RESUMEN
BACKGROUND: Synovial inflammation plays a crucial role in osteoarthritis (OA). Gastrodin (GAS), an active ingredient derived from the Gastrodia elata Blume rhizome, possesses antioxidant and anti-inflammatory pharmacological effects. This research aimed to evaluate the function and molecular mechanism of GAS on human fibroblast-like synoviocytes of osteoarthritis (HFLS-OA) induced by interleukin (IL)-1ß. METHODS: The impact of GAS on the viability of IL-1ß-treated HFLS-OA cells was assessed using the cell counting kit-8 (CCK-8). Quantitative real-time reverse transcription PCR (qRT-PCR) was employed to detect changes in IL-8, IL-6, monocyte chemotactic protein-1 (MCP-1), tumor necrosis factor (TNF)-α, and Gremlin-1 mRNA expression in each group. Corresponding kits were utilized to measure the catalase (CAT) and superoxide dismutase (SOD) activities, as well as the nitric oxide (NO) level. Western blot analysis was conducted to examine the expression of extracellular matrix degradation-associated proteins and nuclear factor kappa-B (NF-κB) pathway-correlated proteins in each group. RESULTS: GAS significantly promoted the proliferation of IL-1ß-induced HFLS-OA cells and concurrently down-regulated Gremlin-1 mRNA expression (p < 0.05). Through the down-regulation of Gremlin-1 expression, GAS exhibited the following effects: decreased IL-8, IL-6, and TNF-α mRNA expression, as well as NO levels (p < 0.05); increased SOD and CAT activities (p < 0.05); down-regulated matrix metallopeptidase 13 (MMP-13) and MMP-1 protein expression levels (p < 0.01); and up-regulated collagen II protein expression level (p < 0.01) in IL-1ß-treated HFLS-OA cells. Additionally, GAS decreased phospho-inhibitory kappa B (p-IκB)/IκB, phospho-inhibitory kappa B kinase (p-IKK)/IKK, and p-p65/p65 ratios in IL-1ß-induced HFLS-OA cells by inhibiting Gremlin-1 expression (p < 0.01). CONCLUSION: GAS demonstrates a positive impact on inflammation, oxidative stress, and extracellular matrix degradation in IL-1ß-mediated HFLS-OA cells. This effect is achieved by suppressing Gremlin-1 expression and reducing NF-κB pathway activity.
Asunto(s)
Alcoholes Bencílicos , Matriz Extracelular , Glucósidos , Inflamación , Interleucina-1beta , FN-kappa B , Estrés Oxidativo , Sinoviocitos , Humanos , Glucósidos/farmacología , Interleucina-1beta/metabolismo , Alcoholes Bencílicos/farmacología , FN-kappa B/metabolismo , Estrés Oxidativo/efectos de los fármacos , Inflamación/metabolismo , Inflamación/patología , Matriz Extracelular/metabolismo , Matriz Extracelular/efectos de los fármacos , Sinoviocitos/efectos de los fármacos , Sinoviocitos/metabolismo , Sinoviocitos/patología , Fibroblastos/metabolismo , Fibroblastos/efectos de los fármacos , Transducción de Señal/efectos de los fármacos , Osteoartritis/patología , Osteoartritis/metabolismo , Osteoartritis/tratamiento farmacológico , Péptidos y Proteínas de Señalización IntercelularRESUMEN
ETHNOPHARMACOLOGICAL RELEVANCE: Salvia miltiorrhiza Bunge is a kind of Chinese herbal medicine known for activating blood circulation and removing blood stasis, with the effect of cooling blood and eliminating carbuncles, and has been proven to have the effect of treating tumors. However, the inhibitory effect of Salvia miltiorrhiza Bunge extracts (Diterpenoid tanshinones) on tumors by inhibiting angiogenesis has not been studied in detail. AIM OF THE STUDY: This study aimed to investigate the anti-gastric cancer effect of diterpenoid tanshinones (DT) on angiogenesis, including the therapeutic effects and pathways. MATERIALS AND METHODS: This experiment utilized network pharmacology was used to identify relevant targets and pathways of Salvia miltiorrhiza Bunge-related components in the treatment of gastric cancer. The effects of DT on the proliferation and migration of human gastric cancer cell line SGC-7901 and human umbilical vein endothelial cell line HUVECs were evaluated, and changes in the expression of angiogenesis-related factors were measured. In vivo, experiments were conducted on nude mice to determine tumor activity, size, immunohistochemistry, and related proteins. RESULTS: The findings showed that DT could inhibit the development of gastric cancer by suppressing the proliferation of gastric cancer cells, inducing apoptosis, and inhibiting invasion and metastasis. In addition, the content of angiogenesis-related factors and proteins was significantly altered in DT-affected cells and animals. CONCLUSIONS: Results suggest that DT has potential as a therapeutic agent for the treatment of gastric cancer, as it can inhibit tumor growth and angiogenesis. It was also found that DT may affect the expression of the angiogenic factor VEGF through the PI3K/Akt/mTOR pathway, leading to the regulation of tumor angiogenesis. This study provides a new approach to the development of anti-tumor agents and has significant theoretical and clinical implications for the treatment of gastric cancer.
Asunto(s)
Abietanos , Diterpenos , Salvia miltiorrhiza , Neoplasias Gástricas , Animales , Ratones , Humanos , Neoplasias Gástricas/tratamiento farmacológico , Fosfatidilinositol 3-Quinasas , Proteínas Proto-Oncogénicas c-akt , Ratones Desnudos , Angiogénesis , Serina-Treonina Quinasas TOR , Transducción de Señal , Diterpenos/farmacología , Diterpenos/uso terapéutico , Salvia miltiorrhiza/químicaRESUMEN
Aluminum chloride is an inorganic polymeric coagulant commonly found in daily life and various materials. Although male reproductive toxicity has been associated with AlCl3 exposure, the underlying mechanism remains unclear. This study aimed to examine the impact of AlCl3 exposure on mitophagy and mitochondrial apoptosis in testicular tissue and mouse spermatocytes. Reactive oxygen species (ROS) and ATP levels were measured in GC-2spd after AlCl3 exposure using a multifunctional enzyme labeler. The changes in mitochondrial membrane potential (MMP) and TUNEL were observed through confocal laser microscopy, and the expression of proteins associated with mitophagy and apoptosis was analyzed using Western blot. Our results demonstrated that AlCl3 exposure disrupted mitophagy and increased apoptosis-related protein expression in testicular tissues. In the in vitro experiments, AlCl3 exposure induced ROS production, suppressed cell viability and ATP production, and caused a decrease in MMP, leading to mitophagy and cell apoptosis in GC-2spd cells. Intervention with N-acetylcysteine (NAC) reduced ROS production and partially restored mitochondrial function, thereby reversing the resulting mitophagy and cell apoptosis. Our findings provide evidence that ROS-mediated mitophagy and cell apoptosis play a crucial role in the toxicity of AlCl3 exposure in GC-2spd. These results contribute to the understanding of male reproductive toxicity caused by AlCl3 exposure and offer a foundation for future research in this area.
RESUMEN
The role and mechanism of Gremlin-1 in osteoarthritis (OA) were expected to be probed in this study. Firstly, an in vitro OA model was constructed by stimulating human chondrocyte cell line CHON-001 with IL-1ß. Next, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and quantitative reverse transcriptase polymerase chain reaction (qRT-PCR) were utilized for assessing the effect of IL-1ß with different concentrations (5, 10, and 20 ng/mL) on the activity and Gremlin-1 messenger RNA of CHON-001 cells, respectively. Besides, the influence of knocking down/over-expressing Gremlin-1 on the inflammatory factors (IL-6, TNF-α, IL-18 and PGE2), oxidative stress-related substances (malondialdehyde [MDA]; superoxide dismutase [SOD]; lactate dehydrogenase [LDH]), extracellular matrix (ECM) degradation-related proteins, and mitogen-activated protein kinase (MAPK) pathway proteins in IL-1ß-stimulated CHON-001 cells were tested by enzyme-linked immunosorbent assay, related kits, qRT-PCR, and western blot, respectively. IL-1ß inhibited CHON-001 cell proliferation and upregulated Gremlin-1 expression in a concentration-dependent manner. Overexpression of Gremlin-1 increased the IL-6, TNF-α, IL-18, PGE2, and MDA levels, enhanced the LDH activity, and decreased the SOD activity in IL-1ß-induced CHON-001 cells; while the effect of Gremlin-1 knockdown on the above factors was in contrast with that of the overexpression. Furthermore, overexpression of Gremlin-1 upregulated protein expression of matrix metalloproteinase (MMP)-3, MMP-13, and ADAMTS4 while downregulated protein expression of collagen III, aggrecan, and SOX-9 in IL-1ß-stimulated CHON-001 cells. Besides, overexpression of Gremlin-1 increased the p-p38/p38 value while decreased the p-JNK/JNK value in L-1ß-stimulated CHON-001 cells; however, knockdown of Gremlin-1 reversed the above results. Gremlin-1 may promote IL-1ß-stimulated CHON-001 cell inflammation and ECM degradation by activating the MAPK signaling pathway.
Asunto(s)
MicroARNs , Osteoartritis , Humanos , Condrocitos/metabolismo , Interleucina-18/metabolismo , Proteínas Quinasas Activadas por Mitógenos/metabolismo , Factor de Necrosis Tumoral alfa/metabolismo , Dinoprostona/metabolismo , Interleucina-6/metabolismo , Células Cultivadas , Inflamación/inducido químicamente , Inflamación/metabolismo , Transducción de Señal , Osteoartritis/metabolismo , Matriz Extracelular/metabolismo , Interleucina-1beta/farmacología , Interleucina-1beta/metabolismo , MicroARNs/metabolismoRESUMEN
Objective: This study aimed to prospectively observe the efficacy and safety of CalliSpheres drug-eluting beads bronchial arterial chemoembolization (DEB-BACE) for refractory non-small-cell lung cancer (NSCLC). Methods: The interventional therapy plan was as follows: 300-500 µm CalliSpheres drug-loaded microspheres were loaded with epirubicin, and then slow embolization of tumor supplying artery was performed after microcatheter superselection. Chest enhanced computed tomography and related hematological examination were reviewed after 2 months of DEB-BACE, and the tumor response after the first interventional therapy was evaluated using modified response evaluation criteria in solid tumors. The overall survival (OS) of patients was determined, and the quality of life and the incidence rate of adverse reactions were observed. Results: From January 2019 to January 2021, 43 patients with refractory NSCLC were enrolled. The patients were followed up until June 2022. All 43 patients underwent DEB-BACE 1.79 ± 0.69 times on average. The 3-, 6-, 12-, and 24-month survival rates were 100%, 86.0%, 41.9%, and 11.8%, respectively. The median OS was 11.5 months. After the first interventional treatment, cough and wheezing significantly improved in 31 patients, hemoptysis was effectively controlled in 12 patients, and superior vena cava compression disappeared in 2 patients after 2 times of treatment. The general health status of the patients after treatment significantly improved compared with that before treatment, including the improvement in physical and emotional functions. Fatigue, nausea and vomiting, dyspnea, and insomnia improved significantly after treatment. No serious adverse events, such as spinal cord injury and cerebral embolism, were observed during the perioperative period. The main adverse reaction after DEB-BACE was chest pain (13/43, grade 1) followed by fever (10/43, grade 1-2), which was significantly relieved within 3-5 days after symptomatic treatment. Other adverse reactions included irritating cough, nausea and vomiting, and bone marrow suppression, and the incidence was less than 20%. Conclusions: DEB-BACE was effective and safe in treating refractory NSCLC, which could significantly improve patients' quality of life and was worthy of clinical promotion and application.
RESUMEN
OBJECTIVE: To analyze the characteristics and prognosis of acute leukemia(AL) with SET-NUP214 fusion gene. METHODS: The clinical data of 17 patients over 14 years old newly diagnosed with SET-NUP214 positive AL admitted in Institute of Hematology and Blood Diseases Hospital from August 2017 to May 2021 were analyzed retrospectively. RESULTS: Among the 17 SET-NUP214 positive patients, 13 cases were diagnosed as T-ALL (ETP 3 cases, Pro-T-ALL 6 cases, Pre-T-ALL 3 cases, Medullary-T-ALL 1 case), AML 3 cases (2 cases M5, 1 case M0) and ALAL 1 case. Thirteen patients presented extramedullary infiltration at initial diagnosis. All 17 patients received treatment, and a total of 16 cases achieved complete remission (CR), including 12 cases in patients with T-ALL. The total median OS and RFS time were 23 (3-50) months and 21 (0-48) months, respectively. Eleven patients received allogeneic hematopoietic stem cell transplantation(allo-HSCT), with median OS time of 37.5 (5-50) months and median RFS time of 29.5 (5-48) months. The median OS time of 6 patients in chemotherapy-only group was 10.5 (3-41) months, and median RFS time of 6.5 (3-39) months. The OS and RFS of patients with transplantation group were better than those of chemotherapy-only group (P=0.038). Among the 4 patients who relapsed or refractory after allo-HSCT, the SET-NUP214 fusion gene did not turn negative before transplantation. While, in the group of 7 patients who have not relapsed after allo-HSCT till now, the SET-NUP214 fusion gene expression of 5 patients turned negative before transplantation and other 2 of them were still positive. CONCLUSION: The fusion site of SET-NUP214 fusion gene is relatively fixed in AL patients, often accompanied by extramedullary infiltration. The chemotherapy effect of this disease is poor, and allo-HSCT may improve its prognosis.
Asunto(s)
Trasplante de Células Madre Hematopoyéticas , Leucemia Mieloide Aguda , Leucemia-Linfoma de Células T del Adulto , Leucemia-Linfoma Linfoblástico de Células T Precursoras , Humanos , Adolescente , Estudios Retrospectivos , Leucemia Mieloide Aguda/terapia , Enfermedad Aguda , Pronóstico , Leucemia-Linfoma de Células T del Adulto/terapia , Proteínas de Complejo Poro NuclearRESUMEN
Monitoring of the microbial community in bioleaching system is essential for control process parameters and enhance the leaching efficiency. Due to the difficulty of sampling, microbial distribution, community succession and bioleaching activity along the vertical depth of bioleaching heaps remain unresolved. This study investigated the geochemical parameters and microbial community structure along a depth profile in a bioleaching heap and leachate. 80 ore samples at different heap depths and 9 leaching solution samples from three bioheaps of Zijin Copper Mine were collected. Microbial composition, mineral types and geochemical parameters of these samples were analyzed by 16S rRNA high-throughput sequencing and a series of chemical measurement technologies. The results revealed that the pH, Cu, Fe and the total sulfur contents were the major factors shaping the composition of the microbial communities in the bioleaching system. The extent of mineral oxidation increased as the sample depth increases, followed by the increasing of sulfur oxidizers. The abundance of sulfur and iron oxidizers including members of Acidithiobacillus, Sulfobacillus and Acidiferrobacter were significantly higher in the leaching heap than in the leaching solution, meanwhile, they showed strong positive interactions with other members within the same genera and iron oxidizer Leptospirillum and Ferroplasma. Besides, Acidithiobacillus negatively interacted with heterotrophs such as Sphingobium, Exiguobacterium, Brevundimonas and so on. On the contrast, members of Leptospirillum and unclassified Archaea were significantly abundant in the leaching solution and revealed strong interactions with members of Thermoplasmatales. The main conclusion of this study, especially the leaching potential of microorganisms prevailing in bioheaps and their relationships with geochemical factors, provides theoretical guidance for future process design such as the control of processing parameters and microbial community in heap leaching.
Asunto(s)
Acidithiobacillus , Microbiota , Cobre , ARN Ribosómico 16S/genética , Bacterias , Hierro , Azufre , Sulfuros , MineralesRESUMEN
Cytochrome P450s are important phase I metabolic enzymes located on endoplasmic reticulum (ER) involved in the metabolism of endogenous and exogenous substances. Our previous study showed that a hepatoprotective agent silybin restored CYP3A expression in mouse nonalcoholic fatty liver disease (NAFLD). In this study we investigated how silybin regulated P450s activity during NAFLD. C57BL/6 mice were fed a high-fat-diet (HFD) for 8 weeks to induce NAFLD, and were administered silybin (50, 100 mg ·kg-1 ·d-1, i.g.) in the last 4 weeks. We showed that HFD intake induced hepatic steatosis and ER stress, leading to significant inhibition on the activity of five primary P450s including CYP1A2, CYP2B6, CYP2C19, CYP2D6, and CYP3A in liver microsomes. These changes were dose-dependently reversed by silybin administration. The beneficial effects of silybin were also observed in TG-stimulated HepG2 cells in vitro. To clarify the underlying mechanism, we examined the components involved in the P450 catalytic system, membrane phospholipids and ER membrane fluidity, and found that cytochrome b5 (cyt b5) was significantly downregulated during ER stress, and ER membrane fluidity was also reduced evidenced by DPH polarization and lower polyunsaturated phospholipids levels. The increased ratios of NADP+/NADPH and PC/PE implied Ca2+ release and disruption of cellular Ca2+ homeostasis resulted from mitochondria dysfunction and cytochrome c (cyt c) release. The interaction between cyt c and cyt b5 under ER stress was an important reason for P450s activity inhibition. The effect of silybin throughout the whole course suggested that it regulated P450s activity through its anti-ER stress effect in NAFLD. Our results suggest that ER stress may be crucial for the inhibition of P450s activity in mouse NAFLD and silybin regulates P450s activity by attenuating ER stress.
Asunto(s)
Enfermedad del Hígado Graso no Alcohólico , Ratones , Animales , Enfermedad del Hígado Graso no Alcohólico/tratamiento farmacológico , Enfermedad del Hígado Graso no Alcohólico/metabolismo , Silibina/farmacología , Silibina/metabolismo , Citocromo P-450 CYP3A/metabolismo , Ratones Endogámicos C57BL , Sistema Enzimático del Citocromo P-450/metabolismo , Dieta Alta en Grasa/efectos adversos , Estrés del Retículo Endoplásmico , Hígado/metabolismoRESUMEN
The medicinal history of Pien Tze Huang is long, and it is the only "double top secret" variety of technology and formula at present. It has the effects of clearing heat and detoxifying, detumescence and pain, cooling blood and removing blood stasis. At present, researchers have analyzed and identified some compounds in Pien Tze Huang and its precious medicinal materials, such as Panax notoginseng, calculus bovis, snake gall and musk, and conducted activity screening, pharmacokinetics and pharmacological related studies on these chemical components. It was found that Pien Tze Huang had a significant effect on the treatment of acute and chronic hepatitis, ulcer, colon cancer, liver cancer and other diseases. The purpose of this paper is to systematically discuss the research achievements of researchers in recent years on the material basis, pharmacological effects and clinical application of Pien Tze Huang, with a view to providing ideas for the further research of Pien Tze Huang.
RESUMEN
OBJECTIVE@#To analyze the characteristics and prognosis of acute leukemia(AL) with SET-NUP214 fusion gene.@*METHODS@#The clinical data of 17 patients over 14 years old newly diagnosed with SET-NUP214 positive AL admitted in Institute of Hematology and Blood Diseases Hospital from August 2017 to May 2021 were analyzed retrospectively.@*RESULTS@#Among the 17 SET-NUP214 positive patients, 13 cases were diagnosed as T-ALL (ETP 3 cases, Pro-T-ALL 6 cases, Pre-T-ALL 3 cases, Medullary-T-ALL 1 case), AML 3 cases (2 cases M5, 1 case M0) and ALAL 1 case. Thirteen patients presented extramedullary infiltration at initial diagnosis. All 17 patients received treatment, and a total of 16 cases achieved complete remission (CR), including 12 cases in patients with T-ALL. The total median OS and RFS time were 23 (3-50) months and 21 (0-48) months, respectively. Eleven patients received allogeneic hematopoietic stem cell transplantation(allo-HSCT), with median OS time of 37.5 (5-50) months and median RFS time of 29.5 (5-48) months. The median OS time of 6 patients in chemotherapy-only group was 10.5 (3-41) months, and median RFS time of 6.5 (3-39) months. The OS and RFS of patients with transplantation group were better than those of chemotherapy-only group (P=0.038). Among the 4 patients who relapsed or refractory after allo-HSCT, the SET-NUP214 fusion gene did not turn negative before transplantation. While, in the group of 7 patients who have not relapsed after allo-HSCT till now, the SET-NUP214 fusion gene expression of 5 patients turned negative before transplantation and other 2 of them were still positive.@*CONCLUSION@#The fusion site of SET-NUP214 fusion gene is relatively fixed in AL patients, often accompanied by extramedullary infiltration. The chemotherapy effect of this disease is poor, and allo-HSCT may improve its prognosis.
Asunto(s)
Humanos , Adolescente , Leucemia-Linfoma Linfoblástico de Células T Precursoras , Estudios Retrospectivos , Leucemia Mieloide Aguda/terapia , Trasplante de Células Madre Hematopoyéticas , Enfermedad Aguda , Pronóstico , Leucemia-Linfoma de Células T del Adulto/terapia , Proteínas de Complejo Poro NuclearRESUMEN
Farnesoid X receptor (FXR), a member of the nuclear receptor superfamily, is a vital ligand-activated transcriptional factor, which is highly expressed in the liver, intestine, and adrenal gland. However, FXR homeostasis is influenced by many factors, such as diet and circadian rhythm, and the expression of FXR differs in diverse organs. Currently, there is no method to monitor the FXR homeostasis in real time, which restricts us from further investigating the function of FXR under physiological and pathological conditions. In this project, classic FXR agonists were selected to be modified to targeting FXR. The photo-cross-linking diazirine group and alkynyl, a click reaction group, were incorporated to the ligands. Through biorthogonal reaction, fluorophore was linked to the ligands to realize the monitoring of FXR expression in cells.
Asunto(s)
Hígado , Receptores Citoplasmáticos y Nucleares , Células Cultivadas , Regulación de la Expresión Génica , Hígado/metabolismo , Receptores Citoplasmáticos y Nucleares/metabolismo , Factores de Transcripción/metabolismoRESUMEN
BACKGROUND: Mild and systematically improving multiple metabolic disorders was a focused view for Compound Danshen Dripping Pills playing synergistic effects through multiple components and multiple targets. The difference in overall therapeutic effects and endogenous metabolic regulation between short- and long-term administration was still unclear. PURPOSE: This study aimed to explore the difference in endogenous metabolic regulation between short- and long-term Compound Danshen Dripping Pills (CDDP) administration against acute myocardial infarction (AMI). METHODS: The model of AMI was induced by ligating the left anterior descending coronary artery. The cardiac protection effects of CDDP were investigated by echocardiography, 1- or 2-week were defined as short- and long-term based on desirable efficacy variability. The entire metabolic changes between short- and long-term administration of CDDP were profiled by UPLC-Q-TOF-MS. In addition, the metabolic regulatory network of CDDP administration against myocardial infarction rats was also compared with those of a typical chemical drug isosorbide 5-mononitrate (ISMN). RESULTS: After 1- or 2-week continuous oral administration, CDDP could significantly alleviate AMI-induced cardiac dysfunction. By using LC-MS-based metabolomics analyses, we systematically investigated the metabolic profiles of plasma and heart tissue samples at fixed exposure time-points (2 h, 24 h) from AMI rats with CDDP treatment. Most interestingly, global endogenous metabolic changes were observed in cardiac samples collected at different stages post consecutive CDDP administration, fluctuating at 2 and 24 h after 1 week but stabilizing after 2 weeks. The disrupted metabolic pathways such as glycerophospholipid, amino acids, fatty acids, and arachidonic acid metabolism were reconstructed after both short- and long-term CDDP treatment, while taurine and hypotaurine metabolism and purine metabolism contributed to the whole efficacy after long-term CDDP administration. CONCLUSION: Long-term CDDP treatment plays prolonged and stable efficacy against AMI compared with short-term treatment by specifically regulating purine and taurine and hypotaurine metabolism and systematically redressing metabolic disorders.
Asunto(s)
Medicamentos Herbarios Chinos , Infarto del Miocardio , Salvia miltiorrhiza , Animales , Canfanos , Cromatografía Liquida , Medicamentos Herbarios Chinos/química , Metabolómica , Infarto del Miocardio/tratamiento farmacológico , Infarto del Miocardio/metabolismo , Panax notoginseng , Purinas , Ratas , Salvia miltiorrhiza/química , Espectrometría de Masas en Tándem , TaurinaRESUMEN
Aim: The 20(S)-ginsenoside Rh2 (Rh2) is being developed as a new antitumor drug. However, to date, little is known about the kinetics of its deglycosylation metabolite (protopanoxadiol) (PPD) following Rh2 administration. The aim of this work was to 1) simultaneously characterise the pharmacokinetics of Rh2 and PPD following intravenous and oral Rh2 administration, 2) develop and validate a mechanism-based pharmacokinetic model to describe the deglycosylation kinetics and 3) predict the percentage of Rh2 entering the systemic circulation in PPD form. Methods: Plasma samples were collected from rats after the I.V. or P.O. administration of Rh2. The plasma Rh2 and PPD concentrations were determined using HPLC-MS. The transformation from Rh2 to PPD, its absorption, and elimination were integrated into the mechanism based pharmacokinetic model to describe the pharmacokinetics of Rh2 and PPD simultaneously at 10 mg/kg. The concentration data collected following a 20 mg/kg dose of Rh2 was used for model validation. Results: Following Rh2 administration, PPD exhibited high exposure and atypical double peaks. The model described the abnormal kinetics well and was further validated using external data. A total of 11% of the administered Rh2 was predicted to be transformed into PPD and enter the systemic circulation after I.V. administration, and a total of 20% of Rh2 was predicted to be absorbed into the systemic circulation in PPD form after P.O. administration of Rh2. Conclusion: The developed model provides a useful tool to quantitatively study the deglycosylation kinetics of Rh2 and thus, provides a valuable resource for future pharmacokinetic studies of glycosides with similar deglycosylation metabolism.
RESUMEN
Two acidophilic strains, designated as ALEF1T and S30H14T, were isolated from acid mine drainage sediment. Cells of both strains were Gram-stain-positive, aerobic, endospore-forming rods. Strains ALEF1T and S30H14T were acidophilic and mesophilic, the former grew at 20-40 °C (optimum, 30 °C) and pH 2.5-4.5 (optimum, pH 3.5), while the latter grew at 20-45 °C (optimum, 30 °C) and pH 2.0-5.5 (optimum, pH 4.5). The 16S rRNA gene-based sequence analysis revealed that strains ALEF1T and S30H14T belonged to the genus Alicyclobacillus, and were phylogenetically close to Alicyclobacillus ferrooxydans TC-34T with 97.1 and 97.4% similarity, respectively. The similarity between the two novel strains was 98.6â%. The average nucleotide identity value between the genome sequences of ALEF1T and S30H14T was 79.5â%, and that between each of the two isolates and A. ferrooxydans TC-34T were 72.0 and 74.3â%. In addition, the digital DNA-DNA hybridization value between ALEF1T and S30H14T was 24.9â%, between strain ALEF1T and A. ferrooxydans TC-34T was 21.7â%, and between S30H14T and A. ferrooxydans TC-34T was 26.3â%, far below the interspecies threshold. Both strains could utilize diverse carbon sources for heterotrophic growth; strain ALEF1T could utilize ferrous iron as the energy source for autotrophic growth. Menaquinone 7 was the only quinone detected in either strain. Both strains contained anteiso-C15â:â0 and anteiso-C17â:â0, while ω-alicyclic fatty acids were not detected. Based on their phylogenetic positions, as well as phenotypic and genomic data, it is considered that strains ALEF1T and S30H14T represent two novel species within the genus Alicyclobacillus, for which the names Alicyclobacillus curvatus sp. nov. (type strain ALEF1T=CGMCC 1.17055T=KCTC 43124T) and Alicyclobacillus mengziensis sp. nov. (S30H14T=CGMCC 1.17050T=KCTC 43125T) are proposed.
Asunto(s)
Alicyclobacillus , Técnicas de Tipificación Bacteriana , Composición de Base , ADN Bacteriano/genética , Ácidos Grasos/química , Filogenia , ARN Ribosómico 16S/genética , Análisis de Secuencia de ADNRESUMEN
Hepatocellular carcinoma (HCC) is an often-fatal malignant tumor with high lethality. Despite advances and significant efficacy in monotherapy, cancer therapy continues to pose several challenges. Novel combination regimens are an emerging strategy for anti-HCC and have demonstrated to be effective. Here, we propose a potential combination for HCC treatment named arsenic trioxide cooperate cryptotanshinone (ACCS). A remarkable synergistic therapeutic effect has been achieved compared with drugs alone in both in vivo and in vitro experiments. Mechanism study indicated that ACCS exerts its therapeutic actions by regulating macrophage-related immunity and glycolysis. ACCS potentiates the polarization of M1 macrophages and elevates the proportion of M1/M2 to remodel tumor immunity. Further molecular mechanism study revealed that ACCS intensifies the glucose utilization and glycolysis in the macrophage by increasing the phosphorylation of AMPK to activating the AMPK singling pathway. In conclusion, ACCS is a highly potential combination regimen for HCC treatment. The therapeutic potential of ACCS as a candidate option for anticancer drugs in restoring the balance of immunity and metabolism deserves further investigation.
Asunto(s)
Antineoplásicos/uso terapéutico , Trióxido de Arsénico/uso terapéutico , Carcinoma Hepatocelular/tratamiento farmacológico , Medicamentos Herbarios Chinos/uso terapéutico , Neoplasias Hepáticas/tratamiento farmacológico , Macrófagos/metabolismo , Fenantrenos/uso terapéutico , Animales , Diferenciación Celular , Citocinas/metabolismo , Combinación de Medicamentos , Sinergismo Farmacológico , Glucólisis , Humanos , Inmunidad Innata , Inmunomodulación , Activación de Macrófagos , Ratones , Ratones Endogámicos BALB C , Células TH1/inmunologíaRESUMEN
We previously showed that oral administration of exogenous glutathione (GSH) exerted a direct and/or indirect therapeutic effect on ischemic stroke rats, but the underlying mechanisms remain elusive. In the current study, we conducted a quantitative proteomic analysis to explore the pathways mediating the therapeutic effect of GSH in cerebral ischemia/reperfusion (I/R) model rats. Rats were subjected to middle cerebral artery occlusion (MCAO) for 2 h followed by reperfusion. The rats were treated with GSH (250 mg/kg, ig) or levodopa (L-dopa, 100 mg/kg, ig) plus carbidopa (10 mg/kg, ig). Neurologic deficits were assessed, and the rats were sacrificed at 24 h after cerebral I/R surgery to measure brain infarct sizes. We conducted a proteomic analysis of the lesion side striatum samples and found that tyrosine metabolism and dopaminergic synapse were involved in the occurrence of cerebral stroke and the therapeutic effect of GSH. Western blot assay revealed that tyrosine hydroxylase (TH) mediated the occurrence of I/R-induced ischemic stroke and the therapeutic effect of GSH. We analyzed the regulation of GSH on endogenous small molecule metabolites and showed that exogenous GSH had the most significant effect on intrastriatal dopamine (DA) in I/R model rats by promoting its synthesis and inhibiting its degradation. To further explore whether DA-related alterations were potential targets of GSH, we investigated the therapeutic effect of DA accumulation on ischemic brain injury. The combined administration of the precursor drugs of DA (L-dopa and carbidopa) significantly ameliorated neurological deficits, reduced infarct size, and oxidative stress, and decreased pro-inflammatory cytokines levels in the striatum of I/R injury rats. More interestingly, exogenous L-dopa/carbidopa could also greatly enhance the exposure of intracerebral GSH by upregulating GSH synthetases and enhancing homocysteine (HCY) levels in the striatum. Thus, administration of exogenous GSH exerts a therapeutic effect on ischemic stroke by increasing intrastriatal DA, and the accumulated DA can, in turn, enhance the exposure of GSH and its related substances, thus promoting the therapeutic effect of GSH.
Asunto(s)
Dopamina/metabolismo , Glutatión/farmacología , Accidente Cerebrovascular Isquémico/patología , Animales , Carbidopa/farmacología , Citocinas/efectos de los fármacos , Modelos Animales de Enfermedad , Homocistina/efectos de los fármacos , Infarto de la Arteria Cerebral Media/patología , Levodopa/farmacología , Masculino , Estrés Oxidativo/genética , Proteómica , Ratas , Ratas Wistar , Daño por Reperfusión/patología , Tirosina 3-Monooxigenasa/efectos de los fármacos , Regulación hacia ArribaRESUMEN
Aim To investigate the effects of bigelovin on mouse model of imiquimod-induced psoriatic itch and its mechanism. Methods Psoriasis-like mouse model was established by applying imiquimod cream on the back skin of mouse. Psoriasis area and severity index, pathological changes, the expression levels of inflammatory factors and related molecular biological data were used as effect indicators. The changes of the above parameters were observed after administration of different concentrations of bigelovin. Then the possible mechanism of the effects was further analysed.Results Compared with the model group, bigelovin significantly decreased the symptoms of skin lesions and reduced the PASI score. Bigelovin alleviated epidermal thickening and reduced the expression of Ki67 in a dose-dependent manner. The expression levels of inflammatory factors were reduced in both skin and serum.The percentage of Th17 cells was reduced and the percentage of Treg cells was increased in the lymph node.In addition, bigelovin also inhibited the phosphorylation of P65 protein and significantly reduced the nuclear localization of P65, suggesting that bigelovin might inhibit the activation of P65 protein. Conclusions The effect of bigelovin on improving the signs and symptoms of imiquimod-induced psoriasis mice may be related to the inhibition of P65 protein phosphorylation in keratinocytes.
RESUMEN
Objective: To compare the efficacy of two induction regimens, namely, idarubicin combined with cytarabine (IA) versus the combination of homoharringtonine, daunorubicin, and cytarabine (HAD) , in adult patients with newly diagnosed de novo acute myeloid leukemia (AML) . Methods: From May 2014 to November 2019, 199 patients diagnosed with AML receiving either the IA or HAD regimens were assessed for overall survival (OS) , relapse-free survival (RFS) , as well as the CR rate and the MRD negative rate after induction therapy. The differences in prognosis between the two induction therapy groups was assessed according to factors, including age, white blood cell (WBC) count, NPM1 mutation, FLT3-ITD mutation, 2017 ELN risk stratification, CR(1) transplantation, and the use of high-dose cytarabine during consolidation therapy, etc. Results: Among the 199 patients, there were 104 males and 95 females, with a median age of 37 (15-61) years. Ninety patients received the IA regimen, and 109 received the HAD regimen. Comparing the efficacy of the IA and HAD regimens, the CR rates after the first induction therapy were 71.1% and 63.3%, respectively (P=0.245) , and the MRD negative rates after the first induction therapy were 53.3% and 48.6%, respectively (P=0.509) . One patient in the IA group and two in the HAD group died within 60 days after induction. The two-year OS was 61.5% and 70.6%, respectively (P=0.835) , and the two-year RFS was 51.6% and 57.8%, respectively (P=0.291) . There were no statistically significant differences between the two groups. Multivariate analysis showed that the ELN risk stratification was an independent risk factor in both induction groups; CR(1) HSCT was an independent prognostic factor for OS and RFS in the IA patients and for RFS in the HAD patients but not for OS in the HAD patients. Age, WBC level, NPM1 mutation, and FLT3-ITD mutation had no independent prognostic significance. Conclusion: The IA and HAD regimens were both effective induction regimens for AML patients.
Asunto(s)
Adolescente , Adulto , Femenino , Humanos , Masculino , Persona de Mediana Edad , Adulto Joven , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Citarabina/uso terapéutico , Daunorrubicina/uso terapéutico , Homoharringtonina/uso terapéutico , Quimioterapia de Inducción , Leucemia Mieloide Aguda/genética , Proteínas Nucleares , Pronóstico , Inducción de Remisión , Estudios RetrospectivosRESUMEN
Objective: To evaluate the efficacy and toxicity profiles of idarubicin, cytarabine, and cyclophosphamide (IAC) in relapse/refractory acute myeloid leukemia (AML) . Methods: This study was a prospective, randomized controlled clinical trial with the registration number NCT02937662. The patients were randomly divided into two groups. The experimental group was treated with an IAC regimen, and the regimen of the control group was selected by doctors according to medication experience. After salvage chemotherapy, allogeneic hematopoietic stem cell transplantation (allo-HSCT) was conducted as far as possible according to the situation of the patients. We aimed to observe the efficacy, safety, and toxicity of the IAC regimen in relapse/refractory AML and to explore which is the better regimen. Results: Forty-two patients were enrolled in the clinical trial, with a median age of 36 years (IAC group, 22 cases and control groups, 20 cases) . ①The objective response rate was 71.4% in the IAC group and 40.0% in the control group (P=0.062) ; the complete remission (CR) rate was 66.7% in the IAC group and 40.0% in the control group (P=0.121) . The median follow-up time of surviving patients was 10.5 (range:1.7-32.8) months; the median overall survival (OS) was 14.1 (range: 0.6-49.1) months in the IAC group and 9.9 (range: 2.0-53.8) months in the control group (P=0.305) . The 1-year OS was 54.5% (95%CI 33.7%-75.3%) in the IAC group and 48.2% (95%CI 25.9%-70.5%) in the control group (P=0.305) , with no significant difference between these two regimens. ②The main hematologic adverse events (AEs) were anemia, thrombocytopenia, and neutropenia. The incidence of grade 3-4 hematologic AEs in the two groups was 100% (22/22) in the IAC group and 95% (19/20) in the control group. The median time of neutropenia after chemotherapy in the IAC group and control group was 20 (IQR: 8-30) and 14 (IQR: 5-50) days, respectively (P=0.023) . ③The CR rate of the early relapse (relapse within 12 months) group was 46.7% and that of the late relapse (relapse after 12 months) group was 72.7% (P=0.17) . The median OS time of early recurrence was 9.9 (range:1.7-53.8) months, and that of late recurrence patients was 19.3 (range: 0.6-40.8) months (P=0.420) , with no significant differences between the two groups. The 1-year OS rates were 45.3% (95%CI 27.2%-63.3%) and 66.7% (95%CI 40.0%-93.4%) , respectively (P=0.420) . Survival analysis showed that the 1-year OS rates of the hematopoietic stem cell transplantation group and non-hematopoietic stem cell transplantation group were 87.5% (95%CI 71.2%-100%) and 6.3% (95%CI 5.7%-18.3%) , respectively. The OS rate of the hematopoietic stem cell transplantation group was significantly higher than that of the non-hematopoietic stem cell transplantation group (P<0.001) . Conclusion: The IAC regimen is a well-tolerated and effective regimen in relapsed/refractory AML; this regimen had similar efficacy and safety with the regimen selected according to the doctor's experience for treating relapsed/refractory AML. For relapsed/refractory patients with AML, allogeneic hematopoietic stem cell transplantation should be attempted as soon as possible to achieve long-term survival.
Asunto(s)
Adulto , Humanos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Ciclofosfamida/uso terapéutico , Citarabina/uso terapéutico , Trasplante de Células Madre Hematopoyéticas , Idarrubicina/uso terapéutico , Leucemia Mieloide Aguda/tratamiento farmacológico , Neutropenia , Estudios Prospectivos , Recurrencia , Estudios RetrospectivosRESUMEN
Asthma is regarded as a chronic inflammation of the airway. Research has highlighted the significance of Vitamin D in asthma. This study explored the mechanism of vitamin D on asthma. The asthma mouse model was established by ovalbumin (OVA) sensitization and treated with vitamin D (50 or 100 ng/ml). The morphological changes of the airway were observed by HE staining. The serum IgE contents and MDA, ROS, and SOD expressions in the bronchoalveolar lavage fluid (BALF) were detected by ELISA. The Th17 and Treg cells were detected using flow cytometry. The RORγt and Foxp 3 expressions were detected by Reverse transcription quantitative polymerase chain reaction (RT-qPCR). IL-17, IL-10, and TGF-ß1 expressions were detected using ELISA. The NF-κB pathway was blocked using the NF-κB pathway inhibitor, Andrographolide sulfonate. The NF-κB pathway-related indexes were detected by western blotting. After blockade of the NF-κB pathway, the IL-17, IL-10, and TGF-G1 expressions were detected. OVA-sensitized asthma induced airway remodeling and elevated IgE content in mice, which was downregulated after vitamin D treatment. MDA and ROS were upregulated and SOD was downregulated in asthmatic mice, while vitamin D inverted the changes. Th17/Treg ratio was imbalanced, RORγt and IL-17 were upregulated, and Foxp 3, IL-10, and TGF-ß1 were downregulated after OVA sensitization, while vitamin D treatment inverted these changes and inhibited the NF-κB-p65 phosphorylation level. After blockade of the NF-κB pathway, IL-17 was downregulated and IL-10 and TGF-ß1 were upregulated. In conclusion, vitamin D rectified the Th17/Treg balance and alleviated airway inflammation by inhibiting the NF-κB pathway in asthmatic mice.