 1.20, p = .55). In a subgroup analysis of 132 pediatric patients with clinically M0 PTC, neither unadjusted HR (2.21, p = .06) nor adjusted HR (1.70, p = .27) of multifocal PTC was significantly higher in comparison to unifocal PTC. CONCLUSION: In this highly selective surgical pediatric patient cohort with PTC, tumor multifocality was not an independent risk factor for decreased DFS.
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Carcinoma Papilar , Neoplasias da Glândula Tireoide , Adulto , Humanos , Criança , Adolescente , Câncer Papilífero da Tireoide/cirurgia , Câncer Papilífero da Tireoide/patologia , Prognóstico , Neoplasias da Glândula Tireoide/patologia , Estudos Retrospectivos , Radioisótopos do Iodo , Carcinoma Papilar/cirurgia , Carcinoma Papilar/patologia , Tireoidectomia , Fatores de Risco , Recidiva Local de Neoplasia/patologiaRESUMO
INTRODUCTION: Nasopharyngeal carcinoma (NPC) responds well to radiotherapy but recurrence and metastasis are common. Currently, there is no widely used biomarker for accurately predicting the recurrence and metastasis of NPC. In this study, we aimed to evaluate the prognostic ability of Epstein-Barr virus (EBV) capsid antigen (VCA-IgA) kinetics by assessing the dynamic changes of VCA-IgA levels in the pre- and post-treatment plasma of patients with NPC and have proposed a prognostic model for clinical use. METHODS: The clinical records of patients with NPC diagnosed at Sun Yat-sen University Cancer Center were retrieved and classified into a respondent (n = 83) or non-respondent (n = 25) cohort based on their response to antitumor therapy. Factors associated with the outcomes of the patients were assessed and incorporated in a nomogram. For internal validation, bootstrapping with 1000 resamples was used. The prediction accuracy and discriminative ability of the nomogram were investigated by calibration and concordance index (C-index) and plotted decision curves to assess the benefits of nomogram-assisted decisions in a clinical context. RESULTS: Plasma VCA-IgA level of the non-respondent cohort at the 6th month after treatment was found significantly higher than the respondent cohort. Post-treatment VCA-IgA level, smoking, and distant metastases were identified as independent risk factors for disease-free survival (DFS), and were used to stratify patients with NPC into three risk groups. The median DFS of the low-, middle- and high-risk groups were 48.5, 35.0, and 15.5 months, respectively. The C-index of the nomogram was 0.848 (95% CI 0.769-0.926), demonstrating good clinical accuracy for predicting the DFS of patients with NPC. The decision curve showed that the nomogram in predicting DFS was better than VCA-IgA level, smoking, and distant metastases. CONCLUSION: The proposed VCA-IgA-based nomogram demonstrated a promising ability to predict the DFS of patients with NPC after antitumor therapy. It could be used as a clinical guidance to improve the therapeutic/surveillance strategies of these patients.
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Infecções por Vírus Epstein-Barr , Neoplasias Nasofaríngeas , Humanos , Carcinoma Nasofaríngeo/terapia , Carcinoma Nasofaríngeo/diagnóstico , Infecções por Vírus Epstein-Barr/complicações , Neoplasias Nasofaríngeas/terapia , Neoplasias Nasofaríngeas/diagnóstico , Herpesvirus Humano 4 , Imunoglobulina ARESUMO
There are no highly effective and safe medicines for clinical treatment of ischemic stroke, although the natural product 3-n-butylphthalide (NBP) has been approved in China for mild and moderate ischemic stroke. To discover more potent anti-cerebral ischemic agents and overcome the low stability by phthalide derivatives, benzofuran-3-one was selected as a core moiety and two types of nitric oxide (NO)-donating groups were incorporated into the structure. In this work, a series of 2,6-disubstituted benzofuran-3-one derivatives were designed and synthesised as NBP analogues, and tested as neuroprotective and antioxidative agents. Compounds 5 (without an NO donor) and 16 (with an NO donor) displayed more potent neuroprotective effects than the established clinical drugs Edaravone and NBP. More importantly, 5 and 16 also exhibited good antioxidative activity without cytotoxicity in rat primary neuronal and PC12 cells. Most active compounds showed good blood-brain barrier permeability in a parallel artificial membrane permeability assay. Furthermore, compound 5 reduced the ischemic infarct area significantly in rats subjected to ischemia/reperfusion injury, downregulated ionised calcium-binding adaptor molecule 1 and glial fibrillary acidic protein in inflammatory cells, and upregulated nerve growth factor.
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Benzofuranos , Isquemia Encefálica , AVC Isquêmico , Fármacos Neuroprotetores , Traumatismo por Reperfusão , Ratos , Animais , Antioxidantes/química , Fármacos Neuroprotetores/farmacologia , Fármacos Neuroprotetores/uso terapêutico , Fármacos Neuroprotetores/química , Traumatismo por Reperfusão/tratamento farmacológico , Isquemia Encefálica/tratamento farmacológico , AVC Isquêmico/tratamento farmacológico , Benzofuranos/farmacologia , Benzofuranos/uso terapêutico , Benzofuranos/químicaRESUMO
Introduction: Helicobacter pylori (H.pylori, Hp) affects billions of people worldwide. However, the emerging resistance of Hp to antibiotics challenges the effectiveness of current treatments. Investigating the genotype-phenotype connection for Hp using next-generation sequencing could enhance our understanding of this resistance. Methods: In this study, we analyzed 52 Hp strains collected from various hospitals. The susceptibility of these strains to five antibiotics was assessed using the agar dilution assay. Whole-genome sequencing was then performed to screen the antimicrobial resistance (AMR) genotypes of these Hp strains. To model the relationship between drug resistance and genotype, we employed univariate statistical tests, unsupervised machine learning, and supervised machine learning techniques, including the development of support vector machine models. Results: Our models for predicting Amoxicillin resistance demonstrated 66% sensitivity and 100% specificity, while those for Clarithromycin resistance showed 100% sensitivity and 100% specificity. These results outperformed the known resistance sites for Amoxicillin (A1834G) and Clarithromycin (A2147), which had sensitivities of 22.2% and 87%, and specificities of 100% and 96%, respectively. Discussion: Our study demonstrates that predictive modeling using supervised learning algorithms with feature selection can yield diagnostic models with higher predictive power compared to models relying on single single-nucleotide polymorphism (SNP) sites. This approach significantly contributes to enhancing the precision and effectiveness of antibiotic treatment strategies for Hp infections. The application of whole-genome sequencing for Hp presents a promising pathway for advancing personalized medicine in this context.
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Infecções por Helicobacter , Helicobacter pylori , Humanos , Claritromicina/farmacologia , Claritromicina/uso terapêutico , Infecções por Helicobacter/tratamento farmacológico , Infecções por Helicobacter/genética , Helicobacter pylori/genética , Antibacterianos/farmacologia , Antibacterianos/uso terapêutico , Amoxicilina/farmacologia , Amoxicilina/uso terapêutico , Resistência Microbiana a Medicamentos , Aprendizado de Máquina , Sequenciamento Completo do Genoma , Farmacorresistência Bacteriana/genética , Testes de Sensibilidade MicrobianaRESUMO
Chemotherapy-induced thrombocytopenia (CIT) is a severe complication in patients with cancer that can lead to impaired therapeutic outcome and survival. Clinically, therapeutic options for CIT are limited by severe adverse effects and high economic burdens. Here, we demonstrate that ketogenic diets alleviate CIT in both animals and humans without causing thrombocytosis. Mechanistically, ketogenic diet-induced circulating ß-hydroxybutyrate (ß-OHB) increased histone H3 acetylation in bone marrow megakaryocytes. Gain- and loss-of-function experiments revealed a distinct role of 3-ß-hydroxybutyrate dehydrogenase (BDH)-mediated ketone body metabolism in promoting histone acetylation, which promoted the transcription of platelet biogenesis genes and induced thrombocytopoiesis. Genetic depletion of the megakaryocyte-specific ketone body transporter monocarboxylate transporter 1 (MCT1) or pharmacological targeting of MCT1 blocked ß-OHB-induced thrombocytopoiesis in mice. A ketogenesis-promoting diet alleviated CIT in mouse models. Moreover, a ketogenic diet modestly increased platelet counts without causing thrombocytosis in healthy volunteers, and a ketogenic lifestyle inversely correlated with CIT in patients with cancer. Together, we provide mechanistic insights into a ketone body-MCT1-BDH-histone acetylation-platelet biogenesis axis in megakaryocytes and propose a nontoxic, low-cost dietary intervention for combating CIT.
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Antineoplásicos , Trombocitopenia , Trombocitose , Humanos , Camundongos , Animais , Megacariócitos , Acetilação , Histonas , Trombocitopenia/induzido quimicamente , Corpos Cetônicos , Dieta , Ácido 3-HidroxibutíricoRESUMO
BACKGROUND: HIV drug resistance increased with the widespread use of antiretroviral drugs, and posed great threat to antiretroviral therapy (ART). Pu'er Prefecture, lying in the southwest of Yunnan Province, China, borders Myanmar, Laos and Vietnam, is also the area where AIDS was discovered earlier, however, in which there has been no information on HIV drug resistance. METHODS: A cross-sectional survey of pretreatment drug resistance (PDR) was conducted in Pu'er Prefecture in 2021. Partial pol gene sequences were obtained to analyze drug resistance and construct genetic transmission network. HIV drug resistance was analyzed using the Stanford University HIVdb algorithm. RESULTS: A total of 295 sequences were obtained, among which 11 HIV-1 strain types were detected and CRF08_BC (62.0%, 183/295) was the predominant one. Drug resistance mutations (DRMs) were detected in 42.4% (125/295) of the sequences. The prevalence of PDR to any antiretroviral drugs, nucleoside reverse transcriptase inhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs) and protease inhibitors (PIs) were 10.8% (32/295), 9.5% (28/295), 1.0% (3/295) and 0.3% (1/295), respectively. The risk of PDR occurrence was higher among individuals with CRF01_AE strain types. HIV-1 molecular network was constructed, in which 56.0% (42/75) of links were transregional, and 54.7% (41/75) of links were associated with Lancang County. Among the sequences in the network, 36.8% (35/95) harbored DRMs, and 9.5% (9/95) were drug resistance strains. Furthermore, 8 clusters had shared DRM. CONCLUSION: The overall prevalence of PDR in this study was in a moderate level, but NNRTIs resistance was very approaching to the threshold of public response initiation. PDR was identified in the transmission network, and DRMs transmission was observed. These findings suggested that the consecutive PDR surveillance should be conducted in this region.
Assuntos
Fármacos Anti-HIV , Infecções por HIV , Soropositividade para HIV , HIV-1 , Fármacos Anti-HIV/farmacologia , Fármacos Anti-HIV/uso terapêutico , Antirretrovirais/uso terapêutico , China/epidemiologia , Estudos Transversais , Farmacorresistência Viral/genética , Genótipo , Infecções por HIV/tratamento farmacológico , Infecções por HIV/epidemiologia , Soropositividade para HIV/tratamento farmacológico , HIV-1/genética , Humanos , Inibidores de Proteases/uso terapêutico , Inibidores da Transcriptase Reversa/uso terapêuticoRESUMO
While biogenic Mn oxides (BioMnOx) generated by Mn(II)-oxidizing bacteria (MOB) have attracted increasing attention, a MOB strain isolated from Mn-polluted sediments was identified and assigned as Enterobacter hormaechei DS02Eh01. Its Mn(II) immobilization activity, plant growth-promoting traits, and biofilm formation capability were investigated. The results showed that strain DS02Eh01 was found to be able to tolerate Mn(II) up to 122 mM. The strain immobilized Mn(II) in aquatic media mainly through extracellular adsorption, bio-oxidation and pH-induced precipitation as well as manganese oxidation. DS02Eh01-derived BioMnOx are negatively charged and have a larger specific surface area (86.70 m2/g) compared to the previously reported BioMnOx. The strain can immobilize Mn(II) at extreme levels, for instance, when it was exposed to 20 mM Mn(II), about 59% of Mn(II) were found immobilized and 17% of Mn(II) were converted to MnOx. The SEM and TEM observation revealed that the DS02Eh01-derived BioMnOx were aggregates doped with granules and microbial pellets. The precipitated Mn(II) and the Mn(III)/Mn(IV) oxides co-existed in BioMnOx, in which Mn(II) and Mn(IV) were found dominant with Mn(II) accounting for 49.6% and Mn(IV) accounting for 41.3%. DS02Eh01 possesses plant growth-promoting traits and biofilm formation capacity even under Mn(II) exposure. Mn(II) exposure at 5 mM was found to stimulate strain DS02Eh01 to form biofilms, from which, the extracted EPS was mainly composed of aromatic proteins. This study reveals that E. hormaechei strain DS02Eh01 possesses the potential in environmental ecoremediation via coupling processes of macrophytes extraction, biochemical immobilization and biosorption.
Assuntos
Compostos de Manganês , Manganês , Biofilmes , Enterobacter/metabolismo , Manganês/metabolismo , Oxirredução , Óxidos/metabolismoRESUMO
OBJECTIVE: Rheumatoid arthritis (RA) is mainly characterized by synovial hyperplasia, angiogenesis, inflammatory cells infiltration. Chymotrypsin is a proteolytic enzyme with anti-inflammatory effects. The current project was intended to test the efficacy and mechanism of chymotrypsin in adjuvant-induced arthritis (AIA) rats to provide an experimental basis for the clinical application of chymotrypsin. METHODS: Sprague-Dawley rats were injected with complete Freund's adjuvant (CFA) in the hind left paw pad to establish an AIA model. Forty rats were randomly divided into five groups (n = 8): blank; CFA model (model); low-dose chymotrypsin (CLD), 0.53 mg/kg; high-dose chymotrypsin (CHD), 1.06 mg/kg; piroxicam, 10 mg/kg. The treatments were performed in the subplantar region of the left hind paw from Day 8 (D8) to Day 28 after adjuvant injection. The body weight, paw diameter, swelling degree of paw, and arthritic score were measured on D0, D7, D14, D21, and D28. All animals were sacrificed on D29. Subsequently, the synovial tissue of the ankle joint of the rats was stained with HE to generate pathological sections for observation of the pathological changes of synovial tissue from the ankle joint. The protein levels of MMP-1, TNF-α, IL-1ß, and IL-6 in the rats' serum were determined by ELISA. Western blotting was used to detect the protein expression of TLR4 and NF-κB in the rat ankle tissue. The mRNA expression of TLR4, NF-κB, IL-1ß, IL-6, and TNF-α in synovial tissue of the ankle joint was detected by RT-qPCR. RESULTS: The body weight of the rats in each group showed an increasing trend, and there was no significant difference in weight between the groups. CHD and piroxicam suppressed paw swelling and arthritic scores and decreased synovial hyperplasia, inflammatory cell infiltration, pannus formation, and bone destruction. Furthermore, the overproduction of MMP-1, TNF-α, IL-1ß, and IL-6 in serum was remarkably attenuated in the chymotrypsin- and piroxicam-treated rats. The protein levels of TLR4 and NF-κB in the synovial tissue of the chymotrypsin group and the piroxicam group were significantly lower than those in the model group. Likewise, the rats treated with chymotrypsin and piroxicam had a substantial decline in the mRNA expression of TLR4, NF-κB, TNF-α, IL-1ß, and IL-6 in synovial tissue. CONCLUSIONS: Chymotrypsin alleviates the joint damage of AIA rats, probably by reducing the expression of MMP-1, TNF-α, IL-1ß, and IL-6 through TLR4/NF-κB signaling pathway.