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1.
Int J Biol Macromol ; 272(Pt 1): 132801, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38825263

RESUMO

The changes of physicochemical, structural and functional properties and the lysinoalanine (LAL) formation during the unfolding and refolding of black soldier fly larvae albumin (BSFLA) induced by acid/alkaline pH shift were explored. The results showed that acid/alkaline conditions induced unfolding of BSFLA structure, but also accompanied by the formation of some large aggregates due to the hydrophobic interactions, hydrogen bonds, and disulfide bonds. Compared with control or pH1.5 shift, pH12 shift treatment significantly increased the electrostatic repulsion, surface hydrophobicity, free sulfhydryl group, and deamidation reactions, but reduced the fluorescence intensity of BSFLA, and these change in protein conformation contributed to increase in solubility, emulsion activity, and emulsion stability. But the content of LAL in BSFLA was increased by 93.39 % by pH 12 shift treatment. In addition, pH1.5 shift modified BSFLA tended to form ß-sheet structure through unfolding and refolding, resulting in the formation of aggregates with larger particle sizes, and reducing the solubility and the LAL content by 7.93 % and 65.53 %, respectively. SDS-PAGE profile showed that pH12/1.5 shifting did not cause irreversible denaturation of protein molecules. Therefore, pH12-shift is good way to improve the functional properties of BSFLA, but the content of LAL should be reduced to make it better used in food.


Assuntos
Interações Hidrofóbicas e Hidrofílicas , Lisinoalanina , Desdobramento de Proteína , Animais , Concentração de Íons de Hidrogênio , Lisinoalanina/química , Larva , Albuminas/química , Dípteros/química , Solubilidade , Redobramento de Proteína/efeitos dos fármacos , Proteínas de Insetos/química , Fenômenos Químicos
2.
Signal Transduct Target Ther ; 9(1): 143, 2024 Jun 07.
Artigo em Inglês | MEDLINE | ID: mdl-38844468

RESUMO

Metastatic pancreatic cancer (mPC) has a dismal prognosis. Herein, we conducted a prospective, multicentre, single-arm, phase II trial evaluating the efficacy and safety of penpulimab and anlotinib in combination with nab-paclitaxel/gemcitabine (PAAG) in patients with first-line mPC (NCT05493995). The primary endpoints included the objective response rate (ORR) and disease control rate (DCR), while secondary endpoints encompassed progression-free survival (PFS), overall survival (OS), and safety. In 66 patients analysed for efficacy, the best response, indicated by the ORR, was recorded at 50.0% (33/66) (95% CI, 37.4-62.6%), with 33 patients achieving partial response (PR). Notably, the DCR was 95.5% (63/66, 95% CI, 87.3-99.1%). The median PFS (mPFS) and OS (mOS) were 8.8 (95% CI, 8.1-11.6), and 13.7 (95% CI, 12.4 to not reached) months, respectively. Grade 3/4 treatment-related adverse events (TRAEs) were reported in 39.4% of patients (26/66). In prespecified exploratory analysis, patients with altered SWI/SNF complex had a poorer PFS. Additionally, low serum CA724 level, high T-cell recruitment, low Th17 cell recruitment, and high NK CD56dim cell scores at baseline were potential predicative biomarkers for more favourable efficacy. In conclusion, PAAG as a first-line therapy demonstrated tolerability with promising clinical efficacy for mPC. The biomolecular findings identified in this study possess the potential to guide the precise clinical application of the triple-combo regimen.


Assuntos
Albuminas , Protocolos de Quimioterapia Combinada Antineoplásica , Desoxicitidina , Gencitabina , Indóis , Paclitaxel , Neoplasias Pancreáticas , Quinolinas , Humanos , Masculino , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/patologia , Feminino , Paclitaxel/administração & dosagem , Paclitaxel/efeitos adversos , Paclitaxel/farmacologia , Pessoa de Meia-Idade , Idoso , Desoxicitidina/análogos & derivados , Desoxicitidina/administração & dosagem , Indóis/administração & dosagem , Indóis/uso terapêutico , Albuminas/administração & dosagem , Albuminas/efeitos adversos , Quinolinas/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Estudos Prospectivos , Adulto , Metástase Neoplásica , Inibidores da Angiogênese/efeitos adversos , Inibidores da Angiogênese/uso terapêutico , Inibidores da Angiogênese/administração & dosagem , Inibidores da Angiogênese/farmacologia , Anticorpos Monoclonais Humanizados/administração & dosagem , Anticorpos Monoclonais Humanizados/uso terapêutico , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Receptor de Morte Celular Programada 1/imunologia
3.
Artigo em Inglês | MEDLINE | ID: mdl-38735125

RESUMO

Protein adducts are vital targets for exploring organophosphorus nerve agents (OPNAs) exposure and identification, that can be used to characterize the chemical burden and initiate chemical safety measures. However, the use of protein adducts as biomarkers of OPNA exposure has developed slowly. To further promote the development of biomarkers in chemical forensics, it is crucial to expand the range of modified peptides and active sites, and describe the characteristics of OPNA adducts at specific reaction sites. This study utilized multi-species and multi-source albumins as the protein targets. We identified 56 peptides in albumins from various species (including human, horse, rat and pig), that were modified by at least two OPNAs. Diverse modification characteristics were observed in response to certain agents: including (1) multiple sites on the same peptide modified by one or more agents, (2) different reactivities at the same site in homologous albumins, and (3) different preferences at the same active sites associated with differences in the biological matrix during exposure. Our studies provided an empirical reference with rationalized underpinnings supported by estimated conformation energetics through molecular modeling. We employed different peptide markers for detection of protein adducts, as (one would do) in forensic screening for identification and quantification of chemical damage. Three characteristic peptides were screened and analyzed in human albumin, including Y287ICENQDSISSK, K438VPQVS443TPTLVEVSR, and Y162LY164EIAR. Stable fragment ions with neutral loss were found from their tandem MS/MS spectra, which were used as characteristic ions for identification and extraction of modified peptides in enzymatic digestion mixtures. Coupling these observations with computer simulations, we found that the structural stability of albumin and albumin-adduct complexes (as well as the effective force that promotes stability of different adducts) changes in the interval before and after adduct formation. In pig albumin, five active peptides existed stably in vivo and in vitro. Most of them can be detected within 30 min after OPNA exposure, and the detection window can persist about half a month. These early findings provided the foundation and rationale for utilizing pig albumin as a sampling target for rapid analysis in future forensic work.


Assuntos
Agentes Neurotóxicos , Compostos Organofosforados , Animais , Humanos , Ratos , Compostos Organofosforados/química , Suínos , Agentes Neurotóxicos/química , Agentes Neurotóxicos/análise , Cavalos , Espectrometria de Massas em Tandem/métodos , Peptídeos/química , Peptídeos/análise , Albuminas/química , Albuminas/metabolismo , Biomarcadores/análise , Biomarcadores/química
5.
J Control Release ; 370: 468-478, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38697314

RESUMO

A critical parameter during the development of protein therapeutics is to endow them with suitable pharmacokinetic and pharmacodynamic properties. Small protein drugs are quickly eliminated by kidney filtration, and in vivo half-life extension is therefore often desired. Here, different half-life extension technologies were studied where PAS polypeptides (PAS300, PAS600), XTEN polypeptides (XTEN288, XTEN576), and an albumin binding domain (ABD) were compared for half-life extension of an anti-human epidermal growth factor receptor 2 (HER2) affibody-drug conjugate. The results showed that extension with the PAS or XTEN polypeptides or the addition of the ABD lowered the affinity for HER2 to some extent but did not negatively affect the cytotoxic potential. The half-lives in mice ranged from 7.3 h for the construct including PAS300 to 11.6 h for the construct including PAS600. The highest absolute tumor uptake was found for the construct including the ABD, which was 60 to 160% higher than the PASylated or XTENylated constructs, even though it did not have the longest half-life (9.0 h). A comparison of the tumor-to-normal-organ ratios showed the best overall performance of the ABD-fused construct. In conclusion, PASylation, XTENylation, and the addition of an ABD are viable strategies for half-life extension of affibody-drug conjugates, with the best performance observed for the construct including the ABD.


Assuntos
Peptídeos , Receptor ErbB-2 , Animais , Meia-Vida , Receptor ErbB-2/metabolismo , Humanos , Linhagem Celular Tumoral , Peptídeos/química , Peptídeos/farmacocinética , Peptídeos/administração & dosagem , Feminino , Camundongos Nus , Albuminas/química , Proteínas Recombinantes de Fusão/farmacocinética , Proteínas Recombinantes de Fusão/química , Proteínas Recombinantes de Fusão/administração & dosagem , Antineoplásicos/administração & dosagem , Antineoplásicos/farmacocinética , Antineoplásicos/química , Camundongos , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Imunoconjugados/farmacocinética , Imunoconjugados/química , Imunoconjugados/administração & dosagem , Camundongos Endogâmicos BALB C , Distribuição Tecidual
6.
J Cancer Res Clin Oncol ; 150(5): 233, 2024 May 06.
Artigo em Inglês | MEDLINE | ID: mdl-38709400

RESUMO

OBJECTIVE: A preclinical study showed that nab-paclitaxel acted as a radiosensitizer and improved tumor radiotherapy in a supra-additive manner. In this study, we aimed to evaluate the clinical efficacy and safety of concurrent chemoradiotherapy (CCRT) with cisplatin and nab-paclitaxel in postoperative early-stage cervical cancer with an unfavorable prognosis. METHODS: Eligible patients with stage IB1-IIA2 (FIGO 2009) cervical carcinoma were recruited retrospectively between August 2018 to May 2021. Patients in both the cisplatin and nab-paclitaxel groups received postoperative radiotherapy and weekly intravenous cisplatin 40 mg/m2 or nab-paclitaxel 100 mg concurrently. An analysis of overall survival, progression-free survival, and adverse reactions was conducted. RESULTS: A total of 105 early-stage cervical cancer patients were included into our study. The median follow-up time was 38.7 months. The 3-year overall survival and progression-free survival in both group was similar. The cycles of chemotherapy in the cisplatin group were less than those in the nab-paclitaxel group (4.5 vs. 5.0; p = 0.001). Patients in the cisplatin group had a significantly higher frequency of hematological adverse events than patients in the nab-paclitaxel group (P < 0.05). Patients in the cisplatin group had a significantly higher frequency of grade 3-4 leukopenia (46.1% vs. 18.9%; P = 0.03), grade 1-2 thrombocytopenia (32.7% vs. 9.5%; P = 0.014) than patients in the nab-paclitaxel group. Gastrointestinal reactions, such as vomiting, nausea, and anorexia were significantly reduced in the nab-paclitaxel group compared with those in the cisplatin group. Regarding the effects on alopecia, the incidence rate of the nab-paclitaxel group was higher than that of the cisplatin group (P = 0.001). There were no differences between the groups in terms of other adverse reactions. CONCLUSION: The results of this study indicate that nab-paclitaxel-based concurrent radiotherapy is tolerable and effective, and can be considered an alternative to cisplatin chemotherapy.


Assuntos
Albuminas , Protocolos de Quimioterapia Combinada Antineoplásica , Quimiorradioterapia , Cisplatino , Paclitaxel , Neoplasias do Colo do Útero , Humanos , Feminino , Neoplasias do Colo do Útero/terapia , Neoplasias do Colo do Útero/patologia , Neoplasias do Colo do Útero/tratamento farmacológico , Cisplatino/administração & dosagem , Cisplatino/efeitos adversos , Cisplatino/uso terapêutico , Paclitaxel/administração & dosagem , Paclitaxel/efeitos adversos , Paclitaxel/uso terapêutico , Pessoa de Meia-Idade , Quimiorradioterapia/métodos , Quimiorradioterapia/efeitos adversos , Estudos Retrospectivos , Albuminas/administração & dosagem , Albuminas/uso terapêutico , Albuminas/efeitos adversos , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Estadiamento de Neoplasias , Idoso
7.
Intensive Care Med ; 50(6): 813-831, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38771364

RESUMO

PURPOSE: This is the first of three parts of the clinical practice guideline from the European Society of Intensive Care Medicine (ESICM) on resuscitation fluids in adult critically ill patients. This part addresses fluid choice and the other two will separately address fluid amount and fluid removal. METHODS: This guideline was formulated by an international panel of clinical experts and methodologists. The Grading of Recommendations Assessment, Development, and Evaluation (GRADE) methodology was applied to evaluate the certainty of evidence and to move from evidence to decision. RESULTS: For volume expansion, the guideline provides conditional recommendations for using crystalloids rather than albumin in critically ill patients in general (moderate certainty of evidence), in patients with sepsis (moderate certainty of evidence), in patients with acute respiratory failure (very low certainty of evidence) and in patients in the perioperative period and patients at risk for bleeding (very low certainty of evidence). There is a conditional recommendation for using isotonic saline rather than albumin in patients with traumatic brain injury (very low certainty of evidence). There is a conditional recommendation for using albumin rather than crystalloids in patients with cirrhosis (very low certainty of evidence). The guideline provides conditional recommendations for using balanced crystalloids rather than isotonic saline in critically ill patients in general (low certainty of evidence), in patients with sepsis (low certainty of evidence) and in patients with kidney injury (very low certainty of evidence). There is a conditional recommendation for using isotonic saline rather than balanced crystalloids in patients with traumatic brain injury (very low certainty of evidence). There is a conditional recommendation for using isotonic crystalloids rather than small-volume hypertonic crystalloids in critically ill patients in general (very low certainty of evidence). CONCLUSIONS: This guideline provides eleven recommendations to inform clinicians on resuscitation fluid choice in critically ill patients.


Assuntos
Cuidados Críticos , Estado Terminal , Soluções Cristaloides , Hidratação , Ressuscitação , Humanos , Hidratação/métodos , Hidratação/normas , Estado Terminal/terapia , Adulto , Cuidados Críticos/métodos , Cuidados Críticos/normas , Soluções Cristaloides/administração & dosagem , Soluções Cristaloides/uso terapêutico , Ressuscitação/métodos , Ressuscitação/normas , Europa (Continente) , Albuminas/uso terapêutico , Albuminas/administração & dosagem , Sepse/terapia
8.
Biofouling ; 40(3-4): 290-304, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38785127

RESUMO

Thermal bubble-driven micro-pumps are an upcoming micro-actuator technology that can be directly integrated into micro/mesofluidic channels, have no moving parts, and leverage existing mass production fabrication approaches. These micro-pumps consist of a high-power micro-resistor that boils fluid in microseconds to create a high-pressure vapor bubble which performs mechanical work. As such, these micro-pumps hold great promise for micro/mesofluidic systems such as lab-on-a-chip technologies. However, to date, no current work has studied the interaction of these micro-pumps with biofluids such as blood and protein-rich fluids. In this study, the effects of organic fouling due to egg albumin and bovine whole blood are characterized using stroboscopic high-speed imaging and a custom deep learning neural network based on transfer learning of RESNET-18. It was found that the growth of a fouling film inhibited vapor bubble formation. A new metric to quantify the extent of fouling was proposed using the decrease in vapor bubble area as a function of the number of micro-pump firing events. Fouling due to egg albumin and bovine whole blood was found to significantly degrade pump performance as well as the lifetime of thermal bubble-driven micro-pumps to less than 104 firings, which may necessitate the use of protective thin film coatings to prevent the buildup of a fouling layer.


Assuntos
Incrustação Biológica , Incrustação Biológica/prevenção & controle , Animais , Bovinos , Albuminas , Dispositivos Lab-On-A-Chip , Soroalbumina Bovina/química
9.
Bioorg Med Chem ; 106: 117754, 2024 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-38728869

RESUMO

To improve the biodistribution of the drug in the tumor, a supramolecular prodrug of SN38 was fabricated in situ between endogenous albumin and SN38 prodrug modified with semaglutide side chain. Firstly, SN38 was conjugated with semaglutide side chain and octadecanedioic acid via glycine linkers to obtain SI-Gly-SN38 and OA-Gly-SN38 prodrugs, respectively. Both SI-Gly-SN38 and OA-Gly-SN38 exhibited excellent stability in PBS for over 24 h. Due to the strong binding affinity of the semaglutide side chain with albumin, the plasma half-life of SI-Gly-SN38 was 2.7 times higher than that of OA-Gly-SN38. Furthermore, with addition of HSA, the fluorescence intensity of SI-Gly-SN38 was 4 times higher than that of OA-Gly-SN38, confirming its strong binding capability with HSA. MTT assay showed that the cytotoxicity of SI-Gly-SN38 and OA-Gly-SN38 was higher than that of Irinotecan. Even incubated with HSA, the SI-Gly-SN38 and OA-Gly-SN38 still maintained high cytotoxicity, indicating minimal influence of HSA on their cytotoxicity. In vivo pharmacokinetic studies demonstrated that the circulation half-life of SI-Gly-SN38 was twice that of OA-Gly-SN38. SI-Gly-SN38 exhibited significantly reduced accumulation in the lungs, being only 0.23 times that of OA-Gly-SN38. The release of free SN38 in the lungs from SI-Gly-SN38 was only 0.4 times that from OA-Gly-SN38 and Irinotecan. The SI-Gly-SN38 showed the highest accumulation in tumors. The tumor inhibition rate of SI-Gly-SN38 was 6.42% higher than that of OA-Gly-SN38, and 8.67% higher than that of Irinotecan, respectively. These results indicate that the supramolecular prodrug delivery system can be constructed between SI-Gly-SN38 and endogenous albumin, which improves drug biodistribution in vivo, enhances tumor accumulation, and plays a crucial role in tumor growth inhibition.


Assuntos
Irinotecano , Pró-Fármacos , Irinotecano/química , Irinotecano/farmacologia , Pró-Fármacos/química , Pró-Fármacos/farmacologia , Pró-Fármacos/síntese química , Animais , Humanos , Camundongos , Distribuição Tecidual , Antineoplásicos/química , Antineoplásicos/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/farmacocinética , Estrutura Molecular , Ensaios de Seleção de Medicamentos Antitumorais , Proliferação de Células/efeitos dos fármacos , Linhagem Celular Tumoral , Camundongos Endogâmicos BALB C , Camundongos Nus , Albuminas/química , Masculino , Relação Estrutura-Atividade , Albumina Sérica Humana/química , Peptídeos Semelhantes ao Glucagon
11.
Pancreas ; 53(6): e492-e500, 2024 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-38767967

RESUMO

OBJECTIVES: To clarify the treatment reality of pancreatic cancer in Japan, focusing on treatment duration and time to death. MATERIALS AND METHODS: We retrospectively analyzed Japanese hospital claims data for patients diagnosed with pancreatic cancer between April 2009 and October 2018 to investigate treatment patterns, duration of first-line chemotherapy, and time to death. RESULTS: Of 81,185 eligible patients, 54.2% were male, the mean age was 71.7 years, and 23.3% (n = 18,884) received chemotherapy as primary treatment. The median treatment duration was 14.1 weeks for the 6.7% of patients who received oxaliplatin, irinotecan, fluorouracil, and leucovorin (FOLFIRINOX; recommended first-line regimen) and 16.9 weeks for the 30.2% of patients who received gemcitabine plus nab-paclitaxel (GEM + nab-PTX). Time to death for patients who received FOLFIRINOX or GEM + nab-PTX was similar (15.4 and 14.8 months, respectively). The duration of first-line chemotherapy regimens tended to increase annually for both regimens. The time to death for all first-line chemotherapy regimens also increased annually. CONCLUSIONS: This study revealed the treatment reality of pancreatic cancer in the real-world Japanese setting. Treatment duration and time to death tended to increase over time and did not differ numerically between FOLFIRINOX and GEM + nab-PTX.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica , Bases de Dados Factuais , Fluoruracila , Irinotecano , Leucovorina , Oxaliplatina , Neoplasias Pancreáticas , Humanos , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/mortalidade , Masculino , Feminino , Japão/epidemiologia , Idoso , Estudos Retrospectivos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Leucovorina/administração & dosagem , Leucovorina/uso terapêutico , Pessoa de Meia-Idade , Fluoruracila/administração & dosagem , Fluoruracila/uso terapêutico , Irinotecano/uso terapêutico , Irinotecano/administração & dosagem , Oxaliplatina/administração & dosagem , Oxaliplatina/uso terapêutico , Paclitaxel/administração & dosagem , Paclitaxel/uso terapêutico , Gencitabina , Duração da Terapia , Desoxicitidina/análogos & derivados , Desoxicitidina/uso terapêutico , Desoxicitidina/administração & dosagem , Fatores de Tempo , Idoso de 80 Anos ou mais , Albuminas/administração & dosagem , Albuminas/uso terapêutico , População do Leste Asiático
12.
J Transl Med ; 22(1): 454, 2024 May 13.
Artigo em Inglês | MEDLINE | ID: mdl-38741158

RESUMO

BACKGROUND: Glycosylation is an enzyme-catalyzed post-translational modification that is distinct from glycation and is present on a majority of plasma proteins. N-glycosylation occurs on asparagine residues predominantly within canonical N-glycosylation motifs (Asn-X-Ser/Thr) although non-canonical N-glycosylation motifs Asn-X-Cys/Val have also been reported. Albumin is the most abundant protein in plasma whose glycation is well-studied in diabetes mellitus. However, albumin has long been considered a non-glycosylated protein due to absence of canonical motifs. Albumin contains two non-canonical N-glycosylation motifs, of which one was recently reported to be glycosylated. METHODS: We enriched abundant serum proteins to investigate their N-linked glycosylation followed by trypsin digestion and glycopeptide enrichment by size-exclusion or mixed-mode anion-exchange chromatography. Glycosylation at canonical as well as non-canonical sites was evaluated by liquid chromatography-tandem mass spectrometry (LC-MS/MS) of enriched glycopeptides. Deglycosylation analysis was performed to confirm N-linked glycosylation at non-canonical sites. Albumin-derived glycopeptides were fragmented by MS3 to confirm attached glycans. Parallel reaction monitoring was carried out on twenty additional samples to validate these findings. Bovine and rabbit albumin-derived glycopeptides were similarly analyzed by LC-MS/MS. RESULTS: Human albumin is N-glycosylated at two non-canonical sites, Asn68 and Asn123. N-glycopeptides were detected at both sites bearing four complex sialylated glycans and validated by MS3-based fragmentation and deglycosylation studies. Targeted mass spectrometry confirmed glycosylation in twenty additional donor samples. Finally, the highly conserved Asn123 in bovine and rabbit serum albumin was also found to be glycosylated. CONCLUSIONS: Albumin is a glycoprotein with conserved N-linked glycosylation sites that could have potential clinical applications.


Assuntos
Glicopeptídeos , Glicoproteínas , Glicosilação , Glicoproteínas/metabolismo , Glicoproteínas/química , Humanos , Glicopeptídeos/metabolismo , Glicopeptídeos/química , Sequência de Aminoácidos , Espectrometria de Massas em Tandem , Animais , Dados de Sequência Molecular , Albuminas/metabolismo , Bovinos , Cromatografia Líquida
13.
Indian J Gastroenterol ; 43(2): 494-504, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38722510

RESUMO

BACKGROUND AND AIMS: Decompensated liver cirrhosis has a poor prognosis, with a median overall survival of two to four years, which is worse than for many oncological disorders. These patients are highly susceptible to infections due to increased systemic inflammation leading to kidney failure and death. The aim was to study the efficacy of albumin in reducing episodes of decompensation, preventing bacterial infection, kidney dysfunction and mortality. METHOD: Study involved patients with Child B or C cirrhosis with an albumin level below 3.0 g/dL, who were administered 20% human albumin weekly with standard medical treatment (SMT) for three months or till serum albumin levels were 4.0 g/dL (whichever is earlier) and compared with age and sex-matched controls who received only SMT. The primary end-point was six-month mortality and the secondary end-points were reduction in infections, kidney dysfunction, ascites recurrence, hepatic encephalopathy (HE), gastrointestinal (GI) bleed and complications of cirrhosis. RESULTS: From September 2021 to January 2023, 88 cases and 86 controls were taken and followed up for six months. Overall, six-month survival was not statistically significant between groups (95.1% vs. 91.9%; p = 0·330). The incidence of recurrence of ascites (34.09% vs. 59.3%, p < 0.001), kidney dysfunction (6.8% vs. 24.4%, p < 0.001), HE (15.9% vs, 37.2%, p = 0.015), spontaneous bacterial peritonitis (SBP) (3.4% vs 17.4%, p = 0.002) and non-SBP infections (7.9% vs. 18.6%, p = 0.038) were significantly less in cases as compared with controls; however, GI bleed (14.8% vs. 17.4%, p = 0.632) was not statistically significant. CONCLUSION: Long-term human albumin acts as a disease-modifying treatment in patients with decompensated cirrhosis.


Assuntos
Cirrose Hepática , Humanos , Cirrose Hepática/complicações , Feminino , Masculino , Pessoa de Meia-Idade , Resultado do Tratamento , Ascite/etiologia , Fatores de Tempo , Infecções Bacterianas/etiologia , Recidiva , Albumina Sérica/administração & dosagem , Albumina Sérica/análise , Idoso , Encefalopatia Hepática/etiologia , Hemorragia Gastrointestinal/etiologia , Adulto , Albuminas/administração & dosagem , Estudos de Casos e Controles
14.
Theranostics ; 14(7): 2675-2686, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38773981

RESUMO

Cyanine dyes are widely used organic probes for in vivo imaging due to their tunable fluorescence. They can form complexes with endogenous albumin, resulting in enhanced brightness and photostability. However, this binding is uncontrollable and irreversible, leading to considerable nonspecific background signals and unregulated circulation time. Methods: Here, we connect varying numbers of 4-(4-iodophenyl) butanoic acid (IP) as albumin-binding moieties (ABM) to the cyanine dye, enabling dynamic and controllable binding with albumin. Meanwhile, we provide a blocking method to completely release the dye from covalent capture with albumin, resulting in specific targeting fluorescence. Furthermore, we evaluate the pharmacokinetics and tumor targeting of the developed dyes. Results: The engineered dyes can dynamically and selectively bind with multiple albumins to change the in situ size of assemblies and circulation time, providing programmable regulation over the imaging time window. The nucleophilic substitution of meso-Cl with water-soluble amino acids or targeting peptides for IP-engineered dye further addresses the nonspecific signals caused by albumin, allowing for adjustable angiography time and efficient tumor targeting. Conclusion: This study rationalizes the binding modes of dyes and proteins, applicable to a wide range of near-infrared (NIR) dyes for improving their in vivo molecular imaging.


Assuntos
Albuminas , Corantes Fluorescentes , Imagem Óptica , Animais , Corantes Fluorescentes/química , Corantes Fluorescentes/farmacocinética , Albuminas/química , Albuminas/metabolismo , Imagem Óptica/métodos , Neoplasias/diagnóstico por imagem , Camundongos , Humanos , Carbocianinas/química , Camundongos Nus , Linhagem Celular Tumoral , Camundongos Endogâmicos BALB C
15.
Food Res Int ; 186: 114380, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38729734

RESUMO

Pea albumins are found in the side stream during the isolation of pea proteins. They are soluble at acidic pH and have functional properties which differ from their globulin counterparts. In this study, we have investigated the aggregation and structural changes occurring to pea albumins under different environmental conditions, using a combination of size-exclusion chromatography coupled with multi-angle laser light scattering (SEC-MALS) and small-angle X-ray scattering (SAXS). Albumins were extracted from a dry fractionated pea protein concentrate by precipitating the globulin fraction at acidic pH. The albumins were then studied at different pH (3, 4, 4.5, 7, 7.5, and 8) values. The effect of heating at 90 °C for 1, 3, and 5 min on their structural changes was investigated using SAXS. In addition, size exclusion of the albumins showed 4 distinct populations, depending on pH and heating conditions, with two large aggregates peaks (∼250 kDa): a dimer peak (∼24 kDa) containing predominantly pea albumin 2 (PA2), and a monomer peak of a molar mass of about 12 kDa (PA1). X-ray scattering intensities as a function of q were modeled as polydisperse spheres, and their aggregation was followed as a function of heating time. Albumins was most stable at pH 3, showing no aggregation during heat treatment. While albumins at pH 7.5 and 8 showed aggregation after heating, solutions at pH 4, 4.5, and 7 already contained aggregates even before heating. This work provides new knowledge on the overall structural development of albumins under different environmental conditions, improving our ability to employ these as future ingredients in foods.


Assuntos
Temperatura Alta , Proteínas de Ervilha , Pisum sativum , Espalhamento a Baixo Ângulo , Difração de Raios X , Concentração de Íons de Hidrogênio , Pisum sativum/química , Proteínas de Ervilha/química , Albuminas/química , Cromatografia em Gel
16.
Artigo em Alemão | MEDLINE | ID: mdl-38759685

RESUMO

Combining albumin dialysis for the removal of hydrophobic substances with classical haemodialysis in the treatment of acute liver failure (ALF) and acute-on-chronic liver failure (ACLF) has a strong theoretical rational and clinical data showed a positive effect on laboratory and partly clinical characteristics of ALF and ACLF. However, neither the MARS nor the Prometheus System has so far been able to demonstrate a mortality benefit in ALF or ACLF patients. To date, only the use of therapeutic plasma exchange (TPE) has demonstrated significant removal of pathogen-associated (PAMPs), damage-associated molecular patterns (DAMPs) and pro-inflammatory cytokines. In addition, TPE also acts simultaneously by replacing protective but depleted mediators, thus improving multiple key pathophysiological principles of both ALF and ACLF. In ALF, both high-volume and standard-volume TPE showed a significant improvement in survival. The data on the use of TPE in ACLF is still sparse, with only two Chinese monocentric studies in patients with exclusively hepatitis B-associated ACLF suggesting potentially improved survival with TPE. The currently recruiting APACHE study will include patients with the modern EASL-CLIF definition of ACLF.


Assuntos
Troca Plasmática , Humanos , Diálise Renal , Albuminas/uso terapêutico , Insuficiência Hepática Crônica Agudizada/terapia , Falência Hepática Aguda/terapia , Falência Hepática/terapia , Resultado do Tratamento
17.
Mol Pharm ; 21(6): 2960-2969, 2024 Jun 03.
Artigo em Inglês | MEDLINE | ID: mdl-38680059

RESUMO

Very late antigen-4 (VLA-4) is a transmembrane integrin protein that is highly expressed in aggressive forms of metastatic melanoma. A small-molecule peptidomimetic, LLP2A, was found to have a low pM affinity binding to VLA-4. Because LLP2A itself does not inhibit cancer cell proliferation and survival, it is an ideal candidate for the imaging and delivery of therapeutic payloads. An analog of [177Lu]Lu-labeled-LLP2A was previously investigated as a therapeutic agent in melanoma tumor-bearing mice, resulting in only a modest improvement in tumor growth inhibition, likely due to rapid clearance of the agent from the tumor. To improve the pharmacokinetic profile, DOTAGA-PEG4-LLP2A with a 4-(p-iodophenyl)butyric acid (pIBA) albumin binding moiety was synthesized. We demonstrate the feasibility of this albumin binding strategy by comparing in vitro cell binding assays and in vivo biodistribution performance of [177Lu]Lu-DOTAGA-PEG4-LLP2A ([177Lu]Lu-1) to the albumin binding [177Lu]Lu-DOTAGA-pIBA-PEG4-LLP2A ([177Lu]Lu-2). In vitro cell binding assay results for [177Lu]Lu-1 and [177Lu]Lu-2 showed Kd values of 0.40 ± 0.07 and 1.75 ± 0.40 nM, with similar Bmax values of 200 ± 6 and 315 ± 15 fmol/mg, respectively. In vivo biodistribution data for both tracers exhibited specific uptake in the tumor, spleen, thymus, and bone due to endogenous expression of VLA-4. Compound [177Lu]Lu-2 exhibited a much longer blood circulation time compared to [177Lu]Lu-1. The tumor uptake for [177Lu]Lu-1 was highest at 1 h (∼15%ID/g) and that for [177Lu]Lu-2 was highest at 4 h (∼23%ID/g). Significant clearance of [177Lu]Lu-1 from the tumor occurs at 24 h (<5%ID/g) while[177Lu]Lu-2 is retained for greater than 96 h (∼10%ID/g). An efficacy study showed that melanoma tumor-bearing mice receiving compound [177Lu]Lu-2 given in two fractions (2 × 14.8 MBq, 14 days apart) had a greater median survival time than mice administered a single 29.6 MBq dose of compound [177Lu]Lu-1, while a single 29.6 MBq dose of [177Lu]Lu-2 imparted hematopoietic toxicity. The in vitro and in vivo data show addition of pIBA to [177Lu]Lu-DOTAGA-PEG4-LLP2A slows blood clearance for a higher tumor uptake, and there is potential of [177Lu]Lu-2 as a theranostic in fractionated administered doses.


Assuntos
Lutécio , Radioisótopos , Animais , Camundongos , Distribuição Tecidual , Linhagem Celular Tumoral , Melanoma/tratamento farmacológico , Melanoma/metabolismo , Humanos , Compostos Radiofarmacêuticos/farmacocinética , Melanoma Experimental/tratamento farmacológico , Melanoma Experimental/metabolismo , Feminino , Integrina alfa4beta1/metabolismo , Integrina alfa4beta1/antagonistas & inibidores , Albuminas , Peptídeos/química , Peptídeos/farmacocinética , Nanomedicina Teranóstica/métodos , Camundongos Endogâmicos C57BL , Dipeptídeos , Compostos de Fenilureia
18.
Poult Sci ; 103(6): 103618, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38564835

RESUMO

The decline in albumen quality resulting from aging hens poses a threat to the financial benefits of the egg industry. Exploring the underlying mechanisms from the perspective of cell molecules of albumen formation is significant for the efficient regulation of albumen quality. Two individual groups of Hy-Line Brown layers with ages of 40 (W40) and 100 (W100) wk old were used in the present study. Each group contained over 2,000 birds. This study assessed the egg quality, biochemical indicators and physiological status of hens between W40 and W100. Subsequently, a quantitative proteomic analysis was conducted to identify differences in protein abundance in magnum tissues between W40 and W100. In the W40 group, significant increases (P < 0.05) were notable for albumen quality (thick albumen solid content, albumen height, Haugh unit), serum indices (calcium, estrogen, and progesterone levels), magnum histomorphology (myosin light-chain kinase content, secretory capacity, mucosal fold, goblet cell count and proportion) as well as the total antioxidant capacity of the liver. However, the luminal diameter of the magnum, albumen gel properties and random coil of the albumen were increased (P < 0.05) in the W100 group. The activity of glutathione, superoxidase dismutase, and malondialdehyde in the liver, magnum, and serum did not vary (P > 0.05) among the groups. Proteomic analysis revealed the identification of 118 differentially expressed proteins between the groups, which comprised proteins associated with protein secretion, DNA damage and repair, cell proliferation, growth, antioxidants, and apoptosis. Furthermore, Kyoto Encyclopedia of Genes pathway analysis revealed that BRCA2 and FBN1 were significantly downregulated in Fanconi anemia (FA) and TGF-ß signaling pathways in W100, validated through quantitative real-time PCR (qRT-PCR). In conclusion, significant age-related variations in albumen quality, and magnum morphology are regulated by proteins involved in antioxidant capacity.


Assuntos
Galinhas , Animais , Galinhas/fisiologia , Galinhas/genética , Feminino , Envelhecimento , Albuminas/metabolismo , Proteômica , Óvulo/fisiologia , Óvulo/química
19.
Am J Physiol Renal Physiol ; 326(6): F1041-F1053, 2024 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-38660713

RESUMO

Beyond glycemic control, SGLT2 inhibitors (SGLT2is) have protective effects on cardiorenal function. Renoprotection has been suggested to involve inhibition of NHE3 leading to reduced ATP-dependent tubular workload and mitochondrial oxygen consumption. NHE3 activity is also important for regulation of endosomal pH, but the effects of SGLT2i on endocytosis are unknown. We used a highly differentiated cell culture model of proximal tubule (PT) cells to determine the direct effects of SGLT2i on Na+-dependent fluid transport and endocytic uptake in this nephron segment. Strikingly, canagliflozin but not empagliflozin reduced fluid transport across cell monolayers and dramatically inhibited endocytic uptake of albumin. These effects were independent of glucose and occurred at clinically relevant concentrations of drug. Canagliflozin acutely inhibited surface NHE3 activity, consistent with a direct effect, but did not affect endosomal pH or NHE3 phosphorylation. In addition, canagliflozin rapidly and selectively inhibited mitochondrial complex I activity. Inhibition of mitochondrial complex I by metformin recapitulated the effects of canagliflozin on endocytosis and fluid transport, whereas modulation of downstream effectors AMPK and mTOR did not. Mice given a single dose of canagliflozin excreted twice as much urine over 24 h compared with empagliflozin-treated mice despite similar water intake. We conclude that canagliflozin selectively suppresses Na+-dependent fluid transport and albumin uptake in PT cells via direct inhibition of NHE3 and of mitochondrial function upstream of the AMPK/mTOR axis. These additional targets of canagliflozin contribute significantly to reduced PT Na+-dependent fluid transport in vivo.NEW & NOTEWORTHY Reduced NHE3-mediated Na+ transport has been suggested to underlie the cardiorenal protection provided by SGLT2 inhibitors. We found that canagliflozin, but not empagliflozin, reduced NHE3-dependent fluid transport and endocytic uptake in cultured proximal tubule cells. These effects were independent of SGLT2 activity and resulted from inhibition of mitochondrial complex I and NHE3. Studies in mice are consistent with greater effects of canagliflozin versus empagliflozin on fluid transport. Our data suggest that these selective effects of canagliflozin contribute to reduced Na+-dependent transport in proximal tubule cells.


Assuntos
Canagliflozina , Túbulos Renais Proximais , Inibidores do Transportador 2 de Sódio-Glicose , Trocador 3 de Sódio-Hidrogênio , Animais , Túbulos Renais Proximais/efeitos dos fármacos , Túbulos Renais Proximais/metabolismo , Túbulos Renais Proximais/enzimologia , Trocador 3 de Sódio-Hidrogênio/metabolismo , Canagliflozina/farmacologia , Inibidores do Transportador 2 de Sódio-Glicose/farmacologia , Camundongos , Masculino , Transportador 2 de Glucose-Sódio/metabolismo , Endocitose/efeitos dos fármacos , Camundongos Endogâmicos C57BL , Albuminas/metabolismo , Mitocôndrias/metabolismo , Mitocôndrias/efeitos dos fármacos , Compostos Benzidrílicos , Glucosídeos
20.
J Mater Chem B ; 12(18): 4441-4450, 2024 May 08.
Artigo em Inglês | MEDLINE | ID: mdl-38639071

RESUMO

In this study, we report a small molecule optical marker BI-CyG derived from the structural engineering of a cyanine scaffold. The developed probe offers suitable advantages over existing cyanine-based albumin specific probes in terms of its excitation and emission wavelengths, which are 760 and 830-832 nm, respectively. Structural tuning of the cyanine architecture leading to extended π-conjugation and resulting in a suitable bathochromic shift in the emission wavelength of the probe is represented in this study. The probe besides emitting in the NIR region, also possesses the desirable characteristics of being a potential target selective optical marker, as established from various biophysical studies. Molecular modelling and simulation studies provided critical insights into the binding of the probe in the protein microenvironment, which was further supported by experimental studies. The probe displayed intracellular albumin selectivity and was utilized for demonstrating alteration in albumin levels in pathological states such as hyperglycemia in hepatic cells. The present study also sheds some light on using BI-CyG as an imaging probe and on the role of metformin as a suitable drug for balancing hyperglycemia-induced reduced intra-hepatic albumin levels. The study, thus, attempts to highlight the structural derivatization of cyanine to afford a potential probe for serum albumin and its deployment to image altering albumin levels in an induced pathological condition, hyperglycemia.


Assuntos
Albuminas , Carbocianinas , Hiperglicemia , Animais , Humanos , Albuminas/química , Albuminas/metabolismo , Carbocianinas/química , Corantes Fluorescentes/química , Corantes Fluorescentes/síntese química , Hiperglicemia/metabolismo , Sondas Moleculares/química , Estrutura Molecular , Imagem Óptica
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