Prevalencia, caracterización y pronóstico de pacientes con sospecha de insuficiencia cardíaca en atención primaria de salud en Chile / Characterization and prognosis of patients with suspected heart failure at primary health care institutions in Chile

Introducción: La insuficiencia cardíaca (IC) tiene alta morbilidad y mortalidad. Su diagnóstico temprano en atención primaria de salud (APS) es un reto dada la baja especificidad de sus criterios clínicos y las limitaciones en acceso a técnicas diagnósticas. Objetivo: Analizar la prevalencia de IC, subtipos y pronóstico de pacientes con disnea y/o edema de extremidades inferiores que consultan en APS. Metodología: Se trata de un estudio prospectivo de 340 pacientes en APS, sin diagnóstico previo de IC. Se realizó una evaluación clínica, electrocardiograma, NT-proBNP "point-of-care", ecocardiografía con interpretación telemática por cardiólogos. Utilizando los algoritmos HFA-PEFF y H2FPEF se clasificaron los pacientes como :1) IC con fracción de eyección (FE) reducida (ICFER); 2) IC con FE preservada (ICFEP) y 3) pacientes sin diagnóstico de IC. Se efectuó un análisis de sobrevida de los diferentes grupos. Resultados: La prevalencia de ICFER fue 8%, ICFEP por HFA-PEFF 42% y por H2FPEF 8%. Los algoritmos sugieren efectuar un estudio complementario en el 47% con HFA-PEFF y 76% con H2FPEF (p<0.05). La sobrevida global a 36 meses fue 90±2% y cardiovascular 95±1%. Usando HFA-PEFF, los pacientes con IC tuvieron menor sobrevida que aquellos sin IC (HR 2.3, IC95% 1.14.9; p=0.029). No hubo diferencias de mortalidad con H2FPEF. Conclusiones: En pacientes de APS que consultan por disnea y/o edema de extremidades inferiores sometidos a evaluación con NT-proBNP y ecocardiografía, se observó una prevalencia de IC de hasta 50%, 8% de ICFER y 42% de ICFEP. La caracterización de IC utilizando HFA-PEFF está asociada al pronóstico vital.

Background: Heart failure (HF) is a condition associated with high morbidity and mortality. Its early diagnosis in primary health care (PHC) represents a substantial challenge, considering its non-specific clinical manifestations and the limitations on timely access to diagnostic techniques. Objective: To evaluate the prevalence of HF, characterize subtypes and determine the prognosis of patients consulting in PHC for dyspnea Edema of the lower extremities. Methods: Prospective study in 340 patients who consulted in PHC, without previous diagnosis of HF. Clinical evaluation, electrocardiogram, NT-proBNP point-ofcare and echocardiography with telematic interpretation by cardiologists were performed. Using the HFA-PEFF and H2FPEF algorithms patients were classified as: 1) HF with reduced ejection fraction (HFREF); 2) HF with preserved ejection fraction (HFPEF) and 3) No HF. Actuarial survival analyses were performed. Results: We observed a prevalence of HFREF of 8%, high probability of HFPEF by HFA-PEFF in 42% and by H2FPEF in 8%. Intermediate probability of HFPEF, requiring complementary study, was observed in 47% of patients with HFA-PEFF and 76% of patients with H2FPEF (p<0.05). Overall survival at 36 months was 90±2% and cardiovascular survival at 36 months was 95±1%. Using HFA-PEFF, patients with HF presented lower overall survival compared to patients with no HF (HR 2.3, 95%CI 1.1-4.9; p=0.029). We did not observe mortality differences with H2FPEF. Conclusions: In patients consulting for dyspnea and/or lower extremity edema at PHC and undergoing evaluation with NT-proBNP and echocardiography, we observed a HF prevalence of 50%. HF classification through HFA-PEFF was associated with lower survival rates.

Broad-spectrum ginsentides are principal bioactives in unraveling the cure-all effects of ginseng

Stress and illness connection is complex and involves multiple physiological systems. Panax ginsengs, reputed for their broad-spectrum "cure-all" effect, are widely prescribed to treat stress and related illnesses. However, the identity of ginseng's "cure-all" medicinal compounds that relieve stress remains unresolved. Here, we identify ginsentides as the principal bioactives that coordinate multiple systems to restore homeostasis in response to stress. Ginsentides are disulfide-rich, cell-penetrating and proteolytic-stable microproteins. Using affinity-enrichment mass spectrometry target identification together with in vitro, ex vivo and in vivo validations, we show that highly purified or synthetic ginsentides promote vasorelaxation by producing nitric oxide through endothelial cells via intracellular PI3K/Akt signaling pathway, alleviate α1-adrenergic receptor overactivity by reversing phenylephrine-induced constriction of aorta, decrease monocyte adhesion to endothelial cells via CD166/ESAM/CD40 and inhibit P2Y12 receptors to reduce platelet aggregation. Orally administered ginsentides were effective in animal models to reduce ADP-induced platelet aggregation, to prevent collagen and adrenaline-induced pulmonary thrombosis as well as anti-stress behavior of tail suspension and forced swimming tests in mice. Together, these results strongly suggest that ginsentides are the principal panacea compounds of ginsengs because of their ability to target multiple extra- and intra-cellular proteins to reverse stress-induced damages.

Protective effect and mechanism of nanoantimicrobial peptide ND-C14 against Streptococcus pneumoniae infection / 世界急诊医学杂志（英文）

@#BACKGROUND: Streptococcus pneumoniae (S. pneumoniae) is a common pathogen that causes bacterial pneumonia. However, with increasing bacterial resistance, there is an urgent need to develop new drugs to treat S. pneumoniae infections. Nanodefensin with a 14-carbon saturated fatty acid (ND-C14) is a novel nanoantimicrobial peptide designed by modifying myristic acid at the C-terminus of human α-defensin 5 (HD5) via an amide bond. However, it is unclear whether ND-C14 is effective against lung infections caused by S. pneumoniae. METHODS: In vitro, three groups were established, including the control group, and the HD5 and ND-C14 treatment groups. A virtual colony-count assay was used to evaluate the antibacterial activity of HD5 and ND-C14 against S. pneumoniae. The morphological changes of S. pneumoniae treated with HD5 or ND-C14 were observed by scanning electron microscopy. In vivo, mice were divided into sham, vehicle, and ND-C14 treatment groups. Mice in the sham group were treated with 25 µL of phosphate-buffered saline (PBS). Mice in the vehicle and ND-C14 treatment groups were treated with intratracheal instillation of 25 µL of bacterial suspension with 2×108 CFU/mL (total bacterial count: 5×106 CFU), and then the mice were given 25 μL PBS or intratracheally injected with 25 μL of ND-C14 (including 20 µg or 50 µg), respectively. Survival rates were evaluated in the vehicle and ND-C14 treatment groups. Bacterial burden in the blood and bronchoalveolar lavage fluid were counted. The lung histology of the mice was assessed. A propidium iodide uptake assay was used to clarify the destructive effect of ND-C14 against S. pneumoniae. RESULTS: Compared with HD5, ND-C14 had a better bactericidal effect against S. pneumoniae because of its stronger ability to destroy the membrane structure of S. pneumoniae in vitro. In vivo, ND-C14 significantly delayed the death time and improved the survival rate of mice infected with S. pneumoniae. ND-C14 reduced bacterial burden and lung tissue injury. Moreover, ND-C14 had a membrane permeation effect on S. pneumoniae, and its destructive ability increased with increasing ND-C14 concentration.

nteraction between FAK/αB-crystalline is important for viability of the glioblastoma cells

Abstract Glioblastoma multiforme is a tumor of the central nervous system. Focal Adhesion Kinase (FAK) and αB-crystalline are two proteins involved in glioblastoma development. In this study, we investigated whether the FAK/αB-crystalline interaction is important for glioblastoma cells, we aimed to investigate the interaction of these two proteins in the glioblastoma multiforme cell line U87-MG. Two peptides named FP01 peptide (derived from αB-crystalline) and FP02 peptide (derived from FAK) were synthesized for this study. Treatment of U87-MG with the peptides FP01 and FP02 in the concentration at 50 µM reduced the viability cellular to around 41% and 51%, respectively. Morphological alterations in the cells treated with the peptides when compared to the control were observed. This study suggests that the interaction between FAK and αB-crystalline is important for the viability of glioblastoma cells

The past, present and future of Alzheimer's disease - part 1: the past / O passado, presente e futuro da doença de Alzheimer - parte 1: o passado

Abstract Background Alzheimer's disease (AD) was described in 1907, and since then it changed from a relatively rare condition to one of the most prevalent diseases. Objective To describe the evolution of the notions of dementias and AD, and to investigate the reasons for the increase in scientific interest in AD. Methods A historical analysis was carried out on knowledge about dementia, the site of mental activity, the relationships between brain diseases and mental activity, and on the advances in research about AD, since its discovery until the publication of the amyloid cascade hypothesis in 1992. A search was carried out in the National Library of Medicine (PubMed) for scientific articles that included the terms dementia or AD over 50 years, from 1972 to 2021. Results The scientific research on AD increased from 615 papers with the term AD in the first decade (1972-1981), to 100,028 papers in the last decade (2012-2021): an increase of 162.6 times whereas publications with the term dementia increased 28.6 times in the same period. In the 1960s and 1970s, a consensus was reached that AD is responsible for the majority of cases of dementia previously known as senile dementia. In the 1980s, beta-amyloid peptide was identified in the core of the senile plaque, hyperphosphorylated tau protein was found in neurofibrillary tangles, and a mutation was discovered in a hereditary form of AD. Conclusion The expansion of the concept of AD to include senile dementia, and the discoveries that occurred in the 1980s greatly expanded research in AD.

Resumo Antecedentes A doença de Alzheimer (DA) foi descrita em 1907 e, desde então, deixou de ser relativamente rara para se tornar uma das doenças mais prevalentes. Objetivo Descrever a evolução das noções sobre demências e DA e investigar as razões do aumento do interesse científico pela DA. Métodos Foi realizada uma análise histórica dos conhecimentos sobre demência, o local da atividade mental, as relações entre doenças cerebrais e a atividade mental, e sobre os avanços na pesquisa sobre a DA, desde a sua descoberta até a publicação da hipótese da cascata amiloide em 1992. Foi realizada uma busca na Biblioteca Nacional de Medicina dos Estados Unidos da América (PubMed) por artigos científicos que incluíssem os termos demência ou DA nos 50 anos, de 1972 a 2021. Resultados A pesquisa científica sobre DA aumentou de 615 artigos com o termo doença de Alzheimer na primeira década (1972-1981), para 100.028 artigos na última década (2012-2021): um aumento de 162,6 vezes enquanto as publicações com o termo demência aumentaram 28,6 vezes no mesmo período. Nas décadas de 1960 e 1970, chegou-se a um consenso de que a DA é responsável pela maioria dos casos de demência, anteriormente conhecida como demência senil. Na década de 1980, o peptídeo beta-amiloide foi identificado no núcleo da placa senil, a proteína tau hiperfosforilada foi encontrada em emaranhados neurofibrilares e uma mutação foi descoberta em uma forma hereditária de DA. Conclusão A expansão do conceito de DA para incluir a demência senil e as descobertas ocorridas na década de 1980 ampliaram enormemente a pesquisa em DA.

El difícil camino de los péptidos natriuréticos en la insuficiencia cardiaca

Esta es una revisión sobre el papel de los péptidos natriuréticos y los intentos de utilizarlos como diana terapéutica a medida que se iba comprendiendo mejor su papel en la fisiopatología de la insuficiencia cardíaca con función sistólica deprimida. Se hace un recuento de su participación en sucesivos estudios fallidos y se explican los motivos de sus fracasos, hasta lograr el éxito deseado con la combinación del sacubitrilo/valsartan, lo que produjo un cambio de paradigma en el manejo de la insuficiencia cardíaca.

This review is conducted on the role of natriuretic peptides and the attempts to use them as a treatment as their role in the pathophysiology of heart failure with depressed systolic function was better understood. A recount of their participation in successive failed studies is provided, explaining the reasons for their failures, until achieving the desired success with the combination of sacubitril/valsartan. This produced a paradigm shift in the management of heart failure.

Fast Skeletal Muscle Troponin and Tropomyosin as a Dietary Source of Antidiabetic and Antihypertensive Bioactive Peptides: An In Silico Study / Troponina y Tropomiosina de Músculo Esquelético como Fuente Alimentaria de Péptidos Bioactivos Antidiabéticos y Antihipertensivos: Estudio In Silico

Background: The nutraceutical properties of food hydrolysates rely on multiple biochemical interactions involving the modulation of enzymes and cellular receptors. Numerous bioactive peptides released from troponin and tropomyosin digestion have been identified. Their characterization has mostly been performed by hydrolysis catalyzed by proteases unrelated to the human digestive system. Objective: This study aimed to determine the bioactive profile of beef, pork, and chicken meat by analyzing the frequency and pharmacokinetics of biopeptides released from troponin and tropomyosin. Methods:In silico digestion and biopeptide release frequency were studied by three parameters; bioactive fragments release frequency (AE), frequency percentage (W), and mean occurrence (AS), all stated on the BIOPEP-UWM platform. Further on, hydrolysis end-products were screened based on gastrointestinal-absorption probability and pharmacokinetic profiling performed on SwissADME, SwissTargetPrediction, and ADME/Tlab bioinformatics web tools. Statistical analyses were performed using a one-way ANOVA test. Results: Dipeptidyl peptidase-IV (DPP-IV) and angiotensin-converting enzyme (ACE) inhibiting biopeptides exhibited the highest release frequency. Moreover, W and ASparameters showed no significant difference (p>0.05) between the myofibrillar isoforms assessed. Seven biopeptides were classified as highly absorbable and reported optimal drug-likeness compliance. Although biopeptides hold good pharmacokinetic properties, the therapeutic potency of biopeptides showed to be lower than those of DPP-IV and ACE-inhibiting drugs. Conclusions: Troponin and tropomyosin are rich dietary sources of bioactive peptides, mainly DPP-IV and ACE inhibitors. Digestion end-products are mainly dipeptides with optimal pharmacokinetic and drug-like properties, suggesting a potential therapeutic application in hypertensive and hyperglycemic disorders

Antecedentes: Las propiedades nutracéuticas de los hidrolizados de alimentos dependen de múltiples interacciones bioquímicos que involucran la modulación de enzimas y receptores celulares. Se han identificado numerosos péptidos bioactivos liberados de la digestión de troponina y tropomiosina, pero su caracterización se ha llevado a cabo principalmente por hidrólisis catalizada por proteasas ajenas al sistema digestivo humano. Objetivo: Este estudio tuvo como objetivo determinar el perfil bioactivo de la carne de res, cerdo y pollo mediante el análisis de la frecuencia y farmacocinética de los biopéptidos liberados de la troponina y la tropomiosina. Métodos: Se estudió la digestión in silico y la frecuencia de liberación de biopéptidos mediante dos parámetros; frecuencia de liberación de fragmentos bioactivos (AE), frecuencia porcentual (W) y ocurrencia media (AS), ambos indicados en la plataforma BIOPEP-UWM. Más adelante, los productos finales de la hidrólisis se examinaron en función de la probabilidad de absorción gastrointestinal y el perfil farmacocinético realizado en las herramientas bioinformáticas SwissADME, SwissTargetPrediction y ADME/Tlab. El análisis estadístico se llevó a cabo mediante una prueba ANOVA de una vía. Resultados: Los biopéptidos inhibidores de la dipeptidil peptidasa IV (DPP-IV) y la enzima convertidora de angiotensina (ECA) exhibieron la mayor frecuencia de liberación. Además, los parámetros W y ASno mostraron diferencias significativas (p> 0.05) entre las isoformas miofibrilares evaluadas. Siete biopéptidos se clasificaron como altamente absorbibles e informaron un cumplimiento óptimo de similitud con el fármaco. Aunque los biopéptidos tienen propiedades farmacocinéticas adecuadas, su potencia terapéutica demostró ser menor que la de los fármacos inhibidores de la DPP-IV y la ACE. Conclusiones: La troponina y la tropomiosina son una fuente dietética rica en péptidos bioactivos, principalmente DPP-IV e inhibidores de la ACE. Los productos finales de la digestión son principalmente dipéptidos con propiedades farmacocinéticas óptimas y similares a la de los fármacos, lo que sugiere una aplicación terapéutica factible en trastornos hipertensivos e hiperglicémicos

Uso de NT-proBNP en el seguimiento ambulatorio de pacientes con insuficiencia cardiaca con fracción de eyección del ventrículo izquierdo reducida en una unidad multidisciplinaria de insuficiencia cardiaca

Introducción: La insuficiencia cardíaca (IC) es un síndrome clínico prevalente a nivel mundial, que se beneficia del abordaje multidisciplinario, pero su seguimiento ambulatorio sigue siendo un reto. La utilidad diagnóstica y pronóstica del NT-proBNP está apoyada en la evidencia actual; pero su uso en el seguimiento aún no ha sido definido. En el presente estudio se busca determinar si la variación en el tiempo del valor de NT-proBNP se relacionó con modificación en el tratamiento farmacológico de pacientes ambulatorios con IC y fracción de eyección del ventrículo izquierdo reducida (FEVI ≤ 40%) de una unidad multidisciplinaria de insuficiencia cardíaca (UMIC). Metodología: Estudio cohorte retrospectivo, de pacientes que cumplieron con los criterios de inclusión: 2 o más cuantificaciones de NT-proBNP en 12 meses y un seguimiento mínimo de 2 años entre los años 2013 y 2017. Resultados: De un total de 566 sujetos integrantes de cohorte activa de UMIC se incluyeron 107 que cumplieron criterios de inclusión; la mayoría hombres (58%), edad mediana de 63 años (Q1;Q3: 55,9;71,2 años), la principal comorbilidad fue hipertensión arterial (71%). En 56% de la población la etiología de IC fue no isquémica y el 50% tenía una clase funcional - NYHA I. La mediana de NT-proBNP basal fue de 698 pg/ml (Q1;Q3: (218;1564 pg/ml), con FEVI basal mediana de 30% (Q1;Q3: 27%;40%). En 55% de los pacientes la variación del valor de NT-proBNP durante el seguimiento se relacionó con modificaciones en el tratamiento farmacológico. Conclusiones: En la mitad de la población de nuestra cohorte se evidenció que los valores de NT-proBNP se relacionaron con cambios en el tratamiento farmacológico, independientemente de la situación clínica.

Introduction: Heart failure (HF) is a prevalent clinical syndrome worldwide, which benefits from a multidisciplinary approach, but its outpatient follow-up remains a challenge. The diagnostic and prognostic utility of NT-proBNP is supported by current evidence, but its use in monitoring has not yet been defined. The present study sought to determine whether the variation over time in the value of NT-proBNP was related to changes in the pharmacological treatment of outpatients with HF and reduced left ventricular ejection fraction (LVEF ≤ 40%) in a multidisciplinary heart failure unit. (MHFU). Methodology: Retrospective cohort study of patients, who met the inclusion criteria: 2 or more quantifications of NT-proBNP in 12 months and a minimum follow-up of 2 years between 2013 and 2017. Results: Of 566 members of the MHFU active cohort, 107 met the inclusion criteria; most men (58%), median age 63 years (Q1;Q3: 55.9;71.2), the main comorbidity was arterial hypertension (71%). The etiology of HF was non-ischemic in 56% of the population, and 50% had a functional class - NYHA I. Median baseline NT-proBNP was 698 pg/ml (Q1;Q3: (218;1564), with median baseline LVEF of 30% (Q1;Q3: 27;40). In 55% of the patients, the variation in the NT-proBNP value during follow-up was related to changes in pharmacological treatment. Conclusions: In half of the population of our cohort, it was shown that NT-proBNP values were related to changes in pharmacological treatment, regardless of the clinical situation.

Introdução: A insuficiência cardíaca (IC) é uma síndrome clínica prevalente em todo o mundo, que se beneficia de uma abordagem multidisciplinar, mas seu acompanhamento ambulatorial continua sendo um desafio. A utilidade diagnóstica e prognóstica do NT-proBNP é suportada pelas evidências atuais, mas seu uso no monitoramento ainda não foi definido. O presente estudo procurou determinar se a variação ao longo do tempo no valor do NT-proBNP estava relacionada a mudanças no tratamento farmacológico de pacientes ambulatoriais com IC e fração de ejeção do ventrículo esquerdo (FEVE ≤ 40%) reduzida em uma unidade multidisciplinar de insuficiência cardíaca. (UMIC). Metodologia: Estudo de coorte retrospectivo de pacientes que preencheram os critérios de inclusão: 2 ou mais quantificações de NT-proBNP em 12 meses e seguimento mínimo de 2 anos entre 2013 e 2017. Resultados: Dos 566 membros da coorte ativa do UMIC, 107 preencheram os critérios de inclusão; maioria dos homens (58%), idade mediana 63 anos (Q1;Q3: 55,9;71,2), a principal comorbidade foi hipertensão arterial (71%). A etiologia da IC foi não-isquêmica em 56% da população, e 50% tinham classe funcional - NYHA I. A mediana basal do NT-proBNP foi de 698 pg/ml (Q1;Q3: (218;1564), com mediana basal FEVE de 30% (Q1;Q3: 27;40). Em 55% dos pacientes, a variação do valor de NT-proBNP durante o seguimento esteve relacionada a mudanças no tratamento farmacológico. Conclusões: Em metade da população do nosso coorte, foi demonstrado que os valores de NT-proBNP estavam relacionados a mudanças no tratamento farmacológico, independentemente da situação clínica.

Ghrelin and glucagon-like peptide-1 according to body adiposity and glucose homeostasis

ABSTRACT Objective: We investigated the biological behavior of ghrelin and glucagon-like peptide-1 (GLP-1) after a standard liquid meal according to body adiposity and glucose homeostasis. Subjects and methods: This cross-sectional study included 41 individuals (92.7% women; aged 38.3 ± 7.8 years; BMI 32.2 ± 5.5 kg/m²) allocated into three groups according to body adiposity and glucose homeostasis, as follows: normoglycemic eutrophic controls (CON, n = 11), normoglycemic with obesity (NOB, n = 15), and dysglycemic with obesity (DOB, n = 15). They were tested at fasting and 30 and 60 min after the ingestion of a standard liquid meal in which we measured active ghrelin, active GLP-1, insulin, and plasma glucose levels. Results: As expected, DOB exhibited the worst metabolic status (glucose, insulin, HOMA-IR, HbA1c) and an inflammatory status (TNF-α) at fasting, besides a more significant increase in glucose than postprandial NOB (p ≤ 0.05). At fasting, no differences between groups were detected in lipid profile, ghrelin, and GLP-1 (p ≥ 0.06). After the standard meal, all groups exhibited a reduction in ghrelin levels between fasting vs. 60 min (p ≤ 0.02). Additionally, we noticed that GLP-1 and insulin increased equally in all groups after the standard meal (fasting vs. 30 and 60 min). Although glucose levels increased in all groups after meal intake, these changes were significantly more significant in DOB vs. CON and NOB at 30 and 60 min post-meal (p ≤ 0.05). Conclusions: Time course of ghrelin and GLP-1 levels during the postprandial period was not influenced by body adiposity or glucose homeostasis. Similar behaviors occurred in controls and patients with obesity, independently of glucose homeostasis.

Study of 68Ga-NODAGA-RGD PET/CT in predicting short-term efficacy of tyrosine kinase inhibitor in the treatment of distant metastatic differentiated thyroid cancer / 中华核医学与分子影像杂志

Objective:To investigate the clinical application of 68Ga-cyclo( L-arginylglycyl- L-α-aspartyl- D-tyrosyl-N6-(((4, 7-bis(carboxymethyl)-1, 4, 7-triazonan-1-yl)acetyl))- L-lysyl) (NODAGA-RGD) PET/CT to evaluate short-term efficacy of tyrosine kinase inhibitor (TKI) in distant metastatic differentiated thyroid cancer (dmDTC). Methods:From October 2019 to March 2023, 13 dmDTC patients (5 males, 8 females; age: 68(65, 69) years) from Nanjing First Hospital were retrospectively enrolled, of which 9 were clinically confirmed as radioactive iodine-refractory differentiated thyroid cancer (RAIR-DTC) and 4 were dmDTC without radioactive iodine treatment. All patients underwent 68Ga-NODAGA-RGD PET/CT to assess neovascularization of the target lesions (TL), and the SUV max and target background ratio (T/B) were recorded. After 3 months of TKI treatment (anrotinib ( n=9) or apatinib ( n=4)), change rates of the maximum diameter of TL and thyroglobulin (Tg) were measured. The correlation of SUV max, T/B and the change rate of the maximum diameter of TL were analyzed by Spearman rank correlation analysis. ROC curve analysis was performed for the effectiveness of the T/B and TKI therapy, and the difference of the remission rate of lesions was analyzed by Fisher exact test. Results:In 13 patients, 36 TL were measured by 68Ga-NODAGA-RGD PET/CT with SUV max of 5.44(3.43, 7.56) and T/B of 5.25(4.50, 7.23). The change rate of the maximum diameter of TL was -30%(-39%, -21%) and the change rate of Tg was -68%(-96%, -52%). T/B was negatively correlated with the change rate of the maximum diameter of TL after TKI therapy ( rs=-0.46, P=0.005), while SUV max was not correlated with the change rate of the maximum diameter of TL ( rs=0.03, P=0.883). ROC curve analysis showed that the optimal cut-off value for T/B was 4.95, with the AUC of 0.698, the sensitivity of 87.5%, and the specificity of 60.0%. Compared to lesions with T/B<4.95, those with T/B≥4.95 showed higher remission rate (2/14 vs 63.6%(14/22); P=0.006). After 3 months of TKI treatment, the disease control rate was 12/13. Conclusion:68Ga-NODAGA-RGD PET/CT can effectively reflect tumor neovascularization, predict efficacy of TKI therapy, and provide powerful imaging evidence for TKI therapy in dmDTC.

Establishment of mouse pancreatic ductal organoids and exploration of its physiological functions / 中华胰腺病杂志

Objective:To establish culture system for mouse pancreatic ductal organoids and investigate the morphology and physiological functions of the organoids.Methods:Pancreatic tissues were taken from C57BL/6 mice (6-8 weeks) and digested by collagenase Ⅳ. The pancreatic ducts were separated and collected and then the pancreatic organoids were cultured in the complete medium after Matrix gel embedding. Morphological evaluation of the organoids was performed after hematoxylin-eosin staining. The expression and localization of markers for organoids were identified by Western Blot and immunofluorescence staining; and the expression and localization of ion channels and antimicrobial peptides of the organoids were detected by agarose gel electrophoresis and immunofluorescence staining.Results:Mouse pancreatic organoids were successfully established, which could be stably passaged for 10 generations. The organoids grew spherically and formed a duct-like structure. The internal cavity corresponded to the lumen of pancreatic duct tissue. The pancreatic organoids stably expressed stem progenitor cell marker gene SOX9 and ductal epithelial cell-specific gene KRT19, which were both localized in the epithelium. The organoids did not express amylase. The organoids maintained stable expression of epithelial ion channels Clcn1, Kcnma1, CFTR, Slc12a5, Slc26a3, Slc26a6 and Scnn1a, low expression of Ano1 and no expression of Clcn3, Kcna1, Kcna2, Kcnd3, Kcnh1, Atp12a, Slc4a4, Slc9a1, Slc12a2 and Slc26a11; and CFTR highly expressed in epithelial cells. The organoids maintained high expression of antimicrobial peptides Reg3a, CRAMP and glycoprotein 2, low expression of Defb1, Defb2, and Defb3 and no expression of Defa1 and Defa4; and both CRAMP and Reg3a were expressed in the epithelial cells and secreted into the lumen of the organoids.Conclusions:Mouse pancreatic organoids are successfully established, which can be stably passaged. The organoids maintain the characteristics of ductal epithelial cells and can be used as an in vitro model to study the physiology of pancreatic ducts.

Dock-able linear and homodetic di,tri,tetra and pentapeptide library from canonical amino acids:SARS-CoV-2 Mpro as a case study / 药物分析学报

Peptide-based therapeutics are increasingly pushing to the forefront of biomedicine with their promise of high specificity and low toxicity.Although noncanonical residues can always be used,employing only the natural 20 residues restricts the chemical space to a finite dimension allowing for comprehensive in silico screening.Towards this goal,the dataset comprising all possible di-,tri-,and tetra-peptide com-binations of the canonical residues has been previously reported.However,with increasing computa-tional power,the comprehensive set of pentapeptides is now also feasible for screening as the comprehensive set of cyclic peptides comprising four or five residues.Here,we provide both the com-plete and prefiltered libraries of all di-,tri-,tetra-,and penta-peptide sequences from 20 canonical amino acids and their homodetic(N-to-C-terminal)cyclic homologues.The FASTA,simplified molecular-input line-entry system(SMILES),and structure-data file(SDF)-three dimension(3D)libraries can be readily used for screening against protein targets.We also provide a simple method and tool for conducting identity-based filtering.Access to this dataset will accelerate small peptide screening workflows and encourage their use in drug discovery campaigns.As a case study,the developed library was screened against severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)main protease to identify po-tential small peptide inhibitors.

Effects of ferrocene position isomerization on the self-assembly behavior and antibacterial effect of coupled cationic peptides / 中国药房

OBJECTIVE To design the two isomers of ferrocene （Fc）-coupled cationic peptides （hereinafter referred to as “peptides”） [Fc-K（C8）FFHK and C8-K（Fc） FFHK] and the control peptide [C8-K（C8）FFHK]， and to explore the effects of Fc position isomerization on the self-assembly behavior and antibacterial effect of peptides. METHODS All isomerized peptides were prepared by standard solid-phase synthesis and purified by reversed-phase high-performance liquid chromatography. The stability of the peptide was analyzed by using UV spectrophotometry to detect UV absorption spectra， and Zeta potential analyzer to determine Zeta potential. The secondary structure was characterized by circular dichroism spectrum （CD）， Fourier transform infrared spectrometer （FTIR）， thioflavin T （ThT） fluorescence spectrum and transmission electron microscopy （TEM）. The differences in antibacterial activity and biocompatibility of the 2 kinds of isomerized peptides were evaluated by in vitro reactive oxygen species （ROS） generation test， growth curve determination test， plate method， cytotoxicity assay and hemolysis test. RESULTS Three peptides with purity higher than 95% were synthesized. The stability test results showed that the UV absorption spectra of Fc-K（C8）FFHK and C8-K（Fc）FFHK remained almost unchanged when placed at room temperature for 24 and 96 hours， and their Zeta potential were decreased by 0.3 mV and 0.5 mV， respectively. Secondary structure characterization results showed that Fc-K（C8）FFHK and C8-K（Fc）FFHK were self-assembled to form twisted nanoribbons and short nanofibers， respectively； C8-K（C8）FFHK was assembled into cylindrical nanofibers. The optical spectrum results showed that there were certain differences in the content of structures such as β-sheet and α-helix. The in vitro ROS generation test results showed that ROS generation efficiency of Fc-K（C8）FFHK at pH 6.0 was higher than C8-K（Fc）FFHK. The results of in vitro antibacterial activity showed that for methicillin-resistant Staphylococcus aureus， both the isomeric peptides had similar minimum inhibitory concentration （MIC） values of 50 μg/mL which were far lower than the control peptide （400 μg/mL）. To Escherichia coli， Fc-K（C8）FFHK had better antibacterial activity than C8-K（Fc）FFHK. Finally， cytotoxicity assay and hemolysis test results showed that both isomeric peptides had good biocompatibility. CONCLUSIONS By wangjingwen8021@163.com coupling Fc， the antibacterial activity of cationic self-assembled peptides can be improved. Regulating the position of Fc in the peptide sequence could regulate the self-assembly behavior and antibacterial effect of the self-assembled peptides.

Coarse-Grained Simulation of Amyloid Nucleation under Cooperative Effects of Peptides / 医用生物力学

Objective To explore the cooperative effect from β-propensity of amyloidogenic peptides on amyloid nucleation and its related products. Methods Based on a coarse-grained model for amyloidogenic peptides containing two states ( a soluble state and a β-sheet-forming state), with the consideration of two kinds of cooperative effects on β-propensity of peptides ( inhibiting and promoting the conformational conversion of peptides), the regulation of cooperative effects from amyloidogenic peptides on amyloid nucleation was analyzed through Monte Carlo simulations. Results In the case of the cooperative effect inhibiting the conformational conversion of peptides, amyloid nucleation occurred only within a certain interval of the peptide concentration, as well as inside the oligomers with certain sizes. Besides, the coexistence of on-pathway and off-pathway oligomers was observed. In the case of the cooperative effect promoting the conformational conversion of peptides, the β-sheet protofibril could be observed at physiological concentration as low as 4 μmol / L. Conclusions In this study, a more realistic coarse-grained model for amyloidogenic peptides was developed by introducing the cooperative effects of local concentration on β-propensity of amyloidogenic peptides, with observation of some intriguing phenomena not reported in previous simulations. The research findings not only improve current understandings about the mechanism of amyloid formation, but also provide theoretic references for the therapeutic strategies for curing neurodegenerative diseases

Application and prospect of artificial intelligence in antimicrobial peptides screening / 中国药科大学学报

@#Antimicrobial peptides (AMPs) are a class of small molecule peptides with broad-spectrum antimicrobial activity.Their unique antimicrobial mechanism can effectively treat infectious diseases, with rare drug resistance.However, though AMPs with antimicrobial activity can be screened by traditional methods, the whole process is complicated.The artificial intelligence (AI) screening method is faster and more convenient, with great potential in exploring new natural antimicrobial peptides.In this paper, strategies related to AMPs screening by AI were summarized and compared, including data sources applied to model training, artificial intelligence machine model and omics data applied to model screening of novel antimicrobial peptides.The application prospects and advantages were reviewed, in hope of providing new ideas for identification, research and development of antimicrobial peptides.

An antibacterial peptides recognition method based on BERT and Text-CNN / 生物工程学报

Antimicrobial peptides (AMPs) are small molecule peptides that are widely found in living organisms with broad-spectrum antibacterial activity and immunomodulatory effect. Due to slower emergence of resistance, excellent clinical potential and wide range of application, AMP is a strong alternative to conventional antibiotics. AMP recognition is a significant direction in the field of AMP research. The high cost, low efficiency and long period shortcomings of the wet experiment methods prevent it from meeting the need for the large-scale AMP recognition. Therefore, computer-aided identification methods are important supplements to AMP recognition approaches, and one of the key issues is how to improve the accuracy. Protein sequences could be approximated as a language composed of amino acids. Consequently, rich features may be extracted using natural language processing (NLP) techniques. In this paper, we combine the pre-trained model BERT and the fine-tuned structure Text-CNN in the field of NLP to model protein languages, develop an open-source available antimicrobial peptide recognition tool and conduct a comparison with other five published tools. The experimental results show that the optimization of the two-phase training approach brings an overall improvement in accuracy, sensitivity, specificity, and Matthew correlation coefficient, offering a novel approach for further research on AMP recognition.

Research advances in peptide‒drug conjugates

Peptide‒drug conjugates (PDCs) are drug delivery systems consisting of a drug covalently coupled to a multifunctional peptide via a cleavable linker. As an emerging prodrug strategy, PDCs not only preserve the function and bioactivity of the peptides but also release the drugs responsively with the cleavable property of the linkers. Given the ability to significantly improve the circulation stability and targeting of drugs in vivo and reduce the toxic side effects of drugs, PDCs have already been extensively applied in drug delivery. Herein, we review the types and mechanisms of peptides, linkers and drugs used to construct PDCs, and summarize the clinical applications and challenges of PDC drugs.

Discovery of an orally effective double-stapled peptide for reducing ovariectomy-induced bone loss in mice

Stapled peptides with significantly enhanced pharmacological profiles have emerged as promising therapeutic molecules due to their remarkable resistance to proteolysis and performance to penetrate cells. The all-hydrocarbon peptide stapling technique has already widely adopted with great success, yielding numerous potent peptide-based molecules. Based on our prior efforts, we conceived and prepared a double-stapled peptide in this study, termed FRNC-1, which effectively attenuated the bone resorption capacity of mature osteoclasts in vitro through specific inhibition of phosphorylated GSK-3β. The double-stapled peptide FRNC-1 displayed notably improved helical contents and resistance to proteolysis than its linear form. Additionally, FRNC-1 effectively prevented osteoclast activation and improved bone density for ovariectomized (OVX) mice after intravenous injection and importantly, after oral (intragastric) administration. The double-stapled peptide FRNC-1 is the first orally effective peptide that has been validated to date as a therapeutic candidate for postmenopausal osteoporosis (PMOP).

Expression and identification of recombinant human interferon λ1 in HEK-293F cells / 中国生物制品学杂志

@#Objective To express recombinant human interferon λ1(rhIFNλ1)by transient transfection in HEK-293F cells and identify it. Methods Two signal peptides[T cell receptor(TCR)and nature signal peptide(NSP)],three vectors[pcDNA3.4,ubiquitous chromatin opening element(UCOE)and PFR]and the target gene rhIFNλ1 were used to construct recombinant plasmids of six signal peptide-vector combinations. Using HEK-293F as host cells,the recombinant plasmids were transfected transiently to express rhIFNλ1 on a shake flask scale. The recombinant plasmid UCOE-Q46-λ with low glycosylation rhIFNλ1 was constructed by using NSP and vector UCOE,and transfected transiently into HEK-293F cells. The expressed product was purified by cation exchange chromatography(HiTrap SP FF),blue gel chromatography(HiTrap Blue HP)and gel filtration chromatography(Sephacryl S-100 HR),which was then analyzed by Western blot and reversed-phase HPLC,and determined for its molecular mass and N-terminal amino acid sequence by mass spectrometry. Results Six recombinant plasmids were constructed correctly as identified by double enzyme digestion and sequencing. With the extension of transfection time,the expression levels of the six expressed products increased gradually,and reached the highest level of10 ～ 20 mg/L at the 6th day of transfection. Double enzyme digestion and sequencing identification proved that the recombinant plasmid UCOE-Q46-λ with low glycosylation rhIFNλ1 was constructed correctly. The recombinant plasmid UCOE-Q46-λwas transfected into HEK-293F cells for 6 d. The purified product of cell culture supernatant showed a relative molecular mass of about 27 800 and a purity of 97. 372%,which showed specific binding to mouse anti-human IL-29/IFNλ1 monoclonal antibody;Two peaks were detected by reversed-phase HPLC,and the peak was showed at 15. 6 min and 20. 0 min respectively;The mass spectrometry molecular mass was about 24 000;The N-terminal five amino acids were G-P-V-P-T.Conclusion The rhIFNλ1 expressed by HEK-293F cells has high purity,which lays a foundation of further study of the protein.

Research progress on antibacterial peptides Epinecidin-1 / 药学实践杂志

The antimicrobial peptide Epinecidin-1 is a kind of small molecule active peptides extracted from Epinephelus coioides，which serves as the first line of defense for innate immune defense system of Epinephelus coioides against various pathogens. In vitro and in vivo studies have confirmed that the antimicrobial peptide Epinecidin-1 not only exhibits broad-spectrum anti-pathogen activities (including bacteria, fungi, viruses, and parasites, etc.), but also has pharmacological activities such as immune regulation, anti-cancer and wound healing. In this paper, the relevant research on the antimicrobial peptide Epinecidin-1 in recent years were summarized, including its mechanism of action, pharmacological activities, potential limitations and application prospects , so as to provide information for further research.