Co-catalpol alleviates fluoxetine-induced main toxicity: Involvement of ATF3/FSP1 signaling-mediated inhibition of ferroptosis.

BACKGROUND: Fluoxetine is often used as a well-known first-line antidepressant. However, it is accompanied with hepatogenic injury as its main organ toxicity, thereby limiting its application despite its superior efficacy. Fluoxetine is commonly traditionally used combined with some Chinese antidepressant prescriptions containing Rehmannia glutinosa (Dihuang) for depression therapy and hepatoprotection. Our previous experiments showed that co-Dihuang can alleviate fluoxetine-induced liver injury while efficiencies, and catalpol may be the key ingredient to characterize the toxicity-reducing and synergistic effects. However, whether co-catalpol can alleviate fluoxetine-induced liver injury and its toxicity-reducing mechanism remain unclear. PURPOSE: On the basis of the first recognition of the dose and duration at which pre-fluoxetine caused hepatic injury, co-catalpol's alleviation of fluoxetine-induced hepatic injury and its pathway was comprehensively elucidated. METHOD AND RESULTS: The hepatoprotection of co-catalpol was evaluated by serum biochemical indexes sensitive to hepatic injury and multiple staining techniques for hepatic pathologic analysis. Subsequently, the pathway by which catalpol alleviated fluoxetine-induced hepatic injury was predicted by network pharmacology to be predominantly the inhibition of ferroptosis. These were validated and confirmed in subsequent experiments with key technologies and diagnostic reagents related to ferroptosis. Further molecular docking showed that activating transcription factor 3 (ATF3) and ferroptosis suppressor protein 1 (FSP1) were the the most prospective molecules for catalpol and fluoxetine among many ferroptosis-related molecules. The critical role of ATF3/FSP1 signaling was further observed by surface plasmon resonance, diagnostic reagents, transmission electron microscopy, Western blot, real-time PCR, immunofluorescence, and immunohistochemistry. Results showed that fluoxetine directly bound to ATF3 and FSP1; agonisting ATF3 or blocking FSP1 abolished the alleviation of catalpol on fluoxetine-induced liver injury, and both exacerbated ferroptosis. Moreover, co-catalpol significantly enhanced the antidepressant efficacy of fluoxetine against depressive behaviours in mice. CONCLUSION: The hepatic impairment properties of fluoxetine were largely dependent on ATF3/FSP1 target-mediated ferroptosis. Co-catalpol alleviated fluoxetine-induced hepatic injury while enhancing its antidepressant efficacy, and that ATF3/FSP1 signaling-mediated inhibition of ferroptosis was involved in its co-administration detoxification mechanism. This study was the first to reveal the hepatotoxicity characteristics, targets, and mechanisms of fluoxetine; provide a detoxification and efficiency regimen by co-catalpol; and elucidate the detoxification mechanism.

Investigation of the principle of concoction by using the processing excipient Glycyrrhiza uralensis Fisch. juice to reduce the main toxicity of Dioscorea bulbifera L. and enhance its main efficacy as expectorant and cough suppressant.

ETHNOPHARMACOLOGICAL RELEVANCE: Dioscorea bulbifera L. (Rhizoma Dioscoreae Bulbiferae; RDB) is commonly used as an expectorant and cough suppressant herb but is accompanied by severe hepatotoxicity. Using the juice of auxiliary herbs (such as Glycyrrhiza uralensis Fisch. (Glycyrrhizae Radix et Rhizoma; GRR) juice) in concocting poisonous Chinese medicine is a conventional method to reduce toxicity or increase effects. Our previous study found that concoction with GRR juice provided a detoxifying effect against the major toxic hepatotoxicity induced by RDB, but the principle for the detoxification of the concoction is unknown to date. AIM OF THE STUDY: The principle of concoction was investigated by using the processing excipient GRR juice to reduce the major toxic hepatotoxicity of RDB, and the efficacy of RDB as an expectorant and cough suppressant was enhanced. MATERIALS AND METHODS: In this study, common factors (RDB:GRR ratio, concocted temperature, and concocted time) in the concoction process were used for the preparation of each RDB concocted with GRR juice by using an orthogonal experimental design. We measured the content of the main toxic compound diosbulbin B (DB) and serum biochemical indicators and performed pathological analysis in liver tissues of mice to determine the best detoxification process of RDB concocted with GRR juice. On this basis, the biological mechanisms of target organs were detected by Western blot and enzyme-linked immunosorbent assay at the inflammation and apoptosis levels. Further, the effects of RDB on expectorant and cough suppressant with GRR juice were evaluated by the conventional tests of phenol red expectorant and concentrated ammonia-induced cough. Lastly, the major compounds in the GRR juice introduced to RDB concoction were determined. RESULTS: RDB concocted with GRR juice significantly alleviated DB content, serum alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase levels, and improved liver pathological damages. The best detoxification process was achieved by using an RDB:GRR ratio of 100:20 at 120 °C for 20 min. Further, RDB concocted with GRR juice down-regulated the protein levels of nuclear factor kappa B (NF-κB), cyclooxygenase 2 (COX-2), and Bcl-2 related X protein (Bax) in the liver and enhanced the expectorant and cough suppressant effects of RDB. Finally, liquiritin (LQ) and glycyrrhizic acid (GA) in the GRR juice were introduced to the RDB concoction. CONCLUSION: Concoction with GRR juice not only effectively reduced the major toxic hepatotoxicity of RDB but also enhanced its main efficacy as an expectorant and cough suppressant, and that the rationale for the detoxification and/or potentiation of RDB was related to the reduction in the content of the main hepatotoxic compound, DB, the introduction of the hepatoprotective active compounds, LQ and GA, in the auxiliary GRR juice, as well as the inhibition of NF-κB/COX-2/Bax signaling-mediated inflammation and apoptosis.

[Gender differences in antidepressant effect of raw Rehmanniae Radix].

For the first time, this study evaluated the gender differences and mechanisms of the antidepressant effects of raw Rehmanniae Radix(RRR) based on the classic depression model with traditional Chinese medicine syndrome of Yin deficiency and internal heat. The depression model with Yin deficiency and internal heat was established by the widely recognized and applied method of thyroxine induction of the classic depression model with Yin deficiency and internal heat(chronic unpredictable mild stress). Male and female mice were simultaneously treated with RRR. The study analyzed indicators of nourishing Yin and clearing heat, conventional antidepressant efficacy test indicators, and important biomolecules reflecting the pathogenesis and prevention and treatment mechanisms of depression, and conducted a correlation analysis of antidepressant efficacy, Yin-nourishing and heat-clearing efficacy, and biological mechanism in different genders, thereby comprehensively assessing the antidepressant effects of RRR on depression of Yin deficiency and internal heat, as well as its gender differences and mechanisms. RRR exhibited antidepressant effects in both male and female mouse models, and its antidepressant efficacy showed gender differences, with a superior effect observed in females. Moreover, the effects of RRR on enhancing or improving hippocampal neuronal pathology, nucleus-positive areas, postsynaptic dense area protein 95, and synaptophysin protein expression were more significant in females than in males. In addition, RRR significantly reversed the abnormal upregulation of nuclear factor(NF)-κB/cyclooxygenase 2(COX2)/NOD-like receptor thermal protein domain associated protein 3(NLRP3) pathway proteins in the hippocampus of both male and female mouse models. The antidepressant effects of RRR were more pronounced in depression female mice with Yin deficiency and internal heat syndrome, possibly due to the improvement of neuronal damage and enhancement of neuroplasticity. The antidepressant mechanisms of RRR for depression with Yin deficiency and internal heat syndrome may be associated with the downregulation of the NF-κB/COX2/NLRP3 pathway to reduce neuronal damage and enhance neuroplasticity.

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.

[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.

Flotation de-inking for recycling paper: contrasting the effects of three mineral oil-free offset printing inks on its efficiency.

Paper for recycling has become a promising raw material for the pulp and paper industry due to its low cost and because it is conducive to sustainable development. Unfortunately, recycled paper contains a high volume of printed paper that is difficult to deink, which restricts its applications. Flotation deinking plays an essential role in the product quality and process cost of wastepaper recycling. This study was performed to evaluate the deinkability of environmentally friendly offset inks by flotation deinking. For this purpose, three mineral oil free series of four-color inks, namely, hybrid light emitting diode ultraviolet (LED-UV), LED-UV, and vegetable oil-based inks, were printed on white lightweight coated papers under laboratory conditions. The deinking methodology involves repulping, deinking agent treatment, flotation, hand sheet making, and evaluation of the produced hand sheets. The obtained results indicated that the hybrid LED-UV prints had the best deinkability. After flotation deinking, the deinking efficiency and the whiteness of the hybrid LED-UV ink increased by 58.1% and 47.6%, respectively. LED-UV ink had a 46.9% increase in the deinking efficiency and a 37.0% increase in the whiteness of the hand sheet. The deinking efficiency of the vegetable oil-based ink was the lowest, at 42.1%, and the whiteness of the hand sheet increased only by 23.8%. The particle size distribution analysis demonstrated that the hybrid LED-UV four-color ink exhibited a larger value of the average particle size than the two other. Scanning electron microscopy revealed that the hybrid LED-UV ink particles on the surface of the fibers were the least abundant after deinking. The physical strength properties of the hand sheets, including tensile index, folding resistance, and interlayer bonding strength of the hybrid LED-UV, LED-UV inks, and vegetable oil-based inks, increased.

[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 mechanism of catalpol: Involvement of the PI3K/Akt/Nrf2/HO-1 signaling pathway in rat hippocampus.

Catalpol is a major compound in Rehmanniae Radix with outstanding medicinal and nutritional values. Our previous studies have demonstrated catalpol's antidepressant effect, but its mechanisms remain unclear. This study aimed to explore the antidepressant mechanisms of catalpol via the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt)/nuclear factor E2-related factor 2(Nrf2)/heme oxygenase-1 (HO-1) pathway. Results demonstrated that chronic unpredictable mild stress (CUMS) for 5 consecutive weeks caused significant decreases in the sucrose preference and the horizontal and vertical scores of open-field test, as well as a significant increase in the swimming-immobility time of rats; catalpol administration significantly reversed the abnormality of these indicators. Further real-time fluorescent quantitative polymerase chain reaction and Western blotting results together showed that CUMS significantly downregulated the expression levels of hippocampal genes and proteins, including PI3K, Akt, Nrf2, HO-1, tropomyosin-related kinase B (TrkB), and brain-derived neurotrophic factor; catalpol administration significantly reversed the abnormal expression of these genes and proteins. CUMS also caused a significant decrease in the hippocampal superoxide dismutase, catalase, glutathione peroxidase, glutathione-s transferase, and reduced glutathione levels, as well as a significant increase in thiobarbituric acid reactive substances level in rats; catalpol administration significantly reversed the abnormality of these indicators. Taken together, this study confirmed for the first time that the antidepressant effect of catalpol on CUMS-induced depression involved the upregulation of the PI3K/Akt/Nrf2/HO-1 signaling pathway, thereby improving the hippocampal neurotrophic, neuroprotective, and antioxidant levels. The PI3K/Akt/Nrf2/HO-1 pathway-related molecules may serve as potential new biomarkers and candidate molecular targets for catalpol's antidepressant effects.

Catalpol Weakens Depressive-like Behavior in Mice with Streptozotocin-induced Hyperglycemia via PI3K/AKT/Nrf2/HO-1 Signaling Pathway.

Depression has huge social risks of high incidence, disability, and suicide. Its prevalence and harm in people with hyperglycemia are 2-3 times higher than in normal people. However, antidepressants with precise curative effects and clear mechanisms for patients with hyperglycemia are currently lacking. Prescriptions containing Radix Rehmannia glutinosa Libosch., a traditional medicinal herb with a wide range of nutritional and medicinal values, are often used as antidepressants in Chinese clinical medicine. Catalpol is one of the main effective compounds of Radix R. glutinosa, with multiple biological activities such as hypoglycemia. Here, the antidepressant effect of catalpol on the pathological state of streptozotocin (STZ)-induced hyperglycemia and the underlying molecular mechanisms were analyzed. Results showed that administering catalpol orally to hyperglycemic mice for 21 consecutive days significantly reversed the abnormalities in tail suspension, forced swimming, and open field tests. Catalpol also reversed the abnormal phosphorylation of phosphoinositide 3-kinase (PI3K) and protein kinase B (AKT) and the abnormal levels of nuclear factor erythroid 2-related factor 2 (Nrf2) protein, heme oxygenase-1 (HO-1), and antioxidants, including superoxide dismutase, glutathione peroxidase, glutathione-s transferase, reduced glutathione, and malondialdehyde in the hippocampus and frontal cortex of STZ-induced hyperglycemic mice. Thus, catalpol attenuates depressive-like behavior in pathological hyperglycemic state, and the antidepressant mechanism could at least be partly attributed to the upregulation of the PI3K/AKT/Nrf2/HO-1 signaling pathway in both brain regions, thus restoring the balance between oxidative and antioxidant damage. These data expanded the scientific understanding of catalpol and provided preclinical experimental evidence for its application.

[Processing technology for reducing toxicity of fried Tripterygium wilfordii in Lysimachia christinae decoction].

On the basis of the previous work of the research group, the orthogonal design method was further used to optimize the processing technology for reducing toxicity of fried Tripterygium wilfordii in Lysimachia christinae Decoction. A total of 9 processed products of T.wilfordii in L.christinae decoction were prepared by four factors and three levels orthogonal design table. The contents of triptolide in T.wilfordii were determined by high performance liquid chromatography(HPLC) before and after processing: 4.27, 3.92, 3.57, 2.75, 2.42, 2.66, 3.51, 1.87, 1.75, 2.03 µg·g~(-1). On this basis, the above processed products were orally given to mice for 28 days. 12 hours after the last administration, food fasting except water was provided, and 24 hours later, the eyeballs were taken for blood and liver tissue. Serum biochemical indexes, liver lipid peroxidation and antioxidant related indexes were detected by kit method. Twenty-eight days after oral administration of raw T.wilfordii, the levels of serum alanine aminotransferase(AST), alanine aminotransferase(ALT), alkaline phosphatase(ALP) and liver malondialdehyde(MDA) in mice increased by 91%(P<0.01), 46%(P<0.05), 73%(P<0.01) and 99%(P<0.01), while the liver antioxidant indexes such as superoxide dismutase(SOD), glutathione(GSH), glutathione peroxidase(GPX) and glutathione-S transferase(GST) significantly decreased(P<0.01). After administration of the processed products, the above indexes were significantly reversed(P<0.01 or P<0.05). Especially, the processing conditions of A_3B_2C_1D_3 had the best detoxification effect on T.wilfordii, which decreased the high levels of AST, ALT, ALP and MDA by 49%(P<0.01), 32%(P<0.01), 42%(P<0.01), and 17%(P<0.05). Therefore, the best processing conditions for T.wilfordii in L.christinae decoction were A_3B_2C_1D_3, namely "15% mass fraction of L.christinae, 1 h moistening time, 160 ℃ frying temperature, and 9 min frying time".

The Effect of Dietary Vitamin K1 Supplementation on Trabecular Meshwork and Retina in a Chronic Ocular Hypertensive Rat Model.

Purpose: The pathophysiologic relationship between vitamin K and glaucoma remains largely unknown. The aim of the study was to explore the effect of dietary vitamin K supplementation in a rat glaucoma model. Methods: Rats were randomly divided into two groups: standard diet and high vitamin K1 (VitK1) diet (300 mg VitK1/kg diet). Induction of chronic ocular hypertension by episcleral vein cauterization was performed on the right eye. The left eye with sham operation served as controls. Rats received standard or high VitK1 diets for 5 weeks after surgery until the end of experiment. Immunohistochemistry analyses of the retina and trabecular meshwork were performed. The change in coagulation function and IOP were evaluated. Results: We observed a significant declined IOP at 2 weeks after surgery in the high VitK1 group compared with the control group. High VitK1 showed no significant effect on the body weight, rat phenotypes, or coagulation function. High VitK1 significantly inhibited the loss of retinal ganglion cells in the retina and increased the expression of matrix gla protein. High VitK1 also ameliorated the collapsed trabecular meshwork structure and increased collagen staining in the trabecular meshwork. Conclusions: High VitK1 intake inhibited the loss of retinal ganglion cells during glaucomatous injury, probably by increasing the expression of matrix gla protein. A transient decrease in the IOP was observed in the high VitK1 group, implying a potential effect of VitK1 on aqueous outflow. Retinal ganglion cells protection by high VitK1 supplementation may be due to the IOP-lowering effects as well as neuroprotective effect. Further research is required to delineate these processes.

Nrf2 participates in mechanisms for reducing the toxicity and enhancing the antitumour effect of Radix Tripterygium wilfordii to S180-bearing mice by herbal-processing technology.

Context: Radix Tripterygium wilfordii Hook. f. (Celastraceae) (LGT) has outstanding curative efficacy; however, side effects include high toxicity, particularly hepatotoxicity and nephrotoxicity. Objective: To investigate detoxification mechanisms of LGT through processing separately with each of these medicinal herbs including Flower Lonicera japonica Thunb. (Caprifoliaceae) (JYH), Radix Paeonia lactiflora Pall. (Ranunculaceae) (BS), Herba Lysimachia christinae Hance (Primulaceae) (JQC), Radix et Rhizoma Glycyrrhiza uralensis Fisch. (Fabaceae) (GC) and Seed Phaseolus radiatus L. (Fabaceae) (LD) in S180-bearing mice by involving nuclear factor (erythroid-derived 2)-like 2 (Nrf2). Materials and methods: LGT raw and processed products were orally administered at 60 mg/kg to KM male mice inoculated with S180 tumour cells for 14 consecutive days, and blood, tumour, liver and kidney were taken to observe the detoxifying effects and biological mechanisms. Results: Herbal-processing technology significantly weakened hepatotoxicity and nephrotoxicity evoked by LGT with ED50 of the converted triptolide in each processed-herb product for serum alanine transaminase, aspartate transaminase, creatinine and urea nitrogen of 9.3, 16.6, 2.5 and 4.2 µg/kg, for liver glutathione, glutathione S-transferase, catalase, tumour necrosis factor-α and interleukin-10 of 114.9, 67.8, 134.1, 7.7, 4171.6 µg/kg, and for kidney 21.9, 20.5, 145.0, 529.7, 19.4 µg/kg, respectively. Moreover, herbal-processing technology promoted the accumulation of Nrf2 into the nucleus, and upregulated mRNA expression of Nrf2 and heme oxygenase-1. Additionally, herbal-processing technology enhanced the tumour inhibition rate with ED50 12.2 µg/kg. Discussion and conclusions: Herbal-processing technology improves the safety and effectiveness of LGT in cancer treatment, and future research may be focused on the Nrf2-related molecules.

Pharmacokinetics and Tissue Distribution of Gingerols and Shogaols from Ginger (Zingiber officinale Rosc.) in Rats by UPLC⁻Q-Exactive⁻HRMS.

Gingerols and shogaols are recognized as active ingredients in ginger and exhibit diverse pharmacological activities. The preclinical pharmacokinetics and tissue distribution investigations of gingerols and shogaols in rats remain less explored, especially for the simultaneous analysis of multi-components. In this study, a rapid, sensitive, selective, and reliable method using an Ultra-Performance Liquid Chromatography Q-Exactive High-Resolution Mass Spectrometer (UPLC-Q-Exactive⁻HRMS) was established and validated for simultaneous determination of eight compounds, including 6-gingerol, 6-shogaol, 8-gingerol, 8-shogaol, 10-gingerol, 10-shogaol, Zingerone, and 6-isodehydrogingenone in plasma and tissues of rats. The analytes were separated on a Syncronis C18 column (100 × 2.1 mm, 1.7 µm) using a gradient elution of acetonitrile and 0.1% formic acid in water at a flow rate of 0.25 mL/min at 30 °C. The method was linear for each ingredient over the investigated range with all correlation coefficients greater than 0.9910. The lowest Lower Limit of quantitation (LLOQ) was 1.0 ng/mL. The intra- and inter-day precisions (Relative Standard Deviation, RSD%) were less than 12.2% and the accuracy (relative error, RE%) ranged from -8.7% to 8.7%. Extraction recovery was 91.4⁻107.4% and the matrix effect was 86.3⁻113.4%. The validated method was successfully applied to investigate the pharmacokinetics and tissue distribution of eight components after oral administration of ginger extract to rats. These results provide useful information about the pharmacokinetics and biodistribution of the multi-component bioactive ingredients of ginger in rats and will contribute to clinical practice and the evaluation of the safety of a Chinese herbal medicine.

Leigongteng (Radix et Rhizoma Tripterygii) via compatibility with Jinqiancao (Herba Lysimachiae): its toxicity-reduced efficacy in H22-bearing mice.

OBJECTIVE: To observe toxicity-reduced effects of Leigongteng (Radix et Rhizoma Tripterygii) (LGT) via compatibility with Jinqiancao (Herba Lysimachiae) (JQC) in H22-bearing mice and investigate the possible underlying mechanism, and further explore whether JQC can enhance LGT-evoked anti-tumor effect. METHODS: H22-bearing mice were orally administered with LGT alone and its compatibility with JQC, and tumors, serum, livers and kidneys were collected to evaluate the toxicity-reduced efficacy and the possible mechanism. RESULTS: LGT evoked significantly elevated biochemical indicators including serum alanine / aspartate transaminase (ALT/AST), creatinine (Cr) and urea nitrogen (BUN) as well as pathological damage in mice, which were all obviously reversed by JQC via compatibility at the ratios from 4/1 to 1/4. Further analysis indicated that pro-inflammatory cytokine tumor necrosis factor-alpha (TNF-α), and malondialdehyde (MDA) levels significantly decreased, while anti-inflammatory cytokine interleukin (IL)-10, and glutathione (GSH), GSH-s transferase (GST), GSH peroxidase (GSH-Px), superoxide dismutase (SOD) and catalase (CAT) levels all increased in livers and kidneys of mice. Besides, after compatibility with JQC at the ratios of 4/1, 2/1, 1/1, 1/2 and 1/4, LGT-decreased tumor weight was further decreased by 48.4%, 57.3%, 54.0%, 49.3% and 52.9%, respectively (all P < 0.01). CONCLUSION: JQC could reduce LGT-induced hepatotoxicity and nephrotoxicity, and enhance the antitumor efficacy via compatibility with JQC, and the toxicity-reduced mechanism could involve inhibiting hepatic and kidney oxidative stress and inflammation.

Detoxication mechanisms of Radix Tripterygium wilfordii via compatibility with Herba Lysimachia christinae in S180-bearing mice by involving Nrf2.

The combined administration between Radix Tripterygium wilfordii Hook F (LGT) and Herba Lysimachia christinae Hance (JQC) belongs to mutual detoxication compatibility of seven emotions in traditional Chinese medicine (TCM) theory. However, until now, the compatibility detoxication mechanisms remain unknown. The present study was undertaken to observe detoxication mechanisms of LGT through compatibility with JQC in tumor-bearing mice by involving NF-E2-related factor 2 (Nrf2)-mediated antioxidant defenses. In addition, influence of compatibility on antitumor activity was also investigated here. Our results demonstrated that compatibility with JQC administration significantly reversed LGT-elevated serum alanine/aspartate transaminase (ALT/AST) levels and alleviated hepatocytes' swelling or degeneration damage, and at the ratio 2/1 (LGT/JQC) produced the strongest detoxication effect. Besides, compatibility with JQC administration reversed not only LGT-elevated hepatic malondialdehyde (MDA) and tumor necrosis factor-α (TNF-α) but also the LGT lowered GSH, glutathione-s transferase (GST), glutathione peroxidase (GPx), superoxide dismutase (SOD), catalase (CAT), and interleukin (IL)-10 levels. Furthermore, compatibility with JQC administration significantly up-regulated protein expression of Nrf2 and mRNA expression of it regulated downstream antioxidant genes such as heme oxygenase-1 (HO-1), NAD(P)H: quinone oxidoreductase-1 (NQO1), and glutamate cysteine ligase catalytic subunit (GCLC). In addition, compatibility with JQC further decreased LGT-decreased tumor weight and at the ratio 2/1 (LGT/JQC) also exerted the strongest synergistic effect. Collectively, through compatibility with JQC exerted detoxication effect on LGT-induced hepatotoxicity and the mechanisms could be at least partly attributed to up-regulation of Nrf2 and its downstream signals, thereby enhancing antioxidant defenses, and inhibiting lipid peroxidation, oxidative stress, and inflammation. Additionally, at the ratio 2/1 (LGT/JQC) exerted the strongest effects on both detoxication and synergism.

Structure-Activity Relationship of Xanthones as Inhibitors of Xanthine Oxidase.

Polygala plants contain a large number of xanthones with good physiological activities. In our previous work, 18 xanthones were isolated from Polygala crotalarioides. Extented study of the chemical composition of the other species Polygala sibirica led to the separation of two new xanthones-3-hydroxy-1,2,6,7,8-pentamethoxy xanthone (A) and 6-O-ß-d-glucopyranosyl-1,7-dimethoxy xanthone (C)-together with 14 known xanthones. Among them, some xanthones have a certain xanthine oxidase (XO) inhibitory activity. Furthemore, 14 xanthones as XO inhibitors were selected to develop three-dimensional quantitative structure-activity relationship (3D-QSAR) using comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) models. The CoMFA model predicted a q² value of 0.613 and an r² value of 0.997. The best CoMSIA model predicted a q² value of 0.608 and an r² value of 0.997 based on a combination of steric, electrostatic, and hydrophobic effects. The analysis of the contour maps from each model provided insight into the structural requirements for the development of more active XO inhibitors.

Ethanol extract of Rehmannia glutinosa exerts antidepressant-like effects on a rat chronic unpredictable mild stress model by involving monoamines and BDNF.

The dried roots of Rehmannia glutinosa Libosch. (Scrophulariaceae) are of both medicinal and nutritional importance. Our previous study has found that the 80% ethanol extract of R. glutinosa (RGEE) produced antidepressant-like activities in mouse behavioral despair depression models. However, its mechanisms are still unclear. The present study aimed to observe the antidepressant-like mechanisms of RGEE on a rat chronic unpredictable mild stress (CUMS) model by involving monoaminergic neurotransmitters and brain-derived neurotrophic factor (BDNF). CUMS-stressed rats were orally given RGEE daily (150, 300, and 600 mg/kg) or fluoxetine hydrochloride (FH) for 3 weeks after starting the CUMS procedure. Sucrose preference test was carried out to observe depression-like behavior, and serum and brain tissues were used for neurochemical and fluorescent quantitative reverse transcription PCR analysis. Results demonstrated that CUMS induced depression-like behavior, whereas RGEE and FH administration inhibited this symptom. Furthermore, CUMS caused excessively elevated levels of serum corticosterone (CORT), an index of hypothalamic-pituitary-adrenal (HPA) axis hyperactivity, in a manner attenuated by RGEE and FH administration. RGEE administration also further elevated monoamine neurotransmitters and BDNF levels, up-regulated the mRNA expression of BDNF and tropomyosin-related kinase B (TrkB) in hippocampus of rats suffering CUMS. Together, our findings suggest that RGEE can improve CUMS-evoked depression-like behavior, and indicate its mechanisms may partially be associated with restoring HPA axis dysfunctions, enhancing monoamineergic nervous systems, and up-regulating BDNF and TrkB expression.

Optimization and validation of the protocol used to analyze the taste of traditional Chinese medicines using an electronic tongue.

Tools to define the active ingredients and flavors of Traditional Chinese Medicines (TCMs) are limited by long analysis times, complex sample preparation and a lack of multiplexed analysis. The aim of the present study was to optimize and validate an electronic tongue (E-tongue) methodology to analyze the bitterness of TCMs. To test the protocol, 35 different TCM concoctions were measured using an E-tongue, and seven replicate measurements of each sample were taken to evaluate reproducibility and precision. E-tongue sensor information was identified and classified using analysis approaches including least squares support vector machine (LS-SVM), support vector machine (SVM), discriminant analysis (DA) and partial least squares (PLS). A benefit of this analytical protocol was that the analysis of a single sample took <15 min for all seven sensors. The results identified that the LS-SVM approach provided the best bitterness classification accuracy (binary classification accuracy, 100%; ternary classification accuracy, 89.66%). The E-tongue protocol developed showed good reproducibility and high precision within a 6 h measurement cycle. To the best of our knowledge, this is the first study of an E-tongue being applied to assay the bitterness of TCMs. This approach could be applied in the classification of the taste of TCMs, and serve important roles in other fields, including foods and beverages.

Analysis of bacterial diversity in two oil blocks from two low-permeability reservoirs with high salinities.

The community diversities of two oil reservoirs with low permeability of 1.81 × 10(-3) and 2.29 × 10(-3) µm(2) in Changqing, China, were investigated using a high throughput sequencing technique to analyze the influence of biostimulation with a nutrient activator on the bacterial communities. These two blocks differed significantly in salinity (average 17,500 vs 40,900 mg/L). A core simulation test was used to evaluate the effectiveness of indigenous microbial-enhanced oil recovery (MEOR). The results indicated that in the two high salinity oil reservoirs, one reservoir having relatively lower salinity level and a narrow salinity range had higher bacterial and phylogenetic diversity. The addition of the nutrient activator increased the diversity of the bacterial community structure and the diversity differences between the two blocks. The results of the core simulation test showed that the bacterial community in the reservoir with a salinity level of 17,500 mg/L did not show significant higher MEOR efficiency compared with the reservoir with 40,900 mg/L i.e. MEOR efficiency of 8.12% vs 6.56% (test p = 0.291 > 0.05). Therefore, salinity levels affected the bacterial diversities in the two low permeability oil blocks remarkably. But the influence of salinity for the MEOR recovery was slightly.

Protective effects of geniposide against Tripterygium glycosides (TG)-induced liver injury and its mechanisms.

Tripterygium glycosides (TG) are commonly used for basic medicine in curing rheumatoid arthritis but with a high incidence of liver injury. Geniposide (GP) has broad and diverse bioactivities, but until now it is still unknown whether GP can protect against TG-induced liver injury. This study, for the first time, observed the possible protection of GP against TG-induced liver injury in mice and its mechanisms underlying. Oral administration of TG (270 mg/kg) induced significant elevation in the levels of serum alanine / aspartate transaminase (ALT/AST), hepatic malondialdehyde (MDA) and pro-inflammatory cytokine tumor necrosis factor-alpha (TNF-α) (all P < 0.01). On the other hand, remarkably decreased biomarkers, including hepatic glutathione (GSH) level, activities of glutathione transferase (GST), glutathione peroxidase (GPx), superoxide dismutase (SOD) and catalase (CAT), and anti-inflammatory cytokine interleukin (IL)-10, were observed following TG exposure (all P < 0.01). Nevertheless, all of these phenotypes were evidently reversed by pre-administration of GP for 7 continuous days. Further analysis showed that the mRNA expression of hepatic growth factor-beta1 (TGF-ß1), one of tissue repair and regeneration cytokines, was enhanced by GP. Taken together, the current research suggests that GP protects against TG-induced liver injury in mice probably involved during attenuating oxidative stress and inflammation, and promoting tissue repair and regeneration.