Radial magnetic resonance image reconstruction with a deep unrolled projected fast iterative soft-thresholding network.

Radially sampling of magnetic resonance imaging (MRI) is an effective way to accelerate the imaging. How to preserve the image details in reconstruction is always challenging. In this work, a deep unrolled neural network is designed to emulate the iterative sparse image reconstruction process of a projected fast soft-threshold algorithm (pFISTA). The proposed method, an unrolled pFISTA network for Deep Radial MRI (pFISTA-DR), include the preprocessing module to refine coil sensitivity maps and initial reconstructed image, the learnable convolution filters to extract image feature maps, and adaptive threshold to robustly remove image artifacts. Experimental results show that, among the compared methods, pFISTA-DR provides the best reconstruction and achieved the highest PSNR, the highest SSIM and the lowest reconstruction errors.

Evaluation of the diagnostic utility on 1.5T and 3.0T 1H magnetic resonance spectroscopy for temporal lobe epilepsy.

BACKGROUND: 1H magnetic resonance spectroscopy (1H-MRS) can be used to study neurological disorders because it can be utilized to examine the concentrations of related metabolites. However, the diagnostic utility of different field strengths for temporal lobe epilepsy (TLE) remains unclear. The purpose of this study is to make quantitative comparisons of metabolites of TLE at 1.5T and 3.0T and evaluate their efficacy. METHODS: Our retrospective collections included the single-voxel 1H-MRS of 23 TLE patients and 17 healthy control volunteers (HCs) with a 1.5T scanner, as well as 29 TLE patients and 17 HCs with a 3.0T scanner. Particularly, HCs were involved both the scans with 1.5T and 3.0T scanners, respectively. The metabolites, including the N-acetylaspartate (NAA), creatine (Cr), and choline (Cho), were measured in the left or right temporal pole of brain. To analyze the ratio of brain metabolites, including NAA/Cr, NAA/Cho, NAA/(Cho + Cr) and Cho/Cr, four controlled experiments were designed to evaluate the diagnostic utility of TLE on 1.5T and 3.0T MRS, included: (1) 1.5T TLE group vs. 1.5T HCs by the Mann-Whitney U Test, (2) 3.0T TLE group vs. 3.0T HCs by the Mann-Whitney U Test, (3) the power analysis for the 1.5T and 3.0T scanner, and (4) 3.0T HCs vs. 1.5T HCs by Paired T-Test. RESULTS: Three metabolite ratios (NAA/Cr, NAA/Cho, and NAA/(Cho + Cr) showed the same statistical difference (p < 0.05) in distinguishing the TLE from HCs in the bilateral temporal poles when using 1.5T or 3.0T scanners. Similarly, the power analysis demonstrated that four metabolite ratios (NAA/Cr, NAA/Cho, NAA/(Cho + Cr), Cho/Cr) had similar distinction abilities between 1.5T and 3.0T scanner, denoting both 1.5T and 3.0T scanners were provided with similar sensitivities and reproducibilities for metabolites detection. Moreover, the metabolite ratios of the same healthy volunteers were not statistically different between 1.5T and 3.0T scanners, except for NAA/Cho (p < 0.05). CONCLUSIONS: 1.5T and 3.0T scanners may have comparable diagnostic potential when 1H-MRS was used to diagnose patients with TLE.

Comparative study of bilateral putamen for patients with severe Parkinson's disease detected by 1H magnetic resonance spectroscopy.

Background: The diagnosis of Parkinson's disease (PD) is challenging because the clinical symptoms overlap with other neurodegenerative diseases. The discovery of reliable biomarkers is highly expected to facilitate clinical diagnosis. Through the analysis of the 1H magnetic resonance spectroscopy (1H-MRS) in the putamen, the purpose of the study was to discuss the possibility of the difference in metabolite concentrations between the left and right putamen as biomarkers for patients with severe PD. Methods: We collected 1H-MRS of unilateral or bilateral putamen from 41 patients and used the independent sample t-test and paired t-test to analyze 4 metabolite concentrations, including choline (Cho), total N-acetyl aspartate (tNAA), total creatine (tCr), and combined glutamate and glutamine; Bonferroni correction was used to correct P values for multiple comparisons. We designed 4 controlled experiments as follows: (I) PD patients versus healthy controls (HCs) in the left putamen; (II) PD patients versus HCs in the right putamen; (III) the left putamen versus the right putamen for PD patients; and (IV) the left putamen versus the right putamen for HCs. Results: No statistically significant differences (P>0.05) were detected among 4 metabolites in the ipsilateral and bilateral putamen for the PD and HCs groups, except for tCr in the left putamen (PD 6.426±0.557, HCs 6.026±0.460, P=0.046) for ipsilateral comparisons. Conclusions: In the bilateral putamen of severe PD patients, there was no statistically significant difference in the 4 metabolites. The difference (P<0.05) in tCr in the left putamen might be a potential biomarker to distinguish HCs from severe patients in clinic. This might provide a reference for the clinical diagnosis and acquisition strategy of 1H-MRS in severe PD.

Transarterial chemoembolization with or without multikinase inhibitors for patients with unresectable hepatocellular carcinoma: a systematic review and meta-analysis of randomized controlled trials.

Background: Randomized controlled trials (RCTs) testing the combination therapy of transarterial chemoembolization (TACE) plus multikinase inhibitor (MKI) in patients with unresectable hepatocellular carcinoma (HCC) have yielded inconsistent results. Methods: In this work, a systematic review and meta-analysis was performed to compare the TACE+MKI combination therapy versus TACE monotherapy in HCC patients with time to progression (TTP) adopted as primary outcome. Results: A total of 10 RCTs comprising 2837 patients receiving combination therapy (TACE plus sorafenib, brivanib, orantinib or apatinib) were included. TACE+MKI significantly prolonged TTP (hazard ratio [HR] 0.74, 95% CI 0.62-0.89, p=0.001) versus TACE monotherapy. Subgroup analysis suggested MKI administration before TACE might be preferable to post-TACE MKI for TTP. TACE+MKI also increased objective response rate (ORR) (risk ratio [RR] 1.17, 95% CI 1.03-1.32, p=0.01), but failed to improve overall survival (OS) (HR 0.98, 95% CI 0.86-1.13, p=0.82) and progression-free survival (PFS) (HR 0.75, 95% CI 0.50-1.12, p=0.16). The incidence of any adverse event (AE) did not significantly differ between TACE+MKI and TACE groups (RR 1.17, 95% CI 0.96-1.42, p=0.01), while serious AEs showed significant difference (RR 1.41, 95% CI 1.26-1.59, p<0.0001). Nevertheless, these AEs showing significant difference were mainly associated with MKI toxicities rather than TACE. Conclusions: TACE+MKI combination therapy improved TTP and ORR but not OS and PFS in patients with unresectable HCC. Further high-quality trials are needed to verify these clinical benefits, and our findings could be very informative for future trial design.

A convergence analysis for projected fast iterative soft-thresholding algorithm under radial sampling MRI.

Radial sampling is a fast magnetic resonance imaging technique. Further imaging acceleration can be achieved with undersampling but how to reconstruct a clear image with fast algorithm is still challenging. Previous work has shown the advantage of removing undersampling image artifacts using the tight-frame sparse reconstruction model. This model was further solved with a projected fast iterative soft-thresholding algorithm (pFISTA). However, the convergence of this algorithm under radial sampling has not been clearly set up. In this work, the authors derived a theoretical convergence condition for this algorithm. This condition was approximated by estimating the maximal eigenvalue of reconstruction operators through the power iteration. Based on the condition, an optimal step size was further suggested to allow the fastest convergence. Verifications were made on the prospective in vivo data of static brain imaging and dynamic contrast-enhanced liver imaging, demonstrating that the recommended parameter allowed fast convergence in radial MRI.

Core Constituents of Caragana sinica Root for Rheumatoid Arthritis Treatment and the Potential Mechanism.

PURPOSE: As a traditional herb product, the root of Caragana sinica (Buc'hoz) Rehder (Chinese name: Jin Quegen [JQG]) has been widely used in folk medicines for rheumatoid arthritis (RA) treatment. However, which herbal constituents exert a core pharmacological role in RA treatment remains a great challenge due to the multiple phytochemical constituents, targets, and pathways. In this work, we aimed to use a new strategy to explore the core herbal constituents and potential mechanisms of JQG against RA for the first time. METHODS: A successively partitioned extract of JQG, bioactive partition screening in vitro and in vivo, qualitative analysis, bioinformatic analysis, molecular docking, and mechanism validation were used in this study. The partitioned extract was used to obtain the bioactive partition, while in vitro anti-inflammatory effects and in vivo anti-arthritis effects in adjuvant-induced arthritis (AIA) rats were applied to screen the bioactive partition with the best efficacy. Qualitative analysis was used to identify bioactive constituents. Bioinformatic analysis was used to explore the potential mechanism for RA treatment. Molecular docking and immunofluorescence were used to validate the underlying mechanism. RESULTS: After successively partitioning extract and bioactive partition screening, ethyl acetate extract (EAE) yielded the best anti-inflammatory effects in vitro and in vivo among JQG extracts. By ultra-performance liquid chromatography (UPLC) coupled with Orbitrap mass spectrometry, a total of 58 constituents were identified in EAE, and 17 constituents were regarded as the core constituents based on their oral bioavailability and drug-like properties. The nuclear factor kappa B (NF-κB) signal pathway was screened as the core pathway of core constituents for RA treatment based on bioinformatic analysis, and the core constituents showed good ligand-receptor binding activity to NF-κB P65. In vitro study demonstrated that EAE could significantly reduce NF-κB P65 transfer from the cytoplasm to the nucleus. CONCLUSION: Our study suggested that the therapeutic efficacy of JQG for RA treatment could be derived from negative regulation of the NF-κB pathway, and EAE of JQG could represent a promising herb product for RA treatment that deserves further development.

Current development and prospects of deep learning in spine image analysis: a literature review.

Background and Objective: As the spine is pivotal in the support and protection of human bodies, much attention is given to the understanding of spinal diseases. Quick, accurate, and automatic analysis of a spine image greatly enhances the efficiency with which spine conditions can be diagnosed. Deep learning (DL) is a representative artificial intelligence technology that has made encouraging progress in the last 6 years. However, it is still difficult for clinicians and technicians to fully understand this rapidly evolving field due to the diversity of applications, network structures, and evaluation criteria. This study aimed to provide clinicians and technicians with a comprehensive understanding of the development and prospects of DL spine image analysis by reviewing published literature. Methods: A systematic literature search was conducted in the PubMed and Web of Science databases using the keywords "deep learning" and "spine". Date ranges used to conduct the search were from 1 January, 2015 to 20 March, 2021. A total of 79 English articles were reviewed. Key Content and Findings: The DL technology has been applied extensively to the segmentation, detection, diagnosis, and quantitative evaluation of spine images. It uses static or dynamic image information, as well as local or non-local information. The high accuracy of analysis is comparable to that achieved manually by doctors. However, further exploration is needed in terms of data sharing, functional information, and network interpretability. Conclusions: The DL technique is a powerful method for spine image analysis. We believe that, with the joint efforts of researchers and clinicians, intelligent, interpretable, and reliable DL spine analysis methods will be widely applied in clinical practice in the future.

Methodology improvement for network pharmacology to correct the deviation of deduced medicinal constituents and mechanism: Xian-Ling-Gu-Bao as an example.

ETHNOPHARMACOLOGICAL RELEVANCE: Network pharmacology is extremely adaptive for investigating traditional ethnic drugs, especially the herbal medicines. However, challenges still hang over many related studies due to the limitations in the methodology of conventional network pharmacology. AIM OF THE STUDY: Our work was aimed to investigate the methodology limitations of conventional network pharmacology with Xian-Ling-Gu-Bao (XLGB) as a representative, meanwhile, propose the strategies for coping with these issues. MATERIALS AND METHODS: Predicted phytochemical constituents formed virtual XLGB. The constituents in realistic XLGB samples was detected by liquid chromatography-mass spectrometry (LC-MS) to correct the constituent deviation resulted from virtual prediction. Multivariate statistical analysis of quantitative target data were used to reveal the relation of target profile between drug and disease. The key constituents and targets were screened and compared between virtual and realistic XLGB through network analysis. After enrichment analysis, reversing network pharmacology was performed to exclude weak targets and re-construct the interaction from key pathways to key targets. Finally, the core constituents and action mechanism of XLGB were deduced. RESULTS: Significant deviation of phytochemical constituents was found between virtual and realistic XLGB. As expected, this deviation led to a cascade of deviation ranging from deduced key constituents to key targets and key pathways. Moreover, many key KEGG pathways were enriched and screened out, however, they were almost irrelevant to the studied disease. These results systemically illustrated the limitations in the methodology of conventional network pharmacology. Importantly, the strategies for coping with these limitations were proposed, such as high-throughput detection of the realistic samples, multivariate analysis of target profile and combined enrichment analysis. Finally, based on the improved network pharmacology, the medicinal constituents and mechanism of XLGB against osteoarthritis were effectively deduced. CONCLUSIONS: Our work highlighted the necessity and proposed the strategies for improving the methodology of conventional network pharmacology. The corrected results from improved network pharmacology provided promising directions for future research on XLGB.

Novel treatment for refractory rheumatoid arthritis with total glucosides of paeony and nobiletin codelivered in a self-nanoemulsifying drug delivery system.

Patients with refractory rheumatoid arthritis (RA) remain a substantial clinical problem, while the overexpression of P-glycoprotein (P-gp) on their lymphocytes may contribute to resistance to anti-rheumatic drugs. This study aims to develop a novel treatment for refractory RA consisting of the combination of total glucosides of paeony (TGPs) and the P-gp inhibitor nobiletin (N), which are codelivered in a self-nanoemulsifying drug delivery system (SNEDDS). Based on the solubility, compatibility, and pseudoternary phase diagram tests, a nano-SNEDDS formulation composed of capryol 90-cremophor EL35-tcranscutol HP (CET) to codeliver TGP and N was developed, and this formulation increased the bioavailability of TGP by 435.04% (indicated with paeoniflorin). A modified adjuvant-induced arthritis (AIA) rat model was verified for the overexpression of P-gp in lymphocytes and resistance to methotrexate (MTX) treatment at the reported anti-inflammatory dosage. CET formulation not only increased the solubility and permeability of TGP but also inhibited the function and expression of P-gp, leading to enhanced bioavailability and intracellular concentration in the lymphocytes of AIA rats and consequently boosting the anti-arthritic effects of TGP. Moreover, TGP and N coloaded CET reduced the expression of P-gp in AIA rats partly by inhibiting the phosphorylated AKT and HIF-1α pathways. In summary, TGP-N coloaded SNEDDS is a novel and effective treatment for refractory RA.

XCloud-pFISTA: A Medical Intelligence Cloud for Accelerated MRI.

Machine learning and artificial intelligence have shown remarkable performance in accelerated magnetic resonance imaging (MRI). Cloud computing technologies have great advantages in building an easily accessible platform to deploy advanced algorithms. In this work, we develop an open-access, easy-to-use and high-performance medical intelligence cloud computing platform (XCloud-pFISTA) to reconstruct MRI images from undersampled k-space data. Two state-of-the-art approaches of the Projected Fast Iterative Soft-Thresholding Algorithm (pFISTA) family have been successfully implemented on the cloud. This work can be considered as a good example of cloud-based medical image reconstruction and may benefit the future development of integrated reconstruction and online diagnosis system.

A New Strategy to Investigate the Efficacy Markers Underlying the Medicinal Potentials of Orthosiphon stamineus Benth.

Orthosiphon stamineus Benth. (OSB) is a well-known herbal medicine exerting various pharmacological effects and medicinal potentials. Owing to its complex of phytochemical constituents, as well as the ambiguous relationship between phytochemical constituents and varied bioactivities, it is a great challenge to explore which constituents make a core contribution to the efficacy of OSB, making it difficult to determine the efficacy makers underlying the varied efficacies of OSB. In our work, a new strategy was exploited and applied for investigating efficacy markers of OSB consisting of phytochemical analysis, in vivo absorption analysis, bioactive compound screening, and bioactive compound quantification. Using liquid chromatography coupled with mass spectrometry, a total of 34 phytochemical components were detected in the OSB extract. Subsequently, based on in vivo absorption analysis, 14 phytochemical constituents in the form of prototypes were retained as potential bioactive compounds. Ten diseases were selected as the potential indications of OSB based on previous reports, and then the overall interaction between compounds, action targets, action pathways, and diseases was revealed based on bioinformatic analysis. After refining key pathways and targets, the interaction reversing from pathways, targets to constituents was deduced, and the core constituents, including tanshinone IIA, sinensetin, salvianolic acid B, rosmarinic acid, and salvigenin, were screened out as the efficacy markers of OSB. Finally, the contents of these five constituents were quantified in three different batches of OSB extracts. Among them, the content of salvianolic acid B was the highest while the content of tanshinone IIA was the lowest. Our work could provide a promising direction for future research on the quality control and pharmacological mechanism of OSB.

Efficacy and safety of Kanglaite injection combined with chemotherapy for women breast cancer: A protocol for systematic review and meta-analysis of randomized clinical trials.

BACKGROUND: Breast cancer was the second cause of cancer death and approximately accounted for 30% of all newly diagnosed cancer in American women. Adjuvant chemotherapy is the preferred treatment approach for breast patients. Kanglaite injection (KI) was commonly used as adjuvant chemotherapy combined with chemotherapy for women breast cancer which could increase chemotherapy efficacy and alleviate chemotherapy drugs induced adverse events, however, the efficacy and safety for KI combined western medicine remains controversial. Thus, we conducted this protocol of systematic review and meta-analysis to estimate the efficacy and safety of KI combined with western medicine for women breast cancer. METHODS: This study will search electronic database included English medicals databases and Chinese databased up to May 2021. The main outcomes of this study include clinical efficacy rate. Adverse reaction rate, Karnofsky Performance Status and immune function were defined as the secondary outcomes. RESULTS: This protocol study will comprehensively evaluate the efficacy and safety of KI combined with chemotherapy for women breast cancer. CONCLUSION: This protocol for systematic review and meta-analysis will evaluate the efficacy and safety of KI combined with chemotherapy for women breast cancer, aiming to provide optimal therapy for women breast cancer patients.

Efficacy and Safety of Topical Therapy With Botanical Products for Melasma: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.

Botanical products have been increasingly popular in topical therapies for melasma, as presumed safer and milder than fully synthetic products. Although the efficacy of different topical botanicals has recently been substantiated through randomized controlled trials (RCTs), there is a lack of sufficiently pooled evidence on their efficacy and safety for the treatment of melasma. Herein, a systematic review and meta-analysis was conducted on the efficacy and safety of topical botanical products for the treatment of melasma, following Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). All RCTs on the use of topical botanical products for the treatment of melasma in humans were included, except for trials enrolling pregnant patients. The primary outcome was Melasma Area and Severity Index (MASI) or its variation. The secondary outcomes included Mexameter® reading, melasma improvement evaluated by participants, and any reported adverse events (AEs). As a result, twelve eligible trials comprising 695 patients with melasma from 6 different countries were included. The topical botanical products contained active ingredients which varied among trials as follows: herb-derived molecule, extracts of a single herb, and extracts of compound herbs. Topical therapy with botanical products significantly improved melasma with a large effect on MASI reduction (SMD -0.79, 95% CI -1.14 to -0.44, p < 0.00001), and a moderate effect on Mexameter® reading reduction (SMD -0.52, 95% CI -0.81 to 0.23, p = 0.0005), when compared with placebo. It also showed a similar improvement of melasma with a better safety profile (RR 0.37, 95% CI 0.15-0.88, p = 0.02), when compared with active-comparators. Botanical products were well-tolerated across studies, with no serious AEs reported. Despite the limitations such as small sample size, short duration of follow up and varied botanical products, this work still represents the best level of evidence currently available on topical use of botanical products on melasma. Moreover, it should be noted that more well-designed studies are needed before recommending topical botanical products as a viable treatment option for melasma. SYSTEMATIC REVIEW REGISTRATION: PROSPERO, identifier: CRD42021256328.

Watt-level diode-pumped continuous-wave Pr:LiYF4 laser at 670 nm and simultaneous dual-wavelength operation at 639 and 670 nm.

We report on blue-diode-pumped continuous-wave Pr:LiYF4 (YLF) visible lasers involving a less investigated 670 nm laser emission. In the free-running regime, a simultaneous dual-wavelength operation at 670 and 639 nm is achieved with a maximum output power of 1.67 W and a slope efficiency of 20.4%. Using a Y3Al5O12 (YAG) plate as an intracavity etalon, we have suppressed the 639 nm emission, and then a single-wavelength laser at 670 nm has been achieved with a maximum output power of 0.96 W and slope efficiency of 12.7%. The directly generated 670 nm laser source from Pr:YLF crystal with watt-level output power has advantages over diode laser or frequency-doubled Nd:YVO4 lasers operating at a similar laser wavelength, which could be used in biomedical technologies.

Nobiletin and its derivatives overcome multidrug resistance (MDR) in cancer: total synthesis and discovery of potent MDR reversal agents.

Our recent studies demonstrated that the natural product nobiletin (NOB) served as a promising multidrug resistance (MDR) reversal agent and improved the effectiveness of cancer chemotherapy in vitro. However, low aqueous solubility and difficulty in total synthesis limited its application as a therapeutic agent. To tackle these challenges, NOB was synthesized in a high yield by a concise route of six steps and fourteen derivatives were synthesized with remarkable solubility and efficacy. All the compounds showed improved sensitivity to paclitaxel (PTX) in P-glycoprotein (P-gp) overexpressing MDR cancer cells. Among them, compound 29d exhibited water solubility 280-fold higher than NOB. A drug-resistance A549/T xenograft model showed that 29d, at a dose of 50 mg/kg co-administered with PTX (15 mg/kg), inhibited tumor growth more effective than NOB and remarkably increased PTX concentration in the tumors via P-gp inhibition. Moreover, Western blot experiments revealed that 29d inhibited expression of NRF2, phosphorylated ERK and AKT in MDR cancer cells, thus implying 29d of multiple mechanisms to reverse MDR in lung cancer.

Nobiletin potentiates paclitaxel anticancer efficacy in A549/T xenograft model: Pharmacokinetic and pharmacological study.

BACKGROUND: Nobiletin (N), a polymethoxylated flavone from citrus fruits, enhanced anti-cancer effects of paclitaxel (PTX) in multi-drug resistance (MDR) cancer cells via inhibiting P-glycoprotein (P-gp) in our previous report. But the in vivo chemo-sensitizing effect of nobiletin is unknown. Moreover, considering the nonlinear pharmacokinetics and narrow therapeutic window of PTX, drug-drug interaction should be explored for using nobiletin with PTX together. PURPOSE: In this study, we wanted to explore whether nobiletin could affect the pharmacokinetic (PK) behavior of PTX and reverse drug resistance in vivo as well as the corresponding mechanisms. STUDY DESIGN AND METHODS: Accurate and sensitive UPLC-MS/MS method was developed for the detection of PTX, and was applied to the pharmacokinetic study in rats. In vivo anti-MDR tumor study was carried out with A549/T xenograft nude mice model. Immunohistochemistry and western blot analysis were used for evaluating the levels of P-gp, Nrf2, and AKT/ERK pathways in MDR tumors. RESULTS: Nobiletin significantly enhanced the therapeutic effects of PTX, and inhibited the MDR tumor sizes in the A549/T xenograft model, while PTX or nobiletin alone did not. We found that nobiletin increased the PTX concentrations in tumor tissues but did not affect the PK behavior of PTX. Notably, Nrf2 and phosphorylation of AKT/ERK expression in MDR tumor tissues were significantly inhibited by giving nobiletin and PTX together. However, nobiletin did not affect the expression of P-gp. CONCLUSION: Nobiletin reversed PTX resistance in MDR tumor via increasing the PTX content in the MDR tumor and inhibiting AKT/ERK/Nrf2 pathways, but without affecting the systematic exposure of PTX, indicating that nobiletin may be an effective and safe MDR tumor reversal agent.

Piperine enhances the bioavailability of silybin via inhibition of efflux transporters BCRP and MRP2.

BACKGROUND: Although silybin serves as a well-known hepatoprotective agent with prominent anti-inflammatory, anti-oxidant and anti-fibrotic activities, its low bioavailability limits its application in the treatment of chronic liver diseases. However, novel formulation products with increased solubility were not sufficient to achieve pharmacologically meaningful concentrations of silybin in the clinical studies even used at high dosage. HYPOTHESIS/PURPOSE: We hypothesized that inhibiting efflux transporter(s) and/or glucuronidation by piperine might enhance the bioavailability and efficacy of silybin. METHODS: Pharmacokinetics of silybin given alone or in-combination with piperine was determined by a validated LC-MS method. A CCl4 induced rat model of liver injury was prepared and verified for comparing the effects of silybin and combination treatment. To investigate the underlying mechanism, the inhibition effects of piperine on transportation of silybin were performed in Caco-2 and transfected MDCKII cell lines as well as sandwich-cultured rat hepatocytes (SCH). Human liver microsomes incubation was used for exploring the modulation effects of piperine on the phase-2 metabolism of silybin. RESULTS: In the present study, we demonstrated for the first time that piperine as a bioenhancer increased the bioavailability of silybin (146%- 181%), contributing to a boosted therapeutic effect in CCl4-induced acute liver-injury rat model. The underlying mechanisms involved that piperine enhanced the absorption of silybin by inhibiting the efflux transporters including MRP2 and BCRP but not MDR1 in Caco-2 and transfected MDCKII cell lines. Moreover, piperine could inhibit the biliary excretion of silybin and conjugated metabolites in sandwich-cultured rat hepatocytes. Notably, we found that piperine did not affect the phase-2 metabolism of silybin. CONCLUSION: Efflux transporters play an important role in the pharmacokinetic behavior of flavolignans, and modulating these transporters by bioenhancer such as piperine could enhance the in vivo absorption of silybin, leading to more effective treatments.

Multiple effects of magnesium isoglycyrrhizinate on the disposition of docetaxel in docetaxel-induced liver injury.

1. Magnesium isoglycyrrhizinate (MgIg) has been extensively used in treating liver injury which is the common adverse reaction of docetaxel (DOC). Due to the narrow therapeutic window, small changes in pharmacokinetic profiles can alter the toxicity and therapeutic efficacy of DOC significantly. The study aimed to explore the effects of MgIg on the disposition of DOC and the potential mechanism in DOC-induced liver injury. 2. Pharmacokinetics and tissues distribution behaviors showed that there was no significant difference between DOC group (DOCG) and MgIg + DOC group (MDOCG). The mRNA and protein levels of cytochrome P450 3A1 (CYP3A1) in liver, intestine, and kidney were significantly upregulated, and the P-glycoprotein (P-gp) was obviously downregulated in MDOCG when compared with DOCG. 3. Immunoglobulin M (IgM), CD8+ were upregulated in DOCG; while in MDOCG, IgM, CD8+ recovered to normal levels and complement C3; CD4+ were upregulated. 4. MgIg had no significant effects on the disposition of DOC in docetaxel-induced liver injury. Additional, potential drug-drug interaction may happen if MgIg co-administered with antitumor drugs which are the substrates of CYP3A4 or P-gp. Hepatoprotective mechanism of MgIg perhaps was through upregulation of C3, CD4+ and downregulation of IgM, CD8+.

Changes in integrity of the gill during histidine deficiency or excess due to depression of cellular anti-oxidative ability, induction of apoptosis, inflammation and impair of cell-cell tight junctions related to Nrf2, TOR and NF-κB signaling in fish.

This study firstly explored the possible effects of dietary histidine on structural integrity and the related signaling factor gene expression in the gills of fish. Young grass carp (Ctenopharyngodon idella) were fed with six diets containing gradual levels of histidine for 8 weeks. The results firstly demonstrated that histidine deficiency caused increases in reactive oxygen species (ROS) contents, and severe oxidative damage (lipid peroxidation and protein oxidation) in the gills of fish, which was partially due to the decreased glutathione (GSH) content and antioxidant enzyme activities [superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), glutathione-S-transferase (GST) and glutathione reductase (GR)]. Further investigations indicated that histidine deficiency caused depressions of those antioxidant enzyme activities are related to the down-regulation of corresponding antioxidant enzyme genes and the related signaling factor Nrf2 mRNA levels. Meanwhile, histidine deficiency induced DNA fragmentation via up-regulation of caspase-3, caspase-8 and caspase-9 expressions that referring to the down-regulation of TOR and S6K mRNA levels. Furthermore, His deficiency down-regulated claudin-b, claudin-c, claudin-3, claudin-12, claudin-15, occludin and ZO-1 transcription in fish gills. These effects were partially related to the up-regulation of pro-inflammatory cytokines, interleukin 1ß (IL-1ß), interleukin 8 (IL-8), tumor necrosis factor-α (TNF-α) and related signaling factor nuclear factor κB P65 (NF-κB P65) mRNA levels, and the down-regulation of anti-inflammatory cytokines, interleukin 10 (IL-10), transforming growth factor ß1 (TGF-ß1) and related signaling factor IκBα mRNA levels. Excessive histidine exhibited negative effects that were similar to histidine deficiency, whereas the optimal histidine levels reversed those negative effects. Taken together, our results showed that histidine deficiency or excess impaired the structural integrity of fish gill by disrupted fish antioxidant defenses and regulating the expression of tight junction protein, cytokines, apoptosis, antioxidant enzymes, NF-κB p65, IκBα, TOR, Nrf2, Keap1 and apoptosis-related genes in the fish gills.

Histidine Prevents Cu-Induced Oxidative Stress and the Associated Decreases in mRNA from Encoding Tight Junction Proteins in the Intestine of Grass Carp (Ctenopharyngodon idella).

Copper (Cu) is a common heavy metal pollutant in aquatic environments that originates from natural as well as anthropogenic sources. The present study investigated whether Cu causes oxidative damage and induces changes in the expression of genes that encode tight junction (TJ) proteins, cytokines and antioxidant-related genes in the intestine of the grass carp (Ctenopharyngodon idella). We demonstrated that Cu decreases the survival rate of fish and increases oxidative damage as measured by increases in malondialdehyde and protein carbonyl contents. Cu exposure significantly decreased the expression of genes that encode the tight junction proteins, namely, claudin (CLDN)-c, -3 and -15 as well as occludin and zonula occludens-1, in the intestine of fish. In addition, Cu exposure increases the mRNA levels of the pro-inflammatory cytokines, specifically, IL-8, TNF-α and its related signalling factor (nuclear factor kappa B, NF-κB), which was partly correlated to the decreased mRNA levels of NF-κB inhibitor protein (IκB). These changes were associated with Cu-induced oxidative stress detected by corresponding decreases in glutathione (GSH) content, as well as decreases in the copper, zinc-superoxide dismutase (SOD1) and glutathione peroxidase (GPx) activities and mRNA levels, which were associated with the down-regulated antioxidant signalling factor NF-E2-related factor-2 (Nrf2) mRNA levels, and the Kelch-like-ECH-associated protein1 (Keap1) mRNA levels in the intestine of fish. Histidine supplementation in diets (3.7 up to 12.2 g/kg) blocked Cu-induced changes. These results indicated that Cu-induced decreases in intestinal TJ proteins and cytokine mRNA levels might be partially mediated by oxidative stress and are prevented by histidine supplementation in fish diet.