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Pyrrolizidine alkaloids (PAs) are widely distributed natural toxins and have been extensively studied for their hepatotoxicity. However, PA-induced pulmonary toxicity remains less studied regarding the initiating mechanism and treatment approaches. Our previous study demonstrated the formation of pyrrole-hemoglobin adducts after PA exposure in vivo, which is suspected to affect the oxygen-carrying capacity of erythrocytes [red blood cells (RBCs)] consequently. The present study aimed to investigate the effects of PAs on the oxygen-carrying capacity of RBCs and the potential of targeting RBC-mediated hypoxia to alleviate PA-induced lung injury. First, rats were treated with retrorsine (RTS) or monocrotaline (MCT) intravenously at 0.2 mmol/kg. The results of Raman spectrometry analysis on blood samples revealed both RTS and MCT significantly reduced the oxygen-carrying capacity of RBCs. Further, MCT (0.2 mmol/kg) was orally given to the rats with or without pretreatment with two doses of erythropoietin (Epo, 500 IU/kg/dose every other day), an RBC-stimulating agent. Biochemical and histological results showed pretreatment with Epo effectively reduced the cardiopulmonary toxicity induced by MCT. These findings provide the first evidence that adduction on hemoglobin, and the resulting RBC damage and impaired oxygen-carrying capacity, are the major initiating mechanism underlying PA-induced pulmonary arterial hypertension (PAH), while targeting the RBC damage is a potential therapeutic approach for PA-induced lung injury.
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Enfermedades Pulmonares , Lesión Pulmonar , Alcaloides de Pirrolicidina , Ratas , Animales , Lesión Pulmonar/patología , Hígado , Alcaloides de Pirrolicidina/toxicidad , Monocrotalina/toxicidad , Enfermedades Pulmonares/patología , Eritrocitos , Hemoglobinas , Hipoxia/patología , OxígenoRESUMEN
Pyrrolizidine alkaloids (PAs) are one of the most significant groups of hepatotoxic phytotoxins. It is well-studied that metabolic activation of PAs generates reactive pyrrolic metabolites that rapidly bind to cellular proteins to form pyrrole-protein adducts leading to hepatotoxicity. Pyrrole-protein adducts all contain an identical core pyrrole moiety regardless of structures of the different PAs; however, the proteins forming pyrrole-protein adducts are largely unknown. The present study revealed that ATP synthase subunit beta (ATP5B), a critical subunit of mitochondrial ATP synthase, was a protein bound to the reactive pyrrolic metabolites forming pyrrole-ATP5B adduct. Using both anti-ATP5B antibody and our prepared anti-pyrrole-protein antibody, pyrrole-ATP5B adduct was identified in the liver of rats, hepatic sinusoidal endothelial cells, and HepaRG hepatocytes treated with retrorsine, a well-studied representative hepatotoxic PA. HepaRG cells were then used to further explore the consequence of pyrrole-ATP5B adduct formation. After treatment with retrorsine, significant amounts of pyrrole-ATP5B adduct were formed in HepaRG cells, resulting in remarkably reduced ATP synthase activity and intracellular ATP level. Subsequently, mitochondrial membrane potential and respiration were reduced, leading to mitochondria-mediated apoptotic cell death. Moreover, pre-treatment of HepaRG cells with a mitochondrial membrane permeability transition pore inhibitor significantly reduced retrorsine-induced toxicity, further revealing that mitochondrial dysfunction caused by pyrrole-ATP5B adduct formation significantly contributed to PA intoxication. Our findings for the first time identified ATP5B as a protein covalently bound to the reactive pyrrolic metabolites of PAs to form pyrrole-ATP5B adduct, which impairs mitochondrial function and significantly contributes to PA-induced hepatotoxicity.
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Hígado/efectos de los fármacos , ATPasas de Translocación de Protón Mitocondriales/metabolismo , Pirroles/metabolismo , Alcaloides de Pirrolicidina/toxicidad , Adenosina Trifosfato/análisis , Animales , Apoptosis/efectos de los fármacos , Células Cultivadas , Hepatocitos/efectos de los fármacos , Humanos , Masculino , Mitocondrias/efectos de los fármacos , Mitocondrias/fisiología , Ratas , Ratas Sprague-DawleyRESUMEN
The purpose of this study was to explore the enhancing effects and the mechanism of monocyclic monoterpene penetration enhancers (menthol and menthone) on the transdermal absorption of ligustrazine hydrochloride (LH). Franz-type diffusion cells were used to determine percutaneous parameters of LH in vitro and surface changes of porcine skin were studied by a scanning electron microscope (SEM). The effects of promoters on the biophysical natures of stratum corneum (SC) were researched by Fourier transform-infrared (FT-IR). Penetration parameters of menthol (p < 0.01) and menthone groups (p < 0.05) were greater than those of the control; morphological changes of skin monitored by SEM demonstrated that the menthone group had the most disruption and desquamation of SC flakes, which resulted from extracted lipids. FT-IR measurements showed menthone had the greatest changes in peak shift and peak area, which resulted from C-H stretching vibrations of SC lipids. The results suggest that the penetration mechanism might include disturbing and extracting SC lipids and the hydrogen bond connection.
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Portadores de Fármacos/química , Monoterpenos/química , Pirazinas/administración & dosificación , Absorción Cutánea , Piel/metabolismo , Vasodilatadores/administración & dosificación , Administración Cutánea , Animales , Pirazinas/farmacocinética , Piel/ultraestructura , Porcinos , Vasodilatadores/farmacocinéticaRESUMEN
Daphne genkwa Sieb.et Zucc. is a well-known medicinal plant. This study was designed to investigate the anticancer effects of total flavonoids in D. genkwa (TFDG) in vitro and in vivo. HT-29 and SW-480 human colorectal cancer cells were cultured to investigate the anticancer activity of TFDG. In addition, the Apc(Min/+) mouse model was applied in the in vivo experiment. Results of the cell experiment revealed that TFDG possessed significant inhibitory effects on HT-29 and SW-480 human colorectal cancer cells (both p < 0.01). Furthermore, our in vivo data showed that after treatment with TFDG, there was a significant increase in life span (both p < 0.01) and tumor numbers were reduced in the colon (both p < 0.01), which was supported by the data of tumor distribution, body weight changes and organ index. Our results also indicated that expressions of interleukin (IL)-1α, IL-1ß, IL-6, granulocyte colony-stimulating factor and granulocyte-macrophage colony-stimulating factor in gut tissue were downregulated by treatments of TFDG, and immunity cytokine secretions in the serum were regulated after oral administration of TFDG. Taken together, these findings suggested that TFDG has a potential clinical utility in colorectal cancer therapeutics, and TFDG's action is likely linked to its ability to regulate immune function and inhibit the production of inflammatory cytokines.
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Neoplasias Colorrectales/tratamiento farmacológico , Daphne/química , Flavonoides/farmacología , Extractos Vegetales/farmacología , Animales , Línea Celular Tumoral/efectos de los fármacos , Colon/patología , Citocinas/metabolismo , Femenino , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL , Plantas Medicinales/químicaRESUMEN
The present study investigated the flavonoids from Abrus cantoniensis against ethanol-induced gastric ulcers in mice. The flavonoids from A. cantoniensis were extracted with ethanol and purified by macroporous resin and polyamide. The 2,2-diphenyl-1-picrylhydrazyl assay was used to measure the antioxidative activities in vitro. The ethanol-induced ulcer mouse model was used to evaluate the gastroprotective activities of the flavonoids from A. cantoniensis. In addition, a method was established to ensure accuracy for animal ulcer evaluation. The flavonoids from A. cantoniensis showed a strong free radical scavenging capacity with an IC50 of 43.83 µg/mL in the 2,2-diphenyl-1-picrylhydrazyl assay. At doses between 28.16-112.67 mg/kg, the flavonoids conspicuously reduced the ulcer index in ethanol-induced mice (p<0.001). Significant differences were found in the levels of superoxide dismutase, catalase, glutathione, and myeloperoxidase in the stomach tissues between the flavonoids from the A. cantoniensis groups and the ethanol control group. The gastroprotective effect of the flavonoids from A. cantoniensis could be due to its antioxidative activity of the defensive mechanism. The data revealed that the flavonoids from A. cantoniensis could be a potential therapeutic agent for gastric ulcer prevention and treatment.
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Abrus/química , Antiulcerosos/farmacología , Antioxidantes/farmacología , Flavonoides/farmacología , Úlcera Gástrica/tratamiento farmacológico , Animales , Antiulcerosos/química , Antioxidantes/química , Catalasa/metabolismo , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Evaluación Preclínica de Medicamentos/métodos , Etanol/efectos adversos , Flavonoides/química , Glutatión/metabolismo , Masculino , Ratones Endogámicos ICR , Estructura Molecular , Peroxidasa/metabolismo , Úlcera Gástrica/inducido químicamente , Úlcera Gástrica/metabolismo , Superóxido Dismutasa/metabolismoRESUMEN
ETHNOPHARMACOLOGICAL RELEVANCE: Di-Long (Pheretima vulgaris) is a classic animal sourced traditional Chinese medicine. It has been used for the treatment of joint inflammation and arthralgia for over two thousand years due to its effects of Tong-Luo-Zhi-Tong (dredging collaterals and alleviating pain). Our previous study showed that Chinese medicine Di-Long has significant anti-rheumatoid arthritis (RA) effects. AIM OF THE STUDY: Considering Di-Long as a potential source of active compounds with specific anti-RA therapeutic effects, this research was to obtain the anti-RA target-specific active fraction from Di-Long extracts (DL), and to further explore the chemical basis and verify the anti-RA mechanism of this active fraction. MATERIALS AND METHODS: Transcriptomic was applied to obtain the main anti-RA targets of DL on human RA fibroblast-like synoviocytes (FLS) and validated by qPCR. The target-corresponding active fraction was isolated from DL by ethanol precipitation and gel chromatography, and analyzed by nanoliter chromatography-mass spectrometry. Anti-RA effects of this active fraction was investigated by collagen-induced arthritis (CIA) in mice, and anti-RA mechanisms were verified in cocultured model of rat FLS and peripheral blood lymphocytes. RESULTS: We confirmed that CXCL10/CXCR3 was the main anti-RA target of DL. The active fraction - A (2182 - 890 Da) was isolated from DL based on its CXCL10 inhibiting effects in RA-FLS. Fraction A contains 195 peptides (192 were newly discovered), 26 of which might be bioactive and were considered to be the chemical basis of its anti-RA effects. Fraction A significantly ameliorated the joint destruction and overall inflammation in CIA mice, and downregulated CXCR3 expression in mice joint. Fraction A inhibited the chemotaxis of Th-cells in rat peripheral blood lymphocytes towards the TNF-α-induced rat FLS through CXCL10/CXCR3 pathway. CONCLUSIONS: Our work indicated that active fraction from DL containing small peptides exhibits promising therapeutic effects for RA through inhibiting CXCL10/CXCR3 chemotaxis.
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Antirreumáticos , Artritis Experimental , Artritis Reumatoide , Quimiocina CXCL10 , Quimiotaxis , Receptores CXCR3 , Membrana Sinovial , Animales , Receptores CXCR3/metabolismo , Quimiocina CXCL10/metabolismo , Artritis Experimental/tratamiento farmacológico , Artritis Reumatoide/tratamiento farmacológico , Masculino , Antirreumáticos/farmacología , Antirreumáticos/aislamiento & purificación , Ratas , Humanos , Quimiotaxis/efectos de los fármacos , Membrana Sinovial/efectos de los fármacos , Membrana Sinovial/metabolismo , Ratones , Ratones Endogámicos DBA , Medicamentos Herbarios Chinos/farmacología , Medicamentos Herbarios Chinos/química , Sinoviocitos/efectos de los fármacos , Sinoviocitos/metabolismoRESUMEN
Alluaudite sodium iron sulfate (NFS) exhibits great potential for use in sodium-ion battery cathodes due to its elevated operating potential and abundant element reserves. However, conventional solid-state methods demonstrate a low heating/cooling rate and sluggish reaction kinetics, requiring a long thermal treatment to effectively fabricate NFS cathodes. Herein, we propose a thermal shock (TS) strategy to synthesize alluaudite sodium iron sulfate cathodes using either hydrous or anhydrous raw materials. The analysis of the phase formation process reveals that TS treatment can significantly facilitate the removal of crystal water and decomposition of the intermediate phase Na2Fe(SO4)2 in the hydrous precursor. In the case of the anhydrous precursor, the kinetics of the combination reaction between Na2SO4 and FeSO4 can be also accelerated by TS treatment. Consequently, pure NFS phase formation can be completed after a substantially shorter time of post-sintering, thereby saving significant time and energy. The TS-treated NFS cathode derived from hydrous precursor exhibits higher retention after 200 cycles at 1C and better rate capability than the counterpart prepared by conventional long-term tube furnace sintering, demonstrating the great potential of this novel strategy.
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Nickel-rich layered oxide LiNixCoyMnzO2 (NCM, x + y + z = 1) is the most promising cathode material for high-energy lithium-ion batteries. However, conventional synthesis methods are limited by the slow heating rate, sluggish reaction dynamics, high energy consumption, and long reaction time. To overcome these challenges, we first employed a high-temperature shock (HTS) strategy for fast synthesis of the NCM, and the approaching ultimate reaction rate of solid phase transition is deeply investigated for the first time. In the HTS process, ultrafast average reaction rate of phase transition from Ni0.6Co0.2Mn0.2(OH)2 to Li- containing oxides is 66.7 (% s-1), that is, taking only 1.5 s. An ultrahigh heating rate leads to fast reaction kinetics, which induces the rapid phase transition of NCM cathodes. The HTS-synthesized nickel-rich layered oxides perform good cycling performances (94% for NCM523, 94% for NCM622, and 80% for NCM811 after 200 cycles at 4.3 V). These findings might also assist to pave the way for preparing effectively Ni-rich layered oxides for lithium-ion batteries.
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Natural killer (NK) cells are lymphocytes with important anti-tumour functions. Cellular metabolism is dynamically regulated in NK cells and strongly influences their responses. Myc is a key regulator of immune cell activity and function, but little is known about how Myc controls NK cell activation and function. In this study, we found that c-Myc is involved in the regulation of NK cell immune activity. In the development of colon cancer, the energy generation disorder of tumor cells promotes the plunder of polyamines of NK cells by tumor cells, resulting in the inhibition of NK cell c-Myc. After inhibition of c-Myc, glycolysis of NK cells was impaired, resulting in decreased killing activity. There are three main types of polyamines: putrescine (Put), spermidine (Spd) and spermine (Spm). We found that the NK cells could reverse the inhibition state of c-Myc and glycolysis energy supply disorder and recover the killing activity of NK cells after giving certain spermidine. These results suggest that polyamine content and glycolysis supply under the regulation of c-Myc play a crucial role in the immune activity of NK cells.
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Neoplasias Colorrectales , Poliaminas , Humanos , Poliaminas/metabolismo , Poliaminas/farmacología , Espermidina/farmacología , Espermidina/metabolismo , Glucólisis , Células Asesinas Naturales/metabolismoRESUMEN
Climate change is difficult to connect with personally, because people only regard the phenomenon as important if it becomes a perceived threat to themselves. Arguments like statistics and policy debates are extrinsic motivators, which do not necessarily align people's own intrinsic motives with those of climate action. Instead, narratives and visual communication can influence viewers implicitly by the way they show and reinforce actions and thoughts that align with climate action. In this design study, we used comics created for human-level climate change influence to promote ideas like future-based thinking, sharing of responsibility, and caring for each other. We also created data visuals that illustrate future consequences of climate change for the purpose of averting negative alternative realities. To see whether our design can affect audience perception of climate change on the human level of goals and desires, we showed the comics to readers unfamiliar with the themes of the stories, presenting them as manga about characters and situations. The survey showed that data stories can affect the way naive readers interpret narratives to align with pro-climate attitudes such as sharing and future-vision, and that readers are focused on the human-level of the data and story as opposed to the physical resource level. Speculative fiction and data visuals provide a potentially effective way to influence individuals' climate change attitudes by showing alternative realities and attributes of collective responsibility and planning-for-the-future as data stories.
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Colorectal cancer (CRC) is the second most lethal cancer and the third most common cancer in the world, and its prognosis is severely affected by high intestinal mucosal permeability and increasing tumor burden. Studies have shown that the expression of hypoxia induce factor 1α (HIF1α) is up-regulated in a variety of tumor tissues, which is related to multiple metabolic reprogramming of tumor cells. However, the role of HIF1α in CRC tumor growth, tumor polyamine metabolism and intestinal mucosal barrier damage has not been studied. Here, we constructed different types of CRC tumor-bearing mice models by inoculating HCT116 cells with different levels of HIF1α expression (knockdown, wild type, overexpression) in the armpits of mice to explore the upstream and downstream regulators of HIF1α, the effects of HIF1α on the growth of CRC, and the CRC polyamine metabolism and its effect on the intestinal mucosal barrier. We found that with the increase of HIF1 gene expression, tumor growth was promoted and intestinal mucosal permeability was increased. The expression of glycolysis-related proteins was up-regulated, the rate-limiting enzyme ODC of polyamine synthesis was decreased, and the transfer protein of polyamine was increased. HPLC showed that the polyamine content in the tumor tissue of the overexpression group HIF1α OE was higher than that of the wild group HIF1α (+/+), and higher than that of the knockdown group HIF1α (-/-), but the content of polyamines in intestinal mucosa was the opposite. After supplementation of exogenous polyamines, the content of polyamines in intestinal mucosa and tumor tissue increased, and the damage of intestinal mucosa was alleviated. In conclusion, upon activation of the MYC/HIF1 pathway, tumor glycolysis is enhanced, tumors require more energy and endogenous polyamine synthesis is reduced. Therefore, in order to meet its growth needs, tumor will rob polyamines in the intestinal mucosa, resulting in intestinal mucosal epithelial barrier dysfunction.
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BACKGROUND: Cognitive impairment has been acknowledged as a core clinical manifestation of bipolar disorder (BD) as well as major depressive disorder (MDD). Determining the prevalence and characteristics of cognitive impairment is important for clinical interventions. This study investigated the prevalence and characteristics of cognitive impairment based on the Measurement and Treatment Research to Improve Cognition Schizophrenia Consensus Cognitive Battery (MCCB) in both BD and MDD. METHOD: One hundred and forty-nine BD II depression, 147 MDD, and 124 demographically matched healthy controls (HC) underwent MCCB cognitive assessment. The prevalence of MCCB cognitive impairment and group difference comparisons were performed. Additionally, association analysis was performed to investigate the relationship between cognitive performance and clinical variables. RESULTS: Compared to the HC group, both BD II depression and MDD groups had a significantly reduced performance for all MCCB cognitive domains (all p < 0.05). The numerical scores for visual learning were lower in the BD II depression group compared to the MDD group. 32.89% of the BD II depression patients had clinically significant impairment (>1.5 SD below the normal mean) in two or more MCCB domains compared to 23.13% for MDD patients. CONCLUSIONS: A high percent of patients in the BD II depression and MDD group exhibited MCCB cognitive impairments with clinical significance. Cognitive impairments were more common in BD II depression patients compared to MDD patients, particularly for visual learning. These findings suggest that clinicians should be aware of the severe cognitive impairment in mood disorders and establish effective cognitive screening and intervention strategies.
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Trastorno Bipolar , Disfunción Cognitiva , Trastorno Depresivo Mayor , Trastorno Bipolar/epidemiología , Trastorno Bipolar/psicología , Disfunción Cognitiva/diagnóstico , Disfunción Cognitiva/epidemiología , Disfunción Cognitiva/etiología , Depresión , Trastorno Depresivo Mayor/diagnóstico , Trastorno Depresivo Mayor/epidemiología , Humanos , Pruebas Neuropsicológicas , PrevalenciaRESUMEN
BACKGROUND: Pyrrolizidine alkaloids (PAs) are common phytotoxins. PA intoxication is reported to cause severe acute liver damage, typically known as hepatic sinusoidal obstruction syndrome (HSOS), but it remains obscure whether the acute liver damage may progress into chronic liver disease characterized by hepatic fibrosis. PURPOSE: This study aims to characterize the biochemical markers of liver injury and histological features of regressive and progressive liver fibrosis, and to examine changes in hepatic gene expression that may underpin mechanisms of fibrogenesis in rats induced by retrorsine (RTS), a representative toxic PA. STUDY DESIGN/METHODS: Rats were gavaged with RTS via two dosing regimens, i.e. a single dose of 40 mg/kg (Group 1) and two doses of 40 mg/kg and 20 mg/kg on day 0 and day 7 (Group 2), respectively. Rats receiving one (Group 3) or two (Group 4) doses of vehicle served as negative controls. The animals were followed for up to 16 weeks by serum biochemical analyses and histological examination, and gene expression assays of liver tissues. RESULTS: Acute liver injury on day 2 manifested as HSOS, characterized by sinusoidal dilation, endothelial cell damage, and elevated serum alanine aminotransferase activity and bilirubin levels. In Group 1, mild liver fibrosis developed at sinusoids and perisinusoidal space surrounding the central veins at week 1 and 2, and thereafter, all liver injury resolved gradually. In Group 2, liver fibrosis progressed within the 16-week observation period. No apparent liver injury was observed in Groups 3 and 4. Compared with negative control groups, RTS induced myofibroblastic activation, TGF-ß1 signaling, and changes in expression of matrix metalloproteinase 9 (MMP-9) and tissue inhibitor of metalloproteinase 1 (TIMP-1). These dynamic changes differed in Groups 1 and 2, corresponding with the regression and progression of liver fibrosis, respectively, in these groups. CONCLUSION: This study has provided in-vivo proof of concept that "one hit" and "two hits" of RTS lead to acute resolving liver injury and chronic progressive liver fibrosis, respectively. These animal models may serve as powerful tools for studying RTS toxicology and related preventive and therapeutic strategies and as positive controls for studying other PA- and non-PA-induced liver injury.
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Enfermedad Hepática Inducida por Sustancias y Drogas/patología , Enfermedad Veno-Oclusiva Hepática , Cirrosis Hepática/patología , Alcaloides de Pirrolicidina , Animales , Enfermedad Veno-Oclusiva Hepática/inducido químicamente , Enfermedad Veno-Oclusiva Hepática/patología , Hígado/patología , Cirrosis Hepática/inducido químicamente , Metaloproteinasa 9 de la Matriz , Alcaloides de Pirrolicidina/toxicidad , Ratas , Inhibidor Tisular de Metaloproteinasa-1 , Factor de Crecimiento Transformador beta1RESUMEN
The hepatotoxic pyrrolizidine alkaloids (PAs) are metabolically activated in the liver to form reactive dehydro-PAs, which generate pyrrole-protein adducts leading to hepatotoxicity. Monocrotaline, but not other PAs, is also pneumotoxic, supposedly due to the migration of the liver-generated corresponding dehydro-PA into the lung to form pyrrole-protein adducts to induce pneumotoxicity. The present study investigated whether other PAs are also pneumotoxic. Metabolic activation of four representative hepatotoxic PAs, monocrotaline, retrorsine, riddelliine and clivorine, was investigated using rat liver or lung S9 incubation. All PAs produced pyrrole-protein adducts significantly in rat liver S9 but negligible in lung S9 fraction, revealing that liver is the key organ responsible for metabolic activation generating dehydro-PAs. Furthermore, these four PAs and another two PAs present in the alkaloid extract of Gynura segetum, a widely used PA-producing herb responsible for human PA poisonings in China, were orally administered to rats using the same hepatotoxic dose of 0.2 mmol/kg. All six PAs induced pneumotoxicity in rats within 48 h. The results demonstrated that pneumotoxicity could be a common phenomenon of PAs and the liver-derived dehydro-PAs might move to the lung and form pyrrole-protein adducts, leading to pulmonary toxicity.
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Pulmón/efectos de los fármacos , Alcaloides de Pirrolicidina/toxicidad , Activación Metabólica , Animales , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos , Medicamentos Herbarios Chinos , Hígado , Monocrotalina , Proteínas , Pirroles , RatasRESUMEN
The flower bud of Daphne genkwa (Genkwa Flos) is a commonly used herbal medicine in Asian countries. Luteolin and apigenin are two recognized active flavonoids in Genkwa Flos. The aim of this study was to investigate the intestinal absorption mechanisms of Genkwa Flos flavonoids using in situ single-pass intestinal perfusion rat model. Using HPLC, we determined its major effective flavonoids luteolin, apigenin, as well as, hydroxygenkwanin and genkwanin in biological samples. The intestinal absorption mechanisms of the total flavonoids in Genkwa Flos (TFG) were investigated using in situ single-pass intestinal perfusion rat model. Comparing the TFG absorption rate in different intestinal segments, data showed that the small intestine absorption was significantly higher than that of the colon ([Formula: see text]). Compared with duodenum and ileum, the jejunum was the best small intestinal site for TFG absorption. The high TFG concentration (61.48[Formula: see text][Formula: see text]g/ml) yielded the highest permeability ([Formula: see text]). Subsequently, three membrane protein inhibitors (verapamil, pantoprazole and probenecid) were used to explore the TFG absorption pathways. Data showed probenecid, a multidrug resistance protein (or MRP) inhibitor, effectively enhanced the TFG absorption ([Formula: see text]). Furthermore, by comparing commonly used natural absorption enhancers on TFG, it was observed that camphor was the most effective. In Situ single-pass intestinal perfusion experiment shows that TFG absorption is much higher in the small intestine than in the colon, and the TFG is absorbed mainly via an active transport pathway with MRP-mediated efflux mechanism. Camphor obviously enhanced the TFG absorption, and this could be an effective TFG formulation preparation method to increase clinical effectiveness after Genkwa Flos administration. Our study elucidated the TFG absorption mechanisms, and provided new information for its formulation preparation.
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Apigenina/metabolismo , Daphne/química , Absorción Intestinal/fisiología , Intestino Delgado/metabolismo , Luteolina/metabolismo , Perfusión , Animales , Apigenina/aislamiento & purificación , Alcanfor/farmacología , Colon/metabolismo , Flores/química , Luteolina/aislamiento & purificación , Masculino , Modelos Animales , Perfusión/métodos , Probenecid/farmacología , Ratas Sprague-DawleyRESUMEN
To elucidate the increasing dissolution and enhancement mechanism of wine-processed Radix Scutellaria (RS) by fractal theory in nitroglycerin (NTG)-induced migraine rats. We prepared three RS from the process with 10% (S1), 15% (S2), 20% (S3) (v/m) rice wine. Mercury intrusion porosimetry and scanning electron microscope were employed to explore the internal structure of RS and the components dissolution of RS was analyzed by HPLC. Rats were randomly allocated into following groups and orally given different solutions for 10days: normal group (NOR, normal saline), model group (MOD, normal saline), Tianshu capsule group (TSC, 0.425mg/kg), ibuprofen group (IBU, 0.0821mg/kg), crude RS group (CRU, 1.04mg/kg) and wine-processed RS group (WP, 1.04mg/kg) followed by bolus subcutaneously injection of NTG (10mg/kg) to induce migraine model except NOR. Biochemical indexes (nitric oxide-NO, calcitonin-gene-related peptide-CGRP, and endothelin-ET) and c-fos positive cells were measured with commercial kits and immunohistochemical method, separately. Total surface area significantly increased in wine-processed RS (p<0.05) while fractal dimension markedly decreased (p<0.05) compared with crude RS. Additionally, S3 owned the highest increase of dissolution including the percentage increase of total extract, total flavonoids and main compounds (all p<0.05 vs S1 and S2). Pharmacodynamic data showed c-fos positive cells significantly decreased (p<0.05) in WP compared with MOD and the level of NO, CGRP, ET in WP was better than that of CRU. Wine-processed RS could be a promising candidate medicine for migraine treatment due to its increased component dissolution.
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Trastornos Migrañosos/inducido químicamente , Trastornos Migrañosos/tratamiento farmacológico , Extractos Vegetales/uso terapéutico , Scutellaria/química , Vino , Animales , Conducta Animal , Fractales , Masculino , Trastornos Migrañosos/sangre , Nitroglicerina , Extractos Vegetales/química , Porosidad , Proteínas Proto-Oncogénicas c-fos/metabolismo , Ratas Sprague-Dawley , SolubilidadRESUMEN
Gastric ulcers are one of the most common gastrointestinal disorders. The aim of this study was to investigate the gastroprotective activity and possible underlying mechanisms of palmatine against acetic acid-induced gastric ulcers in rats. Palmatine was administered orally for 7 consecutive days to treat ulcers. The ulcer area, ulcer inhibition rate, histological section, platelet-activating factor (PAF) level in serum, prostaglandin E2 (PGE2) level in gastric tissue, 5-hydroxytryptamine (5-HT) level in the brain and norepinephrine (NE) level in the adrenal glands were analyzed. Histological results showed that the ulcer areas were significantly decreased by both doses of palmatine (10 and 20 mg/kg/day) compared with the model group, and the ulcer inhibition rates were 51.42% and 60.92%, respectively. Palmatine treatment markedly increased the level of PGE2 and decreased PAF, compared with the model group; however, it had no significant effect on 5-HT and NE levels. The results indicated that palmatine may exert a gastroprotective effect against gastric ulcers, and the mechanisms might be associated with the anti-inflammatory status and the protection of gastric mucosa via increasing PGE2 and decreasing PAF rather than neurohumoral regulation through 5-HT and NE. Thus, palmatine is a potential drug for treatment of gastric ulcers.
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Ácido Acético/efectos adversos , Antiulcerosos/uso terapéutico , Alcaloides de Berberina/uso terapéutico , Úlcera Gástrica/tratamiento farmacológico , Animales , Alcaloides de Berberina/administración & dosificación , Alcaloides de Berberina/farmacología , Masculino , Ratas , Ratas Sprague-Dawley , Úlcera Gástrica/inducido químicamenteRESUMEN
Emodin is an active anthraquinone derivative from Rheum palmatum and some other Chinese herbs and it is traditionally used for treating a variety of diseases. In this study, we investigated the hypocholesterolemic effects and mechanism of emodin on hypercholesterolemia rats. In vitro, capability of emodin binding to sodium deoxycholate which is one kind of bile salts (BAs) was evaluated by detection of surplus content of sodium deoxycholate. In vivo, hypocholesterolemic effects were assessed by determining total cholesterol (TC), triglyceride (TG), low density lipoprotein cholesterol (LDL-C) and high density lipoprotein cholesterol (HDL-C) level of serum and TC, TG level of the liver. Oil red O staining was employed to determine lipid droplet of the liver. The mechanism was explored by BAs in feces, the liver and small intestine. Furthermore, cholesterol 7α-hydroxylase (CYP7A1) activity was measured to evaluate cholesterol's transforming to BAs. The results indicated that TC level of emodin group apparently decreased comparing with model group (p<0.05). Emodin could bind to BAs both in vivo (p<0.05) and in vitro. CYP7A1 activity in emodin group apparently increased comparing with model group (p<0.05). Data suggested that emodin had the potential value for treatment of hypercholesterolemia. The underlying mechanism is probably associated with binding capability to BAs and subsequent increasing expression of CYP7A1.
Asunto(s)
Anticolesterolemiantes/farmacología , Ácidos y Sales Biliares/química , Emodina/farmacología , Hipercolesterolemia/tratamiento farmacológico , Animales , Colesterol/sangre , Colesterol/metabolismo , Colesterol 7-alfa-Hidroxilasa/metabolismo , HDL-Colesterol/sangre , LDL-Colesterol/sangre , Hígado/efectos de los fármacos , Hígado/metabolismo , Masculino , Ratas , Ratas Sprague-Dawley , Triglicéridos/sangre , Triglicéridos/metabolismoRESUMEN
Colorectal cancer is the third most common malignant tumor with high morbidity and mortality. To evaluate the antitumor effect of genkwanin on colorectal cancer enhanced by western high-fat diet, we investigated the activity of genkwanin on HT-29 and SW-480 human colorectal cancer lines in vitro and on the APC(Min/+) mice in vivo. In a cell culture system, six different inflammatory cytokines obviously stimulated two cancer cells growth in a concentration-dependent manner, while genkwanin significantly inhibited HT-29 and SW-480 human colorectal cancer cells proliferation and inflammatory cytokine IL-8 secretion. In the APC(Min/+) mice, the body weights, spleen and thymus indexes and immunity cytokine secretions were significantly improved after oral administration 12.5 and 25mg/kg/day of genkwanin. Besides, the tumor multiplicity changes and inflammatory cytokine levels were markedly reduced in two genkwanin-treated groups. The dysplastic adenomatous changes were also obviously ameliorated in gut histopathology. Taken together, our results indicated that genkwanin had a better antitumor activity partly via enhancing host immunity and decreasing the inflammatory cytokine levels. Genkwanin may be an effective chemotherapeutic agent for the treatment of colorectal cancer.
Asunto(s)
Poliposis Adenomatosa del Colon/tratamiento farmacológico , Antineoplásicos/uso terapéutico , Citocinas/metabolismo , Flavonas/uso terapéutico , Poliposis Adenomatosa del Colon/metabolismo , Animales , Antineoplásicos/química , Peso Corporal , Proliferación Celular , Citocinas/genética , Grasas de la Dieta/administración & dosificación , Grasas de la Dieta/efectos adversos , Femenino , Flavonas/química , Células HT29 , Humanos , Masculino , Ratones , Estructura MolecularRESUMEN
AIM: To investigate the absorption characteristics of the total alkaloids from Mahoniae Caulis (TAMC) through the administration of monterpene absorption enhancers or protein inhibitors. METHOD: The absorption behavior was investigated in an in situ single-pass intestinal perfusion (SPIP) assay in rats. RESULTS: The intestinal absorption of TAMC was much more than that of a single compound or a mixture of compounds (jatrorrhizine, palmatine, and berberine). Promotion of absorption by the bicyclic monoterpenoids (borneol or camphor) was higher than by the monocyclic monoterpenes (menthol or menthone), and promotion by compounds with a hydroxyl group (borneol or menthol) was higher than those with a carbonyl group (camphor or menthone). The apparent permeability coefficient (Papp) of TAMC was increased to 1.8-fold by verapamil, while it was reduced to one half by thiamine. The absorption rate constant (Ka) and Papp of TAMC were unchanged by probenecid and pantoprazole. CONCLUSION: The intestinal absorption characteristics of TAMC might be passive transport, and the intestinum tenue was the best absorptive site. In addition, TAMC might be likely a substrate of P-glycoprotein (P-gp) and organic cation transporters (OCT), rather than multidrug resistance protein (MRP) and breast cancer resistance protein (BCRP). Compared with a single compound and a mixture of compounds, TAMC was able to be absorbed in the blood circulation effectively.