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OBJECTIVE: The observational association between blood metabolites and asthma has been extensively studied. However, it is still unclear whether this association is causal. In this study, we aimed to investigate the causal relationship between blood metabolites and asthma using a bidirectional Mendelian randomization (MR) analysis. Additionally, we aimed to explore the potential mechanisms underlying this relationship. METHODS: The study design involved the use of genetic instruments as instrumental variables (IVs) to fulfill the assumptions of MR analysis. The data on 1,091 metabolites and 309 metabolite ratios were obtained from the Canadian Longitudinal Study on Aging (CLSA), while the data on asthma were obtained from the Integrative Epidemiology Unit (IEU) Open GWAS Project. Utilizing the inverse variance-weighted (IVW) method as the primary MR analysis approach, sensitivity tests were conducted to assess the reliability of the findings, which involved employing Cochran's Q and the MR-Egger intercept. Furthermore, Bayesian weighted MR was used to further test the robustness of the results. Additionally, pathway analysis was conducted to explore the metabolic explanations underlying asthma. RESULT: In our study, a comprehensive MR Analysis identified 10 metabolites and 6 metabolite ratios significantly associated with the development of asthma (FDR < 0.05). The metabolites included glycerophosphocholines(GPCs), glycerophosphoethanolamines(GPEs), and an unknown metabolite. Of these, 1-arachidonoyl-GPC, 1-myristoyl-2-arachidonoyl-GPC, 1-palmitoyl-2-arachidonoyl-GPC, and 1-(1-enyl-palmitoyl)-2-arachidonoyl-GPC were associated with an increased risk of asthma, whereas 1,2-dilinoleoyl-GPC, 1-palmitoyl-2-linoleoyl-GPC, 1,2-dilinoleoyl-GPE, 1 - oleoyl - 2 - linoleoyl - GPE, 1-palmitoyl-2-linoleoyl-GPE, and X-21470 were found to have a protective effect. No heterogeneity and pleiotropy were observed in the significant metabolites (p > 0.05), and each metabolite exhibited a consistent effect direction across all five methods. BWMR analysis results confirmed the significance and direction of effects across exposures, except for Cholesterol to linoleoyl-arachidonoyl-glycerol ratio(p = 0.673). Pathway analysis suggests that glycerophospholipid metabolism may potentially be a mechanism underlying the development of asthma. CONCLUSION: Our MR findings suggest that the identified metabolites and pathways can serve as biomarkers for clinical asthma screening and prevention, while also providing new insights for future mechanistic exploration and drug target selection.
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Objective: The observational association between cathepsin and Parkinson's disease (PD) has been partially explored in previous research. However, the causal relationship remains unclear. In this study, our objective is to investigate the causal link between cathepsin and PD using Mendelian randomization (MR) analysis and elucidate the underlying mechanisms governing their interaction. Methods: Utilizing bidirectional two-sample MR and multivariable MR, we systematically investigates the causal relationship between nine cathepsins and PD. The data pertaining to cathepsins were obtained from the Integrative Epidemiology Unit (IEU) Open GWAS Project, while data related to PD were sourced from versions R9 and R10 of the FinnGen database. The primary analytical method utilized was the inverse variance weighted (IVW), with MR analysis initially conducted using PD data from R9, complemented by a series of sensitivity analyses. Subsequently, replication analysis was performed on the R10 dataset, and meta-analysis were employed to merge the findings from both datasets. To explore potential mechanisms by which Cathepsins may impact PD, MR analyses were performed on significant Cathepsins with alpha-synuclein. MR analysis and colocalization analysis were conducted on expression quantitative trait loci (eQTL) data of gene related to alpha-synuclein with PD data. Result: Forward MR analyses revealed more cathepsin B (CTSB) associated with less PD risk (OR = 0.898, 95%CI: 0.834-0.966, p = 0.004), while more cathepsin H (CTSH) (OR = 1.076, 95%CI: 1.007-1.149, p = 0.029) and more cathepsin S (CTSS) (OR = 1.076, 95%CI: 1.007-1.150, p = 0.030) associated with increasing PD risk. Meta-analyses validated these associations. Multivariate MR Results were consistent with those before adjustment. No significant results were observed in bidirectional MR analysis. In the investigation of the underlying mechanism, our findings demonstrate that CTSB significantly reduces the levels of alpha-synuclein (OR = 0.909, 95%CI: 0.841-0.983, p = 0.017). Concurrently, a genetically determined positive correlation between alpha-synuclein and PD is illuminated by both eQTL MR and colocalization analysis. Conclusion: In conclusion, this MR study yields robust evidence suggesting an association between elevated levels of CTSB and reduced PD risk, mediated by the downregulation of alpha-synuclein levels. Conversely, higher levels of CTSH and CTSS are associated with an increased risk of PD. These findings offer novel insights into the pathophysiological mechanisms of PD and identify potential drug targets for disease prevention and treatment warranting further clinical investigations.
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OBJECTIVE: To study the hepatotoxicity effects in rats with different extract of Fructus Gardeniae. METHOD: Observe the change of appearance, behavior and weight of rats through oral gavage daily for 3 d. Weigh the liver and calculate the liver index. Detect the ALT, AST and TBIL. Observe the liver tissue by optical microscope. RESULT: The weight and index of liver were increased by 3.08 g x kg(-1) aqueous extract, 1.62 g x kg(-1) alcoholic extract and 0.28 g x kg(-1) geniposide, compared to those of the blank group (P < 0.005, P < 0.001) and the activities of ALT, AST and the content of TBIL were also increased, compared to those of the blank group (P < 0.05, P < 0.001). The liver cells were obviously swell, necrotic and changed with inflammatory infiltrate. CONCLUSION: Aqueous extract, alcoholic extract and geniposide displayed hepatotoxicity, and the geniposide which was the main substance of the Fructus Gardeniae might be mainly responsible for the hepatotoxicity.
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Medicamentos Herbarios Chinos/toxicidad , Gardenia , Iridoides/toxicidad , Hígado/patología , Piranos/toxicidad , Alanina Transaminasa/sangre , Animales , Aspartato Aminotransferasas/sangre , Bilirrubina/sangre , Medicamentos Herbarios Chinos/aislamiento & purificación , Femenino , Frutas/química , Gardenia/química , Iridoides/aislamiento & purificación , Masculino , Tamaño de los Órganos/efectos de los fármacos , Plantas Medicinales/química , Piranos/aislamiento & purificación , Distribución Aleatoria , Ratas , Ratas Sprague-DawleyRESUMEN
OBJECTIVE: To investigate the effect of Qingkailing and Methylprednisolone (MP) injection alone or combined on the acute lung injury (ALI) induced by oleic acid in rabbits. METHOD: The rabbits were randomly divided into 11 groups: oleic acid group; control group; treatment groups including low, middle and high dosage groups of Qingkailing and MP alone and combined, respectively. ALI model was established by i.v. oleic acid (0.05 mL x kg(-1)) in these groups, and then i.v. above drugs respectively, while in control group, the same volume of normal saline was given. The respiratory amplitude and rate were observed, and blood samples were taken from cervical artery for blood-gas analysis before and at 30, 60, 120 min after oleic acid or normal saline administration. At the end of experiment, the concentration of LDH, CAT and MDA in the lung tissue were measured and pathologic changes of lung tissue were observed microscopically. RESULT: Compared with oleic acid group, the respiratory amplitude markedly enhanced (P < 0.05) and respiratory rate lowered (P < 0.05) in the low, middle and high dose groups of Qingkailing and MP injection. On the 30 min of treatment, PaO2 increased significantly (P < 0.05) in the low and middle dose groups of combined Qingkailing and MP injection; PaCO2 decreased markedly (P < 0.05) on the 120 min of treatment in each treatment group. The level of LDH significantly increased (P < 0.05), CAT and MDA decreased (P < 0.05) in the middle and high groups of Qingkailing and MP injection. The low and middle dose groups of combined Qingkailing and MP injection can alleviate the pathological changes induced by oleic acid. CONCLUSION: The curative effect of the low dose group of combined Qingkailing and MP for the ALI induced by oleic acid was better than Qingkailing and MP alone, while the big dose groups of Qingkailing and MP alone better than the combination at the same dosage.
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Medicamentos Herbarios Chinos/uso terapéutico , Metilprednisolona/uso terapéutico , Fitoterapia , Síndrome de Dificultad Respiratoria/tratamiento farmacológico , Animales , Antiinflamatorios/uso terapéutico , Análisis de los Gases de la Sangre/métodos , Quimioterapia Combinada , Medicamentos Herbarios Chinos/aislamiento & purificación , Femenino , Pulmón/metabolismo , Pulmón/patología , Masculino , Ácido Oléico , Plantas Medicinales/química , Conejos , Distribución Aleatoria , Síndrome de Dificultad Respiratoria/inducido químicamente , Síndrome de Dificultad Respiratoria/metabolismo , Pruebas de Función RespiratoriaRESUMEN
OBJECTIVE: To investigate the effect of Qingikailing and Shengmai injection alone or combined on the acute lung injury (AL) induced by oleic acid in rabbits. METHOD: The rabbits were randomly divided into 11 groups: oleic acid group; control group; treatment groups including low, middle and high dosage groups of Qingkailing and Shengmai injection alone and combined, respectively. ALI model was established by iv oleic acid (0.05 mL x kg(-1)) in these groups, and then iv above drugs respectively,while in control group, the same volume of normal saline was given. The respiratory amplitude and rate were observed, and blood samples were taken from cervical artery for blood-gas analysis before and at 30, 60, 120 min after oleic acid or normal saline administration. At the end of experiment, the concentration of LDH, CAT and MDA in the lung tissue were measured and pathologic changes of lung tissue were observed microscopically. RESULT: Compared with oleic acid group, the respiratory amplitude markedly enhanced (P < 0.05) in the low and high dose groups of Qingkailing and Shengmai injection. PaO2 increased significantly (P < 0.05) in the low dose group of combined Qingkailing and Shengmai injection, PaCO2 decreased markedly (P < 0.05) in the low dose groups of Qingkailing and Shengmai injection alone and combined. The level of MDA significantly decreased (P < 0.05) in the each group of Qingkailing and Shengmai injection alone, the level of MDA significantly decreased (P < 0.05) and CAT increased (P < 0.05) in the low dose group of combined Qingkailing with Shengmai injection. The low dose group of combined Qingkailing and Shengmai injection can alleviate the pathological changes induced by oleic acid. CONCLUSION: The curative effect of the low dose group of combined Qingkailing with Shengmai injection for the ALI induced by oleic acid was better than Qingkailing and Shengmai injection alone at the same dosage.
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Medicamentos Herbarios Chinos/farmacología , Pulmón/patología , Plantas Medicinales , Respiración/efectos de los fármacos , Síndrome de Dificultad Respiratoria , Animales , Dióxido de Carbono/sangre , Catalasa/sangre , Combinación de Medicamentos , Quimioterapia Combinada , Medicamentos Herbarios Chinos/administración & dosificación , Medicamentos Herbarios Chinos/aislamiento & purificación , Femenino , L-Lactato Deshidrogenasa/metabolismo , Masculino , Malondialdehído/sangre , Ácido Oléico , Oxígeno/sangre , Plantas Medicinales/química , Conejos , Distribución Aleatoria , Síndrome de Dificultad Respiratoria/sangre , Síndrome de Dificultad Respiratoria/inducido químicamente , Síndrome de Dificultad Respiratoria/patología , Síndrome de Dificultad Respiratoria/fisiopatologíaRESUMEN
OBJECTIVE: The acute toxic effects of Aristolochia manshuriensis (GMT) and the total aristolochic acids (TA) were compared in mice with aristolochic acid A (AA) as the dose standard. The dose relationship of the renal toxicity induced by Aristolochia manshuriensis was determined. METHOD: A single dose of GMT extract or TA was given intragastrically to mice at different doses. LD50 values, the blood levels of BUN, Cr and ALT were measured. A histomorphological study was also performed in livers and kidneys of mice. RESULT: LD50 value of GMT extract was 4.4 g x kg(-1) which was equivalent to 40 mg x kg(-1) as calculated by the content of AA in GMT extract, and this value was comparable with LD50 obtained from TA given intragastrically in mice (equivalent to 33 mg x kg(-1) of AA for male and 37 mg x kg(-1) for female). GMT extract caused a significant increase in blood BUN and Cr and an obvious morphological change in kidney in a dose-dependent manner at doses of AA 4.5 mg x kg(-1) and above. Liver damage, characterized by both an increase in blood level of AST and histomorphological change, was observed at doses of AA 25 mg x kg(-1) and above. All changes were in proportion to the doses of AA. CONCLUSION: GMT causes both renal and liver toxicity. The dose leading to nephrotoxicity is much lower than that inducing hepatatoxicity. Aristolochic acids existed in GMT are the main toxic components to cause renal toxicity which is a crucial cause to result in death. The lethality and nephrotoxicity of GMT is in proportion to the doses of AA.
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Aristolochia , Ácidos Aristolóquicos/toxicidad , Medicamentos Herbarios Chinos/toxicidad , Riñón/patología , Alanina Transaminasa/sangre , Animales , Aristolochia/química , Ácidos Aristolóquicos/administración & dosificación , Ácidos Aristolóquicos/aislamiento & purificación , Aspartato Aminotransferasas/sangre , Nitrógeno de la Urea Sanguínea , Creatinina/sangre , Relación Dosis-Respuesta a Droga , Medicamentos Herbarios Chinos/administración & dosificación , Medicamentos Herbarios Chinos/aislamiento & purificación , Femenino , Dosificación Letal Mediana , Hígado/patología , Masculino , Ratones , Ratones Endogámicos ICR , Distribución AleatoriaRESUMEN
OBJECTIVE: To observe the acute and chronic renal toxicity induced by Radix Aristolochiae Fangchi Extract (RAFE) in different doses in rats. METHOD: The conventional method of acute toxicity was used. RAFE at the dose of 25.0 mg x kg(-1) x d(-1), 120.0 mg x kg(-1) x d(-1) and 200.0 mg x kg(-1) x d(-1) and aristolochic acid (AA, 10.0 mg x kg(-1) x d(-1)) were interruptedly administrated to rats for 13 week by gastric tube, and the sample of blood, urine and kidney were collected at 4 week, 8 week and 13 week respectively. The indexes of renal function were measured and the morphology of kidney was observed. RESULT: LD50 of RAFE was 36.8 g x kg(-1) (the crude drug) and the 95% confidence limit was 38.8 - 28.9 g x kg(-1). The changes of renal functions were azotemia, massive proteinuria and the increase of urinary NAGase (beta-N-acetylglucosaminidase) in the earlier period of administration with RAFE in rats. Pathological changes of renal tissue were as follows: acute renal tubular necrosis mainly in the boundary of cortex and medulla was observed in the earlier period, and with the elongation of administration, the pathological process of renal interstitial fibrosis observed in the middle and high groups of RAFE and AA group. CONCLUSION: RAFE at middle and high doses administrated by interrupted gavage above 13 week can cause the injury of renal tubular functions in rats. NAGase can be used as one of observation targets in the earlier period of renal injury.
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Acetilglucosaminidasa/orina , Aristolochia/toxicidad , Ácidos Aristolóquicos/toxicidad , Medicamentos Herbarios Chinos/toxicidad , Túbulos Renales/patología , Animales , Aristolochia/química , Ácidos Aristolóquicos/aislamiento & purificación , Nitrógeno de la Urea Sanguínea , Peso Corporal/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Medicamentos Herbarios Chinos/administración & dosificación , Medicamentos Herbarios Chinos/aislamiento & purificación , Femenino , Fibrosis/inducido químicamente , Masculino , Ratones , Raíces de Plantas/química , Raíces de Plantas/toxicidad , Plantas Medicinales/química , Plantas Medicinales/toxicidad , Proteinuria/inducido químicamente , Distribución Aleatoria , Ratas , Ratas Sprague-DawleyRESUMEN
OBJECTIVE: Following the former report, we continue to observe the chronic renal tubular-interstitial injury induced by Radix Aristolochiae Fangchi Extract(RAFE) in rats in order to understand whether RAFE in different doses causes the renal tubular-interstitial injury or not. METHOD: RAFE at the dose of 25.0 mg x kg(-1) x d(-1), 120.0 mg kg(-1) x d(-1) and 200.0 mg x kg(-1) x d(-1) and aristolochic acid (AA, 10.0 mg x kg(-1) d(-1)) was interruptedly administrated by gastric tube for 22 w and 4 w durg withdrawal. Blood, urine and kidney were taken out respectively in 17 w, 22 w and 26 w to measure the indexes of renal function. The morphology of kidney was observed, and Masson staining of kidney were made respectively to compare RAFE groups with AA group. RESULT: Pathological changes of renal tissue forms were as follows: All RAFE groups and AA group could develop the pathological process of renal tubular injury-chronic renal interstitial fibrosis. The pathologic changes of RAFE were similar with AA. CONCLUSION: RAFE at all doses administrated interruptedly by gastric tube above 13 w caused chronic renal tubulo-interstitium fibrosis. The renal injury in functions and tissue forms in rats were similar with AA closely. The results showed that AA was the main toxic composition of RAFE.
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Aristolochia/toxicidad , Medicamentos Herbarios Chinos/toxicidad , Túbulos Renales/patología , Nefritis Intersticial/inducido químicamente , Plantas Medicinales/toxicidad , Animales , Aristolochia/química , Ácidos Aristolóquicos/aislamiento & purificación , Ácidos Aristolóquicos/toxicidad , Nitrógeno de la Urea Sanguínea , Peso Corporal/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Medicamentos Herbarios Chinos/administración & dosificación , Medicamentos Herbarios Chinos/aislamiento & purificación , Femenino , Fibrosis/sangre , Fibrosis/inducido químicamente , Fibrosis/patología , Masculino , Nefritis Intersticial/sangre , Nefritis Intersticial/patología , Raíces de Plantas/química , Raíces de Plantas/toxicidad , Plantas Medicinales/química , Proteinuria/inducido químicamente , Ratas , Ratas Sprague-DawleyRESUMEN
OBJECTIVE: To compare the protective activity of liver injury induced by D-galactosamine (GalN) between Huangqin-Tang and their metabolites by human intestinal bacteria(HIB). METHOD: The liver injuries in conventional and pseudo-germfree mice were induced by GalN. After oral administration of Huangqin-Tang and their metabolites mixtures by HIB, the serum transaminase (ALT and AST) activities were detected. RESULT: In conventional mice, large and medium doses (20 and 10 g.kg-1) of Huangqin-Tang decoction significantly reduced the increase of serum ALT activity after 18 h GalN treatment. In pseudo-germfree mice, metabolites significantly reduced the ALT levels. However, Huangqing-Tang didn't affect the ALT levels in this kind of mice. To all of the animals, AST levels remained the same after oral Huangqin-tang or their metabolites. CONCLUSION: The metabolism by intestinal bacteria plays a role in pharmacological effects of constituents of Chinese herbal medicine. The metabolites of the constituents by intestinal bacteria were the real active components in vivo.