Effects of diisononyl phthalate on lipid metabolism in HepG2 cells / 环境与职业医学

Background Exposure to diisononyl phthalate (DINP), an endocrine disruptor associated with metabolic diseases and widely used in plastic products, has been linked to the development of several adverse health outcomes in the liver, including non-alcoholic fatty liver disease (NAFLD). Objective To investigate the effects and the possible molecular mechanisms of DINP exposure on lipid metabolism in human hepatocellular carcinoma cells (HepG2 cells). Methods First, HepG2 cells were treated with DINP at three time spots (24, 48, and 72 h) and eleven doses (0, 0.003, 0.01, 0.03, 0.1, 0.3, 1, 3, 10, 30, and 100 mmol·L−1). Cell viability were detected using cell counting kit 8 (CCK8). Intracellular lipid deposition was determined by oil red O staining and lipid content detection, and triglyceride (TG) and cholesterol (TC) were further detected. Finally, the mRNA expression levels were detected by fluorescence quantitative PCR, including fatty acid synthesis related genes [acetyl-CoA carboxylase alpha (Accα), fatty acid synthase (Fasn), malonyl-CoA decarboxylase (Mlycd), and sterol regulatory element binding protein 1 (Srebp1)] and β-oxidation related genes [peroxisome proliferator activated receptor alpha (Pparα), AMP-activated protein kinase (Ampk), carnitine palmitoyltransferase 1A (Cpt-1a), transcription factor A, mitochondrial (Tfam), nuclear respiratory factor 1 (Nrf1), and peroxisome proliferator-activated receptor gamma and coactivator 1 alpha (Pgc1-α)]. Results Compared with the control group (0 mmol·L−1), the no observed adverse effect levels (NOAEL) of HepG2 cell viability were 0.3, 0.1, and 0.1 mmol·L−1 after 24, 48, and 72 h exposure to DINP, respectively, and the corresponding lowest observed adverse effect levels (LOAEL) were 1, 0.3, and 0.3 mmol·L−1, respectively (P<0.05). After exposure to 30 mmol·L−1 and 100 mmol·L−1 DINP for 24 h, the intracellular lipid content, lipid deposition, TG, and TC levels were increased significantly compared with the control group (P<0.01). Compared with the control group, the mRNA expression levels of genes related to fatty acid synthesis, such as Mlycd, Srebp1, Fasn, and Accα, were down-regulated after the 100 mmol·L−1 DINP exposure for 24 h, while the mRNA expression level of Mlycd was up-regulated in the 30 mmol·L−1 group. The β-oxidation related genes such as Ampk, Pparα, and Tfam were up-regulated significantly after the 100 mmol·L−1 DINP exposure, while Cpt-1a mRNA expression level was down-regulated (P<0.05). Conclusion Exposure to DINP at 30 mmol·L−1 and 100 mmol·L−1 can interfere with fatty acid synthesis and β-oxidation in lipid metabolism of HepG2 cells, resulting in lipid deposition.

Effects of an antioxidants cocktail on glucose metabolism at rest, during exercise, and during a glucose load in healthy young subjects

Background: Reactive oxygen species (ROS) regulate glucose metabolism (GM) in skeletal muscle by improving the translocation of GLUT4. Antioxidant supplementation could block this physiological effect, altering glucose signaling during exercise. However, there is limited evidence in humans on whether antioxidant intake affects GM. Therefore, we aimed to determine the effect of an antioxidant cocktail (AOC) on GM at rest and during metabolic challenges. Methods: Ten healthy male subjects received AOC supplementation (1000 mg of Vitamin C, 600 IU of Vitamin E, and 600 mg of α-lipoic acid) or placebo (2.000 mg of talc) before two trials conducted 7 days apart. Trial 1: AOC 120 and 90 minutes before an endurance exercise (EEX) bout at 60 % of maximal oxygen uptake (VO2max); Trial 2: AOC 120 and 90 minutes before an oral glucose tolerance test (OGTT; 75 g glucose). Measurements of gas exchange and capillary blood samples were collected every 15 minutes during both trials. Results: AOC supplementation increased resting glucose levels (p<0.05). During Trial 1 (EEX), the AOC increased carbohydrate oxidation (CHOox) (p= 0.03), without effect in glucose blood levels. During Trial 2 (OGTT), the AOC supplementation had no significant effect on GM parameters. Conclusion: Acute supplementation with AOC increased resting glucose levels and CHOox during EEX in healthy subjects, with no effect on GM during the OGTT.

Antecedentes: Las especies reactivas de oxígeno (ROS) regulan el metabolismo de la glucosa (GM) en el músculo esquelético al mejorar la translocación de GLUT4. La suplementación con antioxidantes podría bloquear este efecto fisiológico, alterando la señalización de la glucosa durante el ejercicio. Sin embargo, existe evidencia limitada en humanos sobre si la ingesta de antioxidantes afecta el GM. Por lo tanto, nuestro objetivo fue determinar el efecto de un cóctel de antioxidantes (AOC) en el GM en reposo y durante desafíos metabólicos. Métodos: Sujetos sanos (sexo masculino; n= 10) recibieron suplementos de AOC (1.000 mg de vitamina C, 600 UI de vitamina E y 600 mg de ácido α-lipoico) o placebo (2.000 mg de talco) previo a dos pruebas realizadas con 7 días de diferencia. Prueba 1: AOC 120 y 90 minutos antes de una serie de ejercicio de resistencia (EEX) al 60% del consumo máximo de oxígeno (VO2max); prueba 2: AOC 120 y 90 minutos antes de una prueba de tolerancia oral a la glucosa (OGTT; 75 g de glucosa). Se obtuvieron datos de intercambio de gaseoso y muestras de sangre capilar cada 15 minutos durante ambas pruebas. Resultados: la suplementación con AOC aumentó los niveles de glucosa en reposo (p<0,05). Durante la prueba 1 (EEX), el AOC aumentó la oxidación de carbohidratos (CHOox) (p= 0,03), sin efecto en los niveles de glucosa en sangre. Durante la prueba 2 (OGTT), la suplementación con AOC no tuvo un efecto significativo en los parámetros de GM. Conclusión: Una suplementación aguda con AOC aumentó los niveles de glucosa en reposo y la CHOox durante EEX en sujetos sanos, sin efecto sobre el GM durante la OGTT.

Oxidación celular y su relación con el consumo de alimentos antioxidantes en estudiantes universitarios

Desde la antigüedad se buscaba la "panacea de la juventud", la alquimia estuvo enfocada en ello y actualmente, estando en el ámbito educativo, se tiene la oportunidad de dar a conocer los productos alimenticios que tienen esa cualidad de ser antioxidantes y retardar el envejecimiento. Objetivo. Evaluar la oxidación celular y su relación con el consumo de alimentos antioxidantes en estudiantes universitarios de Pre grado de la Universidad Nacional de Educación Enrique Guzmán y Valle. Lima, Perú. Materiales y Métodos. La investigación fue de tipo descriptivo explicativo con nivel relacional. La población estuvo conformada por estudiantes de la Facultad de Educación, y por muestreo aleatorio fueron considerados a 36 estudiantes del IX Ciclo, asumiendo que tienen la formación y competencias adecuadas, para salir al mercado laboral después de un ciclo de estudios académicos. Resultados. Se obtuvo que el 94.4 % si sabe que es oxidación celular, el 83.3 % sabe que es un antioxidante y el 88.8 % conoce la importancia del consumo de antioxidantes naturales entre los cuales la naranja es la más conocida por el contenido de antioxidantes, seguido de espinaca, col morada, uva negra, vino tinto y maíz morado. Conclusiones. Los estudiantes universitarios, consumen a diario fruta fresca de la estación, seguido de verduras con carotenos (color naranja) y frutos con licopeno de color rojo.

Since ancient times the "panacea of youth" was sought, alchemy was focused on it and nowadays, being in the educational field, we have the opportunity to make known the food products that have the quality of being antioxidants and delay aging. Objective. To evaluate cellular oxidation and its relationship with the consumption of antioxidant foods in undergraduate university students of the Universidad Nacional de Educación Enrique Guzmán y Valle. Lima, Peru. Materials and Methods. The research was descriptive and explanatory with a relational level. The population consisted of students of the Faculty of Education, and by random sampling 36 students of the IX Cycle were considered, assuming that they have adequate training and competencies to enter the labor market after a cycle of academic studies. Results. It was obtained that 94.4 % know what cellular oxidation is, 83.3 % know what an antioxidant is and 88.8 % know the importance of the consumption of natural antioxidants among which orange is the most known for its antioxidant content, followed by spinach, purple cabbage, black grape, red wine and purple corn. Conclusions. University students consume fresh seasonal fruit daily, followed by vegetables with carotenes (orange color) and fruits with red lycopene.

Desde a antiguidade se buscava a "panaceia da juventude", a alquimia se debruçava sobre ela e hoje, estando no campo educacional, temos a oportunidade de dar a conhecer os produtos alimentícios que têm a qualidade de serem antioxidantes e retardarem o envelhecimento. Objetivo. Avaliar a oxidação celular e sua relação com o consumo de alimentos antioxidantes em estudantes universitários de graduação da Universidade Nacional de Educação Enrique Guzmán y Valle. Lima, Peru. Materiais e métodos. A pesquisa foi descritiva e explicativa com um nível relacional. A população foi formada por alunos da Faculdade de Educação e, por amostragem aleatória, foram considerados 36 alunos do IX Ciclo, supondo-se que eles tenham a formação e as competências adequadas para sair para o mercado de trabalho após um ciclo de estudos acadêmicos. Resultados. Obteve-se que 94,4 % sabem o que é oxidação celular, 83,3 % sabem o que é um antioxidante e 88,8 % sabem a importância do consumo de antioxidantes naturais, entre os quais a laranja é a mais conhecida por seu conteúdo antioxidante, seguida por espinafre, repolho roxo, uvas pretas, vinho tinto e milho roxo. Conclusões. Os estudantes universitários consomem diariamente frutas frescas da estação, seguidas de vegetais com caroteno (cor laranja) e frutas com licopeno vermelho.

Effect of carotenoid pigments extracted from papaya epicarp (Carica papaya) on the characteristics of Frankfurt sausages

The industrialization of papaya generates a large amount of organic waste, which is rich in antioxidant compounds, especially carotenoids. The purpose of the present article was to study the influence of carotenoid pigments extracted from the papaya epicarp as a partial substitute for nitrites in Frankfurt sausages. Four concentrations of lipid extract of papaya epicarp were analyzed in said sausages. While the control sample had 0 % substitution, 25 %, 50 % and 75 % substitution of nitrite was added to the other samples. The sausages were kept at 6 ± 2 °C for 30 days. The chemical composition, pH, water holding capacity, water activity, emulsion stability, color coordinates, texture profile and sensory appearance were analyzed, and for the sausage that presented the best physicochemical parameters, the stability in the time at 0, 10, 20 and 30 days of storage. It was obtained that adding the papaya epicarp extract to a concentration of 25 % did not affect the physicochemical parameters. In addition, the texture and color characteristics, as well as the sensory evaluation showed the best results for said concentration, guaranteeing stability up to a period of 30 days of storage under vacuum packing conditions and under refrigeration (6 ± 2 °C). A new alternative is proposed to minimize the negative action of nitrites in analyzed Frankfurt sausages, replacing them with antioxidant compounds obtained from a raw material of vegetable origin.

La industrialización de la papaya genera residuos orgánicos, ricos en compuestos antioxidantes, especialmente, en carotenoides. El objetivo de la presente investigación fue estudiar la influencia de los pigmentos carotenoides extraídos de epicarpio de la papaya, como sustituto parcial de los nitritos en salchichas Frankfurt. En dichos embutidos, se analizaron cuatro concentraciones de extracto lipídico de epicarpio de papaya; mientras que la mezcla control tenía 0 % de sustitución, se añadió 25, 50 y 75 % de reemplazo de nitrito a las otras muestras. Las salchichas se mantuvieron a 6 ± 2 °C durante 30 días. Se analizó la composición química, el pH, la capacidad de retención de humedad, la actividad de agua, la estabilidad de la emulsión, las coordenadas de color, el perfil de textura y la apariencia sensorial y para el embutido que presentó los mejores parámetros fisicoquímicos, la estabilidad en el tiempo a 0, 10, 20 y 30 días de almacenamiento. Se obtuvo que la adición del extracto de epicarpio de papaya a una concentración del 25 % no afectó los parámetros fisicoquímicos. Además, las características de textura y color, así como la evaluación sensorial, mostraron los mejores resultados para dicha concentración, garantizando la estabilidad, hasta un periodo de 30 días de almacenamiento, en condiciones de envasado al vacío y en refrigeración (6 ± 2°C). Se propone una nueva alternativa para minimizar la acción negativa de los nitritos en las salchichas Frankfurt, sustituyéndolos por compuestos antioxidantes, obtenidos a partir de una materia prima de origen vegetal.

The nuclear factor E2-related factor 2 and age-related macular degeneration / O fator 2 relacionado a NF-E2 e a degeneração macular relacionada à idade

ABSTRACT After the discovery of anti-vascular endothelial growth factor agents as treatment of wet age-related macular degeneration, the number of studies with the objective to understand the molecular mechanisms involved in the age-re lated macular degeneration genesis has increased. The importance of the nuclear factor e2-related factor 2 lies in its activation-derived proteins being involved in the maintenance of the redox balance and consequent prevention of degenerative macular disease. This article aims to present the characteristics of nuclear factor e2-related factor 2 and describe the main nuclear factor e2-related factor 2-activated antioxidant enzymes that contribute to the preservation of vision.

RESUMO Após a descoberta do anti fator de crescimento en dotelial vascular no tratamento da degeneração macular relacionada à idade úmida, muitas pesquisas têm sido realizadas com o intuito de elucidar os mecanismos moleculares envolvidos na gênese da degeneração macular relacionada à idade. O fator nuclear eritroide 2 relacionado ao fator 2 destaca-se pelo fato de diversas proteínas, oriundas de sua ativação, estarem envolvidas na manutenção do equilíbrio do estado redox e consequente prevenção da doença macular degenerativa. Este artigo mostra as características do fator nuclear eritroide 2 relacionado ao fator 2 e descreve as principais enzimas antioxidantes originadas da ativação que contribuem para a preservação da visão.

Efectividad del uso transoperatorio de solución electrolizada de superoxidación para la prevención de infecciones postoperatorias en cirugía de terceros molares / Effectiveness of the trans-operative use of electrolyzed superoxidation solution for the prevention of post-operative infections in third molar surgery

La cirugía de terceros molares es uno de los procedimientos más realizados dentro de la práctica odontológica, generalmente conlleva la prescripción de fármacos, incluidos antibióticos indicados para prevenir la aparición de procesos infecciosos. La resistencia antimicrobiana es considerada como un problema de salud pública a nivel mundial, por lo que el uso de antibióticos debe ser cauteloso. La solución electrolizada de súperoxidación ha demostrado tener efectos bactericidas, virucidas y ha sido utilizada para la prevención y el tratamiento de procesos infecciosos. El objetivo del presente estudio fue demostrar la efectividad de dicha solución en la prevención de infecciones posteriores a la cirugía de terceros molares. Se realizó un estudio aleatorizado, ciego, prospectivo en 20 pacientes utilizando un diseño split mouth, en donde cada paciente fue sujeto control y experimental, en el grupo control se irrigó durante el procedimiento con solución de súperoxidación y no se prescribió antibiótico posterior, mientras que en el grupo control se irrigó con solución fisiológica y se prescribió antibiótico posterior. Se realizaron 40 cirugías en 20 pacientes utilizando en cada paciente ambas terapéuticas. Se analizó el dolor postoperatorio, inflamación y presencia de infección. El dolor y la inflamación fueron ligeramente superiores en el grupo experimental al tercer día; sin embargo, al séptimo día los resultados fueron similares. No se presentó ningún caso de infección postoperatoria. El uso de solución de súperoxidación transoperatoria puede ser una herramienta muy útil en la prevención de infecciones postoperatorias posterior a cirugía de terceros molares en pacientes sanos en cirugías con dificultad leve a moderada (AU)

Third molar surgery is one of the most performed procedures in dental practice, generally involving the prescription of drugs including antibiotics indicated to prevent the onset of infectious processes. Antimicrobial resistance is considered a public health problem worldwide, so the use of antibiotics should be cautious. The electrolyzed super oxidation solution has been shown to have bactericidal and virucidal effects and has been used for the prevention and treatment of infectious processes. The objective of the present study was to demonstrate the effectiveness of said solution in the prevention of infections after third molar surgery. A randomized, blind, prospective study was conducted in 20 patients using a split mouth design where each patient was a control and experimental subject, in the control group they were irrigated during the procedure with super oxidation solution and no subsequent antibiotic was prescribed. while the control group was irrigated with physiological solution and a subsequent antibiotic was prescribed. Forty surgeries were performed on 20 patients using both therapies in each patient. Postoperative pain, inflammation and presence of infection were analyzed. Pain and inflammation were slightly higher in the experimental group on third day, however on seventh day the results were similar. There were no cases of postoperative infection. The use of trans operative super oxidation solution can be a very useful tool in the prevention of postoperative infections after third molar surgery in healthy patients undergoing surgeries with mild to moderate difficulty.(AU)

Proteínas oxidadas de origen animal y su impacto sobre la salud intestinal / Oxidized proteins of animal origin and their impact on intestinal health / Proteínas oxidadas de origem animal e seu impacto na saúde intestinal

Los alimentos de origen animal como la carne de pollo, res, pescado y cerdo poseen una amplia demanda en todo el mundo debido, entre otros aspectos, a su valor nutricional, asociado al alto contenido proteico. No obstante, este tipo de proteínas son susceptibles de sufrir reacciones de oxidación, las cuales pueden mediar procesos de fragmentación, agregación, pérdida de solubilidad, funcionalidad y digestibilidad proteica; eventos implicados en la pérdida de su valor nutricional. En este sentido, las proteínas agrega­das tienden a no ser digeridas en el tracto gastrointestinal y acumularse en el intestino (colon), donde la microbiota colónica las degrada a productos mutagénicos como fenol y p-cresol, lo que incrementa el riesgo de cáncer colorrectal. Por otra parte, los ami­noácidos o péptidos oxidados liberados en la digestión podrían incorporarse en las vías de señalización celular intestinal y favorecer o exacerbar procesos intestinales crónicos como colon irritable o enfermedad de Crohn. Debido al gran interés de esta temática en los últimos años, el objetivo de esta revisión es realizar una descripción general del impacto de proteínas oxidadas de origen animal sobre la salud intestinal.

Animal foods such as chicken, beef, fish and pork are in wide demand throughout the world due, among other things, to their nutritional value, associated with their high protein content. However, this type of protein is susceptible to oxidation reactions, which can mediate processes of fragmentation, aggregation, loss of solubility, functionality, and protein digestibility, which are events involved in the loss of their nutritional value. In this sense, aggregated proteins tend not to be digested in the gastrointestinal tract and accumulate in the intestine (colon), where the colonic microbiota degrades them into mutagenic products such as phenol and p-cresol, which increases the risk of colorectal cancer. On the other hand, the oxidized amino acids or peptides released in digestion could be incorporated into intestinal cell signaling pathways and favor or exacerbate chronic intestinal processes such as irritable bowel syndrome or Crohn's disease. Due to the great interest in this topic in recent years, the objective of this review is to provide a general overview of the impact of oxidized proteins of animal origin on intestinal health.

Alimentos de origem animal como frango, carne bovina, peixe e carne suína são muito procurados em todo o mundo devido, entre outros fatores, ao seu valor nutricional, associado ao seu alto teor de proteínas. No entanto, esse tipo de proteína é suscetível a reações de oxidação, que podem mediar processos de fragmentação, agregação, perda de solubilidade, funcionalidade e digestibilidade da proteína; eventos envolvidos na perda de seu valor nutritivo. Nesse sentido, as proteínas agregadas tendem a não ser digeridas no trato gastrointestinal e se acumulam no intestino (cólon), onde a microbiota colônica as degrada em produtos mutagênicos como fenol e p - cresol, aumentando o risco de câncer colorretal. Por outro lado, os aminoácidos ou peptídeos oxidados liberados na digestão poderiam ser incorporados às vias de sinalização das células intestinais e favorecer ou exacerbar processos intestinais crônicos, como a síndrome do intestino irritável ou a doença de Crohn. Devido ao grande interesse neste tema nos últimos anos, o objetivo desta revisão é fornecer uma descrição geral do impacto das proteínas oxidadas de origem animal na saúde intestinal.

Preclinical anti-apoptotic properties of salidroside for hypoxic-ischemic cerebral damage: a systematic review and meta-analysis / 数字中医药（英文）

@#【Objective】   As the main active ingredient of Tibetan medicine Hongjingtian (Rhodiolae Crenulatae Radix et Rhizoma), salidroside (Sal) has a good anti-apoptotic potential. Currently, there are some conflicting results on the anti-apoptotic mechanisms of Sal. Here we conducted a systematic review and meta-analysis to provide the preclinical evidence of its anti-apoptotic properties in preventing and treating hypoxic-ischemic cerebral damage(HICD). 【Methods】   The literature on the anti-apoptotic potential of Sal in the treatment of HICD from January 1, 1980 to November 9, 2021 was searched online using Chinese databases including Chinese National Knowledge Infrastructure (CNKI), China Science and Technology Journal Database (VIP), and Wanfang Database, and English databases including PubMed and Web of Science. The quality of the included articles was evaluated by the Cochrane Collaboration network bias risk assessment criteria, and meta-analysis was performed using RevMan 5.3 software. 【Results】  A total of 40 articles were finally included. Among the 40 articles, 30 were about in vivo animal experiments and 17 about in vitro cell experiments, and 7 of them included both animal and cell experiments. After analysis, it was found that Sal had significant effects on disease-related indicators of HICD (P < 0.05), such as cerebral infarctsize and brain water content. As to in vivo studies, Sal mainly affects the expressions of apoptotic factors through antiinflammation, anti-oxidation, activation of complement pathway, and regulation of signal transduction and autophagy, thus exerting anti-apoptotic potential in treating HICD. While for in vitro studies, Sal plays the anti-apoptotic role in HICD models mainly through anti-oxidation, anti-inflammation, reduction of Ca2+ overload, regulation of mitochondrial function, signal transduction, and C3 complement. 【Conclusion】  Sal can take anti-apoptotic effects to prevent and treat HICD through mechanisms such as anti-inflammation, anti-oxidation, enhanced autophagy, complement and signal transduction, regulation of mitochondrial membrane potential, and reduction of Ca2 + overload.

Research Progress on Correlation of Glucose Metabolism Mechanism with Invasion and Metastasis of Nasopharyngeal Carcinoma Cells / 肿瘤防治研究

Metastasis is the main cause of cancer-related death. Growing evidence has shown that changes in glucose metabolism in nasopharyngeal carcinoma cells affect the invasion and metastasis of nasopharyngeal carcinoma through many pathways. This review summarizes the molecular mechanism underlying abnormal glucose metabolism in nasopharyngeal carcinoma cells and analyzes its relationship with the invasion and metastasis of nasopharyngeal carcinoma, including aerobic glycolysis, aerobic oxidation, and pentose phosphate pathway. The aim is to provide novel approaches using the relationships among glucose metabolism, invasion, and metastasis in the targeted therapy of nasopharyngeal carcinoma.

Angiogenic property of cobalt and calcium-phosphorus doped coating on titanium surfaces in vitro / 口腔疾病防治

Objective@# To investigate the effect of cobalt (Co) and calcium-phosphate (Ca/P) doped coating on titanium surfaces and their angiogenic effect.@*Methods @# Microarc oxidation (MAO) was used to prepare Co-Ca/P-doped and Co-doped coatings. Titanium (Ti) sheet without MAO treatment was used as control. Scanning electron microscopy (SEM) was used to observe the surface micromorphology of the coatings. Energy dispersive spectrometry (EDS) was also applied to detect the doped chemicals and their contents. Standard soaking solutions of these coatings were prepared using an endothelial cell medium (ECM) solution for subsequent angiogenesis experiments. Human umbilical vein endothelial cells (HUVECs) were cultured on Matrigel with ECM soaking solutions for 4 h and 8 h. The microvessels were observed under a microscope, and the number of microtubules and their interconnecting nodes were analyzed with Image J software. @*Results@# Co doped and Co-Ca/P-doped coatings were successfully prepared by MAO, which was demonstrated by both SEM observation and EDS analysis. SEM observation showed that irregular crystals of the above chemicals were present on both Co and Co-Ca/P-doped coatings, commonly with a diameter <2 μm. However, more crystals were observed on the Co-Ca/P coatings than on the Co coating, and the distribution of the crystals was more homogenous on the Co-Ca/P coatings. However, only polishing scratches were observed on the Ti sample surface. EDS analysis indicated that in contrast to only Co in the Co coating, Co, Ca and P were doped within the Co-Ca/P coating, and none of the three elements were observed on the Ti plate surface. The number of vascular rings and nodes formed by HUVECs in the extract of the Co-Ca/P group was significantly higher than that of the Co group (P<0.05), and the angiogenic effect of these two components was significantly better than that of the Ti group (P<0.05). @*Conclusion@#The Co-Ca/P coating exhibits good angiogenic properties in vitro and is valuable for the development of new titanium implants with high surface bioactivity.

Protective Effect of Alcohol Extract of Phyllanthi Fructus on Silicosis Mice and Its Correlation with Nrf2/ARE Signaling Pathway / 中国实验方剂学杂志

ObjectiveTo explore the effect and underlying mechanism of alcohol extract of Phyllanthi Fructus on silicosis mice induced by silicon dioxide （SiO2）. MethodThirty-six male Kunming mice of SPF grade were randomly divided into a blank group，a model group，high-， medium， and low-dose Phyllanthi Fructus groups （800， 400， 200 mg·kg-1），and a tetrandrine group （0.039 mg·kg-1），with six mice in each group. The silicosis model was induced by static SiO2 exposure in mice except for those in the blank group. After 28 days of administration by gavage，the lung tissues were collected and the organ coefficient was calculated. Hematoxylin-eosin（HE）staining and Masson staining were used to detect the morphology of lung tissues. The content of hydroxyproline （HYP），superoxide dismutase （SOD），malondialdehyde （MDA）， and catalase （CAT） in serum was detected by enzyme-linked immunosorbent assay （ELISA）. Western blot and Real-time polymerase chain reaction（Real-time PCR） were used to detect the protein and mRNA expression of nuclear factor E2-related factor 2 （Nrf2），heme oxygenase-1 （HO-1），NAD（P）H：quinone oxidoreductase 1 （NQO1），and Kelch-like ECH-associated protein 1 （Keap1）， respectively. ResultCompared with the blank group，the model group showed seriously damaged morphological structure of lung tissues with inflammatory cell infiltration and fibrous tissue proliferation， reduced serum content of SOD and CAT（P<0.01），increased content of HYP and MDA（P<0.01）， down-regulated protein and mRNA expression of Nrf2，HO-1， and NQO1（P<0.01），and up-regulated protein and mRNA expression of Keap1 （P<0.05，P<0.01）. Compared with the model group，the high- and medium-dose Phyllanthi Fructus groups showed significantly restored morphological structure of lung tissues with reduced collagen deposition， increased serum content of SOD and CAT（P<0.05，P<0.01），decreased content of HYP and MDA（P<0.01）， up-regulated protein and mRNA expression of Nrf2，HO-1， and NQO1 （P<0.05，P<0.01），and down-regulated protein and mRNA expression of Keap1（P<0.05，P<0.01）. ConclusionThe alcohol extract of Phyllanthi Fructus can inhibit pulmonary fibrosis in silicosis mice，and the underlying mechanism may be related to the regulation of the Nrf2/antioxidant response element （ARE） signaling pathway.

Research progress on pharmacological effects of bilirubin nanoparticles / 中国药房

Bilirubin has good anti-inflammatory， antioxidant and immunomodulatory effects， but its poor water solubility and low bioavailability greatly limit its clinical application. Researchers have developed bilirubin into various nanoparticles， which effectively eliminate the limitation of low solubility of bilirubin with the advantage of dosage form， so that they can maximize its pharmacological activities such as anti-inflammatory， anti-oxidation and immune regulation. Bilirubin nanoparticles have great application potential in a variety of gastrointestinal diseases， liver and kidney diseases， skin diseases， autoimmune diseases， islet transplantation and targeted therapy of tumors （both as a direct anti-tumor drug and as a drug delivery system）. The study of bilirubin nanoparticles will promote the clinical application of bilirubin and the development of related new drugs.

Anemoside B4 regulates fatty acid metabolism reprogramming in mice with colitis-associated cancer / 中国中药杂志

The study aimed to investigate the effect of anemoside B4(B4) on fatty acid metabolism in mice with colitis-associated cancer(CAC). The CAC model was established by azoxymethane(AOM)/dextran sodium sulfate(DSS) in mice. Mice were randomly divided into a normal group, a model group, and low-, medium-, and high-dose anemoside B4 groups. After the experiment, the length of the mouse colon and the size of the tumor were measured, and the pathological alterations in the mouse colon were observed using hematoxylin-eosin(HE) staining. The slices of the colon tumor were obtained for spatial metabolome analysis to analyze the distribution of fatty acid metabolism-related substances in the tumor. The mRNA levels of SREBP-1, FAS, ACCα, SCD-1, PPARα, ACOX, UCP-2, and CPT-1 were determined by real-time quantitative PCR(RT-qPCR). The results revealed that the model group showed decreased body weight(P<0.05) and colon length(P<0.001), increased number of tumors, and increased pathological score(P<0.01). Spatial metabolome analysis revealed that the content of fatty acids and their derivatives, carnitine, and phospholipid in the colon tumor was increased. RT-qPCR results indicated that fatty acid de novo synthesis and β-oxidation-related genes, such as SREBP-1, FASN, ACCα, SCD-1, ACOX, UCP-2, and CPT-1 mRNA expression levels increased considerably(P<0.05, P<0.001). After anemoside B4 administration, the colon length increased(P<0.01), and the number of tumors decreased in the high-dose anemoside B4 group(P<0.05). Additionally, spatial metabolome analysis showed that anemoside B4 could decrease the content of fatty acids and their derivatives, carnitine, and phospholipids in colon tumors. Meanwhile, anemoside B4 could also down-regulate the expression of FASN, ACCα, SCD-1, PPARα, ACOX, UCP-2, and CPT-1 in the colon(P<0.05, P<0.01, P<0.001). The findings of this study show that anemoside B4 may inhibit CAC via regulating fatty acid metabolism reprogramming.

Modification of C20 oxidase in tanshinone biosynthesis pathway / 中国中药杂志

Tanshinones are one of the main effective components of Salvia miltiorrhiza, which play important roles in the treatment of cardiovascular diseases. Microbial heterogony production of tanshinones can provide a large number of raw materials for the production of traditional Chinese medicine(TCM) preparations containing S. miltiorrhiza, reduce the extraction cost, and relieve the pressure of clinical medication. The biosynthetic pathway of tanshinones contains multiple P450 enzymes, and the catalytic element with high efficiency is the basis of microbial production of tanshinones. In this study, the protein modification of CYP76AK1, a key P450-C20 hydroxylase in tanshinone pathway, was researched. The protein modeling methods SWISS-MODEL, Robetta, and AlphaFold2 were used, and the protein model was analyzed to obtain the reliable protein structure. The semi-rational design of mutant protein was carried out by molecular docking and homologous alignment. The key amino acid sites affecting the oxidation activity of CYP76AK1 were identified by molecular docking. The function of the obtained mutations was studied with yeast expression system, and the CYP76AK1 mutations with continuous oxidation function to 11-hydroxysugiol were obtained. Four key amino acid sites that affected the oxidation acti-vity were analyzed, and the reliability of three protein modeling methods was analyzed according to the mutation results. The effective protein modification sites of CYP76AK1 were reported for the first time in this study, which provides a catalytic element for different oxidation activities at C20 site for the study of the synthetic biology of tanshinones and lays a foundation for the analysis of the conti-nuous oxidation mechanism of P450-C20 modification.

Plasma Acylcarnitine and Urinary Organic Acid Profiling for the diagnosis of Fatty Acid Oxidation Disorder and Organic Acidurias using tandem mass spectrometry (MS/MS) and gas chromatography tandem with mass spectrometry (GC-MS): a retrospective study

INTRODUCTION@#Acylcarnitines in plasma and urinary organic acids are essential diagnostic markers for some Inborn Errors of Metabolism (IEM) such as fatty acid oxidation disorders, and disorders related to organic acids metabolism. By virtue of R. A. 9288, Filipino newborn babies are screened for inherited metabolic disorders via the analysis of dried blood spots (DBS) using MS/MS. @*OBJECTIVE@#This study aimed to establish the plasma acylcarnitine (PLAC) and urinary organic acid (UOA) profiles of Filipino newborn babies screened at high risk for IEMS using MS/MS and single quadrupole GC-MS analytical techniques. Further, this study describes the process of determining the true positive cases of fatty acid oxidation disorders and some organic acidurias among screened Filipino newborn babies using different sample types such as plasma and urine via flow injection analysis with tandem mass spectrometry (FIA-MS/MS) and another technique such as gas chromatography in tandem with mass spectrometry (GC-MS).@*METHODOLOGY@#Plasma acylcarnitine and urinary organic acid analyses were performed using Waters® MS/MS and Agilent® single quadrupole GC-MS, respectively. Results obtained from PLAC and UOA databases and IEM registry of the Biochemical Genetics Laboratory (BGL) covering the period 2015-2021 were utilized to account for the number of confirmed cases out of the total number screened positive for IEMs. Descriptive statistics was also used to evaluate the detection rates of FAODs and Organic Acidurias in Filipino newborn babies screened to be high risk.@*RESULTS@#Plasma acylcarnitine analysis was introduced by BGL only in 2015. Data from 2015-2021, indicated 176 true positives out of 1642 babies screened at high risk for FAODs and organic acidurias. The use of plasma and urine samples for measurements in MS/MS and GC-MS yielded a detection rate of 10.7% with 104 Filipino newborn babies afflicted with fatty acid oxidation disorders (FAOD) while 72 were found to be confirmed cases of organic acidurias. Medium-chain acyl-CoA dehydrogenase (MCAD) deficiency was reported to be the most common FAOD with 67 cases. Organic acidurias such as glutaric aciduria type 1 and 3-Methylcrotonyl-CoA carboxylase (3-MCC) deficiency were found to be common with 34 and 26 true positives, respectively. @*CONCLUSION@#The plasma acylcarnitine and urinary organic acid profiles of Filipino newborn babies with fatty acid oxidation disorders and organic acidurias obtained via MS/MS and GC/MS, respectively, were presented in this paper. This study emphasizes the importance of conducting confirmatory testing to establish the true positives from among those Filipino newborns flagged to be at high risk for FAODs or organic aciduria. The confirmatory tests are based on the use of different samples such as urine and plasma in order to detect and quantify biomarkers for FAODs and organic acidurias using two different analytical techniques such as MS/MS and GC-MS. This study warrants further studies directed towards the validation of analytical methodologies for targeted measurements of biomarkers of IEMS in urine and plasma of newborn babies to increase the efficiency of establishing true positives and to determine the efficiency of administration of interventions on Filipino children with genetic disabilities, that is, for monitoring purposes.

Efeitos do D-limoneno no metabolismo energético de camundongos C57/Bl6 com obesidade induzida pela dieta / Effects of D-limonene on the energy metabolism of C57/Bl6 mice with diet-induced obesity

A obesidade está associada ao desenvolvimento de doenças crônicas não transmissíveis como hipertensão, resistência insulínica, dislipidemia e esteatose hepática. O consumo de compostos bioativos impacta na manutenção da saúde e na prevenção de risco de desenvolvimento dessas doenças. Entre os compostos bioativos, os monoterpenos são pouco investigados, apesar da literatura demonstrar efeitos promissores desses compostos sobre o metabolismo. O D-limoneno, o principal monoterpeno encontrado na laranja, é caracterizado por possuir efeitos hipolipemiantes, anti-inflamatórios e anti-obesogênicos. Estudos in vitro e in vivo descrevem sua capacidade de promover a ß-oxidação de ácidos graxos em adipócitos e redução da inflamação. Este estudo teve como objetivo investigar o efeito do D-limoneno no metabolismo e inflamação em um modelo de obesidade induzida por dieta. Para isso, quarenta camundongos machos (C57/Bl6) de 11 semanas de idade, foram distribuídos em 4 grupos, sendo que um dos grupos recebeu ração normolipídica e os demais, ração hiperlipídica. O D-limoneno foi suplementado na ração de dois grupos que receberam dieta hiperlipídica nas concentrações de 0,1%, e 0,8%. Considerando-se a ingestão alimentar dos animais, a ração suplementada com 0,1% D-limoneno correspondeu à ingestão de 0,15 g/kg/dia e ração com 0,8% de D-limoneno correspondeu a 1,3 g/kg/dia. Os animais tiveram o peso e a ingestão alimentar monitorados ao longo da intervenção com duração de 7 semanas. Os camundongos que receberam D-limoneno a 0,1% apresentaram menor ganho de peso e de acúmulo de tecido adiposo, comparado com os animais sem suplementação alimentados com a dieta hiperlipídica. Além disso, o D-limoneno promoveu a diminuição da concentração plasmática de marcadores inflamatórios incluindo TNF-α, INF-γ e IL-6 nos animais dos grupos que foram suplementados com D-limoneno. Entretanto, não houve diferença nos marcadores bioquímicos e metabólicos. Uma limitação do estudo foi o fato das complicações metabólicas associadas ao modelo de obesidade não terem sido plenamente estabelecidas, dados o alojamento individual, à curta duração da exposição à ração hiperlipídica e idade dos animais no início da suplementação. Esse fato pode ter dificultado a observação dos efeitos do D-limoneno na reversão dos parâmetros que seriam normalmente deteriorados pelo desenvolvimento da obesidade. Concluímos que o D-limoneno pode interferir no metabolismo energético, com possível efeito anti-obesogênico e anti-inflamatório. Devido às limitações do modelo, são necessários mais estudos para confirmar esses resultados

Obesity is associated with the development of chronic non-communicable diseases such as hypertension, insulin resistance, dyslipidemia, and hepatic steatosis. The intake of dietary bioactive compounds is associated with the maintenance of health and the prevention of chronic diseases. Among the group of bioactive compounds, monoterpenes are poorly investigated, in spite of several reports of their promising effects on metabolism. D-limonene is the main monoterpene found in oranges, known for its hypolipemic, anti-inflammatory, and anti-obesogenic effects. in vitro and in vivo studies associate D-limonene to increased ß-oxidation of fatty acids in adipocytes and reduced inflammation. This study aimed at investigating the effects of D-limonene on metabolism and inflammation in a diet-induced obesity model. For this purpose, forty male mice (C57/Bl6) were distributed in 4 groups, with one group receiving a normolipidic diet and the others, a high-fat diet. D-limonene was supplemented in the diets of two groups that received high-fat diet at the concentrations of 0.1% and 0.8%. Considering the feed intake, mice receiving D-limonene supplementation at 0.1% ingested in average 0.15 g/kg/day, while the mice receiving the supplemmentation at 0.8%, ingested approximately 1.3 g of D-limonene /kg/day. The animals had their weight and food intake monitored throughout the intervention. Mice that received Dlimonene supplementation at 0.1% showed reduced weight gain and accumulation of adipose tissue compared to the non-supplemented mice fed the high-fat diet. In addition, D-limonene promoted a decrease in hepatic inflammatory markers including TNF-α, INF-γ, and IL-6. However, there was no difference in biochemical and metabolic markers. A limitation of the study was that the metabolic complications associated with the obesity model were not fully established, probably due to the age at the start of the protocol (11 weeks), individual housing and short duration of the exposure to the high-fat feed. This fact may have prevented the observation of the positive effects of D-limonene in reversing parameters that would normally be impaired by the development of obesity. We conclude that D-limonene may interfere in energy metabolism, with a possible anti-obesogenic and anti-inflammatory effect. Due to the limitations of the model, further studies are needed to confirm these findings

The developments of silicosis drugs / 药学学报

Pneumoconiosis is the most common occupational disease in China, which severely endangers people's health. Depending on the inhaled air pollutants, pneumoconiosis is classified as anthracosis, silicosis, asbestosis, etc., among which silicosis is the most common and serious. Silicosis is a systemic, poor prognostic disease characterized by diffuse fibrosis of lung tissue, which is caused by long-term exposure to dust with high levels of free silicon dioxide (SiO2) in the occupational environment. Appropriate treatment in time is important for the disease. Unfortunately, no effective drugs have been approved to delay or even reverse pulmonary fibrosis caused by SiO2. This review briefly classifies potent therapeutic drugs and compounds in term of mechanisms, providing the probability for clinical treatment of silicosis.

Inhibitory effects of N-acetyl-L-cysteine on brain inflammation in mice with periodontitis and Alzheimer’s disease / 西安交通大学学报(医学版)

【Objective】 To explore the effects of periodontitis on the brains of Alzheimer’s disease (AD) mice and the effects of N-acetyl-L-cysteine (NAC) on the periodontium and the brain of AD mice with experimental chronic periodontitis (CP). 【Methods】 Ten wild-type C57 mice were in the blank control group (Group C57), and another 40 3-month-old APP/PS1 transgenic mice were randomly divided into four groups: AD+CP group, AD+CP+NAC group, AD+NAC group, and AD group. The periodontitis model was established in mice in AD+CP group and AD+CP+NAC group by silk ligation. At the same time, mice in AD+CP+NAC group and AD+NAC group were injected with NAC (200 mg/kg). The height of alveolar bone loss was detected after 3 weeks, and the cell morphology of the hippocampus was observed. We determined the expression levels of NLRP3 inflammasome and amyloid-β (Aβ) in the hippocampus as well as the expression levels of interleukin (IL)-1β and IL-18 in the hippocampus and gums by ELISA. 【Results】 Compared with AD group, the height of alveolar bone loss in AD+CP group was higher (P<0.05), and the expression levels of IL-18 in the gum and IL-1β and NLRP3 in the hippocampus were increased significantly (P<0.05). In addition, compared with AD+CP group, the height of alveolar bone loss in AD+CP+NAC group was reduced significantly (P<0.05), the expression levels of IL-1β and IL-18 in the gum were reduced significantly (P<0.05) as well as the expression levels of IL-1β and Aβ in the hippocampus were reduced significantly (P<0.05). Compared with C57 group, the neurons in the hippocampus of AD+CP group were more loose and disordered, and the activation of microglia was increased, while the disarrangement of cells in AD+CP+NAC group was less than that in AD+CP group. 【Conclusion】 Periodontitis can aggravate brain inflammation in AD mice. NAC can effectively reduce alveolar bone resorption in AD mice caused by periodontitis as well as reduce the levels of inflammatory factors in the gum and hippocampus. NAC can effectively reduce the alveolar bone absorption of AD mice caused by periodontitis, reduce the level of inflammatory factors in the gingiva and hippocampus, and reduce the damage of nerve cells in the hippocampus.

Dihydrotanshinone I preconditions myocardium against ischemic injury via PKM2 glutathionylation sensitive to ROS

Ischemic preconditioning (IPC) is a potential intervention known to protect the heart against ischemia/reperfusion injury, but its role in the no-reflow phenomenon that follows reperfusion is unclear. Dihydrotanshinone I (DT) is a natural compound and this study illustrates its role in cardiac ischemic injury from the aspect of IPC. Pretreatment with DT induced modest ROS production and protected cardiomyocytes against oxygen and glucose deprivation (OGD), but the protection was prevented by a ROS scavenger. In addition, DT administration protected the heart against isoprenaline challenge. Mechanistically, PKM2 reacted to transient ROS via oxidization at Cys423/Cys424, leading to glutathionylation and nuclear translocation in dimer form. In the nucleus, PKM2 served as a co-factor to promote HIF-1α-dependent gene induction, contributing to adaptive responses. In mice subjected to permanent coronary ligation, cardiac-specific knockdown of Pkm2 blocked DT-mediated preconditioning protection, which was rescued by overexpression of wild-type Pkm2, rather than Cys423/424-mutated Pkm2. In conclusion, PKM2 is sensitive to oxidation, and subsequent glutathionylation promotes its nuclear translocation. Although IPC has been viewed as a protective means against reperfusion injury, our study reveals its potential role in protection of the heart from no-reflow ischemia.

Reactivation of PPARα alleviates myocardial lipid accumulation and cardiac dysfunction by improving fatty acid β-oxidation in Dsg2-deficient arrhythmogenic cardiomyopathy

Arrhythmogenic cardiomyopathy (ACM), a fatal heart disease characterized by fibroadipocytic replacement of cardiac myocytes, accounts for 20% of sudden cardiac death and lacks effective treatment. It is often caused by mutations in desmosome proteins, with Desmoglein-2 (DSG2) mutations as a common etiology. However, the mechanism underlying the accumulation of fibrofatty in ACM remains unknown, which impedes the development of curative treatment. Here we investigated the fat accumulation and the underlying mechanism in a mouse model of ACM induced by cardiac-specific knockout of Dsg2 (CS-Dsg2 -/-). Heart failure and cardiac lipid accumulation were observed in CS-Dsg2 -/- mice. We demonstrated that these phenotypes were caused by decline of fatty acid (FA) β-oxidation resulted from impaired mammalian target of rapamycin (mTOR) signaling. Rapamycin worsened while overexpression of mTOR and 4EBP1 rescued the FA β-oxidation pathway in CS-Dsg2 -/- mice. Reactivation of PPARα by fenofibrate or AAV9-Pparα significantly alleviated the lipid accumulation and restored cardiac function. Our results suggest that impaired mTOR-4EBP1-PPARα-dependent FA β-oxidation contributes to myocardial lipid accumulation in ACM and PPARα may be a potential target for curative treatment of ACM.