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Biological treatment represents a fundamental component of wastewater treatment plants (WWTPs). The transmission of antibiotic resistance bacteria (ARB) and resistance genes (ARGs) occurred through the continuous migration and transformation, attributed to the residual presence of antibiotics in WWTPs effluent, posing a significant threat to the entire ecosystem. It is necessary to propose novel biological strategies to address the challenge of refractory contaminants, such as antibiotics, ARGs and ARB. This review summarizes the occurrence of antibiotics in wastewater, categorized by high and low concentrations. Additionally, current biological treatments used in WWTPs, such as aerobic activated sludge, anaerobic digestion, sequencing batch reactor (SBR), constructed wetland, membrane-related bioreactors and biological aerated filter (BAF) are introduced. In particular, because microorganisms are the key to those biological treatments, the effect of high and low concentration of antibiotics on microorganisms are thoroughly discussed. Finally, solutions involving functional bacteria, partial nitrification (PN)-Anammox and lysozyme embedding are suggested from the perspective of the entire biological treatment process. Overall, this review provides valuable insights for the simultaneous removal of antibiotics and ARGs in antibiotics wastewater.
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Postoperative atrial fibrillation (POAF) is a common complication following cardiac surgery, which often occurs within 30 postoperative days, especially peaking at 2-3 days. Antiarrhythmic medications such as amiodarone are recommended in clinical practice for the prophylaxis and treatment of POAF. However, conventional oral administration is hindered due to delayed drug action and high risks of systemic toxicity, and emerging localized delivery strategies suffer from a limited release duration (less than 30 days). Herein, we develop a microneedle (MN) patch for localized delivery of amiodarone to the atria in a "First Rapid and Then Sustained" dual-release mode. Specifically, this patch is composed of a needle array integrated with an amiodarone-loaded reservoir for a sustained and steady release for over 30 days; and an amiodarone-containing coating film deposited on the needle surface via the Langmuir-Blodgett technique for a rapid release at the first day. Upon this design, only one MN patch enables a higher drug accumulation in the atrial tissue at the first day than oral administration and simultaneously remains therapeutical levels for over 30 days, despite at a significantly reduced drug dosage (5.08 mg in total versus â¼10 mg per day), thereby achieving ideal preventive effects and safety in a rat model. Our findings indicate that this MN device provides a robust and efficient delivery platform for long-term prophylaxis of POAF.
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Fibrilação Atrial , Agulhas , Fibrilação Atrial/prevenção & controle , Fibrilação Atrial/tratamento farmacológico , Animais , Ratos , Ratos Sprague-Dawley , Amiodarona/administração & dosagem , Amiodarona/química , Antiarrítmicos/administração & dosagem , Antiarrítmicos/química , Antiarrítmicos/farmacologia , Masculino , Sistemas de Liberação de Medicamentos , Complicações Pós-Operatórias/prevenção & controleRESUMO
Infection and poor tissue repair are the key causes of percutaneous implantation failure. However, there is a lack of effective strategies to cope with due to its high requirements of sterilization, soft tissue healing, and osseointegration. In this work, l-arginine (L-Arg) was loaded onto a sulfonated polyetheretherketone (PEEK) surface to solve this issue. Under the infection condition, nitric oxide (NO) and reactive oxygen species (ROS) are produced through catalyzing L-Arg by inducible nitric oxide synthase (iNOS) and thus play a role in bacteria sterilization. Under the tissue repair condition, L-Arg is catalyzed to ornithine by Arginase-1 (Arg-1), which promotes the proliferation and collagen secretion of L929 and rBMSCs. Notably, L-Arg loading samples could polarize macrophages to M1 and M2 in infection and tissue repair conditions, respectively. The results in vivo show that the L-Arg loading samples could enhance infected soft tissue sealing and bone regeneration. In summary, L-Arg loading sulfonated PEEK could polarize macrophage through metabolic reprogramming, providing multi-functions of antibacterial abilities, soft tissue repair, and bone regeneration, which gives a new idea to design percutaneous implantation materials.
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Salvia miltiorrhiza Bge. (S. miltiorrhiza) is a well-known traditional Chinese medicine for the treatment of cardiovascular diseases. The processing of S. miltiorrhiza requires the raw herbs to sweat first and then dry. The aim of this study was to investigate the anti-acute myocardial ischemia (AMI) of S. miltiorrhiza extracts (including tanshinones and phenolic acids) before and after sweating, and to further explore whether the "sweating" primary processing affected the efficacy of S. miltiorrhiza. The AMI animal model was established by subcutaneous injection of isoprenaline hydrochloride (ISO). After treatment, the cardiac function of rats was evaluated by electrocardiogram (ECG), biochemical, and histochemical analysis. Moreover, the regulation of S. miltiorrhiza extracts on the peroxisome proliferator-activated receptor α (PPARα)/retinoid X receptor α (RXRα)/nuclear transcription factor-kappa B (NF-κB) signaling pathway of rats was assessed by the Western blotting. The results showed that sweated and non-sweated S. miltiorrhiza extracts including tanshinones and phenolic acids significantly reduced ST-segment elevation in ECG and the myocardial infarction area in varying degrees. Meanwhile, sweated and non-sweated S. miltiorrhiza reversed the activities of aspartate transaminase (AST), lactic dehydrogenase (LDH), creatine kinase-MB (CK-MB), and superoxide dismutase (SOD), as well as the levels of interleukin-6 (IL-6), interleukin-10 (IL-10), and tumor necrosis factor-α (TNF-α) in AMI rats. Concurrently, the results of Western blotting revealed that S. miltiorrhiza extracts regulated the PPARα/RXRα/NF-κB signaling pathway to exert an anti-inflammatory effect. Most importantly, sweated S. miltiorrhiza tanshinones extracts are more effective than the non-sweated S. miltiorrhiza, and the anti-inflammatory efficacy of tanshinones extract was also better than that of phenolic acid extract. Although phenolic acid extracts before and after sweating were effective in anti-AMI, there was no significant difference between them. In conclusion, both tanshinones and phenolic acids extracts of sweated and non-sweated S. miltiorrhiza promote anti-oxidative stress and anti-inflammatory against AMI via regulating the PPARα/RXRα/NF-κB signaling pathway. Further, the comparations between sweated and non-sweated S. miltiorrhiza extracts indicate that sweated S. miltiorrhiza tanshinones extracts have better therapeutic effects on AMI.
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In order to investigate the effects of strain rate and water saturation on the energy dissipation and crack growth of tuff, uniaxial compression tests were carried out on dry and water saturated tuff with different strain rates using an electro-hydraulic servo press and a 50 mm diameter split Hopkinson pressure rod (SHPB) device. High-speed camera and Image J image analysis software were used to obtain the crack growth process of the specimen under impact load, and fractal dimension was introduced to quantitatively study the crack growth degree. The results show that more than 90% of the energy is stored in the specimen as elastic energy when it reaches the peak stress under static load. The average total energy of water-saturated specimens is 67.55% of that of dry specimens. The average energy dissipation density of water-saturated specimens under 0.3 MPa, 0.4 MPa and 0.5 MPa air pressure is 0.79, 0.91 and 0.92 times of that of dry specimens, respectively. Water-saturated specimens will deteriorate and thus reduce their energy storage and energy absorption effects. The reflected energy, transmitted energy, absorbed energy and incident energy are linear, logarithmic and linear functions, respectively, and the energy absorptivity and specific energy absorptivity of water-saturated specimens are lower than those of dry specimens. Due to the existence of "stefan" effect, the increase of energy dissipation density of water-saturated specimen at high strain rate is greater than that of dry specimen. The mean fractal dimension of water-saturated specimens under 0.3 MPa, 0.4 MPa and 0.5 MPa is 1.09, 1.05 and 1.16 times that of dry specimens. At the same strain rate, the number and width of cracks in water-saturated specimens are larger than that in dry specimens. Water-saturated behavior reduces the energy absorption capacity of tuff, increases the fractal dimension of crack growth, and significantly reduces the resistance of water-saturated rock to external loads.
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The exploration of cell-based drug delivery systems for cancer therapy has gained growing attention. Approaches to engineering therapeutic cells with multidrug loading in an effective, safe, and precise manner while preserving their inherent biological properties remain of great interest. Here, we report a strategy to simultaneously load multiple drugs in platelets in a one-step fusion process. We demonstrate doxorubicin (DOX)-encapsulated liposomes conjugated with interleukin-15 (IL-15) could fuse with platelets to achieve both cytoplasmic drug loading and surface cytokine modification with a loading efficiency of over 70 % within minutes. Due to their inherent targeting ability to metastatic cancers and postoperative bleeding sites, the engineered platelets demonstrated a synergistic therapeutic effect to suppress lung metastasis and postoperative recurrence in mouse B16F10 melanoma tumor models.
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Pulmonary hypertension (PH) is a progressive fatal disease with no cure. Canagliflozin (CANA), a novel medication for diabetes, has been found to have remarkable cardiovascular benefits. However, few studies have addressed the effect and pharmacological mechanism of CANA in the treatment of PH. Therefore, our study aimed to investigate the effect and pharmacological mechanism of CANA in treating PH. First, CANA suppressed increased pulmonary artery pressure, right ventricular hypertrophy, and vascular remodeling in both mouse and rat PH models. Network pharmacology, transcriptomics, and biological results suggested that CANA could ameliorate PH by suppressing excessive oxidative stress and pulmonary artery smooth muscle cell proliferation partially through the activation of PPARγ. Further studies demonstrated that CANA inhibited phosphorylation of PPARγ at Ser225 (a novel serine phosphorylation site in PPARγ), thereby promoting the nuclear translocation of PPARγ and increasing its ability to resist oxidative stress and proliferation. Taken together, our study not only highlighted the potential pharmacological effect of CANA on PH but also revealed that CANA-induced inhibition of PPARγ Ser225 phosphorylation increases its capacity to counteract oxidative stress and inhibits proliferation. These findings may stimulate further research and encourage future clinical trials exploring the therapeutic potential of CANA in PH treatment.
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Canagliflozina , Proliferação de Células , Hipertensão Pulmonar , Estresse Oxidativo , PPAR gama , Animais , Masculino , Camundongos , Ratos , Canagliflozina/farmacologia , Canagliflozina/uso terapêutico , Proliferação de Células/efeitos dos fármacos , Hipertensão Pulmonar/tratamento farmacológico , Hipertensão Pulmonar/metabolismo , Camundongos Endogâmicos C57BL , Miócitos de Músculo Liso/efeitos dos fármacos , Miócitos de Músculo Liso/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Fosforilação/efeitos dos fármacos , PPAR gama/metabolismo , Artéria Pulmonar/efeitos dos fármacos , Artéria Pulmonar/metabolismo , Ratos Sprague-Dawley , Remodelação Vascular/efeitos dos fármacos , Serina/química , Serina/metabolismoRESUMO
Regulatory T cells (Tregs) are essential to the negative regulation of the immune system, as they avoid excessive inflammation and mediate tumor development. The abundance of Tregs in tumor tissues suggests that Tregs may be eliminated or functionally inhibited to stimulate antitumor immunity. However, immunotherapy targeting Tregs has been severely hampered by autoimmune diseases due to the systemic elimination of Tregs. Recently, emerging studies have shown that metabolic regulation can specifically target tumor-infiltrating immune cells, and lipid accumulation in TME is associated with immunosuppression. Nevertheless, how Tregs actively regulate metabolic reprogramming to outcompete effector T cells (Teffs), and how lipid metabolic reprogramming contributes to the immunomodulatory capacity of Tregs have not been fully discussed. This review will discuss the physiological processes by which lipid accumulation confers a metabolic advantage to tumor-infiltrating Tregs (TI-Tregs) and amplifies their immunosuppressive functions. Furthermore, we will provide a summary of the driving effects of various metabolic regulators on the metabolic reprogramming of Tregs. Finally, we propose that targeting the lipid metabolism of TI-Tregs could be efficacious either alone or in conjunction with immune checkpoint therapy.
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AIMS: Acute lung injury (ALI) is a life-threatening lung disease characterized by inflammatory cell infiltration and lung epithelial injury. Icariside II (ICS II), one of the main active ingredients of Herba Epimedii, exhibits anti-inflammatory and immunomodulatory effects. However, the effect and mechanism of ICS II in ALI remain unclear. The purpose of the current study was to investigate the pharmacological effect and underlying mechanism of ICS II in ALI. MAIN METHODS: Models of neutrophil-like cells, human peripheral blood neutrophils, and lipopolysaccharide (LPS)-induced ALI mouse model were utilized. RT-qPCR and Western blotting determined the gene and protein expression levels. Protein distribution and quantification were analyzed by immunofluorescence. KEY FINDINGS: ICS II significantly reduced lung histopathological damage, edema, and inflammatory cell infiltration, and it reduced pro-inflammatory cytokines in ALI. There is an excessive activation of neutrophils leading to a significant production of NETs in ALI mice, a process mitigated by the administration of ICS II. In vivo and in vitro studies found that ICS II could decrease NET formation by targeting neutrophil C-X-C chemokine receptor type 4 (CXCR4). Further data showed that ICS II reduces the overproduction of dsDNA, a NETs-related component, thereby suppressing cGAS/STING/NF-κB signalling pathway activation and inflammatory mediators release in lung epithelial cells. SIGNIFICANCE: This study suggested that ICS II may alleviate LPS-induced ALI by modulating the inflammatory response, indicating its potential as a therapeutic agent for ALI treatment.
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Lesão Pulmonar Aguda , Armadilhas Extracelulares , Flavonoides , Lipopolissacarídeos , Camundongos Endogâmicos C57BL , Neutrófilos , Lesão Pulmonar Aguda/tratamento farmacológico , Lesão Pulmonar Aguda/induzido quimicamente , Lesão Pulmonar Aguda/patologia , Lesão Pulmonar Aguda/metabolismo , Lesão Pulmonar Aguda/imunologia , Animais , Camundongos , Armadilhas Extracelulares/efeitos dos fármacos , Armadilhas Extracelulares/metabolismo , Humanos , Neutrófilos/efeitos dos fármacos , Neutrófilos/metabolismo , Neutrófilos/imunologia , Flavonoides/farmacologia , Masculino , Pulmão/patologia , Pulmão/efeitos dos fármacos , Pulmão/metabolismo , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Inflamação/patologia , Anti-Inflamatórios/farmacologiaRESUMO
BACKGROUND: Narrow-band imaging (NBI) endoscopy is used in various tumor detection and is important in detecting early tumors. OBJECTIVE: To explore the application value of NBI endoscopy in diagnosing pharyngeal tumors. MATERIAL AND METHODS: Ninety-one patients with pharyngeal masses who attended the Department of Otorhinolaryngology, Head and Neck Surgery in Gansu Provincial Hospital from January 2023 to February 2024 were selected, and NBI and white light (WL) endoscopy were applied to examine the pharynx and the relationship between the two was observed. SPSS 25.0 software was used for statistical analysis. RESULTS: The sensitivity of NBI endoscopy for diagnosing laryngeal malignant lesions was 92.0 %, the specificity was 93.0 %, the positive predictive value was 88.5 %, and the negative predictive value was 95.2 %, with a high degree of concordance between the results of NBI endoscopy and the pathology; WL endoscopy had a sensitivity of 64.0 %, a specificity of 76. 7 %, a positive predictive value of 61.5 %, and a negative predictive value of 78.6 %, with WL endoscopic findings had moderate concordance with pathology. The diagnostic accuracy of NBI endoscopy was higher than that of WL endoscopy for both benign and malignant lesions and precancerous lesions. CONCLUSION: NBI endoscopy can detect laryngeal cancer lesions more accurately.
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Endoscopia , Imagem de Banda Estreita , Neoplasias Faríngeas , Sensibilidade e Especificidade , Humanos , Imagem de Banda Estreita/métodos , Neoplasias Faríngeas/diagnóstico por imagem , Masculino , Feminino , Pessoa de Meia-Idade , Idoso , Adulto , Endoscopia/métodos , Valor Preditivo dos Testes , Idoso de 80 Anos ou mais , Neoplasias Laríngeas/diagnóstico por imagem , Neoplasias Laríngeas/patologiaRESUMO
Noncoding RNAs have been shown to play essential roles in hypoxic pulmonary hypertension (HPH). Our preliminary data showed that HPH is attenuated by fibroblast growth factor 21 (FGF21) administration. Therefore, we further investigated the whole transcriptome RNA expression patterns and interactions in a mice HPH model treated with FGF21. By whole-transcriptome sequencing, differentially expressed mRNAs, miRNAs, lncRNAs, and circRNAs were successfully identified in normoxia (Nx) vs. hypoxia (Hx) and Hx vs. hypoxia + FGF21 (Hx + F21). Differentially expressed mRNAs, miRNAs, lncRNAs, and circRNAs regulated by hypoxia and FGF21 were selected through intersection analysis. Based on prediction databases and sequencing data, differentially co-expressed mRNAs, miRNAs, lncRNAs, and circRNAs were further screened, followed by functional enrichment analysis. MAPK signaling pathway and epigenetic modification were enriched and may play fundamental roles in the therapeutic effects of FGF21. The ceRNA regulatory network of lncRNA-miRNA-mRNA and circRNA-miRNA-mRNA was constructed with miR-7a-5p, miR-449c-5p, miR-676-3p and miR-674-3p as the core. In addition, quantitative real-time PCR experiments were employed to verify the whole-transcriptome sequencing data. The results of luciferase reporter assays highlighted the relationship between miR-449c-5p and XR_878320.1, miR-449c-5p and Stab2, miR-449c-5p and circ_mtcp1, which suggesting that miR-449c-5p may be a key regulator of FGF21 in the treatment of PH. Taken together, this study provides potential biomarkers, pathways, and ceRNA regulatory networks in HPH treated with FGF21 and will provide an experimental basis for the clinical application of FGF21 in PH.
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Fatores de Crescimento de Fibroblastos , Hipertensão Pulmonar , RNA Endógeno Competitivo , Animais , Humanos , Masculino , Camundongos , Modelos Animais de Doenças , Fatores de Crescimento de Fibroblastos/uso terapêutico , Perfilação da Expressão Gênica , Redes Reguladoras de Genes , Hipertensão Pulmonar/genética , Hipertensão Pulmonar/tratamento farmacológico , Hipóxia/genética , Camundongos Endogâmicos C57BL , MicroRNAs/genética , RNA Circular/genética , RNA Endógeno Competitivo/genética , RNA Longo não Codificante/genética , RNA Mensageiro/genética , TranscriptomaRESUMO
Adavosertib (ADA) is a WEE1 inhibitor that exhibits a synthetic lethal effect on p53-mutated gallbladder cancer (GBC). However, drug resistance due to DNA damage response compensation pathways and high toxicity limits further applications. Herein, estrone-targeted ADA-encapsulated metal-organic frameworks (ADA@MOF-EPL) for GBC synthetic lethal treatment by inducing conditional factors are developed. The high expression of estrogen receptors in GBC enables ADA@MOF-EPL to quickly enter and accumulate near the cell nucleus through estrone-mediated endocytosis and release ADA to inhibit WEE1 upon entering the acidic tumor microenvironment. Ultrasound irradiation induces ADA@MOF-EPL to generate reactive oxygen species (ROS), which leads to a further increase in DNA damage, resulting in a higher sensitivity of p53-mutated cancer cells to WEE1 inhibitor and promoting cell death via conditional synthetic lethality. The conditional factor induced by ADA@MOF-EPL further enhances the antitumor efficacy while significantly reducing systemic toxicity. Moreover, ADA@MOF-EPL demonstrates similar antitumor abilities in other p53-mutated solid tumors, revealing its potential as a broad-spectrum antitumor drug.
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Antineoplásicos , Neoplasias da Vesícula Biliar , Estruturas Metalorgânicas , Proteínas Tirosina Quinases , Pirimidinonas , Proteína Supressora de Tumor p53 , Estruturas Metalorgânicas/química , Estruturas Metalorgânicas/farmacologia , Neoplasias da Vesícula Biliar/tratamento farmacológico , Neoplasias da Vesícula Biliar/genética , Neoplasias da Vesícula Biliar/patologia , Humanos , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismo , Animais , Linhagem Celular Tumoral , Proteínas Tirosina Quinases/antagonistas & inibidores , Camundongos , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Antineoplásicos/química , Pirazóis/farmacologia , Pirazóis/uso terapêutico , Proteínas de Ciclo Celular/antagonistas & inibidores , Proteínas de Ciclo Celular/metabolismo , Proteínas de Ciclo Celular/genética , Mutações Sintéticas Letais , Espécies Reativas de Oxigênio/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto , Mutação , Camundongos Nus , Dano ao DNA/efeitos dos fármacos , FemininoRESUMO
RATIONALE: Vacuum sealing drainage is a novel technique for wound treatment that is characterized by adequate drainage and promotes wound healing. We report a case in which negative pressure sealing drainage was applied to treat a deep cervical abscess and achieved a good therapeutic effect. PATIENT CONCERNS: The abscess in the neck will go down. DIAGNOSES: Deep neck abscess. INTERVENTIONS: The usual surgical approach to treating this condition is to make a small incision to incise and drain the patient infected area where it is most visibly swollen or fluctuating, and to place a negative pressure drainage device. OUTCOMES: Eleven days after the operation, the patient neck recovered well, there was no infection in the operation area, and the patient was discharged from the hospital with improved symptoms. LESSONS: This proves that the negative pressure closed drainage technique has potential in the treatment of deep neck abscesses and is also an effective choice in promoting wound healing, which is expected to bring better therapeutic effects to patients treated for deep neck abscesses.
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Tratamento de Ferimentos com Pressão Negativa , Humanos , Tratamento de Ferimentos com Pressão Negativa/métodos , Abscesso/cirurgia , Drenagem/métodos , Pescoço/cirurgia , Cicatrização , Resultado do TratamentoRESUMO
Two laboratory-level biological aerated filters (BAF) were constructed to explore their treatment capacity for simulated antibiotic wastewater at high (1 - 16 mg/L) and low (0 - 0.5 mg/L) concentrations. Results showed that BAF was capable of removing both sulfonamides and tetracyclines with an efficiency of over 90 % at 16 mg/L. The main mechanism for removing antibiotics was found to be biodegradation followed by adsorption. Paenarthrobacter was identified as the key genus in sulfonamides degradation, while Hydrogenophaga played a crucial role in tetracyclines degradation. Antibiotics resistant genes such as intI1, sul1, sul2, tetA, tetW and tetX were frequently detected in the effluent, with interception rates ranging from 105 - 106 copies/mL. The dominated microorganisms obtained in the study could potentially be utilized to enhance the capacity of biological processes for treating antibiotics contaminated wastewater. These findings contribute to a better understanding of BAF treating wastewater containing antibiotics and resistant genes.
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Antibacterianos , Águas Residuárias , Antibacterianos/farmacologia , Resistência Microbiana a Medicamentos/genética , Genes Bacterianos/genética , Tetraciclinas , Sulfonamidas , Eliminação de Resíduos LíquidosRESUMO
Biological nanotechnologies have provided considerable opportunities in the management of malignancies with delicate design and negligible toxicity, from preventive and diagnostic to therapeutic fields. Lipoproteins, because of their inherent blood-brain barrier permeability and lesion-homing capability, have been identified as promising strategies for high-performance theranostics of brain diseases. However, the application of natural lipoproteins remains limited owing to insufficient accumulation and complex purification processes, which can be critical for individual therapeutics and clinical translation. To address these issues, lipoprotein-inspired nano drug-delivery systems (nano-DDSs), which have been learned from nature, have been fabricated to achieve synergistic drug delivery involving site-specific accumulation and tractable preparation with versatile physicochemical functions. In this review, the barriers in brain disease treatment, advantages of state-of-the-art lipoprotein-inspired nano-DDSs, and bio-interactions of such nano-DDSs are highlighted. Furthermore, the characteristics and advanced applications of natural lipoproteins and tailor-made lipoprotein-inspired nano-DDSs are summarized. Specifically, the key designs and current applications of lipoprotein-inspired nano-DDSs in the field of brain disease therapy are intensively discussed. Finally, the current challenges and future perspectives in the field of lipoprotein-inspired nano-DDSs combined with other vehicles, such as exosomes, cell membranes, and bacteria, are discussed.
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Epstein-Barr virus (EBV) is a type of human γ-herpesvirus, and its reactivation plays an important role in the development of EBV-driven Burkitt lymphoma (BL). Despite intensive chemotherapy, the prognosis of relapsed/refractory BL patients remains unfavorable, and a definitive method to completely eliminate latent EBV infection is lacking. Previous studies have demonstrated that histone deacetylase (HDAC) inhibitors can induce the transition of EBV from latency to the lytic phase. The lytic activation of EBV can be inhibited by tenofovir, a potent inhibitor of DNA replication. Herein, we explored the antitumor effect and EBV clearance potential of a novel HDAC inhibitor called chidamide, combined with tenofovir, in the treatment of EBV-positive BL. In the study, chidamide exhibited inhibitory activity against HDAC. Moreover, chidamide inhibited BL cell proliferation, arrested cell cycle progression, and induced BL cell apoptosis primarily by regulating the MAPK pathways. Additionally, chidamide promoted the transcription of lytic genes, including BZLF1, BMRF1, and BMLF1 Compared with chidamide alone, the addition of tenofovir further induced growth arrest and apoptosis in EBV-positive BL cells and inhibited the transcriptions of EBV lytic genes induced by chidamide alone. Furthermore, our in vivo data demonstrated that the combination of chidamide and tenofovir had superior tumor-suppressive effects in a mouse model of BL cell tumors. The aforementioned findings confirm the synergistic effect of chidamide combined with tenofovir in inducing growth inhibition and apoptosis in EBV-positive BL cells and provide an effective strategy for eliminating EBV and EBV-associated malignancies. SIGNIFICANCE STATEMENT: High levels of Epstein-Barr virus (EBV)-DNA have consistently been associated with unfavorable progression-free survival and overall survival in EBV-associated lymphomas. Therefore, identifying novel strategies to effectively eradicate tumor cells and eliminate EBV is crucial for lymphoma patients. This study confirmed, for the first time, the synergistic effect of chidamide combined with tenofovir in the treatment of Burkitt lymphoma and the eradication of EBV virus.
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Linfoma de Burkitt , Infecções por Vírus Epstein-Barr , Linfoma , Animais , Camundongos , Humanos , Linfoma de Burkitt/tratamento farmacológico , Linfoma de Burkitt/metabolismo , Linfoma de Burkitt/patologia , Infecções por Vírus Epstein-Barr/complicações , Infecções por Vírus Epstein-Barr/tratamento farmacológico , Infecções por Vírus Epstein-Barr/metabolismo , Herpesvirus Humano 4/genética , Herpesvirus Humano 4/metabolismo , Tenofovir/farmacologia , Tenofovir/uso terapêutico , Tenofovir/metabolismo , Inibidores de Histona Desacetilases/farmacologia , Inibidores de Histona Desacetilases/uso terapêuticoRESUMO
Phototherapy of deep tumors still suffers from many obstacles, such as limited near-infrared (NIR) tissue penetration depth and low accumulation efficiency within the target sites. Herein, stimuli-sensitive tumor-targeted photodynamic nanoparticles (STPNs) with persistent luminescence for the treatment of deep tumors are reported. Purpurin 18 (Pu18), a porphyrin derivative, is utilized as a photosensitizer to produce persistent luminescence in STPNs, while lanthanide-doped upconversion nanoparticles (UCNPs) exhibit bioimaging properties and possess high photostability that can enhance photosensitizer efficacy. STPNs are initially stimulated by NIR irradiation before intravenous administration and accumulate at the tumor site to enter the cells through the HER2 receptor. Due to Pu18 afterglow luminescence properties, STPNs can continuously generate ROS to inhibit NFκB nuclear translocation, leading to tumor cell apoptosis. Moreover, STPNs can be used for diagnostic purposes through MRI and intraoperative NIR navigation. STPNs exceptional antitumor properties combined the advantages of UCNPs and persistent luminescence, representing a promising phototherapeutic strategy for deep tumors.
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Carcinoma in Situ , Neoplasias da Vesícula Biliar , Nanopartículas , Fotoquimioterapia , Humanos , Fármacos Fotossensibilizantes/farmacologia , Fármacos Fotossensibilizantes/uso terapêutico , LuminescênciaRESUMO
Subcutaneous (SC) injection is a common administration route for rapid and efficient delivery of biotherapeutics. However, syringe-based injections usually require professional assistance and are associated with pain and potential risks of infections, thus leading to undesired patient compliance and poor life quality. Herein, this work presents an ultrarapid-acting microneedle (URA-MN) patch for immediate transdermal delivery of therapeutics in a minimally invasive manner. Effervescent agents are incorporated into the tip of URA-MN for rapid generation of CO2 bubbles upon insertion into the skin, immediately powering the biotherapeutics release within a few minutes. The release kinetics of diverse agents including liraglutide (LRT), insulin, and heparin from the URA-MN patches are evaluated in three different mouse models, and the rapid release of biotherapeutics and potent therapeutic effects are achieved with only 5 min administration. Noteworthily, attributed to the short application duration and negligible residuals of MN matrix remaining in the skin, the URA-MN patch shows desirable biocompatibility after six-week administration.
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Sistemas de Liberação de Medicamentos , Pele , Animais , Camundongos , Humanos , Administração Cutânea , Insulina/uso terapêuticoRESUMO
An innovative optical frequency-domain reflectometry (OFDR)-based distributed temperature sensing method is proposed that utilizes a Rayleigh backscattering enhanced fiber (RBEF) as the sensing medium. The RBEF features randomly high backscattering points; the analysis of the fiber position shift of these points before and after the temperature change along the fiber is achieved using the sliding cross-correlation method. The fiber position and temperature variation can be accurately demodulated by calibrating the mathematical relationship between the high backscattering point position along the RBEF and the temperature variation. Experimental results reveal a linear relationship between temperature variation and the total position displacement of high backscattering points. The temperature sensing sensitivity coefficient is 7.814 µm/(m·°C), with an average relative error temperature measurement of -1.12% and positioning error as low as 0.02 m for the temperature-influenced fiber segment. In the proposed demodulation method, the spatial resolution of temperature sensing is determined by the distribution of high backscattering points. The temperature sensing resolution depends on the spatial resolution of the OFDR system and the length of the temperature-influenced fiber. With an OFDR system spatial resolution of 12.5 µm, the temperature sensing resolution reaches 0.418 °C per meter of RBEF under test.
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Dispositivos Ópticos , Temperatura , Sensação TérmicaRESUMO
BACKGROUND: The influencing factors, especially time to treatment (TTT), for T1b/T2 gallbladder cancer (GBC) patients remain unknown. We aimed to identify the influencing factors on survival and surgical approaches selection for T1b/T2 GBC. METHODS: We retrospectively screened GBC patients between January 2011 and August 2018 from our hospital. Clinical variables, including patient characteristics, TTT, overall survival (OS), disease-free survival (DFS), surgery-related outcomes, and surgical approaches were collected. RESULTS: A total of 114 T1b/T2 GBC patients who underwent radical resection were included. Based on the median TTT of 7.5 days, the study cohort was divided into short TTT group (TTT ≤7 days, n = 57) and long TTT group (TTT >7 days, n = 57). Referrals were identified as the primary factor prolonging TTT (p < 0.001). There was no significance in OS (p = 0.790), DFS (p = 0.580), and surgery-related outcomes (all p > 0.05) between both groups. Decreased referrals (p = 0.005), fewer positive lymph nodes (LNs; p = 0.004), and well tumor differentiation (p = 0.004) were all associated with better OS, while fewer positive LNs (p = 0.049) were associated with better DFS. Subgroup analyses revealed no significant difference in survival between patients undergoing laparoscopic or open approach in different TTT groups (all p > 0.05). And secondary subgroup analyses found no significance in survival and surgery-related outcomes between different TTT groups of incidental GBC patients (all p > 0.05). CONCLUSIONS: Positive LNs and tumor differentiation were prognostic factors for T1b/T2 GBC survival. Referrals associating with poor OS would delay TTT, while the prolonged TTT would not impact survival, surgery-related outcomes, and surgical approaches decisions in T1b/T2 GBC patients.