BACKGROUND Liver fibrosis is a global health issue that lacks effective treatments.Tibetan medicine,with a long history,has accumulated rich experience in the treatment of chronic liver diseases.The saffron(Saf)and Ca...BACKGROUND Liver fibrosis is a global health issue that lacks effective treatments.Tibetan medicine,with a long history,has accumulated rich experience in the treatment of chronic liver diseases.The saffron(Saf)and Calculus bovis(Cal b)combination is among the most commonly used medicines in clinical practice in Tibetan medicine for hepatic disease.Its characteristic therapies and drug compatibility provide unique ideas for the treatment of liver fibrosis and have research value and application potential.AIM To investigate the efficacy of the Saf-Cal b therapy in treating liver fibrosis and explored its underlying mechanism.METHODS We initially established a carbon tetrachloride-induced rat liver fibrosis model to assess Saf-Cal b’s anti-fibrotic effects.Subsequently,we conducted network pharmacology analysis to identify the potential therapeutic targets and pathways of Saf-Cal b in liver fibrosis intervention.Finally,we performed in vivo validation of key regulatory targets.RESULTS Saf-Cal b combination therapy exerted superior effects in ameliorating liver fibrosis in model rats compared with Saf or Cal b monotherapy.Through network pharmacology prediction,key targets of the combination were identified.Mechanistic validation revealed that Saf-Cal b inhibited the p38 mitogen-activated protein kinases pathway,which in turn suppressed the transforming growth factor-β/small mother against decapentaplegic pathway.This sequential inhibition led to reduced activation of hepatic stellate cells,a central event in liver fibrosis progression.CONCLUSION These findings demonstrate that Saf-Cal b combination therapy is more effective than either monotherapy in alleviating liver fibrosis,with its therapeutic effect mediated through the p38 mitogen-activated protein kinases/transforming growth factor-β/small mother against decapentaplegic signaling axis,providing a potential therapeutic strategy for liver fibrosis.展开更多
OBJECTIVE:To clarify the effect of Hamayou(Oviductus Ranae) protein hydrolysate(ORPH) on depression and its exact underlying mechanism from a new perspective. METHODS:We used the Chronic Unpredictable Mild Stress(CUMS...OBJECTIVE:To clarify the effect of Hamayou(Oviductus Ranae) protein hydrolysate(ORPH) on depression and its exact underlying mechanism from a new perspective. METHODS:We used the Chronic Unpredictable Mild Stress(CUMS) method to prepare a mouse model of depression and lipopolysaccharide(LPS) to prepare a model of BV2 cellular inflammation to investigate the antidepressant effect and mechanism of action of ORPH. Behavioral changes in mice and cerebral blood flow were detected by behavioral experiments and scatter imaging. Levels of corticosterone(CORT), proinflammatory cytokines and neurotransmitter were detected by enzyme-linked immunosorbent assay. Furthermore, hematoxylin-eosin staining, Tunel staining were used to evaluate the effect of ORPH. The distribution and expression of ionized calcium bindingadaptor molecule-1(Iba-1) in mouse hippocampal tissue and BV2 cells were detected by immunofluorescence. Mitogen-activated protein kinase(MAPK) pathway related protein expression was detected by Western blot. RESULTS:ORPH improved depression-like behavior, ameliorated brain tissue damage and apoptosis, and inhibited microglia activation in brain tissue in mice. In addition, ORPH reduced expression of B-cell lymphoma-2(Bcl-2)-associated X(Bax), cysteinyl aspartate specific proteinase 3(Caspase3), cysteinyl aspartate specific proteinase 9(Caspase9), nuclear factor-kappa B(NF-κB), phosphorylation-p38(p-p38), phosphorylation-Jun Nterminal kinase(p-JNK) proteins, and increased expression of Bcl-2, inhibitory kappa B alpha(IκB-α), phosphorylation-extracellular regulated protein kinases 1/2(p-ERK1/2) proteins. On the other hand, there were fewer Iba-1-positive cells, lower expression of NF-κB, pp38, p-JNK and p-ERK1/2 proteins, and higher expression of IκB-α proteins in BV2 cells in the ORPH group. In addition, ORPH increased 5-hydroxytryptamine, norepinephrine levels and decreased CORT, interleukin-1β(IL-1β), interleukin-6(IL-6), tumor necrosis factor-α(TNF-α) levels. CONCLUSION:ORPH was able to improve depressionlike behaviors and that it took effects by promoting cerebral blood flow, inhibition of hypothalamic-pituitaryadrenal axis overactivation, improving the structural damage of hippocampal tissues, and inhibiting the inflammatory response. ORPH can reduced neuronal damage and inhibiting apoptosis by promoting the MAPK pathway.展开更多
Objective To evaluate the antagonistic effects of N-acetylcysteine(NAC)on mitogen-activated protein kinases(MAPK)pathway activation,oxidative stress and inflammatory responses in rats with lung injury induced by fine ...Objective To evaluate the antagonistic effects of N-acetylcysteine(NAC)on mitogen-activated protein kinases(MAPK)pathway activation,oxidative stress and inflammatory responses in rats with lung injury induced by fine particulate matter(PM2.5).Methods Forty eight male Wistar rats were randomly divided into six groups:blank control group(C1),water drip control group(C2),PM2.5 exposed group(P),low-dose NAC treated and PM2.5 exposed group(L),middle-dose NAC treated and PM2.5 exposed group(M),and high-dose NAC treated and PM2.5 exposed group(H).PM2.5 suspension(7.5 mg/kg)was administered tracheally once a week for four times.NAC of 125 mg/kg,250 mg/kg and 500 mg/kg was delivered intragastrically to L,M and H group respectively by gavage(10 ml/kg)for six days before PM2.5 exposure.The histopathological changes and human mucin 5 subtype AC(MUC5AC)content in lung tissue of rats were evaluated.We investigated IL-6 in serum and bronchoalveolar lavage fluid(BALF)by Enzyme-linked immunosorbent assay(ELISA),MUC5AC in lung tissue homogenate by ELISA,glutathione peroxidase(GSH-PX)in serum and BALF by spectrophotometry,and the expression of p-ERK1/2,p-JNK1/2 and p-p38 proteins by Western blot.All the measurements were analyzed and compared statistically.Results Lung tissue of rats exposed to PM2.5 showed histological destruction and increased mucus secretion of bronchial epithelial cells.Rats receiving NAC treatment showed less histological destruction and mucus secretion.Of P,L,M and H group,MUC5AC in lung tissue,IL-6 in serum and BALF were higher than controls(C1 and C2)(all P<0.05),with the highest levels found in the P group and a decreasing trend with increase of NAC dose.The activity of GSH-PX in serum and BALF of PM2.5 exposed rats(P,L,M and H)was lower than that of controls(all P<0.05),with higher activities found in NAC treated rats(L,M,and H),and an increasing trend with increase of NAC dose.The expressions of p-ERK1/2,p-JNK1/2 and p-p38 proteins in PM2.5 exposed lung tissue(P,L,M and H)was higher than controls(all P<0.05),with decreased levels and dose dependent downregulation found in NAC treated rats.Conclusion NAC can antagonize major MAPK pathway activation,lung oxidative stress and inflammatory injury induced by PM2.5 in rats.展开更多
大鼠肉瘤(rat sarcoma,Ras)基因是实体肿瘤中最常见的原癌基因,由于突变亚型中缺乏药理学上可靶向的口袋,Ras历来被认为是不可成药的靶点。然而,药物设计的改进最终导致了对活性或非活性状态的突变鼠类肉瘤病毒癌基因(kirsten rat sarco...大鼠肉瘤(rat sarcoma,Ras)基因是实体肿瘤中最常见的原癌基因,由于突变亚型中缺乏药理学上可靶向的口袋,Ras历来被认为是不可成药的靶点。然而,药物设计的改进最终导致了对活性或非活性状态的突变鼠类肉瘤病毒癌基因(kirsten rat sarcoma viral oncogene,Kras)具有选择性的抑制剂的开发。其中一些抑制剂已被证明对Kras G12C/G12D突变癌症患者有效,并已成为实践的改变。癌细胞和肿瘤微环境中RAS信号传导的理解不断提高,逐渐探究出新的药物或联合治疗的潜力,目前正在临床试验中进行探索。本文阐述了Ras突变的作用机制及黑色素瘤中Ras突变的特点及近年来该领域的研究进展,旨在展示该突变患者的治疗现状,并对各种新型治疗方法的数据进行归纳和总结,为临床实践方案提供新的治疗思路。展开更多
基金Supported by Tibetan Medicine Administration of Tibet Autonomous Region,No.JJKT2020006Key Research and Development Project of Tibet Autonomous Region,No.XZ202201ZY0019GNational Administration of Traditional Chinese Medicine High-level Key Discipline Construction Project,No.zyyzdxk-2023262.
文摘BACKGROUND Liver fibrosis is a global health issue that lacks effective treatments.Tibetan medicine,with a long history,has accumulated rich experience in the treatment of chronic liver diseases.The saffron(Saf)and Calculus bovis(Cal b)combination is among the most commonly used medicines in clinical practice in Tibetan medicine for hepatic disease.Its characteristic therapies and drug compatibility provide unique ideas for the treatment of liver fibrosis and have research value and application potential.AIM To investigate the efficacy of the Saf-Cal b therapy in treating liver fibrosis and explored its underlying mechanism.METHODS We initially established a carbon tetrachloride-induced rat liver fibrosis model to assess Saf-Cal b’s anti-fibrotic effects.Subsequently,we conducted network pharmacology analysis to identify the potential therapeutic targets and pathways of Saf-Cal b in liver fibrosis intervention.Finally,we performed in vivo validation of key regulatory targets.RESULTS Saf-Cal b combination therapy exerted superior effects in ameliorating liver fibrosis in model rats compared with Saf or Cal b monotherapy.Through network pharmacology prediction,key targets of the combination were identified.Mechanistic validation revealed that Saf-Cal b inhibited the p38 mitogen-activated protein kinases pathway,which in turn suppressed the transforming growth factor-β/small mother against decapentaplegic pathway.This sequential inhibition led to reduced activation of hepatic stellate cells,a central event in liver fibrosis progression.CONCLUSION These findings demonstrate that Saf-Cal b combination therapy is more effective than either monotherapy in alleviating liver fibrosis,with its therapeutic effect mediated through the p38 mitogen-activated protein kinases/transforming growth factor-β/small mother against decapentaplegic signaling axis,providing a potential therapeutic strategy for liver fibrosis.
基金Science and Technology Development Project of Jilin Province:Preparation and Evaluation of an Animal Model of Liverdepression Type Depression (20220505038ZP)Exploring the Material Basis and Action Pathway of the Antipyretic Effect of Baihu Tang based on Histologic Techniques (20240602036RC)。
文摘OBJECTIVE:To clarify the effect of Hamayou(Oviductus Ranae) protein hydrolysate(ORPH) on depression and its exact underlying mechanism from a new perspective. METHODS:We used the Chronic Unpredictable Mild Stress(CUMS) method to prepare a mouse model of depression and lipopolysaccharide(LPS) to prepare a model of BV2 cellular inflammation to investigate the antidepressant effect and mechanism of action of ORPH. Behavioral changes in mice and cerebral blood flow were detected by behavioral experiments and scatter imaging. Levels of corticosterone(CORT), proinflammatory cytokines and neurotransmitter were detected by enzyme-linked immunosorbent assay. Furthermore, hematoxylin-eosin staining, Tunel staining were used to evaluate the effect of ORPH. The distribution and expression of ionized calcium bindingadaptor molecule-1(Iba-1) in mouse hippocampal tissue and BV2 cells were detected by immunofluorescence. Mitogen-activated protein kinase(MAPK) pathway related protein expression was detected by Western blot. RESULTS:ORPH improved depression-like behavior, ameliorated brain tissue damage and apoptosis, and inhibited microglia activation in brain tissue in mice. In addition, ORPH reduced expression of B-cell lymphoma-2(Bcl-2)-associated X(Bax), cysteinyl aspartate specific proteinase 3(Caspase3), cysteinyl aspartate specific proteinase 9(Caspase9), nuclear factor-kappa B(NF-κB), phosphorylation-p38(p-p38), phosphorylation-Jun Nterminal kinase(p-JNK) proteins, and increased expression of Bcl-2, inhibitory kappa B alpha(IκB-α), phosphorylation-extracellular regulated protein kinases 1/2(p-ERK1/2) proteins. On the other hand, there were fewer Iba-1-positive cells, lower expression of NF-κB, pp38, p-JNK and p-ERK1/2 proteins, and higher expression of IκB-α proteins in BV2 cells in the ORPH group. In addition, ORPH increased 5-hydroxytryptamine, norepinephrine levels and decreased CORT, interleukin-1β(IL-1β), interleukin-6(IL-6), tumor necrosis factor-α(TNF-α) levels. CONCLUSION:ORPH was able to improve depressionlike behaviors and that it took effects by promoting cerebral blood flow, inhibition of hypothalamic-pituitaryadrenal axis overactivation, improving the structural damage of hippocampal tissues, and inhibiting the inflammatory response. ORPH can reduced neuronal damage and inhibiting apoptosis by promoting the MAPK pathway.
文摘Objective To evaluate the antagonistic effects of N-acetylcysteine(NAC)on mitogen-activated protein kinases(MAPK)pathway activation,oxidative stress and inflammatory responses in rats with lung injury induced by fine particulate matter(PM2.5).Methods Forty eight male Wistar rats were randomly divided into six groups:blank control group(C1),water drip control group(C2),PM2.5 exposed group(P),low-dose NAC treated and PM2.5 exposed group(L),middle-dose NAC treated and PM2.5 exposed group(M),and high-dose NAC treated and PM2.5 exposed group(H).PM2.5 suspension(7.5 mg/kg)was administered tracheally once a week for four times.NAC of 125 mg/kg,250 mg/kg and 500 mg/kg was delivered intragastrically to L,M and H group respectively by gavage(10 ml/kg)for six days before PM2.5 exposure.The histopathological changes and human mucin 5 subtype AC(MUC5AC)content in lung tissue of rats were evaluated.We investigated IL-6 in serum and bronchoalveolar lavage fluid(BALF)by Enzyme-linked immunosorbent assay(ELISA),MUC5AC in lung tissue homogenate by ELISA,glutathione peroxidase(GSH-PX)in serum and BALF by spectrophotometry,and the expression of p-ERK1/2,p-JNK1/2 and p-p38 proteins by Western blot.All the measurements were analyzed and compared statistically.Results Lung tissue of rats exposed to PM2.5 showed histological destruction and increased mucus secretion of bronchial epithelial cells.Rats receiving NAC treatment showed less histological destruction and mucus secretion.Of P,L,M and H group,MUC5AC in lung tissue,IL-6 in serum and BALF were higher than controls(C1 and C2)(all P<0.05),with the highest levels found in the P group and a decreasing trend with increase of NAC dose.The activity of GSH-PX in serum and BALF of PM2.5 exposed rats(P,L,M and H)was lower than that of controls(all P<0.05),with higher activities found in NAC treated rats(L,M,and H),and an increasing trend with increase of NAC dose.The expressions of p-ERK1/2,p-JNK1/2 and p-p38 proteins in PM2.5 exposed lung tissue(P,L,M and H)was higher than controls(all P<0.05),with decreased levels and dose dependent downregulation found in NAC treated rats.Conclusion NAC can antagonize major MAPK pathway activation,lung oxidative stress and inflammatory injury induced by PM2.5 in rats.
