Huaiqihuang (HQH) granule alleviates cyclophosphamide-induced nephrotoxicity via suppressing the MAPK/NF-κB pathway and NLRP3 inflammasome activation.

CONTEXT: Severe nephrotoxicity greatly limits the clinical use of the common effective chemotherapeutic agent cyclophosphamide (CYP). Huaiqihuang (HQH) is a Chinese herbal complex with various pharmacological activities, widely used for treating kidney disease. OBJECTIVE: This study estimates the protective effect of HQH against CYP-induced nephrotoxicity in rats. MATERIALS AND METHODS: Four groups of 10 Sprague-Dawley rats were pre-treated with once-daily oral gavage of 3 and 6 mg/kg HQH for 5 days before receiving a single dose of CYP (200 mg/kg i.p.) on the 5th day; the control group received equivalent dose of saline. Renal function indices, morphological changes, oxidative stress, apoptosis and inflammatory mediators were measured. In addition, phosphorylation of the NF-κB/MAPK pathway and the activation of the NLRP3 inflammasome were analysed. RESULTS: Both doses of HQH reduced the levels of serum creatinine (31.27%, 43.61%), urea nitrogen (22.66%, 32.27%) and urine protein (12.87%, 15.98%) in the CYP-treated rats, and improved histopathological aberrations. Additionally, HQH decreased the production of MDA (37.02%, 46.18%) and increased the activities of antioxidant enzyme CAT (59.18%, 112.25%) and SOD (67.10%, 308.34%) after CYP treatment. HQH protected against CYP-induced nephrotoxicity by modulating apoptosis-related protein and suppressing the inflammatory responses. Furthermore, the phosphorylation of the NF-κB/MAPK pathway and the activation of the NLRP3 inflammasome were significantly boosted in CYP-treated rats, which was also abrogated by HQH treatment. CONCLUSIONS: HQH effectively protected against CYP-induced nephrotoxicity, which was associated with regulating oxidative stress, apoptosis and inflammation, and so HQH may be a useful agent for treating nephrotoxicity caused by CYP.

A Potential Combination Therapy of Berberine Hydrochloride With Antibiotics Against Multidrug-Resistant Acinetobacter baumannii.

Multidrug-resistant (MDR) Acinetobacter baumannii strains can cause severe infections in intensive care units, and are rapidly developing resistance to the last-resort of existing antibiotics, posing a major global threat to health care system. Berberine hydrochloride (BBH), a kind of isoquinoline alkaloids extracted from Berberis and other plants, has been widely used as an antibacterial medicine for its reliable therapeutic efficiency. The in vitro synergistic effects of BBH with antibiotics against MDR A. baumannii were determined. BBH alone had weak antimicrobial activity (e.g., MIC≥256 mg/L) against MDR A. baumannii. However, it dramatically increased the susceptibility of MDR strains against antibiotics with FICI values <0.5, even reversed their resistance to antibiotics (e.g., tigecycline, sulbactam, meropenem and ciprofloxacin). In vivo study has suggested BBH with sulbactam had stronger antimicrobial efficiency than monotherapy in a neutropenic murine thigh infection model. The antibiotic-sensitizing mechanism of action of BBH was evaluated as well. BBH boosted adeB gene expression and bound to the AdeB transporter protein, resulting in low uptake of BBH, which may contribute to less extrusion of antibiotics by the AdeABC pump. Knockout of the adeB gene increased uptake of BBH and diminished the antibiotic sensitization and synergistic effects between antibiotics and BBH in MDR strains. Together, BBH effectively re-sensitizes this MDR pathogen to a range of antibiotics that have become barely effective due to antibiotic resistance, which indicates BBH may be a promising therapeutic adjuvant candidate to combat MDR A. baumannii.

Altered metabolic profiles and biomarkers associated with astragaloside IV-mediated protection against cisplatin-induced acute kidney injury in rats: An HPLC-TOF/MS-based untargeted metabolomics study.

Cisplatin (CDDP)-induced acute kidney injury (AKI) limits the therapeutic use of CDDP, which urgently needs to be addressed. Our previous study demonstrated that astragaloside IV (AS IV), an active compound of the traditional Chinese herb Astragalus membranaceus, alleviated CDDP-induced AKI. To explore the mechanism, we performed a metabolomics study to explore the altered metabolic pathways and screen for sensitive biomarkers. Twenty-four rats were randomly divided into three groups, which were treated with vehicle solutions (Control), intraperitoneally injected CDDP, and intraperitoneally injected CDDP plus oral AS IV, respectively. Metabolic profiles of serum, urine, and kidney samples were analyzed by high-performance liquid chromatography-time of flight mass spectrometry. There were 38 key metabolites in the urine samples, 20 in the serum samples, and 16 in the kidney samples that were significantly altered due to AS IV-mediated protection against CDDP-induced AKI relative to CDDP-only treatment. CDDP + AS IV co-treatment significantly altered two pathways in the blood (biosynthesis of unsaturated fatty acids and alanine, aspartate, and glutamate metabolism), five pathways in the urine (phenylalanine metabolism; phenylalanine, tyrosine, and tryptophan biosynthesis; arginine biosynthesis; arginine and proline metabolism; and histidine metabolism), and five pathways in the kidneys (glutathione metabolism; alanine, aspartate, and glutamate metabolism; glyoxylate and dicarboxylate metabolism; arginine and proline metabolism; and D-glutamine and D-glutamate metabolism). The metabolic pathways were mainly associated with improvements in inflammatory responses, oxidative stress, and energy metabolism. Adrenic acid in serum and L-histidine and L-methionine in urine were identified as sensitive biomarkers. This study provides new insights to understand the mechanism of AS IV-mediated protection against CDDP-induced AKI and has identified three candidate biomarkers to evaluate preventative treatment and assess therapeutic effectiveness.

Water/pH dual responsive in situ calcium supplement collaborates simvastatin for osteoblast promotion mediated osteoporosis therapy via oral medication.

Calcium supplement is the most commonly adopted treatment for osteoporosis but usually requires high dose and frequency. The modality of calcium supplement is therefore overlooked by current nanomedicine-based osteoporosis therapies without proper oral formulations. Herein, we proposed a tetracycline (Tc) modified and monostearin (MS) coated amorphous calcium carbonate (ACC) platform (TMA) as oral bone targeted and osteoporosis microenvironment (water/pH) responsive carrier for in situ calcium supplement. Moreover, current osteoporosis therapies also fall short of finding suitable molecular target and effective therapeutic regimen to further increase the therapeutic efficacy over available treatment means. As a result, the simvastatin (Sim) was loaded into TMA to construct drug delivery system (TMA/Sim) capable of synergistically activating the bone morphogenetic proteins (BMPs)-Smad pathway to provide a novel therapeutic regimen for osteoblast promotion mediated osteoporosis therapy. Our results revealed that optimized TMA showed high accessibility and oral availability with targeted drug delivery to bone tissue. Most importantly, benefit from the effective in situ calcium supplement and targeted Sim delivery, this therapeutic regime (TMA/Sim) achieved better synergetic effects than conventional combination strategies with promising osteoporosis reversion performance under low calcium dosage (1/10 of commercial calcium carbonate tablet) and significantly attenuated side effects.

Calcium Supplement by Tetracycline guided amorphous Calcium Carbonate potentiates Osteoblast promotion for Synergetic Osteoporosis Therapy.

Background: The calcium supplement is a clinically approved approach for osteoporosis therapy but usually requires a large dosage without targetability and with poor outcome. This modality is not fully explored in current osteoporosis therapy due to the lack of proper calcium supplement carrier. Methods: In this study, we constructed a tetracycline (Tc) modified and simvastatin (Sim) loaded phospholipid-amorphous calcium carbonate (ACC) hybrid nanoparticle (Tc/ACC/Sim). Results: The resulted Tc/ACC/Sim was able to enhance its accumulation at the osteoporosis site. Most importantly, the combination of calcium supplement and Sim offered synergetic osteoblast promotion therapy of osteoporosis with advanced performance than non-targeted system or mono therapy. Conclusion: This platform provides an alternative approach to stimulate bone formation by synergetic promotion of osteoblast differentiation using calcium supplement and Sim.

2-Deoxy-Rh2: A novel ginsenoside derivative, as dual-targeting anti-cancer agent via regulating apoptosis and glycolysis.

20(S)-Rh2 is a ginsenoside isolated from Panax ginseng, which exhibits anti-cancer activities on various human cancer cells. A novel 20(S)-Rh2 derivative, 2-Deoxy-Rh2 was synthesized and hybridized with protopanaxadiol and 2-deoxy-glucose in an attempt to enhance the anticancer activity. Through screening the antitumor effect against various cell lines by MTT assay, 2-Deoxy-Rh2 especially resulted in a concentration-dependent and time-dependent inhibition of viability in MCF-7 human breast cancer cells. Multiple methods were used to explore the cellular and molecular mechanisms of 2-Deoxy-Rh2 as a potent anti-cancer agent. In MCF-7 cells, 2-Deoxy-Rh2 triggered apoptosis, stimulated ROS production and disrupted normal mitochondrial membrane potential. Meantime, 2-Deoxy-Rh2 eff ;ectively suppressed the glucose uptake capabilities and intracellular ATP production. The cellular oxygen consumption rate (OCR) and extracellular acidification rate (ECAR) were significantly decreased in response to 2-Deoxy-Rh2, which were carried out to assess the overall glycolytic flux and mitochondrial respiration. Docking studies and molecular dynamics simulations were performed to verify the binding mode of 2-DG and 2-Deoxy-Rh2 with hexokinase II, with results showing that 2-Deoxy-Rh2 could easily fit into the similar active site of 2-DG, finally binding to hexokinase II to suppress glycolysis. Taken together, the results suggest that 2-Deoxy-Rh2 exhibited remarkable anticancer activity based on regulating mitochondrial apoptosis pathway, dampening glycolysis and inhibiting mitochondrial respiration, which support development of 2-Deoxy-Rh2 as a potential agent for cancer therapy.

Calycosin ameliorates doxorubicin-induced cardiotoxicity by suppressing oxidative stress and inflammation via the sirtuin 1-NOD-like receptor protein 3 pathway.

The limitation of doxorubicin (DOX), which is widely used for the treatment of solid tumors and hematologic malignancies, is a vital problem in clinical application. The most serious of limit factors is cardiotoxicity. Calycosin (CA), an isoflavonoid that is the major active component in Radix astragali, has been reported in many bioactivities including antitumor, anti-inflammatory, and cardioprotection. The aim of the study was to investigate the effects and mechanisms of CA on DOX-induced cardiotoxicity in vitro and in vivo. CA increased H9c2 cell viability and reduced apoptosis induced by DOX via Bcl-2, Bax, and the PI3K-Akt signaling pathway. Moreover, CA prevented DOX-induced oxidative stress in cells by decreasing the generation of reactive oxygen species. Similarly, oxidative stress was inhibited by CA through the increased activities of antioxidant enzymes such as glutathione peroxidase, catalase, and superoxide dismutase and decreased the levels of aspartate aminotransferase, lactate dehydrogenase, and malondialdehyde in vivo. Furthermore, the levels of sirtuin 1 (Sirt1)-NOD-like receptor protein 3 (NLRP3) and related proteins were ameliorated by CA in cells and in mice hearts. When H9c2 cells were treated by Ex527 (Sirt1 inhibitor), the effect of CA on expressions of NLRP3 and thioredoxin-interacting protein was suppressed. In conclusion, the results suggested that CA might be a cotreatment with DOX to ameliorate cardiotoxicity by Sirt1-NLRP3 pathway.

XingNaoJing injection ameliorates cerebral ischaemia/reperfusion injury via SIRT1-mediated inflammatory response inhibition.

Context: XingNaoJing injection (XNJ), extracted from a traditional compound Chinese medicine Angong niuhuang pill, is well known for treating stroke in the clinic, but the specific effects and mechanisms remain unclear.Objective: We investigated the mechanistic basis for the protective effect of XNJ on cerebral ischaemia/reperfusion (I/R) injury.Materials and methods: Five groups of 10 SD rats underwent 2 h of middle cerebral artery occlusion (MCAO) followed by 24 h reperfusion. XNJ at 10 and 15 mL/kg was intraperitoneally administered 24 h before ischaemia and at the onset of reperfusion respectively. The silent information regulator 1 (SIRT1) inhibitor EX527 was intracerebroventricularly injected 0.5 h before reperfusion. Cerebral infarction size, neurological scores, morphological changes, and expression levels of inflammatory mediators and SIRT1 were measured. Furthermore, human brain microvascular endothelial cells (HBMECs) were subjected to 3 h oxygen and glucose deprivation (OGD) followed by 24 h reoxygenation to mimic cerebral I/R in vitro. EX527 pre-treatment occurred 1 h before OGD. SIRT1 and inflammatory mediator levels were analyzed.Results: Both XNJ doses significantly decreased cerebral infarct area (40.11% vs. 19.66% and 9.87%) and improved neurological scores and morphological changes. Inflammatory mediator levels were remarkably decreased in both model systems after XNJ treatment. XNJ also enhanced SIRT1 expression. Notably, the SIRT1 inhibitor EX527 attenuated the XNJ-mediated decrease in inflammation in vivo and in vitro.Conclusions: XNJ improved cerebral I/R injury through inhibiting the inflammatory response via the SIRT1 pathway, which may be a useful target in treating cerebral I/R injury.

XingNaoJing injections protect against cerebral ischemia/reperfusion injury and alleviate blood-brain barrier disruption in rats, through an underlying mechanism of NLRP3 inflammasomes suppression.

The aim of this study was to explore the neuroprotective effect and mechanism of XingNaoJing injections (XNJ) on cerebral ischemia injury and blood-brain barrier (BBB) disruption. Middle cerebral artery occlusion (MCAO) method was applicated to establish the model of cerebral ischemia/reperfusion (I/R) injury in rats. BBB permeability after I/R injury was assessed with the leaking amount of Evans Blue and the expression of occludin and ZO-1. The expression of NOD-like receptor family, pyrin domain containing (NLRP3) was checked to explore the inhibition of inflammation by XNJ. The results showed that XNJ could significantly increase the survival percent, decrease the infarct area and ameliorate neurological deficits and brain damage after I/R injury. Leaking amount of Evans Blue was reduced by XNJ, and the expression of tight junction protein, occludin and ZO-1 was also up-regulated by XNJ, which showed a role of protection on BBB disruption. The expression of NLRP3 was inhibited after exposure of XNJ, which was associated with inhibition of the inflammatory response. In summary, XNJ could suppress NLRP3 inflammasomes and improve BBB disruption and brain damage in rats after cerebral I/R injury, which provided a beneficial insight to further explore XNJ.

Salvianolic Acid B Attenuates Apoptosis of HUVEC Cells Treated with High Glucose or High Fat via Sirt1 Activation.

High glucose and high fat are important inducements for the development and progression of diabetic cardiopathy. Salvianolic acid B (SAB), which is the most abundant and bioactive compound in Danshen, attenuates oxidative stress-related disorders, such as cardiovascular diseases, cerebral ischemia, and diabetes. However, the effect of SAB on diabetic cardiopathy is not clear. The aim of study was to investigate the effect and the underlying molecular mechanisms of SAB on diabetic cardiopathy in vitro model. The human umbilical vein endothelial (HUVEC) cells were treated with high glucose (HG, 30 mM) or high fat (palmitic acid, PA, 0.75 mM) in the presence or absence of SAB (100, 200, and 400 mg/L) and incubated for 24 h. We found that HG or PA induced apoptosis of HUVEC cells, while treatment with SAB inhibited the apoptosis. We also found that SAB reversed HG- or PA-induced oxidative stress, apoptosis cell cytokines production, and expression of thioredoxin-interacting protein (TXNIP). Moreover, SAB increased HG- or PA-induced expression of Sirtuin 1 (Sirt1), a nicotinamide adenine dinucleotide- (NAD+-) dependent histone deacetylase. Exposure of HUVEC cells to Ex527 (Sirt1 inhibitor) suppressed the effect of SAB on acetyl-p53 and procaspase-3 expressions. In conclusion, the results suggested that SAB could attenuate HUVEC cells damage treated with HG or PA via Sirt1 and might be a potential therapy agent for the diabetic cardiopathy treatment.

Prophylactic Therapy of Silymarin (Milk Thistle) on Antituberculosis Drug-Induced Liver Injury: A Meta-Analysis of Randomized Controlled Trials.

Background: Prophylactic therapy with silymarin to prevent the development of antituberculosis drug-induced liver injury (anti-TB DILI) has been under debate. We aimed to evaluate the effect of silymarin in the prevention of anti-TB DILI. Methods: We searched MEDLINE, PubMed, Embase, and Cochrane Central Register of Controlled Trials (CENTRAL) up to 30th November 2018. Randomized controlled trials (RCTs) that compared silymarin and placebo to prevent anti-TB DILI were included. All statistical analyses were conducted using STATA 12.0 software. Standardized mean difference (SMD) and risk ratio (RR) with 95% confidence intervals (CIs) were used to evaluate the effect of silymarin. The quality of included studies was assessed according to Cochrane handbook. Funnel plots and Egger's tests were carried out to evaluate publication bias. Sensitivity analysis was conducted to assess the influence of each study. Results: A total of 1198 patients from five RCTs (585 with silymarin and 613 with placebo groups) were included. Overall, silymarin significantly reduced the occurrence of anti-TB DILI at week 4 [RR: 0.33, 95% CI (0.15, 0.75)]. In addition, silymarin exerted protective effect on liver function in patients undergoing anti-TB drugs [SMD = - 0.15, 95% CI (-0.24, -0.07), P < 0.001 (ALT); SMD =-0.14, 95% CI (-0.23, -0.06), P = 0.001(AST); SMD =-0.12, 95% CI (-0.20, -0.03), P = 0.008 (ALP)]. Silymarin led to similar AEs in placebo groups [OR: 1.09, 95% CI (0.86, 1.39), P = 0.47]. Conclusion: Prophylactic therapy of silymarin is contributed to a noticeably reduced risk of development of anti-TB DILI four weeks after the initiation. In addition, silymarin significantly improved the liver function in patients who are receiving anti-TB drugs.

Ginkgolide A Prevents the Amyloid-ß-Induced Depolarization of Cortical Neurons.

Utilizing the N-methyl-d-aspartate (NMDA) receptor antagonist as a strategy, memantine is the only agent available for clinically treating mild to severe Alzheimer's disease (AD). Our aim was to develop novel similar herb-based drugs. Using a screening platform, ginkgolide A (GA), a pure compound extracted from Ginkgo biloba, was found to attenuate amyloid ß (Aß)-induced abnormal depolarization in mouse primary cortical neurons. Using receptor agonists, it was determined that GA inhibits both NMDA receptors and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors. Furthermore, the Aß-induced increase in c-Jun N-terminal kinase phosphorylation in neurons was prevented by GA. Body weight, glutamate oxaloacetate transaminase, glutamic-pyruvic transaminase, liver histology, and kidney histology were similar when the wild-type/AD animal model mice with and without GA treatment were compared. This pure compound improves the memory of wild-type mice. Our findings indicate that GA has great potential clinically for the treatment of AD because it might target NMDA receptors just like memantine.

Dioscorea bulbifera L. delays the excretion of doxorubicin and aggravates doxorubicin-induced cardiotoxicity and nephrotoxicity by inhibiting the expression of P-glycoprotein in mice liver and kidney.

We aimed to investigate the drug-drug interaction (DDI) between doxorubicin (DOX) and Dioscorea bulbifera L. (DB) solution in mice, and to explore the effect of P-glycoprotein (P-gp) on this type of DDI. The toxicity of DOX in the liver, kidneys, and heart was assessed with alanine aminotransferase (ALT), aspartate aminotransferase (AST), creatinine (Cr), urea nitrogen (BUN), creatine kinase MB (CK-MB), creatine kinase (CK) and histopathology. High-performance liquid chromatography tandem mass spectrometry (HPLC-MS/MS) was used to determine the concentrations of DOX in the serum, liver, kidneys and heart. Immunohistochemistry and western blots were used to determine the expression levels of P-gp in these tissues. Our results demonstrated that, after co-administration of DOX and DB, survival was significantly decreased compared with either administration of DOX or DB alone, or water. Co-administration of DOX and DB induced elevated levels of toxicity in the heart and kidneys, but not the liver, compared with DOX alone. We conclude that concurrent treatment with DOX and DB results in increased levels of toxicity due to the accumulation of DOX in the body. Delayed excretion of DOX is associated with inhibition of P-gp in liver and kidneys.

Xingnaojing Injection Protects against Cerebral Ischemia Reperfusion Injury via PI3K/Akt-Mediated eNOS Phosphorylation.

Xingnaojing (XNJ) injection, derived from traditional Chinese medicine formulation, has a protective effect against stroke, but the underlying mechanism is unclear, which severely limited its clinical application. This research aims to elucidate the role and mechanism of XNJ in reducing cerebral ischemic reperfusion (I/R) injury. Rats received 2 h cerebral ischemia followed by reperfusion of 24 h and were intraperitoneally given 5, 10, or 15 ml/kg XNJ 24 h before ischemia and at the onset of reperfusion, respectively. TTC staining, HE staining, and neurological score were implied to evaluate the effectiveness of XNJ. The protein expressions of PI3K/Akt and eNOS signaling were measured. Experiments were further performed in human brain microvascular endothelial cells (HBMECs) to investigate the protective mechanisms of XNJ. HBMECs were subjected to 3 h oxygen and glucose deprivation following 24 h of reoxygenation (OGD) to mimic cerebral I/R in vitro. PI3K inhibitor LY294002 was added with or without the preconditioning of XNJ. Multiple methods including western blot, immunofluorescence, DAPI staining, JC-1, and flow cytometry were carried out to evaluate the effect of XNJ on HBMECs. XNJ could improve rat cerebral ischemic injury and OGD induced HBMECs apoptosis. In vivo and in vitro researches indicated that the mechanism might be relevant to the activation of PI3K/Akt/eNOS signaling.

The role of Ntcp, Oatp2, Bsep and Mrp2 in liver injury induced by Dioscorea bulbifera L. and Diosbulbin B in mice.

Dioscorea bulbifera L. (DB) is a traditional Chinese herb used in thyroid disease and cancer. However, the clinical use of DB remains a challenge due to its hepatotoxicity, which is caused, in part, by the presence of Diosbulbin B (DIOB), a toxin commonly found in DB extracts. As abnormal expression of hepatobiliary transporters plays an important role in drug-induced liver injury, we assessed the hepatotoxicity induced by DB and DIOB, and explored their impacts on hepatobiliary transporter expression levels. Following liquid chromatography-tandem mass analysis of the DIOB content of DB extract, male ICR mice were randomly orally administered DB or DIOB for 14days. Liver injury was assessed by histopathological and biochemical analysis of liver fuction. The levels of transporter protein and mRNA were determined by western blotting and real-time PCR. Liver function and histopathological analysis indicated that both DB and DIOB could induce liver injury in mice, and that DIOB might be the primary toxic compound in DB. Moreover, down-regulation of Mrp2 blocked the excretion of bilirubin, glutathione disulfide, and bile acids, leading to the accumulation of toxic substrates in the liver and a redox imbalance. We identified down-regulated expression of Mrp2 as potential factors linked to increased serum bilirubin levels and decreased levels of glutathione in the liver and increased liver injury severity. In summary, our study indicates that down-regulation of Mrp2 represents the primary mechanism of DB- and DIOB-induced hepatotoxicity, and provides insight into novel therapies that could be used to prevent DB- and DIOB-mediated liver injury.

An Improved Drugs Screening System Reveals that Baicalein Ameliorates the Aß/AMPA/NMDA-Induced Depolarization of Neurons.

The presence of amyloid-ß (Aß) plaque and tau protein hyperphosphorylation in brain tissue is the pathological hallmark of Alzheimer's disease (AD). At least some Aß neurotoxicity is caused by the presence of excess glutamate that has been induced by Aß accumulation. Memantine is currently the only NMDA receptor inhibitor approved for treating moderate-to-severe AD patients. We utilized primary cortical neurons and DiBAC4(3), a slow-response voltage sensitive fluorescence dye, to create a novel system for screening herbal medicines that allows the identification of pure compounds able to ameliorate Aß-induced abnormal depolarization. The intensity of DiBAC4(3) fluorescence was increased when primary neurons were stimulated by Aß; furthermore, pre-treatment with memantine abolished this change. Using this system, we identified six crude extracts made from herbal medicines that effectively alleviated this Aß-induced abnormal depolarization. Among these herbal medicines, one pure compound, baicalein, which was known to be present in Scutellaria baricalensis and is known to improve memory using an AD mouse model, was identified by our assay. However, the compound's molecular mechanism remained unknown. We found that baicalein, in addition to inhibiting Aß-induced depolarization, possibly functions as an antagonist of AMPA and NMDA receptors. Taken together, we have established a system/platform to identify herbal medicines that ameliorate Aß-induced depolarization of neurons. Equally important, baicalein is a candidate drug with great potential for the treatment of AD patients.

Monoammonium glycyrrhizinate protects rifampicin- and isoniazid-induced hepatotoxicity via regulating the expression of transporter Mrp2, Ntcp, and Oatp1a4 in liver.

CONTEXT: Drug-induced liver injury (DILI) is associated with altering expression of hepatobiliary membrane transporters. Monoammonium glycyrrhizin (MAG) is commonly used for hepatic protection and may have a correlation with the inhibition effect of multidrug resistance-associated protein 2 (Mrp2). OBJECTIVE: This study evaluates the dynamic protective effect of MAG on rifampicin (RIF)- and isoniazid (INH)-induced hepatotoxicity in rats. MATERIALS AND METHODS: Male Wistar rats were randomly divided into four groups of 15 rats. Liver injury was induced by co-treatment with RIF (60 mg/kg) and INH (60 mg/kg) by gavage administration; MAG was orally pretreated at the doses of 45 or 90 mg/kg 3 h before RIF and INH. Rats in each group were sacrificed at 7, 14, and 21 d time points after drug administration. RESULTS: Liver function, histopathological analysis, and oxidative stress factors were significantly altered in each group. The expression of Mrp2 was significantly increased 230, 760, and 990% at 7, 14, and 21 time points, respectively, in RIF- and INH-treated rats. Compared with the RIF and INH groups, Mrp2 was reduced and Ntcp was significantly elevated by 180, 140, and 160% in the MAG high-dose group at the three time points, respectively. The immunoreaction intensity of Oatp1a4 was increased 170, 190, and 370% in the MAG low-dose group and 160, 290, and 420% in the MAG high-dose group at the three time points, respectively, compared with the RIF and INH groups. DISCUSSION AND CONCLUSION: These results indicated that MAG has a protective effects against RIF- and INH-induced hepatotoxicity. The underlying mechanism may have correlation with its effect on regulating the expression of hepatobiliary membrane transporters.

A selective and sensitive method based on UPLC-MS/MS for quantification of momordin Ic in rat plasma: application to a pharmacokinetic study.

A selective and sensitive method was developed and validated based on ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS). This method was applied to quantify momordin Ic in rat plasma. Chromatographic separation was performed on a Hypersil GOLD HPLC C18 column (150mm×4.6mm, 5µm) using an isocratic mobile phase of acetonitrile/water (80:20, v/v) at a flow rate of 0.6mL/min. An electrospray ionization source was applied and operated in negative ion mode; selected reaction monitoring (SRM) mode was used for quantification by monitoring the precursor-to-product ion transitions of m/z 763.4→m/z 455.3 for momordin Ic, and m/z 649.4→m/z 487.3 for IS. Calibration curves showed good linearity over the range of 22.0-2200ng/mL for momordin Ic in rat plasma. The developed method was applied to a pharmacokinetic study of momordin Ic in rats after single intravenous doses at 0.52, 1.56, and 4.67mg/kg. The elimination half-life (t1/2) values were 1.22±0.39, 1.14±0.10, and 1.83±0.39h, respectively. The plasma concentration at 2min (C2min) and area under the curve (AUC) for the intravenous doses of momordin Ic were approximately dose proportional.