Chlorogenic acid, rutin, and quercetin from Lysimachia christinae alleviate triptolide-induced multi-organ injury in vivo by modulating immunity and AKT/mTOR signal pathway to inhibit ferroptosis and apoptosis.

Drug-induced organ injury is one of the key factors causing organ failure and death in the global public. Triptolide (TP) is the main immunosuppressive component of Tripterygium wilfordii Hook. f. (Leigongteng, LGT) for the first-line management of autoimmune conditions, but it can cause serious multi-organ injury. Lysimachia christinae (Jinqiancao, JQC) is a detoxifying Chinese medicine and could suppress LGT's toxicity. It contains many immune enhancement and organ protection components including chlorogenic acid (CA), rutin (Rut), and quercetin (Que). This study aimed to explore the protection of combined treatments of these organ-protective ingredients of JQC on TP-induced liver, kidney, and heart injury and initially explore the mechanisms. Molecular docking showed that CA, Rut, and Que bounded protein kinase B (AKT)/mechanistic target of rapamycin (mTOR) pathway-related molecules intimately and might competitively antagonize TP. Corresponding in vivo results showed that the combination activated TP-inhibited protein of AKT/mTOR pathway, and reversed TP-induced excessive ferroptosis (excessive Fe 2+ and lipid peroxidation malondialdehyde accumulation, decreased levels of antioxidant enzymes catalase, glutathione peroxidase, glutathione-s transferase, reduced glutathione, and superoxide dismutase, and down-regulated P62/nuclear factor erythroid-2-related factor 2/heme oxygenase-1 pathway), and apoptosis (activated apoptotic factor Fas and Bax and inhibited Bcl-2) in the organ of mice to varying degrees. In conclusion, the combined treatments of CA, Rut, and Que from JQC inhibited TP-induced multi-organ injury in vivo, and the mechanism may largely involve immunomodulation and activation of the AKT/mTOR pathway-mediated cell death reduction including ferroptosis and apoptosis inhibition.

[Toxicity attenuation processing technology and mechanism of Rhizoma Dioscoreae Bulbiferae stir-fried with Paeoniae Radix Alba decoction].

This study explored toxicity attenuation processing technology of Rhizoma Dioscoreae Bulbiferae stir-fried with Paeoniae Radix Alba decoction for the first time, and further explored its detoxification mechanism. Nine processed products of Rhizoma Dioscoreae Bulbiferae stir-fried with Paeoniae Radix Alba decoction were prepared by orthogonal experiment with three factors and three levels. Based on the decrease in the content of the main hepatotoxic component diosbulbin B before and after processing of Rhizoma Dioscoreae Bulbiferae by high-performance liquid chromatography, the toxicity attenuation technology was preliminarily screened out. On this basis, the raw and representative processed products of Rhizoma Dioscoreae Bulbiferae were given to mice by gavage with 2 g·kg~(-1)(equival to clinical equivalent dose) for 21 d. The serum and liver tissues were collected after the last administration for 24 h. The serum biochemical indexes reflecting liver function and liver histopathology were combined to further screen out and verify the proces-sing technology. Then, the lipid peroxidation and antioxidant indexes of liver tissue were detected by kit method, and the expressions of NADPH quinone oxidoreductase 1(NQO1) and glutamate-cysteine ligase(GCLM) in mice liver were detected by Western blot to further explore detoxification mechanism. The results showed that the processed products of Rhizoma Dioscoreae Bulbiferae stir-fried with Paeoniae Radix Alba decoction reduced the content of diosbulbin B and improved the liver injury induced by Rhizoma Dioscoreae Bul-biferae to varying degrees, and the processing technology of A_2B_2C_3 reduced the excessive levels of alanine transaminase(ALT) and aspartate transaminase(AST) induced by raw Rhizoma Dioscoreae Bulbiferae by 50.2% and 42.4%, respectively(P<0.01, P<0.01). The processed products of Rhizoma Dioscoreae Bulbiferae stir-fried with Paeoniae Radix Alba decoction reversed the decrease protein expression levels of NQO1 and GCLM in the liver of mice induced by raw Rhizoma Dioscoreae Bulbiferae to varying degrees(P<0.05 or P<0.01), and it also reversed the increasing level of malondialdehyde(MDA) and the decreasing levels of glutathione(GSH), glutathione peroxidase(GPX), and glutathione S-transferase(GST) in the liver of mice(P<0.05 or P<0.01). In summary, this study shows that the optimal toxicity attenuation processing technology of Rhizoma Dioscoreae Bulbiferae stir-fried with Paeoniae Radix Alba decoction is A_2B_2C_3, that is, 10% of Paeoniae Radix Alba decoction is used for moistening Rhizoma Dioscoreae Bulbiferae and processed at 130 ℃ for 11 min. The detoxification mechanism involves enhancing the expression levels of NQO1 and GCLM antio-xidant proteins and related antioxidant enzymes in the liver.

[Preliminary exploration of detoxification mechanism of processing methods on cardiotoxicity induced by radix Tripterygium wilfordii in mice via Nrf2/HO-1 pathway].

This study aims to investigate the detoxification effects of different processing methods on the cardiotoxicity induced by radix Tripterygium wilfordii, and preliminarily explore the detoxification mechanism via the nuclear factor E2-related factor 2(Nrf2)/heme oxygenase 1(HO-1) pathway. The raw and processed products [stir-fried product, product stir-fried with Lysimachiae Herba(JQC), product stir-fried with Phaseoli Radiati Semen(LD), product stir-fried with Paeoniae Radix Alba(BS), product stir-fried with Glycyrrhizae Radix et Rhizoma(GC), and product stir-fried with vinegar(CZ)] of radix T. wilfordii were administrated to mice by gavage at a dose of 2 g·kg~(-1)(based on crude drugs) for 28 days. Twenty-four hours after the last administration, we measured the serum biochemical indexes of mice to evaluate the detoxification effect. Furthermore, we determined the expression of key proteins of Nrf2/HO-1 pathway in mouse heart tissue by Western blot and some oxidation/antioxidation-related indexes by corresponding kits to explore the detoxification mechanism. The administration of the raw product elevated the levels of serum creatine kinase, lactate dehydrogenase, and malondialdehyde, a product of cardiac lipid peroxidation(P<0.01), down-regulated the protein levels of Nrf2 and HO-1(P<0.01), and reduced the levels of total superoxide dismutase, glutathione, glutathione peroxidase, and glutathione S-transferase(P<0.01). However, after the administration of the products stir-fried with JQC, LD, BS, GC, and CZ, the abnormalities of the above indexes induced by the raw product were recovered(P<0.05 or P<0.01). In particular, the product stir-fried with JQC showed the best performance. Taken all together, the cardiotoxicity induced by radix T. wilfordii could be attenuated by stir-frying with JQC, LD, BS, GC, and CZ, and the stir-frying with JQC showed the best detoxification effect. The mechanism might be associated with the cardiac antioxidant defense and oxidative damage mitigation mediated by the up-regulated Nrf2.

Antidepressant effects of 70% ethanolic extract of Lonicerae japonicae flos and it contained chlorogenic acid via upregulation of BDNF-TrkB pathway in the hippocampus of mice.

Lonicera japonica flos (LJF) is a common clinical herb with outstanding medicinal and nutritional value. This study aimed to evaluate the antidepressant effects of LJF's active extract and compound chlorogenic acid (CGA) around brain-derived neurotrophic factor(BDNF)-tropomyosin receptor kinase B (TrkB) pathway. The results showed that LJF's extracts and CGA had significant antidepressant effects, and the antidepressant effects of different extracts of LJF were highly positively correlated with the content of CGA (forced swimming test, r = 0.998; tail suspension test, r = 0.934). Moreover, LJF-70% ethanolic extract and CGA improved chronic unpredictable mild stress-induced depressive behavior, upregulated protein expression levels of BDNF and p-TrkB in the hippocampus, restored the damage of hippocampal neurons, and protected liver from damage. In summary, this study demonstrated for the first time that LJF-70% ethanolic extract was the active extract of LJF in antidepressant and CGA was its active compound, and the antidepressant mechanisms mainly involved the upregulation of BDNF-TrkB signaling pathway in the hippocampus of mice.

Role of BDNF-TrkB signaling in the antidepressant-like actions of loganin, the main active compound of Corni Fructus.

AIMS: Corni Fructus (CF) and some CF-contained prescriptions are commonly used in clinical treatment of depression. This investigation aims to evaluate the main active compound of CF in antidepressant properties and its key target. METHODS: Firstly, this study established a behavioral despair model and used high-performance liquid chromatography method to evaluate the antidepressant-like effects of water extract, 20%, 50%, and 80% ethanol extracts of CF, and its main active compound. Then, this study created chronic unpredictable mild stress (CUMS) model to assess loganin's antidepressant-like properties, and its target was evaluated by quantitative real-time polymerase chain reaction, Western blot, Immunofluorescence, enzyme-linked immunosorbent assay, and tyrosine receptor kinase B (TrkB) inhibitor. RESULTS: Results showed that the different extracts of CF significantly shortened the immobility time in forced swimming and tail suspension tests. Moreover, loganin alleviated CUMS-induced depression-like behavior, promoted neurotrophy and neurogenesis, and inhibited neuroinflammation. Furthermore, K252a blocked the improvement of loganin on depression-like behavior, and eliminated the enhancement of neurotrophy and neurogenesis and the inhibition of neuroinflammation. CONCLUSION: Overall, these results indicated that loganin could be used as a major active compound of CF for the antidepressant-like properties and exerted antidepressant-like actions by regulating brain derived neurotrophic factor (BDNF)-TrkB signaling, and TrkB could be used as key target for itsantidepressant-like actions.

Quercetin reverses chronic unpredictable mild stress-induced depression-like behavior in vivo by involving nuclear factor-E2-related factor 2.

Quercetin is a flavonoid compound rich in many natural plants with a wide range of pharmacological effects and nutritional value. Although previous studies have initially shown the antidepressant effect of quercetin in some models. However, the exact mechanism of the antidepressant effect of quercetin on the depression model induced by chronic unpredictable mild stress (CUMS) is still unclear or has not been clearly elucidated. The present study aimed to investigate the antidepressant effect of quercetin in vivo on a CUMS-induced depression model that is closest to human depression, and to explore its mechanism of action around nuclear factor-E2-related factor 2 (Nrf2) related signaling pathways, for the first time. Our results demonstrated that CUMS for 21 consecutive days caused significant decreases in the sucrose preference, and the horizontal score and vertical score in the open field test of mice respectively by 22.6%, 34.4%, and 66.6% (all P < 0.01), and a significant increase in the immobility time during the forced swimming test by 110.5% (P < 0.01), but fortunately, after chronic oral administration of high dose quercetin at 40 mg/kg, the abnormalities of the above indicators were significantly reversed by 26.2%, 40.1%, 152.7%, 43.5% (all P < 0.01). Further western blot analysis showed that CUMS caused the phosphorylation or expression levels of phosphoinositide 3-kinase (PI3K), protein kinase B (Akt), Nrf2 and heme oxygenase-1 (HO-1) proteins in the hippocampus of mice to significantly down-regulate by 60.0%, 72.1%, 90.0% and 50.1% (all P < 0.01), while after chronic oral administration of high dose quercetin at 40 mg/kg, the abnormalities of these proteins were significantly up-regulated by 85.8%, 182.0%, 325.1% and 60.3% (all P < 0.01). In addition, CUMS also caused significant reduction in the levels of antioxidants including superoxide dismutase (SOD) and glutathione-s transferase (GST) in the mice hippocampus by 51.3%, 40.3% (both P < 0.01), while after chronic oral administration of high dose quercetin at 40 mg/kg, the abnormalities of the above indicators were significantly reversed by 69.2% and 49.5% (both P < 0.01), as well as significant elevation in the levels of lipid peroxide malondialdehyde (MDA), inflammation medium nitric oxide (NO) and inducible nitric oxide synthase (iNOS) by 156.4%, 255.4% and 72.7% (all P < 0.01), while after chronic oral administration of high dose quercetin at 40 mg/kg, the abnormalities of the above indicators were significantly reversed by 45.9%, 26.8% and 55.2% (all P < 0.01). The medium dose of quercetin (20 mg/kg) only reversed some of the above indicators, while the low dose of quercetin (10 mg/kg) had no reversal effect on the above indicators. Collectively, the present study confirmed for the first time that quercetin weakened CUMS-induced depression in vivo, and its mechanism was at least partially attributable to the upregulation of hippocampal Nrf2 and the inhibition of iNOS, thereby correcting the central inflammatory response, and the imbalance between oxidation and antioxidant.

Antidepressant effect of catalpol on corticosterone-induced depressive-like behavior involves the inhibition of HPA axis hyperactivity, central inflammation and oxidative damage probably via dual regulation of NF-κB and Nrf2.

This study aimed to investigate the antidepressant effect and mechanism of catalpol on corticosterone (CORT)-induced depressive-like behavior in mice for the first time. As a result, CORT injection induced depressive-like behaviors of mice in behavioral tests, aggravated the serum CORT, adrenocorticotropic hormone, and corticotropin-releasing hormone levels, and conspicuously elevated the phosphorylations of nuclear factor kappa-B (NF-κB) in the hippocampus and frontal cortex, and down-regulated the expression levels of nuclear factor erythroid-2-related factor 2 (Nrf2). Furthermore, CORT exposure dramatically augmented the levels of inflammatory factors (interleukin-1ß, tumor necrosis factor-α, nitric oxide synthase, and nitric oxide) and lipid peroxidation product malondialdehyde, and attenuated the levels of antioxidants including reduced glutathione, glutathione S-transferase, total superoxide dismutase, and heme oxygenase-1 in the mouse hippocampus and frontal cortex. On the contrary, catalpol administration markedly suppressed the abnormalities of the above indicators. From the overall results, this study displayed that catalpol exerted a beneficial effect on CORT-induced depressive-like behavior in mice possibly via the inhibition of hypothalamus-pituitary-adrenal (HPA) axis hyperactivity, central inflammation and oxidative damage at least partially through dual regulation of NF-κB and Nrf2.