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With recent advances in tumor immunotherapy, chimeric antigen receptor T (CAR-T) cell therapy has achieved unprecedented success in several hematologic tumors, significantly improving patient prognosis. However, in solid tumors, the efficacy of CAR-T cell therapy is limited because of high antigen uncertainty and the extremely restrictive tumor microenvironment (TME). This challenge has led to the exploration of new targets, among which fibroblast activation protein (FAP) has gained attention for its relatively stable and specific expression in the TME of various solid tumors, making it a potential new target for CAR-T cell therapy. This study comprehensively analyzed the biological characteristics of FAP and discussed its potential application in CAR-T cell therapy, including the theoretical basis, and preclinical and clinical research progress of targeting FAP with CAR-T cell therapy for solid tumor treatment. The challenges and future optimization directions of this treatment strategy were also explored, providing new perspectives and strategies for CAR-T cell therapy in solid tumors.
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Lipid nanoparticles (LNPs) coated with functional and biocompatible polymers have been widely used as carriers to deliver oligonucleotide and messenger RNA therapeutics to treat diseases. Poly(ethylene glycol) (PEG) is a representative material used for the surface coating, but the PEG surface-coated LNPs often have reduced cellular uptake efficiency and pharmacological activity. Here, we demonstrate the effect of pH-responsive ethylenediamine-based polycarboxybetaines with different molecular weights as an alternative structural component to PEG for the coating of LNPs. We found that appropriate tuning of the molecular weight around polycarboxybetaine-modified LNP, which incorporated small interfering RNA, could enhance the cellular uptake and membrane fusion potential in cancerous pH condition, thereby facilitating the gene silencing effect. This study demonstrates the importance of the design and molecular length of polymers on the LNP surface to provide effective drug delivery to cancer cells.
The study presents the unique characteristics of small interfering RNA (siRNA)-loaded lipid nanoparticles (LNPs) with different lengths of PGlu(DET-Car), revealing the length of PGlu(DET-Car) critically affects the formation of a stable LNP, the cellular uptake, membrane fusion, and gene silencing abilities.
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HDL are dynamic transporters of diverse molecular cargo and play critical roles in lipid metabolism and inflammation. We have previously reported that HDL transport both host and nonhost small RNAs (sRNA) based on quantitative PCR and sRNA sequencing approaches; however, these methods require RNA isolation steps which have potential biases and may not isolate certain forms of RNA molecules from samples. HDL have also been reported to accept functional sRNAs from donor macrophages and deliver them to recipient endothelial cells; however, using PCR to trace HDL-sRNA intercellular communication has major limitations. The present study aims to overcome these technical barriers and further understand the pathways involved in HDL-mediated bidirectional flux of sRNAs between immune cells. To overcome these technical limitations, SYTO RNASelect, a lipid-penetrating RNA dye, was used to quantify a) overall HDL-sRNA content, b) bidirectional flux of sRNAs between HDL and immune cells, c) HDL-mediated intercellular communication between immune cells, and d) HDL-mediated RNA export changes in disease. Live cell imaging and loss-of-function assays indicate that the endo-lysosomal system plays a critical role in macrophage storage and export of HDL-sRNAs. These results identify HDL as a substantive mediator of intercellular communication between immune cells and demonstrate the importance of endocytosis for recipient cells of HDL-sRNAs. Utilizing a lipid-penetrating RNA-specific fluorescence dye, we were able to both quantify the absolute concentration of sRNAs transported by HDL and characterize HDL-mediated intercellular RNA transport between immune cells.
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Pequeno RNA não Traduzido , Pequeno RNA não Traduzido/genética , Pequeno RNA não Traduzido/metabolismo , Lipoproteínas HDL , Células Endoteliais/metabolismo , Macrófagos/metabolismo , Comunicação Celular , Células Dendríticas/metabolismoRESUMO
PURPOSE: Controlling small interfering RNA (siRNA) activity by external stimuli is useful to exert a selective therapeutic effect at the target site. This study aims to develop a technology to control siRNA activity in a thermo-responsive manner, which can be utilized even at temperatures close to body temperature. METHODS: siRNA was conjugated with a thermo-responsive copolymer that was synthesized by copolymerization of N-isopropylacrylamide (NIPAAm) and hydrophilic N,N-dimethylacrylamide (DMAA) to permit thermally controlled interaction between siRNA and an intracellular gene silencing-related protein by utilizing the coil-to-globule phase transition of the copolymer. The composition of the copolymer was fine-tuned to obtain lower critical solution temperature (LCST) around body temperature, and the phase transition behavior was evaluated. The cellular uptake and gene silencing efficiency of the copolymer-siRNA conjugates were then investigated in cultured cells. RESULTS: The siRNA conjugated with the copolymer with LCST of 38.0°C exhibited ~ 11.5 nm of the hydrodynamic diameter at 37°C and ~ 9.8 nm of the diameter at 41°C, indicating the coil-globule transition above the LCST. In line with this LCST behavior, its cellular uptake and gene silencing efficiency were enhanced when the temperature was increased from 37°C to 41°C. CONCLUSION: By fine-tuning the LCST behavior of the copolymer that was conjugated with siRNA, siRNA activity could be controlled in a thermo-responsive manner around the body temperature. This technique may offer a promising approach to induce therapeutic effects of siRNA selectively in the target site even in the in vivo conditions.
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Temperatura Corporal , Polímeros , RNA Interferente Pequeno/genética , Temperatura , Inativação GênicaRESUMO
BACKGROUND: Choline, as a neurotransmitter acetylcholine precursor, is reportedly associated with cognitive function. Although there are several cohort and animal studies on choline-containing foods and cognitive function, only a few interventional studies were reported. Egg yolk is a rich source of different choline-containing chemical forms, such as phosphatidylcholine (PC), lysophosphatidylcholine (LPC), and α-glycerophosphocholine (α-GPC). This study aimed to investigate the effect of consuming 300 mg of egg yolk choline per day on cognitive function of Japanese adults. METHODS: A 12-week, randomized, double-blind, placebo-controlled, parallel-group study was conducted in 41 middle-aged and elderly males and females (43.9% female) aged ≥ 60 years and ≤ 80 years without dementia. Participants were randomly assigned to placebo and choline groups. The choline group received a supplement containing egg yolk choline (300 mg/day), and the placebo group received an egg yolk supplement free from choline for 12 weeks. Assessments of Cognitrax, Trail Making Tests (TMT) part A and B, the MOS 36-Item Short-Form Health Survey (SF-36), the Simplified Japanese Version of the WHO-Five Well-Being Index (WHO-5), and plasma choline levels were performed before and 6 and 12 weeks after supplement intake. In the present study, 19 subjects (9 in the placebo group and 10 in the choline group) were excluded due to the violation of the discontinuation criteria or participant compliance, and 41 subjects were analyzed. RESULTS: The change amount of verbal memory scores and verbal memory test-correct hit (delay) was significantly higher in the choline group than in the placebo group at baseline-6 and baseline-12 weeks. The plasma free choline level was significantly higher in the choline group compared with the placebo group at 6 weeks. Conversely, the choline group showed significantly lower Cognitrax processing speed scores, symbol digit coding testing correct responses, and SF-36 physical quality of life summary scores compared to the placebo group at 6 weeks. CONCLUSIONS: The results suggested that continued 300 mg/day intake of egg yolk choline improved verbal memory, which is a part of cognitive functions. To confirm the observed effects of egg yolk choline, more well-designed and large-scale studies are warranted. TRIAL REGISTRATION: Study protocols were pre-registered in the Clinical Trials Registration System (UMIN-CTR) (UMIN 000045050).
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Colina , Cognição , Gema de Ovo , Feminino , Humanos , Masculino , Colina/administração & dosagem , Método Duplo-Cego , População do Leste Asiático , Qualidade de Vida , Pessoa de Meia-Idade , IdosoRESUMO
Lipid nanoparticles (LNPs) have been commonly used as a vehicle for nucleic acids, such as small interfering RNA (siRNA); the surface modification of LNPs is one of the determinants of their delivery efficiency especially in systemic administration. However, the applications of siRNA-encapsulated LNPs are limited due to a lack effective systems to deliver to solid tumors. Here, we report a smart surface modification using a charge-switchable ethylenediamine-based polycarboxybetaine for enhancing tumor accumulation via interaction with anionic tumorous tissue constituents due to selective switching to cationic charge in response to cancerous acidic pH. Our polycarboxybetaine-modified LNP could enhance cellular uptake in cancerous pH, resulting in facilitated endosomal escape and gene knockdown efficiency. After systemic administration, the polycarboxybetaine-modified LNP accomplished high tumor accumulation in SKOV3-luc and CT 26 subcutaneous tumor models. The siPLK-1-encapsulated LNP thereby accomplished significant tumor growth inhibition. This study demonstrates a promising potential of the pH-responsive polycarboxybetaine as a material for modifying the surface of LNPs for efficient nucleic acid delivery.
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Nanopartículas , Neoplasias , Camundongos , Animais , RNA Interferente Pequeno/genética , Lipídeos , Neoplasias/tratamento farmacológico , Neoplasias/genética , Concentração de Íons de HidrogênioRESUMO
AIM: Recently, we demonstrated the efficacy of etelcalcetide in the control of secondary hyperparathyroidism (SHPT). This post hoc analysis aimed to evaluate changes in fibroblast growth factor-23 (FGF23) and calciprotein particles (CPPs) after treatment with calcimimetics. METHODS: The DUET trial was a 12-week multicenter, open-label, parallel-group, randomized (1:1:1) study with patients treated with etelcalcetide plus active vitamin D (E + D group; n = 41), etelcalcetide plus oral calcium (E + Ca group; n = 41), or control (C group; n = 42) under maintenance haemodialysis. Serum levels of FGF23 and CPPs were measured at baseline, and 6 and 12 weeks after the start. RESULTS: In the linear mixed model, serum levels of FGF23 in etelcalcetide users were significantly lower than those in non-users at week 6 (p < .001) and week 12 (p < .001). When compared the difference between the E + Ca group and the E + D group, serum levels of FGF23 in the E + Ca group were significantly lower than those in the E + D group at week 12 (p = .017). There were no significant differences in the serum levels of CPPs between etelcalcetide users and non-users at week 6 and week 12, while CPPs in the E + Ca group were significantly lower than those in the E + D group (p < .001) at week 12. CONCLUSION: Etelcalcetide may be useful through suppression of FGF23 levels among haemodialysis patients with SHPT. When correcting hypocalcaemia, loading oral calcium preparations could be more advantageous than active vitamin D for the suppression of both FGF23 and CPPs.
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Fator de Crescimento de Fibroblastos 23 , Hiperparatireoidismo Secundário , Cálcio , Fatores de Crescimento de Fibroblastos , Humanos , Hiperparatireoidismo Secundário/diagnóstico , Hiperparatireoidismo Secundário/tratamento farmacológico , Hiperparatireoidismo Secundário/etiologia , Hormônio Paratireóideo , Peptídeos , Diálise Renal/efeitos adversos , Vitamina DRESUMO
Bacteria form biofilms for their protection against environmental stress and produce virulence factors within the biofilm. Biofilm formation in acidified environments is regulated by a two-component system, as shown by studies on isogenic mutants of the sensor protein of the two-component regulatory system in Streptococcus pyogenes. In this study, we found that the LiaS histidine kinase sensor mediates biofilm production and pilus expression in an acidified environment through glucose fermentation. The liaS isogenic mutant produced biofilms in a culture acidified by hydrochloric acid but not glucose, suggesting that the acidified environment is sensed by another protein. In addition, the trxS isogenic mutant could not produce biofilms or activate the mga promoter in an acidified environment. Mass spectrometry analysis showed that TrxS regulates M protein, consistent with the transcriptional regulation of emm, which encodes M protein. Our results demonstrate that biofilm production during environmental acidification is directly under the control of TrxS.
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Proteínas de Bactérias/fisiologia , Biofilmes/crescimento & desenvolvimento , Streptococcus pyogenes/fisiologia , Antígenos de Bactérias/biossíntese , Proteínas da Membrana Bacteriana Externa/biossíntese , Proteínas de Bactérias/genética , Proteínas de Transporte/biossíntese , Exotoxinas/fisiologia , Histidina Quinase/fisiologia , Concentração de Íons de Hidrogênio , Fosforilação , Regiões Promotoras GenéticasRESUMO
Cancer cells have high iron requirements due to their rapid growth and proliferation. Iron depletion using iron chelators has a potential in cancer treatment. Previous studies have demonstrated that deferoxamine (DFO) specifically chelates Fe(III) and exhibited antitumor activity in clinical studies. However, its poor pharmacokinetics has limited the therapeutic potential and practical application. Although polymeric iron chelators have been developed to increase the blood retention, none of previous studies has demonstrated their potential in iron chelation cancer therapy. Here, we developed polymeric DFO by the covalent conjugation of DFO to poly(ethylene glycol)-poly(aspartic acid) (PEG-PAsp) block copolymers. The polymeric DFO exhibited iron-chelating ability comparable with free DFO, thereby arresting cell cycle and inducing apoptosis and antiproliferative activity. After intravenous administration, the polymeric DFO showed marked increase in blood retention and tumor accumulation in subcutaneous tumor models. Consequently, polymeric DFO showed significant suppression of the tumor growth compared with free DFO. This study reveals the first success of the design of polymeric DFO for enhancing iron chelation cancer therapy.
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Apoptose/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Desferroxamina/farmacologia , Portadores de Fármacos/farmacologia , Quelantes de Ferro/farmacologia , Animais , Linhagem Celular Tumoral , Desferroxamina/química , Portadores de Fármacos/química , Quelantes de Ferro/química , Camundongos , Camundongos Endogâmicos BALB C , Neoplasias Experimentais/tratamento farmacológico , Peptídeos/química , Peptídeos/farmacologia , Polietilenoglicóis/química , Polietilenoglicóis/farmacologiaRESUMO
Intravenously injected high-dose vitamin C (VC) induces extracellular H2O2, which can penetrate into the tumor cells and suppress tumor growth. However, extracellular labile iron ions in the tumor decompose H2O2 via the Fenton reaction, limiting the therapeutic effect. In this regard, we recently developed a polymeric iron chelator that can inactivate the intratumoral labile iron ions. Here, we examined the effect of our polymeric iron chelator on the high-dose VC therapy in in vitro and in vivo. In the in vitro study, the polymeric iron chelator could inactivate the extracellular labile iron ions and prevent the unfavorable decomposition of VC-induced H2O2, augmenting pro-oxidative damage to DNA and inducing apoptosis in cultured cancer cells. Even in the in vivo study, the polymeric iron chelator significantly improved the antitumor effect of VC in subcutaneous DLD-1 and CT26 tumors in mice, while conventional iron chelators could not. This work indicates the importance of modulating tumor-associated iron ions in the high-dose VC therapy and should contribute to a better understanding of its mechanism.
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Antineoplásicos/farmacologia , Ácido Ascórbico/farmacologia , Peróxido de Hidrogênio/química , Quelantes de Ferro/farmacologia , Ferro/química , Polímeros/farmacologia , Animais , Apoptose/efeitos dos fármacos , Feminino , Camundongos , Camundongos Endogâmicos BALB C , Espécies Reativas de Oxigênio/metabolismoRESUMO
Activation of ribosomal RNA (rRNA) synthesis is pivotal during cell growth and proliferation, but its aberrant upregulation may promote tumorigenesis. Here, we demonstrate that the candidate oncoprotein, LYAR, enhances ribosomal DNA (rDNA) transcription. Our data reveal that LYAR binds the histone-associated protein BRD2 without involvement of acetyl-lysine-binding bromodomains and recruits BRD2 to the rDNA promoter and transcribed regions via association with upstream binding factor. We show that BRD2 is required for the recruitment of the MYST-type acetyltransferase KAT7 to rDNA loci, resulting in enhanced local acetylation of histone H4. In addition, LYAR binds a complex of BRD4 and KAT7, which is then recruited to rDNA independently of the BRD2-KAT7 complex to accelerate the local acetylation of both H4 and H3. BRD2 also helps recruit BRD4 to rDNA. By contrast, LYAR has no effect on rDNA methylation or the binding of RNA polymerase I subunits to rDNA. These data suggest that LYAR promotes the association of the BRD2-KAT7 and BRD4-KAT7 complexes with transcription-competent rDNA loci but not to transcriptionally silent rDNA loci, thereby increasing rRNA synthesis by altering the local acetylation status of histone H3 and H4.
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Proteínas de Ciclo Celular/genética , Proteínas de Ligação a DNA/genética , Histona Acetiltransferases/genética , Proteínas Nucleares/genética , Fatores de Transcrição/genética , Acetilação , Carcinogênese/genética , Cromatina/genética , Metilação de DNA/genética , DNA Ribossômico/genética , Histonas/genética , Humanos , RNA Polimerase I/genética , RNA Ribossômico/biossíntese , RNA Ribossômico/genética , Transcrição GênicaRESUMO
In the pursuit of bioactive phytochemicals as a therapeutic strategy to manage metabolic risk factors for type 2 diabetes (T2D), aspalathin, C-glucosyl dihydrochalcone from rooibos (Aspalathus linearis), has received much attention, along with its C-glucosyl flavone derivatives and phlorizin, the apple O-glucosyl dihydrochalcone well-known for its antidiabetic properties. We provided context for dietary exposure by highlighting dietary sources, compound stability during processing, bioavailability and microbial biotransformation. The review covered the role of these compounds in attenuating insulin resistance and enhancing glucose metabolism, alleviating gut dysbiosis and associated oxidative stress and inflammation, and hyperuricemia associated with T2D, focusing largely on the literature of the past 5 years. A key focus of this review was on emerging targets in the management of T2D, as highlighted in the recent literature, including enhancing of the insulin receptor and insulin receptor substrate 1 signaling via protein tyrosine phosphatase inhibition, increasing glycolysis with suppression of gluconeogenesis by sirtuin modulation, and reducing renal glucose reabsorption via sodium-glucose co-transporter 2. We conclude that biotransformation in the gut is most likely responsible for enhancing therapeutic effects observed for the C-glycosyl parent compounds, including aspalathin, and that these compounds and their derivatives have the potential to regulate multiple factors associated with the development and progression of T2D.
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Chalconas/uso terapêutico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Compostos Fitoquímicos/uso terapêutico , Animais , Disponibilidade Biológica , Biotransformação , Chalconas/química , Chalconas/farmacologia , Microbioma Gastrointestinal/efeitos dos fármacos , Humanos , Compostos Fitoquímicos/química , Compostos Fitoquímicos/farmacologia , Resultado do TratamentoRESUMO
Fibroblast growth factor-23 (FGF23) is a hormone indispensable for maintaining phosphate homeostasis. In response to phosphate intake, FGF23 is secreted from osteocytes/osteoblasts and acts on the kidney to increase urinary phosphate excretion. However, the mechanism by which these cells sense phosphate intake remains elusive. Calciprotein particles are nanoparticles of calcium-phosphate precipitates bound to serum protein fetuin-A and are generated spontaneously in solution containing calcium, phosphate, and fetuin-A to be dispersed as colloids. In cultured osteoblastic cells, increase in either calcium or phosphate concentration in the medium induced FGF23 expression, which was dependent on calciprotein particle formation. When transition of calcium-phosphate precipitates from the amorphous phase to the crystalline phase was blocked by bisphosphonate, the calciprotein particle size was reduced and FGF23 expression was augmented, suggesting that small calciprotein particles containing amorphous calcium-phosphate precipitates function as a more potent FGF23 inducer than larger calciprotein particles containing crystalline calcium-phosphate precipitates. In mice, bolus phosphate administration by oral gavage transiently increased circulating calciprotein particle levels followed by a modest increase in FGF23 expression and serum FGF23 levels. However, continuous dietary phosphate load induced robust and persistent increase in circulating calciprotein particles and FGF23 levels. We confirmed by in vivo imaging that calciprotein particles injected intravenously extravasated into the bone marrow and were deposited on the inner surface of the bone, indicating that these particles have direct access to osteoblasts. Thus, we propose that osteoblasts induce FGF23 expression and secretion when they sense an increase in extracellular calciprotein particles following phosphate ingestion.
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Fatores de Crescimento de Fibroblastos , Osteoblastos , Animais , Osso e Ossos , Fator de Crescimento de Fibroblastos 23 , Camundongos , Osteócitos , FosfatosRESUMO
Tannic acid (TA) can form stable complexes with proteins, attracting significant attention as protein delivery systems. However, its systemic application has been limited due to nonspecific interaction. Here, we report a simple technique to prepare systemically applicable protein delivery systems using sequential self-assembly of a protein, TA, and phenylboronic acid-conjugated PEG-poly(amino acid) block copolymers in aqueous solution. Mixing the protein and TA in aqueous solution led to covering of the protein with TA, and subsequent addition of the copolymer resulted in the formation of boronate esters between TA and copolymers, constructing the core-shell-type ternary complex. The ternary complex covered with PEG exhibited a small hydrodynamic diameter of â¼10-20 nm and prevented an unfavorable interaction with serum components, thereby accomplishing significantly prolonged blood circulation and enhanced tumor accumulation in a subcutaneous tumor model. The technique utilizing supramolecular self-assembly may serve as a novel approach for designing protein delivery systems.
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Polietilenoglicóis , Taninos , Ácidos Borônicos , Micelas , PolímerosRESUMO
Physical activity (PA) in the daily life is strongly related to prognosis in patients with or at high risk of heart failure (HF). However, factors limiting habitual exercise and their prognostic impacts remain unknown in HF patients. We sent questionnaires asking factors limiting habitual exercise in the daily life to 8370 patients with Stage A/B/C/D HF in our nationwide registry and received valid responses from 4935 patients (mean age 71.8 years, 71.0% male). Among the 5 components consisting of "busyness", "weak will", "dislike, "socioeconomic reasons" and "diseases" in the questionnaires, "busyness" (34.5%) and "diseases" (34.7%) were the most frequently reported factors limiting habitual exercise, while "socioeconomic reasons" were the least (15.3%). Multiple Cox proportional hazard models indicated that "busyness"and "diseases" were associated with better (hazard ratio (HR) 0.53, 95% confidence interval (CI) 0.39-0.72, P < 0.001) and worse prognosis (HR 1.57, 95% CI 1.21-1.98, P < 0.001), respectively, while other components were not. Furthermore, it was noted that, while prognostic relevance of "busyness" limiting exercise did not differ by age or sex, negative impact of "diseases" was particularly evident in patients with age < 75 years (P for interaction < 0.01). Factors limiting habitual exercise were associated with "busyness" and "diseases", but not with "weak will", "dislike, or "socioeconomic reasons". While "busyness" was associated with better prognosis regardless of age and sex, "diseases" was associated with worse prognosis in younger populations. Thus, physicians may pay more attentions to the reasons that limit exercise in the daily lives of HF patients rather than the low amount of exercise itself.
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Tolerância ao Exercício , Exercício Físico , Hábitos , Conhecimentos, Atitudes e Prática em Saúde , Insuficiência Cardíaca/fisiopatologia , Motivação , Idoso , Idoso de 80 Anos ou mais , Feminino , Nível de Saúde , Insuficiência Cardíaca/diagnóstico , Insuficiência Cardíaca/psicologia , Humanos , Japão , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Sistema de Registros , Inquéritos e QuestionáriosRESUMO
BACKGROUND: Aggregation of solid-phase calcium-phosphate and fetuin-A form nanoparticles called calciprotein particles (CPP). Serum CPP levels are increased in CKD patients and correlated with vascular stiffness and calcification. In this study, we evaluated effects of lanthanum carbonate (LC) and calcium carbonate (CC) on serum CPP levels in hemodialysis (HD) patients. METHODS: Twenty-four (24) HD patients (50% men, age; 68 ± 12 years, dialysis period; 6.2 ± 4.8 years, Kt/v; 1.74 ± 0.34) were treated with CC during 0-8 weeks and then switched to LC during 9-16 weeks. Blood samples were obtained at 0, 8, 16 weeks. Serum CPP levels (TCPP) were measured by the gel-filtration method. Low-density CPP (LCPP) levels were determined by centrifuging the serum samples at 16,000 g for 2 h and measuring CPP levels in the supernatant. The difference between TCPP and LCPP was defined as the high-density CPP (HCPP) level. We evaluated association of TCPP, LCPP, and HCPP with serum calcium (Ca), phosphorus (P), intact PTH, FGF23, Klotho, fetuin-A, aortic calcification index (ACI), LDL cholesterol, and hs-CRP. RESULTS: TCPP and LCPP levels were significantly decreased after switching CC to LC, whereas Ca and P levels were not changed. HCPP levels were below the lower limit quantification in all patients. The changes in P, Ca × P, LDL cholesterol, but not ACI and the changes in hs-CRP, were correlated with the change in TCPP levels. CONCLUSION: The TCPP levels were significantly decreased after switching CC to LC. Non-calcium-containing phosphate binders may be preferable for lowering CPP levels.
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Cálcio/sangue , Hiperfosfatemia/tratamento farmacológico , Lantânio/uso terapêutico , Fosfatos/sangue , alfa-2-Glicoproteína-HS/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Carbonato de Cálcio/uso terapêutico , Substituição de Medicamentos , Feminino , Fator de Crescimento de Fibroblastos 23 , Humanos , Hiperfosfatemia/sangue , Hiperfosfatemia/etiologia , Falência Renal Crônica/complicações , Falência Renal Crônica/terapia , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Diálise RenalRESUMO
Abdominal aortic aneurysm (AAA) is a life-threatening disease. However, no systemically injectable drug has been approved for AAA treatment due to low bioavailability. Polymeric micelles are nanomedicines that have the potential to improve therapeutic efficacy by selectively delivering drugs into disease sites, and research has mainly focused on cancer treatments. Here, we developed a statin-loaded polymeric micelle to treat AAAs in rat models. The micelle showed medicinal efficacy by preventing aortic aneurysm expansion in a dose-dependent manner. Furthermore, the micelle-injected group showed decreased macrophage infiltration and decreased matrix metalloproteinase-9 activity in cases of AAA.
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Aneurisma da Aorta Abdominal/tratamento farmacológico , Sistemas de Liberação de Medicamentos , Inibidores de Hidroximetilglutaril-CoA Redutases , Nanopartículas , Animais , Aneurisma da Aorta Abdominal/induzido quimicamente , Aneurisma da Aorta Abdominal/metabolismo , Aneurisma da Aorta Abdominal/patologia , Modelos Animais de Doenças , Inibidores de Hidroximetilglutaril-CoA Redutases/química , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Macrófagos/metabolismo , Macrófagos/patologia , Masculino , Metaloproteinase 9 da Matriz/metabolismo , Micelas , Nanopartículas/química , Nanopartículas/uso terapêutico , Ratos , Ratos Sprague-DawleyRESUMO
PURPOSE: To investigate the effects of alveolar recruitment maneuver (ARM) during one-lung ventilation (OLV) on end-expiratory lung volume (EELV) of the dependent lung. METHODS: Patients who were planned to undergo lung resection surgery for lung tumors and needed OLV for at least 1 h were included in the study. After turning the patients into the lateral position under total intravenous anesthesia, OLV was commenced using a double-lumen endobronchial tube. EELV was measured using the nitrogen washout technique at 20 min after OLV started (baseline) and 15, 30, 45, 60 min after ARM was performed on the dependent lung. RESULTS: Among 42 patients who completed the study, EELV increased at 15 min after ARM by 20% or greater compared with baseline in 21 patients (responders). Responders were significantly shorter in height (158 vs. 165 cm, p = 0.01) and had smaller preoperative functional residual capacity (2.99L vs. 3.65L, p = 0.02) than non-responders. Before ARM, responders had significantly higher driving pressure (14.2 vs. 12.4 cmH2O, p = 0.01) and lower respiratory system compliance (23.6 vs. 31.4 ml/cmH2O, p = 0.0002) than non-responders. Driving pressure temporarily dropped after ARM in responders, while no significant change was observed in non-responders. Fourteen out of 21 responders kept EELV 20% or more increased EELV than baseline at 60 min after ARM. CONCLUSION: EELV of the dependent lung was increased by 20% or greater in half of the patients responding to ARM. The increased volume of the dependent lung caused by ARM was maintained for 60 min in two-thirds of the responders.
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Ventilação Monopulmonar , Capacidade Residual Funcional , Humanos , Pulmão , Respiração com Pressão Positiva , Volume de Ventilação PulmonarRESUMO
Protein-protein interactions (PPIs) lead the formation of protein complexes that perform biochemical reactions that maintain the living state of the living cell. Although therapeutic drugs should influence the formation of protein complexes in addition to PPI network, the methodology analyzing such influences remain to be developed. Here, we demonstrate that a new approach combining HPLC (high performance liquid chromatography) for separating protein complexes, and the SILAC (stable isotope labeling using amino acids in cell culture) method for relative protein quantification, enable us to identify the protein complexes influenced by a drug. We applied this approach to the analysis of thalidomide action on HepG2 cells, assessed the identified proteins by clustering data analyses, and assigned 135 novel protein complexes affected by the drug. We propose that this approach is applicable to elucidating the mechanisms of actions of other therapeutic drugs on the PPI network, and the formation of protein complexes.
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Aminoácidos/química , Avaliação Pré-Clínica de Medicamentos/métodos , Mapas de Interação de Proteínas/efeitos dos fármacos , Proteínas/química , Proteínas/metabolismo , Proteômica , Células Hep G2 , Humanos , Marcação por Isótopo , Talidomida/farmacologiaRESUMO
Ribosome biogenesis occurs successively in the nucleolus, nucleoplasm, and cytoplasm. Maturation of the ribosomal small subunit is completed in the cytoplasm by incorporation of a particular class of ribosomal proteins and final cleavage of 18S-E pre-rRNA (18S-E). Here, we show that poly(A)-specific ribonuclease (PARN) participates in steps leading to 18S-E maturation in human cells. We found PARN as a novel component of the pre-40S particle pulled down with the pre-ribosome factor LTV1 or Bystin. Reverse pull-down analysis revealed that PARN is a constitutive component of the Bystin-associated pre-40S particle. Knockdown of PARN or exogenous expression of an enzyme-dead PARN mutant (D28A) accumulated 18S-E in both the cytoplasm and nucleus. Moreover, expression of D28A accumulated 18S-E in Bystin-associated pre-40S particles, suggesting that the enzymatic activity of PARN is necessary for the release of 18S-E from Bystin-associated pre-40S particles. Finally, RNase H-based fragmentation analysis and 3Î-sequence analysis of 18S-E species present in cells expressing wild-type PARN or D28A suggested that PARN degrades the extended regions encompassing nucleotides 5-44 at the 3Î end of mature 18S rRNA. Our results reveal a novel role for PARN in ribosome biogenesis in human cells.