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Anaplastic thyroid cancer (ATC) is among the most aggressive and metastatic malignancies, often resulting in fatal outcomes due to the lack of effective treatments. Prosapogenin A (PA), a bioactive compound prevalent in traditional Chinese herbs, has shown potential as an antineoplastic agent against various human tumors. However, its effects on ATC and the underlying mechanism remain unclear. Here, we demonstrate that PA exhibits significant anti-ATC activity both in vitro and in vivo by inducing GSDME-dependent pyroptosis in ATC cells. Mechanistically, PA promotes lysosomal membrane permeabilization (LMP), leading to the release of cathepsins that activate caspase 8/3 to cleave GSDME. Remarkably, PA significantly upregulates three key functional subunits of V-ATPase-ATP6V1A, ATP6V1B2, and ATP6V0C-resulting in lysosomal over-acidification. This over-acidification exacerbates LMP and subsequent lysosomal damage. Neutralization of lysosomal lumen acidification or inhibition/knockdown of these V-ATPase subunits attenuates PA-induced lysosomal damage, pyroptosis and growth inhibition of ATC cells, highlighting the critical role for lysosomal acidification and LMP in PA's anticancer effects. In summary, our findings uncover a novel link between PA and lysosomal damage-dependent pyroptosis in cancer cells. PA may act as a V-ATPase agonist targeting lysosomal acidification, presenting a new potential therapeutic option for ATC treatment.
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Lisossomos , Piroptose , Carcinoma Anaplásico da Tireoide , ATPases Vacuolares Próton-Translocadoras , Lisossomos/metabolismo , Lisossomos/efeitos dos fármacos , Humanos , Piroptose/efeitos dos fármacos , ATPases Vacuolares Próton-Translocadoras/metabolismo , Carcinoma Anaplásico da Tireoide/metabolismo , Carcinoma Anaplásico da Tireoide/patologia , Carcinoma Anaplásico da Tireoide/tratamento farmacológico , Animais , Linhagem Celular Tumoral , Sapogeninas/farmacologia , Camundongos , Camundongos Nus , Neoplasias da Glândula Tireoide/patologia , Neoplasias da Glândula Tireoide/metabolismo , Neoplasias da Glândula Tireoide/tratamento farmacológico , Ensaios Antitumorais Modelo de Xenoenxerto , Camundongos Endogâmicos BALB C , GasderminasRESUMO
Melanoma, a malignant skin cancer arising from melanocytes, exhibits rapid metastasis and a high mortality rate, especially in advanced stages. Current treatment modalities, including surgery, radiation, and immunotherapy, offer limited success, with immunotherapy using immune checkpoint inhibitors (ICIs) being the most promising. However, the high mortality rate underscores the urgent need for robust, non-invasive biomarkers to predict patient response to adjuvant therapies. The immune microenvironment of melanoma comprises various immune cells, which influence tumor growth and immune response. Melanoma cells employ multiple mechanisms for immune escape, including defects in immune recognition and epithelial-mesenchymal transition (EMT), which collectively impact treatment efficacy. Single-cell analysis technologies, such as single-cell RNA sequencing (scRNA-seq), have revolutionized the understanding of tumor heterogeneity and immune microenvironment dynamics. These technologies facilitate the identification of rare cell populations, co-expression patterns, and regulatory networks, offering deep insights into tumor progression, immune response, and therapy resistance. In the realm of biomarker discovery for melanoma, single-cell analysis has demonstrated significant potential. It aids in uncovering cellular composition, gene profiles, and novel markers, thus advancing diagnosis, treatment, and prognosis. Additionally, tumor-associated antibodies and specific genetic and cellular markers identified through single-cell analysis hold promise as predictive biomarkers. Despite these advancements, challenges such as RNA-protein expression discrepancies and tumor heterogeneity persist, necessitating further research. Nonetheless, single-cell analysis remains a powerful tool in elucidating the mechanisms underlying therapy response and resistance, ultimately contributing to the development of personalized melanoma therapies and improved patient outcomes.
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Biomarcadores Tumorais , Imunoterapia , Melanoma , Análise de Célula Única , Microambiente Tumoral , Humanos , Melanoma/terapia , Melanoma/imunologia , Melanoma/diagnóstico , Análise de Célula Única/métodos , Imunoterapia/métodos , Microambiente Tumoral/imunologia , Neoplasias Cutâneas/terapia , Neoplasias Cutâneas/imunologia , Neoplasias Cutâneas/diagnóstico , Animais , Inibidores de Checkpoint Imunológico/uso terapêutico , Inibidores de Checkpoint Imunológico/farmacologia , PrognósticoRESUMO
Cordycepin is a nucleoside molecule found in Cordyceps sinensis and can be obtained through chemical synthesis and biotransformation. Cordycepin has been extensively studied and has been shown to have antitumour activity. This activity includes effects on the autophagy process and inhibition of the MAPK/ERK and Hedgehog pathways. Ultimately, the inhibitory effect of cordycepin on tumour cells is due to the interplay of these effects. Cordycepin was shown to enhance the therapeutic effects of radiotherapy. There is increasing evidence indicating that cordycepin plays an anticancer role in the treatment of various cancers. The present review aims to provide a clear understanding of the antitumour mechanisms of cordycepin and discuss its present application in the treatment of tumours. This information can be an important theoretical basis and provide clinical guidance for the further development of cordycepin as an antitumour drug.
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Desoxiadenosinas , Neoplasias , Humanos , Desoxiadenosinas/uso terapêutico , Desoxiadenosinas/farmacologia , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Animais , Antineoplásicos/uso terapêutico , Antineoplásicos/farmacologia , Autofagia/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacosRESUMO
BACKGROUND: Sunitinib is a multikinase inhibitor used to treat patients with advanced renal cell carcinoma (RCC). However, sunitinib toxicity makes it a double-edged sword. Potent immune modulation by sunitinib extends to nuclear interactions. To address these issues, there is an urgent need for delivery vectors suitable for sunitinib treatment. METHODS: We developed PEGylated liposomes as delivery vectors to precisely target sunitinib (lipo-sunitinib) to RCC tumors. Further investigations, including RNA sequencing (RNA-seq), were performed to evaluate transcriptomic changes in these pathways. DiI/DiR-labeled lipo-sunitinib was used for the biodistribution analysis. Flow cytometry and immunofluorescence (IF) were used to examine immune modulation in orthotopic RCC models. RESULTS: The evaluation of results indicated that lipo-sunitinib precisely targeted the tumor site to induce autophagy and was readily taken up by RCC tumor cells. In addition, transcriptomic assays revealed that following lipo-sunitinib treatment, autophagy, antigen presentation, cytokine, and chemokine production pathways were upregulated, whereas the epithelial-mesenchymal transition (EMT) pathway was downregulated. In vivo data provided evidence supporting the inhibitory effect of lipo-sunitinib on RCC tumor progression and metastasis. Flow cytometry further demonstrated that liposunitinib increased the infiltration of effector T cells (Teffs) and conventional type 1 dendritic cells (cDC1s) into the tumor. Furthermore, systemic immune organs such as the tumor-draining lymph nodes, spleen, and bone marrow exhibited upregulated anticancer immunity following lipo-sunitinib treatment. CONCLUSION: Our findings demonstrated that lipo-sunitinib is distributed at the RCC tumor site, concurrently inducing potent autophagy, elevating antigen presentation, activating cytokine and chemokine production pathways, and downregulating EMT in RCC cells. This comprehensive approach significantly enhanced tumor inhibition and promoted anticancer immune modulation.
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Autofagia , Carcinoma de Células Renais , Neoplasias Renais , Lipossomos , Polietilenoglicóis , Sunitinibe , Carcinoma de Células Renais/tratamento farmacológico , Sunitinibe/farmacologia , Autofagia/efeitos dos fármacos , Animais , Lipossomos/química , Neoplasias Renais/tratamento farmacológico , Camundongos , Linhagem Celular Tumoral , Polietilenoglicóis/química , Humanos , Imunomodulação/efeitos dos fármacos , Antineoplásicos/farmacologia , Antineoplásicos/química , Distribuição Tecidual , Transição Epitelial-Mesenquimal/efeitos dos fármacos , FemininoRESUMO
Although evidence-based interventions can reduce the incidence of central line-associated bloodstream infection (CLABSI), there is a large gap between evidence-based interventions and the actual practice of central venous catheter (CVC) care. Evidence-based interventions are needed to reduce the incidence of CLABSI in intensive care units (ICU) in China. Professional association, guidelines, and database websites were searched for data relevant to CLABSI in the adult ICUs from inception to February 2020. Checklists were developed for both CVC placement and maintenance. Based on the Integrated Promoting Action on Research Implementation in Health Services framework, a questionnaire collected the cognition and practice of ICU nursing and medical staff on the CLABSI evidence-based prevention guidelines. From January 2018 to December 2021, ICU CLABSI rates were collected monthly. Ten clinical guidelines were included after the screening and evaluation process and used to develop the best evidence-based protocols for CVC placement and maintenance. The CLABSI rates in 2018, 2019, and 2020 were 2.98 (9/3021), 1.83 (6/3276), and 1.69 (4/2364), respectively. Notably, the CLABSI rate in 2021 was 0.38 (1/2607). In other words, the ICU CLABSI rate decreased from 1.69 to 0.38 after implementation of the new protocols. Additionally, our data suggested that the use of ultrasound-guidance for catheter insertion, chlorhexidine body wash, and the use of a checklist for CVC placement and maintenance were important measures for reducing the CLABSI rate. The evidence-based processes developed for CVC placement and maintenance were effective at reducing the CLABSI rate in the ICU.
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Infecções Relacionadas a Cateter , Cateterismo Venoso Central , Unidades de Terapia Intensiva , Humanos , Infecções Relacionadas a Cateter/prevenção & controle , Infecções Relacionadas a Cateter/epidemiologia , Cateterismo Venoso Central/efeitos adversos , Cateterismo Venoso Central/métodos , China/epidemiologia , Cateteres Venosos Centrais/efeitos adversos , Prática Clínica Baseada em Evidências/métodos , Guias de Prática Clínica como Assunto , Lista de Checagem , Protocolos ClínicosRESUMO
Chemical investigation on the aqueous extract of Dendrobium aphyllum led to the isolation of thirty-one constituents with structures identified by analysis of the extensive spectroscopic data (1D/2D NMR, MS, UV, and ECD), including previously undescribed two bibenzyls, one furfural, and one phenolic acid, namely trigonopol D (1), trigonopol C (2), dendrofunan A (10), and 6-(4-hydroxy-3-methoxyphenyl)-3,6-dioxohexyl acetate (30), respectively, as well as twenty-seven known ones. Among them, there were one new natural product (11), seven compounds (6-7, 9, 12, 20, 28, 31) described from the genus Dendrobium for the first time, and fifteen compounds (8, 13-17, 19, 21-27, 29) isolated from D. aphyllum for the first time. Further, the antioxidant and anti-inflammatory potentials of fifteen compounds (4-5, 8, 11-12, 14-19, 22, 24, 26, and 29) with significant scavenging capacities against DPPH and hydroxyl radicals, and virtual docking activities inhibiting COX-2 and 5-LOX, respectively. Our study may draw the attention of medicinal plant taxonomists and supply potential quality markers for discrimination of D. aphyllum from other species in Dendrobium genus.
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Anti-Inflamatórios , Antioxidantes , Bibenzilas , Dendrobium , Compostos Fitoquímicos , Dendrobium/química , Antioxidantes/farmacologia , Antioxidantes/isolamento & purificação , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/isolamento & purificação , Anti-Inflamatórios/química , Estrutura Molecular , Bibenzilas/farmacologia , Bibenzilas/isolamento & purificação , Bibenzilas/química , Compostos Fitoquímicos/farmacologia , Compostos Fitoquímicos/isolamento & purificação , Fenantrenos/farmacologia , Fenantrenos/isolamento & purificação , Fenantrenos/química , Fenilpropionatos/isolamento & purificação , Fenilpropionatos/farmacologia , Fenilpropionatos/química , China , Animais , Camundongos , Araquidonato 5-Lipoxigenase/metabolismo , Simulação de Acoplamento Molecular , Furanos/isolamento & purificação , Furanos/farmacologia , Furanos/química , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Ciclo-Oxigenase 2/metabolismoRESUMO
Cancer remains a significant global challenge, with escalating incidence rates and a substantial burden on healthcare systems worldwide. Herein, we present an in-depth exploration of the intricate interplay between cancer cell death pathways and tumor immunity within the tumor microenvironment (TME). We begin by elucidating the epidemiological landscape of cancer, highlighting its pervasive impact on premature mortality and the pronounced burden in regions such as Asia and Africa. Our analysis centers on the pivotal concept of immunogenic cell death (ICD), whereby cancer cells succumbing to specific stimuli undergo a transformation that elicits robust anti-tumor immune responses. We scrutinize the mechanisms underpinning ICD induction, emphasizing the release of damage-associated molecular patterns (DAMPs) and tumor-associated antigens (TAAs) as key triggers for dendritic cell (DC) activation and subsequent T cell priming. Moreover, we explore the contributions of non-apoptotic RCD pathways, including necroptosis, ferroptosis, and pyroptosis, to tumor immunity within the TME. Emerging evidence suggests that these alternative cell death modalities possess immunogenic properties and can synergize with conventional treatments to bolster anti-tumor immune responses. Furthermore, we discuss the therapeutic implications of targeting the TME for cancer treatment, highlighting strategies to harness immunogenic cell death and manipulate non-apoptotic cell death pathways for therapeutic benefit. By elucidating the intricate crosstalk between cancer cell death and immune modulation within the TME, this review aims to pave the way for the development of novel cancer therapies that exploit the interplay between cell death mechanisms and tumor immunity and overcome Challenges in the Development and implementation of Novel Therapies.
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Conjugated molecules with donor-acceptor-donor (D-A-D) moieties have garnered significant attention for their ability to form luminescent metal-organic frameworks (LMOFs). D-A-D molecules feature tunable bandgaps, which can be varied systematically to control the fluorescence wavelength of LMOFs. In this study, we prepared and characterized the fluorescence properties of two porous interpenetrated Zr-organic frameworks (PIZOFs) constructed using 4,4'-(benzo[c][1,2,5]selenadiazole-4,7-diylbis(ethyne-2,1-diyl))dibenzoic acid (L-Se) or 4,4'-(benzo[c][1,2,5]thiadiazole-4,7-diylbis(ethyne-2,1-diyl))dibenzoic acid (L-S) as linkers. The corresponding MOFs are denoted as PIZOF-Se and PIZOF-S, respectively. Through our investigation, we explored the correlation between the structure of the frameworks and their respective optical properties. Our findings revealed that there are distinct differences in the fluorescence properties of the two PIZOFs. Specifically, the fluorescence of PIZOF-S is red-shifted from that characteristic of the corresponding linker, L-S. By contrast, the fluorescence of PIZOF-Se is substantially blue-shifted from that of linker L-Se. The emission of mixed-linker MOFs is explored by combining L-S or L-Se with structurally analogous, but nonfluorescent linker, 4,4'-((perfluoro-1,4-phenylene)bis(ethyne-2,1-diyl))dibenzoic acid (L-F). Based on steady-state and time-resolved photoluminescence experiments, as well as confocal fluorescence microscopy combined with fluorescence lifetime imaging (FILM), we demonstrated that linker engineering is an effective method to tune the emission behavior of LMOFs.
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Introduction: MicroRNAs (miRs) are small noncoding RNAs which are regulators of gene expression and also regulate the genes in heart tissues. The aim of the study was to evaluate the effect of miRs on the expression level of myosin heavy chain (MHC), which is responsible for regulation of cardiac functions in neonatal rat ventricular myocytes and mice. Material and methods: The miRs were suppressed in neonatal rat ventricular myocytes using small interfering RNAs (siRNAs) against Dicer followed by evaluation of MHC levels. For in vivo study the C57 black/6 Jacksonian mice were subjected to the transverse aortic constriction (TAC) procedure. Results: The Dicer siRNA suppressed the endogenous miRs and the α-MHC gene but failed to down-regulate the ß-MHC. Among the 17 selected miRs, miR-29a was found to up-regulate the α-MHC gene significantly but not ß-MHC. The expression of α-MHC was suppressed by silencing the expression of miR-29a. Bioinformatics study done by TargetScan suggested thyroid hormone receptor-ß1 (TR-ß1) as a potential target of miR-29a. Additionally, miR-29a was found to regulate the expression of α-MHC via TR-ß1 signaling. Conclusions: The findings of the present study indicated that miR-29a modulates expression of α-the MHC gene by targeting TR-ß1 in cardiac cells. The study may provide a new direction for treating cardiac failure and cardiac hypertrophy.
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Shewanella oneidensis MR-1 has found widespread applications in pollutant transformation and bioenergy production, closely tied to its outstanding heme synthesis capabilities. However, this significant biosynthetic potential is still unexploited so far. Here, we turned this bacterium into a highly-efficient bio-factory for green synthesis of 5-Aminolevulinic Acid (5-ALA), an important chemical for broad applications in agriculture, medicine, and the food industries. The native C5 pathway genes of S. oneidensis was employed, together with the introduction of foreign anti-oxidation module, to establish the 5-ALA production module, resulting 87-fold higher 5-ALA yield and drastically enhanced tolerance than the wild type. Furthermore, the metabolic flux was regulated by using CRISPR interference and base editing techniques to suppress the competitive pathways to further improve the 5-ALA titer. The engineered strain exhibited 123-fold higher 5-ALA production capability than the wild type. This study not only provides an appealing new route for 5-ALA biosynthesis, but also presents a multi-dimensional modularized engineering strategy to broaden the application scope of S. oneidensis.
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Ácido Aminolevulínico , Engenharia Metabólica , Shewanella , Shewanella/genética , Shewanella/metabolismo , Ácido Aminolevulínico/metabolismoRESUMO
The environmental dissemination of extracellular antibiotic resistance genes (eARGs) in wastewater and natural water bodies has aroused growing ecological concerns. The coexisting chemical pollutants in water are known to markedly affect the eARGs transfer behaviors of the environmental microbial community, but the detailed interactions and specific impacts remain elusive so far. Here, we revealed a concentration-dependent impact of dimethyl phthalate (DMP) and several other types of phthalate esters (common water pollutants released from plastics) on the natural transformation of eARGs. The DMP exposure at an environmentally relevant concentration (10 µg/L) resulted in a 4.8-times raised transformation frequency of Acinetobacter baylyi but severely suppressed the transformation at a high concentration (1000 µg/L). The promotion by low-concentration DMP was attributed to multiple mechanisms, including increased bacterial mobility and membrane permeability to facilitate eARGs uptake and improved resistance of the DMP-bounded eARGs (via noncovalent interaction) to enzymatic degradation (with suppressed DNase activity). Similar promoting effects of DMP on the eARGs transformation were also found in real wastewater and biofilm systems. In contrast, higher-concentration DMP suppressed the eARGs transformation by disrupting the DNA structure. Our findings highlight a potentially underestimated eARGs spreading in aquatic environments due to the impacts of coexisting chemical pollutants and deepen our understanding of the risks of biological-chemical combined pollution in wastewater and environmental water bodies.
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Resistência Microbiana a Medicamentos , Ácidos Ftálicos , Resistência Microbiana a Medicamentos/genética , Águas Residuárias , Biofilmes/efeitos dos fármacos , Poluentes Químicos da Água/toxicidadeRESUMO
Colorectal cancer (CRC), known for its high metastatic potential, remains a leading cause of cancer-related death. This review emphasizes the critical role of immune responses in CRC metastasis, focusing on the interaction between immune cells and tumor microenvironment. We explore how immune cells, through cytokines, chemokines, and growth factors, contribute to the CRC metastasis cascade, underlining the tumor microenvironment's role in shaping immune responses. The review addresses CRC's immune evasion tactics, especially the upregulation of checkpoint inhibitors like PD-1 and CTLA-4, highlighting their potential as therapeutic targets. We also examine advanced immunotherapies, including checkpoint inhibitors and immune cell transplantation, to modify immune responses and enhance treatment outcomes in CRC metastasis. Overall, our analysis offers insights into the interplay between immune molecules and the tumor environment, crucial for developing new treatments to control CRC metastasis and improve patient prognosis, with a specific focus on overcoming immune evasion, a key aspect of this special issue.
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Neoplasias Colorretais , Humanos , Neoplasias Colorretais/patologia , Prognóstico , Resultado do Tratamento , Citocinas/uso terapêutico , Microambiente TumoralRESUMO
OBJECTIVE: Metabolic risks play a key role in the progression of pancreatic cancer. This study aimed to present global, regional and national data on mortality and disability-adjusted life-year (DALY) for pancreatic cancer attributable to metabolic risk and to forecast mortality to 2030 using data from the Global Burden of Disease (GBD). METHODS: Data on mortality and DALYs due to pancreatic cancer attributable to metabolic risks were obtained from GBD 2019. Metabolic risks include high fasting plasma glucose (FPG) and high body mass index (BMI). Total numbers and age-standardized rates per 100,000 people for mortality and DALYs were reported by age, sex, region and country/territory from 1990 to 2019. The "Bayes age-period-cohort" method was used for projections of mortality to 2030. RESULTS: Globally, there was a 3.5-fold increase in the number of pancreatic cancer deaths attributable to metabolic risk, from 22,091 in 1990 to 77,215 in 2019. High-income North America and Central Europe had the highest age-standardized mortality rates (ASMRs) of pancreatic cancer attributable to high FPG and high BMI in 2019, respectively. From 1990 to 2019, the global ASMR of pancreatic cancer attributable to high FPG and high BMI increased. Countries with high healthcare access quality had much higher age-standardized DALY rates. In the next 10 years, the ASMR of pancreatic cancer attributable to high FPG and high BMI will continue to increase. CONCLUSION: Pancreatic cancer mortality and DALYs attributable to metabolic factors remain high, particularly in high-income regions or countries. Studies on the metabolic mechanism of pancreatic cancer and effective treatment strategies are needed.
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Carga Global da Doença , Neoplasias Pancreáticas , Humanos , Fatores de Risco , Teorema de Bayes , Índice de Massa Corporal , Anos de Vida Ajustados por Qualidade de Vida , Saúde GlobalRESUMO
Diabetes mellitus results in numerous complications. Diabetic pulmonary fibrosis (DPF), a late pulmonary complication of diabetes, has not attracted as much attention as diabetic nephropathy and cardiomyopathy. Mangiferin (MF) is a natural small molecular compound that exhibits a variety of pharmacological effects including anti-inflammatory, anti-cancer, anti-diabetes, and anti-fibrosis effects. In this study, we investigated whether long-term diabetes shock induces DPF, and explored whether MF had a protective effect against DPF. We first examined the lung tissues and sections of 20 diabetic patients obtained from discarded lung surgical resection specimens and found that pulmonary fibrosis mainly accumulated around the pulmonary vessels, accompanied by significantly enhanced endothelial-mesenchymal transition (EndMT). We established a mouse model of DPF by STZ injections. Ten days after the final STZ injection, the mice were administered MF (20, 60 mg/kg, i.g.) every 3 days for 4 weeks, and kept feeding until 16 weeks and euthanized. We showed that pulmonary fibrotic lesions were developed in the diabetic mice, which began around the pulmonary vessels, while MF administration did not affect long-term blood glucose levels, but dose-dependently alleviated diabetes-induced pulmonary fibrosis. In human umbilical vein endothelial cells (HUVECs), exposure to high glucose (33.3 mM) induced EndMT, which was dose-dependently inhibited by treatment with MF (10, 50 µM). Furthermore, MF treatment promoted SIRT3 expression in high glucose-exposed HUVECs by directly binding to AMPK to enhance the activity of FoxO3, which finally reversed diabetes-induced EndMT. We conclude that MF attenuates DPF by inhibiting EndMT through the AMPK/FoxO3/SIRT3 axis. MF could be a potential candidate for the early prevention and treatment of DPF.
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Proteínas Quinases Ativadas por AMP , Diabetes Mellitus Experimental , Proteína Forkhead Box O3 , Camundongos Endogâmicos C57BL , Fibrose Pulmonar , Sirtuína 3 , Xantonas , Animais , Xantonas/farmacologia , Xantonas/uso terapêutico , Fibrose Pulmonar/tratamento farmacológico , Fibrose Pulmonar/metabolismo , Sirtuína 3/metabolismo , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Experimental/complicações , Diabetes Mellitus Experimental/metabolismo , Proteína Forkhead Box O3/metabolismo , Masculino , Humanos , Camundongos , Proteínas Quinases Ativadas por AMP/metabolismo , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Estreptozocina , Transdução de Sinais/efeitos dos fármacos , Transição Endotélio-MesênquimaRESUMO
OBJECTIVE: This study compares endoscopic thyroidectomy by gasless unilateral axillary approach (ETGUA) and sternocleidomastoid leading-edge approach (SLEA) with conventional open thyroidectomy (COT) in hemithyroidectomy. The main focus is on the protection of neck muscles (sternocleidomastoid, omohyoid, sternothyroid) and the postoperative function of voice and swallowing yielded through these common approaches. METHODS: A total of 302 patients who underwent hemithyroidectomy were enrolled and divided into three groups: ETGUA (n = 101), SLEA (n = 100), and COT (n = 101). Ultrasound was used to measure the thickness of bilateral neck muscles, including the sternocleidomastoid, omohyoid, and sternothyroid. The changes in thickness on the surgical side compared to the non-surgical side. Analyzed factors included muscle thickness changes, Swallowing Impairment Score (SIS), Voice Handicap Index (VHI), Scar Cosmesis Assessment and Rating (SCAR), Neck Injury Index (NII), surgery duration, drainage volume, hospitalization, and number of lymph nodes. RESULTS: The clinical characteristics among the three groups were consistent except for differences in sex, age, and BMI. Metrics such as sternocleidomastoid muscle, NII, hypocalcemia, postoperative PTH, transient hoarseness, and number of lymph nodes showed no significant differences among the three groups. However, significant differences were found in the duration of surgery, drainage volume, hospitalization period omohyoid muscle, Sternohyoid muscle, VHI, SIS, and SCAR (all p < 0.001). CONCLUSION: In comparison to COT, ETGUA and SLEA demonstrate superiority in protecting neck muscles and preserving voice and swallowing function without compromising surgical safety or radicality.
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Neoplasias da Glândula Tireoide , Tireoidectomia , Humanos , Deglutição , Músculos do Pescoço/patologia , Endoscopia , Esvaziamento Cervical , Neoplasias da Glândula Tireoide/cirurgiaRESUMO
Light provides high temporal precision for neuronal modulations. Small molecules are advantageous for neuronal modulation due to their structural diversity, allowing them to suit versatile targets. However, current optochemical methods release uncaged small molecules with uniform concentrations in the irradiation area, which lack spatial specificity as counterpart optogenetic methods from genetic encoding for photosensitive proteins. Photocatalysis provides spatial specificity by generating reactive species in the proximity of photocatalysts. However, current photocatalytic methods use antibody-tagged heavy-metal photocatalysts for spatial specificity, which are unsuitable for neuronal applications. Here, we report a genetically encoded metal-free photocatalysis method for the optochemical modulation of neurons via deboronative hydroxylation. The genetically encoded photocatalysts generate doxorubicin, a mitochondrial uncoupler, and baclofen by uncaging stable organoboronate precursors. The mitochondria, nucleus, membrane, cytosol, and ER-targeted drug delivery are achieved by this method. The distinct signaling pathway dissection in a single projection is enabled by the dual optogenetic and optochemical control of synaptic transmission. The itching signaling pathway is investigated by photocatalytic uncaging under live-mice skin for the first time by visible light irradiation. The cell-type-specific release of baclofen reveals the GABABR activation on NaV1.8-expressing nociceptor terminals instead of pan peripheral sensory neurons for itch alleviation in live mice.
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BACKGROUND & PURPOSE: Different methods have been exploited to generate amorphous solid dispersions (ASDs) of poorly water-soluble drugs. However, the impact of processing methods on drug stability and dissolution hasn't been studied extensively. The purpose of the current study is to investigate the impact of the two common ASD processing methods, hot-melt extrusion (HME) and spray drying, on the chemical/physical stability and supersaturation of Posaconazole (Posa) based ASDs. METHODS & RESULTS: ASDs with 25% drug loading in hydroxypropylmethylcellulose acetate succinate were prepared using HME, and two types of spray dryers, a Procept Sprayer (ASD-Procept) and a Nano Sprayer (ASD-Nano). The relative physical stability of these ASDs upon exposure to heat and crystalline API seeding followed the order: ASD-Nano > ASD-Procept ≈HME. ASD-Procept and ASD-Nano showed similar chemical stability, slightly less stable than HME under 40°C/75%RH. All three ASDs demonstrated similar supersaturation induction times, and de-supersaturation kinetics with or without crystalline seeds. CONCLUSIONS: Posa ASDs prepared via spray drying were chemically less stable compared with HME, which can be attributed to their smaller particle size and hollow structure allowing oxygen penetration. For ASD-Procept and HME, the detailed phase changes involving recrystallization of amorphous Posa and a solid-solid phase transition from Posa Form I to Form Ia during the seed-induced studies were proposed. Similar dissolution and supersaturation-precipitation kinetics of three Posa ASDs indicated that any residual nanocrystals in the bulk ASDs were not enough to induce crystallization to differentiate ASDs made by three processing methods.
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Triazóis , Solubilidade , Cristalização , Transição de Fase , Composição de Medicamentos/métodosRESUMO
Polyhydroxybutyrate (PHB) is an attractive biodegradable polymer that can be produced through the microbial fermentation of organic wastes or wastewater. However, its mass production has been restricted by the poor utilization of organic wastes due to the presence of inhibitory substances, slow microbial growth, and high energy input required for feedstock sterilization. Here, Vibrio natriegens, a fast-growing bacterium with a broad substrate spectrum and high tolerance to salt and toxic substances, was genetically engineered to enable efficient PHB production from nonsterilized fermentation of organic wastes. The key genes encoding the PHB biosynthesis pathway of V. natriegens were identified through base editing and overexpressed. The metabolically engineered strain showed 166-fold higher PHB content (34.95 wt %) than the wide type when using glycerol as a substrate. Enhanced PHB production was also achieved when other sugars were used as feedstock. Importantly, it outperformed the engineered Escherichia coli MG1655 in PHB productivity (0.053 g/L/h) and tolerance to toxic substances in crude glycerol, without obvious activity decline under nonsterilized fermentation conditions. Our work demonstrates the great potential of engineered V. natriegens for low-cost PHB bioproduction and lays a foundation for exploiting this strain as a next-generation model chassis microorganism in synthetic biology.